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WO1996034866A1 - Imidazo 1,2-a pyridine and imidazo 1,2-a pyridezine derivatives and their use as bone resorption inhibitors - Google Patents

Imidazo 1,2-a pyridine and imidazo 1,2-a pyridezine derivatives and their use as bone resorption inhibitors Download PDF

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Publication number
WO1996034866A1
WO1996034866A1 PCT/JP1996/001103 JP9601103W WO9634866A1 WO 1996034866 A1 WO1996034866 A1 WO 1996034866A1 JP 9601103 W JP9601103 W JP 9601103W WO 9634866 A1 WO9634866 A1 WO 9634866A1
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WIPO (PCT)
Prior art keywords
alkyl
pyridine
nmr
suitable substituent
compound
Prior art date
Application number
PCT/JP1996/001103
Other languages
French (fr)
Inventor
Yoshio Kawai
Shigeki Satoh
Hitoshi Yamazaki
Natsuko Kayakiri
Kousei Yoshihara
Teruo Oku
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9508826.6A external-priority patent/GB9508826D0/en
Priority claimed from GBGB9512972.2A external-priority patent/GB9512972D0/en
Priority claimed from GBGB9516647.6A external-priority patent/GB9516647D0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to JP8533169A priority Critical patent/JPH11505524A/en
Priority to AU53483/96A priority patent/AU5348396A/en
Publication of WO1996034866A1 publication Critical patent/WO1996034866A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel imidazopyridine or imidazopyrazine (hereinafter referred to as
  • imidazopyridine compound and a pharmaceutically acceptable salt thereof which are useful as a medicament.
  • the present invention relates to a novel imidazopyridine compound and a pharmaceutically acceptable salt thereof which are the inhibitors of bone resorption, the inhibitors of bone metastases and useful for the prophylactic and/or therapeutic treatment of bone disease characterized by abnormal bone metabolism such as osteoporosis (especially, postmenopausal osteoporosis); hyper-calcemia; hyperparathyroidism; Paget's bone diseases; osteolysis; hypercalcemia of malignancy with or without bone metastases; rheumatoid arthritis;
  • osteoporosis especially, postmenopausal osteoporosis
  • hyper-calcemia hyperparathyroidism
  • Paget's bone diseases osteolysis
  • hypercalcemia of malignancy with or without bone metastases rheumatoid arthritis
  • periodontitis a periodontitis; osteoarthritis; ostealgia; osteopenia; cancer cachexia; calculosis; lithiasis (especially, urolithiasis); or the like in a human being or an animal.
  • the present invention relates to processes for the preparation of the imidazopyridine derivatives, to a pharmaceutical composition comprising the same and to a method for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal, and to a use of the imidazopyridine compound and pharmaceutically acceptable salts thereof for the prophylactic and/or
  • the imidazopyridine compounds of this invention are new and can be represented by the following general formula (Ii :
  • R 1 is hydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogen or hydroxy (lower) alkyl which may have one or more suitable substituent (s),
  • R 2 is hydrogen, lower alkyl, an acyl group, lower alkoxy,
  • R 3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkyl (lower) alkyl, halogen, an acyl group, acyl (lower) alkyl, acylamino,
  • acylamino (lower) alkyl acyl (lower) alkenyl
  • acyloxy (lower) alkyl acyl (lower) alkylthio (lower) alkyl, amino (lower) alkyl, mono- (or di-) lower alkylamino, lower alkylthio (lower) alkyl, hydrcxyimino (lower) alkyl which may have one or more suitable substituent (s),
  • hydroxy (lower) alkyl which may have one or more suitable substituent (s), hydroxy (lower) alkylthio (lower) alkyl, cyano (lower) alkyl, mono- (or di-) lower alkoxy (lower) alkyl which may have one or more suitable substituent (s), lower alkyl substituted with aryl which may have one or more suitable substituent (s), mono- (or di-) lower alkylamino (lower) alkyl, tri (lower) alkylammonio (lower) - alkyl, lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), hydrazino (lower) alkyl which may have one or more suitable substituent (s), mono- or di- (lower) alkoxy (lower) alkylamino (lower) alkyl,
  • heterocyclicthio heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s),
  • heterocyclicoxy heterocyclicoxy (lower) alkyl
  • heterocyclicaminoimino (lower) alkyl aryl which may have one or more suitable substituent (s), amino, nitro, halo (lower) alkyl, hydroxy (lower) alkylimino (lower) alkyl, hydroxy (lower) alkylamino (lower) alkyl, bis- [hydroxy (lower) alkyl] amino (lower) alkyl,
  • a 1 and A 2 are each lower alkylene which may have one or more suitable substituent (s) or lower alkenylene which may have one or more suitable substituent (s),
  • W is -S-, - (wherein R 4 is hydrogen
  • n are each an integer of 0 or 1]
  • X is vinylene, or a group of the formula : -NHCO-, -NHSO 2 -, -OCO-, -OCH 2 -, -NHCOCO-,
  • -NHCOCH CH-, -NHCOCH 2 -, -NHCONH- or
  • Y is heterocyclic group which may have one or more suitable substituent (s), or aryl which may have one or more suitable substituent (s),
  • Q is CH or N
  • l is an integer of 0 or 1
  • the object compound (I) or a salt thereof can be
  • R 1 , R 2 R 3 X, Y, Q and l are each as defined above,
  • heterocyclicthio (lower) alkyl lower
  • alkylamino (lower) alkyl which may have one or more suitable substituent (s),
  • E is lower alkylene, lower alkenylene or a group of the formula :
  • V is heterocyclic group which may have one or more suitable substituent (s), heterocyclicthio, or lower alkylamino which may have one or more suitable substituent (s), hydroxy (lower) alkylamino, bis-hydroxy (lower) alkylamino, amidinothio or tri-lower alkylphosphite,
  • a 5 is lower alkylene
  • R' is hydrogen or lower alkyl
  • R" is leaving group
  • R"' is lower alkyl, cyclo (lower) alkyl, lower alkyl
  • heterocyclic group which may have one or more suitable substituent (s), lower alkoxy (lower) alkyl, hydroxy (lower) alkyl, amino, heterocyclic group, carboxy (lower) alkyl, protected carboxy (lower) alkyl, lower alkyl substituted with aryl which may have one or more suitable substituent (s) or arylsulfonyl or cyano (lower) alkyl,
  • G 1 is -COOH or -SO 3 H
  • G 2 is -CO- or -SO 2 -
  • X' is halogen
  • a is an integer of 0 to 6
  • b, r, q and u are each an integer of 0 or 1.
  • R 1 , R 2 , R 3 and Q are each as defined above, and X"' is halogen.
  • Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.);
  • a salt with an inorganic base for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline
  • an organic carboxylic or sulfonic acid addition salt e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate,
  • toluenesulfonate etc.
  • a salt with a basic or acidic amino acid e.g., arginine, aspartic acid, glutamic acid, etc.
  • lower is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
  • Suitable example of .”one or more may be the number of 1 to 6, in which the preferred one may be the number of 1 to 4.
  • Suitable “lower alkyl” and “lower alkyl moiety” may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and the like, preferably one having 1 to 5 carbon atom(s).
  • Suitable “lower alkane” may include straight or branched one having 1 to 6 carbon atom(s), such as methane, ethane, propane, isopropane, butane, iscbutane, sec-butane, tert- butane, pentane, 3-pentane, isopentane, tert-pentane,
  • neopentane hexane, isohexane, and the like, i nwhich the more preferred one may be (C 1 -C 4 ) alkane, and the most
  • preferred one may be methane.
  • Suitable “lower alkenyl” and “lower alkenyl moiety” may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1- (or 2- or 3 ⁇ or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)- hexenyi, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1- (or 2-)propenyl, 1-(or 2- or 3-) ethyl-1- (or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example nay be (C 6 -C 4 ) alkenyl, and the most preferred one may be methylvinyl.
  • Suitable "lower alkynyl” may include ethynyl,
  • Suitable "lower alkoxy” may include methoxy, ethoxy, propoxy isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
  • Suitable "aryl” and “aryl moiety” may include phenyl, naphthyl, anthryl and the like.
  • Suitable “leaving group” may include acid residue,
  • tri (lower) alkylammonio as defined below and the like, and suitable examples of “acid residue” may be halogen (e.g., fluorine, chlorine, bromine, iodine.), acyloxy [e.g.,
  • sulfonyioxy e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.
  • lower alkanoyloxy e.g., acetyloxy, propionyloxy, etc.
  • lower alkyl e.g., methyl, ethyl propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.
  • aryl e.g., phenyl, naphthyl, anthryl, etc.
  • ar (lower) alkyl such as phenyl (lower) alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.),
  • di (lower) alkylamino e.g., dimethylaminc, diethylamino, aiiscprcpylamino, ethylmethylaminc, iscpropyimethylaminc, ethylmethylamino, ethylpropyiamino, etc.
  • alkyl (lower) alkoxyamino e.g., methylmethoxyamino
  • tri (lower) alkylammonio may be trimethylammonio, triethylammonio, tripropylammonio, tributylammonio, tripentylammonio, trihexylammonio, or the like, in which the preferred one may be tri(C 1 -C 4 )- aikylammonio, and the most preferred one may be
  • Suitable “acid residue” may include halogen (e.g., fluorine chlorine, bromine, iodine, etc.), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyioxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
  • halogen e.g., fluorine chlorine, bromine, iodine, etc.
  • acyloxy e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyioxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
  • Suitable "lower alkylene” may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
  • Suitable "lower alkenylene” may include straight or branched one having 2 to 6 carbon atom(s) such as vinyiene, propenylene, 1-(or 2-)butenylene, 1-(or 2- or 3-)pentenylene, 1-(or 2- or 3-) hexenylene, methylvinylene, ethylvinyiene, 1-(or 2- or 3-)methyIpropenylene, 1-(or 2- or 3-)- ethylprcpenylene, 1-(or 2- or 3- or 4-)methyl-1-(or 2-)- butenylene, and the like.
  • Suitable "cyclo (lower) alkyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, in which the preferred one may be cyclo (C 4 -C 6 ) alkyl.
  • Suitable "halogen” and “halo” moiety may include
  • Suitable "an acyl group” and “acyl” moiety may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
  • Suitable example of said acyl may be illustrated as follows :
  • aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyi, nonanoyl, decanoyl, undecancyl, dodecanoyl,
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyi, nonanoyl, decanoyl, undecancyl, dodecanoyl,
  • cyclo (lower) alkylcarbonyl e.g., cyclopropylcarbonyl
  • cyclobutylcarbonyl cyclopentylcarbonyi, cyclohexylcarbonyl, etc.
  • protected carboxy such as commonly protected carboxy [e.g., esterified carboxy such as lower or higher
  • alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, iso-propyloxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), etc.]; lower or higher alkylsulfonyl (e.g.,
  • alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
  • di (lower) alkoxyphosphoryl e.g., dimethoxyphosphoryl
  • diethcxyphosphoryl dipropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.
  • a 3 and A 4 are lower alkylene, amino (lower) alkylene or aminophenylene,
  • R 11 is lower alkyl or hydrogen
  • S and t are each integer of 1 to 6, or the like); aromatic acyl such as
  • aroyl e.g., benzoyl, toluoyl, naphthoyl, etc.
  • ar (lower) alkanoyl e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
  • phenylisobutanoyl phenylpentanoyl, phenyIhexanoyl, etc.
  • naphthyl (lower) alkanoyl e.g., naphthylacetyl
  • ar (lower) aikenoyl e.g., phenyl (lower) alkenoyl (e.g., phenylprcpenoyl, phenylbutenoyl, phenylmethaoryloyl, phenylpentenoyi, phenyihexenoyi, etc.),
  • naphthyl (lower) alkenoyl e.g., naphthylpropenoyl
  • ar (lower) alkoxycarbonyl e.g., phenyl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.];
  • aryloxycarbonyl e.g., phenoxycarbonyl
  • aryloxy (lower) alkanoyl e.g., phenoxyacetyl
  • arylcarbamoyl e.g., phenylcarbamoyl, etc.
  • arylthiocarbamoyl e.g., phenylthiocarbamoyl, etc.
  • arylglyoxyloyl e.g., phenylgiyoxyloyl, naphthylglyoxyloyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.
  • heterocyclic acyl such as
  • heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyciicpropanoyl, heterocyclicbutanoyl,
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropencyl, heterocyclicbutenoyl, heterocyclicpentenoyi,
  • heterocyclichexenoyl etc.
  • heterocyclicglyoxyloyl
  • heterocyclicsulfinyl may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
  • heterocyclic group such as
  • heterocyclic group and “heterocyclic moiety” as stated above may have one or more suitable substituent (s) such as exo; halogen (e.g., fluorine, chlorine, bromine, iodine, etc.); hydroxy; aforementioned "heterocyclic group”; tri- halo (lower) alkyl (e.g., trichloromethyl, trifluoromethyl, trichloroethyl, trifiuoroethyl, etc.); lower alkanoyl (e.g., formyl, acetyl, prcpancyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.); aryl (e.g., phenyl, naphthyl, anthryl, etc.); lower alkyl (e.g., methyl, ethyl, propyl
  • acyl moiety as stated above may have one to ten, same or different, suitable substituent (s) such as lower alkyl (e.g., methyl, ethyl, propyl, etc.);
  • lower alkoxy e.g., methoxy.. ethoxy, propoxy, etc.
  • lower alkylthio e.g., methylthio, ethylthio, etc.
  • mono- (or di-) lower alkylamino which may have one or more suitable substituent (s) (e.g., methylamino, ethylamino, oropylamino, dimethylamino, diethylamino, dipropylamino, N- methoxy-N-methylamino, N-ethoxy-N-ethylamino, N- methoxymethyl-N-methylamino, N-methoxyethyl-N-methylamino, etc.); lower alkanoylamino (e.g., acetylamino,
  • prcpionylamino butyrylamino, pentanoylamino, hexanoylamino, etc.
  • cyclo (lower) alkylamino e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylaminc, etc.
  • mono-(or di-) lower alkoxy (lower) alkylamino e.g.,
  • lower alkanoyloxy e.g., acetyloxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, etc.
  • heterocyclic group in which "heterocyclic group" is
  • di-lower alkoxy (lower) alkyl e.g., dimethoxymethyl
  • cyano (lower) alkylamino e.g., cyanomethylamino
  • arylsulfonylamino e.g., phenylsulfonyiamino
  • cyclo (lower) alkyl e.g., cyciopentyl, cyclohexyl, etc.
  • cyclo (lower) alkenyl e.g., cyclohexenyl, cyclohexadienyl, etc.
  • halogen e.g., fluorine, chlorine, bromine, iodine, etc.
  • amino commonly protected amino as mentioned above; hydroxy; commonly protected hydroxy as mentioned below; cyano; nitro; carboxy; carboxy (lower) alkyl;
  • sulfamoyl sulfamoyl; imino; oxo; hydrazino; amino (lower) alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoylcxy; hydroxy (lower) alkyl (e.g., hydroxymethyl, 1-(or 2-)- hydrcxyethyl, 1-(or 2- or 3-) hydroxypropyi, etc.), or the like.
  • amino (lower) alkyl e.g., aminomethyl, aminoethyl, etc.
  • carbamoylcxy hydroxy (lower) alkyl (e.g., hydroxymethyl, 1-(or 2-)- hydrcxyethyl, 1-(or 2- or 3-) hydroxypropyi, etc.), or the like.
  • Suitable "hydroxy protective group” in the term commonly “protected hydroxy” may include acyl as mentioned above, phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyI, trityl, etc.), trisubstituted silyl [e.g., tn (lower) alkylsiiyl (e.g., trimethylsilyl, t-butyldimethylsilyi, etc.), etc.],
  • suitable substituent e.g., benzyl, 4-methoxybenzyI, trityl, etc.
  • trisubstituted silyl e.g., tn (lower) alkylsiiyl (e.g., trimethylsilyl, t-butyldimethylsilyi, etc.
  • Suitable commonly "protected carboxy” may include esterified carboxy and the like.
  • suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.);
  • lower alkenyl ester e.g., vinyl ester, allyl ester, etc.
  • lower alkynyl ester e.g., ethynyl ester, propynyl ester, etc.
  • lower alkoxy (lower) alkyl ester e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxy ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.
  • lower alkylthio (lower) alkyl ester e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester,
  • lower alkanoyloxy (lower) alkyl ester e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
  • lower alkoxycarbonyloxy (lower) alkyl ester e.g.,
  • lower alkanesulfonyl (lower) alkyl ester e.g., mesylmethyl ester, 2-mesyethyl ester, etc.
  • lower alkoxycarbonyloxy (lower) alkyl ester e.g.,
  • ar (lower) alkyl ester for example, phenyl (lower) alkyl ester which may have one or more suitable substituent (s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester,
  • suitable substituent e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester
  • aryl ester which may have one or more suitable substituent (s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyi ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester,
  • lower alkyl silyl ester e.g., methylthioester, ethylthioester, etc.
  • lower alkylthioester e.g., methylthioester, ethylthioester, etc.
  • an acyl group may be carboxy protected carboxy, carbamoyl, lower alkanoyl, lower alkylsulfonyl, aroyl, heterocyclic carbonyl which may have one or more suitable substituent (s), in which the more preferred one may be carboxy, (C 1 -C 4 ) alkoxy carbonyl, carbamoyl, (C 1 -C 4 ) alkanoyl, (C 1 -C 4 ) alkylsulfonyl, benzoyl, carbonyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), carbamoyl substituted with saturated 3 to 8-membered
  • acyl moiety in the term of "acylamino” can be referred to aforementioned “acyl” moiety.
  • acylamino may be ureido, lower alkanoylamino, lower alkoxycarbonylamino, heterocyclic carbonylamino, lower alkanoylamino (lower) alkanoylamino (e.g. acetylaminoacetylamino, acetylaminopropionylamino,
  • propionylaminoacetylamino, propionylaminopropionylamino, etc. mono-(or di-) lower alkylamino (lower) alkanoylamino (e.g., methylaminoacetylamino, dimethylaminoacetylamino, ethylaminoacetylamino, diethylaminoacetylaminc, etc.), lower alkanoyloxy (lower) alkanoylamino [e.g., acetyloxyacetylamino, acetyloxypropionylamino, propionyloxyacetylamino,
  • heterocyclic (lower) alkanoylamino e.g., heterocyclic- carbonylamino, heterocyclic-acetylamino, heterocyclic- propionylamino, etc .
  • lower alkoxy (lower) alkanoylamino e.g., lower alkoxy (lower) alkanoylamino
  • hydroxy (lower) alkanoylamino e.g., hydroxyacetylamino, hydroxypropionylamino, etc.
  • lower alkylsulfonylamino e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, etc.
  • mono-(or di-) lower alkoxy (lower) alkylamino (lower)- alkanoylamino e.g., methoxymethylaminoacetylamino,
  • Suitable "hydroxy (lower) alkyl" moiety in the term of "hydroxy (lower) alkyl which may have one or more suitable substituent (s)" may be hydroxymethyl, 1-(or 2-)hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxypropyl, 1-hydroxy-1- ethylethyl, 1-hydroxy-1-ethylpropyl, 1-hydroxybutyl, 1- (or 2- or 3-)hydroxy-1-(or 2- or 3-)methylpropyl, 1-(or 2- or 3- or 4-)hydroxy-1-(or 2- or 3- or 4-)methylbutyl, 1-(or 2- or 3- or 4- or 5-) hydroxy-1-(or 2- or 3- or 4- or 5-)methylpentyl, 1- (or 2- or 3- or 4- or 5- or 6-) hydroxy-1-(or 2- or 3- or 4- or 5- or 6-)methylhexyl, or the like.
  • hydroxy (lower) alkyl may be hydroxy (C 1 -C 4 )alkyl, and the most preferred one may be hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydrcxy-1-ethylpropyl, 1-hydrcxybuty ⁇ , 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 1-hydroxybutyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl.
  • suitable substituent (s) in the term of "hydroxy (lower) aikyl which may have one or more suitable substituent (s)” may be mono- (or di- or tri-)- haio (lower) alkyl, protected carboxy, hydroxy, aryl,
  • acyl moiety in the term of "acyl (lower) alkyl” can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkyl may be carboxy (lower) alkyl, protected carboy (lower) alkyl,
  • heterocyclic group which may have one or more suitable substituent (s), sulfinyl (lower) alkyl substituted with
  • heterocyclic group which may have one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s), lower alkyl having one or more suitable substituent (s),
  • a 3 is lower alkylene, amino lower alkylene or
  • R 11 is lower alkyl or hydrogen
  • s and t are each integer of 1 to 6
  • methylaminocarbonylmethyl dimethylaminocarbonylmethyl, methylaminocarbonylethyl, 2-dimethylaminocarbonylethyl,
  • lower alkoxy (lower) alkyiaminocarbonyl (lower) alkyl e.g., methoxymethylaminocarbonylmethyl
  • di- (lower) alkoxyphosphoryl (lower) alkyl e.g., di- (lower) alkoxyphosphoryl (lower) alkyl
  • aminocarbonyl (lower) alkyl substituted with heterocyclic group which may have one or more suitable substituent (s) (e.g.
  • thiazolylaminocarbonylmethyl piperidinoaminocarbonylmethyl, morpholinoaminomethyl, methyloxadiazolylaminocarbonylmethyl, trifluoromethylthiadiazolylaminocarbonylmethyl, pyridylaminocarbonylmethyl, aminopyridylaminocarbonylmethyl, etc.), heterocyclic (lower) alkyiaminocarbonyl (lower) alkyl
  • hydrazinocarbonyl (lower) aikyl e.g., hydrazinocarbonylmethyl, hydrazinocarbonylethyl, hydrazinocarbonyipropyl, etc.
  • aminocarbonyl (lower) alkyl substituted with aryl which may have one or more suitable substituent (s) e.g.,
  • arylsulfonylaminocarbonyl (lower) alkyl e.g.,
  • a 3 is (C 1 -C 6 )alkylene, amino (C 1 -C 6 ) alkylene or
  • R 11 is (C 1 -C 6 ) alkyl or hydrogen
  • s and t are each integer of 1 to 6), carbonyl (C 1 -C 4 )alkyl substituted with heterocyclic group which may have 1 to 3 suitable substituent (s),
  • hydrazinocarbonyl (C 1 -C 4 )alkyl aminocarbonyl (C 1 -C 4 ) alkyl substituted with phenyl which may have 1 to 3 suitable substituent (s), cyano (C 1 -C 4 )alkyiaminocarbonyl (C 1 -C 4 )alkyl, phenyisulfonylaminocarbonyl (C 1 -C 4 )alkyl,
  • (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkyiaminocarbonyl (C 1 -C 4 )alkyl and the most preferred one may be carboxymethyl
  • lower alkylthio may be methyl.thio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, or the iike, in which the preferred one nay be (C 1 -C 4 ) alkylthio, and the most preferred one may be
  • cyclo (lower) aikyl (lower) alkyl may be cyclopropylmethyl, cyciobutylmethyl, cyclopentylmethyl, cyciohexylmethyl. cyciopropylethyl, cyclobutylethyl, cyciopentylethyl,
  • cyclohexylethyl or the like, in which the preferred one may be cyclo (C 3 -C 6 ) alkyl (C 1 -C 4 ) alkyl, and the most preferred one may be cyciohexylmethyl.
  • acylamino moiety in the term cf "acyiamino- (lower) alkyl" can be referred to aforementioned “acylamino”.
  • acylamino (lower) alkyl may be lower alkoxycarbonylamino (lower) alkyl, lower
  • alkanoylamino (lower) aikyl alkanoylamino (lower) aikyl, heterocyciic-carbonylamino- (lower) alkyl,
  • the preferred one may be (C 1 -C 4 ) aikoxycarbonylamino- (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkanoylamino (C 1 -C 4 ) alkyl,
  • a 3 and A 4 are each (C 1 -C 6 ) alkylene, amino (C 1 -C 6 )
  • R 11 is (C 1 -C 6 ) alkyl or hydrogen), and the most preferred one may be t-butoxycarbonyl
  • acyl moiety in the terms of "acyl (lower) - alkenyl” can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkenyl can be referred to aforementioned “lower alkenyl”.
  • acyl (lower) alkenyl may be protected carboxy (lower) aikenyl, in which the preferred one may be (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkenyl, and the most preferred one may be ethoxycarbonyivinyl.
  • acyloxy (lower) alkyl can be referred to aforementioned
  • acyloxy (lower) alkyl may be lower alkanoyloxy (lower) alkyl
  • alkylaminocarbonyloxy (lower) alkyl aroyloxy (lower) alkyl, or lower aikyl substituted with
  • a 3 is lower alkyiene, amino (lower) alkylene or
  • R 11 is lower alkyl or hydrogen
  • Ln which the preferred one may be (C 1 -C 4 ) alkanoyloxy- (C 1 -C 4 ) aikyl, cycle (C 3 -C 6 ) alkylcarbamoyloxy- (C 1 -C 4 ) alkyl, carboxy (C 2 -C 4 ) alkanoyloxy- (C 1 -C 4 ) alkyl, succinimidoxycarbonyl- (C 2 -C 4 ) alkanoyloxy (C 1 -C 4 ) alkyl, (C 1 -C 4 )- alkyiaminocarbcnyioxy (C 1 -C 4 ) alkyl,
  • a 3 is (C 1 -C 6 ) alkylene, amino ( C 1 -C 6 ) aikylene or
  • R 11 is (C 1 -C 6 ) alkyl or hydrogen) ,
  • acyl (lower) alkylthio (lower) aikyl can be referred to aforementioned "acyl" moiety.
  • carboxy (lower) alkylthio (lower) aikyl in which the preferred one may be (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkylthio (C 1 -C 4 ) alkyl, and the most preferred one may be
  • amino (lower) alkyl may be amino (C 1 -C 4 ) alkyl, in which the most preferred one may be aminomethyl.
  • alkylamino may be methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropyiamino, butylamino,
  • dihexyiamino or the like, in which the preferred one may be mono-(or di-) (C 1 -C 4 ) alkylamino, and the most preferred one may be methylamino, dimethylamino or diethylamino.
  • the preferred examples of "lower alkylthio (lower) alkyl” may be methylthiomethyl, methylthioethyl, methylthiopropyi, methylthiobutyl, ethylthiomethyl, ethylthioethyl,
  • propylthiopropyl or the like, in which the preferred one may be (C 1 -C 4 ) alkylthio (C 1 -C 4 ) alkyl, and the most preferred one may be methylthiomethyl.
  • hydroxyimino (lower) alkyl which may have one or more suitable substituent (s)
  • (2-hydrcxyethyl) thiomethyl 2-(1-hydrcxyethyl) thioethyl, (1- or 2-hydroxyethyl) thiopropyl, (1- or 2-hydroxyethyl)- thiobutyl, (1- or 2-hydroxyethyl) thiopentyl, (1- or 2- hydroxyethyl) thiohexyl, or the like, in which the preferred one may be hydroxy (C 1 -C 4 ) alkylthio (C 1 -C 4 ) alkyl, and the most preferred one may be (2-hydrcxyethyl) thiomethyl.
  • cyano (lower) alkyl may be cyanomethyl, 1- (or 2-) cyanoethyl, 1-(or 2- or 3-) cyanopropyl, 1-(or 2- or 3- or 4-) cyanobutyl, 1- (or 2- or 3- or 4- or 5-)- yanopentyl, 1- (or 2- or 3- or 4- or 5- or 6-) cyanohexyl, or the like, in which the preferred one may be cyano (C 1 -C 4 ) - aikyl, and the most preferred one may be cyanomethyl or 2- cyanoethyl.
  • Suitable "mono- (or di-) lower alkoxy (lower) alkyl” may be methoxymethyl, methoxyethyl, dimethoxymethyl, dimethoxyethyl, ethoxymethyl, ethoxyethyl, diethoxymethyl, diethoxyethyl, propoxymethyl, propoxyethyl, propoxypropyl, dipropoxymethyl, dipropoxyethyl, dipropoxypropyl, or the like, in which the preferred one may be mono-(or di-) (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl, and the most preferred one may be methoxymethyl,
  • alkoxy (lower) alkyl which may have one or more suitable substituent (s)" may be (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl or
  • the most preferred one may be methoxymethyl, 2-methoxyethyl, 3-diethoxypropyl or trifluoromethylmethoxymethyl .
  • Suitable "lower alkyl substituted with aryl" nay be benzyl, phenethyl, 2-phenylpropyl, naphthylmethyl,
  • naphthylethyl anthryimethyl, 1-anthryiethyl, or the like, in which the more preferred one may be phenyl (C 1 -C 4 ) alkyl, naphthyl (C 1 -C 4 ) alkyl or anthryl (C 1 -C 4 ) alkyl, and the most preferred one may be benzyi.
  • lower alkyl substituted with aryl which may have one or more suitable substituent (s) may be the one which may have 1 to 3 nitro or cyano, such as phenyl (C 1 -C 4 ) aikyl, nitrophenyi (C 1 -C 4 ) alkyl or
  • cyanophenyi (C 1 -C 4 ) aikyl, in which the most preferred one may be benzyl, 4-nitrobenzyl or 3-cyanobenzyl.
  • alkylamino (lower) alkyl may be mono-(or di-) (C 1 -C 4 )- ikylamino (C 1 -C 4 ) alkyl, in which the more preferred one may be dimethvlaminomethyl.
  • tri (lower) alkylammonio (lower)- alkyl may be trimethylammoniomethyl, triethylammonioethyl, tripropylammoniopropyl, tributylammoniobutyl,
  • tripentylammoniopentyl trihexylammoniohexyl, or the like, in which the preferred one may be tri (C 1 -C 4 ) alkylammonio (C 1 -C 4 )- alkyl, and the most preferred one may be
  • heterocyclic group moiety in the term of "lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s)" can be referred to aforementioned “heterocyclic group”.
  • substituent (s) may be imidazoiyi (lower) alkyl, pyridyl (lower) alkyl, morpholino (lower) alkyl,
  • oxiranyl (C 1 -C 4 ) alkyl
  • piperidino (C 1 -C 4 ) aikyl
  • 2-methylimidazolylmethyl 4-ethoxycarbonylpiperidinomethyl, pyrrolidinylmethyl, piperidinomethyl, benzimidazolylmethyl, triazolylmethyl, 3-methyl-5-hydroxypyrazolylmethyl,
  • hydrazino (lower) alkyl having lower alkoxycarbonyl in which the more preferred one may be hydrazino (C 1 -C 4 ) alkyl having (C 1 -C 4 ) alkoxycarbonyl, and the most preferred one may be tert-butoxycarbonylhydrazinomethyl.
  • [mono or di (lower) alkoxy- (lower) alkyl] amino (lower) alkyl may be [mono or di(C 1 -C 4 )- alkoxy(C 1 -C 4 ) alkyl] amino (C 1 -C 4 ) alkyl, in which the more preferred one may be [di (C 1 -C 4 ) alkoxy (C 1 -C 4 ) alkyl] amino- (C 1 -C 4 ) alkyl, and the most preferred one may be
  • (lower) alkylamino (lower) alkyl which may have one or more suitable substituent (s)
  • heterocyclic (lower) alkyl (lower) alkylamino (lower) alkyl having lower alkoxycarbonyl (lower) alkyl,
  • (lower) alkylamino] (lower) alkyl in which the more preferred one may be (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having pyridyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having cyclo (C 3 -C 6 ) alkyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having (C 1 -C 4 ) alkoxy (C 1 -C 4 )- alkyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having pyridyl (C 1 -C 4 )- alkyl, (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl having (C 1 -C 4 )- alkoxycarbonyl (C 1 -C 4 )
  • preferred one may be N-methyl-N-pyridylaminomethyl, N-methyl- N-cyclohexylaminomethyl, N-methyl-N-methoxyethylaminomethyl, N-methyl-N-pyridylmethylaminomethyl,
  • heterocyclic group moiety in the term of "heterocyclic group which may have one or more suitable substituent (s)" can be referred to aforementioned “heterocyclic group”.
  • heterocyclic group which may have one or more suitable substituent (s) may be furyl, pyridyl which may have 1 to 3 substituent (s) selected from the group consisting of halogen, lower alkoxycarbonyl, and lower alkyl, thiazolyl which may have 1 to 3 lower
  • alkanoylamino benzothienyl which may have 1 to 3 halogen, indolyl which may have 1 to 3 substituent (s) selected from the group consisting of halogen and lower alkyl, oxazolyl which may have 1 to 3 lower alkyl, pyranyl which may have 1 to 3 substituent (s) selected from the group consisting of lower alkyl and oxo, pyrrolyl which may have 1 to 3 lower alkyl, phthalimido which may have nitro, phthalimidine which may have nitro, piperidyl which may have 1 to 3 lower alkyl, dihydropyridyl which may have lower alkoxycarbonyl.
  • heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s)
  • heterocyclic group can be referred to aforementioned to “heterocyclic group”.
  • heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s)
  • imidazopyridylthio (lower) alkyl in which the preferred one may be imidazolylthio (C 1 -C 4 ) alkyl, imidazolylthio (C 1 -C 4 ) alkyl having (C 1 -C 4 ) alkyl, benzimidazolyl (C 1 -C 4 ) alkyl,
  • pyridylthio (C 1 -C 4 ) alkyl or imidazopyridylthio (C 1 -C 4 ) alkyl, and the most preferred one may be imidazolylthiomethyl,
  • heterocyclic moiety in the term of “heterocyclicthio” can be referred tc aforementioned
  • heterocyclicthio may be pyridylthio or imidazolylthio.
  • heterocyclic oxy can be referred to aforementioned
  • heterocyclic oxy may be pyridyloxy.
  • heterocyclic oxy (lower) aikyl can be referred to
  • heterocyclic oxy (lower) alkyl may be pyridyloxy (lower) aikyl, in which the more preferred one may be pyridyloxy (C 1 -C 4 ) alkyl, and the most preferred one may be pyridyloxynethyl.
  • aryl which may have one or more suitable eubstituents may be phenyl, naphthyl, anthryl, phenyl having amino, phenyl having di (lower; alkylamino, phenyl having heterocyclic (lower) alkylamino, phenyl having di (lower) alkylamino (lower) alkanoylamino, phenyl having lower aikylsulfcnyiaminc, phenyl having higher alkanoylamino, in which the most preferred one may be phenyl, aminophenyl, dimethylaminophenyl, furyimethylaminophenyl,
  • heterocyclic amincimino (lower) alkyl can be referred to aforementioned “heterocyclic group”.
  • aminoiminc (lower) alkyl may be amincimino (lower) alkyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 ro 4 nitrogen atom(s), in which the more preferred one may be pyridylaminoimino (C 1 -C 4 ) alkyl, and the most preferred one may be 2-pyridylaminoiminopropyl.
  • suitable substituent (s) in the terms cf "lower alkylene which may have one or more suitable substituent (s)” and “lower aikenylene which may have one or more suitable substituent (s)” may be lower alkyl, hydroxy, oxo, or the like, in which the preferred one may be (C 1 -C 4 ) alkyl, hydroxy or oxo, and the most preferred one may be methyl, hydroxy or oxo.
  • suitable substituent (s) in the terms of "aryl which may have one or more suitable substituent (s)” may be halogen, lower alkyl, nitre, lower alkoxy, an acyl group, cyclo (lower) alkyl, mono- (or di- or tri-) halo (lower) alkyl, acylamino, aryl, amino, mono- (or di-)- lower alkylamino, aryloxy, acyl (lower) alkyl, hydroxy,
  • hydroxy (lower) alkyl which may have one or more suitable substituent (s), heterocyclic group which may have one or more suitable substituent (s), mono-(or di-) lower
  • alkylamino (lower) alkyl or acyl (lower) alkyl are preferred examples of "mono-(or di-) lower
  • alkylamino (lower) alkyl may be mono-(or di-) (C 1 -C 4 )- alkylamino (C 1 -C 4 ) alkyl, in which the preferred one nay be di (C 1 -C 4 ) alkylamino (C 1 -C 4 ) aikyl, and the most preferred one may be dimethylaminomethyl.
  • acyl (lower) alkoxy can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkoxy may be protected carboxy (lower) alkoxy, m which the more preferred one may be (C 1 -C 4 ) alkoxycarbonyl (C 1 -C 4 ) alkoxy, and the most preferred one may be ethoxycarbonyimethoxy.
  • suitable substituent (s) in the term cf "naphthyl which may have one or mere suitable substituent (s) " may be lower alkoxy, in which the more preferred one may be (C 1 -C 4 ) alkoxy, and the most preferred one may be methoxy.
  • acyl (lower) alkenyl can be referred to aforementioned “acyl” moiety.
  • acyl (lower) alkenyl can be referred to aforementioned “lower alkenyl”.
  • acyl (lower) alkenyl may be protected carboxy (C 2 -C 6 ) alkenyi, in which the more preferred one may be lower alkoxycarbonyl (C 2 -C 4 ) alkenyl, and the most preferred one may be ethoxycarbonylvinyl.
  • aryloxy may be phenoxy, naphthyloxy, anthryloxy, or the like, in which the most preferred one may be phenoxy.
  • aryl (lower) alkoxy may be phenyl (C 1 -C 6 ) alkoxy, naphthyl (C 1 -C 6 ) alkoxy, anthryl (C 1 -C 6 ) - alkoxy, or the like, in which the preferred one may be phenyl (C 1 -C 4 ) alkoxy, and the most preferred one may be phenylmethoxy.
  • halo (lower) alkyl may be chloromethyl, chloroethyl, bromomethyl, bromoethyl,
  • hydroxy (lower) aikylimino- (lower) alkyl may be hydroxy (C 1 -C 4 ) alkylimino (C 1 -C 4 ) alkyl, in which the more preferred one may be hydroxyethyliminomethyl.
  • ;lower) aikyl may be hydroxy (C 1 -C 4 ) alkylamino (C 1 -C 4 ) alkyl, in which the more preferred one may be hydroxyethylaminomethyl.
  • bis-[hydroxy (lower) alkyl]- amino (lower) alkyl may be bis- [hydroxy (C 1 -C 4 ) alkyl]amino- (C 1 -C 4 ) alkyl, in which the more preferred one may be
  • mercapto (lower) alkyl may be mercapto (C 1 -C 4 ) alkyl, in which the more preferred one may be mercaptomethyl.
  • amidinothio (lower) alkyl may be amidinothio (C 1 -C 4 ) alkyl, in which the more preferred one may be amidinothiomethyl.
  • the compound (la) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or sulfo group or a salt thereof.
  • Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as
  • Suitabie reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g., methanesulfonic acid,
  • substituted phosphoric acid e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorus acid e.g., sulfurous acid, thiosulfuric acid, alkanesulfuric acid (
  • ethanesulfonic acid etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid
  • pentanoic acid isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.
  • aromatic carboxylic acid e.g., benzoic acid, etc.
  • a symmetrical acid anhydride
  • an activated amide with imidazoie, 4-substituted imidazoie, dimethylpyrazole, triazole or tetrazole an activated ester (e.g. cyanomethyl ester, methoxymethyl ester,
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
  • an alkali metal e.g., sodium, potassium, etc.
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) aikylamine e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkylmorphoiine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline or the iike.
  • the compound (lb) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the carboxy group or a salt thereof with the compound (V) or its reactive derivative at the amme group or a salt thereof.
  • the compound (Ic) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the hydroxy group or a salt thereof with the compound (VII) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an acid including Lewis acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkylamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g. sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline or the iike.
  • the base, the acid and/or the starting compound are liquid, they can be used also as a solvent.
  • the compound (Id) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof to Wittig Reaction.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, dimethylsulfoxide, nitromethane, tetrahydrofuran, toluene, methylene chloride, ethylenedichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, dimethylsulfoxide, nitromethane, tetrahydrofuran, toluene, methylene chloride, ethylenedichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the
  • reaction is usually carried out under cooling to heating.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkylamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine,
  • N,N-di (lower) alkylbenzylamine N,N-di (lower) alkylaniline, methyllitium, n-butyllitium, phenyliitium,
  • the compound (le) or a salt thereof can be prepared by reacting the compound (X) or its reactive derivative at the amino group or a salt thereof with the compound (XI) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an acid including Lewis acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
  • the reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metai hydrogencarbonate e.g., sodium
  • alkali metal carbcnate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkyiamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g., sodium methoxide, sodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) aikyianiline or the like.
  • the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent.
  • the compound (If) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the hydroxy group or a salt thereof with the compound (XII) or its reactive derivative at the carboxy group or a salt thereof.
  • Suitable reactive derivative at the hydroxy group of the compound (VI) may include halide, sulfonate, sulfate, diazo compound, and the like.
