WO2006006610A1 - Derivé d'oxopipérazine - Google Patents

Derivé d'oxopipérazine Download PDF

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Publication number
WO2006006610A1
WO2006006610A1 PCT/JP2005/012874 JP2005012874W WO2006006610A1 WO 2006006610 A1 WO2006006610 A1 WO 2006006610A1 JP 2005012874 W JP2005012874 W JP 2005012874W WO 2006006610 A1 WO2006006610 A1 WO 2006006610A1
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group
compound
pharmaceutically acceptable
oxo
atom
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PCT/JP2005/012874
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Japanese (ja)
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Hiroshi Kawamoto
Satoru Ito
Atsushi Satoh
Yasushi Nagatomi
Yukari Hirata
Toshifumi Kimura
Gentaroh Suzuki
Akio Sato
Hisashi Ohta
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Banyu Pharmaceutical Co., Ltd
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Publication of WO2006006610A1 publication Critical patent/WO2006006610A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
    • C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to an oxopiperazine derivative.
  • Glutamate is a neurotransmitter that mediates excitatory transmission in the central nervous system. In addition to various neurotransmitter effects, glutamate has many important brain functions such as neuronal survival and death, differentiation and proliferation, nerve and glial cell development, maturation or plastic changes in neurotransmission efficiency of the developing brain. Related to function (eg, Annual Review of Biophysics and Biomolecular Structures, 23, 3 1 9 (1 994))).
  • glutamate receptors in the central nervous system of mammals are classified into two types: ion channel glutamate receptors and metabotropic glutamate receptors (hereinafter referred to as “mG 1 uR”). ing.
  • An ion channel glutamate receptor is an ion channel that is composed of a complex of different subunit proteins and is opened and closed by the binding of ligands.
  • mG l uR is coupled to GTP-binding protein and acts by regulating intracellular second messenger production or ion channel activity via GTP-binding protein (for example, B rain Research R evi ew s), 26 ⁇ , p. 230 (1998)).
  • Group I (mG l uR l and 5) is a phospholipase for intracellular signaling.
  • group II (mG 1 uR 2 and 3)
  • group III (mG 1 uR4, 6, 7 and 8) regulate cyclic adenosine 1 phosphate by modulating adenylate cyclase activity ( cAMP) suppresses forskolin-stimulated accumulation.
  • cAMP adenylate cyclase activity
  • Group II is selectively activated by LY 354740 described in, for example, Journal of Medicinal Chemistry, 42 ⁇ , page 1027 (1999).
  • III is selectively activated by L-AP 4.
  • various receptors are expressed in a wide range of brain and nervous system, except for mG 1 uR6, which exists specifically in the retina. It has a characteristic distribution in the brain, and it is thought that each receptor plays a different physiological role (for example, Neurochemistry International (Neuroch em istry I nternationa 1), 24 ⁇ , 439 ( 1 994) Eopyo Ichibanbian Joura Nore off, 'Eu ropean Journal of Pharmacology, 375 ⁇ , 277 (1999) etc.).
  • a compound represented by (A) is described (WOO 3/026652).
  • the compound (A) has one NH—S (O) 2 — Ph on the oxopiperazine ring, and has a benzyloxycarbonyl group at the 4-position on the oxopiperazine ring. It is structurally different from the compound according to the present invention.
  • an object of the present invention is to provide a novel substance having an mG 1 uR 1 inhibitory action.
  • the present inventors have found that a specific oxopiperazine derivative has an mG 1 uR l inhibitory action, and completed the present invention.
  • the present invention provides the following compounds (1) to (7) or a pharmaceutically acceptable salt thereof in order to achieve the above object.
  • R 4 and R 5 are each independently a hydrogen atom, a linear or branched lower alkyl group or a cycloalkyl group, or a nitrogen atom in the formula (II), R 4 and R 5 together. Therefore, a 4- to 7-membered nitrogen-containing aliphatic heterocyclic group to be formed (the heterocyclic group may have one oxygen atom as a constituent atom of the ring),
  • R 2 may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, an alkoxy group, a lower alkylsulfonyl group and a hydroxy group in the ring.
  • R 3 represents a hydrogen atom, a halogen atom or a lower alkyl group,
  • R 2 has 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group and a hydroxy group in the ring.
  • a pharmaceutically acceptable salt thereof which is a 6-membered heteroaryl group having 1 or 2 phenyl groups or nitrogen atoms in the ring.
