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WO1998016527A1 - Derives de benzoxepine promoteurs de la liberation d'hormone de croissance - Google Patents

Derives de benzoxepine promoteurs de la liberation d'hormone de croissance Download PDF

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Publication number
WO1998016527A1
WO1998016527A1 PCT/JP1997/003704 JP9703704W WO9816527A1 WO 1998016527 A1 WO1998016527 A1 WO 1998016527A1 JP 9703704 W JP9703704 W JP 9703704W WO 9816527 A1 WO9816527 A1 WO 9816527A1
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WO
WIPO (PCT)
Prior art keywords
compound
salt
formula
benzoxepin
amino
Prior art date
Application number
PCT/JP1997/003704
Other languages
English (en)
Inventor
Kiyoshi Taniguchi
Satoru Kuroda
Kazunori Tsubaki
Yasuyo Shimizu
Hisashi Takasugi
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 AUPO2988A external-priority patent/AUPO298896A0/en
Priority claimed from AUPO6764A external-priority patent/AUPO676497A0/en
Priority claimed from AUPO8753A external-priority patent/AUPO875397A0/en
Application filed by Fujisawa Pharmaceutical Co., Ltd. filed Critical Fujisawa Pharmaceutical Co., Ltd.
Priority to AU67082/98A priority Critical patent/AU6708298A/en
Priority to JP10518191A priority patent/JP2001502319A/ja
Publication of WO1998016527A1 publication Critical patent/WO1998016527A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • 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
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel derivatives and pharmaceutically acceptable salts thereof.
  • the present invention relates to novel derivatives. More particularly, it relates to novel derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities such as promotion activity of growth hormone release, to processes for preparation thereof, to pharmaceutical composition comprising the same, and to a use of the same as a medicament.
  • one object of the present invention is to provide the useful novel derivatives and pharmaceutically acceptable salts thereof which have pharmacological activities such as a promotion activity of growth hormone release, and the like.
  • Another object of the present invention is to provide processes for the preparation of said novel derivatives and pharmaceutically acceptable salts thereof.
  • a further object of the present invention is to provide a pharmaceutical composition comprising, as an active ingredient, said novel derivatives or a pharmaceutically acceptable salt thereof.
  • Still further object of this invention is to provide a use of said novel derivatives or a pharmaceutically acceptable salt thereof as a medicament which promotes activity of growth hormone release for animals and human bodies and they are useful for treatment of obesity in combination with an a 2 or ⁇ Z adrenergic agonist, osteoporosis in combination with parathyroid hormone, the catabolic effects of nitrogen wasting in combination with insulin-like growth factor 1, growth retardation, renal failure or insufficiency, schizophrenia, sleep disorder, skeletal dysplasia, depression, Alzheimer's disease, pulmonary dysfunction, hyperinsulinemia, ulcer, arthritis, cardiac dysfunction, replacement for elderly people, ALS, growth hormone deficient adults, physiological short stature including growth hormone deficient children .Turner's syndrome, intrauterine growth retardation, cachexia and protein loss due to cancer or AIDS and is also useful for stimulating the immune system, accelerating wound healing or bone fracture repair, improvement in muscle strength, and the like.
  • the object compounds of the present invention can be represented by the following general formula(I):
  • R 1 is 3-azetidinyl, 4-piperidyl or a group of the formula:
  • R 4 is hydrogen or amino protective group, and Y is lower alkylene or cyclo(lower) alkylene, R 2 is cyano and R 3 is aryl;
  • R 2 is esterified carboxy and R 3 is ar(lower)alkyl: or R 2 and R 3 are linked together to form
  • A is -(CH 2 ) resort-, in which n is 2, 3 or 4, vinylene or butenylene,
  • X is bond or lower alkylene
  • R 1 , R 2 , R 3 , A, X and Y are each as defined above,
  • R a is amino protective group
  • a 1 is vinylene or butenylene
  • a 2 is ethylene or tetramethylene.
  • Pharmaceutically acceptable salts of the obj ect compounds ( I ) are conventional non-toxic salts and may include an acid addition salt such as an inorganic acid addi tion salt [e. g. hydrochloride, hydrobromide, sul fate, phosphate, etc. ] , an organic acid addition salt [e. g. formate, acetate, trif luoroacetate, maleate, tartrate, methanesulfonate, benzenesul fonate, toluenesulfonate, etc. ] ; a salt with an amino acid [e. g. aspartic acid salt, glutamic acid salt, etc. ] ; and the like.