  • Suitable reactive derivative at the carboxy group of the compound (XII) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.,
  • diphenylphosphoric acid diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorus acid sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g.,
  • methanesuifonic acid ethanesulfonic acid, etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid, pentanoic acid, isopentanoic acid
  • 2-ethylbutyric acid, trichloroacetic acid, etc. aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole,
  • an ester with a N-hydroxy compound e.g.,
  • This reaction is usually carried out in the presence of a base.
  • Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaiine earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonate
  • alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • alkaiine earth metal hydroxide e.g., magnesium hydroxide, calcium hydroxide, etc.
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.
  • alkali metai bicarbonate e.g., sodium bicarbonate, potassium bicarbonate, etc.
  • alkali metai acetate e.g., sodium acetate, potassium acetate, etc.
  • alkaline earth metal phosphate e.g., magnesium phosphate, calcium phosphate, etc.
  • alkali metal hydrogen phosphate e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.
  • organic base such as trialkylamine (e.g., trimethylamine, triethylamine, etc.), pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine,
  • This reaction is usually carried out in a sumble such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a slute such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the
  • the object compound (Ih) or a salt thereof can be prepared by reacting a compound (Ig) or its reactive
  • Suitable reactive derivative at the carboxy group of the compound (Ig) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples cf the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkyiphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.], diaikyiphosphorous acid, suifurous acid, thiosulfuric acid, sulfuric acid, sulfcnic acid [e.g., methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g., acetic acid,
  • N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.] N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.]
  • These reactive derivativee can optionally be selected from them according to the kind of the compound (Ig) tc be used.
  • Suitable salts of the compound (Ig) and its reactive derivative can be referred tc the ones as exemplified for the compound (I).
  • Suitable reactive derivative at the amine group of the compound (XIII) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XIII) with a carbonyl compound such as aidehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (XIII) with a silyl compound such as
  • Suitable salts of the compound (XIII) and its reactive derivative can be referred to the ones as exempiified for the compound (I).
  • the reaction is usually carried cut in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction.
  • a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, aceton
  • reaction when the compound (Ig) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
  • N,N'-diethylcarbodiimide N,N'-diisopropylcarbodiimide
  • ethyl polyphosphate ethyl polyphosphate
  • isopropyl polyphosphate phosphorous oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate
  • the reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal
  • N,N-di (lower) alkylbenzylamine or the like.
  • the reaction temperature is not oritical, and the reaction is usually carried out under cooling to warming.
  • the compound (Ij) or a salt thereof can be prepared by reacting the compound (Ii) or a salt thereof with Grignard Reagent .
  • Suitable Grignard reagent to be used in the present reaction nay include the compound of the formula : R 12 - MgX" (XIV) (wherein R 12 is lower alkyl, and
  • X is halogen.
  • This reaction is usually carried out in a solvent such as tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction ie usually carried out under cooling to heating.
  • the object compound (Il) or a salt thereof can be prepared by subjecting a compound (Ik) or a salt thereof to de-acylation reaction of acylamino group.
  • This reaction is carried out in accordance with a conventional method réelle ae hydrolysis, reduction or the like.
  • Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonte thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline,
  • alkali metal e.g., sodium, potassium, etc.
  • an alkaline earth metal e.g., magnesium, calcium, etc.
  • trialkylamine e.g., trimethylamine, triethylamine, etc.
  • picoline e.g., trimethylamine, triethylamine, etc.
  • Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g., an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • organic acid e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.
  • an inorganic acid e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.
  • trihaloacetic acid e.g. trichloroacetic acid
  • trifluoroacetic acid, etc. or the iike is preferably carried out in the presence of cation trapping agents [e.g. anisoie, phenol, etc.].
  • cation trapping agents e.g. anisoie, phenol, etc.
  • the reaction is usually carried cut in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adverseiy influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling tc warming.
  • the reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
  • metal e.g., tin, zing, iron, etc.
  • metallic compound e.g., chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-tolueneeulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts tc be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum cxide, platinum wire, etc.], palladium catalysts
  • nickel catalysts e.g., reduced nickel, nickel oxide, Raney nickei, etc.
  • cobalt catalysts e.g. reduced cobalt, Raney cobalt, etc.
  • iron catalysts e.g. reduced iron, Raney iron, etc.
  • copper catalysts e.g. reduced copper, Raney copper, Uliman copper, etc.
  • the reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof.
  • a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
  • reaction temperature of this reduction is not oritical and the reaction is usually carried out under cooling tc warming.
  • the compound (Ik) or a salt thereof can be prepared by subjecting the compound ( Ii) or its reactive derivative at the amino group, or a salt thereof to acylation reaction.
  • Suitable acylating agent to be used in the present acylation reaction may include the comoound of the formula :
  • Suitable reactive derivative at the amino group of the compound ( Ii) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound ( Ii) with a carbonyl compound such as aldehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (IC) with a silyl compound such as
  • Suitable reactive derivative of the compound (XV) may include an acid halide, an acid anhydride, an activated ester, and the like.
  • the suitable exampie may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, suifurous acid, thiosulfuric acid, alkaneeulfcnic acid (e.g., methanesulfonic acid,
  • substituted phosphoric acid e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.
  • dialkylphosphorous acid suifurous acid, thiosulfuric acid, alkaneeulfcnic acid (
  • ethanesulfonic acid etc.
  • sulfuric acid alkylcarbonic acid
  • aliphatic carboxylic acid e.g., pivalic acid
  • pentanoic acid isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.
  • aromatic carboxylic acid e.g., benzoic acid, etc.
  • a eymmetrical acid anhydride
  • an activated amide with imidazoie, 4-eubstituted imidazoie, dimethylpyrazole, triazole or tetrazole an activated ester (e.g., cyanomethyl, ester methoxymethyl ester,
  • the reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
  • the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiinu.de;
  • 1-aikoxy-1-chloroethylene triaikyl phcephite; isopropyl poiyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;
  • the reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal
  • N-(lower) alkylmorphorine N,N-di (lower) alkylbenzyiamine, or the iike.
  • the reaction temperature is not oritical, and the reaction is usually carried out under cooling to heating.
  • the compound (Im) or a salt thereof can be prepared by subjecting the compound (Ij) or a salt thereof to acylation reaction. This reaction can be carried out in a similar manner to that of the afore-mentioned Process 10.
  • the reagents to be used and the reaction conditions e.g., solvent, reaction temperature, etc.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (lo) or a salt thereof can be prepared by reacting the compound (In) or a salt thereof with lower alkane eubetituted with oxo (XIV) or a salt thereof.
  • This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformanu.de, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformanu.de, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • the reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
  • reaction ie usually carried out in the presence of an acid including Lewis acid.
  • Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
  • hydrochloric acid hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
  • the acid and/or the starting compound are in liquid, they can be used also as a solvent.
  • the compound (Iq) or a salt thereof can be prepared by reacting the compound (Ip) or a salt thereof with the
  • This reaction can be carried out in a similar manner to that of the afore-mentioned Process 3. and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 3.
  • the reaction conditions e.g., solvent, reaction temperature, etc.
  • the compound (Ila) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or a salt thereof.
  • This reaction is usually carried out in a sumble such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, 1,2- dimethoxyethane, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
  • alcohol e.g., methanol, ethanol, etc.
  • benzene N,N-dimethylformamide
  • tetrahydrofuran toluene
  • methylene chloride ethylene dichloride
  • chloroform 1,2- dimethoxyethane
  • dioxane dioxane
  • diethyl ether diethyl ether
  • the reaction temperature is not oritical and the
  • reaction is usually carried out under cooling to heating.
  • the reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal
  • an alkali metal hydroxide e.g., sodium hydroxide, potassium hydroxide, etc.
  • an alkali metal hydrogencarbonate e.g., sodium
  • alkali metal carbonate e.g., sodium carbonate, potassium carbonate, etc.
  • tri (lower) alkylamine e.g., trimethylamine
  • alkali metal hydride e.g., sodium hydride, etc.
  • alkali metal hydride e.g., sodium hydride, etc.
  • (lower) alkoxide e.g. eodium methoxide, eodium ethoxide, etc.
  • pyridine lutidine, picoline, dimethylaminopyridine, N-(lower) alkylmorphcline, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniiine or the like.
  • the base and/or the etarting compound are in liquid, they can be used also as a solvent.
  • the object compound (I) can be prepared by any process known in this field of the art except the above Processes 1 to 13 and Process A.
  • each of the object compound (I) may include one or more stereoieomer euch ae optical
  • iecmer(s) and geometrical isomer (s) due to asymmetric carbon atom(s) and double bond(s) and all eternal ieomers and mixture thereof are included within the scope of this invention.
  • the pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular;
  • the active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable
  • carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsulee, or euppositories; oreame;
  • the object compound (I) or a pharmaceutically acceptable salt thereof include solvated compound [e.-g., encloeure compound (e.g., hydrate, etc.)].
  • the object compound (I) or a pharmaceutically acceptable salt thereof include both its orystal form and non-orystal form.
  • the object compound (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceuticai
  • composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
  • the pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavaiiability of a drug can be .applied to the pharmaceutical composition of the present invention.
  • the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being or an animal, in the case of intramuecular adminietration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being of an animal, in case of oral administration, a daily dose of 0.001-200 mg of the object compound (I) per kg weight of a human being or an animal ie generally given for the prevention and/or the treatment of aforeeaid dieeases 1 to 4 times a day in a human oemg or an animal .
  • the pharmacological test data of the object compound (I) In order to illuetrate the usefuinees of the object compound (I), the pharmacological test data of the object compound (I).
  • N-Bromosuccinimide (3.74 g) was added to a solution of 8-ethoxycarbonyl-2-methylimidazo [1,2-a]pyridine (4.243 g) in ethanol (40 ml). After stirring at ambient temperature for 30 minutes, the mixture was evaporated in vacuo and the residue was dieeolvea in dichloromethane. The solution was washed with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The orystalline residue was reorystallized from diisopropyl ether to give 3-bromo-8-ethoxycarbonyl-2-methylimidazo [1,2-a]- pyridine (5.1 g).
  • 2,6-Dichlorobenzoyl chloride (2.51 g) wae added to a eolution of 8-amino-2-trifluoromethyIimidazo [1,2-a]pyridine (2.01 g) and triethylamine (1.31 g) in dichloromethane (30 ml). The mixture- wae etirred at ambient temperature for 1 hour ana refluxed overnight. The mixture was diluted with dichloromethane, washed with aqueous saturated eodium bicarbonate and water, dried over sodium sulfate, and evaporated in vacuo.
  • Methyl iodide (354 mg) was added to a solution of 8- (2,6-dichlorobenzoylamino)-3-dimethylaminomethyl-2- methylimidazo [1,2-a] pyridine (940 mg) in a mixture of acetone (30 ml) and tetrahyarofuran (10 ml) at 4°C. The solution was stirred at ambient temperature for 6 hours and evaporated in vacuo.

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Abstract

This invention relates to a novel imidazopyridine compound represented by formula (I), wherein X is vinylene, or a group of the formula (a), Y is heterocyclic group which may have one or more suitable substituent(s), or aryl which may have one or more suitable substituent(s), Q is CH or N, and 1 is an integer of 0 or 1, which are the inhibitors of bone resorption and bone metabolism, to processes for preparation thereof, to a pharmaceutical composition comprising the same and to a method for the treatment of diseases caused by abnormal bone metabolism in human being or an animal.

Description

DESCRIPTION
IMIDAZO 1,2-A PYRIDINE AND IMIDAZO 1,2-A PYRIDEZINE DERIVATIVES AND THEIR USE AS BONE RESORPTION INHIBITORS TECHNICAL FIELD
The present invention relates to a novel imidazopyridine or imidazopyrazine (hereinafter referred to as
"imidazopyridine") compound and a pharmaceutically acceptable salt thereof which are useful as a medicament.
BACKGROUND ART
In Japanese Patent Application Laid-open No.60-48924, No. 60-54379, etc., there are disclosed thionaphten-2- carboxylic acid derivatives and 3-phenyl-4H-1-benzopyran-4- one derivatives inhibiting bone resorption.
DISCLOSURE OF INVENTION
The present invention relates to a novel imidazopyridine compound and a pharmaceutically acceptable salt thereof which are the inhibitors of bone resorption, the inhibitors of bone metastases and useful for the prophylactic and/or therapeutic treatment of bone disease characterized by abnormal bone metabolism such as osteoporosis (especially, postmenopausal osteoporosis); hyper-calcemia; hyperparathyroidism; Paget's bone diseases; osteolysis; hypercalcemia of malignancy with or without bone metastases; rheumatoid arthritis;
periodontitis; osteoarthritis; ostealgia; osteopenia; cancer cachexia; calculosis; lithiasis (especially, urolithiasis); or the like in a human being or an animal.
And further, the present invention relates to processes for the preparation of the imidazopyridine derivatives, to a pharmaceutical composition comprising the same and to a method for the prophylactic and/or therapeutic treatment of above-mentioned diseases in a human being or an animal, and to a use of the imidazopyridine compound and pharmaceutically acceptable salts thereof for the prophylactic and/or
therapeutic treatment of above-mentioned diseases in human being or an animal.
The imidazopyridine compounds of this invention are new and can be represented by the following general formula (Ii :
Figure imgf000004_0001
wherein
R1 is hydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogen or hydroxy (lower) alkyl which may have one or more suitable substituent (s),
R2 is hydrogen, lower alkyl, an acyl group, lower alkoxy,
acyl (lower) alkyl, aryl, cyano, mono- (or di- or tri-)- halo (lower) alkyl, lower alkylthio or hydroxy (lower) alkyl which may have one or more suitable substituent (s), R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkyl (lower) alkyl, halogen, an acyl group, acyl (lower) alkyl, acylamino,
acylamino (lower) alkyl, acyl (lower) alkenyl,
acyloxy (lower) alkyl, acyl (lower) alkylthio (lower) alkyl, amino (lower) alkyl, mono- (or di-) lower alkylamino, lower alkylthio (lower) alkyl, hydrcxyimino (lower) alkyl which may have one or more suitable substituent (s),
hydroxy (lower) alkyl which may have one or more suitable substituent (s), hydroxy (lower) alkylthio (lower) alkyl, cyano (lower) alkyl, mono- (or di-) lower alkoxy (lower) alkyl which may have one or more suitable substituent (s), lower alkyl substituted with aryl which may have one or more suitable substituent (s), mono- (or di-) lower alkylamino (lower) alkyl, tri (lower) alkylammonio (lower) - alkyl, lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), hydrazino (lower) alkyl which may have one or more suitable substituent (s), mono- or di- (lower) alkoxy (lower) alkylamino (lower) alkyl,
(lower) alkylamino (lower) alkyl which may have one or more suitable substituent (s), heterocyclic group which may have one or more suitable substituent (s),
heterocyclicthio, heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s),
heterocyclicoxy, heterocyclicoxy (lower) alkyl,
heterocyclicaminoimino (lower) alkyl, aryl which may have one or more suitable substituent (s), amino, nitro, halo (lower) alkyl, hydroxy (lower) alkylimino (lower) alkyl, hydroxy (lower) alkylamino (lower) alkyl, bis- [hydroxy (lower) alkyl] amino (lower) alkyl,
mercapto (lower) alkyl or amidinothio (lower) alkyl, in which R2 and R3 may be linked together to form
(1) lower alkylene which may have one or more suitable
substituent (s),
(2) lower alkenvlene which may have one or more suitable
substituent (s), or
(3) a group of the formula :
Figure imgf000005_0001
[wherein A1 and A2 are each lower alkylene which may have one or more suitable substituent (s) or lower alkenylene which may have one or more suitable substituent (s),
W is -S-, -
Figure imgf000006_0001
(wherein R4 is hydrogen,
lower alkyl or an acyl .group) and
m and n are each an integer of 0 or 1],
X is vinylene, or a group of the formula : -NHCO-, -NHSO2-, -OCO-, -OCH2-, -NHCOCO-,
-NHCOCH=CH-, -NHCOCH2-, -NHCONH- or
Figure imgf000006_0002
(wherein R5 is lower alkyl),
Y is heterocyclic group which may have one or more suitable substituent (s), or aryl which may have one or more suitable substituent (s),
Q is CH or N, and
l is an integer of 0 or 1,
and a pharmaceutically acceptable salt thereof.
The object compound (I) or a salt thereof can be
prepared by the processes as illustrated in the following reaction schemes.
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000011_0001
Figure imgf000012_0001
Figure imgf000013_0001
wherein
R1 , R2 R3 X, Y, Q and l are each as defined above,
is acylamino ,
is amino,
is lower alkyl substituted with oxo,
is hydroxy (lower) alkyl,
is acyloxy (lower) alkyl,
is hydrogen,
is hydroxy (lower) alkyl,
is lower alkyl substituted with heterocyclic group which
Figure imgf000014_0002
may have one or more suitable substituent (s),
heterocyclicthio (lower) alkyl, lower
alkylamino (lower) alkyl which may have one or more suitable substituent (s),
hydroxy (lower) alkylamino (lower) alkyl,
bis-[hydroxy (lower) alkyl] amino (lower) alkyl,
amidinothio (lower) alkyl or
di-(lower) alkoxyphosphoryl (lower) alkyl,
E is lower alkylene, lower alkenylene or a group of the formula :
Figure imgf000014_0001
V is heterocyclic group which may have one or more suitable substituent (s), heterocyclicthio, or lower alkylamino which may have one or more suitable substituent (s), hydroxy (lower) alkylamino, bis-hydroxy (lower) alkylamino, amidinothio or tri-lower alkylphosphite,
Z is leaving group,
A5 is lower alkylene,
R' is hydrogen or lower alkyl,
R" is leaving group,
R"' is lower alkyl, cyclo (lower) alkyl, lower alkyl
substituted with heterocyclic group which may have one or more suitable substituent (s), lower alkoxy (lower) alkyl, hydroxy (lower) alkyl, amino, heterocyclic group, carboxy (lower) alkyl, protected carboxy (lower) alkyl, lower alkyl substituted with aryl which may have one or more suitable substituent (s) or arylsulfonyl or cyano (lower) alkyl,
G1 is -COOH or -SO3H,
G2 is -CO- or -SO2-,
X' is halogen,
a is an integer of 0 to 6, and
b, r, q and u are each an integer of 0 or 1.
Some of the Starting compound (II) or a salt thereof is novel and can be prepared by the following schemes.
Figure imgf000015_0001
wherein R1, R2, R3 and Q are each as defined above, and X"' is halogen.
Suitable pharmaceutically acceptable salts of the object compound (I) are conventional non-toxic salts and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g., sodium salt, potassium salt, etc.), an alkaline earth metal salt (e.g., calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g., triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.); an inorganic acid addition salt (e.g., hydrochloride, hydrobromide, sulfate, phosphate, etc.);
an organic carboxylic or sulfonic acid addition salt (e.g., formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate,
toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g., arginine, aspartic acid, glutamic acid, etc.).
In the above and subsequent desoriptions of the present specification, suitable examples and illustration of the various definitions which the present invention intends to include within the scope thereof are explained in detail as follows.
The term "lower" is used to intend a group having 1 to 6 carbon atom(s), unless otherwise provided.
The term "higher" is used to intend a group having 7 to 20 carbon atoms, unless otherwise provided.
Suitable example of ."one or more" may be the number of 1 to 6, in which the preferred one may be the number of 1 to 4.
Suitable "lower alkyl" and "lower alkyl moiety" may include straight or branched one having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, and the like, preferably one having 1 to 5 carbon atom(s).
Suitable "lower alkane" may include straight or branched one having 1 to 6 carbon atom(s), such as methane, ethane, propane, isopropane, butane, iscbutane, sec-butane, tert- butane, pentane, 3-pentane, isopentane, tert-pentane,
neopentane, hexane, isohexane, and the like, i nwhich the more preferred one may be (C1-C4) alkane, and the most
preferred one may be methane.
Suitable "lower alkenyl" and "lower alkenyl moiety" may include vinyl, 1-(or 2-)propenyl, 1-(or 2- or 3-)butenyl, 1- (or 2- or 3τ or 4-)pentenyl, 1-(or 2- or 3- or 4- or 5-)- hexenyi, methylvinyl, ethylvinyl, 1-(or 2- or 3-)methyl-1- (or 2-)propenyl, 1-(or 2- or 3-) ethyl-1- (or 2-)propenyl, 1-(or 2- or 3- or 4-)methyl-1-(or 2- or 3-)butenyl, and the like, in which more preferable example nay be (C6-C4) alkenyl, and the most preferred one may be methylvinyl.
Suitable "lower alkynyl" may include ethynyl,
1-propynyl, propargyl, 1-methylpropargyl, 1-(or 2- or 3-)- butynyl, 1-(or 2- or 3- or 4-)pentynyl, 1-(or 2- or 3- or 4- or 5-)hexynyl, and the like, in which more preferable example may be (C2-C4) alkynyl, and the most preferred one may be ethynyl.
Suitable "lower alkoxy" may include methoxy, ethoxy, propoxy isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t-pentyloxy, hexyloxy and the like.
Suitable "aryl" and "aryl moiety" may include phenyl, naphthyl, anthryl and the like.
Suitable "leaving group" may include acid residue,
"tri (lower) alkylammonio" as defined below and the like, and suitable examples of "acid residue" may be halogen (e.g., fluorine, chlorine, bromine, iodine.), acyloxy [e.g.,
sulfonyioxy (e.g., phenylsulfonyloxy, tosyloxy, mesyloxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.], lower alkyl (e.g., methyl, ethyl propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, neopentyl, t-pentyl, hexyl, etc.), aryl (e.g., phenyl, naphthyl, anthryl, etc.), ar (lower) alkyl such as phenyl (lower) alkyl (e.g., benzyl, phenethyl, phenylpropyl, etc.),
di (lower) alkylamino (e.g., dimethylaminc, diethylamino, aiiscprcpylamino, ethylmethylaminc, iscpropyimethylaminc, ethylmethylamino, ethylpropyiamino, etc.), lower
alkyl (lower) alkoxyamino (e.g., methylmethoxyamino,
methylethylamino, ethylmethoxyamino, ethylethoxvamino, etc.) or the like.
The preferred examples of "tri (lower) alkylammonio" may be trimethylammonio, triethylammonio, tripropylammonio, tributylammonio, tripentylammonio, trihexylammonio, or the like, in which the preferred one may be tri(C1-C4)- aikylammonio, and the most preferred one may be
trimethylammonio.
Suitable "acid residue" may include halogen (e.g., fluorine chlorine, bromine, iodine, etc.), acyloxy [e.g., sulfonyloxy (e.g., phenylsulfonyloxy, tosyloxy, mesyioxy, etc.), lower alkanoyloxy (e.g., acetyloxy, propionyloxy, etc.), etc.] and the like.
Suitable "lower alkylene" may include straight or branched one such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene,
methylmethylene, ethylethylene, ethylpropyiene, and the like.
Suitable "lower alkenylene" may include straight or branched one having 2 to 6 carbon atom(s) such as vinyiene, propenylene, 1-(or 2-)butenylene, 1-(or 2- or 3-)pentenylene, 1-(or 2- or 3-) hexenylene, methylvinylene, ethylvinyiene, 1-(or 2- or 3-)methyIpropenylene, 1-(or 2- or 3-)- ethylprcpenylene, 1-(or 2- or 3- or 4-)methyl-1-(or 2-)- butenylene, and the like. Suitable "cyclo (lower) alkyl" may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, in which the preferred one may be cyclo (C4-C6) alkyl.
Suitable "halogen" and "halo" moiety may include
fluorine, bromine, chlorine, and iodine.
Suitable "an acyl group" and "acyl" moiety may include carbamoyl, aliphatic acyl group and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or heterocyclic ring, which is referred to as heterocyclic acyl.
Suitable example of said acyl may be illustrated as follows :
carbamoyl; carboxy;
aliphatic acyl such as lower or higher alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyi, nonanoyl, decanoyl, undecancyl, dodecanoyl,
tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.); cyclo (lower) alkylcarbonyl (e.g., cyclopropylcarbonyl,
cyclobutylcarbonyl, cyclopentylcarbonyi, cyclohexylcarbonyl, etc.); protected carboxy such as commonly protected carboxy [e.g., esterified carboxy such as lower or higher
alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, iso-propyloxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.), etc.], or the like; lower or higher alkylsulfonyl (e.g.,
methylsulfonyl, ethylsulfonyl, etc.); lower or higher
alkoxysulfonyl (e.g., methoxysulfonyl, ethoxysulfonyl, etc.); di (lower) alkoxyphosphoryl (e.g., dimethoxyphosphoryl,
diethcxyphosphoryl, dipropoxyphosphoryl, dibutoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.),
a group of the formulas :
Figure imgf000020_0001
(wherein A3 and A4 are lower alkylene, amino (lower) alkylene or aminophenylene,
R11 is lower alkyl or hydrogen and
S and t are each integer of 1 to 6, or the like); aromatic acyl such as
aroyl (e.g., benzoyl, toluoyl, naphthoyl, etc.);
ar (lower) alkanoyl [e.g., phenyl (lower) alkanoyl (e.g., phenylacetyl, phenylpropanoyl, phenylbutanoyl,
phenylisobutanoyl, phenylpentanoyl, phenyIhexanoyl, etc.), naphthyl (lower) alkanoyl (e.g., naphthylacetyl,
naphthylpropanoyl, naphthylbutanoyl, etc.), etc.];
ar (lower) aikenoyl [e.g., phenyl (lower) alkenoyl (e.g., phenylprcpenoyl, phenylbutenoyl, phenylmethaoryloyl, phenylpentenoyi, phenyihexenoyi, etc.),
naphthyl (lower) alkenoyl (e.g., naphthylpropenoyl,
naphthylbutenoyl, etc.), etc.];
ar (lower) alkoxycarbonyl [e.g., phenyl (lower) alkoxycarbonyl (e.g. benzyloxycarbonyl, etc.), etc.];
aryloxycarbonyl (e.g., phenoxycarbonyl,
naphthyloxycarbonyl, etc.);
aryloxy (lower) alkanoyl (e.g., phenoxyacetyl,
phenoxypropionyl, etc.);
arylcarbamoyl (e.g., phenylcarbamoyl, etc.);
arylthiocarbamoyl (e.g., phenylthiocarbamoyl, etc.);
arylglyoxyloyl (e.g., phenylgiyoxyloyl, naphthylglyoxyloyl, etc.); arylsulfonyl (e.g., phenylsulfonyl, p-tolylsulfonyl, etc.); or the like.
heterocyclic acyl such as
heterocycliccarbonyl;
heterocyclic (lower) alkanoyl (e.g., heterocyclicacetyl, heterocyciicpropanoyl, heterocyclicbutanoyl,
heterocyclicpentanoyl, heterocyclichexanoyl, etc.);
heterocyclic (lower) alkenoyl (e.g., heterocyclicpropencyl, heterocyclicbutenoyl, heterocyclicpentenoyi,
heterocyclichexenoyl, etc.); heterocyclicglyoxyloyl;
heterocyclicsulfinyl; heterocyclicsuifonyl; or the like; and the like. Suitable "heterocyclic group" and "heterocyclic moiety" may include saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero-atom such as an oxygen, sulfur, nitrogen atom and the like.
And, especially preferable one may be heterocyclic group such as
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, pyrroiinyl, imidazolyl, pyrazoiyl, pyridyl, dihydropyridyl, pyrimidyi, pyrazinyl, pyridazinyl, triazolyl (e.g., 4H-1,2 ,4-triazolyl, 1H-1,2,3- triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (e.g., 1H- tetrazolyl, 2H-tetrazolyl, etc.), etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolidinyl, imidazclidinyl,
piperidyl, piperazinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s), for example, indolyl, isoindolyl,
indolinyl, indolizinyl, benzimidazolyl, quinolyl,
isoquinolyi, indazolyl, benzotriazoiyl, phthalimidyl, etc.; unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyi, 1,3,4- oxadiazolyl, 1,2,5-oxadiazolyl, etc.), etc.;
saturated 3 to 3-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example,
morpholinyl, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazciyi, thiadiazoiyi (e.g., 1,2,3-thiadiazolyl, 1,2,4- thiadiazoiyi, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example,
thiazoiidinyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, dihydrodithiinyl,
dihydrodithionyi, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom, for example, furyl, pyranyl, etc.;
saturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing 1 to 2 oxygen atom(s), for example, oxiranyl, oxolanyl, dioxolanyl, tetrahydrofuranyl, etc.;
unsaturated 3 to 8-membered (more preferably 5 or 6- membered) heteromonocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example, dihydrooxathiinyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 4 oxygen atom(s), for example, methylenedioxyphenyl,
benzodioxanyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, benzodithiinyl, etc.;
unsaturated condensed heterocyclic group containing an oxygen atom and 1 to 2 sulfur atom(s), for example,
benzoxathiinyl, etc.; and the like,
and "heterocyclic group" and "heterocyclic moiety" as stated above may have one or more suitable substituent (s) such as exo; halogen (e.g., fluorine, chlorine, bromine, iodine, etc.); hydroxy; aforementioned "heterocyclic group"; tri- halo (lower) alkyl (e.g., trichloromethyl, trifluoromethyl, trichloroethyl, trifiuoroethyl, etc.); lower alkanoyl (e.g., formyl, acetyl, prcpancyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, etc.); aryl (e.g., phenyl, naphthyl, anthryl, etc.); lower alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-pentyl, isopentyl, tert-pentyl, neopentyl, hexyl, isohexyl, etc.); amino; aforementioned "protected carboxy"; and the like.
The acyl moiety as stated above may have one to ten, same or different, suitable substituent (s) such as lower alkyl (e.g., methyl, ethyl, propyl, etc.);
lower alkoxy (e.g., methoxy.. ethoxy, propoxy, etc.);
lower alkylthio (e.g., methylthio, ethylthio, etc.);
mono- (or di-) lower alkylamino which may have one or more suitable substituent (s) (e.g., methylamino, ethylamino, oropylamino, dimethylamino, diethylamino, dipropylamino, N- methoxy-N-methylamino, N-ethoxy-N-ethylamino, N- methoxymethyl-N-methylamino, N-methoxyethyl-N-methylamino, etc.); lower alkanoylamino (e.g., acetylamino,
prcpionylamino, butyrylamino, pentanoylamino, hexanoylamino, etc.); cyclo (lower) alkylamino (e.g., cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylaminc, etc.); mono-(or di-) lower alkoxy (lower) alkylamino (e.g.,
methoxymethylamino, methoxyethylamino, methoxypropylamino, ethoxymethylamino, ethoxyethylamino, ethoxypropylamino, etc.); hydroxy (lower) alkylamino (e.g., hydroxymethylamino, hydroxyethylamino, hydroxypropylamino, hydroxypentylamino, hydroxyhexylamino, etc.); heterocyclic (lower) alkylamino, in which "heterocyclic moiety" is aforementioned "heterocyclic" moietv; heterocyclicamino which may have one or more suitable
substituent (s), in which "heterocyclic" moiety is
aforementioned "heterocyclic" moiety;
lower alkanoyloxy (e.g., acetyloxy, propionyloxy, butyryloxy, pentanoyloxy, hexanoyloxy, etc.);
heterocyclic group, in which "heterocyclic group" is
aforementioned "heterocyclic group";
di-lower alkoxy (lower) alkyl (e.g., dimethoxymethyl,
dimethcxyethyl, dimethcxypropyi, diethcxymethyl,
diethoxyethyl, diethoxypropyl, etc.);
arylamino which may have one or more suitable substituent (s)
(e.g., phenylamino, dimethylaminophenylamino,
trifluoromethylphenylamino, trifluorcmethylnaphthylamino, trifluoromethylanthrylaminc, etc.);
cyano (lower) alkylamino (e.g., cyanomethylamino,
cyanoethylamino, cyanopropylamino, cyanobutylamino,
cyanopentylamino, cyanohexylamino, etc.);
arylsulfonylamino (e.g., phenylsulfonyiamino
naphthylsulfonylamino, anthrylsulfcnylamino, etc.);
protected carboxy (lower) alkylamino (e.g.,
methoxycarbonylmethylamino, methoxycarbonylethylamino, ethoxycarbonylmethylamino, ethoxycarbonylethylaminc, etc.); tri-halo (lower) alkylamino (e.g., 2,2,2-trifluoroethylamino,
1-(trifluoromethyl) ethylaminc,
2-(trifluoromethyl)propyIaminc, etc.);
cyclo (lower) alkyl (e.g., cyciopentyl, cyclohexyl, etc.);
cyclo (lower) alkenyl (e.g., cyclohexenyl, cyclohexadienyl, etc.);
halogen (e.g., fluorine, chlorine, bromine, iodine, etc.); amino, commonly protected amino as mentioned above; hydroxy; commonly protected hydroxy as mentioned below; cyano; nitro; carboxy; carboxy (lower) alkyl;
commonly protected carboxy as mentioned below; sulfo;
sulfamoyl; imino; oxo; hydrazino; amino (lower) alkyl (e.g., aminomethyl, aminoethyl, etc.); carbamoylcxy; hydroxy (lower) alkyl (e.g., hydroxymethyl, 1-(or 2-)- hydrcxyethyl, 1-(or 2- or 3-) hydroxypropyi, etc.), or the like.
Suitable "hydroxy protective group" in the term commonly "protected hydroxy" may include acyl as mentioned above, phenyl (lower) alkyl which may have one or more suitable substituent (s) (e.g., benzyl, 4-methoxybenzyI, trityl, etc.), trisubstituted silyl [e.g., tn (lower) alkylsiiyl (e.g., trimethylsilyl, t-butyldimethylsilyi, etc.), etc.],
tetrahydropyranyl and the like.
Suitable commonly "protected carboxy" may include esterified carboxy and the like. And suitable example of said ester may be the ones such as lower alkyl ester (e.g., methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, etc.);
lower alkenyl ester (e.g., vinyl ester, allyl ester, etc.); lower alkynyl ester (e.g., ethynyl ester, propynyl ester, etc.);
lower alkoxy (lower) alkyl ester (e.g., methoxymethyl ester, ethoxymethyl ester, isopropoxy ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.);
lower alkylthio (lower) alkyl ester (e.g., methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester,
isopropoxythiomethyl ester, etc.);
mono-(or di- or tri-) halo (lower) alkyl ester (e.g.,
2-iodoethyl ester, 2,2,2-trichloroethyl ester, etc.);
lower alkanoyloxy (lower) alkyl ester (e.g., acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester,
hexanoyloxymethyl ester, 1-acetoxyethyl ester,
2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.);
lower alkoxycarbonyloxy (lower) alkyl ester (e.g.,
ir.ethoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyioxymethyl ester, 1-(or 2-) [methoxycarbonyloxy] ethyl ester,
1-(or 2-) [ethoxycarbonyloxyj ethyl ester,
1- (or 2-) [propoxycarbonyloxy] ethyl ester,
1-(or 2-) [isopropoxycarbonyloxy] ethyl ester, etc.);
lower alkanesulfonyl (lower) alkyl ester (e.g., mesylmethyl ester, 2-mesyethyl ester, etc.);
lower alkoxycarbonyloxy (lower) alkyl ester (e.g.,
methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester,
z-butoxycarbonyloxymethyl ester,
1-(or 2-)methoxycarbonyloxyethyl ester,
1-(or 2-) ethoxycarbonyloxyethyl ester,
1-(or 2-)propoxycarbonyloxyethyl ester,
1- (or 2-) isopropoxycarbonyloxyethyl ester, etc.);
phthalidylidene (lower) alkyl ester, or
(5-lower alkyl-2-oxo-1,3-dioxol-4-yl) (lower) alkyl ester
[e.g., (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo- 1,3-dioxol-4-yl) ethyl ester, etc.];
ar (lower) alkyl ester, for example, phenyl (lower) alkyl ester which may have one or more suitable substituent (s) (e.g., benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester,
bis (methoxyphenyl) methyl ester, 3, 4-dimethoxybenzyl ester, 4-hydroxy-3, 5-di-t-butylbenzyl ester, etc.);
aryl ester which may have one or more suitable substituent (s) such as substituted or unsubstituted phenyl ester (e.g., phenyl ester, tolyl ester, t-butylphenyi ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester,
4-methoxyphenyl ester, etc.);
tri (lower) alkyl silyl ester; lower alkylthioester (e.g., methylthioester, ethylthioester, etc.) and the like.
The preferred examples of "an acyl group" may be carboxy protected carboxy, carbamoyl, lower alkanoyl, lower alkylsulfonyl, aroyl, heterocyclic carbonyl which may have one or more suitable substituent (s), in which the more preferred one may be carboxy, (C1 -C4) alkoxy carbonyl, carbamoyl, (C1-C4) alkanoyl, (C1-C4) alkylsulfonyl, benzoyl, carbonyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), carbamoyl substituted with saturated 3 to 8-membered
heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 tc 3 nitrogen atom(s), carbonyl substituted with saturated 3 to S-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s) having (C1-C4) alkyl, and the most preferred one may be carboxy, methoxycarbonyl, ethoxycarbonyl,
isopropoxycarbonyl, carbamoyl, acetyl, methylsulfonyl, benzoyl, morphclinccarbonyl, N-methylpiperidylcarbonyl or pyridylcarbonyl.
Suitable "acyl" moiety in the term of "acylamino" can be referred to aforementioned "acyl" moiety.
The preferred examples of "acylamino" may be ureido, lower alkanoylamino, lower alkoxycarbonylamino, heterocyclic carbonylamino, lower alkanoylamino (lower) alkanoylamino (e.g. acetylaminoacetylamino, acetylaminopropionylamino,
propionylaminoacetylamino, propionylaminopropionylamino, etc.), mono-(or di-) lower alkylamino (lower) alkanoylamino (e.g., methylaminoacetylamino, dimethylaminoacetylamino, ethylaminoacetylamino, diethylaminoacetylaminc, etc.), lower alkanoyloxy (lower) alkanoylamino [e.g., acetyloxyacetylamino, acetyloxypropionylamino, propionyloxyacetylamino,
propionyloxypropionylamino, etc.),
heterocyclic (lower) alkanoylamino (e.g., heterocyclic- carbonylamino, heterocyclic-acetylamino, heterocyclic- propionylamino, etc .), lower alkoxy (lower) alkanoylamino
(e.g., methoxyacetylamino, ethoxyacetylamino,
methoxypropionylamino, ethoxypropionylamino, etc.),
hydroxy (lower) alkanoylamino (e.g., hydroxyacetylamino, hydroxypropionylamino, etc.), lower alkylsulfonylamino (e.g., methylsulfonylamino, ethylsulfonylamino, propylsulfonylamino, butylsulfonylamino, pentylsulfonylamino, hexylsulfonylamino, etc.), or mono-(or di-) lower alkoxy (lower) alkylamino (lower)- alkanoylamino (e.g., methoxymethylaminoacetylamino,
bis (methoxymethyl) aminoacetylamino,
methoxyethylaminoacetylamino,
bis (methoxyethyl) aminoacetylamino, etc.), in which the more preferred one may be ureido, (C1-C4)alkanoylamino,
(C1-C4) alkoxycarbonylamino, carbonylamino substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), (C1-C4) - alkanoylamino (C1-C4) alkanoylamino, di (C1-C4)alkylamino- (C1-C4) alkanoylamino, (C1-C4 ) alkanoyloxyC1-C4) alkanoylamino, (C1-C4)alkanoylamino substituted with saturated 3 to 8- membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), (C1-C4)alkoxy (C1-C4)- alkanoylamino, hydroxy (C1-C4)alkanoylamino, (C1-C4)- alkylsulfonylamino or bis [(C1-C4)alkoxy (C1-C4)alkyl]amino (C1-C4)alkanoylamino and the most preferred one may be ureido, acetylamino, t-butoxycarbonylamino,
morpholinocarbonylamino, acetylaminoacetylamino,
dimethylaminoacetylamino, acetyloxyacetylamino,
morpholinoacetylamino, methoxyacetylamino,
hydroxyacetylamino, methylsulfonylamino or
dimethoxyethylaminoacetylamino. Suitable "hydroxy (lower) alkyl" moiety in the term of "hydroxy (lower) alkyl which may have one or more suitable substituent (s)" may be hydroxymethyl, 1-(or 2-)hydroxyethyl, 1-hydroxy-1-methylethyl, 2-hydroxypropyl, 1-hydroxy-1- ethylethyl, 1-hydroxy-1-ethylpropyl, 1-hydroxybutyl, 1- (or 2- or 3-)hydroxy-1-(or 2- or 3-)methylpropyl, 1-(or 2- or 3- or 4-)hydroxy-1-(or 2- or 3- or 4-)methylbutyl, 1-(or 2- or 3- or 4- or 5-) hydroxy-1-(or 2- or 3- or 4- or 5-)methylpentyl, 1- (or 2- or 3- or 4- or 5- or 6-) hydroxy-1-(or 2- or 3- or 4- or 5- or 6-)methylhexyl, or the like.
