WO2014157437A1 - Dérivé propellane - Google Patents

Dérivé propellane Download PDF

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Publication number
WO2014157437A1
WO2014157437A1 PCT/JP2014/058717 JP2014058717W WO2014157437A1 WO 2014157437 A1 WO2014157437 A1 WO 2014157437A1 JP 2014058717 W JP2014058717 W JP 2014058717W WO 2014157437 A1 WO2014157437 A1 WO 2014157437A1
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carbon atoms
moiety
alkoxy
alkyl
hydroxy
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PCT/JP2014/058717
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Japanese (ja)
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長瀬博
藤井秀明
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学校法人北里研究所
日本ケミファ株式会社
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Publication of WO2014157437A1 publication Critical patent/WO2014157437A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems

Definitions

  • the present invention relates to a propeller derivative having an opioid ⁇ receptor agonistic action.
  • ⁇ , ⁇ , and ⁇ Three types of opioid receptors, ⁇ , ⁇ , and ⁇ , are known, and morphine that exhibits a strong affinity for ⁇ receptors has long been used as an analgesic.
  • analgesic action of morphine is powerful, it is known to cause adverse events such as dependence formation, respiratory depression, and constipation through the ⁇ receptor.
  • ⁇ receptors also have analgesic effects, but ⁇ receptor agonists are known not to participate in adverse events seen in morphine. Therefore, it is considered that an agonist selective for the ⁇ receptor may be an analgesic superior to morphine, and research on its creation has been actively conducted.
  • Non-Patent Documents 1 to 7 It has also been reported that ⁇ receptor agonists can become anxiolytics and antidepressants. However, no ⁇ receptor agonist has yet been approved as a therapeutic or prophylactic agent.
  • Patent Document 1 the following formula (A),
  • Non-Patent Document 9 discloses that the following formula (C),
  • An object of the present invention is to provide a propeller derivative represented by the following general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt or solvate of the compound, and a solvate thereof.
  • the object is to provide analgesics, anxiolytics and antidepressants contained as ingredients.
  • R 1 is (a) hydrogen, (b) C 1-6 alkyl, (c) C 6-10 aryl, (d) C 2-6 alkenyl, (e) cycloalkylalkyl (of the cycloalkyl moiety The number of carbon atoms is 3 to 6, the number of carbon atoms in the alkylene portion is 1 to 5.), (f) Aralkyl (the number of carbon atoms in the aryl portion is 6 to 10, and the number of carbon atoms in the alkylene portion is 1 to 5.
  • a 7-membered ring may be formed, R 2 is hydrogen, hydroxy, halogen, cyano, carbamoyl, C 1-6 alkoxy, C 6-10 aryloxy, C 1-6 alkanoyloxy, nitro, amino, C 1-8 alkylamino, aralkylamino (of the aryl moiety)
  • the number of carbon atoms is 6 to 10, the number of carbon atoms of the alkylene moiety is 1 to 5.
  • acylamino the number of carbon atoms of the acyl moiety is 2 to 6
  • V represents CH or N;
  • W, X, Y and Z each independently represent CR 3 or N.
  • R 3 is hydrogen, halogen, nitro, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, C 1-6 alkyl substituted with 1 to 3 halogens, hydroxy substituted C 1-6 alkyl, to three halogen substituted C 1-6 alkoxy, hydroxy substituted C 1-6 alkoxy, C 1-6 C 1-6 alkyl alkoxy-substituted phenyl, cyano, isothiocyanato, SR 6, SOR 6, SO 2 R 6, (CH 2) r COOR 6, SO 2 NR 7 R 8, CONR 7 R 8, (CH 2) r NR 7 R 8 or (CH 2) r N (R 7) COR 8 Or two R 3 bonded to adjacent carbons together represent methylenedioxy,
  • R 6 represents hydrogen or C 1-6 alkyl
  • the present invention also relates to a pharmaceutical comprising the propellane derivative represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof. .
  • the present invention also includes a propellane derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. It is related with the pharmaceutical composition to contain.