  • an acid addition salt such as an inorganic acid addi tion salt [e. g. hydrochloride, hydrobromide, sul fate, phosphate, etc. ]
  • an organic acid addition salt e. g. formate, acetate, trif l
  • each of the object compound (I) may include one or more stereoisomer such as optical isomer(s) and geometrical isomer(s) due to asymmetric carbon atom(s) and double bond(s) and all such isomers and mixture thereof are included within the scope of this invention.
  • the starting compound (I I) and (IV) or a salt thereof can be prepared by the procedures described in the Preparat ions ment ioned later or by a conventional method.
  • lower is intended to mean 1 to 6 carbon atom(s), preferably 1 to 4 carbon atom(s), unless otherwise indicated.
  • Amino protective group may include acyl such as lower alkanoyl [e. g. formyl, acetyl, propionyl, pivaloyl, hexanoyl, etc. ] , mono(or di or tri)halo
  • (lower)alkanoyl e. . chloroacetyl, bromoacetyl, dichloroacetyl, trif luoroacetyl, e tc.
  • lower alkoxycarbonyl e. g. methoxycarbonyl, e thoxycarbony l , propoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, hexyloxycarbonyl, etc.
  • carbamoyl, aroyl e.g. benzoyi, toluoyl, naphthoyl, etc.
  • ar(lower)alkanoyl e. g.
  • aryloxycarbonyl e.g. phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • aryloxy(lower)alkanoyl e.g. phenoxyacetyl, phenoxypropionyl, etc.
  • arylglyoxyloyl e.g. phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • ar(lower)alkoxycarbonyl which may have suitable substituent(s) [e.g.
  • ar(lower)alkyl such as ar(lower)alkylidene which may have substituent(s) [e.g. benzyl idene, hydroxybenzylidene, etc.], mono (or di or tri)phenyl(lower)alkyl [e.g. benzyl, phenethyl, benzhydryl, trityl, etc.]; and the like.
  • Suitable "acyl” may include carbamoyl, aliphatic acyl and acyl group containing an aromatic ring, which is referred to as aromatic acyl, or an heterocyclic ring, which is referred to as heterocyclic acyl.
  • This acyl group may be derived, for example, from an organic carboxylic acid, an organic carbonic acid, an organic sulfuric acid, an organic sulfonic acid and an organic carbamic acid.
  • 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, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridacanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.
  • alkanoyl e. g. formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2, 2-dimethylpropanoy
  • lower or higher cycloalkylcarbonyl e. g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.
  • lower or higher alkanesulfonyl e. g. methanesulfonyl, ethanesulfonyl, etc.
  • lower or higher alkoxysulfonyl e. g. methoxysulfonyl, ethoxysulfonyl, etc.
  • Aromatic acyl such as aroyl [e. g. benzoyi, toluoyl, naphthoyl, etc. ] ; ar (lower) alkanoyl [e.g. phenyl(lower)alkanoyl , etc. ] or the like.
  • the acyl moiety as stated above may have 1 to 5, same or different, suitablesubstituent(s) such as halogen [e. g. fluorine, chlorine, bromine or iodine] , lower alkyl [e. g.
  • Suitable "aryl” may include phenyl , tolyl, xylyl, esityl, cumenyl, naphtyl, and the like, in which the preferred one is C 6 -C ⁇ 0 aryl and the most preferred one is phenyl.
  • ester moiety of an esterified carboxy may be the ones such as lower alkyl ester(e. . methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1— cyclopropylethyl ester, etc. )
  • lower alkyl ester e. . methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tert-butyl ester, pentyl ester, hexyl ester, 1— cyclopropylethyl ester, etc.
  • Suitable "ar (lower)alkyl” may include trityl, benzhydryl, benzyl, phenythyl, and the like.
  • Suitable "lower alkylene” may include straight or branched one having 1 to 6 carbon atom (s) , such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamet hylene and hexamethyl ene, methyl trimethy l ene, dimethylmethylene.
  • cyclo (lower) al kylene may include cycl opropylene , cyclopentylene and cyclohexylene.