The preferred examples of "hydroxy (lower) alkyl" may be hydroxy (C1-C4)alkyl, and the most preferred one may be hydroxymethyl, 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-hydrcxy-1-ethylpropyl, 1-hydrcxybutyϊ, 2-hydroxyethyl, 3-hydroxy-3-methylbutyl, 1-hydroxybutyl, 2-hydroxypropyl or 2-hydroxy-2-methylpropyl.
The preferred examples of "suitable substituent (s) " in the term of "hydroxy (lower) aikyl which may have one or more suitable substituent (s)" may be mono- (or di- or tri-)- haio (lower) alkyl, protected carboxy, hydroxy, aryl,
cyclo (lower) alkyl or heterocyclic group, in which the
preferred one may be tri-halo (C1-C4)aikyl, (C1-C4)- alkoxycarbonyl, hydroxy, phenyl, cyclo (C3-C6)alkyl, or unsaturated heteromonocyclic group consisting of 1 to 4 nitrogen atom(s), and the most preferred one may be
trifluoromethyl, ethoxycarbonyl, hydroxy, phenyl, cyclohexyl or pyridyl.
Suitable "acyl" moiety in the term of "acyl (lower) alkyl" can be referred to aforementioned "acyl" moiety.
The preferred examples of "acyl (lower) alkyl" may be carboxy (lower) alkyl, protected carboy (lower) alkyl,
carbamoyl (lower) alkyl, lower alkanoyl (lower) alkyl,
aroyl (lower) alkyl, carbonyl (lower) alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), sulfonyl (lower) alkyl substituted with
heterocyclic group which may have one or more suitable substituent (s), sulfinyl (lower) alkyl substituted with
heterocyclic group which may have one or more suitable substituent (s), lower alkyl having
Figure imgf000031_0001
(wherein A3 is lower alkylene, amino lower alkylene or
aminophenylene,
R11 is lower alkyl or hydrogen, and
s and t are each integer of 1 to 6),
(mono- or di-) lower alkyiaminocarbonyl (lower) alkyl which may have one or more suitable substituent (s) (e.g.,
methylaminocarbonylmethyl, dimethylaminocarbonylmethyl, methylaminocarbonylethyl, 2-dimethylaminocarbonylethyl,
N-methoxy-N-methylaminocarbonylmethyl,
N-methoxyethyl-N-methylaminocarbonylmethyl,
trifluoromethylaminocarbonylmethyl,
trifluoroethylaminocarbonylmethyl,
cyanomethylaminocarbonyimethyl,
cyanoethylaminocarbonyimethyl, cyanomethylaminocarbonylethyl, etc.), cyclo (lower) alkyiaminocarbonyl (lower) alkyl (e.g.
cyclopropylaminocarbonylmethyl,
cyclobutylaminccarbcnylmethyl,
cyciopentylaminocarbonylmethyl,
cyciohexylaminocarbonylmethyl, etc.),
lower alkoxy (lower) alkyiaminocarbonyl (lower) alkyl (e.g., methoxymethylaminocarbonylmethyl,
methoxyethylaminocarbonylmethyl,
methoxypropylaminocarbonylmethyl,
bis (methoxymethylamino) carbonylmethyl,
bibs (methoxyethylamino) carbonylmethyl, etc.),
di- (lower) alkoxyphosphoryl (lower) alkyl (e.g.,
dimethoxyphosphorylmethyl, diethoxypncsphoryimethyl, dipropoxyphosphorylethyl, dibutoxyphosphorylethyl, dipentyl- cxyphosphorylethyl, dihexyloxyphosphorylpropyl, etc.), mono-(or di-) hydroxy (lower) alkyiaminocarbonyl (lower) alkyl (e.g., hydroxymethylaminocarbonylmethyl,
hydroxyethylaminocarbonylmethyl,
dihydroxymethylaminocarbonylmethyl,
dihydroxyethylaminocarbonylmethyl, etc.),
aminocarbonyl (lower) alkyl substituted with heterocyclic group which may have one or more suitable substituent (s) (e.g.
thiazolylaminocarbonylmethyl, piperidinoaminocarbonylmethyl, morpholinoaminomethyl, methyloxadiazolylaminocarbonylmethyl, trifluoromethylthiadiazolylaminocarbonylmethyl, pyridylaminocarbonylmethyl, aminopyridylaminocarbonylmethyl, etc.), heterocyclic (lower) alkyiaminocarbonyl (lower) alkyl
(e.g., pyridylmethylaminocarbonylmethyl,
tetrahydrofuranylmethylaminocarbonylmethyl,
furanylmethylaminocarbonylmethyl,
morpholinoethylaminocarbonylmethyl,
thienylmethylaminccarbcnylmethyl,
imidazolylethylaminocarbonylmethyl, etc.),
hydrazinocarbonyl (lower) aikyl (e.g., hydrazinocarbonylmethyl, hydrazinocarbonylethyl, hydrazinocarbonyipropyl, etc.), aminocarbonyl (lower) alkyl substituted with aryl which may have one or more suitable substituent (s) (e.g.,
dimethylaminophenylaminocarbonylmethyl,
trifluoromethylphenylaminocarbonylmethyl,
anilinophenylaminocarbonylmethyl,
aminophenylaminocarbonylmethyl, etc.),
cyano (lower) alkyiaminocarbonyl (lower) alkyl (e.g.,
cyanomethylaminocarbonylmethyl,
cvanoethylaminocarbonylmethyl, cyanomethylaminocarbonylethyl, cyanoethylaminocarbonylethyl, etc.),
arylsulfonylaminocarbonyl (lower) alkyl (e.g.,
phenylsulfonylaminocarbonylmethyl,
phenylsulfonylaminocarbonylethyl, phenylsulfonylaminocarbonylpropyl, etc.),
protected carboxy (lower) alkyiaminocarbonyl (lower) aikyl (e.g. methoxycarbonylmethylaminocarbcnylmethyl,
ethoxycarbonylmethylaminocarbonylmethyl,
1-(or 2-)methoxycarbonylethylaminccarbonylmethyl,
1-(or 2-) ethoxycarbonylethylaminocarbonylethyl, etc.), in which the preferred one may be (C1-C4)alkoxycarbonyl- (C1-C4)aikyl, (C1-C4) alkanoyl (C1-C4) alkyl, carbamoyl- (C1-C4)aikyl, carboxy (C1-C4)aikyl, lower aikyl having
Figure imgf000033_0001
(wherein A3 is (C1-C6)alkylene, amino (C1-C6) alkylene or
aminophenylene,
R11 is (C1-C6) alkyl or hydrogen, and
s and t are each integer of 1 to 6), carbonyl (C1-C4)alkyl substituted with heterocyclic group which may have 1 to 3 suitable substituent (s),
sulfonyl (C1-C4)alkyl substituted with heterocyclic group which may have 1 to 3 suitabie substituent (s),
sulfinyl (C1-C4)alkyl substituted with heterocyclic group which may have 1 to 3 suitable substituent (s),
mono-(or di-) (C1-C4)alkyiaminocarbonyl (C1-C4)alkyl which may have 1 to 3 suitable substituent (s),
cyclo (C3-C6) alkyiaminocarbonyl (C1-C4)alkyl,
(C1-C4)alkoxy (C1-C4) alkyiaminocarbonyl (C1-C4) alkyl,
di- (C1-C4)alkoxyphosphoryl (C1-C4)aikyl,
mono- (or di-) hydroxy (C1-C4) alkyiaminocarbonyl (C1-C4)alkyl, aminocarbonyl (C1-C4)alkyl substituted with heterocyclic group which may have 1 to 3 suitabie substituent(s), heterocyclic (C1-C4)alkyiaminocarbonyl (C1-C4)alkyl,
hydrazinocarbonyl (C1-C4)alkyl, aminocarbonyl (C1-C4) alkyl substituted with phenyl which may have 1 to 3 suitable substituent (s), cyano (C1-C4)alkyiaminocarbonyl (C1-C4)alkyl, phenyisulfonylaminocarbonyl (C1-C4)alkyl,
(C1-C4) alkoxycarbonyl (C1-C4) alkyiaminocarbonyl (C1-C4)alkyl, and the most preferred one may be carboxymethyl,
carboxyethyl, methoxycarbonyimethyl, methoxycarbonylethyl, ethoxycarbonyimethyl, ethoxycarbonylethyl, benzoylmethyl, carbamoylmethyl, acetylmethyl, t-butoxycarbonylmethyl, morpholinocarbonylmethyl, pyridylcarbonylmethyl,
chlorothienylcarbonylmethyl, pyrrolinylcarbonylmethyl, acetylpiperazinylcarbonylmethyl,
phenylpiperazinylcarbonylmethyl,
methylpiperazinylcarbonylmethyl,
hydroxypiperidinocarbonylmethyl,
4-pyridylpiperazinylcarbonylmethyl, imidazolylsulfonylmethyl, methylimidazolylsulfonylmethyl, imidazolylsulfinylmethyl, dimethylaminocarbonyimethyl, dimethylaminocarbonylethyl, trifluoromethylmethylaminocarbonylmethyl,
cyanomethylaminocarbonylmethyl,
cyclopentylaminocarbonylmethyl,
methoxyethylaminocarbonylmethyl,
dimethoxyethylaminocarbonylmethyl,
N-methoxy-N-methylaminocarbonyimethyl,
N-methoxyethyl-N-methylaminocarbcnylmethyl,
dimethoxyphosphorylmethyl, diethoxyphcsphorylmethyl,
hydroxyethylaminocarbonylmethyl,
dihydroxyethylaminocarbonylmethyl,
trifluoromethylthiadiazolylaminocarbonylmethyl,
thiazolylaminocarbonylmethyl, piperidinoaminocarbcnylmethyl, morphoiincaminocarbonylmethyl,
pyridyl-N-methylaminocarbonylmethyl,
methyloxadiazolyiaminocarbonyimethyl. pyridyiaminocarbonylmethyl, aminopyridylaminocarbonylmethyl, pyridyimethylaminocarbonylmethyl,
tetrahydrofuranyimethylaminocarbonylmethyl,
trifluorothiadiazolylaminocarbonylmethyl,
furanylmethylaminocarbonylmethyl,
morpholinoethylaminocarbonylmethyl,
thienyimethylaminocarbonylmethyl,
imidazolylethylaminccarb ylmethyl,
aniiinophenylaminocarbon methyl,
aminophenylaminccarbonylm thyl, hydrazinocarbonylmethyl, dimethylaminophenylaminocarbonyimethyl,
trifluoromethylphenylaminocarbcnyimethyl,
phenylsulfcnyiaminocarbonylmethyl,
1-methoxycarbonylethylaminocarbonyimethyl or
ethoxycarbonyimethylaminocarbonylmethyl.
The preferred examples of "mono-(or di- or tri-)- halo (lower) alkyl" may be
fiuoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, bromomethyl, dibromomethyl, tribromomethyl, 1-(or 2-) fluoroethyl, 1-(or 2-)bromoethyl, 1-(or 2-) chloroethyl, 1, 1-difiuoroethyl, 2,2-difluoroethyl, or the like, in which the preferred one may be mono- (or di- or tri-) halo (C1-C4) alkyl, and the most preferred one may be difluoromethyl or trifluoromethyl.
The preferred examples of "lower alkylthio" may be methyl.thio, ethylthio, propylthio, butylthio, pentylthio, hexylthio, or the iike, in which the preferred one nay be (C1-C4) alkylthio, and the most preferred one may be
methylthio.
The preferred exampies of
"cyclo (lower) aikyl (lower) alkyl" may be cyclopropylmethyl, cyciobutylmethyl, cyclopentylmethyl, cyciohexylmethyl. cyciopropylethyl, cyclobutylethyl, cyciopentylethyl,
cyclohexylethyl, or the like, in which the preferred one may be cyclo (C3-C6) alkyl (C1-C4) alkyl, and the most preferred one may be cyciohexylmethyl.
Suitabie "acylamino" moiety in the term cf "acyiamino- (lower) alkyl" can be referred to aforementioned "acylamino".
The preferred examples cf "acylamino (lower) alkyl" may be lower alkoxycarbonylamino (lower) alkyl, lower
alkanoylamino (lower) aikyl, heterocyciic-carbonylamino- (lower) alkyl,
Figure imgf000036_0001
(wherein A3 and A4 are each lower alkylene,
amino (lower) alkylene or aminophenylene, and R11 is lower alkyl or hydrogen),
in which the preferred one may be (C1-C4) aikoxycarbonylamino- (C1-C4) alkyl, (C1-C4) alkanoylamino (C1-C4) alkyl,
carbonylamino (C1-C4) alkyl substituted with saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s).
Figure imgf000037_0001
(wherein A3 and A4 are each (C1-C6) alkylene, amino (C1-C6)
alkvlene or aminoohenvlene, and
R11 is (C1-C6) alkyl or hydrogen), and the most preferred one may be t-butoxycarbonyl
aminomethyl, acetylammomethyl or
morphoiinocarbonylaminomethyl .
Suitable "acyl" moiety in the terms of "acyl (lower) - alkenyl" can be referred to aforementioned "acyl" moiety.
Suitabie " (lower) alkenyl" moiety in the term of
"acyl (lower) alkenyl" can be referred to aforementioned "lower alkenyl".
The preferred examples of "acyl (lower) alkenyl" may be protected carboxy (lower) aikenyl, in which the preferred one may be (C1-C4) alkoxycarbonyl (C1-C4) alkenyl, and the most preferred one may be ethoxycarbonyivinyl. Suitable "acyl" moiety in the term of
"acyloxy (lower) alkyl" can be referred to aforementioned
"acyl" moiety.
The preferred examples of "acyloxy (lower) alkyl" may be lower alkanoyloxy (lower) alkyl,
cyclo (lower) alkylcarbonyloxy (lower) alkyl,
carboxy (lower) alkanoyloxy (lower) alkyl, protected
carboxyoxy (lower) aikyl, protected
carboxy (lower) alkanoyloxy (lower) alkyl, lower
alkylaminocarbonyloxy (lower) alkyl, aroyloxy (lower) alkyl, or lower aikyl substituted with
Figure imgf000038_0001
(wherein A3 is lower alkyiene, amino (lower) alkylene or
aminophenylene, and
R11 is lower alkyl or hydrogen), Ln which the preferred one may be (C1-C4) alkanoyloxy- (C1-C4) aikyl, cycle (C3-C6) alkylcarbamoyloxy- (C1-C4) alkyl, carboxy (C2-C4) alkanoyloxy- (C1-C4) alkyl, succinimidoxycarbonyl- (C2-C4) alkanoyloxy (C1-C4) alkyl, (C1-C4)- alkyiaminocarbcnyioxy (C1-C4) alkyl,
(C1-C4) aikoxycarbonyioxy (C1-C4) aikyl, benzoyloxy (C1-C4) alkyl, or lower alkyl substituted with
Figure imgf000039_0001
(wherein A3 is (C 1-C6) alkylene, amino ( C1 -C6) aikylene or
aminophenyiene, and
R11 is (C 1 -C6) alkyl or hydrogen) ,
and the most preferred one may be acetyioxymethyl ,
1-acetyloxyethyl , cyciohexylcarbonyloxymethyl,
methoxycarbonyioxymethyl , carboxybutanoyloxymethyl ,
succinimidyloxycarbonylbutanoyioxymethyl ,
ethyiaminocarbcnyloxymethyl ,
Figure imgf000039_0002
ethoxcarbonyloxymethyl or benzoylcxymethyl
Suitable "acyl" moiety in the term of
"acyl (lower) alkylthio (lower) aikyl" can be referred to aforementioned "acyl" moiety. The preferred examples of
"acyl (lower) alkylthio (lower) alkyl" may be protected
carboxy (lower) alkylthio (lower) aikyl, in which the preferred one may be (C1-C4) alkoxycarbonyl (C1-C4) alkylthio (C1-C4) alkyl, and the most preferred one may be
ethoxycarbonylmethylthiomethyl.
The preferred examples of "amino (lower) alkyl" may be amino (C1-C4 ) alkyl, in which the most preferred one may be aminomethyl.
The preferred exampies of "mono-(or di-) lower
alkylamino" may be methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dipropyiamino, butylamino,
dibutylamino, pentylamino, aipentylaminc, hexylamino,
dihexyiamino, or the like, in which the preferred one may be mono-(or di-) (C1-C4) alkylamino, and the most preferred one may be methylamino, dimethylamino or diethylamino. The preferred examples of "lower alkylthio (lower) alkyl" may be methylthiomethyl, methylthioethyl, methylthiopropyi, methylthiobutyl, ethylthiomethyl, ethylthioethyl,
ethylthioprcpyl, propylthiomethyl, propylthioethyl,
propylthiopropyl, or the like, in which the preferred one may be (C1-C4) alkylthio (C1-C4) alkyl, and the most preferred one may be methylthiomethyl.
The preferred examples of "hydroxyimino (lower) alkyl which may have one or more suitable substituent (s)" may be hydroxyiminomethyl, 1-hydrcxyiminoethyl, hydroxyimino-1- methylethyl, hydroxyiminc-1-methylpropyl, hydroxyimino-1- methylpropyi, hydroxyimino-1-amino-methyl, 2-hydroxyimino-2- amino-ethyl, hydroxyimino-1-aminopropyl, or the like, in which the preferred one may be hydroxyimino (C1-C4) alkyl which may have amme, and the most preferrec one may be 1-hydroxyiminoethyl or 2-hydroxyimino-2-aminoethyl.
The preferred examples of
"hydroxy (lower) alkylthio (lower) alkyl" may be
hydroxymethylthiomethyl, 2-hydroxymethylthioethyl,
2-hydroxymethylthiopropyl, 4-hydroxymethylthiobutyl,
5-hydroxymethylthiopentyl, hydroxymethylthiohexyl,
(2-hydrcxyethyl) thiomethyl, 2-(1-hydrcxyethyl) thioethyl, (1- or 2-hydroxyethyl) thiopropyl, (1- or 2-hydroxyethyl)- thiobutyl, (1- or 2-hydroxyethyl) thiopentyl, (1- or 2- hydroxyethyl) thiohexyl, or the like, in which the preferred one may be hydroxy (C1-C4) alkylthio (C1-C4) alkyl, and the most preferred one may be (2-hydrcxyethyl) thiomethyl. The preferred examples of "cyano (lower) alkyl" may be cyanomethyl, 1- (or 2-) cyanoethyl, 1-(or 2- or 3-) cyanopropyl, 1-(or 2- or 3- or 4-) cyanobutyl, 1- (or 2- or 3- or 4- or 5-)- yanopentyl, 1- (or 2- or 3- or 4- or 5- or 6-) cyanohexyl, or the like, in which the preferred one may be cyano (C1-C4) - aikyl, and the most preferred one may be cyanomethyl or 2- cyanoethyl.
Suitable "mono- (or di-) lower alkoxy (lower) alkyl" may be methoxymethyl, methoxyethyl, dimethoxymethyl, dimethoxyethyl, ethoxymethyl, ethoxyethyl, diethoxymethyl, diethoxyethyl, propoxymethyl, propoxyethyl, propoxypropyl, dipropoxymethyl, dipropoxyethyl, dipropoxypropyl, or the like, in which the preferred one may be mono-(or di-) (C1-C4) alkoxy (C1-C4) alkyl, and the most preferred one may be methoxymethyl,
2-methoxyethyl or 3-diethoxypropyl.
The preferred examples of "mono- (or di-) lower
alkoxy (lower) alkyl which may have one or more suitable substituent (s)" may be (C1-C4) alkoxy (C1-C4) alkyl or
tri-halo (C1-C4) alkyl (C1-C4) alkoxy (C1-C4) alkyl, and
the most preferred one may be methoxymethyl, 2-methoxyethyl, 3-diethoxypropyl or trifluoromethylmethoxymethyl .
Suitable "lower alkyl substituted with aryl" nay be benzyl, phenethyl, 2-phenylpropyl, naphthylmethyl,
naphthylethyl, anthryimethyl, 1-anthryiethyl, or the like, in which the more preferred one may be phenyl (C1-C4) alkyl, naphthyl (C1-C4) alkyl or anthryl (C1-C4) alkyl, and the most preferred one may be benzyi.
The preferred examples of "lower alkyl substituted with aryl which may have one or more suitable substituent (s)" may be the one which may have 1 to 3 nitro or cyano, such as phenyl (C1-C4) aikyl, nitrophenyi (C1-C4) alkyl or
cyanophenyi (C1-C4) aikyl, in which the most preferred one may be benzyl, 4-nitrobenzyl or 3-cyanobenzyl.
The preferred examples of "mono-(or di-) lower
alkylamino (lower) alkyl" may be mono-(or di-) (C1-C4)- ikylamino (C1-C4) alkyl, in which the more preferred one may be dimethvlaminomethyl.
The preferred exampie of "tri (lower) alkylammonio (lower)- alkyl" may be trimethylammoniomethyl, triethylammonioethyl, tripropylammoniopropyl, tributylammoniobutyl,
tripentylammoniopentyl, trihexylammoniohexyl, or the like, in which the preferred one may be tri (C1-C4) alkylammonio (C1-C4)- alkyl, and the most preferred one may be
trimethylammoniomethyl.
Suitable "heterocyclic group" moiety in the term of "lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s)" can be referred to aforementioned "heterocyclic group".
The preferred examples of "lower aikyl substituted with heteocyclic group which may have one or nore suitable
substituent (s)" may be imidazoiyi (lower) alkyl, pyridyl (lower) alkyl, morpholino (lower) alkyl,
pyrrolidinyl (lower) alkyl, tetrazolyl (lower) alkyl,
piperidino (lower) alkyl, benzimidazolyl (lower) alkyl,
triazolyl (lower) aikyl, oxiranyl (lower) aikyl, lower alkyl substituted with methylenedicxyphenyl having halogen, lower alkyl substituted with piperazine having (lower) alkyl, lower aikyl substituted with oxadiazole having (lower) alkyl, lower alkyl substituted with imidazoie having aryl, lower alkyl substituted with imidazoie having lower alkyl, lower alkyl substituted with piperidine having protected carboxy, lower alkyl substituted with pyrazoie having hydroxy and lower alkyl, lower alkyl substituted with oxadiazole having lower alkyl, lower alkyl substituted with imidazopyridine, lower alkyl substituted with piperidine having hydroxy, lower alkyl substituted with piperazine having lower alkanoyl or lower alkyl substituted with piperazine having protected carboxy, in which the more preferred one may be imidazolyl (C1-C4)- alkyl, pyridyl (C1-C4) alkyl, morpholino (C1-C4) alkyl,
pyrrolidinyl (C1-C4) alkyl, tetrazolyl (C1-C4) alkyl,
oxiranyl (C1-C4) alkyl, piperidino (C1-C4) aikyl,
benzimidazolyl (C1-C4) alkyl, triazolyl (C1-C4) alkyl,
(C1-C4) alkyl substituted with methylenedioxyphenyl having halogen, (C1-C4) alkyl substituted with piperazine having (C1-C4) alkyl, (C1-C4) alkyl substituted with oxadiazole having (C1-C6) alkyl, (C1-C4) alkyl substituted with imidazoie having phenyl, (C1-C4) alkyl substituted with imidazoie having
(C1-C4) alkyl, (C1-C4) alkyl substituted with piperidine having (C1-C4) alkoxycarbonyl, (C1-C4) aikyl substituted with pyrazoie having hydroxy and (C1-C4) alkyl, (C1-C4) alkyl substituted with oxadiazole having (C1-C4) alkyl, (C1-C4) alkyl substituted with imidazopyridine, (C1-C4) alkyl substituted with
piperidine having hydroxy, (C1-C4) alkyl substituted with piperazine having (C1-C4) alkanoyl or (C1-C4) alkyl substituted with piperazine having (C1-C4) alkoxycarbonyl, and the most preferred one may be imidazolylmethyl, pyridyimethyl, 3-pyridylpropyl, morpholinomethyl, 2-morpholinoethyl,
2-pyrrolidinylethyl, tetrazolylmethyl, oxiranylmethyl, chloromethylenedioxyphenylmethyl, N-methylpiperazinylpropyl, 5-methyloxadiazolylmethyl, 4-phenylimidazolylmethyl,
2-methylimidazolylmethyl, 4-ethoxycarbonylpiperidinomethyl, pyrrolidinylmethyl, piperidinomethyl, benzimidazolylmethyl, triazolylmethyl, 3-methyl-5-hydroxypyrazolylmethyl,
5-methyloxadiazolylmethyl, imidazopyridylmethyl,
hydroxypiperidylmethyl, acetylpiperazinylmethyl,
ethoxycarbonylpiperazinylmethyl or imidazolylethyl.
The preferred examples of "hydrazino (lower) alkyl which may have one or more suitable substituent (s) " may be
hydrazino (lower) alkyl having lower alkoxycarbonyl, in which the more preferred one may be hydrazino (C1-C4) alkyl having (C1-C4) alkoxycarbonyl, and the most preferred one may be tert-butoxycarbonylhydrazinomethyl.
The preferred examples of "[mono or di (lower) alkoxy- (lower) alkyl] amino (lower) alkyl" may be [mono or di(C1-C4)- alkoxy(C1-C4) alkyl] amino (C1-C4) alkyl, in which the more preferred one may be [di (C1-C4) alkoxy (C1-C4) alkyl] amino- (C1-C4) alkyl, and the most preferred one may be
N,N-dimethoxyethylaminomethyl.
The preferred examples of " (lower) alkylamino (lower) alkyl which may have one or more suitable substituent (s)" may be (lower) alkylamino (lower) alkyl having heterocyclic group, (lower) alkylamino (lower) alkyl having cyclo (lower) alkyl, (lower) alkylamino (lower) alkyl having lower alkoxy (lower) - alkyl, (lower) alkylamino (lower) alkyl having
heterocyclic (lower) alkyl, (lower) alkylamino (lower) alkyl having lower alkoxycarbonyl (lower) alkyl,
(lower) alkylamino (lower) alkyl having carboxy (lower) alkyl, (lower) alkylamino (lower) alkyl having carbamoyl (lower) alkyl. (lower) alkylamino (lower) alkyl having cyano (lower) alkyl, (lower) alkylamino (lower) alkyl having hydroxy (lower) alkyl, (lower) alkylamino (lower) alkyl having halo (lower) alkyl,
(lower) alkylamino (lower) alkyl having heterocyclicthio- (lower) alkyl or (lower) alkylamino (lower) alkyl having [di-
(lower) alkylamino] (lower) alkyl, in which the more preferred one may be (C1-C4) alkylamino (C1-C4) alkyl having pyridyl, (C1-C4) alkylamino (C1-C4) alkyl having cyclo (C3-C6) alkyl, (C1-C4) alkylamino (C1-C4) alkyl having (C1-C4) alkoxy (C1-C4)- alkyl, (C1-C4) alkylamino (C1-C4) alkyl having pyridyl (C1-C4)- alkyl, (C1-C4) alkylamino (C1-C4) alkyl having (C1-C4)- alkoxycarbonyl (C1-C4) alkyl, (C-,-C4) alkylamino (C1-C4) alkyl having carboxy (C1-C4) alkyl, (C1-C4) alkylamino (C1-C4) alkyl having carbamoyl (C1-C4) alkyl, (C1-C4) alkylamino (C1-C4) alkyl having cyano (C2~C4) alkyl, (C1-C4) alkylamino (C1-C4) alkyl having hydroxy (C1-C4) alkyl, (C1-C4) alkylamino (C1-C4) alkyl having halo (C1-C4) alkyl, (C1-C4) alkylamino (C1-C4) alkyl having imidazolylthio (C1-C4) alkyl or (C1-C4) alkylamino (C1-C4) alkyl having di (C1-C4) alkylamino (C1-C4) alkyl, and the most
preferred one may be N-methyl-N-pyridylaminomethyl, N-methyl- N-cyclohexylaminomethyl, N-methyl-N-methoxyethylaminomethyl, N-methyl-N-pyridylmethylaminomethyl,
N-methyl-N-pyridylethylaminomethyl,
N-methyl-N-ethoxycarbonylmethylaminomethyl,
N-methyl-N-carboxymethylaminomethyl,
N-methyl-N-carbamoylmethylaminomethyl,
N-methyl-N-cyanomethylaminomethyl,
N-meth.yl-N-hydroxyethylaminomethyl,
N-methyl-N-bromoethylaminomethyl,
N-methyl-N-imidazolylthioethylaminomethyl or
N-methyl-N-(N',N'-dimethyl)ethylaminomethyl.
Suitable "heterocyclic group" moiety in the term of "heterocyclic group which may have one or more suitable substituent (s)" can be referred to aforementioned "heterocyclic group".
The preferred examples of "heterocyclic group which may have one or more suitable substituent (s)", may be furyl, pyridyl which may have 1 to 3 substituent (s) selected from the group consisting of halogen, lower alkoxycarbonyl, and lower alkyl, thiazolyl which may have 1 to 3 lower
alkanoylamino, benzothienyl which may have 1 to 3 halogen, indolyl which may have 1 to 3 substituent (s) selected from the group consisting of halogen and lower alkyl, oxazolyl which may have 1 to 3 lower alkyl, pyranyl which may have 1 to 3 substituent (s) selected from the group consisting of lower alkyl and oxo, pyrrolyl which may have 1 to 3 lower alkyl, phthalimido which may have nitro, phthalimidine which may have nitro, piperidyl which may have 1 to 3 lower alkyl, dihydropyridyl which may have lower alkoxycarbonyl.
Suitable "heterocyclic" moiety in the term of
"heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s)" can be referred to aforementioned to "heterocyclic group".
The preferred examples of "heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s)" may be imidazolylthio (lower) alkyl, imidazolylthio (lower) alkyl having lower alkyl, pyridylthio (lower) alkyl
benzimidazolylthio (lower) alkyl, or
imidazopyridylthio (lower) alkyl, in which the preferred one may be imidazolylthio (C1-C4) alkyl, imidazolylthio (C1-C4) alkyl having (C1-C4) alkyl, benzimidazolyl (C1-C4) alkyl,
pyridylthio (C1-C4) alkyl or imidazopyridylthio (C1-C4) alkyl, and the most preferred one may be imidazolylthiomethyl,
3-methylimidazolylthiomethyl, benzimidazolylthiomethyl imidazolylthioethyl, pyridylthiomethyl or
imidazopyridylthiomethyl. Suitable "heterocyclic" moiety in the term of "heterocyclicthio" can be referred tc aforementioned
"heterocyciic group".
The preferred examples cf "heterocyclicthio" may be pyridylthio or imidazolylthio.
Suitable "heterocyclic" moiety in the term of
"heterocyclic oxy" can be referred to aforementioned
"heterocyclic group".
The preferred examples of "heterocyclic oxy" may be pyridyloxy.
Suitable "heterocyclic" moiety in the term of
"heterocyclic oxy (lower) aikyl" can be referred to
aforementioned "heterocyclic group".
The preferred examples of "heterocyclic oxy (lower) alkyl" may be pyridyloxy (lower) aikyl, in which the more preferred one may be pyridyloxy (C1-C4) alkyl, and the most preferred one may be pyridyloxynethyl. The preferred examples of "aryl which may have one or more suitable eubstituents" may be phenyl, naphthyl, anthryl, phenyl having amino, phenyl having di (lower; alkylamino, phenyl having heterocyclic (lower) alkylamino, phenyl having di (lower) alkylamino (lower) alkanoylamino, phenyl having lower aikylsulfcnyiaminc, phenyl having higher alkanoylamino, in which the most preferred one may be phenyl, aminophenyl, dimethylaminophenyl, furyimethylaminophenyl,
dimethylaminoacetylaminophenyl, methylsulfonylaminophenyl, iauroylaminophenyl.
Suitable "heterocyciic" moiety in the term of
"heterocyclic amincimino (lower) alkyl" can be referred to aforementioned "heterocyclic group".
The preferrec examples of "heterocyclic
aminoiminc (lower) alkyl" may be amincimino (lower) alkyl substituted with unsaturated 3 to 8-membered heteromonocyclic group containing 1 ro 4 nitrogen atom(s), in which the more preferred one may be pyridylaminoimino (C1-C4) alkyl, and the most preferred one may be 2-pyridylaminoiminopropyl.
The preferred examples of "suitable substituent (s)" in the terms cf "lower alkylene which may have one or more suitable substituent (s)" and "lower aikenylene which may have one or more suitable substituent (s)" may be lower alkyl, hydroxy, oxo, or the like, in which the preferred one may be (C1-C4) alkyl, hydroxy or oxo, and the most preferred one may be methyl, hydroxy or oxo.
The preferred examples of "suitable substituent (s)" in the terms of "aryl which may have one or more suitable substituent (s)" may be halogen, lower alkyl, nitre, lower alkoxy, an acyl group, cyclo (lower) alkyl, mono- (or di- or tri-) halo (lower) alkyl, acylamino, aryl, amino, mono- (or di-)- lower alkylamino, aryloxy, acyl (lower) alkyl, hydroxy,
hydroxy (lower) alkyl which may have one or more suitable substituent (s), heterocyclic group which may have one or more suitable substituent (s), mono-(or di-) lower
alkylamino (lower) alkyl or acyl (lower) alkyl. The preferred examples of "mono-(or di-) lower
alkylamino (lower) alkyl" may be mono-(or di-) (C1-C4)- alkylamino (C1-C4) alkyl, in which the preferred one nay be di (C1-C4) alkylamino (C1-C4) aikyl, and the most preferred one may be dimethylaminomethyl.
Suitable "acyl" moiety in the term of
"acyl (lower) alkoxy" can be referred to aforementioned "acyl" moiety.
The preferred examples of "acyl (lower) alkoxy" may be protected carboxy (lower) alkoxy, m which the more preferred one may be (C1-C4) alkoxycarbonyl (C1-C4) alkoxy, and the most preferred one may be ethoxycarbonyimethoxy.
The preferred examples of "suitable substituent (s)" in the term cf "naphthyl which may have one or mere suitable substituent (s) " may be lower alkoxy, in which the more preferred one may be (C1-C4) alkoxy, and the most preferred one may be methoxy. Suitable "acyl" moiety in the term of
"acyl (lower) alkenyl" can be referred to aforementioned "acyl" moiety.
Suitable " (lower) alkenyl" moiety in the term of
"acyl (lower) alkenyl" can be referred to aforementioned "lower alkenyl".
The preferred exampies of "acyl (lower) alkenyl" may be protected carboxy (C2-C6) alkenyi, in which the more preferred one may be lower alkoxycarbonyl (C2-C4) alkenyl, and the most preferred one may be ethoxycarbonylvinyl.
The preferred examples of "aryloxy" may be phenoxy, naphthyloxy, anthryloxy, or the like, in which the most preferred one may be phenoxy. The preferred examples of "aryl (lower) alkoxy" may be phenyl (C1-C6) alkoxy, naphthyl (C1-C6) alkoxy, anthryl (C1-C6) - alkoxy, or the like, in which the preferred one may be phenyl (C1-C4) alkoxy, and the most preferred one may be phenylmethoxy.
The preferred examples of "halo (lower) alkyl" may be chloromethyl, chloroethyl, bromomethyl, bromoethyl,
fiuoromethyl, fluoroethyl, iodopropyl, iodobutyl or the like, in which the more preferred one may be halo (C1-C4) alkyl, and the most preferred one may be chloromethyl or bromoethyl. The preferred examples of "hydroxy (lower) aikylimino- (lower) alkyl" may be hydroxy (C1-C4) alkylimino (C1-C4) alkyl, in which the more preferred one may be hydroxyethyliminomethyl. The preferred examples of "hydroxy (lower) alkylamino-
;lower) aikyl" may be hydroxy (C1-C4) alkylamino (C1-C4) alkyl, in which the more preferred one may be hydroxyethylaminomethyl.
The preferred examples of "bis-[hydroxy (lower) alkyl]- amino (lower) alkyl" may be bis- [hydroxy (C1-C4) alkyl]amino- (C1-C4) alkyl, in which the more preferred one may be
bis-[hydrcxyethyl] aminomethyl.
The preferred examples of "mercapto (lower) alkyl" may be mercapto (C1-C4) alkyl, in which the more preferred one may be mercaptomethyl.
The preferred examples of "amidinothio (lower) alkyl" may be amidinothio (C1-C4) alkyl, in which the more preferred one may be amidinothiomethyl.
The processes for preparing the object compound (I) of the present invention are explained in detail in the
following.
Process 1
The compound (la) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivative at the amino group or a salt thereof with the compound (III) or its reactive derivative at the carboxy group or sulfo group or a salt thereof.
Suitable reactive derivative at the amino group of the compound (II) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (II) with a carbonyl compound such as aldehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (II) with a silyl compound such as
N,O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (II) with phosphorus trichloride or phosgene, and the like.
Suitabie reactive derivative of the compound (III) may include an acid halide, an acid anhydride, an activated ester, and the like. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g., methanesulfonic acid,
ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid,
pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride;
an activated amide with imidazoie, 4-substituted imidazoie, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g. cyanomethyl ester, methoxymethyl ester,
dimethyliminomethyl [(CH3)2 +N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyiazophenyl ester, phenylthio ester, p-nitrophenyl thioester, p-oresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyi thioester, etc.); an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)- pyridone, N-nydroxysuccinimide, N-hydroxybenzotriazole,
N-hydroxyphthaiimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); and the like. These reactive derivatives can
optionally be selected from them according to the kind of the compound (III) to be used.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal (e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
an alkali metal hydrogencarbonate (e.g., sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri (lower) aikylamine (e.g., trimethylamine, triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal
(lower) alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower) alkylmorphoiine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline or the iike. Process 2
The compound (lb) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivative at the carboxy group or a salt thereof with the compound (V) or its reactive derivative at the amme group or a salt thereof.
This reaction can be carried out in a similar manner to that of the aforementioned Process 1, and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 1. Process 3
The compound (Ic) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the hydroxy group or a salt thereof with the compound (VII) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an acid including Lewis acid.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
(e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
an alkali metal hydrogencarbonate (e.g., sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri (lower) alkylamine (e.g., trimethylamine,
triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal
(lower) alkoxide (e.g. sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline or the iike. When the base, the acid and/or the starting compound are liquid, they can be used also as a solvent.
Process
The compound (Id) or a salt thereof can be prepared by reacting the compound (VIII) or a salt thereof with the compound (IX) or a salt thereof to Wittig Reaction.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, dimethylsulfoxide, nitromethane, tetrahydrofuran, toluene, methylene chloride, ethylenedichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the
reaction is usually carried out under cooling to heating.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
(e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
an alkali metal hydrogencarbonate (e.g., sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri (lower) alkylamine (e.g., trimethylamine,
triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal
(lower) alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium t-butoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine,
N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniline, methyllitium, n-butyllitium, phenyliitium,
1,5-diazabicyclo [4.3.0] non-5-ene, or the iike.
When the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent. Process 5
The compound (le) or a salt thereof can be prepared by reacting the compound (X) or its reactive derivative at the amino group or a salt thereof with the compound (XI) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an acid including Lewis acid.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
The reaction may be also carried out in the presence of an inorganic or an organic base such as an alkali metal
(e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.),
an alkali metai hydrogencarbonate (e.g., sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbcnate (e.g., sodium carbonate, potassium carbonate, etc.), tri (lower) alkyiamine (e.g., trimethylamine,
triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal
(lower) alkoxide (e.g., sodium methoxide, sodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower) alkyimorpholine, N,N-di (lower) alkylbenzylamine, N,N-di (lower) aikyianiline or the like. When the base, the acid and/or the starting compound are in liquid, they can be used also as a solvent.
Process 6
The compound (If) or a salt thereof can be prepared by reacting the compound (VI) or its reactive derivative at the hydroxy group or a salt thereof with the compound (XII) or its reactive derivative at the carboxy group or a salt thereof.
Suitable reactive derivative at the hydroxy group of the compound (VI) may include halide, sulfonate, sulfate, diazo compound, and the like.
Suitable reactive derivative at the carboxy group of the compound (XII) may include an acid halide, an acid anhydride, an activated ester, and the like. The suitable example may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g.,
dialkylphosphoric acid, phenylphosphoric acid,
diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorus acid, sulfurous acid, thiosulfuric acid, alkanesulfuric acid (e.g.,
methanesuifonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid, pentanoic acid, isopentanoic acid,
2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a symmetrical acid anhydride; an activated amide with imidazole,
4-substituted imidazoie, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)2 +N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2 ,4-dinitrophenyl ester, trichlorophenyl ester,
pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester, p-nitrophenyl thioester, p-oresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinoiyl thioester, etc.);
an ester with a N-hydroxy compound (e.g.,
N,N-dinethyIhydroxylamine, 1-hydroxy-2- (1H) -pyridone,
N-hydroxysuccinimide, N-hydroxybenzotriazoie,
N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H-benzotriazole, etc.); and the like. These reaction derivatives can
optionally be selected from them according to the kind of the compound (XII) to be used.
