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WO1998035941A1 - Nouveaux derives du benzolactame, et compositions a usage medical les contenant - Google Patents

Nouveaux derives du benzolactame, et compositions a usage medical les contenant Download PDF

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Publication number
WO1998035941A1
WO1998035941A1 PCT/JP1998/000597 JP9800597W WO9835941A1 WO 1998035941 A1 WO1998035941 A1 WO 1998035941A1 JP 9800597 W JP9800597 W JP 9800597W WO 9835941 A1 WO9835941 A1 WO 9835941A1
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Prior art keywords
substituent
lower alkyl
compound
optionally
aryl
Prior art date
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PCT/JP1998/000597
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English (en)
Japanese (ja)
Inventor
Sanji Hagishita
Tetsuo Okada
Masafumi Fujimoto
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to AU58804/98A priority Critical patent/AU5880498A/en
Publication of WO1998035941A1 publication Critical patent/WO1998035941A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel benzolactam derivative and a pharmaceutical composition containing the same.
  • the present invention relates to compounds useful as medicaments and uses thereof. Specifically, a novel benzolactam derivative having an anti-feeding action, an anti-myocardial infarction action, an anti-angina pectoris action, and a hypotensive action, and an anti-feeding agent containing the same, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, Regarding antihypertensive agent.
  • a novel benzolactam derivative having an anti-feeding action, an anti-myocardial infarction action, an anti-angina pectoris action, and a hypotensive action, and an anti-feeding agent containing the same, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, Regarding antihypertensive agent.
  • Neuropeptide Y (hereinafter abbreviated as NPY) is a peptide consisting of 36 amino acids and is located in the central nervous system such as the hypothalamus, hippocampus, medulla oblongata, and spinal cord, and in peripheral tissues the heart, embryo, spleen, and gastrointestinal tract Etc. are distributed in nerve fibers of the blood vessel wall.
  • N P Y One of the central actions of N P Y is the feeding promoting action. It has been known that administration of NPY into the rat intraventricular and paraventricular nuclei stimulates eating behavior and increases the amount of carbohydrate ingested. It also plays an important role in regulating the release of neurotransmitters, especially in the hypothalamus.
  • NPY In peripheral tissues, NPY is secreted from nerve fibers together with noradrenaline, causing smooth muscle contraction of blood vessels and the like and myocardial contraction. Noradrenaline causes transient contraction, whereas NPY has a persistent contractile action, so vasomotion is governed by NPY when noradrenaline withers due to strong or repeated stimulation It has been implicated in circulatory disorders.
  • NPY antagonists include benzothiophene derivatives, sulfonylquinoline derivatives described in USP 5,504,941, USP 5,555,241, WO96 / 144,073, Various compounds have been reported, including benzylamine derivatives, but all have completely different structures from the compound of the present invention. Disclosure of the invention
  • the present application provides a novel compound having excellent NPY antagonism. Specifically, the present invention is based on formula (I):
  • R 1 and R 2 are each independently hydrogen, halogen, hydroxy, nitro, lower alkyl optionally having substituents, lower alkoxy optionally having substituents, carboxy An optionally substituted carbamoyl, an optionally substituted lower alkoxycarbonyl or an optionally substituted lower alkoxycarbonylamino,
  • lower alkyl optionally having substituent (s) (However, excluding unsubstituted methyl.
  • the substituent herein means (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl,
  • Aryl lower alkyl optionally having substituent (s)
  • the substituents are (1) halogen, (2) hydroxy, (3) benzyloxy, (4) substituent (where the substituent is lower alkoxycarbonyl, acyl, aryl, substituted amino or imino) (5) lower alkoxy optionally having a substituent, (6) carboxy, (7) lower alkoxycarbonyl,
  • R 16 is an imino or a substituent which may have a substituent (where the substituent is a lower alkoxycarbonyl or cyano) (where the substituent is a cyano or nitro)
  • R 16 is an imino or a substituent which may have a substituent (where the substituent is a lower alkoxycarbonyl or cyano) (where the substituent is a cyano or nitro)
  • R 16 is an imino or a substituent which may have a substituent (where the substituent is a lower alkoxycarbonyl or cyano) (where the substituent is a cyano or nitro)
  • R 17 is amino, lower alkylthio or aryloxy which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl),
  • the substituents are (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8 ) Cycloalkenyl, (9) nitro, (10) cyano, (11) —NH C (—NR 6 ) NR 7 R 8 (where R 6 is hydrogen, cyano or nitro, and R 7 and R 8 are each Independently hydrogen or lower alkyl) or
  • Aryl lower alkyl optionally having substituent (s)
  • Aryloxy optionally having a substituent or
  • R 9 and R 1 ° are each independently hydrogen, hydroxy, halogen, acyl, lower alkyl optionally having substituent (s), lower alkyl which may have substituent (s) Lower alkyl, aryl which may have a substituent, heterocyclyl which may have a substituent, lower alkyl which may have a substituent, cyclo which may have a substituent Alkyl, arylsulfonyl which may have a substituent or amino which may have a substituent)
  • R 11 is hydrogen, hydroxy, lower alkyl which may have a substituent, lower alkoxy which may have a substituent, amino which may have a substituent, Aryl which may have, aryl lower alkyl which may have a substituent or heterocyclyl which may have a substituent,
  • R 12 and R 13 are each independently hydrogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), may have substituent (s) Diamino, aryl which may have a substituent, lower alkyl which may have a substituent, aryloxy which may have a substituent, heterocyclyl which may have a substituent or R 12 is a lower alkyl which may have a substituent, or R 12 and R 13 are taken together to form an optionally substituted heterocyclyl),
  • R 14 and R 15 are each independently hydrogen, lower alkyl which may have a substituent, aryl which may have a substituent or May also be aryl lower alkyl
  • X is CH 2 , S or ⁇
  • n 1 or 2.
  • R 3 is lower alkyl which may have a substituent
  • R 4 is NHCONR 9 R 1 G , and R 9 and R 1 . Is not an aryl group which may have a substituent,
  • R 3 is unsubstituted aryl lower alkyl, and R 4 is NHCOR 5 , R 5 is not lower alkyl which may have a substituent,
  • R 5 is NHC 0 NR 9 R 10 .
  • the present invention also provides a drug containing Compound (I) as an active ingredient, more specifically, an NP antagonist, and more specifically, an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and a hypotensive agent. Further, the present invention provides a method for suppressing eating and a method for treating myocardial infarction, angina pectoris and hypertension, characterized by administering the compound (I). In yet another aspect, the present invention provides the use of the compound (I) for producing a medicament for controlling anorexia and treating myocardial infarction, angina and hypertension.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • “Lower alkyl” means straight-chain or branched alkyl having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and isoptyl. , Sec —butyl, tert —butyl, n —pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n —heptyl, isoheptyl, n —octyl, isooctyl, n —nonyl and n —decyl, etc. Is included.
  • “Lower alkyl optionally having substituent (s)” means lower alkyl optionally substituted at one or more substituents.
  • the "lower alkyl optionally having substituent (s)" for R 3 means that the unsubstituted methyl is Not included, examples of the substituent include: (i) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl, (7) lower alkoxycarbonyl, ( 8) may have a substituent group Ashiru, (9) Amino, (10) nitro, (11) Xia Bruno, (12) - NHC (- NR 1 8) NR 1 9 R 20 ( wherein R 1 8 , R 19 and R 20 are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) Rubamoyl which may be substituted by lower alkyl.
