WO1998041510A1 - Nouveaux derives du benzolactame et compositions medicamenteuses les contenant - Google Patents

Nouveaux derives du benzolactame et compositions medicamenteuses les contenant Download PDF

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Publication number
WO1998041510A1
WO1998041510A1 PCT/JP1997/000814 JP9700814W WO9841510A1 WO 1998041510 A1 WO1998041510 A1 WO 1998041510A1 JP 9700814 W JP9700814 W JP 9700814W WO 9841510 A1 WO9841510 A1 WO 9841510A1
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substituent
lower alkyl
compound
aryl
optionally
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PCT/JP1997/000814
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English (en)
Japanese (ja)
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Sanji Hagishita
Tetsuo Okada
Masafumi Fujimoto
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Shionogi & Co., Ltd.
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Priority to PCT/JP1997/000814 priority Critical patent/WO1998041510A1/fr
Publication of WO1998041510A1 publication Critical patent/WO1998041510A1/fr

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    • 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
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • 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
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D267/14—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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 effect, an anti-myocardial infarction effect, an anti-anginal effect, and an antihypertensive effect and an anti-feeding agent containing the same, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, an antihypertensive agent About.
  • a novel benzolactam derivative having an anti-feeding effect, an anti-myocardial infarction effect, an anti-anginal effect, and an antihypertensive effect and an anti-feeding agent containing the same, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, an antihypertensive agent About.
  • Neuropeptide Y (hereinafter abbreviated as NPY) is a peptide consisting of 36 amino acids, which is located in the central nervous system such as the hypothalamus, hippocampus, medulla oblongata, and spinal cord. It is distributed on nerve fibers in the blood vessel wall present in the spleen, digestive tract, and the like.
  • N P Y One of the central actions of N P Y is the feeding promoting action. It is known that administration of NPY into the rat intraventricular and hypothalamic paraventricular nuclei stimulates feeding behavior and increases the amount of carbohydrates consumed mainly. 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. NPY has a persistent contraction effect, whereas vasomotion is governed by NPY when norepinephrine witherates due to strong or repeated stimuli, whereas noradrenaline causes a transient contraction Has been implicated in circulatory disorders.
  • JP-A-6-172723 Compounds having a structure similar to that of the compound of the present invention are described in JP-A-6-172723, JP-A-8-277271, and the like. Each of these compounds has a growth hormone. No mention is made of the ability to promote mon release, the ability to disclose angiotensin I converting enzyme inhibitory action, or the NPY antagonism.
  • NPY antagonists include benzothiophene derivatives, sulfonylquinoline derivatives described in US Pat. No. 5,504,944, US Pat. No. 5,555,241, WO 96 / 143,073, Various compounds including benzylamine derivatives have been reported, but all have completely different structures from the compound of the present invention. Disclosure of the invention
  • the present invention provides a novel compound having an excellent neuropeptide Y antagonism.
  • R 1 and R 2 are each independently hydrogen, nitrogen, hydroxy, nitro, a lower alkyl optionally having a substituent, a lower alkoxy optionally having a substituent, Carboxy, lower alkoxycarbonyl optionally having substituent (s) or lower alkoxycarbonylamino which may have substituent (s), and R 3 is
  • the substituents are (1) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) cycloalkyl, (6) cycloalkenyl, (7) lower alkoxycarbonyl, (8) which may have a substituent Ashiru, (9) ⁇ Mi Bruno, (10) d Toro, (11) Shiano, (12) - NHC (- NR 1 8) NR 19 R 20 (where R 18 , R 19 and R 2 are each independently hydrogen, hydroxy or lower alkoxycarbonyl) or (13) lower alkyl Good strength Lubamoyle.), I) aryl lower alkyl optionally having substituent (s)
  • the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) substituent (where the substituent means lower alkoxycarbonyl, acyl, aryl, substituted amino) Or an imino), (5) lower alkoxy optionally having a substituent, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) Nitro, (10) Asil,
  • R 16 is a substituent (where the substituent is a lower alkoxycarbonyl or cyano) or an imino or a substituent which may have a substituent (where the substituent is a cyano or nitro
  • R 17 is a lower alkylene which may have a substituent (where the substituent is a lower alkoxycarbonyl or a lower alkyl), an amino, a lower alkylthio or an aryloxy which may have a substituent. Yes) or
  • heterocyclyl lower alkyl which may have a substituent
  • Aryl lower alkyl optionally having substituent (s)
  • the substituent is halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, acyloxy, acylthio, mercapto, cyano or nitro),
  • Aryloxy optionally having a substituent or
  • R 9 and R 1 D are each independently hydrogen, arsenate Dorokishi, halogen, ⁇ shea Le, lower alkyl which may have a substituent and may ⁇ reel optionally substituted lower alkyl
  • R 11 is hydrogen, hydroxy, lower alkyl optionally having substituent (s), aryl which may have substituent (s), lower alkyl which may have substituent (s) or Heterocyclyl optionally having a group
  • R 12 and R 13 are each independently hydrogen, hydroxy, lower alkyl optionally having substituent (s), lower alkoxy optionally having substituent (s), or may have substituent (s) Amino, aryl which may have a substituent, aryl alkyl which may have a substituent, aryloxy which may have a substituent, and aryl which may have a substituent Having terocyclyl or substituents 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 a substituent which may have a substituent.