This reaction is usually carried out in the presence of a base.
Suitable base may include, for example, an inorganic base such as alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), alkaiine earth metal hydroxide (e.g., magnesium hydroxide, calcium hydroxide, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, cesium carbonate, etc.), alkaline earth metal carbonate
(e.g., magnesium carbonate, calcium carbonate, etc.), alkali metai bicarbonate (e.g., sodium bicarbonate, potassium bicarbonate, etc.), alkali metai acetate (e.g., sodium acetate, potassium acetate, etc.), alkaline earth metal phosphate (e.g., magnesium phosphate, calcium phosphate, etc.), alkali metal hydrogen phosphate, (e.g., disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.) or the like, and an organic base such as trialkylamine (e.g., trimethylamine, triethylamine, etc.), pyridine, picoline, N-methylpyrrolidine, N-methylmorpholine,
1,5-diazabicyclo [4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]- octane, 1,5-diazabicyclo [5.4.0]undecene-5 or the like.
This reaction is usually carried out in a soivent such as benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the
reaction is usually carried out under cooling to heating. Process 7
The object compound (Ih) or a salt thereof can be prepared by reacting a compound (Ig) or its reactive
derivative at the carboxy group or a salt thereof with a compound (XIII) or its reactive derivative at the amino group or a salt thereof.
Suitable reactive derivative at the carboxy group of the compound (Ig) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
Suitable examples cf the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid [e.g. dialkyiphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.], diaikyiphosphorous acid, suifurous acid, thiosulfuric acid, sulfuric acid, sulfcnic acid [e.g., methanesulfonic acid, etc.], aliphatic carboxylic acid [e.g., acetic acid,
propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.] or aromatic carboxylic acid
[e.g., benzoic acid, etc.]; a symmetrical acid anhydride;
an activated amide with imidazoie, 4-substituted imidazoie, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H- benzotriazole; or an activated ester [e.g. cyanomethyl ester,
+
methoxymethyl ester, dimethyliminomethyl [(CH3)2N=CH-] ester, x^inyi eeter, propargyl ester, p-nitrophenyl ester, 2,4- dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenyiazophenyl ester, phenyl thioester, p-nitrcphenyl thioester, p-oresyl thioester, carboxymethyl thioester, pyranyi ester, pyridyl ester, piperidyl ester, 8-quinolyI thioester, etc.], or an ester with a N-hydroxy compound [e.g., N,N-dimethylhydroxyamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole, etc.], and the like. These reactive derivativee can optionally be selected from them according to the kind of the compound (Ig) tc be used.
Suitable salts of the compound (Ig) and its reactive derivative can be referred tc the ones as exemplified for the compound (I).
Suitable reactive derivative at the amine group of the compound (XIII) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (XIII) with a carbonyl compound such as aidehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (XIII) with a silyl compound such as
bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsiiyl)urea or the iike; a derivative formed by reaction of the compound (XIII) with phosphorus trichloride or phosgene, and the like.
Suitable salts of the compound (XIII) and its reactive derivative can be referred to the ones as exempiified for the compound (I).
The reaction is usually carried cut in a conventional solvent such as water, alcohol [e.g., methanol, ethanol, etc.], acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not adversely influence the reaction. These conventional solvent may also be used in a mixture with water.
In this reaction, when the compound (Ig) is used in a free acid form or its salt form, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide;
N-cyclohexyl-N'-morpholinoethylcarbodiimide;
N-cyclohexyl-N'-(4-diethylaminocyclohexyl) carbodiimide;
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide;
N,N'-carbonylbis-(2-methylimidazoIe); pentamethyleneketene-N-cyclohexylimine;
diphenylketene-N-cycichexylimine; ethoxyacetylene;
1-aikoxy-1-chloroethylene; trialkyiphosphite;
ethyl polyphosphate; isopropyl polyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformate
[e.g. ethyl chloroformate, isopropyl chloroformate, etc.]; triphenyiphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt;
2-ethyl-5-(m-sulfophenyl) isoxazolium hydroxide intramoiecula. salt; 1-(p-chlorobenzenesulfonyioxy)-6-chloro-1H- benzotriazole; so-called Vilsmeier reagent prepared by the reaction cf N,N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus
oxychloride, methanesulfonyl chloride, etc.; or the like.
The reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal
carbonate, alkali metal bicarbonate, tri (lower) alkylamine, pyridine, N-(lower) alkyimorpholine,
N,N-di (lower) alkylbenzylamine, or the like.
The reaction temperature is not oritical, and the reaction is usually carried out under cooling to warming.
Process 8
The compound (Ij) or a salt thereof can be prepared by reacting the compound (Ii) or a salt thereof with Grignard Reagent .
Suitable Grignard reagent to be used in the present reaction nay include the compound of the formula : R12 - MgX" (XIV) (wherein R12 is lower alkyl, and
X" is halogen.) This reaction is usually carried out in a solvent such as tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the reaction ie usually carried out under cooling to heating.
Process 5
The object compound (Il) or a salt thereof can be prepared by subjecting a compound (Ik) or a salt thereof to de-acylation reaction of acylamino group.
This reaction is carried out in accordance with a conventional method euch ae hydrolysis, reduction or the like.
The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid. Suitable base may include an inorganic base and an organic base such as an alkali metal [e.g., sodium, potassium, etc.], an alkaline earth metal [e.g., magnesium, calcium, etc.], the hydroxide or carbonate or bicarbonte thereof, trialkylamine [e.g., trimethylamine, triethylamine, etc.], picoline,
1,5-diazabicycio [4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]- octane, 1,8-diazabicyclo [5.4.0]undec-7-ene, or the like.
Suitable acid may include an organic acid [e.g., formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc.].
The elimination using Lewis acid such as
trihaloacetic acid [e.g. trichloroacetic acid,
trifluoroacetic acid, etc.] or the iike is preferably carried out in the presence of cation trapping agents [e.g. anisoie, phenol, etc.].
The reaction is usually carried cut in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, tetrahydrofuran, a mixture thereof or any other solvent which does not adverseiy influence the reaction. A liquid base or acid can be also used as the solvent. The reaction temperature is not oritical and the reaction is usually carried out under cooling tc warming.
The reduction method applicable for the elimination reaction may include chemical reduction and catalytic reduction.
Suitable reducing agents to be used in chemical
reduction are a combination of metal [e.g., tin, zing, iron, etc.] or metallic compound [e.g., chromium chloride, chromium acetate, etc.] and an organic or inorganic acid [e.g., formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-tolueneeulfonic acid, hydrochloric acid, hydrobromic acid, etc. ] .
Suitable catalysts tc be used in catalytic reduction are conventional ones such as platinum catalysts [e.g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum cxide, platinum wire, etc.], palladium catalysts
[e.g., spongy palladium, palladium black, palladium oxide, palladium on carbon, colloidal palladium, palladium on barium, sulfate, palladium on barium carbonate, etc.], nickel catalysts [e.g., reduced nickel, nickel oxide, Raney nickei, etc.], cobalt catalysts [e.g. reduced cobalt, Raney cobalt, etc.], iron catalysts [e.g. reduced iron, Raney iron, etc.], copper catalysts [e.g. reduced copper, Raney copper, Uliman copper, etc.] and the like.
The reduction is usually carried out in a conventional solvent which does not adversely influence the reaction such as water, methanol, ethanol, propanol, N,N-dimethylformamide, or a mixture thereof. Additionally, in case that the above- mentioned acids to be used in chemical reduction are in liquid, they can also be used as a solvent. Further, a suitable solvent to be used in catalytic reduction may be the above-mentioned solvent, and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc., or a mixture thereof.
The reaction temperature of this reduction is not oritical and the reaction is usually carried out under cooling tc warming.
Process 10
The compound (Ik) or a salt thereof can be prepared by subjecting the compound ( Ii) or its reactive derivative at the amino group, or a salt thereof to acylation reaction.
Suitable acylating agent to be used in the present acylation reaction may include the comoound of the formula :
R13 - OH (XV)
(wherein R13 is acyl)
or its reactive derivative, or a salt thereof.
Suitable reactive derivative at the amino group of the compound ( Ii) may include Schiff's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound ( Ii) with a carbonyl compound such as aldehyde, ketone or the iike; a silyl derivative formed by the reaction of the compound (IC) with a silyl compound such as
N,O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide or the like; a derivative formed by the reaction of the compound (Id) with phosphorus trichloride or phosgene, and the like.
Suitable reactive derivative of the compound (XV) may include an acid halide, an acid anhydride, an activated ester, and the like. The suitable exampie may be an acid chloride; acid azide; a mixed acid anhydride with an acid such as substituted phosphoric acid (e.g., dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzyiphosphoric acid, halogenated phosphoric acid, etc.), dialkylphosphorous acid, suifurous acid, thiosulfuric acid, alkaneeulfcnic acid (e.g., methanesulfonic acid,
ethanesulfonic acid, etc.), sulfuric acid, alkylcarbonic acid, aliphatic carboxylic acid (e.g., pivalic acid,
pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.); aromatic carboxylic acid (e.g., benzoic acid, etc.); a eymmetrical acid anhydride;
an activated amide with imidazoie, 4-eubstituted imidazoie, dimethylpyrazole, triazole or tetrazole; an activated ester (e.g., cyanomethyl, ester methoxymethyl ester,
dimethyliminomethyl [(CH3)2 +N=CH-] ester, vinyl ester, propargyl ester, p-nitrophenyi ester, 2, 4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl eeter, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenyl thioester, p-oresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, etc.); an ester with a N-hydroxy compound (e.g., N,N-dimethylhydroxy1amine,
1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide,
N-hydroxybenzotriazole, N-hydroxyphthalimide,
1-hydroxy-6-chloro-1H-benzotriazoie, etc.); and the like. These reactive derivatives can optionally be selected from them according to the kind of the compound (XV) to be used.
The reaction is usually carried out in a conventional solvent such as water, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride,
tetrahydrofuran, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which do not adversely affect the reaction, or the mixture thereof.
When the compound (XV) is used in free acid form or its salt form in the reaction, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiinu.de;
N-cyclohexyl-N'-morpholinoethylcarbodiimide);
N -cyclohexyl-N'-(4-diethylaminocyclohexyl) carbodiimide; N,N'-diisoprcpylcarbodiimide;
N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide;
N,N-carbonylbis (2-methylimidazole);
pentamethyleneketene-N-cyclohexylimine;
diphenyiketene-N-cyclohexylimine, ethoxyacetylene;
1-aikoxy-1-chloroethylene; triaikyl phcephite; isopropyl poiyphosphate; phosphorous oxychloride (phosphoryl chloride); phosphorous trichloride;
thionyl chloride; oxalyl chloride; triphenylphosphite;
2-ethyI-7-hydroxybenzisoxazoiium salt; 2-ethyl-5- (m- suifophenyl) isoxazolium hydroxiae intra-molecuiar salt;
1-(p-chlorobenzenesulfonyioxy)-6-chloro-1H-benzotriazoie; so-called Vilsmeier reagent prepared by the reaction of
N,N-dimethylformamide with thionyl chloride, phosgene, phosphorous oxychloride, etc.; or the like.
The reaction may also be carried out in the presence of an organic or inorganic base such as an alkali metal
bicarbonate, tri (lower) alkylamine, pyridine,
N-(lower) alkylmorphorine, N,N-di (lower) alkylbenzyiamine, or the iike.
The reaction temperature is not oritical, and the reaction is usually carried out under cooling to heating.
Process 11
The compound (Im) or a salt thereof can be prepared by subjecting the compound (Ij) or a salt thereof to acylation reaction. This reaction can be carried out in a similar manner to that of the afore-mentioned Process 10. and
therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 10.
Process 12
The compound (lo) or a salt thereof can be prepared by reacting the compound (In) or a salt thereof with lower alkane eubetituted with oxo (XIV) or a salt thereof.
This reaction is usually carried out in a solvent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformanu.de, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the reaction is usually carried out under cooling to heating.
The reaction ie usually carried out in the presence of an acid including Lewis acid.
Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trifluoroacetic acid, etc.] and an inorganic acid [e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, zinc halide (e.g., zinc chloride, zinc bromide, etc.), etc.] and the like.
When the acid and/or the starting compound are in liquid, they can be used also as a solvent.
Process 13
The compound (Iq) or a salt thereof can be prepared by reacting the compound (Ip) or a salt thereof with the
compound (XV) or a salt thereof.
This reaction can be carried out in a similar manner to that of the afore-mentioned Process 3. and therefore the reagents to be used and the reaction conditions (e.g., solvent, reaction temperature, etc.) can be referred to those of the Process 3.
The procese for preparing the etarting compound (Ila) ie expiained in detail in the following.
Process A
The compound (Ila) or a salt thereof can be prepared by reacting the compound (XVI) or a salt thereof with the compound (XVII) or a salt thereof.
This reaction is usually carried out in a soivent such as water, alcohol (e.g., methanol, ethanol, etc.), benzene, N,N-dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, 1,2- dimethoxyethane, dioxane, diethyl ether or any other solvents which do not adversely affect the reaction, or the mixture thereof.
The reaction temperature is not oritical and the
reaction is usually carried out under cooling to heating.
The reaction is usually carried out in the presence of an inorganic or an organic base such as an alkali metal
(e.g., sodium, potassium, etc.), an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide, etc.), an alkali metal hydrogencarbonate (e.g., sodium
hydrogencarbonate, potassium hydrogencarbonate, etc.), alkali metal carbonate (e.g., sodium carbonate, potassium carbonate, etc.), tri (lower) alkylamine (e.g., trimethylamine,
triethylamine, diisopropylethylamine, etc.), alkali metal hydride (e.g., sodium hydride, etc.), alkali metal
(lower) alkoxide (e.g. eodium methoxide, eodium ethoxide, etc.), pyridine, lutidine, picoline, dimethylaminopyridine, N-(lower) alkylmorphcline, N,N-di (lower) alkylbenzylamine, N,N-di (lower) alkylaniiine or the like.
When the base and/or the etarting compound are in liquid, they can be used also as a solvent.
Among the starting compounds (II) to (XVI), some of them are novel compounds. They can be prepared by the similar manners to those disclosed in Preparations 1 and 2 mentioned later in the present specification, or any process known in this field of the art for preparing structurally analogous compounds thereto.
The object compound (I) can be prepared by any process known in this field of the art except the above Processes 1 to 13 and Process A.
The compounds obtained by the above Processes 1 to 13 and Process A can be isolated and purified by a conventional method such as pulverization, reorystallization,
columnchromatography, reprecipitation or the like.
It is to be noted that each of the object compound (I) may include one or more stereoieomer euch ae optical
iecmer(s) and geometrical isomer (s) due to asymmetric carbon atom(s) and double bond(s) and all euch ieomers and mixture thereof are included within the scope of this invention.
The pharmaceutical composition of the present invention can be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains the object compound (I) or a pharmaceutically acceptable salt thereof, as an active ingredient in admixture with an organic or inorganic carrier or excipient which is suitable for rectal; pulmonary (nasal or buccal inhalation); ocular;
external (topical); oral administration; parenteral
(including subcutaneous, intravenous and intramuscular) administrations; insufflation (including aerosols from metered dose inhalator); nebulizer; or dry powder inhalator.
The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable
carriers in a solid form such as granules, tablets, dragees, pellets, troches, capsulee, or euppositories; oreame;
ointmente; aerosols; powdere for insufflation;
in a liquid form such as solutione, emuleions, or suspensione for injection; ingeetion; eye drope; and any other form euitable for use. And, if neceseary, there may be included in the above preparation auxiliary substance euch ae
stabilizing, thickening, wetting, emulsifying and coloring agente; perfumee or buffer; or any other commonly may be used as additives.
The object compound (I) or a pharmaceutically acceptable salt thereof include solvated compound [e.-g., encloeure compound (e.g., hydrate, etc.)].
The object compound (I) or a pharmaceutically acceptable salt thereof include both its orystal form and non-orystal form.
The object compound (I) or a pharmaceutically acceptable salt thereof is/are included in the pharmaceuticai
composition in an amount sufficient to produce the desired effect upon the process or condition of diseases.
The pharmaceutical composition of the present invention can be manufactured by the conventional method in this field of the art. If necessary, the technique generally used in this field of the art for improving the bioavaiiability of a drug can be .applied to the pharmaceutical composition of the present invention.
While the dosage of therapeutically effective amount of the object compound (I) varies from and also depends upon the age and condition of each individual patient to be treated, in the case of intravenous administration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being or an animal, in the case of intramuecular adminietration, a daily dose of 0.001-100 mg of the object compound (I) per kg weight of a human being of an animal, in case of oral administration, a daily dose of 0.001-200 mg of the object compound (I) per kg weight of a human being or an animal ie generally given for the prevention and/or the treatment of aforeeaid dieeases 1 to 4 times a day in a human oemg or an animal . In order to illuetrate the usefuinees of the object compound (I), the pharmacological test data of the
representative compound of the compounds (I) ie ehown in the following. Test Compound (I) 8-(2,6-Dichlorobenzoylamino)-3-hydroxymethyl-2- trifluoromethyl-imidazo [1,2-a]pyridine hydrochloride
Test (Bone organ cuiture) :
Test Method
Caivariae from Wistar rate were excised and cultured in wells of 12-weil culture plates containing 2 ml of Dulbecco's modified minimum essential medium supplemented with 10% fetal bovine serum and 10-8M human parathyroid hormone fragment (1-34) [PTH] in the presence cf the test compound. In control dishes, PTH was not added. Control and PTH control were exposed to an equivalent concentration of the vehicle. Six daye later, the concentration of calcium in the medium was measured by methylxylenol blue method and the percentage cf inhibition of PTH-induced bone reeorption wae calculated according to following formula.
Inhibition (% )
Figure imgf000070_0002
Test Result
Figure imgf000070_0001
The following Preparations and Examples are given for the purpoee of illustrating the present invention in more detail. Preparation 1
A solution of 2, 3-diaminopyridine (6.27 g) and 1-chloro- 3, 3, 3-trifluoroacetone (8.4 g) in ethanol (110 ml) was refluxed for 20 hours. The reaction mixture was evaporated in vacuo, and the residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained solid was collected with diisopropyl ether to give 8-amino-2- trifluoromethylimidazo[1,2-a] pyridine (3.09 g).
NMR (CDCl3, δ) : 4.62 (2H, br s), 6.40 (1H, d,
J=7.5Hz), 6.71 (1H, t, J=7.5Hz), 7.58 (1H, d,
J=7.5Hz), 7.81 (1H, e)
FAB-Mass: 202 (M+H)+
Preparation 2
A mixture of 2, 3-diaminopyridine (2.18 g), ethyl 3- chloro-4-oxovalerate (2.88 g) and sodium bicarbonate (1.68 g) in 1,2-dimethoxyethane (40 ml) was stirred at 50°C for 30 minutes and then, refluxed for 6 hours. After separation of the insoluble matter by decantation and evaporation in vacuo, the residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer wae
separated, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel. 4N Hydrogen chloride in ethyl acetate wae added to the obtained solid and the solution was evaporated in vacuo. The residue was orystallized from ethanol to give 8- amino-3-ethoxycarbonylmethyI-2-methylimidazo [1,2-a] pyridine hydrochloride (899 mg).
mp : 222-223°C
NMR (DMSO-d6, δ) : 1.20 (3H, t, J=7Hz), 2.45 (3H, s), 4.11 (2H, q, J=7Hz), 4.24 (2H, s), 6.57 (2H, br s), 6. 90 ( 1H, d, J=8Hz), 7 .20 ( 1H, t, J=8Hz), 7 .92 ( 1H, d, J=8Hz )
Preparation 3
A mixture of 2,3-diaminopyridine (436 mg) and 1-bromo- 3,3-dimethyl-2-butanone (836 mg) in ethanol (5 ml) was refluxed for 20 hours. The reaction mixture was cooled and the separated solid was collected and washed with ethanol to give 8-amino-2-(1,1-dimethylethyl) imidazo [1,2-a]pyridine hydrobromide (830 mg).
mp : >250°C
NMR (CDCl3:CD3OD = 1:1, δ) : 1.53 (9H, s), 6.98 (1H, d, J=7Hz), 7.12 (1H, t, J=7Hz), 7.62 (1H, s), 7.87 (1H, d, J=7Hz)
The following compounds (Preparations 4 to 14) were obtained according to a similar manner to that of Preparation 1. Preparation 4
8-Amino-2-(2,2-dimethylpropyi) imidazo [1,2-a]pyridine NMR (CDCl3, δ) : 1.00 (9H, s), 2.65 (2H, s), 4.49 (2H, br s), 6.27 (1H, d, J=7Hz), 6.54 (1H, t, J=7Hz), 7.27 (1H, s), 7.53 (1H, d, J=7Hz)
Preparation 5
8-Amino-2-ethylinidazo [1,2-a]pyridine
NMR (CDCl3, δ) : 1.34 (3H, t, J=7.5Hz), 2.82 (2H, q), 4.42 (2H, br e), 6.28 (1H, dd, J=7.5Hz and 1.0Hz), 6.53 (1H, t, J=7.5Hz), 7.27 (1H, e), 7.52 (1H, dd,
J=7.5Hz and 1.0Hz)
Preparation 6
8-Amincimidazo [1,2-a]pyridine
NMR (CDCl3, δ) : 4.52 (2H, br e), 6.31 (1H, d, J=7Hz), 6 . 61 ( 1H, t , J=7Hz), 7 . 52 ( 2H, s), 7 . 60 ( 1H, a, J=7Hz )
Preparation 7
8-Amino-2-phenylimidazo[1,2-a]pyridine
mp : 138-139°C
Preparation 8
8-Amino-2-methyl-3-benzylimidazc [1,2-a]pyridine
mp : >250°C
NMR (CDCl3, δ) : 2.50 (3H, s), 4.21 (2H, e), 4.43 (2H, br e), 6.29 (1H, d, J=7Hz), 6.50 (1H, t, J=7Hz), 7.05-7.35 (6H, m) Preparation 9
8-Amino-3-ethoxycarbonyl-2-methylimidazo [1, 2-a]pyridine NMR (CDCI3, δ) : 1.43 (3H, t, J=7Hz), 2.71 (3H, s),
4.42 (2H, q, J=7Hz), 4.48 (2H, br s), 6.55 (1H, d, J=7Hz), 6.78 (1H, t, J=7Hz), 8.72 (1H, d, J=7Hz)
Preparation 10
8-Amino-2-ethoxycarbonylimidazo [1,2-a] pyridine
NMR (CDCl3/ δ) : 1.43 (3H, t, J=7.5Hz), 4.47 (2H, q, J=7.5Hz), 4.68 (2H, br s), 6.32 (1H, d, J=7.5Hz), 6.68 (1H, t, J=7.5Hz), 7.57 (1H, d, J=7.5Hz), 8.10
(1H, e)
Preparation 11
8-Amino-3-ethoxycarbonyl-2-trifluoromethylimidazo- [1,2-a]pyriaine
oil
NMR (CDCl3, δ) : 1.35 (3H, t, J=7Hz), 4.34 (2H, q,
J=7Hz), 6.62 (1H, d, J=7Hz), 6.95 (1H, t, J=7Hz), 8.80 (1H, d, J=7Hz) Preparation 12
3-Acetyl-8-amino-2-methylimidazo [1,2-a]pyridine
mp : 191-193°C
NMR (CDCl3, δ) : 2.61 (3H, s), 2.79 (3H, e), 4.50 (2H, m), 6.62 (1H, d, J=8Hz), 6.83 (1H, t, J=8Hz), 9.16
(1H, a, J=8Hz)
Preparation 13
8-Amino-3-methoxy-2-methylimidazo [1,2-a]]pyridine mp : 120-122°C
NMR (CDCl3, δ) : 2.42 (3H, s), 3.96 (3H, s), 4.39 (2H, br s), 6.23 (1H, d, J=8Hz), 6.59 (1H, t, J=8Hz), 7.38 (1H, d, J=8Hz) Preparation 14
8-Amino-2-ethoxycarbonyl-3-methylimidazo [1,2-a] pyridine mp : 146-147°C
NMR (CDCl3, δ) : 1.46 (3H, t, J=7Hz), 2.77 (3H, e),
4.49 (2H, q, J=7Hz), 4.58-4.70 (2H, .m), 6.34 (1H, d, J=8Hz), 6.73 (1H, t, J=8Hz), 7.38 (1H, a, J=8Hz)
Preparation 15
To a suspensicn of 2, 3-diaminopyriaine (1.09 g) in 1,2- dimethoxyethane (11 mi) was added 3-bromo-1,1,1- trifiuoroacetone (1.09 ml) dropwise at 4°C. The mixture was etirrea at 4°C for 15 minutee and at ambient temperature for 2 hours. Tc the reaction mixture was added ethyl acetate (11 ni) ana the mixture was stirred at ambient temperature for 2 hours. The separated solid was ccilected and washed with ethyl acetate to give 3-amino-1,2-dihydro-2-imino-1-(2-oxo- 3,3,3-trifluoropropyl) pyridine hydrobromide (2.786 g).
mp : 155-166°C
NMR (DMSO-d6, δ) : 4.83 (1H, a, J=15Hz), 5.17 (1H, d,
J=15Hz), 6.40 (2H, br s), 7.04 (1H, t, J=7Hz), 7.25 (1H, a, J=7Hz;, 7.65 (1H, d, J=7Hz), 3.70 (1H, s) Preparation 16
A solution of 3-amino-1,2-dihydro-2-imino-1-(2-oxo- 3,3,3-trifluoropropyl)pyridine hydrobromide (2.75 g) in water (11 ml) was stirred at 90°C for 2 houre. The reaction mixture was cooled and to the mixture was added a eolution of potassium carbonate (750 mg) in water (2.5 ml) dropwise. The mixture was stirred at ambient temperature for 1 hour and the separated solid was collectea, washed with water and dried to give 8-amino-2-trifluoromethylimidazo [1, 2-a]pyridine (1.545 g).
mp : 101-I03°C
NMR (CDCl3, δ) : 4.62 (2H, br s), 6.40 (1H, d,
J=7.5Hz), 6.71 (1H, t, J=7.5Hz), 7.58 (1H, d, J=7.5Hz), 7.81 (1H, s)
Preparation 17
A. mixture of 8-chloro-2-methylimidazo [1,2-a]pyrazine (120 mg) and 3M solution of ammonia in methanol (5 ml) was heated in a sealed tube at 120°C for 3 days. The reaction mixture was cooled and evaporated in vacuo. The solid residue was purified by flash column chromatography on silica gel and the obtained orystalline resiaue wae triturated with diisopropyl ether to give 8-amino-2-methylimidazo [1, 2-a] - pyrazine (55 mg).
NMR (CDCl3, δ) : 2.44 (3H, e), 5.40 (2H, br e),
7.23-7.29 (2H, m), 7.43 (1H, d, J=5Hz)
ESI-MASS (M++1) = 149
Preparation 18
A mixture of 3-acetyl-8-amino-2-methylimicazo [1,2-a]- pyridine (1.00 g), acetic anhydride (700 mg), and acetic acid (0.5 ml) in methylenechloride (10 ml) was stirred for 30 minutes at ambient temperature. After concentration in vacuo, the residue was partitioned between chloroform and aσueous saturated sodium bicarbonate. The separated organic layer was dried over sodium, sulfate and evaporated in vacuo. The obtained orude eolid was triturated with diisopropyl ether tc give 3-acetyl-8-acetylamino-2-methylimidazo [1,2-a]- pyridine (1.18 g).
mp : 174-175°C
NMR (CDCl3, δ) : 2.31 (3H, s), 2.62 (3H, e), 2.79 (3H, e), 7.00 (1H, t, J=8Hz), 8.40 (1H, a, J=8Hz), 8.53 (1H, n), 9.37 (1H, a, J=8Hz) Preparation 19
A mixture of 8-acetylanino-3-(1-hyaroxy-1-methylethyl)- 2-methylimidazo[l, 2-a] pyridine (929 mg) and aqueous 3N-ecdium hydroxide (4 ml) in ethanol (9 nl) wae stirred for 4 hours at 80°C. The mixture was extracted with methylene chloride and the extract was aried over sodium eulfate and evaporated in vacuo. The obtained oil wae orystaliized from diisopropyl ether to give 8-amino-3-(1-hydroxy-1-methylethyl)-2- methylimidazo[1,2-a]pyridine (706 mg).
mp : 175-177°C
NMR (CDCl3, δ) : 1.73 (6H, s), 2.41 (3H, s), 2.70 (1H, m), 4.38 (2H, m), 6.28 (1H, d, J=8Hz), 6.51 (1H, t, J=8Hz), 8.20 (1H, d, J=8Hz)
The following compound was cbtained according to a eimilar manner to that of Preparation 19.
Prepararion 20
3-Bromo-8-carboxy-2-methylimidazo [1,2-a]pyridine
mp : 191-195°C
NMR (DMSO-d6, δ) : 2.41 (3H, s), 7.20 (1H, t, J=7Hz),
7.98 (1H, d, J=7Hz), 8.52 (1H, a, J=7Hz)
Preparation 21
N-Bromosuccinimide (3.74 g) was added to a solution of 8-ethoxycarbonyl-2-methylimidazo [1,2-a]pyridine (4.243 g) in ethanol (40 ml). After stirring at ambient temperature for 30 minutes, the mixture was evaporated in vacuo and the residue was dieeolvea in dichloromethane. The solution was washed with aqueous saturated sodium bicarbonate and brine, dried over magnesium sulfate and evaporated in vacuo. The orystalline residue was reorystallized from diisopropyl ether to give 3-bromo-8-ethoxycarbonyl-2-methylimidazo [1,2-a]- pyridine (5.1 g).
mp : 76-78°C
NMR (CDCl3, δ) : 1.44 (3H, t, J=7Hz), 2.56 (3H, s),
4.50 (2H, q, J=7Hz), 6.98 (1H, t, J=7Hz), 7.96 (1H, a, J=7Hz), 8.23 (1H, d, J=7Hz)
Preparation 22
A solution of methylmagnesium bromide in tetrahydrofuran (0.96M, 5.74 ml) was added to a solution of 3-acetyl-8- acetylamino-2-methylimidazo [1,2-a] pyridine (510 mg) in tetrahydrofuran (10 ml) dropwise with ice-cooling. The mixture wae stirred at ambient temperature for 1 hour and to the mixture was added methylmagnesium bromide (2.3 ml). The mixture was stirred for 2 hours, quenched with aqueous saturated ammonium chloride and partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 8-acetylamino-3-(1-hydroxy-1-methylethyl)- 2-methylimiaazo [1,2-a]pyridine (amorphous).
NMR (CDCl3, δ) : 1.76 (6H, s), 2.28 (3H, e), 2.43 (3H, s), 2.63 (1H, m), 6.70 (1H, t, J=8Hz), 8.06 (1H, d, J=8Hz), 8.48 (1H, d, J=8Hz), 8.60 (1H, m) Example 1
2,6-Dichlorobenzoyl chloride (2.51 g) wae added to a eolution of 8-amino-2-trifluoromethyIimidazo [1,2-a]pyridine (2.01 g) and triethylamine (1.31 g) in dichloromethane (30 ml). The mixture- wae etirred at ambient temperature for 1 hour ana refluxed overnight. The mixture was diluted with dichloromethane, washed with aqueous saturated eodium bicarbonate and water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was orystallized from diisopropyl ether to give 8-(2,6- dichlorobenzoylamino)-2-trifluoromethylinidazo [1,2-a]pyridine (750 mg).
mp: 190-195°C
NMR (CDCl3, δ) : 6.99 (1H, t, J=7.5Hz), 7.32-7.44 (3H, m), 7.92 (1H, s), 7.95 (1H, d, J=7.5Hz), 8.52 (1H, dd, J=7.5 and 1.5Hz), 8.75 (1H, br s)
The following compound was obtained according to a similar manner to that of Example 1.
Example 2
8-(2,6-Dichlorobenzoylaminc)-2-methylimiaazo [1,2-a]- pyridine
mp : I97-198°C
NMR (CDCl3, δ) : 2.42 (3H, s ) , 6.79 (1H, t, J=7Hz),
7.30-7.40 (4H, m), 7.83 (1H, d, J=7Hz), 8.33 (1H, a, J=7Hz), 8.70 (1H, br s) Example 3
A mixture of 8-amino-3-ethoxycarbonylmethyl-2- methylimidazo [1,2-a] pyridine hydrochloride (890 mg), 2,6- dichlorobenzcyl chloride (760 mg) and N-methylmorpholine (833 mg) in N,N-dimethylacetamide (5 ml) was stirred at 60°C for 3 hours. The mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, and evaporated in vacuo. The residue wae purified by column chromatography on silica gel and the obtained solid was collected with ethanol to give 8-(2,6-dichlorobenzoylamino)-3-ethoxycarbonylmethyl- 2-methylimidazo [1,2-a]pyridine (805 mg).
mp : 168-170°C
NMR (CDCl3, δ) : 1.26 (3H, t, J=7Hz), 2.42 (3H, s),
3.87 (2H, s), 4.18 (2H, q, J=7Hz), 6.88 (1H, t, J=8Hz), 7.30-7.40 (3H, m), 7.80 (1H, d, J=8Hz),
8.38 (1H, d, J=8Hz), 8.75 (1H, br e)
Example 4
37% Hydrochloric acid (0.25 ml) wae added to a solution of 8-(2,6-dichlorobenzoylamino)-2-trifluoromethylimidazo [1,2- a]pyridine (150 g) and formaldehyde 37% solution in water (0.5 ml) in acetic acid (2 ml). The mixture was stirred at 85°C for 20 hours and evaporated in vacuo. The residue was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel, and the obtained cil wae orystallized from a nixture of aiethyl ether and n-hexane to give 8-(2,6- dichlorobenzoylaminc)-3-hydroxymethyI-2- trifluoromethylimidazo [1,2-a]pyridine (82 mg).
mp: 215-219°C
NMR (CDCl3, δ) : 2.26 (1H, t, J=7Hz), 5.10 (2H, d,
J=7Hz), 7.04 (1H, t, J=7Hz), 7.27-7.40 (3H, m), 8.10 (1H, a, J=7Hz), 8.56 (1H, d, J=7Hz), 8.79 (1H, br s)
Example 5
A. mixture of 8- ( 2 , 6-dichlorobenzoylamino ) -2- nethylimidazo [ 1 , 2-a ] pyridine ( 50 mg), dimethyiamine hydrochloride (15 mg) and 37% formalin (19 mg) in acetic acid (1 ml) was stirred at 60°C for 1 hour. The mixture was evaporatec in vacuo and the residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was orystallized from diisopropyl ether to give 8-(2,6-dichlorobenzcylamino)-3- dimethylaminomethyl-2-methylimidazo [1,2-a]pyridine (38 mg). mp : 173-175°C
NMR (CDCl3, δ) : 2.26 (6H, e), 2.40 (3H, s), 3.67 (2H, s), 6.86 (1H, t, J=8Hz), 7.30-7.41 (3H, m), 8.01 (1H, d, J=8Hz), 8.49 (1H, d, J=8Hz), 8.78 (1H, br
Example 6
Methyl iodide (354 mg) was added to a solution of 8- (2,6-dichlorobenzoylamino)-3-dimethylaminomethyl-2- methylimidazo [1,2-a] pyridine (940 mg) in a mixture of acetone (30 ml) and tetrahyarofuran (10 ml) at 4°C. The solution was stirred at ambient temperature for 6 hours and evaporated in vacuo. The residual solid was triturated with ethyl acetate to give [[8-(2,6-dichlorobenzoylamino)-2-methylimidazo- [1,2-a]pyridin-3-yl]methyl] trimethylammonium iodide (1.37 g).
NMR (DMSO-d6, δ) : 2.48 (3H, s), 3.10 (9H, s), 4.97
(2H, s), 7.09 (1H, t, J=8Hz), 7.44-7.56 (3H, m),
8.24 (1H, a, J=8Hz), 8.56 (1H, d, J=8Hz)
Example 7
In aqueous sodium hydroxide (2.08 ml) wae added to a eolution of 8-(2,6-dichlorobenzoyiamino)-3- ethoxycarbonylmethyl-2-methylimidazo [1,2-a]pyridine (705 mg) in a mixture of tetrahydrofuran (4 ml) and methanol (4 ml). A.fter etirring at ambient temperature for 3 hours, the organic eoivent was evaporated in vacuo. The aqueous residue was neutralized with 1N-hydrcchloric acid. The separated eolid wae collected and waehed with water and ethyl acetate tc give 3-carboxymethyl-8-(2,6-dichlorobenzoylamino)-2- methylimidazofl, 2-a] pyridine (656 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.32 (3H, s), 4.00 (2H, e), 6.90
(1H, t, J=8Hz), 7.44-7.55 (3H, m), 8.03-8.08 (2H, m)
Example 8
A. mixture of [[8-(2,6-dichIorobenzoylamino)-2- methylimidazo [ 1,2-a]pyridin-3-yljmethyl] trimethylammonium iodide (30C mg) ana imidazoie (197 mg) in ethanol (3 ml) wae refluxed for 4 houre. The reaction mixture wae evaporated in vacuo and the reeidue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was
orystallized from diisopropyl alcohol to give 6-(2,6- dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2- methylimidazo [1, 2-a]pyridine (99 mg).
mp : 249-251°C
NMR (CDCl3, δ) : 2.51 (3H, s), 5.40 (2H, s), 6.83-6.90 (2H, m), 7.10 (1H, s), 7.30-7.41 (3H, m), 7.46-7.53 (2H, m), 8.42 (1H, d, J=8Hz), 8.70 (1H, br s)
Example 9
To a mixture cf S-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-trifluoromethyIimidazo [1,2-a] pyridine
hydrochloride (177 mg) and thionyl chloride (0.06 ml) in dichloromethane wae added pyridine (1 drop). The mixture was stirred at ambient temperature for 30 minutes ana evaporated in vacuo. The residue wae partitioned between
dichloromethane and aqueoue saturatea sodium bicarbonate.
The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The reeiaue wae dissolved in N,N- dimethylformamide (2 ml) and to the solution was added potassium carbonate (111 mg) and 2-mercaptoimidazole (60 mg). The mixture was etirred at ambient temperature for 1 hour and poured into a mixture of ice ana water. The eeparated oil was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel ana the obtained oil wae oryetallized from
diieopropyl ether to give 8-(2,6-dichlorobenzoylamino)-3- (imidazol-2-yl) thiomethyl-2-trifluoromethylimidazo [1,2-a]- pyridine (170 mg).
mp : 218-220°C
NMR (DMSO-d6, δ) : 4.63 (2H, s), 6.85-7.20 (2H, br), 7.17 (1H, t, J=8Hz), 7.43-7.58 (3H, m), 8.27 (1H, d, J=8Hz), 8.30 (1H, a, J=8Hz)
Example 10
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (91 mg) and 1-hydroxybenzotriazole (64 mg) were added to a suspension of 3-carboxymethyl-8- (2,6- dichlorobenzoyiamino)-2-methylimidazo [1,2-a]pyridine (150 mg) in N,N-dimethylformamide (1.5 ml), and the mixture was stirred at ambient temperature for 30 minutes. 2-Methoxy- ethylamine (36 mg) wae added to the mixture, and the mixture was stirred at ambient temperature overnight. The mixture was partitioned between ethyl acetate and water, and the organic layer was eeparated. The aqueoue layer wae extracted with ethyl acetate. The combined organic layer was washed with water and brine, dried over eodium eulfate, and
evaporated in vacuo. The reeidue wae purified by column chromatography on eilica gel. 10% Methanolic hydrogen chloride (3 ml) wae aaded to the obtained eolid and the eolution was evaporated in vacuo. The residue wae
orystallized from a mixture of ethancl and diethyl ether to give 8-(2,6-dichlorobenzoylamino)-3-[N-(2- methoxyethyl) carbamoyl]methyl-2-methylimidazo [1,2-a]pyridine hydrochloride (119 mg).
mp : 227-231°C
NMR (DMSO-d6, δ) : 2.47 (3H, s), 3.19-3.27 (5H, m),
3.30-3.38 (2H, m), 4.03 (2H, s), 7.43-7.65 (4H, m), 8.38 (1H, t, J=8Hz), 8.52 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz) The following compound was obtained according to a similar manner to that of Example 10.