  • R 4 is “V) lower alkyl optionally having substituent (s)
  • examples of the lower alkyl substituent include halogen, hydroxy, lower alkoxy, acyl, carboxyl, lower alkoxycarbonyl, and cycloalkyl.
  • the substituent is a lower alkyl, an aryl-lower alkyl which may have a substituent, and a carbamoyl which may have a substituent (where the substituent is a lower alkyl, aryl, Lower alkyl, etc.),
  • Examples of the substituent for the “lower alkyl optionally having substituent (s)” for R 5 include (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, and (5) lower alkoxy. Carbonyl, (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) nitro,
  • lower alkyl optionally having substituent (s) are not particularly limited. In the case where there is no bond, examples thereof include halogen, hydroxy, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, amino, nitro, cyano and the like.
  • alkyl moiety of “lower alkoxy”, “lower alkoxycarbonyl” and “lower alkoxyl ryponylamino” is the same as the above “lower alkyl”.
  • substituent of "lower alkoxy optionally having substituent (s)” include hydroxy, halogen, lower alkoxy, acyl, carboxyl, lower alkoxycarbonyl, cycloalkyl, amino, nitro and cyano.
  • Aryl includes phenyl, naphthyl, anthracenyl, indenyl, phenanthryl and the like.
  • Aryl optionally having a substituent means a group optionally having one or more substituents at any position of the above aryl.
  • substituent of the “aryl which may have a substituent” of R 9 and R 10 include, for example, halogen, hydroxy, lower alkyl which may have a substituent, and a substituent.
  • Aryl lower alkyl, aryl lower alkoxy which may have a substituent (lower alkyl, halogen or hydroxy) and Substituent (lower alkyl, halogen or human Dorokishi) heterocyclyl may have a hetero Scicli Ruo alkoxy, and the like to which may have
  • aryl which is condensed with a saturated carbocycle, such as indanyl.
  • substituents of "aryl which may have a substituent (s)" include, for example, halogen, hydroxy, lower alkyl, lower alkoxy, carboxyl, lower alkoxycarbonyl, cycloalkyl, cycloalkyl Alkenyl, acyl, amino, nitro, cyano, aryl and the like can be mentioned.
  • Aryl lower alkyl which may have a substituent (s) means aryl lower alkyl which may be substituted with one or more substituents at any position of a lower alkyl moiety or an aryl moiety.
  • substituents include halogen, hydroxy, lower alkyl, lower alkoxy which may be substituted with aryl, carboxy, lower alkoxycarbonyl, acyl, cycloalkyl, cycloalkenyl, amino, nitro and cyano, unless otherwise specified. And the like.
  • optionally substituted amino substituted amino
  • substituted amino substituted lower alkyl, optionally substituted lower alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (However, acetyl is excluded), lower alkoxycarbonyl, arylalkoxycarbonyl, lower alkylsulfonyl, and optionally substituted rubamoyl
  • R 16 is an imino or a substituent which may have a substituent (where the substituent is lower alkoxycarbonyl or cyano). Is nitro
  • R 17 is a lower alkylene which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl). Or (13) heterocyclyl lower alkyl and the like.
  • aryl portion of “aryloxy” is synonymous with the above “aryl”, and “aryloxy optionally having a substituent” means that aryl has one or more substituents at any position. Means good. Examples of the substituent include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, nitro, cyano and the like.
  • aryl part and the lower alkyl part of “aryl lower alkoxy” are the same as the above “aryl” and “lower alkyl", respectively.
  • Aryl lower alkoxy which may have a substituent means that the aryl or lower alkyl moiety may have one or more substituents at any position, and the substituent Examples thereof include halogen, hydroxy, lower alkoxy, aryl lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, amino, nitro, cyano and the like.
  • Heterocyclyl means a heterocyclyl having at least one heteroatom in the ring arbitrarily selected from ⁇ , S and N. Specifically, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl , Triazinyl, pyrrolinyl, isoxazolyl, oxazolyl, oxaziazolyl, isotizazolyl, thiazolyl, thiadiazolyl, furyl, chenyl, ethyleneoxydinyl, dioxanyl, thiiranyl, oxaxiolanil, azedinidinyl, piranilinyl, piranilinyl , Morpholinyl, benzazepine, etc., monocyclic heterocyclyl and indolyl, benzimidazolyl, indazolyl, indazo
  • heterocyclyl optionally having substituent (s) examples include lower alkyl, halogen, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, aryl, substituent (halogen, hydroxy, lower alkoxycarbonyl) Optionally substituted with lower alkyl, heterocyclyl, carbamoyl, cyano, nitro, and optionally substituted (lower alkyl, halogen or hydroxy) And arylsulfonyl, oxo, and the like, and may have a substituent at one or more arbitrary positions.
  • heterocyclyl part and the lower alkyl part of “heterocyclyl lower alkyl” are the same as the above “heterocyclyl” and “lower alkyl".
  • “Heterocyclyl lower alkyl optionally having substituent (s)” means heterocyclyl lower alkyl optionally having one or more substituents at any position of heterocyclyl and lower alkyl. Examples of the substituent include the above-mentioned "heterocyclyl optionally having substituent (s)” and the substituent of "lower alkyl optionally having substituent (s)".
  • heterocyclyl of "heterocyclylamino optionally having substituent (s)", “heterocyclyloxy optionally having substituent (s)” and “heterocyclylthio optionally having substituent (s)” The moieties and substituents are the same as in the above “heterocyclyl optionally having substituent (s)”.
  • Preferred examples of the heterocyclyl moiety include imidazolyl and triazolyl, and preferred examples of the substituent include alkyl, amino and phenyl.
  • amino optionally having substituent (s) includes substituted and unsubstituted amino
  • substituents may have one or two substituents.
  • substituents include a hydroxy, a lower alkyl optionally having a substituent, and a substituent unless otherwise specified.
  • Acyl means an acyl having 1 to 10 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isoptyryl, benzoyl, 'relyl, bivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl and crotonoyl, and cyclohexyl.
  • Xan's power Includes aliphatic acyl such as luponyl or benzoyl, aroyl and the like.
  • substituent of the "optionally substituted acyl” include halogen, hydroxy, lower alkyl, lower alkoxy, ethoxylate, lower alkoxycarbonyl, acyl, and optionally substituted amino, nitro, Examples include cyano, aryl, lower aryl alkyl, and heterocyclyl.
  • optionally substituted rubamoyl includes substituted and unsubstituted rubamoyl, and the substituents include hydroxy, lower alkyl, cycloalkyl, aryl, and substituents. And lower alkyl, amino and lower alkylamino.
  • Cycloalkyl is a carbon ring having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, bicyclopentyl, bicyclohexyl, and bicyclo Heptyl, bicyclooctyl, bicyclononyl, bicyclodecyl and the like.
  • cycloalkyl optionally having substituent (s) includes hydroxy, halogen, lower alkyl, lower alkoxycarbonyl, lower alkoxy, aryl, heterocyclyl, etc., and one or more arbitrary Positions may be substituted with these substituents.
  • “Cycloalkenyl” is a carbon ring having 3 to 10 carbon atoms having one or more double bonds at any position.
  • cyclopentenyl cyclobutenyl, cyclopentyl And phenyl, cyclohexenyl, cycloheptenyl, cycloheptenyl, cyclooctenyl, cyclohexenyl, cyclononenyl, cyclodecenyl and the like.