  • Aryl lower alkyl is independently hydrogen, lower alkyl which may have a substituent, aryl which may have a substituent, or a substituent which may have a substituent.
  • 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 Q , and R 9 and R 1 . Is not aryl which may have a substituent,
  • R 3 is unsubstituted arylalkyl lower alkyl, and R 4 is NHCOR 5 , R 5 is not lower alkyl which may have a substituent,
  • R 5 is NHCONR 9 R 1 G.
  • the present invention relates to a medicament containing the compound (I) as an active ingredient, more specifically, a neuropeptide Y antagonist, more specifically, an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and an antihypertensive.
  • a neuropeptide Y antagonist more specifically, an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, and an antihypertensive.
  • the present invention provides a method for suppressing eating and a method for treating cardiomyocardial infarction, angina pectoris, and hypertension, which are characterized by administering compound (I).
  • the present invention provides use of Compound (I) for producing a medicament for suppressing eating and treating myocardial infarction, angina and hypertension.
  • BEST MODE FOR CARRYING OUT THE INVENTION As used herein, “halogen” includes fluorine, chlorine, bromine and iodine.
  • “Lower alkyl” means a straight or branched alkyl having 1 to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. , N-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl and the like.
  • “Lower alkyl optionally having substituent (s)” means lower alkyl which may be substituted at any position by one or more substituents.
  • the “lower alkyl optionally having substituent (s)” for R 3 does not include unsubstituted methyl.
  • R 4 is “V) lower alkyl optionally having substituent (s)
  • examples of the lower alkyl substituent include halogen, hydroxy, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, Nitro, cyano, amino which may have a substituent
  • the substituent is lower alkyl, aryl which may have a substituent lower alkyl, the substituent which may have a substituent (where the substituent is lower alkyl, aryl lower alkyl, etc.) ,
  • Examples of the substituent of the “optionally substituted lower alkyl” for R 5 include:) halogen, (2) hydroxy, (3) lower alkoxy, (4) carboxy, (5) lower alkoxycarbonyl , (6) acyl, (7) cycloalkyl, (8) cycloalkenyl, (9) Nitro, (10) Siano,
  • substituents of “optionally substituted lower alkyl” include, unless otherwise specified, halogen, hydroxy, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, and the like. Examples include alkyl, amino, nitrite, cyano, and the like.
  • alkyl portion of “lower alkoxy”, “lower alkoxyl propyl” and “lower alkoxycarbonylamino” is the same as the above “lower alkyl”.
  • substituents for “lower alkoxy optionally having a substituent”, “lower alkoxycarbonyl optionally having a substituent” and “lower alkoxycarbonylamino optionally having a substituent” include Examples include droxy, halogen, lower alkoxy, acyl, carboxy, lower alkoxycarbonyl, cycloalkyl, amino, nitro and cyano.
  • Aryl includes phenyl, naphthyl, anthracenyl, indenyl, phenanthrenyl and the like.
  • Aryl which may have a substituent means a group which may have one or more substituents at any position of the aryl.
  • Examples of the substituent of the “aryl which may have a substituent” of R 9 and R 10 include halogen, hydroxy, lower alkyl which may have a substituent, and a substituent.
  • aryl which may have a substituent (s) include, for example, halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, cycloalkyl, cycloalkyl Alkenyl, acyl, amino, nitro, cyano, aryl and the like can be mentioned.
  • aryl lower alkyl The lower alkyl portion and the aryl portion of “aryl lower alkyl” are the same as the above “lower alkyl” and “aryl”, respectively.
  • Aryl lower alkyl optionally having substituent (s) means aryl lower alkyl which may be substituted with one or more substituents at the lower alkyl portion or at any position of the aryl portion.
  • substituents include, unless otherwise specified, halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, cycloalkyl, cycloalkenyl, amino, nitro, and cyano.
  • substituents of the “aryl lower alkyl optionally having substituent (s)” for R 3 include (1) halogen, (2) hydroxy, (3) benzyloxy, and (4) substituent (wherein Is a lower alkoxycarbonyl, an acyl, an aryl, a substituted amino or an imino), an optionally substituted lower alkyl, (5) an optionally substituted lower alkoxy, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, (9) nitro, (10) acyl,
  • R 16 is an imino or a substituent which may have a substituent (where the substituent is lower alkoxycarbonyl or silane) (where the substituent is a cyano or a nitro).