Example 11
8-(2,6-Dichlorobenzoylamino)-3-[[N-(3-methoxypropyl)- carbamoyl]methyl]-2-methylimidazo[1,2-a]pyridine
hydrochloride
mp : 150-160°C
NMR (DMSO-d6, δ) : 1.59-1.69 (2H, m), 2.48 (3H, s),
3.10 (2H, q, J=7Hz), 3.20 (3H, s), 3.31 (2H, t, J=7Hz), 4.00 (2H, s), 7.42-7.65 (4H, m), 8.24 (1H, t, J=7Hz), 8.52 (1H, d, J=8Hz), 8.60 (1H, d, J=8Hz)
Example 12
4N Hydrogen chloride in ethyl acetate (0.1 ml) was added to a solution of 8-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-trifluoromethylimidazo [1, 2-a]pyridine (100 mg) in ethyl acetate (3 ml). The separated solid was
collected and washed with ethyl acetate to give 8-(2,6- dichlorobenzoylamino)-3-hydroxymethyl-2-trifluoromethyl- imidazo [1,2-a]pyridine hydrochloride (87 mg).
mp: 175-177°C
NMR (CDCl3:CD3OD=9:1, δ) : 4.99 (2H, s), 7.20 (1H, t, J=7Hz), 7.25-7.40 (3H, m), 8.27 (1H, d, J=7Hz), 8.30 (1H, d, J=7Hz) The following compounds (Example 13 to 14) were obtained according to a similar manner to that of Example 12.
Example 13
8-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-2- trifluoromethyl-imidazo [1,2-a] pyridine methanesulfonate.
mp : 166-168°C
NMR (DMSO-d6, δ) : 2.39 (3H, s), 4.93 (2H, s), 7.18 (1H, t, J=8Hz), 7.45-7.58 (3H, m), 8.29 (1H, d, J=8Hz), 8.35 (1H, d, J=8Hz)
Example 14
8-(2,6-Dichlorobenzoylamino)-3-(imidazol-2- yl) thiomethyl-2-trifluoromethylimidazo [1,2-a]pyridine
hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 4.85 (2H, s), 7.28 (1H, t, J=8Hz), 7.43-7.58 (3H, m), 7.74 (2H, s), 8.39 (1H, d,
J=8Hz), 8.56 (1H, d, J=8Hz)
Example 15
A mixture of [[8-(2,6-dichlorobenzoylamino)-2- methylimidazo [1,2-a]pyridin-3-yl]methyl] trimethylammonium iodide (600 mg) and imidazoie (394 mg) in 2-propanol (6 ml) was refluxed for 1.5 hours. The reaction mixture was
evaporated in vacuo and the residue was partitioned between dichloromethane and aqueous saturated sodium bicarbonate.
The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was
dissolved in 10% methanolic hydrogen chloride (2 ml). The solution was evaporated in vacuo and the residue was
orystallized from ethanol to give 8-(2,6- dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2- methylimidazo [1,2-a]pyridine dihydrochloride (338 mg). mp : 262°C (dec.)
NMR (DMSO-d6, δ) : 2.6C (3H, s), 6.00 (2H, s), 7.39
(1H, m), 7.49-7.61 (3H, m), 7.72 (1H, s), 7.78 (1H, s), 8.54-8.67 (2H, m), 9.21 (1H, s)
The following compounds (Examples 16 to 51) were
obtainec according to a similar manner to that of Example 2.
Example 16
8-(2,6-Dichlorobenzoylamino)-2-(1,1-dimethylethyl)- imidazo [1, 2-a]pyridine
mp : 232-233°C
NMR (CDCl3, δ) : 1.38 (9H, s), 6.76 (1H, t, J=7Hz),
7..30-7.45 (4H, m), 7.82 (1H, d, J=7Hz), 8.28 (1H, d, J=7Hz)
Example 17
8-(2-Chloro-6-methylbenzoylamino)-3-(1-hydroxy-1- methylethyl)-2-methylimidazo [1,2-a]pyridine
mp : 220-222°C
NMR (CDCl3:CD30D = 20:1, δ) : 1.76 (6H, s), 2.42 (3H, s), 2.47 (3H, e), 6.81 (1H, t, J=8Hz), 7.17 (1H, m), 7.25-7.30 (3H, m), 8.37 (1H, d, J=8Hz), 8.58 (1H, d, J=8Hz)
Example 18
8-(2,6-Dichlorobenzcylamino)-2-(2,2-dimethylpropyl)- imidazo [1, 2-a]pyriaine
mp : 201-202°C
NMR (CDCl3, δ) : 0.98 (9H, e), 2.62 (2H, e), 6.80 (1H, t, J=7Hz), 7.30-7.45 (4H, m), 7.85 (1H, d, J=7Hz), 8.31 (1H, a, J=7Hz)
Example 19
8-(2-Chiorobenzoylamino)-2-methylimidazo [1,2-a] pyridine mp : 110°C
NMR (CDCI3, δ) : 2.43 (3H, e), 6.79 (1H, t, J=7.5Hz), 7.33-7.52 (4H, m), 7.72 (1H, dd, J=1.5Hz and
7.5Hz), 7.83 (1H, dd, J=l .5Hz and 7.5Hz), 8.29 (1H, dd, J=1.5Hz and 7.5Hz), 9.07 (1H, br s)
Example 20
8-Benzoylamino-2-methylimidazo [1,2-a]pyridine
mp : 114-115°C
NMR (CDCI3, δ) : 2.46 (3H, s), 6.78 (1H, t, J=7.5Hz),
7.35 (1H, e), 7.47-7.62 (3H, m), 7.80 (1H, dd, J=1.5Hz ana 7.5Hz), 8.02 (2H, dd, J=1.5Hz and
7.5Hz), 8.27 (1H, dd, J=l .5Hz and 7.5Hz), 9.22 (1H, br s)
Example 21
2-MethyI-8-(2-methyIbenzoyIamino) imidazo [1,2-a]pyridine mp : 124-128°C
NMR (CDCI3, δ) : 2.43 (3H, s), 2.55 (3H, s), 6.79 (1H, t, J=7.5Hz), 7.24-7.43 (4H, m), 7.61 (1H, d,
J=7.5Hz), 7.82 (1H, dd, J=1.5Hz and 7.5Hz), 8.29 (1H, dd, J=1.5Hz and 7.5Hz), 8.85 (1H, br s)
Example 22
8-(Biphenyi-2-yI) carbonylamino-2-methylimidazo [1,2-a]- pyridine
NMR (CDCl3, δ) : 2.35 (3H, e), 6.68 (1H, t, J=7.5Hz), 7.20-7.57 (9H, m), 7.69-7.78 (2H, m), 8.09 (1H, a, J=7.5Hz), 8.51 (1H, br s)
Example 23
8-(2-Methoxybenzoylaminc)-2-methylimidazo [1,2-a] pyridine mp : 123-124°C Example 24
8-(2,6-Dimethylbenzoylamino)-2-methylimidazo- [1,2-a] pyridine
mp : 95-102°C
Example 25
8-(2,6-Difluorobenzoylamino)-2-methylimidazo- [1,2-a]pyridine
mp : 183-185°C
NMR (CDCl3, δ) : 2.42 (3H, s), 6.78 (1H, t, J=7.5Hz),
6.96-7.08 (2H, m), 7.35 (1H, s), 7.45 (1H, m), 7.81 (1H, dd, J=7.5Hz and 1.5Hz), 8.28 (1H, dd, J=7.5Hz and 1.5Hz), 8.99 (1H, br s) Example 26
8-(2,6-Dichloro-3-methoxybenzoylamino)-2- methylimidazo [1,2-a] pyridine
mp : 210-211°C Example 27
8-(2,6-Dichloro-3-nitrobenzoylamino)-2- methylimidazo [1,2-a]pyridine
mp : 227-231°C Example 28
8-(2,4-Dichlorobenzoylamino)-2-trifluoromethylimidazo- [1,2-a]pyridine
mp : 139-140°C
NMR (CDCl3, δ) : 6.98 (1H, t, J=7.5Hz), 7.41 (1H, dd, J=7.5Hz and 1.5Hz), 7.54 (1H, d, J=2Hz), 7.70 (1H, a, J=7.5Hz), 7.93 (1H, dd, J=7.5Hz and 2Hz), 8.41 (1H, a, J=7.5Hz), 9.17 (1H, br s)
Example 29
8-(2,6-Dichlorobenzoylamino)-2-ethylimidazo [1,2-a]- pyridine
mp : 174-176°C
NMR (CDCl3, δ) : 1.32 (3H, t, J=7.5Hz), 2.79 (2H, q,
J=7.5Hz), 6.80 (1H, t, J=7.5Hz), 7.31-7.42 (4H, m), 7.85 (1H, dd, J=7.5Hz and 1.0Hz), 8.32 (1H, dd,
J=7.5Hz and 1.0Hz), 8.72 (1H, br s)
Example 30
8-(2,6-Dichlorobenzoylanino) imidazo [1,2-a] pyridine mp : 163-164°C
NMR (CDCI3, δ) : 6.87 (1H, t, J=7Hz), 7.30-7.40 (3H, m), 7.50 (1H, s), 7.60 (1H, e), 7.92 (1H, d,
J=7Hz), 8.35 (1H, d, J=7Hz), 8.92 (1H, br s) Example 31
8-(2,6-Dichlorobenzoylamino)-2-phenylimidazo [1,2-a]- pyridine
mp : 224-226°C
NMR (CDCl3, δ; : 6.85 (1H, t, J=7Hz), 7.25-7.50 (6H, m), 7.83 (1H, s), 7.85-7.95 (3H, m), 8.37 (1H, d,
J=7Hz), 9.00 (1H, br s)
Example 32
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-benzylimidazo- [1,2-a]pyridine
mp : 100-106°C
NMR (CDCl3, δ) : 2.47 (3H, s), 4.25 (2H, s), 6.72 (1H, t, J=7Hz), 7.05-7.15 (2H, m), 7.20-7.40 (6H, m), 7.48 (1H, d, J=7Hz), 8.32 (1H, d, J=7Hz)
Example 33
8-(2,6-Dichlorobenzoylamino)-2,3-dimethylimidazo- [1,2-a] pyridine
mp : 224-226°C
NMR (CDCl3, δ) : 2.49 (3H, s), 2.51 (3H, e), 6.87 (1H, t, J=7Hz), 7.25-7.40 (3H, m) 7 7.60 (1H, d, J=7Hz), 8.32 (1H, d, J=7Kz)
Example 34
8-(2,6-Dichlorobenzoylamino)-3-ethoxycarbonyI-2- methylimidazo [1,2-a] pyridine
mp : 145-149°C
NMR (CDCl3, δ) : 1.48 (3H, t, J=7.5Hz), 2.71 (3H, s),
4.47 (2H, q, J=7.5Hz), 7.06 (1H, t, J=7.5Hz), 7.35- 7.44 (3H, m), 8.58 (1H, dd, J=7.5Hz and 1.0Hz),
8.80 (1H, br s), 9.06 (1H, dd, J=7.5Hz and 1.0Hz)
Example 35
8-(2,6-Dichlorobenzoylamino)-2-ethoxycarbonylimidazo- [1,2-a]pyridine
mp : 213-215°C
NMR (CDCl3, δ) : 1.41 (3H, t, J=7.5Hz), 4.45 (2H, q,
J=7.5Hz), 6.95 (1H, t, J=7.5Hz), 7.33-7.45 (3H, m), 7.91 (1H, da, J=7.5Hz and 1.5Hz), 8.19 (1H, s), 8.49 (1H, dd, J=7.5Hz and 1.5Hz), 8.91 (1H, br s)
Example 36
8-(2-Chloro-6-methylbenzoylamino)-2- trifluoromethylimidazo [1,2-a] pyridine
NMR (CDCl3, δ) : 2.42 (3H, s), 6.98 (1H, t, J=7Hz),
7.18 (1H, m), 7.25-7.35 (2H, m), 7.91 (1H, s), 7.93 (1H, d, J=7Hz), 8.51 (1H, d, J=7Hz), 8.67 (1H, br s) Example 37
8-(2,6-Dichlorobenzoylamino)-3-ethoxycarbonyl-2- trifluoromethylimidazo [1,2-a] pyridine
mp : 206-207°C
NMR (CDCI3, δ) : 1.45 (3H, t, J=7Hz), 4.48 (2H, q,
J=7Hz), 7.22 (1H, t, J=7Hz), 7.30-7.45 (3H, n), 8 . 70 ( 1H, a, J=7Hz), 8 .79 ( 1H, br s), 9.13 ( 1H, d, J=7Hz )
Example 38
2-Methyl-8-(2,4,6-tribromobenzoyiamino)imidazo- [1,2-a]pyridine
mp : 200-201.5°C
NMR (CDCl3, δ) : 2.43 (3H, s), 6.80 (1H, t, J=8Hz), 7.37 (1H, s), 7.78 (2H, s), 7.83 (1H, a, J=8Hz), 8.29 (1H, d, J=8Hz), 8.70 (1H, br s)
Example 39
8-(2,5-Dichlorobenzoylamino)-2-methylimidazo- [1,2-a]pyridine
mp : ~140°C (dec.)
NMR (CDCI3, δ) : 2.43 (3H, s), 6.80 (1H, t, J=8Hz),
7.35 (1H, s), 7.40 (2H, s), 7.70 (1H, s), 7.82 (1H, d, J=8Hz), 8.24 (1H, a, J=8Hz), 9.10 (1H, br e) Example 40
8-[3,5-3ie(1,1-dimethylethyl)benzoylamino]-2- methylimidazo [1,2-a] pyridine
mp : 104-107°C
NMR (CDCI3, δ) : 1.40 (18H, s), 2.47 (3H, s), 6.79
(1H, t, J=8Hz), 7.36 (1H, e), 7.64 (1H, t, J=2Hz),
7.78-7.82 (3H, m), 8.24 (1H, d, J=8Hz), 9.20 (1H, br s)
Example 41
8-(3-3utoxy-2,6-dichlorobenzoylamino)-2- methylimidazo [1,2-a]pyridine
mp : 73-83°C
NMR (CDCI3, δ) : 1.00 (3H, t, J=6Hz), 1.42-1.60 (2H, m), 1.83 (2H, quint., J=6Hz), 2.42 (3H, s), 4.08 (2H, t, J=6Hz), 6.79 (1H, t, J=8Hz), 6.93 (1H, d, J=8Hz), 7.30 (1H, d, J=8Hz), 7.35 (1H, s), 7.82 (1H, d, J=8Hz), 8.33 (1H, d, J=8Hz), 8.68 (1H, br s) Example 42
8-(2,6-DimethcxybenzoyIamino)-2-methyIimidazo- [1,2-a]pyriaine
mp : 154-156°C (dec.)
NMR (CDCl3, δ) : 2.41 (3H, s), 3.81 (6H, s), 6.59 (2H, a, J=8Hz), 6.77 (1H, t, J=8Hz), 7.27-7.38 (2H, m),
7.78 (1H, d, J=8Hz), 8.39 (1H, d, J=8Hz), 8.73 (1H, br s)
Example 43
8-(2,6-Dichloro-3-nitrobenzoylamino)-3-(1-hydroxy-1- methylethyl)-2-methylimidazo[1,2-a]pyridine
1 mp : 229-230°C
NMR (DMSO-d6, δ) : 1.65 (6H, s),. 2.47 (3H, s), 5.46
(1H, e), 6.87 (1H, t, J=8Hz), 7.83 (1H, d, J=8Hz), 8.06 (1H, d, J=8Kz), 8.18 (1H, a, J=8Hz), 8.63 (1H, a, J=8Hz)
Example 44
3-Acetyl-8-(2,6-dichlorobenzoyiamino)-2- methylimidazo [1, 2-a] pyridine
mp : 236-238°C
NMR (CDCI3, δ) : 2.62 (3H, s), 2.77 (3H, s), 7.08 (1H, t, J=8Hz), 7.30-7.43 (3H, m), 8.63 (1H, d, J=8Hz), 8.87 (1H, br s), 9.45 (H, d, J=8Hz)
Example 45
8-(2,6-Dichlorobenzoylamino)-3-methoxy-2- methylimidazo [1,2-a] pyridine
mp : 238-240°C
NMR (CDCI3, δ) : 2.40 (3H, s), 3.98 (3H, s), 6.82 (1H, t , J=8Hz), 7 .28-7 . 40 ( 3H, m), 7 . 69 ( 1H, d, J=8Hz), 8 . 27 ( 1H, d, J=8Hz j , 8 . 67 ( 1H, m)
Example 46
2-Methyl-8-(1-naphthoylamino)imidazo[1,2-a]pyridine mp : 167-169°C
NMR (CDCl3, δ) : 2.41 (3H, s), 6.85 (1H, t, J=8Hz),
7.35 (1H, s), 7.50-7.62 (3H, m), 7.80-8.05 (4H, m),
8.38-8.47 (2H, m), 9.15 (1H, br s)
Example 47
8-(2,6-Dichlorobenzoylamino)-2-ethoxycarbonyl-3- methylimidazo [1,2-a] pyridine
mp : 254-256°C
NMR (CDCI3, δ) : 1.43 (3H, t, J=7Hz), 2.80 (3H, e),
4.47 (2H, q, J=7Hz), 6.98 (1H, t, J=8Hz), 7.31-7.42 (3H, m), 7.71 (1H, d, J=8Hz), 8.49 (1H, d, J=8Hz), 8.95 (1H, br e) Example 48
8-(2,6-Dichlorocinnamoyianino)-2-methylimidazo- [1,2-a]pyridine
mp : -210°C (dec.)
NMR (CDCI3, δ) : 2.47 (3H, s), 6.79 (1H, t, J=8Hz),
6.95 (1H, d, J=15Kz), 7.20 (1H, m), 7.32-7.42 (3H, n), 7.80 (1H, d, J=8Hz), 7.93 (1H, d, J=15Hz), 8.30 (1H, d, J=8Hz), 8.88 (1H, br s)
Example 49
3-Bromo-8-[N-(2,6-dichlorophenyl)carbamoyl]-2- methylimidazo[1,2-a]pyridine
mp : 237-239°C
NMR (CDCI3, δ) : 2.50 (3H, s), 7.10 (1H, t, J=7Hz),
7.16-7.28 (1H, m), 7.45 (2H, d, J=9Hz), 8.24 (1H, d, J=7Hz), 8.32 (1H, d, J=7Hz) Example 50
2-Methyl-8-phenyiglyoxyloylaminoimidazo[1,2-a]pyridine mp : 149.5-150.0°C
NMR (CDCl3, δ) : 2.49 (3H, s), 6.79 (1H, t, J=7Hz), 7.36 (1H, s), 7.45-7.60 (2H, m), 7.67 (1H, t,
J=7Hz), 7.84 (1H, d, J=7Hz), 8.18 (1H, d, J=7Hz),
8.40 (2K, d, J=7Hz)
Example 51
8-(2,6-DichlorophenyIacetylamino)-2-methylimidazo- [1,2-a] pyridine
mp : 180°C
NMR (CDCl3, δ) : 2.45 (3H, s), 4.26 (2H, s), 6.70 (1H, t,. J=7.5Hz), 7.21 (1H, t, J=7.5Hz), 7.33 (1H, s), 7.37 (2H, d, J=7.5Hz), 7.75 (1H, dd, J=7.5Hz and
1.5Hz), 8.07 (1H, dd, J=7.5Hz and 1.5Hz), 8.75 (1H, br s)
Example 52
A. mixture of 8-amino-2-methylimidazo[1,2-a]pyridine hydrochloride (734 mg), 2,5-dichlorobenzenesulfonyl chloride (1.23 g) and triethylamine (1.01 g) in dichloromethane (14 ml) was stirred at ambient temperature overnight. The mixture was washed with water and aqueous saturated sodium bicarbonate, dried over sodium sulfate and evaporated in vacuo. The orystalline residue was reorystallized from ethanoi to give 8-(2,5-dichlorobenzenesulfonylamino)-2- methylimidazo [1,2-a]pyridine (210 mg).
mp : 210-214°C
NMR (CDCl3, δ) : 2.42 (3H, s), 6.63 (1H, t, J=7.5Hz),
7.09 (1H, dd, J=7.5Hz and i.5Hz), 7.29 (1H, s), 7.33-7.44 (2H, m), 7.70 (1H, da, J=7.5Hz and
1.5Hz), 8.17 (1H, a, J=1.5Hz) Example 53
A mixture of 8-amino-2-methylimidazo[1,2-a]pyridine hydrochloride (367 mg), 1,1'-carbonyldiimidazoie (357 mg) and triethylamine (303 mg) in 1,4-aioxane (7 nl) was stirred at ambient temperature for 14 hours. 1,1'-Carbonyldiimidazoie (49 mg) was added to the mixture and after 1 hour, 2,6- dimethylpiperidine (283 mg) was added. The mixture was etirred at 60°C for 3 hours and diluted with a mixture of dichloromethane and ethanol (8:2). The solution was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 8-(2,6-dimethylpiperidin-1- yl) carbonyIamino-2-methylimidazo [1,2-a]pyridine (176 mg). oil
NMR (CDCI3, δ) : 1.38 (6H, d, J=7Hz), 1.49-1.88 (6H, m), 2.43 (3H, s), 4.39-4.54 (2H, m), 6.70 (1H, t, J=8Hz), 7.30 (1H, s), 7.66 (1H, d, J=8Hz), 7.91 (1H, d, J=8Hz), 8.00 (1H, br s) Example 54
A mixture of 8-amino-2-trifluoromethylimidazo- [1,2-a] pyridine (1.0 g) and 2,6-dichlorophenyl isocyanate (940 mg) in dichloromethane (20 ml) wae stirred at ambient temperature overnight. The separated eolid was collected and washea with dichloromethane and hexane to give 8-[3-(2,6- dichlorophenyl)ureido]-2-trifluoromethylimidazo [1,2-a]- pyridine (1.32 g). The eecond orop wae obtained from the mother liquid (0.43 g).
mp : 204-205°C
NMR (DMSO-d6, δ) : 7.02 (1H, t, J=7.5Hz), 7.36 (1H, t,
J=7.5Hz), 7.58 (2H, d, J=7.5Hz), 7.99 (1H, d,
J=7.5Hz), 8.23 (1H, d, J=7.5Hz), 8.60 (1H, e), 9.29 (1H, s), 9.49 (1H, s) The following compound was obtained according to a similar manner to that of Example 2.
Example 55
8-(2,6-Dichlorobenzoylamino)-2-methylimidazo- [ 1 ,2-a]pyrazine
NMR (CDCl3, δ) : 2.30 (3H, s), 6.74 (1H, d, J=6Hz),
6.90 (1H, s), 7.23-7.35 (3H, m), 7.62 (1H, d, J=6Hz), 8.83 (1H, s)
ESI-MASΞ (M++1) : 321
Example 56
A mixture of 8-(2,6-dichlorobenzoylamino)-2- methylimidazo [1,2-a] pyridine (296 mg), 4-pyridinecarbaldehyde (856 mg) and cone, hydrochloric acid (1.6 ml) in acetic acid (8 ml) was stirred at 100°C for 1 day. The reaction mixture was cooled and evaporated in vacuo. To the residue was added aqueous saturated sodium bicarbonate and the separated oil was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel. The less polar fractions were combined and evaporated in vacuo. The residue was orystallized from diethyl ether to give 8-(2,6-dichlorobenzoylamino)-2-methyl- 3-(pyridin-4-yl) carbonylimidazo [1,2-a]pyridine (230 mg).
mp : 234-236°C
NMR (DMSO-d6, δ) : 2.40 (3H, s), 7.32 (1H, t, J=7Hz), 7.45-7.55 (3H, m), 7.64 (2H, a, J=6Hz), 8.47 (1H, a, J=7Hz), 8.80 (2H, d, J=6Hz), 9.28 (1H, d, J=7Hz) The more polar fractions were combined and evaporated in vacuo. The residue was diseolved in methanolic hydrogen chloride and the eolution wae evaporated in vacuo. The residue was orystallized from diethyl ether to give 8- (2, 6- dichlorobenzoylamino)-3-hydroxy(pyridin-4-yl)methyl-2- methylimidazo[1,2-a]pyridine dihydrochloride (80 mg). mp : 209-212°C
NMR (DMSO-d6, δ) : 6.68 (1H, s), 7.33 (1H, t, J=7Hz), 7.50-7.60 (3H, m), 8.02 (2H, d, J=6Hz), 8.27 (1H, d, J=7Hz), 8.60 (1H, d, J=7Hz), 8.85 (2H, d,
J=6Hz), 11.65 (1H, s)
The following compound wae obtained according to a similar manner to that of Example 56. Example 57
8-(2,6-Dichlorobenzoylamino)-3-hydroxy (pyridin-4- yl) methyl-2-trifluoromethylinidazo [1,2-a] pyridine
dihydrochloride
mp : -230°C
NMR (DMSO-d6, δ) : 6.66 (1H, s), 7.07 (1H, t, J=7Hz),
7.45-7.60 (3H, m), 7.85 (2H, d, J=6Hz), 8.12 (1H, d, J=7Hz), 8.27 (1H, d, J=7Hz), 8.79 (2H, d,
J=6Hz) Example 58
A mixture of 8-(2,6-dichlorobenzoylamino)-2- methylimidazo [1,2-a]pyridine (1.5 g), 37% formalin (5 ml) and cone, hydrochloric acid (2.7 ml) in acetic acid (22 ml) was stirred at 85°C for 5 hours. The mixture was evaporated in vacuo and toiuene (20 ml) was added tc the mixture. The mixture was evaporated in vacuo and to the nixture wae added aqueoue eaturated eodiun bicarbenate. The eeparated oil wae extracted with a nixture cf dichloronethane and ethanol
(8:2). The extract wae washed with brine, dried over sodiun sulfate and evaporated in vacuo. The residue was purified by colunn chromatography on silica gel. The obtained oil was orystallized from ethyl acetate and reorystallized from ethanol tc give 8- (2,6-dichlorobenzoylamino)-3-hydroxymethyl- 2-methylimidazo [1,2-a]pyridine (1.27 g).
mp : >250°C NMR (CDCl3:CD3OD = 9:1, δ) : 2.40 (3H, s), 4.88 (2H, s), 6.93 (1H, t, J=7Hz), 7.30-7.45 (3H, m), 8.03 (1H, d, J=7Hz), 8.42 (1H, a, J=7Hz) The following compounds (Examples 59 to 60) were
obtained according to a similar manner to that of Example 58.
Example 59
8-(2-Chloro-6-methylbenzoylamino)-3-hydroxymethyl-2- trifiuoromethylimiaazo [1, 2-a] pyridine
mp : 204-206°C
NMR (CDCl3, δ) : 2.29 (1H, t, J=7Hz), 2.40 (3H, s),
5.09 (2H, d, J=7Hz), 7.04 (1H, t, J=7Hz), 7.15 (1H, m), 7.20-7.30 (2H, m), 8.08 (1H, d, J=7Hz), 8.57 (1H, d, J=7Hz), 8.78 (1H, br s)
Example 60
8-(2,6-Dichlorobenzoylamino)-3-N,N- dimethylaminomethylimidazo [1,2-a]pyridine
NMR (CDCl3, δ) : 2.25 (6H, s), 3.70 (2H, s), 6.90 (1H, t, J=8Hz), 7.29-7.40 (4H, m), 8.10 (1H, d, J=8Hz), 8.38 (1H, d, J=8Hz), 8.87 (1H, m)
Example 61
A mixture of 8-(2,6-dichlorobenzoylamino)-2-(1,1- aimethylethyl) imidazo [1,2-a]pyridine (181 mg) and
N-bromosuccinimide (89 mg) in a mixture of ethanol (2 mi) and tetrahydrofuran (2 ml) was stirred at ambient temperature for 1 hour. The reaction mixture was partitioned between
dichloromethane and aqueous saturated sodium bicarbonate.
The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The obtained oil was orystallized from a mixture of diethyl ether and hexane to give 3-bromo-8- (2,6-dichlorobenzoylamino)-2-(1,1-aimethylethyl)imidazo- [1,2-a]pyridiine (190 mg). mp : 163-165°C
NMR (CDCl3, δ) : 1.49 (9H, n), 6.98 (1H, t, J=7Hz),
7.30-7.45 (3H, m), 7.90 (1H, d, J=7Hz), 8.35 (1H, d, J=7Hz), 8.77 (1H, br s)
The following compounds (Examples 62 to 93) were
obtained according to a similar nanner to that of Example 61.
Example 62
3-Bromo-8-(2,6-dichlorobenzoylamino)-2-(2,2- dimethylpropyl) imidazo [1,2-a]pyridine
mp : 146-149°C
NMR (CDCl3, δ) : 1.00 (9H, s), 2.65 (2H, s), 6.97 (1H, t, J=7Hz), 7.30-7.45 (3H, m), 7.88 (1H, d, J=7Hz), 8.40 (1H, d, J=7Hz), 8.79 (1H, br s)
Example 63
3-Bromo-8-(2,6-dichlorobenzcylamino)-2- methylimidazo [1,2-a] pyridine
mp : 236-239°C
NMR (DMSO-d6, δ) : 2.38 (3H, s), 7.08 (1H, t,
J=7.5Hz), 7.43-7.58 (3H, n), 8.08 (1H, a, J=7.5Hz), 8.18 (1H, d, J=7.5Hz) Example 64
3-Bromo-8-(2-chlorobenzoylamino)-2-methylimidazo- [1,2-a] pyridine
mp : 166-169°C
NMR (DMSO-d6, δ) : 2.37 (3H, s), 7.08 (1H, t,
J=7.5Hz), 7.40-7.66 (4K, m), 8.08 (2H, d, J=7.5Hz)
Example 65
3-3enzoylaminc-3-bromo-2-methyIimidazo[1,2-a]pyridine mp : 147-148°C
NMR (DMSO-d6, δ) : 2.39 (3H, e), 7.08 (1H, t, J=7 . 5Hz), 7 . 53-7 . 70 ( 3H, m), 7 . 95- 8 . 14 ( 4H, m), 9 . 97 ( 1H, br s )
Example 66
3-Bromo-2-methyl-8-(2-methyIbenzoylamino)imidazo- [1,2-a]pyridine
mp : 146-150°C
NMR (CDCl3, δ) : 2.41 (3H, s), 2.53 (3H, e), 6.94 (1H, t, J=7.5H∑), 7.25-7.45 (3H, m), 7.60 (1H, dd, J=1.5Hz and 7.5Hz), 7.81 (1H, dd, J=1.5Hz and
7.5Hz), 8.35 (1H, dd, J=1.5Hz and 7.5Hz), 8.79 (1H, br e)
Example 67
8- (Biphenyl-2-yl)carbonylamino-3-bromo-2- methylimidazo [1,2-a]pyridine
mp : 138-140°C
NMR (CDCl3, δ) : 2.36 (3H, e), 6.85 (1H, t, J=7.5Hz), 7.21-7.60 (8H, m), 7.70-7.81 (2H, m), 8.20 (1H, d, J=7.5Hz), 8.47 (1H, br s)
Example 68
3-Bromo-8-(2-methoxybenzoylamino)-2-methylimidazo- [1,2-a]pyridine
mp : 158-160°C
NMR (CDCl3, δ) : 2.49 (3H, s), 4.21 (3H, s), 6.90 (1H, t, J=7.5Hz), 7.06-7.20 (2H, m), 7.54 (1H, td,
J=7.5Kz and 1.5Hz), 7.79 (1H, dd, J=1.5Hz and
7.5Hz), 8.29-8.40 (2H, m)
Example 69
3-3rono-8-(2,6-dimethylbenzoylamino)-2- methylimidazo[1,2-a]pyridine
mp : 120-123°C
NMR (CDCl3, δ) : 2.38 (6H, si, 2.42 (3H, s), 6.96 (1H, t, J=7.5HZ), 7.07 (2H, d, J=7.5Hz), 7.21 (1H, d, J=7.5Hz), 7.83 (1H, dd, J=7.5Hz and 1.5Hz), 8.43 (1H, dd, J=7.5Hz and 1.5Hz), 8.60 (1H, br s) Example 70
3-Bromo-8-(2,6-difluorobenzoylamino)-2- methylimiaazo[1,2-a]pyridine
mp : 224-227°C
NMR (CDCI3, δ) : 2.43 (3H, s), 6.91-7.06 (3H, m), 7.44 (1H, m), 7.82 (1H, dd, J=7.5Hz and i.5Hz), 8.38
(1H, dd, J=7.5Hz and 1.5Hz), 9.05 (1H, br e)
Example 71
3-Bromo-8-(2,6-dichloro-3-methoxybenzoylamino)-2- methylimidazo [1,2-a] pyridine
mp : 229-230°C
NMR (DMSO-d6, δ) : 2.37 (3H, s), 3.91 (3H, s), 7.08
(1H, t, J=7.5Hz), 7.25 (1H, d, J=7.5Hz), 7.48 (1H, d, J=7.5Hz), 8.08 (1H, d, J=7.5Hz), 8.17 (1H, d, J=7.5Hz)
Example 72
3-Bromo-8-(2,6-dichloro-3-nitrobenzoylamino)-2- methylimidazo[1,2-a]pyridine
mp : 247-248°C (dec.)
NMR (CDCI3:CD3OD = 20:1, δ) : 2.40 (3H, s), 7.03 (1H, t, J=7.5Hz), 7.61 (1H, d, J=7.5Hz), 7.92 (1H, dd, J=7.5Hz and 1.5Hz), 7.98 (1H, d, J=7.5Hz), 8.44 (1H, dd, J=7.5Hz and 1.5Hz)
Example 73
3-Bromo-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 186-188°C
NMR (CDCI3, δ) : 7.13 (1H, t, J=7.5Hz), 7.33-7.45 (3H, m), 7.99 (1H, dd, J=7.5Hz and-1.5Hz), 8.58 (1H, ad, J=7.5Hz and 1.5Hz), 8.72 (1H, br s)
Example 74
3-Bromo-8-(2,4-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 162-164°C
NMR (CDCl3, δ) : 7.11 (1H, t, J=7.5Hz), 7.40 (1H, dd, J=7.5Hz and 1.5Hz), 7.52 (1H, d, J=1.5Hz), 7.75 (1H, d, J=7.5Hz), 7.97 (1H, dd, J=7.5Hz and 1.5Hz),
8.49 (1H, d, J=7.5Hz), 9.21 (1H, br e)
Example 75
3-Brcmo-8-(2,6-dichlorobenzoylanino)-2-ethylimidazo- [1,2-a]pyridine
mp : 226-228°C
NMR (CDCl3, δ) : 1.29 (3H, t, J=7.5Hz), 2.77 (2H, q,
J=7.5Hz), 6.96 (1H, t, J=7.5Hz), 7.29-7.41 (3H, m), 7.85 (1H, dd, J=7.5Hz and 1.5Hz), 8.41 (1H, dd, J=7.5Hz and 1.5Hz), 8.79 (1H, br s)
Example 76
3-Bromo-8-(2,6-dichlorobenzoylamino)imidazo- [1,2-a]pyridine
mp : 200-203°C
NMR (CDCl3, δ) : 7.40 (1H, t, J=7Hz), 7.25-7.35 (3H, m), 7.47 (1H, s), 7.91 (1H, d, J=7Hz), 8.45 (1H, d, J=7Hz), 9.10 (1H, br s) Example 77
3-Bromo-8-(2,6-dichlorobenzoyIamino)-2- phenylimidazo[1,2-a]pyridine
mp : 210-211°C
NMR (CDCl3, δ) : 7.02 (1H, t, J=7Hz), 7.30-7.50 (6H, m), 7.96 (1H, d, J=7Hz), 8.07 (2H, d, J=7Hz), 8.48 (1H, d, J=7Hz), 9.10 (1H, br e)
Example 78
3-Bromo-8-(2,6-dichlorobenzoylamino)-2- ethoxycarbonylimidazo[1,2-a]pyridine
mp : 249-250°C
NMR (CDCl3, δ) : 1.45 (3H, t, J=7.5Hz), 4.50 (2H, q,
J=7.5Hz), 7.11 (1H, t, J=7.5Hz), 7.33-7.45 (3H, m), 8.00 (1H, d, J=7.5Hz), 8.58 (1H, dd, J=7.5Hz and 1.5Hz), 8.90 (1H, br s)
Example 79
3-Bromo-2-nethyl-8-phenylgIyoxyloylaninoinidazo- [1,2-a]pyridine
np : 162-163°C
NMR (CDCl3, δ) : 2.49 (3H, s), 6.93 (1H, t, J=7Hz),
7.53 (2H, t, J=7Hz), 7.68 (1H, t, J=7Hz), 7.85 (1H, d, J=7Hz), 8.27 (1H, d, J=7Hz), 8.41 (2H, d,
J=7Hz), 10.00 (1H, br s)
Example 80
3-Bromo-8-(2,5-dichlorobenzeneeulfonylamino)-2- methylimidazo[1,2-a]pyridine
mp : 194-198°C
Example 81
3-Bromo-8-[3-(2,6-dichlorophenyl)ureido]-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 226-228°C
NMR (DMSO-d6, δ) : 7.19 (1H, t, J=7.5Hz), 7.47 (1H, t,
J=7.5Hz), 7.58 (2H, d, J=7.5Hz), 8.06-8.15 (2H, m), 9.31 (1H, s), 9.45 (1H, s)
Example 82
3-3rono-8-(2,6-dichlorophenyiacetylanino)-2- methylimidazo[1,2-a]pyridine
mp : 185-186°C
NMR (CDCl3, δ) : 2.47 (3H, s), 4.28 (2H, s), 6.86 (1H, t, J=7.5Hz), 7.22 (1H, t, J=7.5Hz), 7.39 (2H, d, J=7.5Hz), 7.78 (1H, dd, J=1.5Hz and 7.5Hz), 8.18
(1H, dd, J=1.5Hz and 7.5Hz), 8.86 (1H, br e)
Example 83
3-Bromo-2-methyl-8-(1-naphthoylamino)imidazo- [1,2-a]pyridine
mp : 179-180°C
NMR (CDCl3, δ) : 2.40 (3H, e), 6.59 (1H, t, J=8Hz),
7.50-7.63 (3H, m), 7.79-7.96 (3H, m), 8.00 (1H, d, J=8Hz), 8.44 (2H, t, J=8Hz), 9.00 (1H, br e)
Example 84
3-Bromo-2-methyl-8-(2,4,6-tribromobenzoylamino)- imidazo[1,2-a]pyridine
mp : 192-195°C
NMR (CDCl3, δ) : 2.45 (3H, e), 6.96 (1H, t, J=8Hz),
7.78 (2H, e), 7.85 (1H, d, J=8Hz), 8.38 (1H, d, J=8Hz), 8.66 (1H, br s)
Example 85
3-Bromo-8-(2,6-dichlorocinnamoylamino)-2- methylimidazo[1,2-a]pyridine
mp : 219-221°C
NMR (CDCl3, δ) : 2.48 (3H, s), 6.91 (1H, a, J=15Hz), 6.94 (1H, t, J=8Hz), 7.20 (1H, m), 7.39 (2H, a, J=8Hz), 7.81 (1H, d, J=8Hz), 7.95 (1H, d, J=15Hz),
8.39 (1H, a, J=8Hz), 8.74 (1H, br e)
Example 86
3-Bromo-8-(2,5-dichlorobenzoylamino)-2- methylinidazo[1,2-a]pyridine mp : 200-201.5°C
NMR (CDCI3, δ) : 2.43 (3H, s), 6.94 (1H, t, J=8Hz), 7.41 (2H, s), 7.73 (1H, s), 7.83 (1H, a, J=8Hz), 8.32 (1H, a, J=8Hz), 9.08 (1H, br s)
Example 87
8-[3,5-3is(1,1-dimethylethyl)benzoylamino]-3-bromo-2- nethylinidazo[1,2-a]pyridine
mp : 121°C
NMR (CDCl3, δ) : 1.40 (18H, s), 2.47 (3H, s), 6.94
(1H, t, J=8Hz), 7.64 (1H, s), 7.78-7.84 (3H, m), 8.34 (1H, d, J=8Hz), 9.19 (1H, br s)
Example 88
3-Bromo-8-(3-butoxy-2,6-dichlorobenzoylamino)-2- nethylinidazo[1,2-a]pyridine
np : 144-146°C
NMR (CDCl3, δ) : 1.00 (3H, t, J=6Hz), 1.43-1.60 (2H, m), 1.83 (2H, quint., J=6Hz), 2.42 (3H, e), 4.07 (2H, t, J=6Hz), 6.90-7.00 (2H, m), 7.30 (1H, d,
J=8Hz), 7.83 (1H, d, J=8Hz), 8.41 (1H, d, J=8Hz), 8.66 (1H, br e)
Example 89
3-Bromo-8-(2,6-dimethoxybenzoylamino)-2- nethyliniaazo[1,2-a]pyridine
np : 223°C (dec.)