  • a to A 5 each independently represent a methine group, or any one or two of A to A 5 is a nitrogen atom, and the remaining 3 or 4 is a 10 to A 40 represents a chin group.
  • a 4 Any one or two of them is a nitrogen atom, the remaining 2 or 3 is a methine group, and R 6 , R 6G and R 61 are independently a hydrogen atom, a halogen atom,
  • the compound according to the above (1) or a pharmaceutically acceptable salt thereof which is a group represented by the following: a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group or a hydroxy group.
  • R 1 is a linear or branched lower alkyl group or a cycloalkoxy group.
  • the compound represented by the formula (I) is 4— (2′-fluoro-bibiphenyl-2-yl) _ 3—oxopiperazine 1 _carboxylic acid tert-butyl ester, 4- (biphenyl 1 3 —Yl) 1-oxopiperazine 1 _carboxylic acid tert-butinoresestenole,
  • DHPG 5-dihydroxyphenyglycine
  • mG 1 uR 1 selective antagonist (3 a S, 6 a S) — 6 a— naphta 1 en— 2— y 1 methy 1— 5— me thy 1 iden— hexahydro— eye 1 openta [c] furan— 1— one (hereinafter referred to as “B AY 36— 7620”) reduces the cortical infarct volume in the rat subdural hemorrhage model (for example, In the European Journal of Pharmacology (see Eu ropean Journal of Pharmorology), 428 ⁇ , 203 (2001), etc.) and other selective antagonists R 1 28494, rat middle cerebral artery ligation There is a
  • niGluRl inhibitors may have a protective effect against cerebral disorders such as cerebral infarction or transient ischemic attack.
  • the compounds of the above (1) to (7) having a mG 1 uR 1 inhibitory action or pharmaceutically acceptable salts thereof are useful for the prevention or treatment of cerebral disorders such as cerebral infarction or transient ischemic attack. It is considered useful.
  • DHPG showed a similar response to dopamine stimulation suggests that mG 1 uR l and mG 1 u R 5 are involved in mental dysfunction in the nucleus accumbens. This suggests the possibility of improving the symptoms.
  • the compounds of the above (1) to (7) having a mG 1 uR 1 inhibitory action or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of mental dysfunction such as schizophrenia. .
  • the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for prevention or treatment of drug dependence.
  • mGluRl inhibitors may be preventive or therapeutic agents for Parkinson's disease.
  • the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of Parkinson's disease.
  • Reflux esophagitis is the most common upper gastrointestinal disorder.
  • Current drug therapy aims to suppress gastric acid secretion or neutralize gastric acid in the esophagus.
  • the main mechanism involved in reflux has been thought to be due to chronic tension decline in the lower esophageal sphincter.
  • Gastroenterol Clinical North America Gastroenterol Clin. No rth Am.
  • TLE SR which indicates the temporary relaxation of the lower esophageal sphincter, is defined according to Gastroenterology (Gastroen tetrology), 109 (2), 601 pp. 1 6 10 (1 995).
  • the term “reflux” is defined as gastric juice that can flow from the stomach into the esophagus. This is because the mechanical barrier is temporarily lost in such a state.
  • the word “GERD”, which indicates reflux esophagitis, is the veilers clinical gastroente This is a definition according to J. Kazuichi Kuchiguchi (Baillier e's Clinical Ga stroenterology), 14 pp. 759 pp. 774 (2000). Due to the physiological and pathophysiological significance described above, the compounds (1) to (7) or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of gastrointestinal disorders.
  • aryl group means a hydrocarbon ring aryl group having 6 to 14 carbon atoms, and examples thereof include a phenyl group and a naphthyl group.
  • “Lower alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group.
  • Tert-butyl group pentyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, Isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3 —Dimethylbutyl group, 2,3-dimethylbutyl group,
  • Examples include 3,3-dimethylbutyl group, 1_ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group and the like.
  • Alkoxy group means that a hydrogen atom of a hydroxy group is substituted with the lower alkyl group. For example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, hexyloxy group, And an isohexyloxy group.
  • alkylsulfonyl group means a group in which the alkyl group and the sulfonyl group are bonded.
  • the compound according to the present invention has an mG 1 uR 1 inhibitory action.