  • R 17 is a lower alkylene which may have a substituent (where the substituent is lower alkoxycarbonyl or lower alkyl). Or aryloxy) or (13) heterocyclyl lower alkyl.
  • aryl moiety of “aryloxy” is synonymous with the above “aryl”, and “aryloxy optionally having a substituent” means that aryl may have one or more substituents at any position.
  • substituents 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.
  • optionally substituted aryl lower alkoxy means that the aryl or the lower alkyl moiety may have one or more substituents at any position. Examples thereof include halogen, hydroxy, lower alkoxy, aryl lower alkoxy, hydroxyl, lower alkoxycarbonyl, acyl, amino, nitro, and cyano.
  • Heterocyclyl means a heterocyclyl having at least one heteroatom in the ring arbitrarily selected from ⁇ , S and N, and specifically, pyrrolyl, imidazolyl, virazolyl, pyridyl, Pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolinyl, isoxazolyl, oxazolyl, oxaziazolyl, isotizazolyl, thiazolyl, thiadiazolyl, furyl, chenyl, ethylenoxyzinyl, dioxanyl, thiylanyl, thioxalanyl, thioxalanyl, thioxalanyl, thioxalanyl, thioxalanyl Monocyclic heterocyclyl and indolyl such as dinyl, imidazolidinyl, birazolidinyl, piperidinyl, piperaz
  • heterocyclyl which may have a substituent examples include lower alkyl, phenyl, hydrogen, hydroxy, lower alkoxy, carboxy, lower alkoxyl propyl, amino, aryl, substituent (halogen). , Hydroxy, amino which may be substituted with lower alkoxycarbonyl), aryl which may have lower alkyl, heterocyclyl, carbamoyl, cyano, nitro, and substituents (lower alkyl, halogen or hydrogen). Aryloxy), oxo and the like which may have (droxy), and may have a substituent at one or more arbitrary positions.
  • heterocyclyl portion and the lower alkyl portion of “heterocyclyl lower alkyl” are the same as those of 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)".
  • “Amino optionally having a substituent” includes substituted and unsubstituted aminos, and may have one or two substituents. Unless otherwise specified, examples of the substituent include hydroxy, lower alkyl optionally having substituents, aryl which may have substituents, and substituents. And lower alkyl such as lower alkyl.
  • “Acyl” means an acyl having 1 to 10 carbon atoms, such as formyl, acetyl, peptyl pionyl, butyryl, isoptyryl, nodrelyl, vivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl and Crotonyl, cyclo Includes aliphatic acyl or arylo such as hexanecarbonyl and benzoyl.
  • substituent of “optionally substituted acyl” include halogen, hydroxy, lower alkyl, lower alkoxy, carboxy, lower alkoxycarbonyl, acyl, and optionally substituted substituent. Examples include mino, nitro, cyano, aryl, lower arylalkyl, and heterocyclyl.
  • optionally substituted carbamoyl includes substituted and unsubstituted carbamoyl, and the substituents include hydroxy, lower alkyl, cycloalkyl, aryl, and substituents. And aryl lower alkyl.
  • Cycloalkyl is a carbocyclic ring having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexyl, cyclononyl, cyclodecyl, bicyclopentyl, bicyclohexyl, 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., at one or more arbitrary positions. May be replaced by these substituents.
  • the term "compound (I)” also includes a pharmaceutically acceptable salt capable of forming each compound.
  • “Pharmaceutically acceptable salts” include, for example, 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, succinic acid; salts of organic bases such as ammonium, trimethylammonium, triethylammonium; alkalis such as sodium and potassium Examples thereof include metal salts or salts of alkaline earth metals such as calcium and magnesium.
  • the compound (I) of the present invention also includes a hydrate thereof, and one molecule of the compound (I) may be bound to any number of water molecules.
  • the compound of the present invention can exist as an optical isomer. These racemic mixtures are included.
  • All of the compounds (I) have an antifeedant effect, a therapeutic effect on myocardial infarction, a therapeutic effect on angina pectoris, and a hypotensive effect.
  • the following compounds are particularly preferable.