  • the preferred embodiments of the object compounds are as follows.
  • R 1 is 3-azetidinyl, 4-piperidyl or a group of the formula :
  • R 4 is hydrogen or acyl (e. g. lower alkoxycarbonyl, etc. ), and
  • Y is lower alkylene or cyclo (lower) alkylene ;
  • X is bond or lower alkylene ;
  • R 5 is acyl (e.g. lower alkanesulfonyl, etc.),
  • R 2 is cyano
  • Ra is aryl (e. g. phenyl, etc. ),
  • Rb is esterified carboxy (e. g. lower alkoxycarbonyl, etc. ),
  • Rb is ar (lower) alkyl (e. g. benzyl, etc. ).
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or its reactive derivatives at the carboxy group or a salt thereof with the compound (III) or its reactive derivatives at the amino group or a salt thereof.
  • the starting compound (II) or a salt thereof are novel and can be prepared by the manners of Preparations mentioned below or a similar manner thereto.
  • Suitable reactive derivative at the carboxy group of the compound (II) may include an acid halide, an acid anhydride, an activated amide, an activated ester, and the like.
  • Suitable examples of the reactive derivatives may be an acid chloride; an acid azide; a mixed acid anhydride within acid such as substituted phosphoric acid [e. g. dialkylphosphoric acid, phenylphosphoric acid, diphenylphosphoric acid, dibenzylphosphoric acid, halogenated phosphoric acid, etc.], dialkylphosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkylcarbonic acid, (lower)alkanesulfonic 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 imidazole, 4- substituted imidazole, dimethylpyrazole, triazole or tetrazole; or an activated ester [e. g.
  • Suitable salts of the compound (II) and its reactive derivative may be a base salt such as an alkali metal salt [e.g. sodium salt, pottasium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e. . trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc.], or the like, and an acid addition salt as exemplified for the compound (I).
  • an alkali metal salt e.g. sodium salt, pottasium salt, etc.
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an ammonium salt e. a trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenz
  • Suitable reactive derivative at the amino group of the compound (III) may include Schiff 's base type imino or its tautomeric enamine type isomer formed by the reaction of the compound (III) with a carbonyl compound such as aldehyde, ketone or the like; a silyl derivative formed by the reaction of the compound (III) with a silyl compound such as bis(trimethylsilyl)acetamide, mono(trimethyl -syliy)acetamide, bis(trimethylsilyl)urea or the like; a derivative formed by reaction of the compound (III) with phosphorus trichloride or phosgene, and the like.
  • Suitable salts of the compound (III) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
  • the reaction is usually carried out 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, acetonitrile,
  • the reaction when the compound (II) 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 carbodiimide or a salt thereof [e.g. N, N'- dicyclohexylcarbodiimide ; N-cyclohexyl-N ' -morpholinoethylcarbodiimide ; N- cyclohexyl-N'-(4-di-ethylaminocyclohexyl ) carbodiimide; N, N'-diethylcarbodiimide,
  • a conventional condensing agent such as carbodiimide or a salt thereof
  • reaction may also be carried out in the presence of an inorganic or organic base such as an alkali metal bicarbonate, tri(lower)alkylamine, pyridine,
  • N-( lower) alky Tmorpholine N, N-di(lower)alkylbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling, at ambient temperature or under warming.
  • the compound (lb) or a salt thereof can be prepared by subjecting a compound (la) or a salt thereof to removal reaction of the amino-protective group in R 4 .
  • the starting compound (la) or a salts thereof are prepared by the process 1.
  • Suitable salts of the compounds (la) and (lb) can be referred to the ones as exemplified for the compound (I).
  • This reaction is carried out in accordance with a conventional manner such as 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 bicarbonate thereof, hydrazine, trialkylamine [e.g. trimethylamine, triethylamine, etc.], picoline, 1, 5-diazabicyclo[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.
  • an alkali metal e.g. sodium, potassium, etc.
  • an alkaline earth metal e.g. magnesium, calcium, etc.
  • the hydroxide or carbonate or bicarbonate thereof hydrazine
  • trialkylamine e.g. trimethylamine, triethylamine, etc.
  • picoline 1, 5-di
  • Suitable acid may include an organic acid [e. g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trif luoroacetic acid, etc.], an inorganic acid [e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, , etc. ] and an acid addition salt compound [e. g. pyridine hydrochloride, etc. ] .