  • the term "compound (I)” also includes a pharmaceutically acceptable salt capable of forming each compound.
  • pharmaceutically acceptable salts include salts of mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, and hydrobromic acid; formic acid, acetic acid, tartaric acid, lactic acid, citrate, Salts of organic acids such as fumaric acid, maleic acid, and succinic acid: salts of organic bases such as ammonium, trimethylammonium, and triethylammonium; salts of alkali metals such as sodium and potassium or calcium; Salts of alkaline earth metals such as magnesium can be mentioned.
  • the compound (I) of the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be bound to an arbitrary number of water molecules.
  • the compound of the present invention can exist as an optical isomer, and the present invention includes each optically active isomer and a racemic mixture thereof.
  • All of the compounds (I) have an antifeedant effect, a therapeutic effect on myocardial infarction, a therapeutic effect on angina pectoris, and an antihypertensive effect.
  • the following compounds are particularly preferred.
  • R 1 and R 2 are each independently hydrogen, hydroxy, or an optionally substituted lower alkoxy (hereinafter abbreviated as R 12-1) compound, more preferably each independently A hydrogen or lower alkoxy (hereinafter abbreviated as R 12 -2)
  • R 3 lower alkyl optionally substituted with R 3
  • the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) A lower alkyl optionally having a substituent (wherein the substituent is a lower alkyloxy group such as luponyl, acyl, aryl, substituted amino or imino),
  • the substituent means lower alkyl, arylalkyl which may have a substituent, lower alkyl, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl) , Lower alkylsulfonyl or optionally substituted rubamoyl),
  • R 16 is an imino or a substituent which may have a substituent (where the substituent is lower alkoxycarbonyl or cyano) (where the substituent is cyano or nitro)
  • R 17 is a lower alkylene which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl), which is an amino, a lower alkylthio or an aryloxy which may have a substituent.
  • R 3 is abbreviated as R 3-1)
  • R 3 is aryl lower alkyl which may have a substituent, and the substituent is (2) hydroxy, (3) benzyloxy,
  • the substituent means lower alkyl, aryl lower alkyl which may have a substituent, heterocyclyl lower alkyl, heterocyclylcarbonyl, acyl (excluding acetyl), lower alkoxycarbonyl, arylalkoxycarbonyl) , A lower alkylsulfonyl or an optionally substituted rubamoyl Yes) or
  • R 16 ′ is imino optionally substituted with tert-butoxycarbonyl and R 17 ′ is amino optionally substituted with tert-butoxycarbonyl
  • R 3 is abbreviated as R 3-2
  • R 3 is an aryl lower alkyl which may have a substituent [wherein the substituent means a substituent (l-rubamoyl, lower-alkyl lumbamoyl, lower-alkylaminocarbamoyl or tert-butoxycarbonyl)] (Hereinafter, R 3 is abbreviated as R 3-3);
  • R 3 is an aryl lower alkyl which may have a substituent [wherein the substituent is an amino which may have a substituent (lower alkyl group rubamoyl or tert-butoxycarbonyl)].
  • R 3-4 A compound (hereinafter, R 3 is abbreviated as R 3-4),
  • R 3 is an aryl lower alkyl which may have a substituent [wherein the substituent is an unsubstituted amino, NH C ONH—iso-Pr, NH C ONH—tert_Bu or NH B oc] (hereinafter, R 3 is abbreviated as R 3-5), 3) R 4 force
  • the substituents are (1) nodogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl, (6) acyl, (7) cycloalkyl, (8 ) Cycloalkenyl, (9) nitro, (10) cyano,
  • R 9 ′ and R 10 ′ each independently represent hydrogen, acyl, lower alkyl optionally having substituents, aryl lower alkyl optionally having substituents, and substituents Optionally substituted, heterocyclyl optionally substituted, heterocyclyl lower alkyl, cycloalkyl, arylsulfonyl or optionally substituted amino),
  • R 11 ′ is hydrogen, lower alkyl which may have a substituent or aryl which may have a substituent
  • R 12 ′ and R 13 ′ each independently represent hydrogen. , Hydroxy, aryl, optionally substituted, amino or heterocyclyl
  • R 4 is abbreviation R 4 — 1)
  • NHC ONR 9 '' R 1 0 '' (Where R 9 ′′ and R 1 o ′′ are each independently (1) hydrogen, (2) lower alkyl optionally substituted with hydroxy,
  • R 1 1 '' is Ri a lower alkyl der have a hydrogen or human Dorokishi
  • R 1 2 '' and R 1 3 '' are each independently hydrogen, substituted May be reel or heterocyclyl
  • R 14 ′′ and R 15 ′′ are each independently hydrogen, aryl or aryl lower alkyl
  • R 4 is abbreviated as R 4-2)
  • R 1 '' is Ri a lower alkyl der have a hydrogen or hydroxy
  • R 1 2 '''and R 1 3' '' is one of hydrogen, the other is hydrogen, heat Dorokishi Or phenyl or benzothiazolyl which may have
  • R 14 '''and R 15 ''' are hydrogen and the other is phenyl or benzyl
  • R 4 is abbreviated as R 4-3)
  • R 9 ′ ′′ and R 10 ′ ′ ′ is hydrogen and the other is (1) lower alkyl
  • R 4 is abbreviated as R 4-4)
  • R 4 is abbreviated as R 4-5
  • R 1 and R 2 are R 12-1, and R 3 is R 3-1. More preferably R 1 and R 2 R 1 2-1, R 3 is R 3 - compound is 2, more preferably R 1 and R 2 R 1 2-2, R 3 is R 3 — A compound that is 3,
  • R 1 and R 2 are R 12-2, and R 3 is R 3-4.