  • R 1 and R 2 are each independently hydrogen, hydroxy, or an optionally substituted lower alkoxy (hereinafter abbreviated as R 12-1), and more preferably Compounds each independently being hydrogen or lower alkoxy (hereinafter abbreviated as R 12_2),
  • a compound which is particularly preferably both hydrogen hereinafter abbreviated as R 12-3), 2) an aryl lower alkyl in which R 3 may have a substituent
  • the substituent means (1) halogen, (2) hydroxy, (3) benzyloxy, (4) lower alkyl which may have a substituent (where the substituent means lower alkyloxycarbonyl, (5) lower alkoxy which may have a substituent, (6) carboxy, (7) lower alkoxycarbonyl, (8) cyano, ( 9) Nitro, (10) Asil,
  • the substituent means lower alkyl, aryl 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) (wherein the substituent is cyano or nitro)
  • R 17 is a lower alkylene which may have a substituent (where the substituent is a lower alkoxycarbonyl or a lower alkyl); Lower alkylthio or aryloxy) or (13) Heterocyclyl lower alkyl
  • R 3 is abbreviated as R 3 — 1)
  • the aryl lower alkyl 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, arylalkoxy) Carbonyl, lower alkylsulfonyl or optionally substituted rubamoyl) or
  • R 3 is abbreviated as R 3_2)
  • the substituent on the aryl lower alkyl is an amino which may have a substituent (wherein the substituent is optionally substituted rubamoyl or tert-butoxycarbonyl).
  • R 3 is R 3 - abbreviated as a 3) compound,
  • the substituent on the aryl lower alkyl is an amino which may have a substituent (lower alkyl group rubamoyl or tert-butoxycarbonyl) (hereinafter, R 3 is abbreviated as R 3 -4)
  • R 3 is abbreviated as R 3 -4)
  • the substituent of aryl lower alkyl is unsubstituted amino, NHC ⁇ NH—iso—Pr, NHCONH—tert—Bu or NHBoc (hereinafter, R 3 is R 3 —5) Abbreviated as a compound),
  • 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,
  • R 9 ′ and R 10 ′ are each independently hydrogen, acyl, lower alkyl optionally having substituent (s), aryl lower alkyl optionally having substituent (s), Aryl, optionally substituted heterocyclyl, 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, and R 12 ′ and R 13 ′ each independently represent hydrogen. , Hydroxy, lower alkyl optionally having substituent (s), amino or heterocyclyl)
  • R 4 is abbreviation R 4 — 1)
  • R 9 ′′ and R 10 ′′ are each independently (1) hydrogen, (2) lower alkyl optionally substituted with hydroxy,
  • the substituent means halogen, carboxy, tetrazolyl, sulfate residue ( ⁇ SO 3 H or its metal salt), pyridyl, hydroxy, tetrahydroxylanyloxy, benzyloxy, halogen) Good lower alkoxy, sulfamoyl, nitro or lower alkylamino),
  • substituents are lower alkyl, lower alkoxy, hydroxy, toluene sulphonyl; tert-butoxycarbonylamino or aryl lower alkyl optionally substituted with amino, or carbamoyl) or
  • R 1 1 '' is hydrogen, but it may also have a lower alkyl or human Dorokishi Fueeru
  • R 1 2 '' and R 1 3 '' each independently have a hydrogen or a substituent Or lower alkyl which may be
  • R 14 ′′ and R 15 ′′ are each independently hydrogen, aryl or aryl lower alkyl
  • R 4 is abbreviated as R 4 — 2), More preferably
  • R 9 ′ ′′ and R 10 ′ ′ ′ is hydrogen and the other is substituted with (1) lower alkyl, (2) halogen, hydroxy, nitro or lower alkylamino. Phenyl or (3) heterocyclyl),
  • R 11 '' is phenyl which may have hydroxy
  • R 12 '''' and R 13 ''' are one hydrogen and the other is hydrogen or hydroxy. Or lower alkyl which may be present) or
  • R 4 is abbreviated as R 4 _3
  • R 4 is abbreviated as R 4 — 4);
  • R 1 and R 2 are R 12 — 3 and R 3 is R 3 — 5, 7)
  • R 1 and R 2 are R 12 —2 and R 4 is R 4 —3;
  • R 1 and R 2 are R 12 — 3 and R 4 is R 4 _4,
  • R 3 is R 3 is - is 4, R 4 is R 4 - compound is 4, and most preferably R 3 is R 3 - is 5, R 4 is R 4 - compound is 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 4-11
  • 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 — 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 _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 — 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 — 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 — 1, R 3 is R 3 — 4, and R 4 is R 4 — 1, A compound wherein 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 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 R 1 2 - a 1, R 3 is R 3 _ 1, compounds wherein X is CH 2, R 1 and R 2 R 1 2 - is 1, R A compound wherein 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, X A compound of which is CH 2 ,
  • R 3 is R 3 3 and R 4 is R 4 — 1.