  • organic acid e. g. formic acid, acetic acid, propionic acid, trichloroacetic acid, trif luoroacetic acid, etc.
  • an inorganic acid e. g. hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, , etc.
  • an acid addition salt compound e. g. pyridine hydrochloride, etc.
  • Lewis acid such as trihaloacetic acid [e. g. trichloroacetic acid, trif luoroacetic acid, etc. ] or the like is preferablycarried out in the presence of cation trapping agents [e. g. anisole, phenol, etc.].
  • the reaction is usually carried out in a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, diethtyl ether, dioxane, chloroform, tetrachloromethane, tetrahydrofuran, ethyl acetate, a mixture thereof or any other solvent which does not adversely, influence the reaction.
  • a solvent such as water, an alcohol [e.g. methanol, ethanol, etc.], methylene chloride, diethtyl ether, dioxane, chloroform, tetrachloromethane, tetrahydrofuran, ethyl acetate, a mixture thereof or any other solvent which does not adversely, influence the reaction.
  • a liquid base or acid can be also used as the solvent.
  • the reaction temperature is not critical and the reaction is usually carried out under cooling, at ambient temperature or under heating.
  • 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, zinc, 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, trif luoroacetic acid, p- toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.].
  • metal e. g. tin, zinc, iron, etc.
  • metallic compound e. g. chromium chloride, chromium acetate, etc.
  • organic or inorganic acid e. g. formic acid, acetic acid, propionic acid, trif luoroacetic acid, p- toluenesulfonic acid, hydrochloric acid, hydrobromic acid, etc.
  • Suitable catalysts to be used in catalytic reduction are conventional ones such as platinum catalysts [e. g. platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, 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 nickel, 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, Ullman 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, aceton, or a mixture thereof in case that the above-mentioned acid 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 diethtyl ether, dioxane, tetrahydrofuran, etc. , or a mixture thereof.
  • reaction temperature of this reduction is not critical and the reaction is usually carried out under cooling , at ambient temperature or under heating.
  • the compound (Id) or a salt thereof can be prepared by subjecting a compound (Ic) or a salt thereof to reduction reaction.
  • Suitable salts of the compounds (Ic) and (Id) can be referred to the ones as exemplified for the compound (I).
  • This reaction can be carried out in a similar manner to that of the aforementioned Process 2.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (IV) or its reactive derivatives at the amino group or a salt thereof with the compound (V) or its reactive derivatives at the carboxy group or a salt thereof.
  • the starting compound (IV) or salts thereof are novel and can be prepared by the manners of Preparations mentioned below or a similar manner thereto.
  • Suitable salts of the compound (IV) and its reactive derivative can be referred to the ones as exemplified for the compound (I).
  • Suitable salts of the compound (V) and its reactive derivative may be a base salt such as an alkali metal salt [e.g. sodium salt, pottassium salt, etc.], an alkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], an ammonium salt, an organic base salt [e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzylethylenediamine salt, etc.], or the like, and an acid addition salt as exemplified for the compound (I).
  • an alkali metal salt e.g. sodium salt, pottassium salt, etc.
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an ammonium salt e. g. trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, N,N'- dibenzy
  • the compounds obtained by the above processes can be isolated and purified by a conventional manner such as pulverization, recrystallization, column chromatography, reprecipitation, or the like.
  • the object compounds (I) thus obtained can be converted to its salt by a conventional manner.
  • the object compounds (I) and pharmaceutically acceptable salt thereof may include a solvate [e.g., enclosure compound (e.g., hydrate, etc.)].
  • a solvate e.g., enclosure compound (e.g., hydrate, etc.)].
  • the object compounds (I) and pharmaceutically acceptable salts thereof are expected to possess excellent pharmacological activities such as promotion activity of growth hormone release for animals and human bodies and they are useful for treatment of obesity in combination with an a 2 or ⁇ Z adrenergic agonist, osteoporosis in combination with parathyroid hormone, the catabolic effects of nitrogen wasting in combination with insulin-like growth factor 1, growth retardation, renal failure or insufficiency, schizophrenia, sleep disorder, skeletal dysplasia, depression, Alzheimer's disease, pulmonary dysfunction, hyperinsulinemia, ulcer, arthritis, cardiac dysfunction, replacement for elderly people, ALS, growth hormone deficient adults, physiological short stature including growth hormone deficient children .Turner's syndrome, intrauterine growth retardation, cachexia and protein loss due to cancer or AIDS and is also useful for stimulating the immune system, accelerating wound healing or bone fracture repair, improvement in muscle strength, and the like.