  • the present invention also includes a propellane derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. It relates to analgesics containing.
  • the present invention also includes a propellane derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt thereof or solvate thereof as an active ingredient. It relates to the anxiolytic drug contained. Furthermore, the present invention provides a propeller derivative represented by the above general formula (I), a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound or a solvate thereof as an active ingredient. As an antidepressant.
  • R 1 is hydrogen, C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms). 10 wherein the alkylene moiety has from 1 to 5 carbon atoms, wherein the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy.
  • W, X, Y and Z are the same or different and are selected from CH, C—C 1-6 alkyl, C-halogen, C-hydroxy and C—C 1-6 alkoxy; Or a propeller derivative described in (1) to (5) above, a tautomer, stereoisomer, pharmaceutically acceptable salt of the compound, or a solvate thereof.
  • R 1 is hydrogen, C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
  • R 2 is hydroxy or C 1-6 alkoxy
  • V, W, X, Y and Z are the propeller derivatives represented by the above general formula (I), wherein the compound is a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or their Solvate.
  • R 1 is hydrogen, C 1-6 alkyl or aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms); R 2 is hydroxy or C 1-6 alkoxy, and V, W, X, Y and Z are the propeller derivatives represented by the above general formula (I), wherein the compound is a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or their Solvate.
  • R 1 is hydrogen, C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has carbon atoms 6 to 10 and the alkylene moiety has 1 to 5 carbon atoms.)
  • R 2 is C 1-6 alkoxy and V, W, X, Y and Z are the propeller derivatives represented by the above general formula (I), wherein the compound is a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or their Solvate.
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms).
  • alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy;
  • R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, or carbamoyl;
  • V is CH, W, X, Y, and Z are the same or different and
  • CR 3 is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms).
  • alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy;
  • R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, or carbamoyl;
  • V is CH, W, X, Y and Z are the same or different and are selected from CH, C—C 1-6 alkyl, C-halogen, C-hydroxy and C—C 1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms).
  • alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy;
  • R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, or carbamoyl;
  • V is CH,
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms).
  • alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy;
  • R 2 is hydroxy or C 1-6 alkoxy,
  • V is CH, W, X, Y, and Z are the same or different and
  • CR 3 is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms).
  • alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy;
  • R 2 is hydroxy or C 1-6 alkoxy,
  • V is CH, W, X, Y and Z are the same or different and are selected from CH, C—C 1-6 alkyl, C-halogen, C-hydroxy and C—C 1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
  • R 1 is C 1-6 alkyl, cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms, the alkylene moiety has 1 to 5 carbon atoms) or aralkyl (the aryl moiety has 6 to 6 carbon atoms).
  • alkylene moiety has from 1 to 5 carbon atoms, and the alkyl moiety is substituted by either hydroxy, 1-6 halogen, or C 1-6 alkoxy; R 2 is hydroxy or C 1-6 alkoxy, V is CH,
  • R 1 is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C 1-6 alkoxy, R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, or carbamoyl; V is CH, W, X, Y, and Z are the same or different and CR 3 is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
  • R 1 is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C 1-6 alkoxy, R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, or carbamoyl; V is CH, W, X, Y and Z are the same or different and are selected from CH, C—C 1-6 alkyl, C-halogen, C-hydroxy and C—C 1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
  • R 1 is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C 1-6 alkoxy, R 2 is hydroxy, C 1-6 alkoxy, C 1-6 alkanoyloxy, or carbamoyl; V is CH, A propellane derivative represented by the above general formula (I) wherein W, X, Y and Z are CH, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof; object.
  • R 1 is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C 1-6 alkoxy, R 2 is hydroxy or C 1-6 alkoxy, V is CH, W, X, Y, and Z are the same or different and CR 3 is a propellan derivative represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or Their solvates.
  • R 1 is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C 1-6 alkoxy, R 2 is hydroxy or C 1-6 alkoxy, V is CH, W, X, Y and Z are the same or different and are selected from CH, C—C 1-6 alkyl, C-halogen, C-hydroxy and C—C 1-6 alkoxy; Or a tautomer, stereoisomer or pharmaceutically acceptable salt of the compound or a solvate thereof.