  • R 1 and R 2 R 1 2-1, R 4 is R 4 - compound is 2, more preferably R 1 and R 2 R 1 2-2, R 4 is R 4 — A compound that is 3,
  • R 1 and R 2 are R 12-2 and R 4 is R 4-14;
  • R 1 and R 2 are R 12-2, and X is CH 2 ,
  • R 3 is R 3 2
  • R 4 is R 4-2
  • R 3 is R 3 2
  • R 4 is R 4-4
  • R 3 is R 3 2
  • R 4 is R 4-5
  • R 3 is R 3 3
  • R 4 is R 4-2
  • R 3 is R 3 3
  • R 4 is R 4-4
  • R 3 is R 3 3 R 4 is R 4-5, A compound wherein R 3 is R 3-4 and R 4 is R 4-2,
  • R 3 is R 3- 4, compounds wherein R 4 is R 4-4, and most preferably R 3 is R 3- 5, compounds wherein R 4 is R 4-5,
  • R 3 is R 3 _ 3 and X is CH 2 ;
  • R 1 and R 2 are R 12-1, R 3 is R 3-1, and R 4 is R 4-1,
  • R 1 and R 2 are R 12-1, R 3 is R 3-1 and R 4 is R 4-12,
  • R 1 and R 2 are R 12-1, R 3 is R 3-1 and R 4 is R 4-3,
  • R 1 and R 2 are R 12-2, R 3 is R 3-1 and R 4 is R 4-4,
  • R 1 and R 2 are R 12-2, R 3 is R 3-1 and R 4 is R 4-5,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-2, and R 4 is R 4-1,
  • R 1 and R 2 are R 12—1, R 3 is R 3—2, and R 4 is R 4—2 Compound,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-2, and R 4 is R 4-3,
  • R 1 and R 2 are R 12-2, R 3 is R 3-2, and R 4 is R 4-4;
  • R 1 and R 2 are R 12-2, R 3 is R 3-2 and R 4 is R 4-5;
  • R 1 and R 2 are R 12 -1, R 3 is R 3-3, and R 4 is R 4-1,
  • R 1 and R 2 are R 12 -1, R 3 is R 3 -3 and R 4 is R 4-2,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3, and R 4 is R 4-3,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3 and R 4 is R 4-4,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3 and R 4 is R 4-5,
  • R 1 and R 2 are R 12 _ 1, R 3 is R 3-4, and R 4 is R 4-1,
  • R 1 and R 2 are R 12 -1, R 3 is R 3 -4 and R 4 is R 4-2
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and R 4 is R 4-3,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and R 4 is R 4-4,
  • R 1 and R 2 is R 1 2-2, R 3 is R 3- 4, R 4 is a R 4-5 Compound,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, and R 4 is R 4-1,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, and R 4 is R 4-2,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, and R 4 is R 4-3,
  • R 1 and R 2 are R 12-3, R 3 is R 3-5, and R 4 is R 4-4,
  • R 1 and R 2 are R 12-3, R 3 is R 3-5, and R 4 is R 4-5,
  • R 1 and R 2 is R 1 2- 1, R 3 is R 3- 1, X is CH 2 der Ru compound, R 1 and R 2 is R 1 2-1, A compound wherein R 3 is R 3-2 and X is CH 2 ;
  • R 1 and R 2 are R 12-2, R 3 is R 3-3 and X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and X is CH 2 ,
  • R 1 and R 2 are R 12-1, R 4 is R 4-2, and X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 4 is R 4-3 and X is CH 2 , More preferably, a compound wherein R 1 and R 2 are R 12-3, R 4 is R 4-4, and X is CH 2 ,
  • R 3 is R 3-1, R 4 is R 4-3 and X is CH 2 ;
  • R 3 is R 3-1, R 4 is R 4-4 and X is CH 2 ;
  • R 3 is R 3-1 and R 4 is R 4-5 and X is CH 2 ;
  • R 3 is R 3-2, R 4 is R 4-5, and X is CH
  • R 3 is R 3-3, R 4 is R 4-5 and X is CH 2
  • R 3 is R 3-4 and R 4 is R 4-5
  • X is CH 2
  • R 1 and R 2 are R 12 -1, R 3 is R 3-1 and R 4 is R 4-1;
  • R 1 and R 2 are R 12-1, R 3 is R 3-2, and R 4 is R 4-11,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-3, and R 4 is R 4-1,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and R 4 is R 4-1,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, and R 4 is R 4-1,
  • R 1 and R 2 are R 12-1, R 3 is R 3-1, and R 4 is R 4-2,
  • R 1 and R 2 are R 12 — 1, R 3 is R 3 — 2, and R 4 is R 4 -2,
  • R 1 and R 2 are R 12 -1, R 3 is R 3 -3 and R 4 is R 4-2,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and R 4 is R 4-2,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, and R 4 is R 4-2,
  • R 1 and R 2 are R 12—1, R 3 is R 3—1, and R 4 is R 4—3 Compound,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-2, and R 4 is R 4-3,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3, and R 4 is R 4-3,
  • R 1 and R 2 are R 12 — 2, R 3 is R 3 — 4, and R 4 is R 4 — 3,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, and R 4 is R 4-3,
  • R 1 and R 2 are R 12 — 1, R 3 is R 3 — 1, and R 4 is R 4 — 4,
  • R 1 and R 2 are R 12 — 1, R 3 is R 3 — 2, and R 4 is R 4 — 4,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3 and R 4 is R 4-4,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and R 4 is R 4-4,
  • R 1 and R 2 are R 12-3, R 3 is R 3-5, and R 4 is R 4-4,
  • R 1 and R 2 are R 12 _1, R 3 is R 3-1 and R 4 is R 4-5,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-2 and R 4 is R 4-5,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3 and R 4 is R 4-5,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, and R 4 is A compound which is R 4-5,
  • R 1 and R 2 are R 12-3, R 3 is R 3-5, and R 4 is R 4-5,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-2, R 4 is R 4 -1 and X is CH 2 ,
  • R 1 and R 2 are R 12 -1, R 3 is R 3 -3, R 4 is R 4-1 and X is CH 2 ,
  • R 1 and R 2 are R 12 — 2, R 3 is R 3 — 4, R -1 is R 4-1, and X is CH 2,
  • R 1 and R 2 are R 12-2, R 3 is R 3 — 5, R 4 is R 4-1 and X is CH 2 ,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-1, R 4 is R 4-2, and X is CH 2 ;
  • R 1 and R 2 are R 12 -1, R 3 is R 3 — 2, R 4 is R 4-2, and X is CH 2 ,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-3, R 4 is R 4-2 and X is CH 2 ;
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, R 4 is R 4-2 and X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, R 4 is R 4-2, and X is CH 2 ,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-1, R 4 is R 4-3, and X is CH 2 ,
  • R 1 and R 2 are R 12 2—1, R 3 is R 3—2, R 4 is R 4—3, A compound wherein X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 3 is R 3-3, R 4 is R 4-3, and X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, R 4 is R 4-3 and X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 3 is R 3-5, R 4 is R 4-3, and X is CH 2 ,
  • R 1 and R 2 are R 12 -1, R 3 is R 3-1, R 4 is R 4-4, and X is CH 2 ;
  • R 1 and R 2 are R 12-2, R 3 is R 3-3, R 4 is R 4-4 and X is CH 2 ,
  • R 1 and R 2 are R 12-2, R 3 is R 3-4, R 4 is R 4-4, and X is CH 2 ,
  • R 1 and R 2 are R 12-3, R 3 is R 3-5, R 4 is R 4-4 and X is CH 2
  • R 1 and R 2 are R 12 -1, R 3 is R 3 -1, R 4 is R 4 -5 and X is CH,
  • R 1 and R 2 are R 12-1, R 3 is R 3-2, R 4 is R 4-5 and X is CH 2 ;
  • R 1 and R 2 are R 12-2, R 3 is R 3-3, R 4 is R 4-5 and X is CH 2 ;
  • R 1 and R 2 are R 12-2, R 3 is R 3 _4, R 4 is R 4-5, and X is CH 2 ,
  • R 1 and R 2 are R 12—3, R 3 is R 3—5, and R 4 is A compound wherein R 4—5 and X is CH 2
  • compound b is obtained by reducing compound a.
  • the reduction reaction uses, for example, palladium-carbon, triphenylphosphine-water, tin (II) chloride, lithium aluminum hydride, etc., and alcohol tetrahydrofuran such as methanol, ethanol, etc. as a solvent.
  • the reaction may be carried out under conditions that do not impair other functional groups.
  • compound b has an acetic acid derivative (eg, guanidinoacetic acid, (1—trityl—1H—imidazo-l- 4-yl) acetic acid, N—C bz _ i3— Alanine) to produce the target compound by a coupling reaction.
  • acetic acid derivative eg, guanidinoacetic acid, (1—trityl—1H—imidazo-l- 4-yl
  • reaction may be carried out using ice-cooled to room temperature, preferably ice-cooled, for several tens of hours using tetrahydrofuran, dimethylformamide, getyl ether, dichloromethane, or the like. If necessary, triethylamine, dimethylaminopyridine or the like may be used as a catalyst, and the reaction may be carried out in the presence of 1-hydroxybenzotriazole.