  • X is CH 2
  • R 3 is R 3 4 and R 4 is R 4 — 1 and X is CH 2
  • R 3 force, R 3 5 and R 4 is R 4 — 1 and X is CH 2
  • R 3 force R 3 1 and R 4 is R 4 — 2 and X is CH 2 A compound
  • R 3 force R 3 2 R 4 is R 4 — 2 and X is CH 2
  • R 3 force R 33, R 4 is R 4 — 2 and X is CH 2 A compound
  • R 3 force R 34, R 4 is R 4 -2 and X is CH 2
  • R 3 force R 35, R 4 is R 4 — 2 and X is CH 2 A compound, where the R 3 force is R 3 1, R 4 is R 4 — 3 and X is CH 2 , and the R 3 force is R 32 2, where R 4 is R 4 — 3 and X is CH 2 A compound, wherein R 3 is R 33, R 4 is R 4-3 and
  • R 1 and R 2 are R 12 _1, R 3 is R 3 — 1, and R 4 is R 4-11,
  • 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 — 2, R 3 is R 3 — 4, and R 4 is R 4 — 1,
  • R 1 and R 2 are R 1 2 — 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 forces R 1 2 — 1, R 3 force 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 _ 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,
  • R 1 and R 2 are R 12 — 1, R 3 is R 3 — 2, and the R 4 force 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, A compound wherein 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 12-1, R 3 is R 3 — 1, 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 — 2, R 4 is R 4 — 1 and X is CH 2 ,
  • R 1 and R 2 are R 1 2 — 1, R 3 force R 3 — 3, R 4 force R 4 _ 1, and X is CH 2 ,
  • R 1 and R 2 are R 12 — 2, R 3 is R 3 — 4, R 4 is R 4-1, and X is CH 2 ,
  • R 1 and R 2 are R 12 — 2, R 3 is R 3 — 5, R 4 force 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 force — 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 3 is R 3 _ 5
  • R 4 is R 4 — 2
  • 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 — 1, R 3 is R 3 — 2, 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 — 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 1 2 — 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 _ 1, R 3 is R 3 — 2, 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
  • compound b is obtained by reducing compound a.
  • the reduction reaction uses, for example, palladium-carbon, triphenylphosphine monohydrate, tin (II) chloride, lithium aluminum hydride, etc., and alcohols such as methanol and ethanol as solvents, tetrahydrofuran.
  • the reaction may be performed under such conditions that other functional groups are not damaged.
  • Compound a is a mosquito using a known compound described in J. Med. Chem., 28, 1511 (19985) or J. Chem. Soc 196 692 1
  • a compound synthesized by a conventional method according to the method described in 76 may be used.
  • compound b has an acetic acid derivative (eg, guanidinoacetic acid, (1-trityl-1H-imidazole-4-yl) acetic acid, N _ C bz — 0 — Alanine), and the desired compound can be produced by a coupling reaction.
  • Coupling reagents include DCC (dicyclohexyl carpoimide), WSCD (1—ethyl-3— (3—dimethylaminopropyl) carpoimide—hydrochloride) and DPPA (diphenyl phosphorylamide).
  • the reaction may be carried out under ice-cooling to room temperature, preferably under ice-cooling for several tens of hours using tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane or the like as a solvent. If necessary, triethylamine, dimethylaminopyridine and the like may be used as a catalyst, and the reaction may be performed in the presence of 1-hydroxybenzotriazole.
  • the amide compound can also be prepared by a conventional method using a conventional acylating agent corresponding to the target compound (for example, acid chlorides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride, and active esters).
  • a conventional acylating agent corresponding to the target compound for example, acid chlorides such as acetyl chloride and propionyl chloride, acid anhydrides such as acetic anhydride, and active esters.
  • an alkyl carbamate compound group can also be obtained by reacting the compound b with a carbonic acid carbonate (for example, an alkyl carbonate or an arylalkyl carbonate).
  • a carbonic acid carbonate for example, an alkyl carbonate or an arylalkyl carbonate.
  • the reaction may be performed in the presence of a base such as potassium carbonate, sodium hydroxide, triethylamine or the like using ethyl acetate, dioxane, acetonitrile or the like as a solvent.
  • compound b is an isocyanate compound having a substituent corresponding to the target compound (eg, lower alkyl isocyanate, aryl isocyanate)
  • the target compound eg, lower alkyl isocyanate, aryl isocyanate
  • compound c Acetonitrile, dimethylformamide, methylene chloride, tetrahydrofuran, or the like is used as a solvent, and triethylamine is used as a catalyst if necessary. The reaction may be performed for minutes to several days.
  • compound b and a phenolic compound having a substituent corresponding to the target compound can be prepared in a solvent such as dimethylformamide or acetonitrile under ice-cooling or heating. After reacting for several hours to tens of hours, the desired compound can be obtained by reacting with amino having a substituent corresponding to the desired compound. If necessary, the reaction can be suitably promoted by using triethylamine as a catalyst.
  • an amino compound for example, aniline which may have a substituent
  • the desired compound can also be obtained by reacting an aminobenzothiazole, a lower alkylamine, or the like which may have an amino group.
  • the reaction is Acetonitrile, tetrahydrofuran or the like may be used as a solvent, and if necessary, a reaction may be carried out using ice-cooled to heated, preferably around room temperature, tens of minutes to tens of hours using triethylamine as a catalyst.