  • R 1 is cycloalkylalkyl (the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms), and the alkyl moiety is hydroxy, 1 to 6 halogens, Or substituted by either C 1-6 alkoxy, R 2 is hydroxy or C 1-6 alkoxy, V is CH,
  • C 1-6 alkyl includes methyl, ethyl, propyl, i-propyl, butyl, t-butyl, pentyl, neopentyl, hexyl and the like.
  • C 1-6 alkyl substituted with 1 to 3 halogens includes 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl or 3,3,3-trimethyl Examples include fluoropropyl.
  • Examples of C 2-6 alkenyl include 2-propenyl and 3-methyl-2-butenyl.
  • Cycloalkylalkyl (wherein the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) is substituted with C 3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl Methyl, ethyl and the like.
  • Aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) includes a benzyl group or a phenethyl group.
  • C 3-6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 6-10 aryl includes phenyl or naphthyl.
  • heteroaryl including 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms
  • heteroaryl include pyridyl, furyl, imidazolyl, pyrimidinyl, pyrazinyl and thiazolyl.
  • Heteroarylalkyl (heteroaryl contains 1 to 4 heteroatoms selected from N, O and S as ring members, and the alkylene moiety has 1 to 5 carbon atoms) includes (pyridine-2- Yl) methyl, (pyridin-3-yl) methyl, (pyridin-4-yl) methyl, (furan-2-yl) methyl, (furan-3-yl) methyl, (imidazol-2-yl) methyl, Imidazol-4-yl) methyl, (imidazol-5-yl) methyl, (thiazol-2-yl) methyl, (thiazol-4-yl) methyl, (thiazol-5-yl) methyl, 2- (pyridin-2) -Yl) ethyl, 2- (pyridin-3-yl) ethyl, 2- (pyrazol-1-yl) ethyl, 2- (thiophen-2-yl) ethyl, or 2- (thiophen
  • Examples of C 1-6 alkanoyl include acetyl and propionyl.
  • Examples of C 1-6 alkoxy include methoxy, ethoxy, propoxy and the like.
  • Examples of C 1-6 alkanoyloxy include acetoxy and the like.
  • Examples of alkoxycarbonyl (the number of carbon atoms in the alkoxy moiety is 1 to 6) include methoxycarbonyl and ethoxycarbonyl.
  • Examples of the halogen include fluorine, chlorine, bromine and the like.
  • Examples of C 1-6 alkoxy substituted with 1 to 3 halogens include fluoromethoxy and trifluoromethoxy.
  • Examples of phenylalkyl include benzyl and the like.
  • Examples of C 6-10 aryloxy include phenoxy.
  • Examples of C 1-8 alkylamino include methylamino and ethylamino.
  • Examples of aralkylamino (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms) include benzylamino and the like.
  • Examples of acylamino (acyl moiety has 2 to 6 carbon atoms) include acetylamino and the like.
  • Examples of the alkylcarbamoyl include ethylcarbamoyl and the like.
  • Examples of the dialkylcarbamoyl (the alkyl moiety has 1 to 6 carbon atoms) include diethylcarbamoyl and the like.
  • Examples of the C 1-6 alkyl substituted with hydroxy include 2-hydroxyethyl and the like.
  • Examples of the C 1-6 alkoxy substituted with hydroxy include 2-hydroxyethoxy and the like.
  • the 4- to 7-membered ring in which R 4 , R 5 and the N atom are combined and may further contain a heteroatom selected from N, O and S includes a piperidine ring, a piperazine ring or a morpholine ring.
  • the pharmaceutically acceptable salt is preferably an acid addition.
  • the acid addition salt include salts with organic acids or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, camphorsulfonate, and the like.
  • the stereoisomers include cis, trans Examples include isomers, racemates and optically active substances.
  • the propeller derivatives represented by the above general formula (I) tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds or solvates thereof, the solvates are the present invention. Or a pharmaceutically acceptable solvate thereof, including hydrates.