  • the object compounds (I) of the present invention and pharmaceutically acceptable salts thereof are used in the form of the conventional pharmaceutical preparation which contains said compounds as an active ingredient, in admixture with a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • a conventional pharmaceutically acceptable carrier such as an organic or inorganic solid or liquid excipient suitable for oral, parenteral or external administration.
  • auxiliary substance such as stabilizing agent, wetting or emulsifying agent, buffer or any other commonly used additives.
  • the effective ingredient may usually be administered with a unit dose of 0.001 mg/kg to 100 mg/kg/day, preferably 0.01 mg/kg to 50 mg/kg, 1 to 4 times a day. However, the above dosage may be increased or decreased according to age, weight and conditions of the patient or the administering method.
  • N-benzalglycine methylester (1.18 g) in tetrahydrofuran (5 ml) was added dropwise to a stirred suspension of potassium tert-butoxide (0.75 g) in tetrahydrofuran (7 ml) at -70 °C and then a solution of 4-chloromethyl-2, 3-dihydro-l-benzoxepine (1.08 g) in tetrahydrofuran (5 ml) was added dropwise therein at the same temperature. The resulting mixture was stirred at same temperature for 2 hours.
  • reaction mixture was cooled to 5 °C and the reaction was quenched with 2N aqueous hydrochloric acid(700ml). The resulting mixture was stirred for 1. 5 hours at ambient temperature. After the tetrahydrofuran was evaporated, the resulting aqueous solution was washed with ethyl acetate and the organic layer was reextracted with 2N aqueous hydrochloric acid. The aqueous layers were combined, washed with ethyl acetate and concentrated in vacuo.
  • Ethyl 3-benzyl-l-[(2R)-2-tert-butoxycarbonylamino-3-(2, 3-dihydro-l- benzoxepin-4-yl)propionyl]piperidine-3-carboxylate was prepared according to the similar manner as that of Preparation 14, except substituting ethyl 3- benzylpiperidine-3-carboxylate hydrochloride for l-methanesulfonylspiro[indoline -3, 4 '-piperidine]hydrochloride, as a foam.
  • 2-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl) methanesulfonate was prepared from 2-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl) ethanol by a conventional method as a foam.
  • 5-(2-Iodoethyl)-2, 3, 4, 5-tetrahydro-l-benzoxepine was prepared from 2-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl) methanesulfonate by a conventional method as an oil.
  • 2-Acetylamino-2- [2-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl)ethyl]malonic acid diethyl ester was prepared from 5- (2-iodoethyl) -2, 3, 4, 5-tetrahydro-l - benzoxepine by a conventional method as a white solid.
  • FT IR(KBr) 3257, 1753, 1741, 1643, 1547, 1487, 1373, 1234, 1207cm 1 . ⁇ ; 1. 11-1. 34C6H, m), 1. 40-2. 30C11H, m), 2. 70-2. 90 C1H, m), 3. 50-3. 70 (1H, m), 4. 08-4.
  • 2-Acetylamino-4-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl)butyric acid was prepared from 2-acetylamino-2-[2-(2, 3, 4, 5-tetrahydro -l-benzoxepin-5-yl) ethyl] malonic acid diethyl ester by a conventional method as a white solid.
  • Preparation 38 l-Ethyl-3-(3 ' -dimethylaminopropyl)carbodiimide(0. 34ml) was added to a mixture of 2-tert-butoxycarbonylamino-4-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl)- butyric acid (470mg) , l-methanesu lfonylspiro [indol ine-3, 4 ' -piperidine] hydrochloride (436mg) and l-hydroxybenzotriazole(162mg) in dichloromethane(20ml) at ambient temperature, and the resulting mixture was stirred at the same temperature overnight.
  • 2-tert-butoxycarbonylamino-4-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl)- butyric acid 470mg
  • reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and saturated sodium hydrogen carbonate in water.