  • compound b and an isothiocyanate compound having a substituent corresponding to the target compound can be obtained by using acetonitrile, dimethylformamide, tetrahydrofuran or the like as a solvent.
  • the reaction may be carried out under ice-cooling to heating, preferably around room temperature for several hours to several tens of hours.
  • Thiocarbonyldiimidazole and an amino compound having a substituent corresponding to the target compound can be prepared by reacting the compound with a solvent such as acetonitrile or tetrahydrofuran at 180 ° C to room temperature for several minutes to The target compound can be obtained by reacting for several hours.
  • a compound in which R 4 is a thiolide obtained by the above-mentioned method and methyl iodide may be combined with acetonitrile or the like.
  • the reaction is carried out in a solvent under ice-cooling to room temperature, preferably around room temperature for several minutes to several hours.
  • the thus obtained thiomethyl compound and the amine compound corresponding to the target compound are reacted with methanol, ethanol or the like as a solvent at room temperature to under heating, preferably at about 50 to 80 X: for several tens minutes to several hours. Then, the desired compound may be obtained.
  • compound b and a hydrogen iodide salt of a methylisothiourea compound are reacted with alcohol for several tens hours to several hours.
  • the target compound can also be obtained by heating and refluxing for days.
  • R 4 ′ has hydroxy as a substituent and the substituent of R 4 is an ester sulfate residue
  • the compound having R 4 ′ is dissolved in a solvent such as pyridine to obtain sulfur trioxide
  • the gin complex is added and the mixture is stirred at 0 ° C. to under heating for several tens of hours to several days.
  • Hydroxide Na Application Benefits um La if necessary, R 4 is E sulfate dissolved in a solution such as hydroxide Ca Li um Provides compounds where ester residue (OS_ ⁇ 3 H or a metal salt thereof).
  • R 4 ′ has hydroxy as a substituent and the desired substituent of R 4 is alkoxyalkyl which may be substituted
  • the compound is mixed with potassium carbonate in a solvent such as acetone. Add the alkyl halide corresponding to the target compound and heat for several hours to several days to obtain the target compound.
  • R 4 ′ has a nitrogen atom as the substituent and the target substituent of R 4 is guanidino
  • the compound having the R 4 ′ is treated with palladium oxide by a conventional method in a solvent such as methanol acetate. Reduction using a reducing agent such as 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
  • the compound having R 4 ′ is degassed with ethanol and degassed sodium hydroxide.
  • the reaction is carried out in a solvent such as an aqueous solution at 0 ° C. to under heating for several tens of minutes to several tens of hours, the desired compound having R 4 is obtained.
  • R 4 ' is has an amino-terminated if end of R 4 of interest is amino-de, R 4' in the compound having the compound and couplings having a carboxylic acid corresponding to the desired compound
  • the desired compound having R 4 can be obtained.
  • triethylamine, dimethylaminopyridine, or the like may be used as a catalyst, and 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 to room temperature for tens of minutes to several hours.
  • a solvent such as dimethylformamide or tetrahydrofuran
  • acylation may be carried out using a commonly used acylating agent such as acetyl chloride.
  • the compound having R 4 ′ is dissolved in a solution of tetrahydrofuran, dimethylformamide, etc. Add a solution of the corresponding lower alkylsulfonyl chloride in tetrahydrofuran, dimethylformamide, etc., and cool under ice to room temperature for several minutes to several hours. If the reaction is carried out for a period of time, the desired compound having R 4 is obtained.
  • the compound having R 4 ′ and the phenylisourea compound which may have a substituent can be obtained by reacting N-cyano-N-methyl-O-phenylisodiarea) in an alcohol such as ethanol or propanol at room temperature to 130 ° C. for several tens of hours to several days. If triethylamine is used as necessary, the reaction can proceed favorably.
  • N-alkylation is carried out using bases such as potassium carbonate-potassium iodide, sodium hydride, potassium hydroxide, n-tetrabutylammonium halide, and tert-potassium salt of butyl acetate.
  • the reaction may be carried out in the presence of a solvent such as tetrahydrofuran, dioxane, dimethyl ether, dimethylformamide or the like under ice-cooling to room temperature, preferably around room temperature for several tens of minutes to several tens of hours.
  • a solvent such as tetrahydrofuran, dioxane, dimethyl ether, dimethylformamide or the like
  • the compound having R 3 ′ and the sulfonyl chloride derivative having the target substituent can be converted to tetrahydrofuran.
  • a solvent such as dimethylformamide
  • the compound having R 3 ′ and the amidine compound are allowed to react for several hours to several days at around room temperature to obtain guar.
  • a dizine compound can be produced.
  • amidine compound examples include pyrazolyl amidines (for example, N, N'-bis-amidinopyrazole, N, N'-bis-Cbz methylthioamidine) and nitrogannidines (for example, methylthionitroamidine).