  • the “mG 1 uR l inhibitory action” may be any substance that inhibits the function of mG 1 uR 1, for example, mG 1 uR 1 inhibitory action. Those having 1 uR 1 antagonistic activity and those that are non-antagonistic and have mG 1 uR 1 receptor antagonistic activity are included.
  • Examples of the “linear or branched lower alkoxy group” represented by R 1 include a methoxy group, an ethoxy group, an n -propoxy group, an isopropoxy group, an n-butoxy group, and a tert-butoxy group. Of these, n-propoxy group, isopropoxy group, tert-butoxy group and the like are preferable.
  • Examples of the “straight chain or branched lower alkyl group” represented by R 1 include, for example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, 1-methyl-pro And a pyrrole group, a tert-butyl group, a 1-ethynolepropyl group, and the like.
  • an isopropyl group, a butyl tert-group, a 1-methyl-propyl group, a 1-ethylloop pill group, and the like are preferable.
  • a group or a tert-butyl group is more preferred.
  • Examples of the “linear or branched lower alkyl group” represented by R 4 or R 5 include, for example, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a tert-butyl group, and 1_methylol.
  • —Propyl group, 1-ethyl-butyl group and the like can be mentioned, and among these, methyl group, ethyl group, isopropyl group, tert-butyl group and the like are preferable, and methyl group, isopropyl group and tert-butyl group are more preferable.
  • Examples of the “cycloalkyl group” represented by R 4 or R 5 include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like, and a cyclopropyl group or a cyclobutyl group is preferable.
  • a cyclopropyl group is more preferable.
  • R 1 may be an alkoxy group, a cycloalkoxy group or a formula (II)-
  • R 2 represents a “5- to 6-membered unsaturated heterocycle having 1 to 3 heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen” in the ring.
  • furyl group enyl group, pyrrolyl group, imidazolyl group, triazolyl group, pyrazolyl group, thiazolyl group, thiadiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, pyridinyl group, pyrimidinyl group, pyridazinyl group, And pyridyl group.
  • Examples of the “partially unsaturated heterocycle having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom” in R 2 include the following formulas: (III)
  • halogen atom of the substituent is, for example, preferably a fluorine atom, a chlorine atom, a bromine atom.
  • the “lower alkyl group” for the substituent is, for example, preferably a methyl group, an ethyl group, an isopropyl group.
  • alkoxy group examples include a methoxy group, an ethoxy group, and n
  • the “branched alkyl group having 3 to 10 carbon atoms” represented by R 2 is, for example, the following formula (IV)
  • R 2 more specifically, for example, a tert-butyl group, a phenyl group, a fluorophenyleno group, a methinophenyl group, a cyanphenyl group, a nitrophenyl group, a methoxyphenyl group, a hydroxyphenyl group, a pyridinyl group Of these, tert-butyl, phenyl, fluorophenyl, and pyridinyl are preferred.
  • 6-membered heteroaryl group having 1 or 2 nitrogen atoms in the ring include a pyridinyl group, a pyradyl group, a pyrimidinyl group, and a pyridazinyl group. , Pyridinyl group, pyrimidinyl group, etc. Is preferred.
  • R 2 and R 2 together form a naphthyl group, quinolinyl group, isoquinolinyl group, quinazolinyl group, quinoxalinyl group or cinnolinyl group, a halogen atom or lower alkyl group as a substituent of the group 1 to 3 may be included.
  • R 2 has 2 or 3 substituents, these may be the same or different.
  • the condensed ring formed by combining R 2 and R 1 which may be substituted with 1 to 3 halogen atoms or lower alkyl groups for example, a naphthyl group, A quinolinyl group, an isoquinolinyl group, etc. are mentioned, Among these, a naphthyl group etc. are preferable.
  • a to A 5 each independently represent a methine group, or any one or two of A b to A 5 is a nitrogen atom, and the remaining 3 or 4 Indicates a methine group.
  • a 4 Is To A 4 . Any one or two of them is a nitrogen atom, the remaining 2 or 3 is a methine group, and R 6 , R 6G and R 61 are independently a hydrogen atom, a halogen atom, A lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group or a hydroxy group] is preferred. From the above, the formula (I) according to the present invention
  • each symbol is the same as above] Specifically, for example, 4— (2′—fluoro-biphenyl 2-3-f) 1-oxopiperazine 1-Strong Norevonic acid tert-Butyl ester, 4- (Bifinole _ 3—Inole)-3-oxopiperazine 1 _Strong Norebonic acid tert-Butinore Estenole, 4— (2'-Methyl monobiphenyl) 3—yl) 1 3-oxopiperazine 1-carboxylic acid tert-butinoreestenole, 4-(2 '-black-one bifue-nore 1 3-inole) 1 3-oxo 1-piperazine 1 1-carvone Acid tert-butyl ester, 3 _oxo 4- (3-pyridine-1--2-yl monophenyl) monopiperazine mono 1-carboxylic acid tert-butyl ester, 3-oxo 4- (3-ter
  • the compound (I) according to the present invention can be produced using a known reaction means or according to a method known per se.