NMR (CDCl3, δ) : 2.42 (3H, e), 3.82 (6H, e), 6.59 (2H, a, J=8Hz), 6.93 (1H, t, J=8Hz), 7.34 (1H, t,
J=8Hz), 7.79 (1H, d, J=8Hz), 8.48 (1H, a, J=8Hz),
8.76 (1H, br e)
Example 90
3-Bromo-8-(2,6-dinethylpiperidin-1-yl)carbonyiamino-2- methylimidazo[1,2-a]pyridine NMR (CDCI3, δ) : 1.37 (6H, d, J=7Hz), 1.50-1.87 (6H, m), 2.43 (3H, s), 4.38-4.53 (2H, m), 6.34 (1H, t, J=8Hz), 7.66 (1H, a, J=8Hz), 7.93 (1H, br s), 8.00 (1H, d, J=8Hz)
Example 91
3-Chloro-8-(2,6-dichlorobenzoylamino)-2- methylimidazo[1,2-a]pyridine
mp : 212-214°C
NMR (DMSO-d6, δ) : 2.37 (3H, s), 7.08 (1H, t,
J=7.5Hz), 7.42-7.55 (3H, m), 8.09 (1H, dd, J=l .5Hz and 7.5Hz), 8.18 (1H, dd, J=1.5Hz and 7.5Hz)
Example 92
3-Chloro-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 209-213°C
NMR (CDCl3, δ) : 7.14 (1H, t, J=7.5Hz), 7.33-7.45 (3H, m), 7.94 (1H, dd, J=7.5Hz and 1.5Hz), 8.57 (1H, dd, J=7.5Hz and 1.5Hz), 8.69 (1H, br s)
Example 93
3-Bromo-8-(2,6-dichIorobenzoylamino)-2- methylimidazo[1,2-a]pyrazine
mp : 183-185°C
NMR (CDCl3, δ) : 2.29 (3H, s), 6.80 (1H, d, J=7Hz),
7.23-7.35 (3H, m), 7.70 (1H, d, J=7Hz), 8.80 (1H, s) Example 94
To a solution of 8-(2,6-dichlorobenzoylamino)-2- methylimidazo[1,2-a]pyridine (300 mg) and pyridine (741 mg) in dichloromethane (3 ml) wae added methyl chloroformate (0.36 ml). The solution was stirred at ambient temperature overnight and evaporated in vacuo. The crystalline residue was triturated with ethanol to give 8-(2,6-dichlorobenzoyl- amino)-3-(1,4-dihydro-1-methoxycarbonylpyridin-4-yl)-2- methylimidazo[1,2-a]pyridine (427 ng).
np : 209-211°C (dec.)
NMR (CDCl3, δ) : 2.40 (3H, s), 3.90 (3H, e), 4.73-4.90
(3H, n), 6.80 (1H, t, J=8Hz), 6.92-7.15 (2H, n), 7.30-7.40 (3H, m), 7.90 (1H, d, J=8Hz), 8.36 (1H, d, J=8Hz), 8.75 (1H, m) Example 95
Fuming nitric acid (6 drops) was added dropwise to a mixture of 8-(2,6-dichlorobenzoylamino)-2-methylinidazo- [1,2-a]pyridine (320 ng) in sulfuric acid (1.5 nl) over the period of 30 minutes with ice cooling. The nixture was poured into cold water and nade alkaline with aqueous saturated sodium bicarbonate to give a orude solid. The obtained solid was partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The separated organic layer wae dried over eodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained solid was triturated with diethyl ether to give 8-(2,6-dichlorobenzoylamino)-2-methyl-3- nitroimidazo[1,2-a]pyridine (128 mg).
mp : 261-263°C (dec.)
NMR (CDCl3, δ) : 2.82 (3H, s), 7.21-7.30 (1H, m),
7.33-7.44 (3H, a), 8.73-8.80 (2H, m), 9.15 (1H, d, J=8Hz)
Example 96
A nixture of 3-bromo-8-(2,6-dichlorobenzoylamino-2- trifluoromethylimidazo [1,2-a] pyridine (300 mg),
2-(tributyletannyl)pyridine (341 mg) and
tetrakis (triphenylphosphine) palladium (15 mg) in 1,4-dioxane
(6 ml) was refluxed for 18 hours. The mixture was evaporated in vacuo and the residue wae purified by column chromatography on silica gel. The obtained oil was
orystallized from ethanol and the orystalline was dissolved in methanolic hydrogen chloride. The solution was evaporated in vacuo ana the residue wae orystallized from ethanol to give 8-(2,6-dichlorcbenzoylamino)-3-(pyridin-2-yl)-2- trifluoronethylimidazo [1,2-a]pyridine hydrochloride (65 mg). mp : 206-208°C
NMR (DMSO-d6, δ) : 7.17 (1H, t, J=8Hz), 7.49-7.63 (4H, m), 7.75 (1H, d, J=8Hz), 8.10 (1H, t, J=8Hz), 8.35 (1H, d, J=8Hz), 8.42 (1H, d, J=8Hz), 8.87 (1H, m)
The following compounds (Examples 97 to 99) were
obtained according to a similar manner to that of Example 96. Example 97
8-(2,6-Dichlorobenzoylamino)-3-(pyridin-3-yl)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 217-219°C
NMR (CDCl3, δ) : 7.00 (1H, t, J=8Hz), 7.35-7.45 (3H, m), 7.53 (1H, m), 7.70 (1H, d, J=8Hz), 7.83 (1H, n), 8.58 (1H, d, J=8Hz), 8.72-8.82 (3H, n)
Example 98
3-(3-Aninophenyl)-8-(2,6-dichlorobenzoylanino)-2- trifiuoromethylimidazo[1,2-a]pyridine
mp : 204-206°C
NMR (CDCl3, δ) : 3.86 (2H, br s), 6.75 (1H, m), 6.84
(2H, a, J=8Hz), 6.92 (1H, t, J=8Hz), 7.30-7.43 (4H, m), 7.79 (1H, d, J=8Hz), 8.51 (1H, d, J=8Hz), 8.80 (1H, br e)
Example 99
8-(2,6-Dichlorobenzoylamino)-3-(furan-3-yl)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 206-207°C NMR (CDCl3, δ) : 6.63 (1H, s), 6.99 (1H, t, J=8Hz),
7.32-7.43 (3H, m), 7.66 (1H, s), 7.73 (1H, s), 7.84 (1H, d, J=8Hz), 8.52 (1H, d, J=8Hz), 8.74 (1H, br s)
Example 100
A mixture of 8-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-trifluoromethylimidazo[1,2-a]pyridine (200 mg), triethylamine (100 mg) and methanesulfonyl chloride (68 mg) in 1,2-dichloroethane (2 ml) was stirred at ambient temperature for 1 hour to give 8-(2,6-dichlorobenzoylamino)- 3-methylsulfonyloxymethyl-2-trifluoromethylimidazo[1,2-a]- pyridine as the orude product. To the orude product was added dimethylamine hydrochloride (44 mg) and the mixture was refluxed overnight. The mixture was diluted with
dichloromethane, washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was
orystallized from diisopropyl ether to give 8-(2,6- dichlorobenzoylamino)-3-dimethylaminomethyl-2- trifluoromethylimidazo[1,2-a]pyridine (146 mg).
mp : 190-193°C
NMR (CDCl3, δ) : 2.25 (6H, s), 3.84 (2H, s), 6.98 (1H, t, J=8Hz), 7.31-7.43 (3H, m), 8.17 (1H, d, J=8Hz), 8.52 (1H, d, J=8Hz), 8.69 (1H, s)
The following compounds (Examples 101 to 121) were obtained according to a similar manner to that of Example 100.
Example 101
8-(2,6-Dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2- methylimidazo[1,2-a]pyridine
mp : 244-245°C (dec.)
NMR (DMSO-d6, δ) : 2.47 (3H, s), 5.73 (2H, s), 6.22 (1H, m), 6.96 (1H, t, J=8Hz), 7.'41 (1H, m), 7.46- 7.54 (3H, m), 7.85 (1H, m), 8.10 (1H, d, J=8Hz), 8.30 (1H, d, J=8Hz) Example 102
3-[2-(tert-Butoxycarbonyl)hydrazinomethyl]-8-(2,6- dichlorobenzoylamino)-2-methylimidazo[1,2-a]pyridine
mp : 229-230°C
NMR (CDCl3, δ) : 1.49 (9H, s), 2.38 (3H, s), 4.02 (1H, m), 4.20-4.26 (2H, m), 6.80 (1H, t, J=8Kz), 7.07
(1H, m), 7.31-7.40 (3H, n), 7.95 (1H, d, J=8Hz), 8.19 (1H, n), 9.00 (1H, n)
Example 103
8-(2,6-Dichlorobenzoylanino)-3-(morpholin-4-yl)methyl-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 173-174°C
NMR (CDCl3, δ) : 2.50 (4H, t, J=6Hz), 3.69 (4H, t,
J=6Hz), 3.93 (2H, s), 7.01 (1H, t, J=8Hz), 7.32- 7.44 (3H, m), 8.18 (1H, d, J=8Hz), 8.55 (1H, d,
J=8Hz), 8.74 (1H, s)
Example 104
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[(4- phenylimidazol-1-yl)methyl]imidazo[1,2-a]pyridine
mp : 246-248°C (dec.)
NMR (CDCl3, δ) : 5.42 (2H, s), 6.87 (1H, t, J=8Hz),
7.08 (1H, s), 7.20-7.28 (1H, m) , 7.30-7.41 (4H, m), 7.53 (1H, d, J=8Hz), 7.58 (1H, s), 7.71 (2H, d, J=8Hz), 8.42 (1H d, J=8Hz), 8.70 (1H, m) and
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[(5- phenylimidazoI-1-yl)methyl]imidazo[1,2-a]pyridine mp : 146-148°C
NMR (CDCl3, δ) : 5.37 (2H, s), 6.75 (1H, t, J=8Hz),
7.12 (1H, s), 7.16 (1H, d, J=8Hz), 7.30-7.51 (8H, m), 8.37 (1H, d, J=8Hz), 8.64 (1H, m)
Example 105
8-(2,6-Dichlorobenzoylamino)-3-(piperidin-1-yl)methyl-2- trifluoromethylimidazo[1,2-a]pyridine dihydrochloride
mp : 236-243°C
NMR (DMSO-d6, δ) : 1.30-1.90 (6H, m), 3.00-3.16
(2H, m), 3.46-3.61 (2H, m), 4.81 (2H, s), 7.28 (1H, t, J=8Hz), 7.47-7.59 (3H, m), 8.40 (1H, d, J=8Hz), 8.77 (1H, d, J=8Hz) Example 106
3-[Bis(2-methoxyethyl)]aminomethyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride (amorphous)
NMR (CDCl3, δ) : 3.20-3.65 (4H, m), 3.40 (6H, s),
3.80-4.08 (4H, m), 4.97 (2H, s), 7.25 (1H, br s),
7.32-7.44 (3H, m), 8.67 (1H, d, J=8Hz), 8.71 (1H, s), 9.09 (1H, br s)
Example 107
8-(2,6-Dichlorobenzoylamino)-3-(pyrrolidin-1-yl)methyl- 2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 1.80-1.95 (2H, m), 1.98-2.15 (2H, m), 3.05-3.25 (2H, m), 3.48-3.72 (2H, m), 4.97 (2H, d, J=7Hz), 7.28 (1H, t, J=8Hz), 7.47-7.58 (3H, m),
8.40 (1H, d, J=8Hz), 8.77 (1H, d, J=8Hz)
Example 108
8-(2,6-Dichlorobenzoylamino)-3-[N-methyl-N-(pyridin-2- yl)aminomethyl]-2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride
mp : 155-165°C
NMR (DMSO-d6, δ) : 2.90 (3H, s), 5.39 (2H, s), 7.03
(1H, t, J=8Hz), 7.20 (1H, t, J=8Hz), 7.39 (1H, m), 7.47-7.58 (3H, m), 8.03 (1H, t, J=8Hz), 8.18 (1H, d, J=6Hz), 8.28 (1H, d, J=8Hz), 8.35 (1H, d, J=8Hz)
Example 109
8-(2,6-Dichlorobenzoylamino)-3-[(4- ethoxycarbonylpiperidin-1-yl)methyl]-2- trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 188°C
ESI-MASS : 543 (M+H)+ Example 110
8-(2,6-Dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2- trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 6.03 (2H, s), 7.26 (1H, t, J=8Hz), 7.47-7.59 (3H, m), 7.70 (2H, d, J=7Hz), 8.39 (1H, d, J=8Hz), 8.56 (1H, d, J=8Hz), 9.14 (1H, s)
Example 111
8-(2,6-Dichlorobenzoylamino)-3-(2-methylimidazol-1- yl)methyl-2-trifluoromethylimidazo[1,2-a]pyridine
hydrochloride
NMR (DMSO-d6, δ) : 2.73 (3H, s), 5.90 (2H, s), 7.23
(1H, t, J=8Hz), 7.31 (1H, s), 7.48-7.59 (4H, m), 8.37 (1H, d, J=8Hz), 8.40 (1H, d, J=8Hz)
Example 112
8-(2,6-Dichlorobenzoylamino)-3-(1,2,4-triazol-1- yl)methyl-2-trifluoromethylimidazo[1,2-a]pyridine
hydrochloride
mp : 144-148°C NMR (DMSO-d6, δ) : 6.00 (2H, s), 7.24 (1H, t, J=8Hz), 7.46-7.57 (3H, m), 7.98 (1H, s), 8.33 (1H, d, J=8Hz), 8.60 (1H, a, J=8Hz), 8.81 (1H, s) Example 113
8-(2,6-Dichlorobenzoylamino)-3-(pyridin-3-yl)oxymethyl- 2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 6.44 (2H, e), 7.29 (1H, t, J=8Hz), 7.48-7.59 (3H, m), 7.91 (1H, dd, J=8Hz and 2Hz),
8.08 (1H, dd, J=8Hz and 2Hz), 8.38-8.45 (2H, m), 8.53-8.60 (2H, m)
Example 114
8-(2,6-Dichlorobenzoylamino)-3-(N-ethylcarbamoyl)- oxymethyl-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 172-174°C
NMR (CDCl3, δ) : 1.13 (3H, t, J=7Hz), 3.23 (2H,
quint., J=7Hz), 4.72 (1H, br), 5.55. (2H, s), 7.07 (1H, t, J=8Hz), 7.30-7.45 (3H, m), 8.19 (1H, d,
J=8Hz), 8.57 (1H, d, J=8Hz), 8.76 (1H, br s)
Example 115
8-(2,6-Dichlorobenzoylamino)-3-(N,N-dimethylamino)- methyl-2-trifluoromethylimidazo[1,2-a]pyridine
dihydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.85 (6H, s), 4.85 (2H, s), 7.27 (1H, t, J=8Hz), 7.45-7.58 (3H, m), 8.40 (1H, a, J=8Hz), 8.75 (1H, d, J=8Hz)
Example 116
8-(2,6-Dichlorobenzoylamino)-3-[N-methyl-N-(pyridin-3- yl)methylamino]methyl-2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride yl)methylamino]methyl-2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride
mp : 160-173°C
NMR (CD3OD, δ) : 2.58 (3H, s), 4.26 (2H, br s), 4.59 (2H, br s), 7.26 (1H, t, J=8Hz), 7.41-7.55 (3H, m),
8.01 (1H, t, J=8Hz), 8.49-8.53 (2H, m), 8.61 (1H, d, J=8Hz), 8.77 (1H, d, J=8Hz), 8.90 (1H, s)
Example 117
3-(N-Cyclohexyl-N-methylamino)methyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 219-223°C
NMR (DMSO-d6, δ) : 1.14-1.75 (6H, m), 1.81-1.98 (2H, m), 2.11-2.28 (2H, m), 2.65 (3H, d, J=7Hz), 3.41-
3.57 (1H, m), 4.62-4.75 (1H, m), 4.99-5.08 (1H, m), 7.29 (1H, t, J=8Hz), 7.46-7.58 (3H, m), 8.40 (1H, d, J=8Hz), 8.68 (1H, d, J=8Hz) Example 118
8-(2,6-Dichlorobenzoylamino)-3-[N-methyl-N-[2-(pyridin- 2-yl)ethyl]amino]methyl-2-trifluoromethylimidazo[1,2-a]- pyridine dihydrochloride
mp : 150-159°C
NMR (DMSO-d6, δ) : 2.81 (3H, s), 3.47 (2H, t, J=7Hz),
3.65 (2H, t, J=7Hz), 4.88 (2H, s), 7.25 (1H, t, J=8Hz), 7.48-7.72 (5H, m), 8.12-8.20 (1H, m), 8.39 (1H, d, J=8Hz), 8.61-8.70 (2H, m) Example 119
8-(2,6-Dichlorobenzoylamino)-3-[N-(2-methoxyethyl)-N- methylamino]methyl-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 75-104°C
NMR (DMSO-d6, δ) : 2.77 (3H, s), 3.36 (3H, s), 3.40- (1H, d, J=8Hz), 8.64 (1H, d, J=8Hz)
Example 120
8-(2,6-Dichlorobenzoylanino)-3-(N-ethoxycarbonylmethyl- N-methylamino)methyl-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 135-143°C
NMR (DMSO-d6, δ) : 1.23 (3H, t, J=7Hz), 2.62 (3H, br s), 4.19 (2H, q, J=7Hz), 4.50-4.77 (2H, br) , 4.80- 5.20 (2H, br), 7.27 (1H, r, J=8Hz), 7.45-7.58 (3H, m), 8.36 (1H, a, J=8Kz), 8.65 (1H, d, J=8Hz)
Example 121
8-(2,6-Dichlorobenzoylamino)-3-(imidazol-1-yl)methyl-2- trifiuoromethylimiaazo[1,2-a]pyridine (100 mg)
mp : 240-242°C
NMR (CDCl3, δ) : 5.59 (2H, s), 6.90 (1H, e), 7.04 (1H, t, J=8Hz), 7.10 (1H, s), 7.33-7.44 (3H, m), 7.59- 7.64 (2H, m), 8.59 (1H, d, J=8Hz), 8.74 (1H, br s)
The following compound was obtained according to a similar manner to that of Example 6.
Example 122
[8-(2,6-Dichlorobenzoylamino)imidazo[ 1 ,2-a]pyridin-3- yl]methyltrimethylammonium iodide
mp : 211°C
- NMR (DMSO-d6, δ) : 3.10 (9H, e), 5.00 (2H, s), 7.16
(1H, t, J=8Hz), 7.45-7.57 (3H, m), 7.90 (1H, s), 8.27 (1H, d, J=8Hz), 8.65 (1H, d, J=8Hz)
ESI-MASS : 318 (M+- (Me3N+I))
The following compounde (Examples 123 to 125) were obtained according to a similar manner to that of Example 7. Example 123
3-Carboxy-8-(2,6-dichlorobenzoylamino)-2- methylimidazo[1,2-a]pyriaine
mp : 220-221°C
NMR (DMSO-d6, δ) : 2.63 (3H, s), 7.18 (1H, t,
J=7.5Hz), 7.44-7.59 (3H, m), 8.32 (1H, d, J=7.5Hz), 9.09 (1H, d, J=7.5Hz)
Example 124
2-Carboxy-8-(2,6-dichlorobenzoylamino)-3- methylimidazo[1,2-a]pyridine
mp : >250°C
NMR (DMSO-d6, δ) : 2.75 (3H, e), 7.05 (1H, t, J=8Hz), 7.44-7.57 (3H, m), 8.18 (2H, dd, J=3Hz and 8Hz)
Example 125
Sodium 3-bromo-8-(2,6-dichlorobenzoylamino)imidazo- [1,2-a]pyridin-2-carboxylate
mp : >250°C
NMR (DMSO-d6, δ) : 7.11 (1H, t, J=7.5Hz), 7.45-7.60
(3H, m), 8.12-8.23 (2H, m)
Example 126
A mixture of [8-(2,6-dichlorobenzoylamino)-2- methylimidazo[1,2-a]pyridin-3-yl]methyltrimethylammonium iodide (300 mg) and eodium cyanide (30 mg) in N,N- dimethylformamide (1.5 ml) was stirred at 90°C for 20
minutes. The mixture wae partitioned between ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained solid was triturated with diethyl ether to give 3- cyanomethyl-8-(2,6-dichlorobenzoylamino)-2-methylimidazo- [1,2-a]pyridine (111 mg).
mp : 251-255°C NMR (CDCl3, δ) : 2.44 (3H, s), 3.98 '(2H, e), 7.00 (1H, t, J=8Hz), 7.30-7.41 (3H, m), 7.75 (1H, d, J=8Hz), 8.46 (1H, d, J=8Hz), 8.70 (1H, br s) Example 127
Sodium hydride (60%, 46 ng) was added to 2,2,2- trifluoroethanol (1.5 ng) at 4°C. The nixture was etirred at ambient temperature for 15 minutes and to the mixture was added [8-(2,6-dichlorobenzoylamino)-2-methylimidazo [1,2-a]- pyridin-3-yl]methyltrimethylammonium ioaide (300 mg) at 4°C. Then, the mixture was refluxed for 4 hours, cooled and partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separatea, washed with brine, dried over sodiun sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was orystallized from diethyl ether to give 8-(2,6-dichlorobenzoylamino)-2-methyl-3-(2,2,2- trifluoroethoxy)methylimidazo[1,2-a]pyridine (120 mg).
mp : 176-177°C
NMR (CDCl3, δ) : 2.43 (3H, s), 3.78 (2H, q, J=9Hz),
4.95 (2H, s), 6.90 (1H, t, J=8Hz), 7.30-7.40 (3H, m), 7.89 (1H, d, J=8Hz), 8.43 (1H, d, J=8Hz), 8.69 (1H, br s) The following compound was obtained according to a similar manner to that of Example 127.
Example 128
3-Cyanomethyl-8-(2,6-dichlorobenzoylamino)imidazo- [1,2-a]pyridine
mp : 216-218°C
NMR (CDCl3, δ) : 4.02 (2H, s), 7.06 (1H, t, J=8Hz), 7.30-7.40 (3H, m), 7.53 (1H, e), 7.79 (1H, d,
J=8Hz), 8.48 (1H, a, J=8Hz), 8.90 (1H, br s) The following compounds (Examples 129- to 133) were obtained according to a similar manner to that of Example 9.
Example 129
8-(2,6-Dichlorobenzoylamino)-3-(1-methylimidazol-2- yl)thiomethyl-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 201-202CC
NMR (DMSO-d6, δ) : 3.38 (3H, s), 4.63 (2H, s), 6.90
(1H, s), 7.20 (1H, t, J=8Hz), 7.26 (1H, s), 7.45- 7.60 (3H, m), 8.29-8.38 (2H, m)
Example 130
8-(2,6-Dichlorobenzoylamino)-3-formyl-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 219-222°C
NMR (CDCl3, δ) : 7.32 (1H, t, J=8Hz), 7.36-7.48 (3H, m), 8.76 (1H, br s), 8.84 (1H, d, J=8Hz), 9.36 (1H, d, J=8Hz), 10.22 (1H, s) Example 131
8-(2,6-Dichlorobenzoylamino)-3-methoxycarbonyloxymethyl- 2-trifluoromethylimidazo[1,2-a]pyridine
mp : 170-175°C
NMR (CDCl3, δ) : 3.83 (3H, s), 5.62 (2H, s), 7.10 (1H, t, J=8Hz), 7.33-7.43 (3H, m), 8.08 (1H, d, J=8Hz),
8.60 (1H, d, J=8Hz), 8.73 (1H, s)
Example 132
8-(2,6-Dichlorobenzoylamino)-3-(3-methyleulfonylamino- phenyl)-2-trifluoromethylimidazo[1,2-a]pyridine
mp : -153°C
NMR (CDCl3, δ) : 3.09 (3H, e), 6.74 (1H, br e), 6.98 (1H, t, J=8Hz), 7.28-7.44 (6H, m), 7.57 (1H, t, J=8Hz), 7.76 (1H, d, J=8Hz), 8.54 (1H, d, J=8Hz), 8.83 (1H, br s) Example 133
8-(2,6-Dichlorobenzoylamino)-3-(3-lauroylaminophenyl)-2- trifluoromethylimidazo [1,2-a]pyridine
mp : 155-157°C
NMR (CDCl3, δ) : 0.88 (3H, t, J=7Hz), 1.20-1.42 (16H, m), 1.68-1.80 (2H, m), 2.40 (2H, t, J=7Hz), 6.93 (1H, t, J=8Hz), 7.20 (1H, m), 7.32-7.43 (3H, m), 7.51 (1H, t, J=8Hz), 7.64-7.71 (2H, m), 7.80 (1H, d, J=8Hz), 8.52 (1H, d, J=8Hz), 8.78 (1H, br s)
The following compounds (Examples 134 to 159) were obtained according to a similar manner to that of Example 10.
Example 134
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[N-(3- trifluoromethylphenyl)carbamoyl]methylimidazo[1,2-a]pyridine hydrochloride
mp : 182-203°C
NMR (DMSO-d6, δ) : 2.53 (3H, s), 4.35 (2H, s), 7.43
(1H, d, J=8Hz), 7.47-7.66 (5H, m), 7.82 (1H, d,
J=8Hz), 8.12 (1H, s), 8.63 (1H, d, J=8Hz), 8.70 (1H d, J=8Hz)
Example 135
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[N-(pyridin-4- yl)methylcarbamoyl]methylimidazo[1,2-a]pyridine
dihydrochloride
mp : 195-205°C
NMR (DMSO-d6, δ) : 2.50 (3H, s), 4.24 (2H, s), 4.55
(2H, d, J=7Hz), 7.50-7.64 (4H, m), 7.88 (2H, d,
J=8Hz), 8.64 (1H, d, J=8Hz), 8.68 (1H, d, J=8Hz), 8.84 (2H, d, J=8Hz), 9.18 (1H, t, J=7Hz)
Example 136
8-(2,6-Dichlorobenzoylamino)-3-[[N-(2-hydroxyethyl)]- carbamoylmethyl]-2-methylimidazo[1,2-a]pyridine mp : 214-217°C
NMR (CDCl3, δ) : 2.38 (3H, s), 3.34 (2H, t, J=6Hz), 3.60 (2H, t, J=6Hz), 3.82 (2H, s), 6.92 (1H, t, J=8Hz), 7.30-7.44 (3H, m), 7.82 (1H, d, J=8Hz),
8.43 (1H, d, J=8Hz)
Example 137
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[[N-(thiazol-2- yl)]carbamoylmethyl]imidazo[1,2-a]pyridine hydrochloride
mp : 201-205°C
NMR (DMSO-d6, δ) : 2.51 (3H, s), 4.40 (2H, s), 7.25
(1H, d, J=5Hz), 7.50-7.65 (5H, m), 8.65-8.69 (2H, m) Example 138
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[4-(pyridin-2- yl)piperazin-1-yl-carbonylmethyl]imidazo[1,2-a]pyridine trihydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.57-4.02 (8H, m),
4.40 (2H, s), 6.94 (1H, t, J=8Hz), 7.31 (1H, br), 7.48-7.65 (4H, m), 7.96 (1H, br) , 8.10 (1H, d, J=8Hz), 8.49 (1H, d, J=8Hz), 8.65 (1H, d, J=8Hz) Example 139
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[(morpholin-4- yl)carbonylmethyl]imidazo[1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.46 (3H, s), 3.46 (2H, t, J=7Hz), 3.55-3.67 (4H, m), 3.73 (2H, t, J=7Hz), 4.31 (2H, s), 7.48 (1H, t, J=8Hz), 7.54-7.66 (3H, m), 8.44 (1H, d, J=8Hz), 8.60 (1H, d, J=8Hz)
Example 140
8-(2,6-Dichlorobenzoylamino)-3-[(4-hydroxypiperidin-1- yl) carbonylmethyl]-2-methylimidazo[1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 1.20-1.93 (4H, m), 2.46 (3H, s), 3.00-3.13 (1H, m), 3.27-3.40 (1H, m), 3.69-3.90
(4H, m), 4.30 (2H, s), 7.45 (1H, m), 7.54-7.67 (3H, m), 8.40 (1H, d, J=8Hz), 8.55 (1H, d, J=8Hz)
Example 141
8-(2,6-Dichlorobenzoylamino)-3-[[N-(furan-2-yl-methyl)]- carbamoylmethyl]-2-methylimidazo[1,2-a]pyridine hydrochloride mp : 231-233°C
NMR (DMSO-d6, δ) : 2.46 (3H, s), 4.07 (2H, s), 4.28
(2H, d, J=7Hz), 6.26 (1H, d, J=3Hz), 6.40 (1H, t, J=3Hz), 7.48 (1H, m), 7.52-7.64 (4H, m), 8.52 (1H, d, J=8Hz), 8.60 (1H, d, J=8Hz), 8.72 (1H, t, J=7Hz)
Example 142
3-[(N-Cyclopentyl)carbamoylmethyl]-8-(2,6- dichlorobenzoylamino)-2-methylimidazo[1,2-a]pyridine
hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 1.33-1.58 (4H, m), 1.60-1.70 (2H, m), 1.75-1.89 (2H, m), 2.48 (3H, s), 3.83-4.05 (3H, m), 7.50 (1H, m), 7.43-7.55 (3H, m), 8.31 (1H, d,
J=8Hz), 8.50-8.61 (2H, m)
Example 143
8-(2,6-Dichlorobenzoylamino)-3-[(N,N- dimethylaminoacetylamino)phenyl]-2-trifluoromethylimidazo- [1,2-a]pyridine hydrochloride
mp : ~203°C
NMR (CDCl3, δ) : 2.88 (3H, s), 2.90 (3H, s), 4.20 (2H, d, J=3Hz), 7.10 (1H, t, J=8Hz), 7.37 (1H, d,
J=8Hz), 7.48-7.60 (3H, m), 7.63 (1H, t, J=8Hz), 7 . 80-7 . 89 ( 2H, m), 7 . 93 ( 1H, d, J=8Hz), 8 . 32 ( 1H, d, J=8Hz )
Example 144
3-[[N-(2-Aminophenyl)]carbamoylmethyl]-8-(2,6- dichlorobenzoylamino)-2-methylimidazo[1,2-a]pyridine hydrochloride
mp : -242°C
NMR (DMSO-d6, δ) : 2.56 (3H, s), 4.36 (2H, s), 7.08 (1H, m), 7.12-7.22 (2H, m), 7.36 (1H, d, J=8Hz),
7.50-7.66 (4H, m), 8.66 (1H, d, J=8Hz), 8.80 (1H, d, J=8Hz), 10.40 (1H, br s), 11.56 (1H, br s)
Example 145
2-Carbamoyl-8-(2,6-dichlorobenzoylamino)-3- methylimidazo[1,2-a]pyridine
mp : >250°C
NMR (DMSO-d6, δ) : 2.73 (3H, s), 7.05 (1H, t, J=8Hz), 7.40-7.48 (2H, m), 7.48-7.59 (3H, m), 8.14 (1H, d, J=8Hz), 8.20 (1H, d, J=8Hz)
Example 146
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[[N-(2- anilinophenyl)]carbamoylmethyl]imidazo[1,2-a]pyridine
mp : 224-226°C
NMR (CDCl3, δ) : 1.82 (3H, s), 4.48 (2H, s), 6.77 (1H, t, J=8Hz), 6.99 (1H, d, J=8Hz), 7.10-7.14 (2H, m), 7.18-7.39 (7H, m), 7.46-7.53 (3H, m), 7.81 (1H, d, J=8Hz), 8.10 (1H, d, J=8Hz), 8.30 (1H, d, J=8Hz), 8.64 (1H, m)
Example 147
8-(2,6-Dichlorobenzoylamino)-3-[(N-methoxy-N- methyl)carbamoyl]methyl-2-methylimidazo[1,2-a]pyridine
mp : 169-171°C NMR (CDCI3, δ) : 2.42 (3H, s), 3.19 (3H, s), 3.67 (3H, s), 4.01 (2H, s), 6.85 (1H, t, J=8Hz), 7.28-7.40 (3H, m), 7.95 (1H, d, J=8Hz), 8.35 (1H, d, J=8Hz), 8.69 (1H, br s)
Example 148
8-(2,6-Dichlorobenzoylamino)-3-[[N-(2-methoxyethyl)]- carbamoylmethyl]imidazo[1,2-a]pyridine hydrochloride
mp : 218-220°C
NMR (DMSO-d6, δ) : 3.21-3.28 (5H, m), 3.36 (2H, t,
J=5Hz), 4.05 (2H, s), 7.47 (1H, m), 7.51-7.64 (3H, m), 8.02 (1H, s), 8.38 (1H, m), 8.50 (1H, d,
J=8Hz), 8.54 (1H, d, J=8Hz) Example 149
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[N-[(1S)-1- methoxycarbonylethyl]carbamoylmethyl]imidazo[1,2-a]pyridine hydrochloride
mp : 188-196°C
NMR (DMSO-d6, δ) : 1.31 (3H, d, J=8Hz), 2.47 (3H, s),
4.07 (2H, m), 4.28 (1H, m), 7.40-7.70 (4H, m), 8.47 (1H, d, J=8Hz), 8.56 (1H, d, J=8Hz), 8.78 (1H, d, J=8Hz) Example 150
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[[N-(2- morpholinoethyl)]carbamoylmethyl]imidazo[1,2-a]pyridine dihydrochloride
mp : 222-226°C
NMR (DMSO-d6, δ) : 2.49 (3H, s), 3.00-3.30 (4H, m),
3.30-3.70 (4H, m), 3.80-4.00 (4H, m), 4.15 (2H, s), 7.40-7.70 (4H, m), 8.60-8.70 (2H, m), 8.75 (1H, d, J=8Hz) Example 151
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[N-[(pyridin-3- yl)methyl]carbamoylmethyl]imidazo[1,2-a]pyridine
dihydrochloride
mp : 180-189°C
NMR (DMSO-d6, δ) : 2.49 (3H, s), 4.17 (1H, s), 4.45 (2H, d, J=7Hz), 7.40-7.70 (4H, m), 7.88 (1H, d, J=7.8Hz), 8.28 (1H, d, J=8Hz), 8.59 (1H, d, J=8Hz), 8.64 (1H, d, J=8Hz), 8.74 (1H, d, J=7Hz), 8.75 (1H, s), 9.03 (1H, t, J=7Hz)
Example 152
8-(2,6-Dichlorobenzoylamino)-2-methyl-3- (carbamoylmethyl)imidazo[1,2-a]pyridine hydrochloride
mp : 180-200°C
NMR (DMSO-d6, δ) : 2.47 (3H, s), 3.97 (2H, s), 7.26 (1H, s), 7.40-7.70 (5H, m), 8.50 (1H, d, J=8Hz), 8.56 (1H, d, J=8Hz) Example 153
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-(N,N- dimethylcarbamoylmethyl)imidazo[1,2-a]pyridine hydrochloride mp : >250°C
NMR (DMSO-d6, δ) : 2.45 (3H, s), 2.88 (3H, s), 3.16
(3H, s), 4.28 (2H, s), 7.55 (1H, t, J=8Hz), 7.50-
7.70 (3H, m), 8.42 (1H, d, J=8Hz), 8.57 (1H, d, J=8Hz)
Example 154
8-(2,6-Dichlorobenzoylamino)-3-[N-(2-methoxyethyl)-N- methylcarbamoyl]methyl-2-methylimidazo[1,2-a]pyridine
hydrochloride
mp : 222-223°C
NMR (DMSO-d6, δ) : 2.43 (9/5H, s), 2.47 (6/5H, s),
2.88 (9/5H, d, J=3Hz), 3.19 (6/5H, s), 3.26 (9/5H, s), 3.38 (6/5H, d, J=3Hz), 3.40-3.25 (4H, m), 4.30 (4/5H, s), 4.33 (6/5H, s), 7.43-7.67 (4H, m), 8.30 (3/5H, d, J=8Hz), 8.39 (2/5H, d, J=8Hz), 8.58 (1H, d, J=8Hz)
Example 155
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[[N- (tetrahydrofuran-2-yl)methylcarbamoyl]methyl]imidazo- [1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 1.40-1.55 (1H, m), 1.71-1.94 (3H, m), 2.47 (3H, s), 3.05-3.23 (2H, m), 3.55-3.40 (3H, m), 4.03 (2H, s), 7.49 (1H, t, J=8Hz), 7.52-7.66 (3H, m), 8.38 (1H, t, J=6Hz), 8.53 (1H, d, J=8Hz), 8.59 (1H, d, J=8Hz)
Example 156
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[[N-(2- thienyl)methylcarbamoyl]methyl]imidazo[1,2-a]pyridine
hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.46 (3H, s), 4.07 (2H, s), 4.44
(2H, d, J=6Hz), 6.94-6.99 (2H, m), 7.40 (1H, d, J=4Hz), 7.43-7.65 (4H, m), 8.51 (1H, d, J=8Hz), 8.59 (1H, d, J=8Hz), 8.84 (1H, t, J=6Hz)
Example 157
8-(2,6-Dichlorobenzoylamino)-2-methyl-3-[[N-(5- trifluoromethyl-1,3,4-thiadiazol-2-yl)]carbamoylmethyl]- imidazo[1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.50 (3H, s), 4.51 (2H, s), 7.47
(1H, t, J=8Hz), 7.52-7.65 (3H, m), 8.54-8.67 (2H, m) Example 158
8-(2,6-DichIorobenzoylamino)-2-methyl-3-[(N- piperidino)carbamoylmethyl]imidazo[1,2-a]pyridine
dihydrochloride
mp : 178-191°C
NMR (DMSO-d6, δ) : 1.40-1.80 (6H, m), 2.48 (2H, m), 3.05-3.15 (2H, m), 4.13-4.25 (2H, m), 7.50-7.65 (4H, m), 8.51-8.90 (2H, m) Example 159
3-Bromo-2-carbamoyl-8-(2,6-dichlorobenzoylamino)- imidazo[1,2-a]pyridine
mp : >250°C
NMR (CDCl3, δ) : 5.48-5.55 (2H, m), 7.10 (1H, t,
J=8Hz), 7.22-7.30 (3H, m), 7.95 (1H, d, J=8Hz),
8.52 (1H, d, J=8Hz), 8.92 (1H, br s)
Example 160
Amixture of 8-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-trifluoromethylimidazo[1,2-a]pyridine (100 mg), acetic anhydride (31 mg) and pyridine (40 mg) in
dichloromethane (5 ml) wae etirred at ambient temperature for 1 day. The reaction mixture wae evaporated in vacuo and the residue was purified by column chromatography on silica gel. The obtained oil was orystallized from a nixture of ethyl acetate and hexane to give 3-acetoxynethyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine (85 mg).
mp : 191-193°C
NMR (CDCl3, δ) : 2.10 (3H, s), 5.55 (2H, s), 7.08 (1H, t, J=7Hz), 7.30-7.45 (3H, m), 8.03 (1H, d, J=7Hz), 8.58 (1H, d, J=7Hz), 8.71 (1H, br s)
The following compound was obtained according to a similar manner to that of Example 160. Example 161
3-Acetoxymethyl-8-(2,6-dichlorobenzoyIamino)-2- methylimidazo[1,2-a]pyridine
mp : 210-213°C
NMR (CDCl3, δ) : 2.06 (3H, s), 2.48 (3H, e), 5.40 (2H, e), 6.91 (1H, t, J=7Hz), 7.30-7.40 (3H, m), 7.91 (1H, d, J=7Hz), 8.41 (1H, d, J=7Hz), 8.73 (1H, br s) Example 162
A mixture of 8-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-trifluoromethylimidazo[1,2-a]pyridine (1.01 g), giutaric anhydride (342 mg), pyridine (257 mg) and
4-dimethylaminopyridine (10 mg) was stirred at ambient temperature overnight. The reaction mixture was washed with 1N-hydrochloric acid and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was crystallized from diethyl ether to give 3-(4- carboxybutanoyloxymethyl)-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine (750 mg).
mp : 190-192°C
NMR (CDCl3:CD30D = 20:1, δ) : 1.95 (2H quint., J=7Hz), 2.37 (2H, t, J=7Hz), 2.44 (2H, t, J=7Hz), 5.55 (2H, s), 7.13 (1H, t, J=8Hz), 7.33-7.45 (3H, m), 8.09
(1H, d, J=8Hz), 8.62 (1H, a, J=8Hz)
Exampie 163
A mixture of 8-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-methylimidazo[1,2-a]pyridine (125 mg), acetic anhydride (55 mg) and pyridine (57 ng) in dichloronethane wae etirred at ambient temperature overnight. The nixture was evaporated in vacuo and to the residue was added toluene.