  • pyrazolyl amidines for example, N, N'-bis-amidinopyrazole, N, N'-bis-Cbz methylthioamidine
  • nitrogannidines for example, methylthionitroamidine
  • R 3 ′ When the terminal of R 3 ′ is cyano and the terminal of the intended substituent R 3 is amidino, first, an alcohol is added under an acid catalyst such as hydrochloric acid to obtain an immediate compound. Next, the desired compound is obtained by reacting with an amino compound such as ammonium chloride for several hours at room temperature to 10 ° ⁇ : using ethanol or the like as a solvent.
  • an acid catalyst such as hydrochloric acid
  • An isocyanate or an 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.
  • R 3 ′ is amino and the intended substituent R 3 is cyano guanidinium dinitroamidino, diphenylcarbanocarbide amide, 1,1-dimercapto—2_n
  • R 3 is cyano guanidinium dinitroamidino
  • diphenylcarbanocarbide amide, 1,1-dimercapto—2_n A phenoxy compound and a thiomethyl compound are synthesized by reacting troethane and the like. Thereafter, the compound is reacted with an amino compound having a desired substituent in a solvent such as methanol at room temperature to heating to obtain the desired compound.
  • R 4 a lower alkyl optionally having substituent (s)
  • R 1 , R 2 RRX and n are as defined above, and H a 1 represents halogen
  • a compound e is obtained by reacting a known compound d described in J. Med. Chem., 28'1511 (19985) with a cyano compound.
  • 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 converted to R 4 in the same manner as described above.
  • Compound c is obtained by the conversion reaction.
  • 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.
  • compound (a) or compound (e) can be obtained by first subjecting compound a or compound e to the same substitution reaction as above for R 3 , then reducing, and finally subjecting it to the same conversion reaction as above to R 4 . .
  • the group is protected with an appropriate protecting group in advance, and treated with an acid at an appropriate stage.
  • the protecting group may be removed by a conventional method such as
  • hydroxy-protecting group examples include lower alkyl, aralkyl (such as benzyl), trialkylsilyl (such as tert-butyldimethylsilyl), alkoxyalkyl (such as methoxymethyl), tetrahydrobiranil, acetyl (such as acetyl), and alkyl.
  • Sulfonyl methanesulfonyl, trifluoromethanesulfonyl, etc.
  • amino-protecting group examples include lower alkoxycarbonyl (tert-butylcarbonyl), diaralkyloxycarbonyl (benzyloxycarbonyl), and amides (phthalimid).
  • the compound (I) of the present invention exhibits a strong neuropeptide Y antagonistic action, and can be administered to a human-containing animal as a medicament.
  • the compound of the present invention as an NP Y antagonist is applicable as an antifeedant, and is useful for the treatment and / or prevention of obesity, bulimia and anorexia nervous in which NP Y is involved.
  • cardiovascular diseases such as myocardial infarction, angina pectoris, congestive heart failure, hypertension, arrhythmia, arteriosclerosis, organ circulatory insufficiency based on vasospasm, bronchial asthma, glucoseuria, schizophrenia, depression, It can be used for treatment and Z or prevention of Alzheimer's disease, Parkinson's disease, sleep disorder, gastrointestinal motility disorder, sexual dysfunction, inflammation, respiratory disease, hormonal secretion abnormality, and the like.
  • Compound (I) of the present invention as an antifeedant, a therapeutic agent for myocardial infarction, a therapeutic agent for angina pectoris, a hypotensive
  • Oral administration may be carried out in a usual dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to a conventional method.
  • any commonly used dosage form can be suitably administered, for example, injections such as intramuscular administration and intravenous administration, suppositories, transdermal absorption agents, and inhalants.
  • 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.
  • pharmaceutical additives such as excipients, binders, wetting agents, disintegrating agents, lubricants, and diluents which are suitable for the dosage form.
  • Pharmaceutical preparations In the case of an injection, the preparation may be prepared by sterilizing with an appropriate carrier.
  • lactose, sucrose, glucose, starch, calcium carbonate or crystalline cellulose are used as excipients, and methylcellulose, carboxylmethylcellulose, hydroxypropylcellulose, gelatin or poly is used as a binder.
  • Disintegrators such as carboxymethylcellulose, carboxymethylcellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate; disintegrators; talc, stealine as lubricants Examples include magnesium acid or macrogol.
  • power resin, macrogol or methylcellulose can be used as a suppository base.
  • solubilizing agents When preparing a liquid preparation or an emulsion or suspension injection, usually used solubilizing agents, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents and the like are used. It may be added as appropriate, 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, or an antihypertensive agent depends on the patient's age, body weight, type and degree of disease, administration route, etc. Although it is desirable to set the dose in the case of oral administration to adults, it is usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. . In the case of parenteral administration, it varies greatly depending on the route of administration, but is usually 0.00 O O l O mgZ kg Z days, preferably within the range of 0.01 to lmg / kg / day. It may be administered once or several times a day.
