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WO1996039382A1 - Derives de l'uree utilises comme antagonistes de 5-ht - Google Patents

Derives de l'uree utilises comme antagonistes de 5-ht Download PDF

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Publication number
WO1996039382A1
WO1996039382A1 PCT/JP1996/001500 JP9601500W WO9639382A1 WO 1996039382 A1 WO1996039382 A1 WO 1996039382A1 JP 9601500 W JP9601500 W JP 9601500W WO 9639382 A1 WO9639382 A1 WO 9639382A1
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Prior art keywords
alkyl
phenyl
formula
compound
salt
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PCT/JP1996/001500
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English (en)
Inventor
Kiyotaka Ito
Glen W. Spears
Toshio Yamanaka
Keiko Harada
Yuka Hotta
Masayuki Kato
Original Assignee
Fujisawa Pharmaceutical Co., Ltd.
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Priority to JP9500302A priority Critical patent/JPH11506468A/ja
Publication of WO1996039382A1 publication Critical patent/WO1996039382A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/38—Amides of thiocarboxylic acids
    • C07C327/48—Amides of thiocarboxylic acids having carbon atoms of thiocarboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/58—Derivatives of thiocarboxylic acids, the doubly-bound oxygen atoms being replaced by nitrogen atoms, e.g. imino-thio ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/12—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 chain containing hetero atoms as chain links

Definitions

  • the present invention relates to novel urea derivatives and a pharmaceutically acceptable salt thereof. More
  • 5-hydroxytryptamine (5-HT) antagonism pharmacological activities such as 5-hydroxytryptamine (5-HT) antagonism and the like.
  • Said urea derivatives or a pharmaceutically acceptable salt thereof are useful as a 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders,
  • CNS central nervous system
  • migraine migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
  • the urea derivatives of the present invention are novel and can be represented by the formula (I) :
  • R 1 is cyano, thiocarbamoyl
  • R 4 is hydrogen, lower alkyl which may have
  • a 1 is lower alkylene
  • n 0 or 1
  • R 5 is morpholino, piperidino, 4-arylpiperazin-
  • a 2 is lower alkylene, or a group of the formula in which R 6 and R 7 are each hydrogen, optionally
  • alkylimino (optionally substituted aryl) methyl or lower alkyl which may have optionally substituted aryl, and
  • a 3 is lower alkylene
  • R 2 is hydrogen
  • R 1 and R 2 are linked together to form
  • R 8 is amino or acylamino
  • R 9 is hydrogen, acyl or lower alkyl which may have optionally substituted aryl, and R 3 is 1-lower alkylindolyl, benzofuranyl,
  • dihydrobenzofuranyl or optionally substituted aryl.
  • the object compoundsan be prepared by the following main processes :
  • R 1 , R 2 and R 3 are each as defined above.
  • object compounds (I) prepared by the above Processes 1 to 4 can be achieved conversion of their side chain within the scope of the compounds of the present invention as shown in the Examples below.
  • Suitable salt of the compounds (I), (II), (III), (IV), (V), (VI), (VII), (VIII) and (IX) are conventional non-toxic pharmaceutically acceptable salt 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.
  • an alkaline earth metal salt e.g. calcium salt, magnesium salt, etc.
  • an ammonium salt e.g. sodium salt, potassium salt, cesium salt, etc.
  • 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.
  • an organic carboxylic or sulfonic acid addition salt e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.
  • a salt with a basic or acidic amino acid e.g.
  • arginine aspartic acid, glutamic acid, etc.
  • the preferable example thereof is an acid addition salt.
  • lower is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
  • pyridyl (lower) alkyl and “thienyl (lower) alkyl” may include straight or branched one, having 1 to 6 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, preferably one having 1 to 4 carbon atoms, and the like, in which the most preferred one is methyl, ethyl, propyl or butyl.
  • Suitable "lower alkylene” is one having 1 to 6 carbon atom(s) and may include methylene, ethylene, methylmethylene, trimethylene, propylene, tetramethylene, methyltrimethylene, hexamethylene, and the like, in which the preferred one is methylene or methylmethylene.
  • Suitable "optionally substituted aryl” includes aryl (e.g. phenyl, naphthyl, etc.) which may have suitable substituent (s) such as lower alkyl as mentioned above, lower alkoxy (e.g. methoxy, ethoxy, propoxy, etc.), halogen (e.g. fluoro, chloro, bromo, etc.), trihalo (lower) alkoxy (e.g.