  • the compound (I) according to the present invention can be produced not only by a synthesis method in a normal liquid phase but also by a method using a solid phase such as a combinatorial synthesis method or a parallel synthesis method, which has been developed in recent years. it can.
  • the (1-1), (1-2), (1-3) or (1-4) included in the compound (I) according to the present invention can be produced, for example, by the following method.
  • This step is a process for producing compound (3) by reacting 4-Boc-piperazinone (I) with I-mouthed 3-benzene benzene (2) in the presence of a base and a catalyst. It is.
  • the amount of the base used in this step is usually 1 to 100 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (1).
  • the amount of the compound (2) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 0.1 equivalent of the compound (1).
  • reaction can be carried out using 1,3-dibromobenzene, 1,3-jodobenzene, or the like.
  • Examples of the catalyst used include copper iodide, copper chloride (1), and copper acetate (I I). Of these, copper iodide is preferred.
  • the amount of the catalyst used is 1% mol to 200% mol, preferably 5% mol to 20% mol, relative to 1 equivalent of the compound (1).
  • the reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction.
  • Specific examples include DMF, N-methylpyrrolidone, dioxane, THF, DMS O, and water. Of these, DMF, N-methylpyrrolidone or dioxane is preferred.
  • the reaction temperature in this step is usually 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.
  • the reaction time in this step is usually 30 minutes to 7 days, preferably 6 hours to
  • the compound (3) thus obtained can be isolated or purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • This step is a combination of the compound (3) obtained in Step 1 in the presence of a catalyst and a base.
  • This is a method for producing the compound (I-1) according to the present invention by reacting the product (4).
  • the reaction in this step is a so-called Suzuki coupling reaction.
  • the amount of compound (3) used is usually 1 to 1 per 1 equivalent of compound (4).
  • the catalyst to be used for example, P d (PPh 3) 4 , P d 2 (dba) 3, P d C 1 2 (dppf) 2 and the like.
  • the amount of the catalyst used is usually 1 to 200% mole, preferably 5 to 20% mole, relative to 1 equivalent of the compound (4).
  • the amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (4).
  • Examples of the compound (4) used include 2_pyridine boric acid, 3-pyridin boric acid, 4 monopyridine boric acid, and pyrimidine 1 5_boric acid.
  • Any solvent can be used as long as it does not interfere with the reaction.
  • DMF N-dimethylformamide
  • NMP N —Methylpyrrolidone
  • THF tetrahydrofuran
  • D MSO dimethyl sulfoxide
  • water etc.
  • Toluene, DMF and NMP are preferred.
  • the reaction temperature is generally 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.
  • the reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours.
  • the compound (1-1) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc., or in the next step. Can be attached.
  • This reaction can be performed using methods described in the literature (for example, Protective Groups in Organic Synthesis, TW G reen, 2 te, John W i 1 ey & Sons, 1 991 Year, etc.), a method according to it, or a combination thereof with a conventional method, specifically, for example, monoethanol hydrochloride or TFA.
  • the reaction time is usually 10 minutes to 2 days, preferably 10 minutes to 2 hours.
  • This step is a process for producing the compound (1-2) according to the present invention by reacting the compound (5) obtained in the step 3 with a carboxylic acid compound (6-1) or a reactive derivative thereof. It is.
  • This reaction is a method described in the literature (eg, peptide synthesis fundamentals and experiments, Nobuo Izumiya et al., Maruzen, 1983, Comprehensive Organic Synthesis (C omp r ehensive Organic Synthesis), No. 6, Pergamon Press, 1 99, 1), etc., or a combination of these and conventional methods to perform normal amide formation reactions.
  • it can be carried out by using a condensing agent known to those skilled in the art, or by an ester activation method, a mixed acid anhydride method, an acid chloride method, a carbodiimide method, etc. available to those skilled in the art. You can.