  • the amide compound can be prepared by a conventional method using an ordinary acylating agent corresponding to the target compound (for example, acid chlorides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride, active esters, etc.). Can be manufactured.
  • an ordinary acylating agent corresponding to the target compound for example, acid chlorides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride, active esters, etc.
  • an alkyl carbamate compound group can be obtained by reacting compound b with a carbonic acid carbonate (eg, alkyl chlorocarbonate, arylalkyl carbonate).
  • a carbonic acid carbonate eg, alkyl chlorocarbonate, arylalkyl carbonate
  • the reaction may be carried out using ethyl acetate, dioxane, acetonitrile or the like as a solvent in the presence of a base such as carbon dioxide, sodium hydroxide, or triethylamine.
  • compound b is an isocyanate compound having a substituent according to the target compound (for example, lower alkyl isocyanate, aryl isocyanate, etc.) )
  • the target compound for example, lower alkyl isocyanate, aryl isocyanate, etc.
  • compound c Acetonitrile, dimethylformamide, methylene chloride, tetrahydrofuran, etc. are used as the solvent, and if necessary, triethylamine is used as the catalyst, and the reaction is carried out under ice-cooling to warming, preferably around room temperature for several tens of minutes to several days. It should be done.
  • Compound b and a phenyl carbonate compound having a substituent corresponding to the target compound are mixed in a solvent such as dimethylformamide or acetonitrile under ice-cooling to heating. After reacting for several hours to several tens of hours, the target compound can be obtained by reacting with an amino having a substituent corresponding to the target compound. If necessary, if triethylamine is used as a catalyst, the reaction can proceed favorably.
  • an amino compound for example, aniline which may have a substituent
  • the compound of interest can also be obtained by the reaction of aminobenzothiazole, lower alkylamine, etc.
  • the reaction may be carried out using acetonitrile, tetrahydrofuran, or the like as a solvent, and using triethylamine as a catalyst, if necessary, under ice-cooling to heating, preferably at room temperature for several tens to several tens of hours.
  • the compound b and an isothiocyanate compound having a substituent corresponding to the target compound can be obtained by cooling the compound b with ice-cooling using acetonitrile, dimethylformamide, tetrahydrofuran or the like as a solvent.
  • the reaction may be carried out under heating, preferably around room temperature, for several hours to several tens of hours.
  • the compound obtained by the above-mentioned method wherein R 4 is a thiolide and methyl iodide are mixed in a solvent such as acetonitrile under ice-cooling to room temperature.
  • the reaction is preferably performed at around room temperature for several minutes to several hours.
  • the thus obtained thiomethyl compound and the amine compound corresponding to the target compound can be obtained by using methanol, ethanol, or the like as a solvent at room temperature to under heating, preferably at about 50 to 80 ° C for several tens to several hours.
  • the desired compound may be obtained by the reaction.
  • compound b and a hydrogen iodide salt of a methylisothiourea compound eg, 3- (thiazole-2-yl) methylisothiourea, 3-phenylmethylisothiourea, etc.
  • a methylisothiourea compound eg, 3- (thiazole-2-yl) methylisothiourea, 3-phenylmethylisothiourea, etc.
  • R 4 ′ has hydroxy as a substituent and the substituent of R 4 is a sulfate residue
  • the compound having R 4 ′ is converted to a sulfur trioxide pyridine complex in a solvent such as pyridine.
  • the mixture is stirred under heating at 0 ° C for several tens of hours to several days.
  • Further sodium reduction hydroxide if necessary, R 4 is dissolved in a solution such as potassium hydroxide to obtain a compound which is a sulfuric acid ester residue (OS 0 3 H or a metal salt).
  • R 4 ′ has hydroxy as a substituent and the desired substituent of R is alkoxyalkyl which may be substituted
  • potassium carbonate and an alkyl corresponding to the target compound are dissolved in a solvent such as acetone. Add 8 lights and heat for several hours to several days to obtain the target compound.
  • R 4 ′ has ditrogandino as a substituent and the intended substituent of R 4 is guanidino
  • the compound having R 4 ′ is prepared by a conventional method in a solvent such as acetic acid Z-methanol. Reduction using a reducing agent such as palladium-carbon gives the target compound in which R 4 is guanidino.
  • R 4 ′ has acetylthio as a substituent and the target substituent of R 4 is mercapto, a compound having R 4 ′ is degassed with ethanol and degassed aqueous sodium hydroxide solution, etc.
  • the reaction is carried out at 0 ° C. under heating for several tens of minutes to several tens of hours, the desired compound having R 4 can be obtained.
  • R 4 ' is has a terminal amino, when end of R 4 of interest is amino-de, R 4' in the compound having the compound and force Ppuri ing reagent having a carboxylic acid corresponding to the desired compound Is reacted under ice-cooling to room temperature for several hours to several tens of hours using dry tetrahydrofuran or the like as a solvent to obtain the desired compound having R 4 .
  • a catalyst such as triethylamine or dimethylaminopyridine may be used. The reaction may be performed in the presence of 1-hydroxybenzotriazole.
  • the compound having R 4 ′ and the substituted isocyanate corresponding to the target compound may be reacted in a solvent such as dimethylformamide or tetrahydrofuran at 0 ° C. to room temperature for several tens minutes to several hours, and acetyl chloride may be used.
  • a solvent such as dimethylformamide or tetrahydrofuran
  • acetyl chloride may be used.
  • the acylation may be carried out using a commonly used acylating agent such as
  • the lower alkylsulfonyl chloride corresponding to the target compound is added to a solution of the compound having R 4 ′ in tetrahydrofuran, dimethylformamide, or the like. Then, a solution of the compound R 4 in tetrahydrofuran, dimethylformamide, or the like is added, and the mixture is reacted under ice-cooling to room temperature for several minutes to several hours to obtain a compound having the desired R 4 .
  • R 4 'end of a Amino when end of R 4 is Ru may Guanijino der substituted, R 4' compounds which may have a substituent phenylene Ruisourea compound having (e.g.
  • the desired compound can be obtained by reacting N-cyano-N-methyl _ ⁇ 1-phenylisodiarea) in an alcohol such as ethanol or propanol at room temperature to 130 ° C for several tens of hours to several days. . The reaction can proceed favorably if triethylamine is used as necessary.
  • Compound c and a halogen derivative having a substituent corresponding to the target compound are subjected to an N-alkylation reaction, Produce compound (I).
  • N—Alkylation is carried out by potassium carbonate, potassium hydride, sodium hydride, potassium hydroxide, n-tetrabutylammonium halide, and tert—potassium butyl alcohol. Using tetrahydrofuran, dioxane, getyl ether, dimethylformamide, etc.
  • the compound having R 3 ′ and the sulfonyl chloride derivative having the target substituent can be obtained by using tetrahydrofuran, benzene, etc.
  • the reaction can be carried out at ⁇ 80 ° C. in the presence of a catalyst such as triethylamine, dimethylaminopyridine or the like at ⁇ 80 ° C. (: 0 ° C. for several tens of minutes to several hours) to obtain a substituted or disubstituted sulfonamide. it can.
  • guanidine compound can be produced by reacting the compound having the compound with the amidine compound for several hours to several days.
  • amidine compound include pyrazolylamidines (eg, N, N′-bis-amidinopyrazole, N, N′-bis-Cbz methylthioamidine) and nitroguanidines (eg, methylthionitroamidine).