  • N,N-di (lower alkyl) amino e.g. N,N- dimethylamino, etc.
  • N,N-di (lower alkyl) amino e.g. N,N- dimethylamino, etc.
  • lower alkyl which may have optionally substituted aryl means lower alkyl as mentioned above, which may have
  • Suitable "4-arylpiperazin-1-yl” may include
  • Suitable " (lower alkylimino) (optionally substituted aryl) methyl” may include (methylimino) (phenyl) methyl, and the like.
  • acylamino 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.
  • acyl may be illustrated as follows : Carbamoyl; Thiocarbamoyl;
  • 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,
  • alkanoyl e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,
  • tridecanoyl tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc.
  • lower or higher alkoxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl, heptyloxycarbonyl, etc.
  • alkylsulfonyl e.g., methylsulfonyl, ethylsulfonyl, etc.
  • alkoxysulfonyl e.g., methoxysulfonyl, ethoxysulfonyl, etc.
  • cyclo (lower) alkylcarbonyl e.g., cyclopentylcarbonyl, cyclohexylcarbonyl, etc.; 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, phenylhexanoyl, etc.
  • naphthyl (lower) alkanoyl e.g., naphthylacetyl
  • ar (lower) alkenoyl e.g., phenyl (lower) alkenoyl (e.g., phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.),
  • naphthyl (lower) alkenoyl e.g., naphthylpropenoyl
  • ar (lower) alkoxycarbonyl e.g., phenyl (lower) alkoxycarbonyl
  • aryloxycarbonyl e.g., phenoxycarbonyl, naphthyloxycarbonyl, etc.
  • aryloxy (lower) alkanoyl e.g., phenoxyacetyl
  • arylglyoxyloyl e.g., phenylglyoxyloyl, naphthylglyoxyloyl, etc.
  • arylsulfonyl e.g., phenylsulfonyl, p-tolylsulfonyl, etc.; or the like;
  • Heterocyclic acyl such as
  • heterocyclic (lower) alkanoyl e.g., heterocyclicacetyl, heterocyclicpropanoyl, heterocyclicbutanoyl,
  • heterocyclic (lower) alkenoyl e.g., heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl,
  • heterocyclichexenoyl etc.
  • heterocyclicglyoxyloyl or the like
  • heterocycliccarbonyl means, in more detail, saturated or
  • heterocyclic group may be heterocyclic group such as
  • unsaturated condensed heterocyclic group containing 1 to 4 nitrogen atom(s) for example, indolyl, isoindolyl, indolinyl, indolizinyl, benzimidazolyl (e.g. 1H- benzimidazolyl, etc.), quinolyl, isoquinolyl,
  • tetrahydroisoquinolyl e.g. 1,2,3,4-tetrahydroisoquinolyl, etc.
  • indazolyl benzotriazolyl, quinazolinyl, quinoxalinyl, phthalazinyl, etc.
  • benzotriazolyl quinazolinyl, quinoxalinyl, phthalazinyl, etc.
  • acyl moiety as stated above may have one to ten, same or different, suitable substituent (s).
  • R 1 , R 2 and R 3 are as follows.
  • R 1 is cyano, thiocarbamoyl
  • R 4 is hydrogen, lower alkyl, phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl (lower) alkoxycarbonyl, phenyl, lower alkoxyphenyl, lower alkylthio or 1-lower alkylindolyl,
  • a 1 is lower alkylene
  • n 0 or 1
  • R 5 is morpholino, piperidino, 4-phenylpiperazin-
  • a 2 is lower alkylene, or
  • R 6 and R 7 are each hydrogen, phenyl, lower
  • alkanoyl phenyl (lower) alkoxycarbonyl, pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower
  • alkylimino (phenyl) methyl, lower alkyl, phenyl (lower) alkyl, naphthyl (lower) alkyl, (mono- or di- or trilower alkyl) phenyl- (lower) alkyl, (mono- or di- or trilower alkoxy) phenyl (lower) alkyl, (mono- or di- or trihalo) phenyl (lower) alkyl,
  • a 3 is lower alkylene
  • R 2 is hydrogen
  • R 1 and R 2 are linked together to form
  • R 8 is amino or lower alkanoylamino
  • R 9 is hydrogen, phenyl (lower) alkoxycarbonyl or phenyl (lower) alkyl, and
  • R 3 is 1-lower alkylindolyl, benzofuranyl,
  • R 1 , R 2 and R 3 arellows.