The nixture was evaporated in vacuo and the residue was disecived in N,N-dimethylformamide (2 ml). To the solution wae added 4-hydroxypyridine (95 mg) and potaeeium carbonate (207 mg) and the mixture was stirred at 80°C for 2 hours. The mixture was cooled, poured into a mixture of ice and water and extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was diseolved in
methanolic hydrogen chloride. The solution was evaporated and the reeidue wae orystallized from ethanol to give 8-(2,6- dichlorobenzoylamino)-2-methyl-3-(pyridin-4- yl)oxymethylimidazo[1,2-a]pyriaine dihydrochloride (107 mg). mp : 255-258°C
NMR (DMSO-d6, δ) : 2.60 (3H, s), 6.14 (2H, s), 7.30-
7.45 (3H, m), 7.50-7.60 (3H, m), 8.50-8.64 (4H, m)
Example 164
To a solution of 2-carbamoyl-8-(2,6- dichlorobenzoylamino)-3-methylimidazo[1,2-a]pyridine (2.5 g) in N,N-dimethylformamide (25 ml) was added thionylchloride (1.51 ml) dropwise. The mixture was stirred at ambient temperature for 2 hours and poured into water. The aqueous mixture was neutralized with aqueous saturated sodium
bicarbonate. The separated solid was collected and washed with water to give 2-cyano-8-(2,6-dichlorobenzoylamino)-3- methylimidazo [1,2-a] pyridine (1.99 g).
mp : >250°C
NMR (DMSO-d6, δ) : 2.64 (3H, s), 7.16 (1H, t, J=8Hz), 7.45-7.58 (3H, m), 8.22 (1H, d, J=8Hz), 8.28 (1H, d, J=8Hz)
Example 165
A mixture of 3-bromo-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo [1,2-a]pyridine (136 mg),
4-mercaptopyridine (111 mg) and potaseium carbonate (138 mg) in N,N-dimethylformamide (5 ml) wae etirred at 120°C for 3 houre. The reaction mixture was cooled and poured into a mixture of ice and water and the separated oil wae extracted with ethyl acetate, ϊhe extract wae washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was dissolved in methanolic hydrogen chloride. The solution was evaporated in vacuo ana the residue was orystallized from ethyl acetate to give 8-(2,6- dichlorobenzoylamino)-3-(pyridin-4-yl)thio-2- trifluoromethylimidazo[1,2-a]pyridine hydrochloride (87 mg). mp : 225-235°C
NMR (DMSO-d6, δ) : 7.32 (1H, t, J=7Hz), 7.45-7.60 (5H, m), 8.33 (1H, d, J=7Hz), 8.52 (1H, a, J=7Hz), 8.58 (2H, d, J=6Hz)
Example 166
A mixture of 3-bromo-8-(2,6-dichIorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine (500 mg),
(trimethylsilyl) acetylene (420 mg), palladium chloride (20 mg), triphenyiphosphine (58 mg), triethylamine (1.11 g) and copper iodide (26 mg) in acetonitrile (5 mi) was refluxed for 18 hours. The mixture was diluted with ethyl acetate, washed with brine, dried over sodium sulfate ana evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 8-(2,6-dichIorobenzoyiamino)-2- trifluoromethyl-3-[(trimethylsilyl)ethynyl]imidazo[1,2-a]- pyridine (amorphous, 70 mg).
NMR (CDCl3, δ) : 0.32 (9H, S), 7.10 (1H, t, J=8Hz),
7.32-7.42 (3H, n), 8.07 (1H, d, J=8Hz), 8.59 (1H, d, J=8Hz), 8.66 (1H, n)
Example 167
Tetrabutylannoniun fluoride (l.OM solution in
tetrahydrofuran, 0.016 nl) was added to a solution of 8-(2,6- dichlorobenzoylanino)-2-trifluoromethyl-3-[(trimethylsilyl)- ethynyl]imidazo[1,2-a]pyridine (65 mg) in tetrahydrofuran (1 ml) at 4°C. The mixture was stirred at ambient temperature for 30 minutes and evaporatea in vacuo. The residue wae purified by column chromatography on eilica gel and the obtained oil wae orystallized from a mixture of ethanol and water to give 3-ethynyI-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine (31 mg).
mp. 190-194°C
NMR (CDCl3, δ) : 3.45 (1H, s), 7.12 (1H, t, J=8Hz), 7.33-7.43 (3H, m), 8.11 (1H, a, J=8Hz), 8.61 (1H, d, J=8Hz), 8.68 (1H, br s)
Example 168
A. mixture of 8-(2,6-dichlorobenzoylamino)-3-(1,4- dihydro-1-methoxycarbonylpyridin-4-yl)-2-methylimidazo- [1,2-a]pyridine (300 mg), sodium iodide (147 mg) and
tetrabutylammonium hydrogen sulfate (22 mg) in dimethyl sulfoxide (4 ml) was etirred at 120°C for 8 hours. The mixture was cooled and poured into water. The separated solid was collected, dried in vacuo and purified by column chromatography on silica gel. The obtained orystalline was triturated with ethanol and dissolved in methanolic hydrogen chloride. The solution was evaporated in vacuo and the residue was orystallized from ethanol to give 8-(2,6- dichlorobenzoylamino)-2-methyl-3-(pyridin-4-yl)imidazo- [1,2-a]pyriaine hydrochloride (103 mg).
np : 255-260°C
NMR (CDCl3:CD30D = 20:1, δ) : 2.73 (3H, s), 7.37-7.44
(3H, n), 7.50 (1H, n), 8.10-8.16 (2H, n), 8.45 (1H, n), 9.02-9.10 (2H, n), 9.12 (1H, d, J=8Hz)
Example 169
Hydrogen peroxide (30%, 0.95 ml) wae added to a mixture of 3-cyanomethyl-8-(2,6-dichlorobenzoylamino)-2- methylimidazo [1,2-a] pyridine (100 ng) and aqueoue sodium hydroxide (1N, 0.66 ml) in ethanol (2 ml). The mixture was stirred at ambient temperature for 30 minutes and neutralized with IN-hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with aσueous saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was
orystallized from diisopropyl alcohol to give 3- carbamoyimethyl-8-(2,6-dichlorobenzoylamino)-2- methylimidazo [1, 2-a] pyridine (27 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.32 (3H, s), 3.78 (3H, s), 6.89
(1H, t, J=8Hz), 7.08 (1H, br s), 7.41-7.54 (3H, m), 8..06 (2H, t, J=8Hz)
Example 170
A mixture of 3-bromo-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo [1,2-a]pyridine (300 mg), phenylboric acid (121 mg) and tetrakis (triphenylphosphine) palladium (15 mg) in a mixture of aσueous sodium carbonate (2M, 1.7 ml) and 1, 2-dimethoxyethane (3 ml) was refluxed for 3 hours. The nixture was partitioned between ethyl acetate and aqueous saturated sodiun bicarbonate. The organic layer was
eeparated, washed with brine, dried over sodiun sulfate and evaporated in vacuo. The resiaue wae purified by column chromatography on eilica gel and the obtained oil wae
orystallized from diisopropyl ether to give 8-(2,6- dichlorobenzoylamino)-3-phenyl-2-trifluoromethylimidazo- [1,2-a]pyridine (116 mg).
mp : -139°C
NMR (CDCl3, δ) : 6.93 (1H, t, J=8Hz), 7.33-7.44 (3H, n), 7.44-7.51 (2H, n), 7.51-7.60 (3H, n), 7.73 (1H, d, J=8Hz), 8.52 (1H, d, J=8Hz), 8.84 (1H, br s) Example 171
To a solution of sodium carbonate (81 mg) in water (0.5 ml) wae added hydroxylamine hydrochloride (53 mg), ethanol (7 ml) and 3-cyanomethyl-8-(2,6-dichlorobenzoylamino)-2- methylimidazo[1,2-a]pyridine (230 mg). The mixture was refluxed for 6 hours and poured into water. The separated solid was collected, washed with water and dried. The solid wae dissolved in 4N-hydrogen chloride in ethyl acetate and the solution was evaporated in vacuo. The residue was orystaliized from a mixture of diisopropyl alcohol and ethyl acetate to give 8-(2,6-dichlorobenzoylamino)-3-(N- hydroxyamidino)methyl-2-methylinidazo[1,2-a]pyridine
hydrochloride (169 ng).
mp : 196-198°C
NMR (DMSO-d6, δ) : 2.50 (3H, e), 4.46 (2H, s), 7.45-
7.63 (4H, n), 8.50 (1H, m), 8.69 (1H, m), 8.83 (1H, br s), 11.10 (1H, br s), 11.78 (1H, br s)
Example 172
Acetic anhydride (21 mg) wae added to a mixture of 8- (2,6-dichlorobenzoylamino)-3-(N-hydroxyamidino)methyl-2- methylimidazo [1, 2-a] pyridine hydrochloride (80 mg) and sodium acetate (15 mg) in acetic acid (1 ml). The mixture was stirred at ambient tenperature for 30 minutes and at 80°C for 5 houre. The mixture was evaporated in vacuo and the residue wae partitioned between ethyl acetate and aqueous saturated sodium bicarbonate. The organic layer was separated, dried over sodiun sulfate and evaporated in vacuo. The residue was purified by preparative TLC and the obtained oil was
orystallized from diethyl ether to give 8-(2,6- dichlorobenzoylamino)-2-nethyl-3-(5-nethyl-1,2,4-oxadiazol-3- yl)nethylinidazo[1,2-a]pyridine (18 ng).
mp : 215-216°C
NMR (CDCl3, δ) : 2.49 (3H s), 2.53 (3H, s), 4.28 (2H, e), 6.87 (1H, t, J=8Hz), 7.28-7.40 (3H, m), 7.88 (1H, a, J=8Hz), 8.37 (1H, d, J=8Hz), 8.72 (1H, m)
Example 173
A. solution of 3-acetoxymethyl-8-(2,6- dichlorobenzoylamino)-2-methyIimidazo [1,2-a]pyridine (100 mg) in methanol (5 ml) was refluxed for 5 houre. The reaction mixture wae evaporated in vacuo and the residue was
orystallized from diethyl ether to give 8-(2,6- dichlorobenzoylaminc)-3-methoxymethyl-2-methylimiaazo- [1,2-a]pyridine (72 mg).
mp : 178-180°C
NMR (CDCl3, δ) : 2.45 (3H, s), 3.33 (3H, s), 4.72 (2H, s), 6.88 (1H, t, J=7Hz), 7.30-7.40 (3H, m), 7.90 (1H, d, J=7Hz), 8.40 (1H, d, J=7Hz), 8.69 (1H, br s)
Example 174
A mixture of 3-bromo-2-carbamoyl-8-(2,6- dichlorobenzoylamino) imidazo [1,2-a]pyridine (200 mg) and thionyl chloride (1 ml) in 1,4-dioxane was refluxed for 8 hours. The mixture was cooled and poured into a mixture of ice and water. The mixture wae neutralized with aqueous saturated sodiun bicarbonate and extracted with ethyl
acetate. The extract was washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was
orystallized from diethyl ether to give 3-bromo-2-cyano-8- (2,6-dichlorobenzoylamino) imidazo [1, 2-a]pyridine (33 mg).
mp : >250°C
NMR (CDCl3:CD3OD = 20:1, δ) : 7.20 (1H, t, J=8Hz),
7.35-7.46 (3H, m), 7.94 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz) Example 175
4-Hydroxypyridine (95 mg) was added to a suspension of sodium hydride (24 mg) in N,N-dimethylformamide (3 ml) at 4°C. The mixture was stirred at ambient temperature for 30 minutes and to the mixture was added cuprous oxide (108 mg) and 3-bromo-8-(2,6-dichlorobenzoyIanino)-2-methylimidazo- [1,2-a]pyridine (200 mg). The nixture was stirred at 100°C for 5 hours, cooled and poured into a mixture of ice and water. The separated oil was extracted with ethyl acetate and the extract was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil wae orystallized from diethyl ether to give 3-bromo-8-[2-chloro- 6-(pyridin-4-yl)oxybenzoylamino]-2-methylimidazo[1,2-a]- pyridine (110 mg).
mp : 177-178°C
NMR (CDCl3, δ) : 2.49 (3H, s), 6.66 (1H, d, J=7Hz),
6.90 (1H, d, J=7Hz), 7.00-7.10 (3H, m), 7.12 (1H, t, J=7Hz), 7.27 (1H, d, J=7Hz), 8.11 (1H, d,
J=7Hz), 8.38 (2H, d, J=5Hz)
The following comounds (Examples 176 to 177) were obtained according to a similar manner to that of
Preparation 22.
Example 176
8-(2,6-Dichlorobenzoylamino)-3-(1-hydroxy-1- methylethyl)-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 220-222°C
NMR (DMSO-d6, δ) : 1.68 (6H, s), 5.91 (1H, s), 7.09
(1H, t, J=7Hz), 7.45-7.60 (3H, m), 8.18 (1H, d, J=7Hz), 8.92 (1H, d, J=7Hz) Example 177
8-(2,6-Dichlorobenzoylamino)-3-(1-hydroxy-1- methylethyl)-2-methylimidazo[1,2-a]pyridine
mp : 248°C (dec.)
NMR (CDCl3:CD30D = 20:1, δ) : 1.77 (6H, s), 2.49 (3H, s), 6.81 (1H, t, J=8Hz), 7.31-7.43 (3H, m), 8.38 (1H, d, J=8Hz), 8.60 (1H, d, J=8Hz)
Example 178
A mixture of 3-[[N-(2-aminophenyl)]carbamoylmethyl]-8- (2,6-dichlorobenzoylamino)-2-methylimidazo[1,2-a]pyridine hydrochloride (120 mg) and 10% hydrogenchloride in methanol (0.3 ml) in ethanol (3 ml) was refluxed for 8 hours. After evaporation in vacuo, the obtained residue was orystallized from ethanol to give 3-[(1H-benzimidazol-2-yl)methyl]-8-(2,6- dichlorobenzoylamino)-2-methylimidazo[1,2-a]pyridine
dihydrochloride (34 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 2.55 (3H, s), 5.15 (2H, s), 7.41 (1H, m), 7.46-7.53 (2H, m), 7.53-7.64 (3H, m), 7.71
(2H, dd, J=3Hz and 8Hz), 8.60 (1H, m), 8.67 (1H, m)
Example 179
A mixture of 8-(2,6-dichlorobenzoylamino)-3- hydroxymethyl-2-trifluoromethylimidazo[1,2-a]pyridine (162 mg) and triethylsilane (464 mg) in trifluoroacetic acid (2 ml) was stirred at ambient temperature for 2 days. The reaction mixture was evaporated in vacuo and partitioned between dichloromethane and aqueous saturated sodium
bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was orystallized from a mixture of diethyl ether and diisopropyl ether to give 8-(2,6-dichlorobenzoylamino)-3- methyl-2-trifluoromethylimidazo [1,2-a] pyridine (84 mg). mp : 248-250°C
NMR (CDCl3, δ) : 2.62 (3H, s), 7.01 (1H, t, J=8Hz),
7.30-7.43 (3H, m), 7.71 (1H, d, J=8Hz), 8.48 (1H, d, J=8HZ), 8.75 (1H, br e)
Example 180
A mixture of 3-(4-carboxybutanoyloxymethyl)-8-(2,6- dichlorobenzoylanino)-2-trifluoromethylimidazo [1,2-a] pyridine (700 mg), disuccinimidyl carbonate (1.04 g) and pyridine (380 mg) in acetonitrile (50 ml) was etirred at ambient
temperature overnight. The reaction mixture was evaporated in vacuo. The residue was diseolved in ethyl acetate and the insoluble solid was filtered. The filtrate was washed with aqueous saturated sodium bicarbonate, dried over sodiun sulfate and evaporated in vacuo to give 8-(2,6- dichlorobenzoylanino)-3-(4-succinimidoxycarbonyl- butanoyloxymethyl)-2-trifluoromethylimidazo[1,2-a]pyridine (amorphous, 933 mg).
NMR (CDCl3, δ) : 2.08 (2H, quint., J=7Hz), 2.50 (2H, t, J=7Hz), 2.71 (2H, t, J=7Hz), 2.83 (4H, s), 5.57
(2H, s), 7.09 (1H, t, J=8Hz), 7.30-7.45 (3H, m), 8.05 (1H, d, J=8Hz), 8.57 (1H, d, J=8Hz), 8.72 (1H, br s) Example 181
A mixture of 8-(2,6-dichlorobenzoylamino)-3-(4- euccininidoxycarbonylbutanoyloxynethyl)-2- trifluoromethylimidazo [1,2-a] pyriaine (123 mg),
aminomethylenebis (phosphonic acid) (77 mg) and triethylamine (162 mg) in N,N-dimethylformamide (3 ml) and water (0.5 ml) was stirred at ambient temperature for 3 hours. To the mixture was added IN-hydrochloric acid (1.6 ml) and the mixture was evaporated in vacuo. Azeotropic evaporation of the residue with ethanol was repeated 3 times and the
reeidual gum wae waehed by decantation with hot ethyl acetate 3 times. The residue was solidified from diisopropyl ether, collected and washed with a small amount of water to give 4- [[8-(2,6-dichlorobenzoylamino)-2-trifluoromethylimidazo- [1,2-a]pyridin-1-yl]methoxycarbonyl]- butanoylaminomethylenebis (phosphonic acid) (25 mg)
NMR (DMSO-d6, δ) : 1.73 (2H, quint., J=7Hz), 2.21 - (2H, t, J=7Hz), 2.34 (2H, t, J=7Hz), 4.46 (1H, dt, J=9Hz and 20Hz), 5.57 (2H, s), 7.23 (1H, t, J=8Hz), 7.45- 7.60 (3H, m), 8.32 (1H, d, J=8Hz), 8.45 (1H, d, J=8Hz)
FAB-MASS : 691 (M+H)+, 713 (M+Na)+
Example 182
m-Chloroperbenzoic acid (55 mg) was added to a solution of 8-(2,6-dichlorobenzoylamino)-3-(1-methylimidazol-2- yl) thiomethyl-2-trifluoromethylimidazo [1,2-a] pyridine (102 mg) in dichloromethane (5 ml) at 4°C. The mixture was stirred at ambient temperature for 5 hours, washed with aqueous sodium thiosulfate (5%), aqueous saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel. The first fractions were evaporated in vacuo and the residue was orystallized from diethyl ether to give 8-(2,6- dichlorobenzoylamino)-3-(1-methylimidazol-2-yl)- sulfonylmethyl-2-trifluoromethylimidazo [1,2-a] pyridine (35 mg).
mp : 223-224°C
NMR (DMSO-d6, δ) : 3.74 (3H, s), 5.52 (2H, s), 7.13
(1H, s), 7.18 (1H, t, J=8Hz), 7.45-7.60 (4H, m),
8.32 (1H, d, J=8Hz), 8.40 (1H, d, J=8Hz)
The second fractions were evaporated in vacuo and the residue was orystallized from diethyl ether to give 8-(2,6- dichlorobenzoylamino)-3-(1-methylimidazol-2-yl)- sulfinylmethyl-2-trifluoromethylimidazo [1,2-a]pyridine mp : 194-195°C
NMR (DMSO-d6, δ) : 3.77 (3H, s), 5.12 (1H, d, J=15Hz), 5.38 (1H, d, J=15Hz), 7.15 (1H, s), 7.15 (1H, t, J=8Hz), 7.45 (1H, s), 7.45-7.60 (3H, m), 8.31 (1H, d, J=8Hz)-, 8.48 (1H, a, J=8Hz)
Example 183
A mixture of 8-(2,6-dichlorobenzoylamino)-2-methyl-3- nitroimidazo[1,2-a]pyridine (400 mg), iron (302 mg) and acetic acid (2 ml) in a mixture of tetrahydrofuran (4 ml) and ethanol (8 ml) wae refluxed for 2 houre. After filtration of insoluble materials, the obtained filtrate was evaporated with toluene in vacuo. The residue was partitioned between ethyl acetate and aσueous saturated sodium bicarbonate. The organic layer was separated, dried over sodium sulfate and evaporated in vacuo to give a orude solid. The solid was dissolved in hot methanol and the solution was filtered. The filtrate was treated with exceeeive 10% hydrogen chloride in methanol and evaporated in vacuo. The obtained solid was triturated with hot isopropyl alcohol to give 3-amino-8-(2,6- dichlorobenzoylamino)-2-methylimidazo[1,2-a]pyridine
hydrochloride (153 mg).
np : 262°C (dec.)
NMR (DMSO-d6, δ) : 5.43-5.72 (2H, m), 7.43 (1H, t,
J=8Hz), 7.52-7.64 (3H, m), 8.31 (1H, d, J=8Hz), 8.48 (1H, d, J=8Hz)
Example 184
A mixture of 3-acetyl-8-(2,6-dichlorobenzoylamino)-2- methylimidazo[1,2-a]pyridine (125 mg) and sodium borohydride in methanol (3 ml) was etirred at ambient temperature for 3 hours. To the reaction mixture was added water and the separated solid was collected and washed with water to give 8-(2,6-dichlorobenzoylamino)-3-(1-hydroxyethyl)-2- methylimidazo[1,2-a]pyridine (105 mg).
mp : 206-21C°C
NMR (CDCl3, δ) : 1.59 (3H, d, J=7Hz), 2.26 (3H, s),
3.27 (1H, br s), 5.32 (1H, q, J=7Hz), 6.80 (1H, t, J=7Hz), 7.20-7.35 (3H, m), 8.20 (1H, d, J=7Hz),
8.35 (1H, a, J=7Hz), 8.94 (1H, br s)
Example 185
Sodiun cyanoborohydride (183 ng) was added portionwise to a nixture of 3-(3-aninophenyl)-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine (150 mg) and 37% formaldehyde in water (522 ng) in
tetrahydrofuran (2 nl) and nethanol (1.5 ml) at ambient temperature with stirring. During the reaction period of 3 hours, the mixture was kept to pH 3 by addition of 1N- hydrochloric acid. A.fter brought to pH 2 with 1N- hydrochloric acid, the mixture was made alkaline with aqueous saturated sodium bicarbonate. The eeparated oil was
extracted with ethyl acetate and the extract was washed with aσueous saturated sodium bicarbonate and brine. The organic layer wae dried over sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on eilica gel and the obtained oil was orystallized from a mixture of ethanol and water to give 8-(2,6-dichlorobenzoylamino)-3-(3- dimethylaminophenyl)-2-trifluoromethylimidazo[1,2-a]pyridine (93 mg).
mp : 204-205°C
NMR (CDCl3, δ) : 3.00 (6H, s), 6.72-6.80 (2H, m),
6.84-6.93 (2H, m), 7.33-7.44 (4H, m), 7.80 (1H, d, J=8Hz), 8.50 (1H, d, J=8Hz), 8.82 (1H, br e)
Example 186
A mixture of 3-cyanomethyl-8-(2,6- dichlorobenzoylamino)imidazo[1,2-a]pyridine (773 mg) and IN aqueoue sodium hydroxide (5 ml) in ethanol (7 ml) was stirred for 6 hours at 90°C. After cooling to ambient temperature, the mixture was neutralized with IN-hydrochloric acid. The separated solid was collected and washed with water to give 3-carboxymethyl-8-(2,6-dichlorobenzoylamino)imidazo[1,2-a]- pyridine (451 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 4.04 (2H, s), 6.95 (1H, t, J=8Hz), 7.42-7.55 (4H, m), 8.10 (1H, d, J=8Hz), 8.12 (1H, d, J=8Hz),
ESI-MASS : 364 (M++1)
Example 187
Sodium cyanoborohydride (33 mg) was added portionwise to a mixture of 3-(3-aminophenyl)-8-(2,6-dichlorobenzoylamino)- 2-trifluoromethylimidazo[1,2-a]pyridine (150 mg) and 2- furaldehyde (34 mg) in methanol (3 ml) at ambient temperature with stirring. During the reaction period of 2 hours, the mixture was kept to pH 3 by addition of IN-hydrochloric acid. After brought to pH 2 with IN-hydrochloric acid, the residue was made alkaline with aqueous saturated . sodium bicarbonate. The separated oil was extracted with ethyl acetate and the extract was washed with aqueous saturated sodium bicarbonate. The organic layer was dried over sodium sulfate and
evaporated in vacuo. The residue was purified by column chromatography on silica gel and the obtained oil was
orystallized from a mixture of ethanol and water to give 8- (2,6-dichlorobenzoylamino)-3-[3-(furan-2- yl)methylamino]phenyl]-2-trifluoromethylimidazo[1,2- a]pyridine (141 mg).
mp : 211-213°C
NMR (CDCl3, δ) : 4.28 (1H, m), 4.36 (2H, d, J=7Hz),
6.26 (1H, d, J=3Hz), 6.37 (1H, d, J=3Hz), 6.72 (1H, m), 6.80-6.85 (2H, m), 6.90 (1H, t, J=8Hz), 7.31- 7.44 (5H, m), 7.73 (1H, d, J=8Hz), 8.50 (1H, d, J=8Hz), 8.81 (1H, br s) Example 188
Sodium hydride (60%, 48 mg) wae added to a eolution of 3-chloro-8-(2,6-dichlorobenzoylamino)-2-methylimidazo- [1,2-a]pyridine (354 mg) in N,N-dimethylformamide (7 ml). The mixture was stirred at ambient temperature for 30 minutes and methyl iodide (710 mg) was added to the mixture. After stirring at ambient temperature for 1 hour, the mixture was partitioned between dichloromethane and water. The organic layer was separated, waehed with water, dried over eodium sulfate ana evaporated in vacuo. The residue was dissolved in diethyl ether and the solution was extracted with IN- hydrochloric acid. The aqueous solution was neutralized with aqueous saturated eodium bicarbonate and extracted with dichloromethane. The extract wae dried over sodium sulfate and evaporated in vacuo. The residue was orystallized from a mixture of diethyl ether and hexane to give 3-chloro-8-[N- (2,6-dichIorobenzoyl)]methylamino-2-methylimidazo [1,2-a]- pyridine (217 mg).
mp : 138-139°C
The following compounds (Examples 189 to 194) were obtained according to a similar manner to that of Example 12.
Example 189
8-(2,6-Dichlorobenzoylamino)-2,3-dimethylimidazo- [1,2-a]pyridine hydrochloride
mp : >250°C
NMR (CDCl3, δ) : 2.50 (3H, s), 2.56 (3H, e), 7.25-7.45 (4H, m), 7.87 (1H, d, J=7Hz), 9.03 (1H, d, J=7Hz)
Example 190
8-(2-Chloro-6-methylbenzoylamino)-3-hydroxymethyl-2- trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 168-173°C
NMR (CDCl3:CD3OD = 9:1, δ) : 2.37 (3H, e), 4.99 (2H, e), 7.10-7.25 (4H, m), 8.28 (1H,- d, J=7Hz), 8.73 (1H, d, J=7Hz)
Example 191
8-(2,6-Dichlorobenzoylamino)-3-(1-hydroxy-1- methylethyl)-2-methylimidazo[1,2-a]pyridine hydrochloride mp : 248-250°C
NMR (DMSO-d6, δ) : 1.20 (6H, S), 2.58 (3H,S), 7.45
(1H, t, J=7Hz), 7.50-7.65 (3H, n), 8.63 (1H, d, J=7Hz), 9.00 (1H, a, J=7Hz)
Example 192
8-(2,6-Dichlorobenzoylanino)-3-(1-hydroxy-1- nethylethyl)-2-trifluoromethylimidazo[1,2-a]pyridine
hydrochloride
mp : 134-137°C
NMR (DMSO-d6, δ) : 1.68 (6H, e), 7.08 (1H, t, J=7Hz), 7.45-7.60 (3H, m), 8.18 (1H, d, J=7Hz), 8.91 (1H, d, J=7Hz)
Example 193
8-(2,6-Dichlorobenzoylamino)-3-methoxy-2- methylimidazo[1,2-a]pyridine hydrochloride
mp : 191-193°C
NMR (CDCl3, δ) : 2.60 (3H, m), 4.13 (3H, n), 7.28-7.41 (4H, m), 7.92 (1H, d, J=8Hz), 9.00(1H, d, J=8Hz)
Example 194
8-(2,6-Dichlorobenzoylamino)-3-(1-methylimidazol-2- yl)thionethyl-2-trifluoronethylinidazo[1,2-a]pyridine
hydrochloride
mp : 155-165°C
NMR (DMSO-d6, δ) : 3.69(3H, s), 4.83 (2H, s), 7.28 (1H, s), 7.45-7.57 (3H, m), 7.72 (1H, s), 7.87(1H, s), 8.88(1H, d, J=8Hz), 8.58 (1H, d, J=8Hz) Example 195
To a suspension of 8-(2,6-dichlorobenzoyIamino)-3- hydroxymethyl-2-trifluoromethylimidazo[1,2-a]pyridine (20.0 g) in dichloromethane (400 ml) was added thionyl chloride (7.2 ml) and pyridine (1 ml) dropwise. The nixture was stirred for two and half hours at ambient temperature. The reaction mixture was evaporated under reduced pressure and the reeidue wae diluted with toluene (200 ml) and evaporated under reduced preeeure three times. The residual solid was triturated with diethyl ether (200 ml) to give 3- chIoromethyl-8-(2,6-dichlorobenzoyiamino)-2-trifluoromethylimidazo [1,2-a] pyridine (20.4 g) as a pale yellow eoiid.
mp : 200-203°C
NMR (CDCl3, δ) : 5.05 (2H, s), 7.17 (3H, t, J=8Hz), 7.30-7.45 (3H, m), 7.98 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz), 8.73 (1H, e)
Exampie 196
To a solution of potassium cyanide (925 mg) in water (7 ml) was added acetonitrile (30 ml) and 3-chloromethyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo [1,2-a]pyridine (3.0 g). The mixture was stirred for 20 minutee at 45°C and then diluted with water (30 mi). The mixture wae etirred for 30 minutee in an ice bath and the precipitate was filtered and washed with water to give 3-cyanomethyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine (1.9 g).
mp : 210-213°C
NMR (CDCl3, δ) : 4.21 (2H, s), 7.19 (1H, t, J=8Hz), 7.32-7.47 (3H, m), 7.90 (1H, d, J=8Hz), 8.64 (1H, d, J=8Hz), 8.70 (1H, s)
The following compound was obtained according to a similar manner to that of Example 186. Example 197
3-Carboxymethyl-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : >250°C
NMR (DMSO-d6, δ) : 4.22 (2H, e), 7.16 (1H, t, J=8Hz), 7.44-7.58 (3H, m), 8.28 (1H, d, J=8Hz), 8.38 (1H, a, J=8Hz)
The following conpounds [Examples 198 to 212] were obtained according to a similar manner to that of Example 10.
Example 198
3-Carbamoylmethyl-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : >260°C
NMR (CDCl3, δ) : 4.01 (2H, s), 7.07 (1H, t, J=8Hz),
7.35-7.45 (3H, n), 8.00 (1H, d, J=8Hz), 8.58 (1H, d, J=8Hz) Example 199
3-(N-Cyanomethylcarbamoylmethyl)-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine mp : 248-251°C
NMR (CDCl3, δ) : 4.05 (2H, s), 4.12 (2H, s), 7.09 (1H, t, J=8Hz), 7.33-7.46 (3H, m), 8.01 (1H, d, J=8Hz),
8.60 (1H, d, J=8Hz)
Example 200
8-(2,6-Dichlorobenzoylamino)-3-[N-(2-hyaroxyethyl)- carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 239-241°C
NMR (CDCl3, δ) : 3.35 (2H, t, J=5Hz), 3.63 (2H, t,
J=5Hz), 4.00 (2H, s), 7.05 (1H, t, J=8Hz), 7.32- 7.45 (3H, m), 8.05 (1H, d, J=8Hz), 8.58 (1H, d, J=8Hz) ESI-MASS : 475 (M++1)
Example 201
8-(2,6-Dichlorobenzoylanino)-3-[N-(2-methoxyethyl)- carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 184-186°C
NMR (CDCl3, δ) : 3.31 (3H, s), 3.98 (2H, e), 5.98 (1H, br e), 7.05 (1H, t, J=8Hz), 7.32-7.45 (3H, m), 8.0i (1H, d, J=8Hz), 8.54 (1H, d, J=8Hz), 8.70 (1H, e) ESI-MASS : 489 (M++1)
Example 202
8-(2,6-Dichlorobenzoylamino)-3-[N-(pyridin-3-yl)- carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 236-238°C
NMR (DMSO-d6, δ) : 4.39 (2H, e), 7.14 (1H, t, J=8Hz), 7.30-7.40 (1H, m), 7.42-7.58 (3H, m), 8.01 (1H, d, J=8Hz), 8.24-8.32 (2H, m), 8.41 (1H, d, J=8Hz), 8.73 (1H, s)
Example 203
8-(2,6-Dichlorobenzoylamino)-3-[N-(2-aminopyridin-3-yl)- carbamoylmethyl]-2-trifluoromethylinidazo[1,2-a]pyridine
np : 240-243°C
NMR (CDCl3, δ) : 4.20 (2H, s), 6.72 (1H, dd, J=8Hz and
4Hz), 7.07 (1H, t, J=8Hz), 7.30-7.47 (3H, m), 7.57 (1H, a, J=8Hz), 7.95 (1H, a, J=8Hz), 8.10 (1H, d, J=8Hz), 8.60 (1H, d, J=8Hz)
ESI-MASS : 523.1 (M++1)
Exanple 204
8-(2,6-Dichlorobenzoylanino)-3-(N-furfurylcarbamoyl- methyl)-2-trifluoronethylinidazo[1,2-a]pyridine
mp : 180-183°C
NMR (CDCl3, δ) : 4.00 (2H, s), 4.41 (2H, d, J=6Hz), 5.91 (1H, br), 6.19 (1H, d, J=4Hz), 6.30 (1H, d, J=4Hz), 7.03 (1H, t, J=8Hz), 7.33 (1H, s), 7.34- 7.44 (3H, m), 8.05 (1H, d, J=8Hz), 8.54 (1H, d, J=8Hz), 8.73 (1H, s)
Example 205
8-(2,6-Dichlorobenzoylamino)-3-[N-[2-(imidazoI-4-yl)- ethyl]carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]- pyridine hydrochloride
mp : 180-190°C
NMR (DMSO-d6, δ) : 2.82 (2H, t, J=6Hz), 3.40 (2H, q, J=6Hz), 4.07 (2H, e), 7.12 (1H, t, J=8Hz), 7.44 (1H, e), 7.45-7.58 (3H, m), 8.22 (1H, d, J=8Hz), 8.26 (1H, d, J=8Hz), 8.76 (1H, t, J=6Hz), 9.01 (1H, e)
Example 206
8-(2,6-Dichlorobenzoylamino)-3-[N-(pyridin-2-yl)- carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 238-240°C
NMR (DMSO-d6, δ) : 4.48 (2H, s), 7.10-7.20 (2H, m),
7.46-7.57 (3H, m), 7.85 (1H, t, J=8Hz), 7.95 (1H, d, J=8Hz), 8.78 (1H, d, J=8Hz), 8.37 (1H, d,
J=8Hz), 8.42 (1H, d, J=8Hz)
Example 207
8-(2,6-Dichlorobenzoylamino)-3-[[N-(pyridin-2-yl)- methyl]carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]- pyridine hydrochloride
mp : >250°C
NMR (CDCl3, δ) : 4.09 (2H, s), 4.53 (2H, d, J=5Hz),
6.98-7.23 (4H, m), 7.29-7.45 (3H, m), 7.67 (1H, t, J=8Hz), 8.09 (1H, d, J=8Hz), 8.45-8.55 (2H, m), 8.74 (1H, s) ESI-MASS : 522 (M++1)
Example 208
8-(2,6-Dichlorobenzoylaminc)-3-[[N-(pyridin-3-yl)- methyl]carbamoyimethyl]-2-trifluoromethylimidazo[1,2-a]- pyridine hydrochloride
mp : 167-180°C
NMR (DMSO-d6, δ) : 4.21 (2H, e), 4.50 (2H, d, J=6Hz), 7.12 (1H, t, J=8Hz), 7.40-7.57 (3H, m), 8.05 (1H, t, J=8Hz), 8.25 (1H, d, J=8Hz), 8.37 (1H, d,
J=8Hz), 8.46 (1H, d, J=8Hz), 8.83 (1H, e), 9.12 (1H, s)
Example 209.
8-(2,6-Dichlorobenzoylamino)-3-[[N-(pyridin-4-yl)- methyl]carbamoylmethyl]-2-trifluoromethylinidazo[1,2-a]- pyridine hydrochloride
np : 175-200°C
NMR (DMSO-d6, δ) : 4.29 (2H, e), 4.59 (2H, d, J=6Hz), 7.14 (1H, t, J=8Hz), 7.45-7.58 (3H, m), 7.92 (2H, d, J=8Hz), 8.27 (2H, a, J=8Hz), 8.39 (2H, d,
J=8Hz), 8.89 (2H, d, J=8Hz), 9.19 (1H, s)
Example 210
8-(2 ,6-Dichlorobenzoylamino)-3-[[N-methyl-N-(pyridin-2- yl)methyl]carbamoylmethyl]-2-trifluoromethylimidazo[1,2-a]- pyridine hydrochloride
mp : 218-225°C
NMR (DMSO-d6, δ) : 2.88 (6/5H, e), 3.32 (9/5H, s),
4.48 (2H, s), 4.78 (6/5H, s), 4.92 (4/5H, s), 7.07-
7.21 (1H, m), 7.45-7.57 (3H, m), 7.63-7.70 (1H, m), 7.97 (1H, t, J=8Hz), 8.19-8.30 (2H, m), 8.34 (1H, d, J=8Hz), 8.73 (1H, d, J=8Hz) Example 211 8-(2,6-Dichlorobenzoylamino)-3-(morpholinocarbonyl- methyl)-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 256-257°C
NMR (CDCl3, δ) : 3.60-3.75 (8H, m), 4.13 (2H, s), 7.00 (1H, t, J=8Kz), 7.32-7.43 (3H, m), 8.02 (1H, d,
J=8Hz), 8.52 (1H, d, J=8Hz), 8.71 (1H, s) ESI-MASS : 501 (M++1)
Example 212
3-(N-Carbamoylmethyl-N-methylaminomethyl)-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine mp : 219-222°C
NMR (CDCl3, δ) : 2.38 (3H, s), 3.14 (2H, s), 4.05 (2H, s), 5.45 (1H, s), 6.40 (1H, s), 7.07 (1H, t,
J=8Hz), 7.30-7.44 (3H, m), 8.12 (1H, d, J=8Hz),
8.56 (1H, d, J=8Hz), 8.81 (1H, s)
Example 213
A mixture of 8-(2,6-dichlorobenzoylamino)-3-[N-(2- aminopyridin-3-yl)carbamoylmethyl]-2-trifluoromethylimidazo- [1,2-a]pyridine (60 mg) and methanesulfonic acid (12 mg) was dissolved in ethanol (1.2 ml) at 60°C. The resulting
solution was concentrated in vacuo and the obtained oil was orystallized from diethyl ether to give 8-(2,6-dichlorobenzoyiamino)-3-[N-(2-aminopyridin-3-yl)carbamoylmethyl]-2- trifluoromethylimidazo[1,2-a]pyriaine methanesulfonate (59 mg).
mp : 252-253°C
NMR (DMSO-d6, δ) : 2.34 (3H, e), 4.40 (2H, s), 6.90
(1H, t, J=8Hz), 7.16 (1H, t, J=8Hz), 7.46-7.56 (3H, m), 7.82-7.92 (3H, m), 8.02 (1H, d, J=8Hz), 8.28 (1H, d, J=8Hz), 8.40 (1H, d, J=8Hz), 10.04 (1H, s), 11.26 (1H, s) The following compound was obtained according to a similar manner to that of Example 213.
Example 214
8-(2,6-Dichlorobenzoylanino)-3-(imidazo[5,4-b]pyridin-2- yl)methyl-2-trifluoromethylinidazo[1,2-a]pyridine
nethaneeulfonate
np : 205-212°C
NMR (DMSO-d6, δ) : 5.01 (2K, s), 7.15 (1H, t, J=8Hz), 7.45-7.58 (4H, n), 8.25-8.33 (2H, n), 8.38 (1H, d, J=8Hz), 8.50 (1H, d, J=6Hz)
The following conpound was obtained according to a sinilar nanner to that of Example 7. Example 215
3-(N-Carboxymethyl-N-methylaminomethyl)-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimiaazo[1,2-a]pyridine NMR (DMSO-d6, δ) : 2.21 (3H, e), 3.32 (2H, s), 4.12
(2H, s), 7.15 (1H, t, J=8Hz), 7.45-7.57 (3H, m), 8.29 (1H, d, J=8Hz), 8.69 (1H, d, J=8Hz)
ESI-MASS : 473 (M++1)
The following compounds [Exanples 216 to 2261 were obtainea according to a sinilar nanner to that of Example
100.