  • An isocyanate or isothiocyanate can be reacted with a compound in which the terminal of R 3 ′ is amino to obtain a peridode compound or a thioperido compound.
  • the terminal of R 3 ' is amino and the desired substituent R 3 is cyanoguanidino or nitroamidino, diphenylcyanocarboimidate, 1,1-dimercapto-12-nitroethane, etc. are reacted.
  • a known compound d described in J. Med. Chem., 28, 1511 (1895) is reacted with a cyano compound to obtain a compound e.
  • the cyano compound include sodium cyanide, potassium cyanide, and copper cyanide.
  • the compound e is subjected to a reaction such as hydrolysis and reduction by a conventional method, and is subjected to a conversion reaction to R 4 in the same manner as described above to obtain a compound c.
  • the compound (I) is obtained by subjecting R 3 to a substitution reaction in the same manner as described above.
  • Compound (I) can be produced by the above-mentioned method, but can also be produced by exchanging each step according to the reaction. For example, it can be obtained by first subjecting compound a or compound e to the same substitution reaction of R 3 as described above, then reducing, and finally subjecting the same to a conversion reaction to R 4 as described above. .
  • the group is protected with an appropriate protecting group in advance, and acid treatment or the like is performed at an appropriate stage.
  • the protecting group may be removed according to the conventional method.
  • hydroxy protecting group examples include lower alkyl, aralkyl (benzyl and the like), trialkylsilyl (tert-butyldimethylsilyl and the like), alkoxyalkyl (methoxymethyl and the like), tetrahydroviranyl, isyl (acetyl and the like), and alkylsulfonyl. (Methanesulfonyl, trifluoromethanesulfonyl, etc.).
  • Examples of the protecting group for amino include lower alkoxycarbonyl (such as tert-butylcarbonyl), diaralkyloxycarbonyl (such as benzyloxycarbonyl), and amide. (Phthalimid and the like).
  • the present compound (I) exhibits a strong NPY antagonistic activity and can be administered as a medicament to animals containing humans.
  • the compound of the present invention as an N P Y antagonist is applicable as an antifeedant, and is useful for the treatment and / or prevention of obesity, bulimia and anorexia nervous in which N P Y is involved.
  • cardiovascular diseases such as myocardial infarction, angina pectoris, congestive heart failure, hypertension, arrhythmia, arteriosclerosis, organ circulatory failure based on vasospasm, bronchial asthma, diabetes, schizophrenia, depression, Alzheimer's dementia , Parkinson's disease, sleep disorders, gastrointestinal motility disorders, sexual dysfunction, inflammation, respiratory diseases, hormonal abnormalities, etc., and can be used for Z or prevention.
  • a therapeutic agent for myocardial infarction When the compound (I) of the present invention is administered as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina, or a hypotensive agent, it can be administered either orally or parenterally.
  • Oral administration may be carried out according to a conventional method by preparing a tablet, granule, powder, capsule, pill, liquid, syrup, buccal, sublingual or the like in a usual dosage form.
  • any commonly used dosage form such as injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorbents and inhalants, can be suitably administered.
  • oral administration is preferred.
  • an effective amount of the compound (I) of the present invention is mixed with various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants and diluents which are suitable for the dosage form.
  • various pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants and diluents which are suitable for the dosage form.
  • It can be a pharmaceutical preparation. In the case of injections, the preparation may be prepared by sterilizing with an appropriate carrier.
  • excipients such as lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose
  • binders such as methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin or polyvinylpyrrolidone
  • disintegrants As carboxymethylcellulose, carboxymethylcellulose sodium, starch, sodium alginate, powdered agar or lauryl sulfate Lubricants include talc, magnesium stearate, and McGall gall.
  • a suppository base cocoa butter, Mackerel gall, methyl cellulose, or the like can be used.
  • a commonly used solubilizing agent, suspending agent, emulsifier, stabilizer, preservative, isotonic agent, etc. may be appropriately used. It may be added, and in the case of oral administration, a flavoring agent, a fragrance and the like may be added.
  • the dose of the compound (I) of the present invention as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and an antihypertensive agent depends on the patient's age, body weight, type and degree of disease, administration route, and the like. It is desirable to set above, but for oral administration to adults, it is usually 0.05 to 100 mg Zk gZ days, preferably within the range of 0.1 to 1 O mg / kg / day . In the case of parenteral administration, the power varies greatly depending on the route of administration. Usually, it is in the range of 0.05 to 10 mgZkg / day, preferably in the range of 0.01 to 1 mgZkg / day. It may be administered once or several times a day.
  • potassium hydroxide powder (0.613 mmo :) was mixed with compound 2 (0.429 mmo1) obtained in the first step and tetra-n-butylammonium bromide.
  • the reaction mixture was added to a solution of meta- (tert-butoxycarbonylamino) benzyl bromide in dimethylformamide (5.0 ml), and stirred at room temperature for 2 hours.
  • the meta- (tert-butoxycarbonylamino) benzyl bromide used was synthesized by a conventional method using 3-aminobenzyl alcohol.
  • N-alkyl was obtained in the same manner as in Example 1, Step 2.
  • the compound (1-22) (0.061 mmo 1) was dissolved in 4 N—hydrogen chloride / ethyl acetate solution (2.5 ml) under ice cooling and stirred at room temperature for 36 hours. The resulting precipitate was dried to give the title compound.
  • Step 1 3-Azido-1 — (3-Cyanobenzyl) 1-2,3,4,5-Tetrahydro-1H-1 —Benzozepin-2-one (Compound 6)
  • the compound (1-24) (0.317 mm 01) was dissolved in dry ethanol (0.5 ml) and dry chloroform (10.0 ml) and stirred under ice-cooling. And saturated with hydrogen chloride gas.
  • the mixture was alkalified with a 10 N sodium hydroxide solution, and the layers were separated.
  • the foam layer was washed with water and an aqueous potassium carbonate solution, and the solvent was distilled off.
  • Ammonium chloride (0.375 mmol) and 75% ethanol (10.0 ml) were added to the residue, and the mixture was heated and stirred at 70 ° C for 4 hours, and then stirred at room temperature for 16 hours.
  • the ethanol was distilled off, and a precipitate formed by adding 10% hydrochloric acid and ethyl acetate was filtered, washed with ethyl acetate, and dried to obtain the title compound.
  • Example 25 25 From the compound obtained in the first step, the title compound was obtained in the same manner as in the second and third steps of Example 24.
  • Example 25 5 Using compound 9 obtained in the second step, the title compound was obtained in the same manner as in Example 16, the first step.
  • Elemental analysis value (as CSSH NAOS.O.ISCSHU.O.IHSO)
  • Step 1 3- (3_ (tert-Butoxycarbonylamino) benzyl)-3- (3- (2-tert-butyl-dimethylsilyloxy) phenylperoxide) -2,3,4,5-tetrahi Dro-1H-1 -Benzozepin-2-one
  • Compound 11 Compound obtained by protecting the hydroxy group of ortho-nitrophenol with tert-butyldimethylsilyl group and reducing the ditro group in a conventional manner ( Performed using 2- (tert-butyldimethylsilicyloxy) aniline; 0.174 mmo 1) and Example 9 5 compound 9 (0.262 mmo 1) obtained in the second step
  • the title compound was obtained by the method of Example 32.