  • R 1 is cyano, thiocarbamoyl,
  • R 4 is hydrogen or phenyl (lower) alkoxycarbonyl
  • a 1 is lower alkylene
  • R 4 is phenyl or 1-lower alkylindolyl
  • a 1 is lower alkylene
  • R 4 is hydrogen, lower alkyl, phenyl (lower) alkyl, di (lower alkoxy) phenyl (lower) alkyl, phenyl or lower alkoxyphenyl,
  • R 5 is morpholino, piperidino, 4-phenylpiperazin-
  • a 2 is lower alkylene, or
  • R 6 and R 7 are each hydrogen, phenyl, lower
  • alkanoyl phenyl (lower) alkoxycarbonyl, pyridyl (lower) alkyl, thienyl (lower) alkyl, 3,4-dihydroisoquinolinyl, (lower
  • alkylimino (phenyl)methyl, lower alkyl, phenyl (lower) alkyl, naphthyl (lower) alkyl, (mono- or di- or trilower
  • R 2 is hydrogen
  • R 3 is 1-lower alkylindolyl, benzofuranyl, dihydrobenzofuranyl or N,N-di (lower alkyl) aminophenyl.
  • the object compound (I) or a salt thereof can be prepared by reacting the compound (II) or a salt thereof with 1,1'-carbonyldiimidazole and continuously by reacting the obtained compound (III) or a salt thereof with the compound (IV) or a salt thereof.
  • the present reaction is usually carried out in a solvent such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, hexane,
  • a solvent such as dioxane, dimethylsulfoxide, dimethylformamide, diethylformamide, dimethylacetamide, benzene, hexane,
  • the reaction temperature is not critical and the
  • reaction is usually carried out under cooling, at ambient temperature or under heating.
  • the object compound (I) or a salt thereof can be
  • the reaction can be carried out in a similar manner to that of the aforementioned Process 1.
  • the object compound (I) or a salt thereof can be
  • Curtius Rearrangement reaction may be carried out by using a conventional reagent such as diphenylphosphoryl azide.
  • the reaction may be also carried out in the presence of an organic or inorganic base such as an alkali metal
  • N- (lower) alkylmorphorine N,N-di (lower) alkyIbenzylamine, or the like.
  • the reaction temperature is not critical, and the reaction is usually carried out under cooling to heating.
  • the object compound (I) or a salt thereof can be prepared by subjecting the compound (VIII) or a salt thereof to Curtius Rearrangement reaction and continuously by reacting the obtained compound (IX) or a salt thereof with the compound (II) or a salt thereof.
  • the object compound (I) of the present invention can be isolated and purified in a conventional manner, for example, extraction, precipitation, fractional crystallization, recrystallization, chromatography, and the like.
  • the object compound (I) thus obtained can be converted to its salt by a conventional method.
  • acceptable salt thereof may include a solvate [e.g.,
  • enclosure compound e.g., hydrate, etc.
  • the object compound (I) of the present invention are novel and exhibit pharmacological activities such as 5-HT antagonism, especially, 5-HT 2C antagonism, and the like and therefore are useful as 5-HT antagonist for treating or preventing central nervous system (CNS) disorders such as anxiety, depression, obsessive compulsive disorders,
  • CNS central nervous system
  • migraine migraine, anorexia, Alzheimer's disease, sleep disorders, bulimia, panic attacks, withdrawal from drug abuse such as cocaine, ethanol, nicotine and benzodiazepines,
  • the affinity of test drugs for the 5-HT 2C binding site can be determined by assessing their ability to displace
  • [ 3 H]-mesulergine in the rat prefrontal cortex was similar to that of Pazos et al, 1984.
  • the membrane suspension (500 ⁇ l) was incubated with
  • Test drugs (10 -6 M) were added in a volume of 100 ⁇ l. The total assay volume was 1000 ⁇ l.
  • IC 50 values were determined using a four parameter logistic program (DeLean 1978) and the pKi (the negative logarithm of the inhibition constant) calculated from the Cheng Prusoff equation where :
  • the object compound (I) of the present invention are used in the form of conventional pharmaceutical preparation which contains said compound as an active ingredient, in admixture with
  • pharmaceutically acceptable carriers such as an organic or inorganic solid or liquid excipient which is suitable for oral, parenteral and external administration.