  • amide-forming reagents include thionyl chloride, oxalyl chloride, N, N-dicyclohexylcarbodiimide, 1-methyl-2-bromopyridinium iodide, N, N′-carboninoresidimidazole, diphenyl.
  • Phospholinole chloride diphenylphosphoryl azide, ⁇ , ⁇ '—disuccinimidinole canolebonate, N, N' —disuccimidyloxalate, 1-ethyl-1-3- (3-dimethylaminopropyl)
  • Examples thereof include carbodiimide hydrochloride, chloroethyl formate, chlorobutyl isobutyl formate or benzotriazo-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate, and examples thereof include thiol chloride, 1 _Ethyl_3_ (3-Dimethylaminopropyl) carbodiimide hydrochloride, ⁇ , ⁇ -di Preferred is hexylcarbodiimide or benzotriazo 1-yloxytris (dimethylamino) phosphonium hexafluorophosphate.
  • Condensation aids used include, for example, N-hydroxybenzotriazole hydrate, N-hydroxysuccinimide, N-hydroxy-5-norbornene-2,3-dicarboxyimide, or 3-hydroxyl-3 , 4-dihydro 4-oxo-1,2,3-benzotriazole and the like, among which N-hydroxybenzotriazole and the like are preferable.
  • the amount of compound (6-1) or reactive derivative used varies depending on the type of compound and solvent used and other reaction conditions, but usually 1 to 50 equivalents, preferably 1 to 50 equivalents per 1 equivalent of compound (5) Is 2 to 10 equivalents.
  • the amount of the amide-forming reagent used varies depending on the type of compound and solvent used and other reaction conditions, but usually 1 to 50 equivalents, preferably 2 to 10 equivalents, per 1 equivalent of the normal compound (5) It is.
  • the amount of the condensation aid used varies depending on the compound used, the type of solvent and other reaction conditions, but is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (5).
  • the amount of base used varies depending on the compound used, the type of solvent, and other reaction conditions, but is usually 1 to 50 equivalents, preferably 2 to 5 equivalents, relative to 1 equivalent of normal compound (5). .
  • the reaction solvent used in this step is not particularly limited. Specifically, for example, chlorohonolem, salt methylene chloride, THF, jetyl ether, DMF,
  • NMP dioxane
  • DMSO dioxane
  • toluene benzene
  • xylene xylene
  • black mouth form methylene chloride, THF, jetyl ether, DMF, NMP, toluene, benzene or xylene are preferable.
  • the reaction temperature in this step is usually from 78 ° C to 150 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 1 2 hours.
  • the base, amide-forming reagent and condensation aid used in this step can be used alone or in combination.
  • This step is a method for producing the compound (I-3) according to the present invention by reacting the compound (5) obtained in the above step 3 with the compound (6-2) in the presence of a base.
  • the base used in this step include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1, 8—Jazabicyclo [5. 4. 0] Wunde force 7—Yen (DBU), 1, 5—Zazabicyclo [4. 3. 0] Nonah 1—5-Nen (DBN), etc.
  • a class of aliphatic amines for example, aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc., among which, for example, tertiary aliphatic amines are preferred.
  • aromatic amines such as pyridine, 4-dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc., among which, for example, tertiary aliphatic amines are preferred.
  • Triethylamine, N, N-diisopropylethylamine, pyridine and the like are preferable.
  • the amount of the base used is usually 1 to the amount of solvent with respect to 1 equivalent of compound (5).
  • the amount of the compound (6-2) used is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of the compound (5).
  • the reaction solvent used in this step is not particularly limited as long as the reaction is not hindered. Specifically, for example, black form, methylene chloride, THF, dimethyl ether, DMF, NMP, dioxane, DMSO, toluene, benzene, xylene, etc., among these, black form, chloride Preference is given to methylene, THF, jetyl ether, DMF, NMP, toluene, benzene or xylene.
  • the reaction temperature in this step is 178 ° C to 150 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 12 hours.
  • the thus obtained compound (1-3) according to the present invention can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like. Can do.
  • This step is a method for producing the compound (I-3) according to the present invention by reacting the compound (5) with the compound (6-3).
  • the amount of (6-3) used is usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (5).
  • reaction in this step may be performed using a base.
  • Examples of the base used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylolpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8- Jazabisik Mouth [5. 4. 0] Third-class aliphatic amines such as Wunde 7-Yen (DBU), 1, 5-Azabicyclo [4. 3.