  • 6-Aminobenzotriazole (0.261 mmo1) obtained by reducing 5_nitrobenzotriazole by a conventional method and the compound 9 (0.252 mm) obtained in the second step of Example 25
  • the title compound was obtained by the method of Example 32 using o 1).
  • Example 25 5 The title compound was obtained using Compound 9 (0.472 mmo 1) obtained in the second step and the isocyanate obtained by the method of Example 32.
  • Example 25 Compound 9 (0.183 mo 1) obtained in the second step and literature (J. Chem. Soc., Chem. Commun., 82 (197) 3) A solution of 4-phenoxycarbonylaminobenzoic acid (0.195 mmo 1) in dimethylformamide as described in
  • Step 1 3-Azide-1 (3- (tert-butoxycarbonylamino) benzyl) 1-7-Methoxy 2,3,4,5-tetrahydro-1H-1-benzazepine-2 ON (Compound 15)
  • Example 12 From the compound 20 (0.43 mmo 1) described in the literature (Chem. Pharm. Bu 3 4, 1128 (1986)), the same as Example 12 was obtained. After N-alkylation by the method, deprotection was carried out in the same manner as in Example 16, Step 3, to give the title compound.
  • Compound 5 (0.717 mmo 1) was N-alkylated in the same manner as in Example 12 and then reduced in the manner of Example 15 to obtain the title compound.
  • the title compound was obtained from the compound (0.177 mmo 1) obtained in the first step in the same manner as in Example 62, the second step.
  • Example 6 1 From compound 21 (0.204 mmo 1) obtained in the first step and N—C bz — / 3 —alanine (0.235 mmol), Example 6 2 second step The title compound was obtained in the same manner as in.
  • the compound 32 (2.50 g) obtained in the third step was dissolved in 10 ml of methylene chloride, trifluoroacetic acid (5 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour. Toluene (5 ml) was added, and the mixture was evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate. The crystals were washed with water, dried and evaporated to dryness under reduced pressure to obtain a foamy compound 33 (1.90 g).
  • Step 5 3- (3- (4-Hydroxyphenyl) -12-methylisothioperide) 1-111 (3- (3-isopropylureido) benzyl) 1-2,3,4,5- Tetrahydro—1H—1—Benazepine—2—one (Compound 34)
  • the compound 34 (200 mg) obtained above was dissolved in a 20% methylamine solution in ethanol (2 ml), heated in a sealed tube at 70 ° C for 6 hours, and dried under reduced pressure. The residue was developed and eluted with butanol-acetic acid / water (5: 1: 1) using silica gel thin layer chromatography. The product is shaken with ethyl acetate and sodium carbonate water, and the ethyl acetate layer is dried under reduced pressure to give a foamy compound.
  • Example 8 5 The compound 30 (lOOmg) obtained in the second step was dissolved in 1 ml of acetonitrile, phenylisocyanate (50 mg) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. Ether was added to the reaction solution, and the mixture was allowed to stand. The precipitated crystals were collected by filtration to obtain a compound (1-87) (97 mg).
  • Step 1 1 1 (3 — (N'-Isopropylureide) benzyl) — 3 — ( ⁇

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Abstract

L'invention porte sur des composés de formule générale (I) ou leurs sels pharmacocompatibles ou les hydrates des deux. Dans ladite formule: R1 et R2 sont chacun indépendamment H, halogène, etc.; R3 est un groupe alkyle inférieur facultativement substitué, un groupe alkyle inférieur arylé facultativement substitué, etc.; R4 est NHCOR5, NHCONR9R10, etc.; R5 est un groupe alkyle inférieur facultativement substitué; R?9 et R10¿ sont chacun indépendamment H, un groupe alkyle inférieur facultativement substitué, etc.; X est CH¿2? etc.; et n est 1 ou 2. L'invention porte également sur des compositions à usage médical les contenant.
PCT/JP1998/000597 1997-02-18 1998-02-13 Nouveaux derives du benzolactame, et compositions a usage medical les contenant Ceased WO1998035941A1 (fr)

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JP03357397A JP2002241368A (ja) 1997-02-18 1997-02-18 新規ベンゾラクタム誘導体およびそれを含有する医薬組成物
JP9/33573 1997-02-18
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6127414A (en) * 1997-09-23 2000-10-03 Astra Aktiebolag NPY antagonists
JP2001106673A (ja) * 1999-07-26 2001-04-17 Banyu Pharmaceut Co Ltd ビアリールウレア誘導体
WO2001034571A1 (fr) * 1999-11-09 2001-05-17 Eli Lilly And Company COMPOSES CONTENANT DES β-ACIDES AMINES UTILES POUR INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
WO2001077086A1 (fr) * 2000-04-11 2001-10-18 Dupont Pharmaceuticals Company LACTAMES SUBSTITUES UTILISES EN TANT QU'INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)
WO2002010159A1 (fr) * 2000-08-02 2002-02-07 Bristol-Myers Squibb Company INHIBITEURS LACTAMES DU FXa CONVENANT AU TRAITEMENT DE LA THROMBOSE
EP1313426A4 (fr) * 1998-12-24 2003-05-28 Bristol Myers Squibb Pharma Co Benzodiazepines succinoylamino utilisees comme inhibiteurs de la production de proteine a-beta
EP1229913A4 (fr) * 1999-11-18 2005-01-19 Antexpharma Inc 1-benzazepines substituees et leurs derives
FR2901555A1 (fr) * 2006-05-24 2007-11-30 Sanofi Aventis Sa 2-alcoxy-3,4,5-trihydroxy-alkylamide-benzothiazepine, leur preparation, compositions les contenant et utilisation
US7354914B2 (en) 2000-06-01 2008-04-08 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US7507735B2 (en) 2004-06-17 2009-03-24 Cytokinetics, Inc. Compounds, compositions and methods
US7550453B2 (en) 2004-11-29 2009-06-23 Aventis Pharma Sa 2-alkoxy-3,4,5-trihydroxy-alkylamides, preparation thereof, compositions containing them and use thereof
US7585855B2 (en) 2004-11-29 2009-09-08 Aventis Pharma Sa Bengamides with a substituted caprolactam cycle, method for the preparation thereof, compositions containing them and use thereof
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US7994162B2 (en) 2006-05-24 2011-08-09 Sanofi-Aventis 2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazepines, the preparation and use thereof, and compositions containing the same
US7994161B2 (en) 2006-05-24 2011-08-09 Sanofi-Aventis Derivatives of 2-alkoxy-3,4,5-trihydroxy-alkyl amides, preparation and use thereof, and compositions containing the same
EP2484679A3 (fr) * 2006-12-29 2012-10-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par n3-hétéroaryle et N5-hétéroaryle triazoles substitués utiles comme inhibiteurs de axl
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
WO2016139181A1 (fr) 2015-03-02 2016-09-09 Apeiron Biologics Ag Dérivés tétrahydrothiazépine bicycliques utiles pour le traitement de maladies infectieuses et/ou néoplasiques