  • the organic layer was separated, washed with water and brine, dried over magunesium sulfate, and evaporated in vacuo to give l'-[2-amino-4-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl)
  • 3-(Iodomethyl)chroman(4.3g) was prepared from 3-(methanesulfonyloxy methyl) choroman by a conventional as an oil.
  • 2-Acetylamino-3- (chroman-3-yl) propionic acid was prepared from 2- acetylamino-2- [(chroman-3-yl)methyl] malonic acid diethyl ester by a conventional method as an oil.
  • 2-Amino-3-(chroman-3-yl)propionic acid hydrochloride was prepared from 2 -acetylamino-3-(chroman-3-yl) propionic acid by a conventional method as a white solid.
  • 2-tert-Butoxycarbonylamino-3-(chroman-3-yl)propionic acid was prepared from 2-amino-3-(chroman-3-yl) propionic acid hydrochloride by a conventional method as an oil.
  • Acetaminomalonic acid diethyl ester(2.49g) was added to a solution of sodium(262mg) in ethanol(6.7ml) and a solution of(S)-2, 3, 4, 5-tetrahydro-l- benzoxepin-4-yl methanesulfonate(978mg) in tetrahydrofuran(5.5ml) was added dropwise thereto with stirring at room temperature. The resulting mixture was stirred under reflux for 22 hours, cooled to room temperature, and evaporated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was saparated, washed with brine, dried over magnesium sulfate, and evaporated in vacuo.
  • ⁇ NMROCDCl ⁇ ; 1.40, 1.42 and 1.45C9H, each s), 1.35-2.25C9H, m), 2.60-3.30(4H, ), 2.92(3H, s), 3.60-4.35(5H, m), 4.62GH, m), 4.8K1H, m), 5.3K1H, m), 6.90-7.
  • reaction mixture was extracted with ethyl acetate and the extract was washed successively with IN hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, and brine, dried over magnesium sulfate, and evaporated in vacuo to afford(4S, 5R)-5-acetoxy-2, 3, 4, 5-tetrahydro-l-benzoxepine
  • Example 1 l-Ethyl-3- (3 ' -dimethylaminopropyl)carbodiimide (89 mg) was added to a mixture of 2- [ [2-(tert-butoxycarbonylamino)-2, 2-dimethyl-l-oxoethyl]amino ]-3-(2, 3-dihydro-l-benzoxepin-4-yl)propionic acid (200 mg) 1-methanesulfonylspiro- [indoline-3, 4 ' -piperidine] hydrochloride (145 mg), and 1-hydroxybenzotriazole (78 mg) in N, N-dimethylformamide (4 ml) at ambient temperature and the resulting mixture was stirred at the same temperature overnight.
  • a colorless powder mp 154-168°C(dec. ) (from diethyl ether).
  • IR(film) 3400-3100, 2730, 2550, 2200, 1660, 1620cm "1 .
  • NMR(CD 3 OD) ⁇ 1.43 and 1.49(3H, each s), 1.58(3H, s), 1.65 ⁇ 2.25(4H, m), 2.55-2.8 (3H, m), 2.95-3.15GH, m), 3.45-3.65GH, m), 4.1-4.35(3H, m), 4.65-4.8GH, m), 5.15-5.25 GH, m), 6.25GH, s), 6.81-6.97(2H, m), 7.03-7.16(2H, m), 7.30-7.51 (5H, m). (+)APCI MS m/z : 487(M + +1).
  • IR(film) 3380-3200, 2650, 2560, 2520, 2230, 1660, 1625, 1220cm "1 .
  • NMR(CD 3 0D) ⁇ 1.55, 1.58, 1.59, and 1.62(6H, each s), 1.7-2.25(9H, m), 2.7-3.15 (3H, m), 3.4-4.0GH, m), 4.1-4.75(4H, m), 4.95-5.1GH, m), 6.85-7.25(4H, m), 7.4-7.55(5H, m).
  • Example 8 l-Ethyl-3-(3 ' -dimethylaminopropyDcarbodimide hydrochloride(179mg) was added to a mixture of l'-[(2R)-2-amino-3-[(4S)-2, 3, 4, 5-tetrahydro-l-benzoxepin-4 -yl]propionyl]-l-methanesulfonylspiro[indoline-3, 4 '-piperidine] (300ml), N-tert- butoxycarbonyl- ⁇ -methylalanine(145mg) and l-hydroxybenzotriazole(l ⁇ lmg) in dichloromethane(20ml) at 5°C with stirring.