  • DBU Wunde 7-Yen
  • DBU 5-Azabicyclo
  • the reaction time in this step is usually 30 minutes to 7 days, preferably 30 minutes to 12 hours.
  • the thus obtained compound (1_4) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • the compound (I-11) according to the present invention can also be produced by the following method.
  • R represents a lower alkyl group, and other symbols are the same as above]
  • the compound (4a) to be used include, for example, 4-tributylstannyl pyridine, 2-tributylstanninopyridine, 2_tributylstanninothiophene, 2-tributinorestandifuran, 2_tributylstane Ninolepyrazine, 2-tributylstannylpyrimidine, trimethylphenyltin, trimethyl (2-pyridyl) tin, and the like.
  • Examples of the catalyst used include P d (PP h 2 ) 4 and P d 2 (dba) 2 .
  • the amount of the catalyst used is usually 1 to 200% mol, preferably 5 to 20% mol, relative to 1 equivalent of compound (3).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • examples thereof include toluene, DMF, NMP, THF, DMSO and the like. Among these, toluene, DMF, NMP and the like are preferable.
  • R 2 G represents a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a cyano group, a nitro group, a lower alkoxy group, a lower alkylsulfonyl group and a hydroxy group in the ring. 3 may have a fuunyl group or nitrogen atom, sulfur A 5- to 6-membered unsaturated heterocycle having 1 to 3 heteroatoms selected from the group consisting of atoms and oxygen atoms, the other symbols are the same as above]
  • This step is a method for producing a compound (3-1) by reacting a 4-Boc-piperazinone (1) with a compound (2-1) in the presence of a base and a catalyst.
  • Examples of the base used in this step include potassium phosphate, sodium carbonate or carbonated lithium.
  • the amount of the base used in this step is usually 1 to 100 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of compound (1).
  • the amount of the compound (2-1) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (1).
  • Examples of the catalyst used include copper iodide, copper chloride (1), and copper acetate (I I). Of these, copper iodide is preferred.
  • the amount of the catalyst used is 1% mol to 200% mol, preferably 5% mol to 20% mol, per 1 equivalent of the compound (1).
  • the reaction solvent used in this step is not particularly limited as long as it does not interfere with the reaction. Specifically, for example, DMF, NMP, dioxane, THF,
  • Examples thereof include DMS O or water, and among these, DMF, NMP or dioxane is preferred.
  • the reaction temperature in this step is usually 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.
  • the compound (3-1) obtained in the step 5 and the compound (4-1) are reacted in the presence of a catalyst and a base to produce the compound (1-5) according to the present invention. It is a method.
  • the reaction in this step is a so-called Suzuki coupling reaction.
  • the amount of the compound (3-1) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (4-1).
  • the compound (4_1) to be used include, for example, ferroboric acid, methoxyphenyl borenolic acid, methino feneno borenoic acid, bromo phen eno boroboric acid, black feneno boroboric acid, nitro phen eno boroboric acid, acetyl thiophene.
  • the catalyst to be used for example, P d (PP h 3) 4, P d 2 (dba) 3, P d C 1 2 (dppf) 2 and the like.
  • the amount of the catalyst to be used is generally 1 to 200% mol, preferably 5 to 20% mol, relative to 1 equivalent of compound (4-1).
  • Examples of the base used include sodium carbonate and potassium carbonate.
  • the amount of the base used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of the compound (4-1).
  • reaction solvent can be used as long as it does not interfere with the reaction.
  • toluene, DMF, NMP, dioxane, THF, DMSO, water and the like can be mentioned. Of these, toluene, DMF and NMP are preferable.
  • the reaction temperature is generally 0 ° C to 150 ° C, preferably 50 ° C to 120 ° C.
  • the reaction time is usually 30 minutes to 7 days, preferably 6 to 12 hours.
  • the compound (1-5) according to the present invention thus obtained is isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, solvent extraction, crystallization, reprecipitation, chromatography, etc. Or it can attach to the next process, without isolating and purifying.
  • This step is a method for producing the compound (5-1) by removing the Boc group of the compound (I 1-5) obtained in the step 6.
  • reaction in this process is the method described in the literature (for example, Protective Group Organic Synthesis, TW G reen, 2nd fe, John Wiley & Sons, 1991, etc. ), A method according to it, or a combination thereof with a conventional method, specifically, for example, hydrochloric acid monomethanol or TFA, etc., and the same method as in step 2, It is possible to carry out the same methods or a combination of these with conventional methods.