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WO2004089919A1 (fr) * 2003-04-02 2004-10-21 Banyu Pharmaceutical Co., Ltd. Derive de cyclohexanecarboxamido
US7211573B2 (en) * 2004-12-08 2007-05-01 Hoffmann-La Roche Inc. Malonamide derivatives
ITMI20050909A1 (it) * 2005-05-19 2006-11-20 Acraf Uso di un benzoil derivato dal 3-ammino-carbazolo per la produzione di un farmaco per il trattamento di un disturbo associato alla produzione di prostaglandina e2-pge2-
ITMI20051523A1 (it) * 2005-08-03 2007-02-04 Acraf Composto del 3-ammino-carbazolo composizione farmaceutica che lo contiene e metodo per prepararlo

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US6127414A (en) * 1997-09-23 2000-10-03 Astra Aktiebolag NPY antagonists
US7718795B2 (en) 1998-12-24 2010-05-18 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of aβ protein production
US7456172B2 (en) 1998-12-24 2008-11-25 Bristol-Myers Squibb Pharma Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US7304049B2 (en) 1998-12-24 2007-12-04 Bristol-Myers Squibb Pharma Company Succinoylaminobenzodiazepines as inhibitors of Aβ protein production
EP1313426A4 (fr) * 1998-12-24 2003-05-28 Bristol Myers Squibb Pharma Co Benzodiazepines succinoylamino utilisees comme inhibiteurs de la production de proteine a-beta
US7053084B1 (en) 1998-12-24 2006-05-30 Bristol-Myers Squibb Company Succinoylamino benzodiazepines as inhibitors of Aβ protein production
US6297233B1 (en) 1999-02-09 2001-10-02 Bristol-Myers Squibb Company Lactam inhibitors of FXa and method
JP2001106673A (ja) * 1999-07-26 2001-04-17 Banyu Pharmaceut Co Ltd ビアリールウレア誘導体
WO2001034571A1 (fr) * 1999-11-09 2001-05-17 Eli Lilly And Company COMPOSES CONTENANT DES β-ACIDES AMINES UTILES POUR INHIBER LA LIBERATION ET/OU LA SYNTHESE DU PEPTIDE β-AMYLOIDE
EP1229913A4 (fr) * 1999-11-18 2005-01-19 Antexpharma Inc 1-benzazepines substituees et leurs derives
US7276495B2 (en) 2000-04-11 2007-10-02 Bristol-Myers Squibb Pharma Company Substituted lactams as inhibitors of Aβ protein production
WO2001077086A1 (fr) * 2000-04-11 2001-10-18 Dupont Pharmaceuticals Company LACTAMES SUBSTITUES UTILISES EN TANT QU'INHIBITEURS DE PRODUCTION DE PROTEINE A$g(b)
US7354914B2 (en) 2000-06-01 2008-04-08 Bristol-Myers Squibb Pharma Company Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
US7456278B2 (en) 2000-06-01 2008-11-25 Bristol-Myers Squibb Pharma Corporation Lactams substituted by cyclic succinates as inhibitors of Aβ protein production
WO2002010159A1 (fr) * 2000-08-02 2002-02-07 Bristol-Myers Squibb Company INHIBITEURS LACTAMES DU FXa CONVENANT AU TRAITEMENT DE LA THROMBOSE
US6511973B2 (en) 2000-08-02 2003-01-28 Bristol-Myers Squibb Co. Lactam inhibitors of FXa and method
US10385023B2 (en) 2004-06-17 2019-08-20 Cytokinetics, Inc. Compounds, compositions and methods
US7507735B2 (en) 2004-06-17 2009-03-24 Cytokinetics, Inc. Compounds, compositions and methods
US10975034B2 (en) 2004-06-17 2021-04-13 Cytokinetics, Inc. Compounds, compositions and methods
US8110595B2 (en) 2004-06-17 2012-02-07 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
US12264133B2 (en) 2004-06-17 2025-04-01 Cytokinetics, Incorporated Compounds, compositions and methods
US10035770B2 (en) 2004-06-17 2018-07-31 Cytokinetics, Incorporated Compounds, compositions and methods
US9643925B2 (en) 2004-06-17 2017-05-09 Cytokinetics, Incorporated Compounds, compositions and methods
US9150564B2 (en) 2004-06-17 2015-10-06 Cytokinetics, Inc. Compounds, compositions and methods
US8871769B2 (en) 2004-06-17 2014-10-28 Cytokinetics, Inc. Ureas and their use in the treatment of heart failure
US8513257B2 (en) 2004-06-17 2013-08-20 Cytokinetics, Incorporated Ureas and their use in the treatment of heart failure
US8101617B2 (en) 2004-06-17 2012-01-24 Amgen, Inc. Disubstituted ureas and uses thereof in treating heart failure
US7585855B2 (en) 2004-11-29 2009-09-08 Aventis Pharma Sa Bengamides with a substituted caprolactam cycle, method for the preparation thereof, compositions containing them and use thereof
US7550453B2 (en) 2004-11-29 2009-06-23 Aventis Pharma Sa 2-alkoxy-3,4,5-trihydroxy-alkylamides, preparation thereof, compositions containing them and use thereof
US7825120B2 (en) 2005-12-15 2010-11-02 Cytokinetics, Inc. Certain substituted ((piperazin-1-ylmethyl)benzyl)ureas
US8445495B2 (en) 2005-12-15 2013-05-21 Cytokinetics, Inc. Certain Chemical entities, compositions and methods
US8871768B2 (en) 2005-12-15 2014-10-28 Cytokinetics, Inc. Certain chemical entities, compositions and methods
US7989455B2 (en) 2005-12-19 2011-08-02 Cytokinetics, Inc. Compounds, compositions and methods
US7994161B2 (en) 2006-05-24 2011-08-09 Sanofi-Aventis Derivatives of 2-alkoxy-3,4,5-trihydroxy-alkyl amides, preparation and use thereof, and compositions containing the same
WO2007135294A3 (fr) * 2006-05-24 2008-01-17 Sanofi Aventis 2-alcoxy-3,4,5-trihydroxy-alkylamide-benzothiazepine, leur préparation, compositions les contenant et utilisation
US7994162B2 (en) 2006-05-24 2011-08-09 Sanofi-Aventis 2-alkoxy-3,4,5-trihydroxy-alkylamide-benzazepines, the preparation and use thereof, and compositions containing the same
US7960373B2 (en) 2006-05-24 2011-06-14 Sanofi-Aventis 2-alkoxy-3,4,5-trihydroxyalkylamide-benzothiazepines preparation thereof, compositions containing them and use thereof
FR2901555A1 (fr) * 2006-05-24 2007-11-30 Sanofi Aventis Sa 2-alcoxy-3,4,5-trihydroxy-alkylamide-benzothiazepine, leur preparation, compositions les contenant et utilisation
US8796259B2 (en) 2006-12-29 2014-08-05 Rigel Pharmaceuticals, Inc. N3-heteroaryl substituted triazoles and N5-heteroaryl substituted triazoles useful as axl inhibitors
US9650391B2 (en) 2006-12-29 2017-05-16 Rigel Pharmaceuticals Inc. N3-heteroaryl substituted triazoles and N5-heteroaryl substituted triazoles useful as Axl inhibitors
EP2484679A3 (fr) * 2006-12-29 2012-10-10 Rigel Pharmaceuticals, Inc. Triazoles substitués par n3-hétéroaryle et N5-hétéroaryle triazoles substitués utiles comme inhibiteurs de axl
US10472341B2 (en) 2015-03-02 2019-11-12 Apeiron Biologics Ag Bicyclic tetrahydrothiazepine derivatives useful for the treatment of neoplastic and/or infectious diseases
WO2016139181A1 (fr) 2015-03-02 2016-09-09 Apeiron Biologics Ag Dérivés tétrahydrothiazépine bicycliques utiles pour le traitement de maladies infectieuses et/ou néoplasiques

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