  • Ethyl l-[(2R)-2-(2-amino-2-methylpropionylamino)-3-(2, 3-dihydro-l- benzoxepin-4-yl)propionyl]-3-benzylpiperidine-3-carboxylate hydrochloride was prepared according to a similar manner to that of Example 9 as a white powder.
  • FT IR(KBr) 1724.1, 1675.8, 1633.4, 1569.8, 1544.7, 1517.7, 1490.7, 1454.1, 1444. 4cm 1 .
  • N- [1- [(1-Methanesulf onylspiro [indoline-3, 4 ' -piperidine] -1 ' -yDcarbonyl] - 2-(benzofuran-2-yl)ethyl] -2-tert-butoxycarbonylamino-2-methylpropanamide was prepared according to a similar manner to that of Example 8 as a foam.
  • ⁇ NIO CDCL ⁇ ; 1.38-2.00G9H, m), 2.60-3.30(7H, m), 3.60-3.90C2H, m), 4.00-4.20 (IH, m), 4.45-4.65GH, m), 4.89(1H, s), 5.30-5.50GH, m), 6.10-7.60C9H, m).
  • N- [1- [(1-Methanesulf onylspiro [indoline-3, 4 ' -piperidine] -1 ' -yDcarbonyl] - 2-(benzofuran-2-yl)ethyl]-2-amino-2-methylpropanamide hydrochloride was prepared according to a similar manner to that of Example 9 as a white powder.
  • N-[1- [1-Methanesulfonylspiro[indoline-3, 4 ' -piperidine]-1 '-yDcarbonyl]-2 -(2, 3-dihydrobenzofuran-2-yl)ethyl] -2-amino-2-methyl-propanamide hydrochloride was prepared according to a similar manner to that of Example 9 as a white solid.
  • Example 28 l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(301mg) was added to a solution of 1 '-[2-amino-4-(2, 3, 4, 5-tetrahydro-l-benzoxepin-5-yl) butanoyl]-l-methanesulfonylspiro[indoline-3, 4 '-piperidine] (520mg), N-tert-butoxycarbonyl- a -methylalanine(238mg) and l-hydroxybenzotriazole(165mg) in dichloromethane(20ml) at ambient temperature, and the resulting mixture was stirred at the same temperature overnight.
  • reaction mixture was partitioned between ethyl acetate and water.
  • the organic layer was washed with water and brine, dried over magunesium sulfate, and evaporated in vacuo.
  • the residue was chromatographed (n-bexane-ethyl acetate) over silica gel, and active fractions were concentrated in vacuo to give a foam.
  • N-[1-[(1-Methanesulf onylspiro [indoline-3, 4 '-piperidine] -1' -yDcarbonyl] - 2-(chroman-3-yl)ethyl]-2-tert-butoxycarbonylamino-2-methylpropanamide was prepared according to a similar manner to that of Example 8 as a foam.
  • N-[1- [(1-Methanesulfonylspiro [indoline-3, 4 ' -piperidine]-1 ' -yDcarbonyl]- 2-(chroman-3-yl)ethyl]-2-amino-2-methylpropanamide hydrochloride was prepared according to a similar manner to that of Example 9 as a white solid.
  • FT IR(KBr) 2927, 1633, 1525, 1491, 1462, 1346, 1228, 1159, 1117cm 1 .
  • Example 33 l-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (85mg) was added to a stirred mixture of l'-[(2R)-2-amino-3-(2, 3, 4, 5-tetrahydro-l-benzoxepin -4-yl)propianyl] -1-methanesulf onylspiro- [indoline-3, 4 ' -piperidine] (74.2mg), 1- tert-butoxycarbonylazetidine-4-carboxylic acid (74.2mg) , and 1- hydroxybenzotriazole(46.8mg) in dichloromethane(20mg).
  • Example 34 l-Ethyl-3-(3 ' -dimethylaminopropyDcarbodiimide hydrochloride(85mg) was added to a stirred mixture of l'-[(2R)-2-amino-3-(2, 3, 4, 5-tetrahydro-l-benzoxepin -4-yl)propionyl]-l-methanesulfonylspiro-[indoline-3, 4 '-piperidine] (140mg), 1-tert -butoxycarbonyl-4-isonipecotic acid(65.9mg) and l-hydroxybenzotriazole(46.9mg) in dichloromethane(l ⁇ ml).