  • the compound (5-1) obtained in the step 7 is reacted with the carboxylic acid derivative (6-1) or a reactive derivative thereof to produce the compound (I-6) according to the present invention. It is a method to do. '
  • reaction in this step can be carried out by the same method as in Step 4-11, a method analogous thereto, or a combination of these with conventional methods.
  • the ichigo compound (1-6) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. it can.
  • This step is a method for producing the compound (I-7) according to the present invention by reacting the compound (I-15) obtained in the step 5 with the compound (6-2).
  • reaction in this step can be carried out by the same method as in Step 4-12, a method analogous thereto, or a combination of these with conventional methods.
  • the thus obtained compound (I-16) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • This step is a method for producing the compound (I-7) according to the present invention by reacting the compound (5) obtained in the above step 5 with the compound (6-3).
  • reaction in this step can be carried out by the same method as in Step 4-13, a method analogous thereto, or a combination of these with conventional methods.
  • the thus obtained compound (I-18) can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • the compound (I_5) can also be produced by the following method.
  • R G represents a lower alkyl group, and other symbols are the same as above]
  • This step is a method for producing the compound (I-15) according to the present invention by reacting the compound (3-1) with the compound (4-1b) in the presence of a catalyst.
  • the reaction in this step is a so-called S tille coupling reaction.
  • Specific examples of the compound (4b) used include, for example, 4 monotributyls Tandirubiridine, 2_tributylstannylrubiridine, 2-tributylstanninorethiophene, 2-tribiti ⁇ / stanninolefuran, 2_tribhistanninorepyrazine, 2-tributylstannylpyrimidine, trimethylphenyltin, trimethyl ( 2-pyridyl) tin and the like.
  • RG in the compound (4b) represents a lower alkyl group, and for example, a methyl group, an ethyl group, a propyl group, a butyl group and the like are preferable.
  • the amount of the compound (4b) used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of the compound (3-1).
  • Examples of the catalyst used include P d (PPh 2 ) 4 and P d 2 (dba) 2 .
  • the amount of the catalyst to be used is generally 1 to 200% mol, preferably 5 to 20% mol, relative to 1 equivalent of compound (3-1).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • examples thereof include toluene, DMF, NMP, THF, DMSO and the like. Among these, toluene, DMF, NMP and the like are preferable.
  • reaction in this step can be carried out by the same method as in Step 1, a method analogous thereto, or a combination of these and conventional methods.
  • the compound (1-9) or (1-10) thus obtained can be obtained by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography. It can be isolated and purified by the same method or can be subjected to the next step without isolation and purification.
  • This step is a method for producing the compound (5-2) or (5-3) by removing the B oc group of the compound (1_9) or (1-10) obtained in the step 9 above.
  • the reaction in this step is performed according to the method described in the literature (for example, Protective Group Organic Organic Synthesis, T. W, Green 2nd edition, John Wiley & Sons, 199 1 , Etc.), a method according to it, or a combination thereof with a conventional method, specifically, for example, hydrochloric acid monomethanol or TFA, etc., and the same method as in step 2, this Or a combination of these and conventional methods.
  • the compound (5-2) or (5-3) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, crystallization, solvent extraction, reprecipitation, chromatography, etc. Or it can attach to the next process, without isolating and purifying.
  • This step comprises reacting the compound (5-2) or (5-3) obtained in the step 10 with a carboxylic acid compound (6-1) or a reactive derivative thereof, to thereby obtain the compound according to the present invention.
  • This is a method for producing (I — 9-1) or (I — 1 0 — 1).
  • reaction in this step can be carried out by the same method as in Step 4-11, a method analogous thereto, or a combination of these with conventional methods.
  • This step consists of compound (5-2) or (5-3) and compound obtained in step 10 above.
  • (6-2) is a method for producing a compound (1-9-2) or (1-10-2) according to the present invention.
  • the thus obtained compound (26) can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. it can.
  • reaction in this step can be carried out by the same method as in Step 4-13, a method analogous thereto, or a combination of these with conventional methods.
  • the compound (1-9-3) or (1-10-3) thus obtained can be obtained by known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be isolated and purified.