  • Example 1 the present invention will be described in more detail with reference to Examples, but these Examples do not limit the present invention.
  • Example 1 Compound 2 (0.343 mmol) obtained in the first step, orthomethylbenzoylmethylpromide (0.412 mmol), potassium carbonate (0.411 mmol) 1), dimethylformamide (5.0 ml) was added to potassium iodide (0.034 mmol), and the mixture was stirred at room temperature for 18 hours.
  • the compound (1-22) (0.061 mm01) was dissolved in 4N-hydrogen chloride Z-ethyl acetate solution (2.5 ml) under ice-cooling, and the mixture was stirred at room temperature for 36 hours. The resulting precipitate was dried to give the title compound.
  • Step 1 3-Azide-1-(3-Cyanobenzyl)-2, 3, 4, 5-Tetrahydro-1 ⁇ -1-1-benzoxazepin-1-2-one (Compound 6)
  • Example 1 The title compound was obtained by N-alkylation according to the method of the second step.
  • Step 1 3-Azido 1- (3- (tert-butoxycarbonylamino) benzyl) 1,2,3,4,5-tetrahydro 1H-1 -Benzozepine 1-2-one (Compound 8)
  • Step 1 3-azido1-1- (2- (tert-butoxycarbonylamino) benzyl) 1-2,3,4,5-tetrahydro-1H-1 -benzazepine_2-one (compound 1 0)
  • the title compound was obtained from the compound 10 (0.315 mmo 1) obtained in the first step in the same manner as in Example 25, the second step.
  • Example 24 25 The title compound was obtained from the compound obtained in the first step 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, Example 16 gave the title compound in the same manner as in the first step.
  • a sulfur trioxide pyridin complex (0.97 mmol) was added to a pyridine solution of the compound (I-30) (0.211 mm 01), and the mixture was stirred at room temperature for 110 hours. Concentrated, added water and filtered. 0.1 N sodium hydroxide solution (3.5 ml) , And then washed with black-mouthed form, and extracted twice with 1-butanol. After the organic layer was washed with water and dried (anhydrous magnesium sulfate), the solvent was distilled off to obtain the title compound.
  • the title compound was obtained by the method of 32.
  • 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).
  • Example 25 5 To a solution of compound 9 (0.524 mol) obtained in the second step in acetonitrile (6.0 ml) was added carbonyldiimidazole (1.05 mmo 1), and the mixture was added at room temperature. Stir for 1 hour. Ice water was poured into the reaction mixture, and the solvent was distilled off. After extraction with ethyl acetate twice, the organic layer was washed with water, dried (anhydrous magnesium sulfate), and the solvent was distilled off. To the obtained residue (0.251 mmol) was added a 1 M-dimethylaminenotetrahydrofuran solution (0.25 ml), and the mixture was stirred at room temperature for 18 hours. Was. The mixture was acidified with 10% hydrochloric acid and extracted twice with ethyl acetate. After washing with water and drying (anhydrous magnesium sulfate), the solvent was distilled off to obtain the title compound.
  • the title compound was obtained from the compound 13 (0.107 mmo 1) obtained in the first step by the method of Example 55 second step.
  • the title compound was obtained from the compound 23 (0.720 mmol) obtained in the first step by the same method as in Example 62, second step.
  • Example 6 2 from the compound 9 obtained in the second step and various carboxylic acid compounds.
  • the compounds of Examples 66 to 70 were obtained in the same manner as in the process.
  • Example 2 5 Performed from compound 9 (0.262 mmo 1) obtained in the second step and carboxylic acid compound (0.068 mmo 1) described in JP-A-7-165722.
  • Example 6 2 The title compound was obtained in the same manner as in the second step.
  • the title compound was obtained from the compound (0.177 mmol) obtained in the first step in the same manner as in Example 62, the second step.
  • Example 24 Using a variety of substituted isocyanates from compound 24 obtained in the first step, Example 24 was carried out in the same manner as in the third step. The compounds of 7 to Example 80 were obtained.

Abstract

Composés représentés par la formule générale (I); sels pharmaceutiquement acceptables desdits composés, ou leurs hydrates; compositions pharmaceutiques contenant lesdits composés; méthode permettant d'inhiber la prise alimentaire, caractérisée par l'administration desdits composés; méthode permettant de traiter l'infarctus du myocarde, l'angine de poitrine et l'hypertension; et utilisation desdits composés pour préparer des compositions médicamenteuse permettant d'inhiber la prise alimentaire, ainsi que de traiter l'infarctus du myocarde, l'angine de poitrine et l'hypertension.
PCT/JP1997/000814 1997-03-14 1997-03-14 Nouveaux derives du benzolactame et compositions medicamenteuses les contenant WO1998041510A1 (fr)

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