  • pharmaceutical preparations may be in solid form such as tablet, granule, powder, capsule, or liquid form such as solution, suspension, syrup, emulsion, lemonade and the like.
  • auxiliary substances such as lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, terra alba, sucrose, corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cacao butter, ethylene glycol, and the like.
  • the dosage of the compound (I) may vary from and also depend upon the age, conditions of the patient, a kind of diseases or conditions, a kind of the compound (I) to be applied, etc. In general amounts between 0.01 mg and about 500 mg or even more per day may be administered to a patient. An average single dose of about 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 1 mg, 20 mg, 50 mg, 100 mg of the object compound (I) of the present invention may be used in treating diseases.
  • the following Preparations and Examples are given for the purpose of illustrating the present invention.
  • N-(Benzofuran-5-yl)-N'-(3-cyanophenyl)urea was prepared in a similar manner to that of Example 1. mp : 180-187°C
  • N-(Benzofuran-5-yl)-N'-(3-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
  • N-(1-Methylindol-5-yl)-N'-(3-piperidinomethylphenyl)urea was prepared in a similar manner to that of Example 13.
  • Example 16 N-(1-Methylindol-5-yl)-N'-(3-morpholinomethylphenyl)urea was prepared in a similar manner to that of Example 13.
  • N-(1-Methylindol-5-yl)-N'-(4-phthalimidomethylphenyl)- urea was prepared in a similar manner to that of Example 13.
  • N-[3-(1-Formylaminoethyl)phenyl]-N'-[1-methylindol-5- yl]urea was prepared in a similar manner to that of Example 13.
  • N-[3-(N-Methylanilino)methylphenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example 13.
  • N-(1-Methylindol-5-yl)-N'-[3-(1,2,3,4- tetrahydroquinolin-1-yl)methylphenyl]urea was prepared in a similar manner to that of Example 13.
  • N-(1-Methylindol-5-yl)-N'-(3-anilinomethylphenyl]urea was prepared in a similar manner to that of Example 13.
  • N-(1-Methylindol-5-yl)-N'-(3-phthalimidomethylphenyl)- urea was prepared in a similar manner to that of Example 13. mp : 222-226°C
  • N-(1-Methylindol-5-yl)-N'-(3-diphenylaminomethylphenyl)- urea was prepared in a similar manner to that of Example 13. mp : 194-195°C
  • N-[3-(1-Anilinoethyl)phenyl]-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
  • N-(8-Formylamino-5,6,7,8-tetrahydro-2-naphthyl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
  • N-(2-Benzyloxycarbonyl-l,2,3,4-tetrahydroisoquinolin-5- yl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
  • Example 32 N-(1-Benzyloxycarbonyl-1,2,3,4-tetrahydroquinolin-5-yl)- N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 13.
  • N-(1-Methylindol-5-yl)-N'-[3-[N-benzyloxycarbonyl-N-(4- methylbenzyl)aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 34.
  • Example 37 N-(3-Cyanophenyl)-N'-(4-dimethylaminophenyl)urea was prepared in a similar manner to that of Example 36.
  • N-(3-Cyanophenyl)-N'-(2,3-dihydrobenzo[b]furan-7-yl)urea was prepared in a similar manner to that of Example 36.
  • N-(1-Methylindol-5-yl)-N'-(4-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
  • N-(3-Thiocarbamoylphenyl)-N'-(4-dimethylaminophenyl)urea was prepared in a similar manner to that of Example 2.
  • N-(4-Amidinophenyl)-N'-(1-methylindol-5-yl)urea hydroiodide was prepared in a similar manner to that of
  • N-(1-Methylindol-5-yl)-N'-[4-(phenylamidino)phenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
  • N-(1-Methylindol-5-yl)-N'-[3-(3-phenylpropyl)- amidinophenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
  • N-(1-Methylindol-5-yl)-N'-[3-(2-phenylethyl)- amidinophenyl]urea hydroiodide was prepared in a similar manner to that of Example 6.
  • N-(4-Aminomethylphenyl)-N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 52.
  • N-(2,3-Dihydrobenzo[b]furan-7-yl)-N'-(3- aminomethylphenyl)urea was prepared in a similar manner to that of Example 52.
  • N-(1-Methylindol-5-yl)-N'-[3-[(4-methylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 57.
  • N-(1-Methylindol-5-yl)-N'-[3-(methylaminomethyl)- phenyl]urea maleate was prepared in similar manners to those of Example 34, and then Example 57.