Example 216
3-(N-Cyanomethyl-N-methylaminomethyl)-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine mp : 206-210°C
NMR (CDCl3, δ) : 2.47 (3H, e), 3.50 (2H, e), 4.08 (2H, s), 7.05 (1H, t, J=8Hz), 7.32-7.45 (3H, m), 8.02 (1H, d, J=8Hz), 8.57 (1H, d, J=8Hz), 8.73 (1H, s) ESI-MASS : 456 (M++1) Example 217
8-(2,6-Dichlorobenzoylamino)-3-[[N-(2-hydroxyethyl)-N- methyl]aminomethyl]-2-trifluoromethylimidazo[1,2-a]pyridine mp : 214-218 °C
NMR (CDCl3, δ) : 2.13 (1H, br), 2.28 (3H, e), 2.67
(2H, t, J=6Hz), 3.70 (2H, σ, J=6Hz), 4.02 (2H, e), 7.02 (1H, t, J=8Hz), 7.29-7.45 (3H, m), 8.13 (1H, d, J=8Hz), 8.55 (1H, d, J=8Hz), 8.80 (1H, s)
ESI-MASS : 461 (M++1)
Example 218
8-(2,6-Dichlorobenzoylamino)-3-(4-ethoxycarbonyl- piperazin-1-yl)methyl-2-trifluoromethylimidazo[1,2-a]pyridine mp : 213-216°C
NMR (CDCl3, δ) : 1.25 (3H, t, J=6Hz), 2.46 (4H, br s),
3.47 (4H, br s), 3.95 (2H, e), 4.14 (2H, q, J=6Hz), 7.01 (1H, t, J=8Hz), 7.32-7.44 (3H, m), 8.16 (1H, d, J=8Hz), 8.55 (1H, d, J=8Hz), 8.74 (1H, s) Example 219
8-(2,6-Dichlorobenzoylaminc)-3-[[N-(2-hydroxyethyl)-N- methylamino]methyl]-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 238-240°C
NMR (DMSO-d6, δ) : 2.79 (3H, br) , 3.43 (4H, br) , 3.35
(2H, br), 7.29 (1H, t, J=8Hz), 7.47-7.60 (3H, m), 8.39 (1H, d, J=8Kz), 8.65 (1H, d, J=8Hz) ESI-MASS : 461 (M++1) Example 220
8-(2,6-Dichlorobenzoylamino)-3-[[N-[2-(N',N'- dimethylamino)ethyl]-N-methylamino]methyl]-2- trifluoronethylinidazo[1,2-a]pyridine dihydrochloride
np : 168-175°C
NMR (DMSO-d6, δ) : 3.33-4.00 (15H, br), 7.70 (1H, t, J=8Hz), 7 . 58-7 . 95 ( 3H, m), 8 . 35 ( 1H, d, J=8Hz), 8 .50-8 . 70 ( 1H, br)
Example 221
8-(2,6-Dichlorobenzoylamino)-3-[[N-(pyridin-2-yl)methyl- N-methylamino]methyl]-2-trifluoromethylimidazo[1,2-a]pyridine dihydrochloride
mp : 169-174°C
NMR (DMSO-d6, δ) : 2.70 (3H, s), 4.62 (2H, s), 4.82 (2H, s), 7.30 (1H, t, J=8Hz), 7.45-7.67 (6H, m),
8.05 (1H, t, J=8Hz), 8.66-8.75(2H, m), 8.88
(1H, d, J=8Hz)
ESI-MASS : 508 (M++1) Example 222
3-[N,N-bis(2-Hydroxyethyl)aminomethyl]-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 195-198°C
NMR (DMSO-d6, δ) : 3.10-3.70 (4H, br) , 3.82 (4H, br),
5.01 (2H, br), 7.30 (1H, t, J=8Hz), 7.47-7.60 (3H, m), 8.40 (1H, d, J=8Hz), 8.64 (1H, d, J=8Hz)
ESI-MASS : 491 (M++1) Example 223
8-(2,6-Dichlorobenzoylamino)-3-(4-hydroxypiperidin-1- yl)methyl-2-trifluoromethylimidazo[1,2-a]pyridine
hydrochloride
mp : 198-205°C
NMR (DMSO-d6, δ) : 1.60-2.05 (3H, m), 3.05-3.70 (6H, m), 4.75-4.92 (2H, m), 7.28 (1H, t, J=8Hz), 7.47- 7.58 (3H, m), 8.39 (2H, d, J=8Hz), 8.78 (1H, t, J=8Hz)
ESI-MASS : 487 (M++1) Example 224
3-(4-Acetylpiperazin-1-yl)methyl-8-(2,6-dichlorobenzoyl- amino)-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride mp : 230-232°C
NMR (DMSO-d6, δ) : 2.02 (3H, s), 3.40-3.75 (10H, br), 7.25 (1H, t, J=8Hz), 7.45-7.58 (3H, m), 8.37 (1H, d, J=8Hz), 8.67 (1H, br)
ESI-MASS : 514 (M++1) Example 225
8-(2,6-Dichlorobenzoylamino)-3-[2-(imidazol-1-yl)ethyl]- 2-methylimiaazo[1,2-a]pyridine
mp : >250°C
NMR (DMSO-d6, δ) : 2.03 (3H, e), 3.33 (2H, t, J=6Hz), 4.18 (2H, t, J=6Hz), 6.83 (1H, s), 6.88 (1H, t,
J=7Hz), 7.10 (1H, s), 7.41 (1H, s), 7.42-7.53 (3H, m), 8.05 (1H, d, J=7Hz), 8.12 (1H, d, J=7Hz)
Example 226
8-(2,6-Dichlorobenzoylamino)-3-[2-(imidazol-1-yl)ethyl]- 2-trifluoromethylimidazo[1,2-a]pyridine
mp : 252-254°C
NMR (DMSO-d6, δ) : 3.54 (2H, t, J=6Hz), 4.26 (2H, t,
J=6Hz), 6.81 (1H, s), 7.05-7.12 (2H, m), 7.43-7.57 (4H, m), 8.21-8.28 (2H, m)
Example 227
A mixture of 8-(2,6-dichlorobenzoylamino)-3-formyl-2- trifluoromethylimidazo [1, 2-a]pyridine (200 mg) and 2- aminoethanol (33 mg) in ethanol (4 ml) was refluxed for 10 houre. The reaction nixture wae cooled to ambient
temperature and the precipitate wae filtered and washed with ethanol (3 ml) to give (EZ)-8-(2,6-dichlorobenzoylamino)-3- [N-(2-hydroxyethyl)iminomethyl]-2-trifluoromethylimidazo- [1,2-a]pyridine (198 mg). mp : 236-238°C
NMR (CDCl3, δ) : 2.00 (1H, t, J=6Hz), 3.85 (2H, t,
J=6Hz), 3.92-4.00 (2H, m), 7.13 (1H, t, J=8Hz), 7.33-7.43 (3H, m), 8.68 (1H, d, J=8Hz), 8.71 (1H, s), 8.92 (1H, s), 9.55 (1H, d, J=8Hz)
Example 228
A mixture of (EZ)-8-(2,6-dichlorobenzoylamino)-3-[N-(2- hydroxyethyl)iminomethyl]-2-trifluoromethylimidazo[1,2-a]- pyridine (180 mg) and sodium cyanoborohydride in
dichloromethane (2 ml) and methanol (1 ml) was stirred overnight at ambient temperature. The reaction mixture was evaporated under reduced pressure. The residue was diluted with dichloromethane (10 ml) and washed with water (5 ml). The organic layer was dried over sodium sulfate and
evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel with 1% methanol in dichloromethane (V/V) as an eluent. The obtained product was treated with hydrogen chloride in ethanol (7N, 1 ml). The precipitate was filtered and washed with ethanol to give 8-(2,6-dichlorobenzoylamino)-3-[N-(2-hydroxyethyl)- aminomethyl]-2-trifluromethylimidazo[1,2-a]pyridine
hydrochloride (75 mg).
mp : 244-246°C
NMR (DMSO-d6, δ) : 3.14 (2H, br t, J=6Hz), 3.73 (2H, br), 4.75 (2H, s), 5.32 (1H, br), 7.27 (1H, t, J=8Hz), 7.46-7.58 (3H, m), 8.36 (1H, d, J=8Hz), 8.66 (1H, d, J=8Hz), 9.26 (1H, br) The following compound was obtained according to a similar manner to that of Examples 227 and 228.
Example 229
8-(2,6-Dichlorobenzoylamino)-3-[N-(2-hydroxyethyl)- aminomethyl]-2-trifluoromethylimidazo[1,2-a]pyridine mp : 213-215°C
NMR (CDCl3, δ) : 2.82 (2H, t, J=5Hz), 3.69 (2H, t,
J=5Hz), 4.28 (2H, s), 7.01 (1H, t, J=8Hz), 7.32- 7.43 (3H, m), 8.15 (1H, a, J=8Hz), 8.53 (1H, a, J=8Hz), 8.78 (1H, e)
Example 230
To a mixture of 8-(2,6-dichlorobenzoylamino)-3-[[N-(2- hydroxyethyl)-N-methylaminojmethyl]-2-trifluoromethylimidazo- [1,2-a]pyriaine (140 mg) and carbon tetrabromide (121 mg) in dichloromethane (5 nl) was added triphenylphosphine (119 ng) portionwise and the mixture was stirred for 30 minutes at ambient temperature. The reaction mixture was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel with 20% ethyl acetate in n-hexane (V/V) as an eluent. The fractione containing product were evaporated under reduced pressure. The residue was orystallized spontaneously and the orystal was triturated with diisopropyl ether to give 3-[[N-(2-bromoethyl)-N- methyl]aminomethyl]-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine (144 mg).
mp : 182-184°C
NMR (CDCl3, δ) : 2.25 (3H, s), 2.90 (2H, t, J=6Hz),
3.47 (2H, t, J=6Hz), 4.00 (2H, s), 7.00 (1H, t, J=8Hz), 7.30-7.45 (3H, m), 8.36 (1H, d, J=8Hz),
8.54 (1H, a, J=8Hz), 8.70 (1H, s)
The following compound was obtained according to a similar manner to that of Example 230.
Example 231
3-(2-Bromoethyl)-8-(2,6-dichlorobenzoyIanino)-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 170-171°C
NMR (CDC1-5, δ) : 3.52-3.70 (4H, m), 7.04 (1H, t, J=7Hz), 7 . 30-7 . 43 ( 3H, m), 7 . 90 ( 1H, d, J=7Hz), 8 . 52 ( 1H, d, J=7Hz), 8 . 71 ( 1H, br s )
Example 232
A mixture of 3-[[N-(2-bromoethyl)-N-methyl]aminomethyl]- 8-(2,6-dichlorobenzoylamino)-2-trifluoromethylimidazo [1,2-a]- pyridine (100 mg), 2-mercaptoimidazole (23 mg), potassium carbonate (53 mg) and potassium iodide (63 mg) in N,N- dimethylformamide (1 ml) was stirred for 1.5 hours at ambient temperature. The reaction mixture was partitioned between ethyl acetate and water and the organic layer was washed with water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was treated with hydrogen. chloride in ethanol (7N, 1 ml) and evaporated. The residue was orystallized spontaneously and triturated with ethyl acetate to give 8-(2,6-dichlorobenzoylamino)-3- [[N-[2-(imidazol-2-yl)thioethyl]-N-methylamino]methyl]-2- trifluoromethylimidazo[1,2-a]pyridine dihydrochloride (91 mg).
mp : 231-233°C
NMR (DMSO-d6, δ) : 2.65 (3H, s), 3.39 (2H, br), 3.74
(2H, br), 4.70 (2H, br), 7.25 (1H, t, J=8Hz), 7.47- 7.57 (3H, m), 7.72 (2H, s), 8.38 (1H, d, J=8Hz), 8.65 (1H, d, J=8Hz)
The following compounds [Examples 233 to 2381 were obtained according to a similar manner to that of Example 232.' Example 233
8-(2,6-Dichlorobenzoylamino)-3-(pyridin-2-yl)thiomethyl- 2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 186-188°C
NMR (DMSO-d6, δ) : 5.02 (2H, s), 7.16-7.23 (2H, m),
7.35 (1H, d, J=8Hz), 7.45-7.57 (3H, m), 7.65-7.72 (1H, m), 8.30 (1H, a, J=8Hz)~, 8.-47 (1H, d, J=8Hz), 8.51 (1H, dd, J=6 and 2Hz)
ESI-MASS : 497 (M++1) Example 234
8-(2,6-Dichlorobenzoylamino)-3-(pyridin-4-yl)thiomethyl- 2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : >210°C
NMR (DMSO-d6, δ) : 5.18 (1H, s), 7.27 (1H, t, J=8Hz), 7.46-7.58 (3H, m), 7.90-7.96 (2H, m), 8.36 (1H, d,
J=8Hz), 8.55 (1H, d, J=8Hz), 8.70 (2H, d, J=6Hz) ESI-MASS : 497 (M++1)
Example 235
3-(BenzimidazoI-2-yl)thiomethyl-8-(2,6-dichlorobenzoyl- amino)-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride mp : >250°C
NMR (DMSO-d6, δ) : 5.13 (2H, s), 7.24 (1H, t, J=8Hz),
7.33 (2H, m), 7.42-7.56 (3H, m), 7.61 (2H, m), 8.32 (1H, d, J=8Hz), 8.61 (1H, d, J=8Hz)
Example 236
8-(2,6-Dichlorobenzoylamino)-3-(imidazo[5,4-b]pyridin-2- yl)thiomethyl-2-trifluoromethylimidazo[1,2-a]pyridine
hydrochloride
np : >250°C
NMR (DMSO-d6, δ) : 5.22 (2H, s), 7.25 (1H, t, J=8Hz), 7.37-7.57 (4H, m), 8.18 (1H, d, J=8Hz), 8.33 (1H, d, J=8Hz), 8.41 (1H, d, J=5Hz), 8.60 (1H, d, J=8Hz) ESI-MASS : 537 (M++1)
Example 237
8-(2,6-Dichlorobenzoylamino)-3-(imidazol-2-yl)thio-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 147-151°C NMR (DMSO-d6, δ) : 6.90 (1H, br), 7.-15 (1H, br), 7.30 (1H, d, J=8Hz), 7.45-7.58 (3H, m), 8.40 (1H, a, J=8Hz), 8.52 (1H, d, J=8Hz) Example 238
8-(2,6-Dichlorobenzoylamino)-3-[2-(imidazol-2- yl)thioethyl]-2-trifluoromethylimidazo[1,2-a]pyridine
mp : 123-127°C
NMR (DMSO-d6, δ) : 3.24 (2H, t, J=7Hz), 3.48 (2H, t, J=7Hz), 7.02 (1H, br s), 7.13 (1H, t, J=7Hz), 7.20
(1H, br s), 7.43-7.58 (3H, m), 8.26 (1H, d, J=7Hz), 8.56 (1H, d, J=7Hz)
Example 239
To a solution of sodium sulfide (136 mg) in
N,N-dimethylformamide (2 ml) was added 3-chloromethyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine (200 mg) portionwise and the mixture was stirred for 2 hours at ambient temperature. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The reeidue wae oryetallized
spontaneously and the orystal was triturated with diisopropyl ether to give 8-(2,6-dichlorobenzoylamino)-3-mercaptomethyl- 2-trifluoromethylimidazo[1,2-a]pyridine (186 mg).
mp : 163-173°C
NMR (CDCl3, δ) : 4.23 (2H, s), 7.01 (1H, t, J=8Hz),
7.30-7.46 (3H, m), 7.65 (1H, d, J=8Hz), 8.57 (1H, d, J=8Hz), 8.75 (1H, e)
Example 240
A mixture of 3-chloromethyI-8-(2,6-dichlorobenzoyl- amino)-2-trifluoromethylimidazo[1,2-a]pyridine (127 mg) and thiourea (29.7 mg) in ethanol (2 ml) was stirred at ambient temperature for 2 houre. The mixture was evaporated in vacuo and the residue was orystallized from ethyl acetate to give 3-(amidinothiomethyl)-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine hydrochloride (116 mg) mp : 215-218°C
NMR (DMSO-d6, δ) : 5.17 (1H, s), 7.29 (1H, t, J=8Hz), 7.45-7.60 (3H, m), 8.36 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz), 9.45 (4H, m)
The following compounds [Examoles 241 to 2451 were obtained according to a similar manner to that of Example 12
Example 241
8-(2,6-Dichlorobenzoylamino)-3-(imidazol-2-yl)thio-2- trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 7.35 (1H, t, J=8Hz), 7.45-7.60 (5H, m), 8.49 (1H, d, J=8Hz), 8.58 (1H, d, J=8Hz)
Example 242
8-(2,6-Dichlorobenzoylamino)-3-[2-(imidazol-2- yl)thioethyl]-2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : 160-170°C
NMR (DMSO-d6, δ) : 3.46 (2H, t, J=7Hz), 3.61 (2H, t, J=7Hz), 7.18 (1H, t, J=7Hz), 7.44-7.58 (3H, m),
7.72 (2H, s), 8.28 (1H, d, J=7Hz), 8.42 (1H, d, J=7Hz)
Example 243
8-(2,6-Dichlorobenzoylanino)-3-[2-(imidazol-1-yl)ethyl]- 2-methylimidazo[1,2-a]pyridine dihydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 2.09 (3H, s), 3.58 (2H, t, J=6Hz),
4.45 (2H, t, J=6Hz), 7.45-7.62 (5H, m), 7.69 (1H, s), 7.85 (1H, e), 8.65-8.80 (2H, m), 9.08 (1H, e) Example 244
8-(2,6-Dichlorobenzoylamino)-3-[2-(imidazol-1-yl)ethyl]- 2-trifluoromethylimidazo[1,2-a]pyridine hydrochloride
mp : >250°C
NMR (DMSO-d6, δ) : 3.68 (2H, t, J=6Hz), 4.49 (2H, t, J=6Hz), 7.20 (1H, t, J=7Hz), 7.43-7.58 (3H, m), 7.67 (1H, s), 7.78 (1H, s), 8.33 (1H, d, J=7Hz),
8.51 (1H, d, J=7Hz), 9.05 (1H, s) Example 245
8-(2,6-Dichlorobenzoylamino)-3-(2-hydroxy-2- methylpropyl)-2-methylimidazo[1,2-a]pyridine hydrochloride mp : >250°C
NMR (DMSO-d6, δ) : 1.20 (6H, s), 2.47 (3H, s), 3.10 (2H, s), 7.42 (1H, t, J=7Hz), 7.50-7.65 (3H, m),
8.59 (1H, d, J=7Hz), 8.71 (1H, d, J=7Hz)
Example 246
To a solution of 8-(2,6-dichlorobenzoylamino)-3- (imidazol-2-yl)thio-2-trifluoromethylimidazo[1,2-a]pyridine (118 mg) in dichloromethane (2 ml) was added
m-chloroperbenzoic acid and the mixture was stirred at ambient temperature for 2 hours . The resulting mixture was purified by column chromatography on silica gel and the less polar fractions were combined and evaporated in vacuo. The obtained oil was orystallized from diethyl ether to give 8- (2,6-dichlorobenzoylamino)-3-(imidazol-2-yl)sulfonyl-2- trifluoromethylimidazo[1,2-a]pyridine (8.5 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 7.39 (2H, br), 7.45-7.60 (4H, m),
8.52 (1H, d, J=8Hz), 8.96 (1H, d, J=8Hz)
The more polar fraction was combined and concentrated in vacuo. The residual oil was orystallized from diethyl ether to give 8-(2,6-dichlorobenzoylamino)-3-(imidazol-2- yl)sulfinyl-2-trifluoromethylimidazo[1,2-a]pyridine (75 mg). mp : 236-239°C
NMR (DMSO-d6, δ) : 7.25-7.40 (3H, m), 7.45-7.60 (3H, m), 8.47 (1H, d, J=8Hz), 8.62 (1H, d, J=8Hz)
Example 247
To a suspension of sodium borohydride (26 mg) in tetrahydrofuran (1.5 ml) at 0°C was added boron trifluoride diethyl etherate (0.11 ml) and stirred for 30 minutes at the same temperature. To the mixture was added 3-carboxymethyl- 8-(2,6-dichlorobenzoylamino)-2-trifluoromethylimidazo- [1,2-a]pyridine (150 mg) and the mixture was stirred for 30 minutes at the same temperature and 2 days at ambient temperature. To the mixture was added methanol (0.5 ml) and IN-hydrochloric acid (2 ml) and the mixture was stirred for 1 hour at 60°C. The mixture was extracted with ethyl acetate and the extract was dried over sodium sulfate and evaporated under reduced pressure. The residue was orystallized from diisopropyl ether to give 8-(2,6-dichlorobenzoylamino)-3-(2- hydroxyethyl)-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine (113 mg).
mp : 174-176°C
NMR (CDCl3, δ) : 1.88 (1H, t, J=5Hz), 3.31 (2H, t,
J=5Hz), 3.95 (2H, q, J=5Hz), 6.99 (1H, t," J=8Hz), 7.30-7.43 (3H, m), 8.01 (1H, d, J=8Hz), 8.49 (1H, d, J=8Hz), 8.83 (1H, s)
The following compound was obtained according to a similar manner to that of Example 247.
Example 248
8-(2,6-Dichlorobenzoylamino)-3-(2-hydroxyethyl)-2- methylimidazo[1,2-a]pyridine
mp : 214-216°C
NMR (DMSO-d6, δ) : 3.04 (2H, t, J=6Hz), 3.60 (2H, q. J=6Hz), 4.75 (1H, ,t, J=6Hz), 6.87 (1H, t, J=7Hz), 7.40-7.55 (3H, m), 8.01 (1H, d, J=7Hz), 8.12 (1H, d, J=8Hz) Example 249
To a solution of sodium ethoxide (36 mg) in ethanol (2 ml) was added ethyl acetoacetate (69 mg) and then 3- chloromethyl-8-(2,6-dichlorobenzoylamino)-2- trifluoromethylimidazo[1,2-a]pyridine (150 mg) and the mixture was stirred for 3 hours at 50°C. The pH of mixture was adjusted to 3-4 with IN-hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was evaporated under reduced pressure. The residue and hydrazine monohydrate (34 mg) was dissolved in isopropanol (1 ml) and the mixture was refluxed overnight. The mixture was evaporated under reduced pressure and the residue was orystallized from diethyl ether to give 8-(2,6-dichlorobenzoylamino)-3-(5- hydroxy-3-methylpyrazol-4-yl)methyl-2- trifluoromethylimidazo[1,2-a]pyridine (75 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 1.91 (3H, s), 2.09 (1H, s), 4.05 (2H, s), 7.09 (1H, t, J=8Hz), 7.45-7.55 (3H, m), 8.15-8.25 (2H, m) Example 250
To a suspension of 3-carboxymethyl-8-(2,6- dichlorobenzoylamino)-2-trifluoromethylimidazo[1,2-a]pyridine (200 mg) in dichloromethane (2 ml) was added oxalyl chloride (81 μl) and N,N-dimethylformamide (1 drop). The mixture was stirred for 1 hour at ambient temperature and then evaporated under reduced pressure. The residue was dissolved in
dichloromethane (2 ml). To the solution was added
acetylhydrazine and the mixture was stirred for 2 hours at ambient temperature. The precipitate was filtered and waehed with water. The obtained solid was suspended in phosphorus oxychloride (1.5 ml) and refluxed for 5 hours. The reaction mixture was evaporated under reduced preesure. The residue was poured into ice-water and neutralized with aσueous sodium hydrogen carbonate. The aqueous suspension was extracted with ethyl acetate and extract was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel with ethyl acetate as eluent. The fractions containing product were evaporated under reduced preeeure. The reeidue wae orystallized from isopropyl ether to give 8-(2,6- dichlorobenzoylamino)-3-(2-methyl-1,3,4-oxadiazol-5- yl)methyl-2-trifluoromethylimidazo[1,2-a]pyridine (83 mg). mp : 210-213°C
NMR (CDCl3, δ) : 2.49 (3H, s), 4.66 (2H, e), 7.05 (1H, t, J=8Hz), 7.32-7.43 (3H, m), 8.02 (1H, d, J=8Hz),
8.55 (1H, d, J=8Hz), 8.69 (1H, s)
Example 251
A solution of 8-(2,6-dichlorobenzoylamino)-3-[N-(2- aminopyridin-3-yl)carbamoylmethyl]-2-trifluoromethylimidazo- [1,2-a]pyridine (100 mg) in acetic acid (1 ml) was refluxed overnight. The mixture was evaporated under reduced
pressure. The residue was orystallized from dichloromethane to give 8-(2,6-dichlorobenzoylamino)-3-(imidazo[5,4-b]- pyridine-2-yl)methyl-2-trifluoromethylimidazo[1,2-a]pyridine (72 mg).
mp : >250°C
NMR (DMSO-d6, δ) : 4.85 (2H, s), 7.10-7.20 (2H, m),
7.47-7.58 (3H, m), 7.87 (1H, d, J=8Hz), 8.23-8.38 (3H, m), 11.30 (1H, s)
Example 252
To a etirred mixture of 8-(2,6-dichlorobenzoylamino)-3- (2-hydroxyethyl)-2-methylimidazo [1,2-a] pyridine (1.00 g) and N-bromosuccinimide (588 mg) in dichloromethane (20 ml) was added triphenylphosphine (792 mg) in dichloromethane (2 ml) dropwise in an ice bath and the reeulting mixture wae stirred at ambient temperature for 1 hour. The mixture was purified by column chronatography on silica gel and the obtained oil was orystallized fron diethyl ether to give 3-(2-bromoethyl)- 8-(2,6-dichIorobenzoylanino)-2-methylimidazo[1,2-a]pyridine (640 mg).
mp : 208-210°C
NMR (CDCl3, δ) : 3.40-3.60 (4H, n), 6.88 (1H, t,
J=7Hz), 7.28-7.42 (3H, n), 7.72 (1H, d, J=7Hz),
8.35 (1H, d, J=7Hz), 8.71 (1H, br s)
Example 253
Thionyl chloride (377 mg) was added to methanol (10 ml) dropwise at -70°C and to the mixture was added
3-carboxymethyl-8-(2,6-dichlorobenzoylamino)-2- methylimidazo [1,2-a]pyridine (400 mg). The mixture was stirred for 10 minutes and allowed to warm to ambient
temperature gradually. Then, the mixture was refluxed for 2 hours, allowed to cool to ambient temperature and partitioned between dichloromethane and aqueous saturated sodium
bicarbonate. The organic layer was separated, washed with brine, dried and evaporated in vacuo. The orystailine residue was triturated with diisopropyl ether to give 8-(2,6- dichlorobenzoylamino)-3-methoxycarbonylmethyl-2- methylimidazo[1,2-a]pyridine (360 mg).
mp : 172-173°C
NMR (DMSO-d6, δ) : 2.31 (3H, s), 3.63 (3H, s), 4.12
(2H, s), 6.90 (1H, t, J=7Hz), 7.41-7.55 (3H, m), 8.02-8.10 (2H, m)
The following compound wae obtained according to a sinilar manner to that of Example 253. Example 254 8-(2,6-Dichlorobenzoylamino)-3-methoxycarbonylmethyl-2- trifluoromethylimidazo[1,2-a]pyridine
mp : 168-169°C
NMR (CDCl3, δ) : 3.72 (3H, s), 4.09 (2H, s), 7.03 (1H, t, J=7Hz), 7.30-7.43 (3H, m), 7.82 (1H, d, J=7Hz),
8.53 (1H, d, J=7Hz), 8.70 (1H, br e)
The following compounde [Examples 255 to 2561 were obtained according to a similar manner to that of Preparaτion 22.
Example 255
8-(2,6-Dichlorobenzoylamino)-3-(2-hydroxy-2- methylpropyl)-2-methylimidazo[1,2-a]pyridine
mp : 245-246°C
NMR (DMSO-d6, δ) : 1.14 (6H, s), 2.31 (3H, e), 2.95
(2H, e), 4.48 (1H, s), 6.80 (1H, t, J=7Hz), 7.42- 7.57 (3H, m), 8.00 (1H, d, J=7Hz), 8.23 (1H, d, J=7Hz)
Example 256
8-(2,6-Dichlorobenzoylanino)-3-(2-hyaroxy-2- nethylpropyl)-2-trifluoronethylinidazo[1,2-a]pyridine
no : 213-215°C
NMR (CDCl3, δ) : 1.35 (6H, s), 1.42 (1H, s), 3.21 (2H, s), 6.91 (1H, t, J=7Hz), 7.30-7.42 (3H, n), 8.22 (1H, d, J=7Hz), 8.46 (1H, d, J=7Hz), 8.75 (1H, s)
Example 257
A. solution of 3-chloromethyl-8-(2,6- dichlorobenzoylanino)-2-trifluoronethylinidazo[1,2-a]pyridine (200 mg) m triethylphosphite (0.5 nl) was stirred for 7 houre at 100°C. The reaction nixture was diluted with toluene (3 ml) and evaporated under reduced preseure. The reeidue was orystallized spontaneously and the orystal wae triturated with diethyl ether to give 8- (2, 6- dichlorobenzoylamino)-3-diethoxyphosphorylmethyl-2- trifluoromethylimidazo[1,2-a]pyriaine (110 mg).
mp : 193-196°C
NMR (CDCI3, δ) : 1.28 (6H, t, J=6Hz), 3.61 (2H, a, J=20Hz), 4.69 (4H, quint., J=6Hz), 7.04 (1H, t, J=8Hz), 7.32-7.43 (3H, m), 8.05 (1H, a, J=8Hz), 8.53 (1H, d, J=8Hz), 8.72 (1H, s)

Claims

C L A I M S
1 . A compound of the formula :
Figure imgf000165_0001
wherein
R1 is hydrogen, lower alkyl, an acyl group, amino, acylamino, nitro, halogen or hydroxy (lower) alkyl which may have one or more suitable substituent (s),
R2 is hydrogen, lower alkyl, an acyl group, lower alkoxy, acyl (lower) alkyl, aryl, cyano, mono- (or di- or tri-)- halo (lower) alkyl, lower alkylthio or hydroxy (lower) alkyl which may have one or more suitable substituent (s),
R3 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cyclo (lower) alkyl (lower) alkyl, halogen, an acyl group, acyl (lower) alkyl, acylamino,
acylamino (lower) alkyl, acyl (lower) alkenyl,
acyloxy (lower) alkyl, acyl (lower) alkylthio (lower) alkyl, amino (lower) alkyl, mono- (or di-) lower alkylamino, lower alkylthio (lower) alkyl, hydroxyimino (lower) alkyl which nay have one or nore suitable substituent (s),
hydroxy (lower) alkyl which nay have one or nore suitable substituent (s), hydroxy (lower) alkylthio (lower) alkyl, cyano (lower) alkyl, nono- (or di-) lower alkoxy (lower) alkyl which nay have one or nore euitable substituent (s), lower alkyl substituted with aryl which nay have one or more suitable substituent (s), mono- (or di-) lower alkylamino (lower) alkyl, tri (lower) alkylammonio (lower)- alkyl, lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), hydrazino (lower) alkyl which may have one or more suitable substituent (s), mono- or di- (lower) alkoxy (lower) alkylamino (lower) alkyl,
(lower) alkylamino (lower) alkyl which may have one or more suitable substituent (s), heterocyclic group which may have one or more euitable substituent (s),
heterocyclicthio, heterocyclicthio (lower) alkyl which may have one or more suitable substituent (s),
heterocyclicoxy, heterocyclicoxy (lower) alkyl,
heterocyclicaminoimino (lower) alkyl, aryl which may have one or more suitable substituent (s), amino, nitro, halo (lower) alkyl, hydroxy (lower) alkylimino (lower) alkyl, hydroxy (lower) alkylamino (lower) alkyl,
bis- [hydroxy (lower) alkyl] amino (lower) alkyl,
mercapto (lower) alkyl or amidinothio (lower) alkyl, in which R2 and R3 may be linked together to form
(1) lower alkylene which may have one or more suitable
substituent (s),
(2) lower alkenylene which may have one or more suitable
substituent (s), or
(3) a group of the formula :
Figure imgf000166_0001
[wherein A1 and A2 are each lower alkylene which may have one or more suitable substituent (s) or lower alkenylene which may have one or more suitable substituent (s), W is -S-, -
Figure imgf000167_0001
(wherein R4 is hydrogen,
lower alkyl or an acyl group) and
m and n are each an integer of 0 or 1],
X is vinylene, or a group of the formula :
-NHCO-, -NHSO2-, -OCO-, -OCH2-, -NHCOCO-,
-NHCOCH=CH-, -NHCOCH,-, -NHCONH- or
Figure imgf000167_0002
(wherein R5 is lower alkyl),
Y is heterocyclic group which nay have one or nore suitable substituent (s), or aryl which may have one or more suitable substituent (s),
Q is CH or N, and
l is an integer of 0 or 1,
and a pharmaceutically acceptable ealt thereof.
2. A compound of claim 1, wherein
R1 is hydrogen,
R2 is hyarogen, lower alkyl, an acyl group, aryl, cyano or mono- (or di- or tri-) halo (lower) alkyl,
R3 is hyarogen, lower alkyl, lower alkynyl, lower alkoxy,
halogen, an acyl group, acyl (lower) alkyl,
acyloxy (lower) alkyl, hydroxyimino (lower) alkyl which may have one or more suitable substituent (s),
hydroxy (lower) alkyl which may have one or more euitable eubetituent (s), cyano (lower) alkyl, mono (or di-) lower alkoxy (lower) alkyl which may have one or more suitable substituent (s), lower alkyl substituted with aryl which may have one or more suitable substituent (s), mono- (or di-) lower alkylamino (lower) alkyl, hydrazino (lower) alkyl which may have one or more suitable substituent (s), mono- (or di-) lower alkoxy (lower) alkylanino (lower) alkyl. N- (lower) alkylamino (lower) alkyl which- may have one or more suitable substituent (s), lower alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), heterocyclic group which may have one or more suitable substituent (s),
heterocyclicthio, heterocyclicthio (lower) alkyl which may have one or more euitable substituent (s),
heterocyclicoxy (lower) alkyl, aryl which may have one or more suitable substituent (s), amino, nitro,
halo (lower) alkyl, hydroxy (lower) alkylimino (lower) alkyl, hydroxy (lower) alkylamino (lower) alkyl,
bis- [hydroxy (lower) alkyl] amino (lower) alkyl,
mercapto (lower) alkyl or amidinothio (lower) alkyl,
X is a group of the formula :
-NHCO-, -NHSO2-, -NHCOCO-, -NHCOCH=CH-, -NHCOCH2-,
-NHCONH- or
Figure imgf000168_0001
(wherein R5 is lower alkyl), Y is heterocyclic group which may have one or more suitable substituent (s), or aryl which may have one or more suitable substituent (s), ana
l is an integer of 1.
3. A compound of claim 2, wherein
R1 is hydrogen,
R2 is lower alkyl or mono- (or di- or tri-) halo (lower) alkyl, R3 is hydroxy (lower) alkyl which may have one or more suitable substituent (s), lower alkyl eubetituted with
heterocyclic group which may have one or more euitable substituent (s), acyl (lower) alkyl or
heterocyclicthio (lower) alkyl,
X ie a group of the formula :
-NHCO-,
Y ie a group of the formula :
Figure imgf000169_0001
[wherein R7, R8, R9 and R10 are each hydrogen, halogen or lower alkyl],
Q is CH, and
l is an integer of 1.
4. A compound of claim 3, which is shown by the following formula :
Figure imgf000169_0002
wherein
R2 is tri-halo (lower) alkyl or lower alkyl,
R3 is hydroxy (lower) alkyl, lower alkyl substituted with
unsaturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s), lower
alkoxy (lower) alkyiaminocarbonyl (lower) alkyl or
heterocyclicthio (lower) alkyl (wherein heterocyclic group is unsaturated 5 or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atom(s)),
Y is a group of the formula :
Figure imgf000170_0001
[wherein R7, R8, R9 and R10 are each hydrogen o:
halogen].
5. A compound of claim 4, wherein
Y is a group of the formula :
Figure imgf000170_0002
(wherein R7 is halogen,
R8 is hydrogen,
R9 is hydrogen,
R10 is halogen.
6. A procese for preparing a compound of claim 1, or a ealt thereof,
which comprieee reacting a compound of the formula :
Figure imgf000170_0003
wherein Y ie ae defined in claim 1,
E is lower alkylene, lower alkenylene, or a group of the formula :
Figure imgf000171_0001
(wherein G1 is -COOH or -SO3H, and
b ie an integer of 0 or 1),
or ite reactive derivative at the carboxy or sulfo group or a salt thereof, with a compound of the formula :
Figure imgf000171_0002
wherein R1, R2, R3 and Q are each as defined in claim 1, and
R' is hydrogen or lower alkyl,
or its reactive derivative at the amino group
or a salt thereof, to give a compound of the formula :
Figure imgf000171_0003
wherein R1, R2, R3, Y, R', E, Q and b are each ae defined above, and
G2 is -CO- or -SO2-,
or a salt thereof, or
(ii) subjecting a compound of the formula :
Figure imgf000172_0001
wherein R1, R2, X, Y, Q and l are each as defined in claim 1, and
ie hydrogen,
Figure imgf000172_0003
or a salt thereof, with lower alkane substituted with oxo to give a compound of the formula :
Figure imgf000172_0002
wherein R1, R2, X, Y, Q and l are each as defined above, and
is hydroxy (lower) alkyl,
Figure imgf000173_0002
or a salt thereof, or
(iii) reacting a compound of the formula :
NH2-R"' wherein R"' is lower alkyl, cyclo (lower) alkyl, lower
alkyl substituted with heterocyclic group which may have one or more suitable substituent (s), lower alkoxy (lower) alkyl, hydroxy (lower) alkyl, amino, heterocyclic group, carboxy (lower) alkyl, protected carboxy (lower) alkyl, lower alkyl
substituted with aryl which may have one or more suitable substituent (s),
arylsulfonyl or cyano (lower) alkyl, or its reactive derivative at the amino group or a salt thereof, with a compound of the formula :
Figure imgf000173_0001
wherein R1, R2, X, Y, Q and l are each as defined in
claim 1, and a is an integer of 0 to 6,
or its reactive derivative at the carboxy group, or a salt thereof, to give a compound of the formula :
Figure imgf000174_0001
wherein R1, R2, R"', X, Y, Q, l and a are each as
defined above,
or a salt thereof, or
(iv) reacting a compound of the formula :
V - H wherein V is heterocyclic group which may have one or more suitable substituent (s),
heterocyclicthio, lower alkylamino which may have one or more suitable
substituent (s), hydroxy (lower) alkylamino, bis-hydroxy (lower) alkylamino, amidinothio or tri-lower alkylphosphite,
with a compound of the formula :
Figure imgf000175_0001
wherein R1, R2, X, Y, Q and l are each as defined in
claim 1,
Z is leaving group, and
A5 is lower alkylene,
or a salt thereof, to give a compound of the formula
Figure imgf000175_0002
wherein R1, R2, X, Y, Q and l are each as defined above, is lower alkyl substituted with heterocyclic
Figure imgf000175_0003
group which may have one or more suitable substituent (s), heterocyclicthio (lower) - alkyl, lower alkylamino (lower) alkyl which may have one or more euitable substituent (s), hydroxy (lower) alkylamino- (lower)alkyl, bis-[hydrhxy (lower) alkyl] - amino (lower) alkyl, amidinothio (lower) - alkyl or di- (lower) alkoxwphosphoryl- (lower)alkyl,
or a salt thereof.
7. A pharmaceutical composition which comprises, as an
active ingredient, a compound of claim 1 or a
pharmaceutically acceptable salt thereof in admixture with pharmaceutically acceptable carriers or excipients.
8. Use of a compound of claim 1 or a pharmaceutically
acceptable salt thereof for the manufacture of a
medicament.
9. A compound of claim 1 or a pharmaceutically acceptable salt thereof for use as a medicament.
10. A method for the prophylactic and/or the therapeutic
treatment of diseases caused by abnormal bone metabolism which comprises administering a compound of claim 1 or a pharmaceutically acceptable salt thereof to a human being or an animal.
PCT/JP1996/001103 1995-05-01 1996-04-23 Imidazo 1,2-a pyridine and imidazo 1,2-a pyridezine derivatives and their use as bone resorption inhibitors WO1996034866A1 (en)

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