  • Ethyl 3-benzyl-l-[2-(2-tert-butoxycarbonylamino-2-methylpropionylamino)- 3-(2, 3-dihydro-l-benzoxepin-4-yl)propionyl]piperidine-3-carboxylate was prepared in a similar manner to thet of Example 1.
  • Example 28 ⁇ ; 1.25-2.20G3H, m), 2.65-3.45(7H, m), 3.60-4.60 (6H, m), 5.00-5.20

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Abstract

Composé de benzoxépine pharmaceutiquement utile défini par la formule (I), dans laquelle R1 est 3-azétidinyl, 4-pipéridyl ou un groupe de la formule -Y-NHR4 dans laquelle R4 est hydrogène ou un groupe amino protecteur et Y est alkylène inférieur ou cycloalkylène (inférieur), R2 est cyano et R3 est aryle; R2 est carboxy estérifié et R3 est aralkyle (inférieur); ou R2 et R3 sont liés pour former (a) dans laquelle R5 est acyle, A est -(CH¿2?)n-, dans lequel n est 2, 3 ou 4, vinylène ou buténylène, X est la liaison ou alkylène inférieur et (b) est pipéridino, et sels pharmaceutiquement acceptables de ce composé. Le composé ou sel pharmaceutiquement acceptable de la présente invention présente une excellente activité promotrice de la libération d'hormone de croissance chez l'animal et dans l'organisme humain.
PCT/JP1997/003704 1996-10-15 1997-10-15 Derives de benzoxepine promoteurs de la liberation d'hormone de croissance WO1998016527A1 (fr)

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AU67082/98A AU6708298A (en) 1996-10-15 1997-10-15 Benzoxepine derivatives which promote release of growth hormone
JP10518191A JP2001502319A (ja) 1996-10-15 1997-10-15 成長ホルモンの放出を促進するベンズオキセピン誘導体

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WO1998051687A1 (fr) * 1997-05-14 1998-11-19 Fujisawa Pharmaceutical Co., Ltd. Derives piperidino favorisant la liberation de l'hormone de croissance
WO1999058501A1 (fr) * 1998-05-11 1999-11-18 Novo Nordisk A/S Composes possedant des proprietes de liberation d'hormone de croissance
WO2000049037A1 (fr) * 1999-02-19 2000-08-24 Eli Lilly And Company Sectetagogues d'hormone de croissance
US6303620B1 (en) 1998-05-11 2001-10-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
EP1363631A4 (fr) * 2001-03-02 2005-11-16 Bristol Myers Squibb Co Composes utiles comme modulateurs des recepteurs de la melanocortine et compositions pharmaceutiques renfermant ceux-ci
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998051687A1 (fr) * 1997-05-14 1998-11-19 Fujisawa Pharmaceutical Co., Ltd. Derives piperidino favorisant la liberation de l'hormone de croissance
CZ301276B6 (cs) * 1998-05-11 2009-12-30 Novo Nordisk A/S Piperidinový derivát vykazující schopnost uvolnování rustového hormonu
WO1999058501A1 (fr) * 1998-05-11 1999-11-18 Novo Nordisk A/S Composes possedant des proprietes de liberation d'hormone de croissance
US6303620B1 (en) 1998-05-11 2001-10-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
US6992097B2 (en) 1998-08-18 2006-01-31 Eli Lilly And Company Growth hormone secretagogues
EP1930021A2 (fr) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Nouveaux dérivés d'amide en tant que secrétagogues d'hormone de croissance
WO2000049037A1 (fr) * 1999-02-19 2000-08-24 Eli Lilly And Company Sectetagogues d'hormone de croissance
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
EP1363631A4 (fr) * 2001-03-02 2005-11-16 Bristol Myers Squibb Co Composes utiles comme modulateurs des recepteurs de la melanocortine et compositions pharmaceutiques renfermant ceux-ci
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
US7396846B2 (en) 2002-04-09 2008-07-08 Eli Lilly And Company Growth hormone secretagogues
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2017075535A1 (fr) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Méthodes de traitement de troubles neurodégénératifs

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