  • N-(1-Methy ⁇ ndol-5-yl)-N'-(1,2,3,4- tetrahydroisoquinolin-7-yl)urea was prepared in a similar manner to that of Example 57.
  • N-(1-Methylindol-5-yl)-N'-(1,2,3,4- tetrahydroisoquinolin-5-yl)urea was prepared in a similar manner to that of Example 57.
  • N-(1-Methylindol-5-yl)-N'-(1,2,3,4-tetrahydroquinolin-5- yl)urea was prepared in a similar manner to that of Example 57.
  • N-(1-Methylindol-5-yl)-N'-(1,2,3,4-tetrahydroquinolin-7- yl)urea was prepared in a similar manner to that of Example
  • N-(8-Amino-5,6,7,8-tetrahydro-2-naphthyl)-N'-(1- methylindol-5-yl)urea was prepared in a similar manner to that of Example 64.
  • N-(1-Methylindol-5-yl)-N'-[3-[[(imino)(phenyl)methyl]- aminomethyl]phenyl]urea hydroiodide was prepared in a similar manner to that of Example 66.
  • N-(1-Methylindol-5-yl)-N'-[3-[[(1-methylindol-5- yl)(imino)methyl]aminomethyl]phenyl]urea hydroiodide was prepared in a similar manner to that of Example 66.
  • Example 66 prepared in a similar manner to that of Example 66.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2-fluorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N'-[3-[(3-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N'-[3-[(4-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N*-[3-[(4-chlorobenzylamino)- methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N'-[3-[(3,5-dichlorobenzylamino) methyl]phenyl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N'-[3-[(N-methyl-N-benzylamino)- methyl]phenyl] urea was prepared in a similar manner to that of Example 73.
  • N-(4-(Dibenzylaminomethyl)phenyl]-N'-[1-methylindol-5- yl]urea was prepared in a similar manner to that of Example 73.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2,6-dimethoxybenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-(3- pyridylmethylaminomethyl)phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2,5-difluorobenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2-methoxybenzyl)- aminomethyl] phenyl] urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-[(1-naphthyl)- methylaminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2,4,6-trimethoxybenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-[3-(1-Benzylaminoethyl)phenyl]-N'-(1-methylindol-5- yl)urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2,4,6-trimethylbenzyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-(Benzo[b]furan-7-yl)-N'-(3-cyanophenyl)urea was prepared in a similar manner to that of Example 1.
  • N-(Benzo[b]furan-7-yl)-N'-(3-thiocarbamoylphenyl)urea was prepared in a similar manner to that of Example 2.
  • N-(1-Methylindol-5-yl)-N'-[3-[(2-thienylmethyl)- aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-[[(3- trifluoromethoxyphenyl)methyl]aminomethyl]phenyl]urea was prepared in a similar manner to that of Example 84.
  • N'-(1-methylindol-5-yl)urea was prepared in a similar manner to that of Example 84.
  • N-(1-Methylindol-5-yl)-N'-[3-(phenethylammomethyl)- phenyl]urea was prepared in a similar manner to that of Example 84.

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Abstract

L'invention se rapporte à un composé de la formule (I) dans laquelle R1 représente cyano, thiocarbamoyle, un groupe de la formule (a) dans laquelle R4 représente hydrogène, alkyle inférieur pouvant présenter un aryle éventuellement substitué, un acyle, un aryle éventuellement substitué, un alkylthio inférieur ou 1-alkylindolyle inférieur, A1 représente alkylène inférieur, et m et n valent chacun 0 ou 1, un groupe de la formule -A2-R5 dans laquelle R5 représente morpholino, pipéridino, 4-arylpipérazine-1-yle, 1,2,3,4-tétrahydroisoquinoléine-2-yle ou imidazol-1-yle, et A2 représente alkylène inférieur ou un groupe de la formule (b) dans laquelle R6 et R7 représentent chacun hydrogène, aryle éventuellement substitué, acyle, pirydylalkyle(inférieur), thiénylalkyle(inférieur), 3,4-dihydroisoquinoléinyle, (alkylimino inférieur) (aryle éventuellement substitué), méthyle ou alkyle inférieur pouvant présenter un aryle éventuellement substitué, et A3 représente alkylène inférieur, et R2 représente hydrogène; ou bien R1 et R2 sont liés entre eux pour former les groupements (1), (2) ou (3) dans lesquels R8 représente amino ou acylamino, et R9 représente hydrogène, acyle ou alkyle inférieur pouvant présenter un aryle éventuellement substitué et R3 représente 1-alkylindolyle inférieur, benzofuranyle, dihydrobenzofuranyle ou aryle éventuellement substitué. L'invention se rapporte également à un sel pharmaceutiquement acceptable de ce composé qui peut être utilisé comme médicament dans le traitement prophylactique ou curatif des maladies induites par 5-HT.