  • the compound (c) of the present invention is synthesized from the compound (a) by any of the following methods.
  • Compound (a) as a starting material is synthesized by a known method (J. Org. Chem., 2008, 73, 8093 and Bioorg. Med. Chem. Lett., 2011, 21, 4104) and a method analogous thereto.
  • Method a A method of reacting compound (a) with compound (b) in the presence of an acid such as methanesulfonic acid in a solvent such as ethanol.
  • Method b A method of reacting compound (a) with compound (a) in the presence of a base such as potassium hydroxide in a solvent such as ethanol-water.
  • a base such as potassium hydroxide
  • a solvent such as ethanol-water.
  • the first step compound (e) is prepared by a known de-N-alkylation method (Bioorg. Med. Chem. Lett., 2010, 20) comprising the reaction of compound (a) with chloroformate and subsequent decarbamate reaction. , 6302 etc.) or a method analogous thereto.
  • Second Step The compound (f) of the present invention is synthesized from the compound (e) according to the method described in the first step of production method 1.
  • the compound (c-1) of the present invention is synthesized from the compound (f) by a normal N-alkylation reaction, a reductive amination reaction, or a reduction reaction with lithium aluminum hydride followed by amidation.
  • Fourth Step The compound (d-1) of the present invention is synthesized from the compound (c-1) according to the method described in the second step of Production Method 1.
  • Method B
  • the first step compound (h) is synthesized from the compound (g) by the method described in the first step in Method A of Production Method 2 or a method using diethyl azodicarboxylate (Synthetic Communications, 1995, 25, 829, etc.).
  • the Compound (g) as a starting material is synthesized by a known method (J. Org. Chem., 2008, 73, 8093 and Bioorg. Med. Chem. Lett., 2011, 21, 4104) and a method analogous thereto.
  • the second step compound (i) is synthesized from compound (h) according to the method described in the third step in Method A of Production Method 2.
  • the third step compound (a-1) is synthesized by reacting compound (i) with a mineral acid such as hydrochloric acid in a solvent such as tetrahydrofuran (THF) or methanol.
  • a Lewis acid may be used instead of the mineral acid.
  • the compounds (c-1) and (d-1) of the present invention are synthesized, respectively.
  • Production method 3 When the propeller derivative represented by the above general formula (I) is R 2 is hydrogen, cyano or CONH 2 , and V is CH:
  • R 21 represents hydrogen, cyano or CONH 2 , and R 1 , W, X, Y and Z are the same as described above.
  • the compound (k) of the present invention in which R 2 in the general formula (I) is hydrogen, cyano or CONH 2 is obtained from the compound (j) using the method described in the first step of production method 1 and a method analogous thereto. Can be synthesized.
  • the starting material (j) is synthesized from the compound (l) by any of the following methods.
  • the conversion from the second step compound (m) to compound (n) is carried out by trifluoromethanesulfonylation reaction using N-phenylbis (trifluoromethanesulfonimide) or trifluoromethanesulfonic anhydride.
  • the conversion from the third step compound (n) to the compound (o) is performed by a reduction reaction under a palladium catalyst (such as the method described in Tetrahedron Letters, 2010, 51, 2359).
  • the conversion from the fourth step compound (o) to the compound (j-1) is performed according to the method described in the third step in Method B of Production Method 2 and a method analogous thereto.
  • the first step compound (p) is synthesized from the compound (n) by a cyanation reaction under a palladium catalyst.
  • the conversion from the second step compound (p) to the compound (j-2) is performed according to the method described in the third step in Method B of Production Method 2 and a method analogous thereto.
  • the third step compound (j-3) is synthesized from the compound (j-2) using a usual hydrolysis reaction in addition to the method shown in the above reaction formula.
  • Production Method 4 When the propeller derivative represented by the above general formula (I) is R 2 is amino and V is CH:
  • the first step compound (q) is carried out by a cross-coupling reaction between compound (n) and benzophenone imine in the presence of a palladium catalyst, followed by an acid hydrolysis reaction.