PCT/JP1996/001500 1995-06-06 1996-06-04 Derives de l'uree utilises comme antagonistes de 5-ht WO1996039382A1 (fr)

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WO1998024785A1 (fr) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht
WO1999014197A1 (fr) * 1997-09-12 1999-03-25 Smithkline Beecham Plc Isoquinoleines substituees en tant qu'anticonvulsifs
WO1999015526A3 (fr) * 1997-09-19 1999-05-20 Smithkline Beecham Plc Nouveaux composes
WO1999025709A1 (fr) * 1997-11-18 1999-05-27 Smithkline Beecham P.L.C. Derives d'isoquinoline et leur utilisation therapeutique
WO1999067204A1 (fr) * 1998-06-22 1999-12-29 Astrazeneca Ab Nouveaux composes
WO2000008022A1 (fr) * 1998-08-05 2000-02-17 Smithkline Beecham Plc Derives uree
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
US6335445B1 (en) * 1997-03-24 2002-01-01 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
WO2002070467A1 (fr) * 2001-02-26 2002-09-12 4Sc Ag Derives de diphenyluree, de diamide d'acide diphenyloxalique et de diamide d'acide diphenylsulfurique et leur utilisation comme medicaments
WO2003087087A3 (fr) * 2002-04-09 2003-12-18 Astex Technology Ltd Composes pharmaceutiques
US7241758B2 (en) 1999-11-16 2007-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
EP2036564A1 (fr) 1999-12-06 2009-03-18 H.Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht
US7579352B2 (en) 1997-12-11 2009-08-25 Janssen Pharmaceutica N.V. Retinoic acid mimetic anilides
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US8076348B2 (en) 2005-08-08 2011-12-13 Astellas Pharma Inc. Acylguanidine derivative or salt thereof
AU2011253934B2 (en) * 2004-06-17 2012-11-22 Cytokinetics, Inc. Substituted urea derivatives for treating cardiac diseases
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
US8513257B2 (en) 2004-06-17 2013-08-20 Cytokinetics, Incorporated Ureas and their use in the treatment of heart failure
WO2024178127A1 (fr) * 2023-02-21 2024-08-29 1Cbio, Inc. Composés hétérocycliques et procédés pour les utiliser

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CA2557158A1 (fr) * 2004-02-20 2005-09-01 Astellas Pharma Inc. Agents prophylactiques contre la migraine
US20230124361A1 (en) * 2020-02-12 2023-04-20 Curadev Pharma Pvt. Ltd. Small molecule sting antagonists

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WO1992005170A1 (fr) * 1990-09-13 1992-04-02 Beecham Group Plc Urees d'indole utilisees comme antagonistes de recepteur de 5-ht
WO1993018028A1 (fr) * 1992-03-12 1993-09-16 Smithkline Beecham Plc Derives d'indole utilises comme antagonistes de 5ht¿1c?
WO1994014801A1 (fr) * 1992-12-29 1994-07-07 Smithkline Beecham Plc Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b?
WO1995006044A1 (fr) * 1993-08-20 1995-03-02 Smithkline Beecham Plc Derives d'amide et d'uree en tant qu'antagonistes du recepteur 5ht1d

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WO1992005170A1 (fr) * 1990-09-13 1992-04-02 Beecham Group Plc Urees d'indole utilisees comme antagonistes de recepteur de 5-ht
WO1993018028A1 (fr) * 1992-03-12 1993-09-16 Smithkline Beecham Plc Derives d'indole utilises comme antagonistes de 5ht¿1c?
WO1994014801A1 (fr) * 1992-12-29 1994-07-07 Smithkline Beecham Plc Derives heterocycliques de l'uree antagonistes de 5ht2c et 5h¿2b?