  • the second step compound (r) is synthesized by reacting compound (q) with benzyl chloroformate in the presence of a base such as triethylamine in a solvent such as dichloromethane.
  • the third step compound (s) is synthesized by one of the methods described in the first step of production method 1 or a method analogous thereto.
  • the compound (x) of the present invention can be obtained from the compound (a-2) to the compound (a) according to the method shown in the above reaction route (method according to the reaction route described in J. Med. Chem. 1991, 34, 1715). It is synthesized via u) and the inventive compound (w).
  • Other compounds included in the general formula (I) can also be produced by a combination of the above synthesis methods and the methods described in Examples below.
  • the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts of the compounds or solvates thereof prevent acute pain and chronic pain. It can be used as a prophylactic and therapeutic agent for pain treatment in accompanying diseases, rheumatoid arthritis, osteoarthritis, cancer pain with strong pain such as bone tumor, diabetic neuropathic pain, postherpetic neuralgia, visceral pain, etc. it can.
  • the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers, pharmaceutically acceptable salts or solvates thereof such as depression, panic disorder, Drugs for anxiety, stress disorders (PTSD, acute stress disorder), and other mental disorders with anxiety (antidepressants, anxiolytics, etc.) include urinary incontinence, myocardial ischemia, hypertension, Parkinson's disease It can be used as a prophylactic and therapeutic drug.
  • the propeller derivatives represented by the above general formula (I), tautomers, stereoisomers or pharmaceutically acceptable salts of the compounds or solvates thereof are administered orally to humans or not It can be administered by an appropriate administration method such as oral administration. It can also be used in combination with other analgesics.
  • a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
  • a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like.
  • usual excipients, disintegrants, binders, lubricants, pigments and the like are used.
  • lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca), etc., as the lubricant, magnesium stearate,
  • binders include talc and the like, and hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
  • Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of injections.
  • the active ingredient is the propeller derivative represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound or a pharmaceutically acceptable salt thereof.
  • the solvate is administered at 0.1 ⁇ g to 1 g / day, preferably 0.001 to 200 mg / day for injection, and 1 ⁇ g to 10 g / day, preferably 0.01 to 2000 mg / day for oral administration.
  • it can be increased or decreased depending on age, symptoms, etc.
  • the reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure.
  • a saturated aqueous sodium hydrogen carbonate solution and 25% aqueous ammonia solution were added, and the mixture was extracted with chloroform.
  • the organic layer was dried over sodium sulfate and concentrated under reduced pressure.
  • the resulting crude product was purified by silica gel column chromatography to obtain the title compound 7 (1.26 g, 79%) as a white amorphous.
  • the obtained crude product was purified by silica gel column chromatography to obtain a colorless oily substance (180 mg).
  • Lithium aluminum hydride 120 mg, 3.16 mmol was suspended in THF (3.2 mL), concentrated sulfuric acid (84.2 ⁇ l, 1.58 mmol) was added dropwise at 0 ° C., and the mixture was stirred at 0 ° C. for 15 minutes.
  • a colorless oily substance (180 mg) obtained above in THF (6 mL) solution was added dropwise at 0 ° C. and stirred for 30 minutes, then warmed to room temperature and stirred for 1 hour.
  • a 25% aqueous ammonia solution (10 mL) was added, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure.
  • Opioid receptor binding test The binding affinity of the compounds of the present invention for ⁇ , ⁇ and ⁇ opioid receptors was examined.
  • the murine cerebral membrane fraction was used for the assay of ⁇ and ⁇ receptors, and the guinea pig cerebellar membrane fraction was used for the assay of ⁇ receptor.
  • ⁇ DAMGO, ⁇ : DPDPE, and ⁇ : U69,593 were each used at 1 ⁇ M.
  • Each receptor membrane fraction is reacted with the radioligand and various concentrations of the specimen for a predetermined time. After the B / F separation, the amount of radioactivity remaining on the filter is measured with a liquid scintillation counter, and the binding inhibition rate of the test compound ( IC 50 value) was calculated.