WO1995006044A1 (fr) * 1993-08-20 1995-03-02 Smithkline Beecham Plc Derives d'amide et d'uree en tant qu'antagonistes du recepteur 5ht1d

Cited By (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998024785A1 (fr) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Derives d'indole-uree presentant des proprietes d'antagonistes de 5-ht
US6335445B1 (en) * 1997-03-24 2002-01-01 Societe De Conseils De Recherches Et D'applications Scientifiques (S.C.R.A.S.) Derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them
WO1999014197A1 (fr) * 1997-09-12 1999-03-25 Smithkline Beecham Plc Isoquinoleines substituees en tant qu'anticonvulsifs
WO1999015526A3 (fr) * 1997-09-19 1999-05-20 Smithkline Beecham Plc Nouveaux composes
WO1999025709A1 (fr) * 1997-11-18 1999-05-27 Smithkline Beecham P.L.C. Derives d'isoquinoline et leur utilisation therapeutique
US6274594B1 (en) 1997-11-18 2001-08-14 Smithkline Beecham P.L.C. Isoquinoline derivatives and their therapeutical use
US7579352B2 (en) 1997-12-11 2009-08-25 Janssen Pharmaceutica N.V. Retinoic acid mimetic anilides
WO1999067204A1 (fr) * 1998-06-22 1999-12-29 Astrazeneca Ab Nouveaux composes
US6777561B1 (en) 1998-06-22 2004-08-17 Astrazeneca Canada Inc. Compounds
WO2000008022A1 (fr) * 1998-08-05 2000-02-17 Smithkline Beecham Plc Derives uree
US7241758B2 (en) 1999-11-16 2007-07-10 Boehringer Ingelheim Pharmaceuticals, Inc. Compounds useful as anti-inflammatory agents
EP1232150B1 (fr) * 1999-11-16 2007-10-10 Boehringer Ingelheim Pharmaceuticals Inc. Derives d'uree utilises comme agents anti-inflammatoires
EP2036564A1 (fr) 1999-12-06 2009-03-18 H.Lundbeck A/S Combinaison d'un inhibiteur du recaptage de la serotonine et d'un antagoniste, d'un agoniste inverse ou d'un agoniste partiel de 5-ht
US7229986B2 (en) 2000-05-16 2007-06-12 Takeda Pharmaceutical Company Ltd. Melanin-concentrating hormone antagonist
WO2001087834A1 (fr) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Antagoniste de l'hormone de concentration de la melanine
US6949567B2 (en) 2001-02-26 2005-09-27 4Sc Ag Compounds for the treatment of protozoal diseases
WO2002070467A1 (fr) * 2001-02-26 2002-09-12 4Sc Ag Derives de diphenyluree, de diamide d'acide diphenyloxalique et de diamide d'acide diphenylsulfurique et leur utilisation comme medicaments
WO2003087087A3 (fr) * 2002-04-09 2003-12-18 Astex Technology Ltd Composes pharmaceutiques
US10035770B2 (en) 2004-06-17 2018-07-31 Cytokinetics, Incorporated Compounds, compositions and methods
US10385023B2 (en) 2004-06-17 2019-08-20 Cytokinetics, Inc. Compounds, compositions and methods
AU2011253934B2 (en) * 2004-06-17 2012-11-22 Cytokinetics, Inc. Substituted urea derivatives for treating cardiac diseases
US12264133B2 (en) 2004-06-17 2025-04-01 Cytokinetics, Incorporated Compounds, compositions and methods
US8513257B2 (en) 2004-06-17 2013-08-20 Cytokinetics, Incorporated Ureas and their use in the treatment of heart failure
AU2011253934C1 (en) * 2004-06-17 2013-08-22 Cytokinetics, Inc. Substituted urea derivatives for treating cardiac diseases
US8871769B2 (en) 2004-06-17 2014-10-28 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
US10975034B2 (en) 2004-06-17 2021-04-13 Cytokinetics, Inc. Compounds, compositions and methods
US9150564B2 (en) 2004-06-17 2015-10-06 Cytokinetics, Inc. Compounds, compositions and methods
US9643925B2 (en) 2004-06-17 2017-05-09 Cytokinetics, Incorporated Compounds, compositions and methods
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US8076348B2 (en) 2005-08-08 2011-12-13 Astellas Pharma Inc. Acylguanidine derivative or salt thereof
US8871768B2 (en) 2005-12-15 2014-10-28 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
WO2024178127A1 (fr) * 2023-02-21 2024-08-29 1Cbio, Inc. Composés hétérocycliques et procédés pour les utiliser

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GB9511355D0 (en) 1995-08-02
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