  • the Ki value was calculated from the obtained IC 50 value using the following formula.
  • Ki IC 50 / (1 + L / Kd) L: Concentration of radioligand used Kd: Kd value of radioligand Further, the ⁇ -receptor selectivity in the opioid receptor was determined by calculating the ratio ( ⁇ / ⁇ or ⁇ / ⁇ ) between the Ki value for ⁇ or ⁇ and the Ki value for ⁇ .
  • DAMGO [D-Ala 2 , N-MePhe 4 , Gly-Ol] enkephalin
  • DPDPE [D-Pen 2 , D-Pen 5 ] enkephalin
  • U69,593 (+)-(5 ⁇ , 7 ⁇ , 8 ⁇ ) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzeneacetamide
  • the compounds of the present invention showed selective affinity for the opioid ⁇ receptor.
  • Opioid receptor function test The functional activity of the compounds of the present invention against ⁇ , ⁇ and ⁇ opioid receptors was examined.
  • Method A cell membrane fraction was prepared using CHO cells (catalog number and accession number are listed below) stably expressing human opioids ⁇ , ⁇ , and ⁇ receptors.
  • a reaction solution 50 mM [Tris (hydroxymethyl) aminomethane] -HCl pH 7.4, 5 mM MgCl 2 , 1 mM EGTA, 100 mM NaCl
  • test compound 30 ⁇ M GDP and 100 pM [ 35 S] GTP ⁇ S

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Abstract

L'invention concerne un dérivé propellane représenté par la formule générale (I) (dans laquelle R1 représente un atome d'hydrogène, un groupe alkyle en C1-6, un groupe cycloalkylalkyle (dans lequel le nombre d'atomes de carbone dans la fraction cycloalkyle est 3 à 6 et le nombre d'atomes de carbone dans la fraction alkylène est 1 à 5), un groupe aralkyle (dans lequel le nombre d'atomes de carbone dans la fraction aryle est 6 à 10 et le nombre d'atomes de carbone dans la fraction alkylène est 1 à 5) ou similaires ; R2 représente un groupe hydroxy, un groupe alcoxy en C1-6 ou similaires ; V représente CH ou N ; W, X, Y et Z représentent indépendamment CR3 ou N, où un cas dans lequel chacun de W, X, Y et Z représente N est exclus et W, X, Y et Z peuvent être identiques ou différents les uns des autres lorsque chacun d'au moins deux de W, X, Y et Z représente CR3 ; et R3 représente un atome d'hydrogène, un atome d'halogène, un groupe nitro, un groupe alkyle en C1-6 ou similaires), un tautomère, stéréo-isomère ou sel pharmaceutiquement acceptable du composé ou un solvate du composé ou du tautomère, stéréo-isomère ou sel pharmaceutiquement acceptable, qui peut être utilisé comme agent analgésique ou similaire.
PCT/JP2014/058717 2013-03-27 2014-03-27 Dérivé propellane WO2014157437A1 (fr)

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JP2013-066941 2013-03-27
JP2013066941A JP2016106072A (ja) 2013-03-27 2013-03-27 プロペラン誘導体

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008001859A1 (fr) * 2006-06-30 2008-01-03 School Juridical Person Kitasato Gakuen AGONISTE DES RÉCEPTEURS δ DES OPIOÏDES
CN101402636A (zh) * 2008-11-05 2009-04-08 中国科学院上海药物研究所 一类螺桨烷类化合物及其制备方法和用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008001859A1 (fr) * 2006-06-30 2008-01-03 School Juridical Person Kitasato Gakuen AGONISTE DES RÉCEPTEURS δ DES OPIOÏDES
CN101402636A (zh) * 2008-11-05 2009-04-08 中国科学院上海药物研究所 一类螺桨烷类化合物及其制备方法和用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
IDA, Y. ET AL., BIOORGANIC & MEDICINAL CHEMISTRY, vol. 20, 2012, pages 949 - 961 *
LI, F. ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, 2009, pages 4603 - 4606 *

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