  • the compound according to the present invention can be converted into a pharmaceutically acceptable salt or ester by a conventional method, and the salt or ester is obtained by using the compound included in the compound (I) or (I) according to the invention. It can be produced according to a conventional method.
  • the compound (I) when the compound (I) has a basic group derived from, for example, an amino group or a pyridinyl group in the molecule, the compound is treated with an acid. Can be converted into the corresponding pharmaceutically acceptable salts.
  • the acid addition salt examples include hydrohalides such as hydrochloride, hydrofluoride, hydrobromide, and hydroiodide; nitrate, perchlorate, sulfate, phosphate, carbon Inorganic acid salts such as acid salts; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate, p- Aryl sulfonates such as toluene sulfonate; organic acid salts such as fumarate, succinate, citrate, tartrate, oxalate, maleate; and glutamate, aspartate Examples thereof include acid addition salts which are organic acids such as amino acids such as salts.
  • the compound of the present invention when the compound of the present invention has an acidic group in the group, for example, a carboxyl group or the like, the corresponding pharmacology can also be obtained by treating the compound with a base.
  • a base Can be converted into a salt which is acceptable to the environment.
  • the base addition salt include alkali metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, salts with organic bases such as guanidine, triethylamine, and dicyclohexylamine. Is mentioned.
  • the compound of the present invention may exist as any hydrate or solvate of a free compound or a salt thereof.
  • the compound according to the present invention may have a stereoisomer or a tautomer such as an optical isomer, a diastereoisomer, or a geometric isomer depending on the mode of the substituent. Needless to say, all of these isomers are included in the compounds of the present invention. Furthermore, it goes without saying that any mixture of these isomers is also encompassed by the compounds according to the present invention.
  • the compound according to the present invention the aromatic hydrogen in the compound tritium, a methylation group 3 H 3 C, 1 4 CH 3, in Ita_ ⁇ _Ita 3, fluorine in 1 8 F, the carbonyl group It can also be used as Rajioraberu body by conversion to isotopes of 1 1 C etc. carbon.
  • the compound of the present invention When used clinically, it may be formulated by adding a pharmaceutically acceptable additive according to the administration form.
  • additives various additives usually used in the pharmaceutical field can be used.
  • gelatin Lactose, Sucrose, Titanium oxide, Starch, Crystalline cellulose, Hydroxypropylmethylenocellulose, Carboxymethyl cenololose, Corn starch, Microcrystalline wax, White petrolatum, Magnesium aluminate metasilicate, Hydrous calcium phosphate, Quenic acid, Quenic acid Trisodium, hydroxypropylsenololose, sorbitol, sorbitan fatty acid ester, polysorbate, sucrose fatty acid ester, polyoxyethylene, hydrogenated castor oil, polybylpyrrolidone, magnesium stearate, light anhydrous keic acid, talc, vegetable oil Benzyl alcohol, gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin
  • the mixture of the compound of the present invention and the above-mentioned additives should be used as a solid preparation (tablets, capsules, condyles, powders, suppositories, etc.) or a liquid preparation (syrup, elixir, injection, etc.) Can do.
  • These preparations can be prepared according to usual methods in the pharmaceutical field.
  • the liquid preparation may be dissolved or suspended in water or other appropriate medium at the time of use.
  • they may be dissolved or suspended in physiological saline or budu sugar solution as necessary, and buffering agents or preservatives may be added.
  • These preparations can contain the compound of the present invention in a proportion of 1.0 to 100% by weight, preferably 1.0 to 60% by weight.
  • the compound of the present invention can be formulated according to the following formulation examples. (Formulation Example 1)
  • the dose and frequency of administration vary depending on the sex, age, weight, symptom of the patient, and the type and range of the desired treatment effect.
  • 0.01 to 100 mg / kg, preferably 0.0 S lmgZkg per adult is administered in divided doses from ⁇ to several times.
  • 0.001 to: 1 OmgZkg, preferably 0.001 to 0 ⁇ lmgZkg is administered in 1 to several divided doses.
  • Wakogel (registered trademark) C-300 manufactured by Wako Pure Chemical Industries, Ltd. or KP-Si1 (registered trademark) Silica prepacked column manufactured by Biotage Corporation was used for the Siri-force gel force ram chromatography.
  • Kiese 1 ge 1 TM 60 F 254 , Art. 5744 manufactured by Merck was used for the preparative thin layer chromatography.
  • Basic silica gel column chromatography is Chromatorex (registered trademark) NH (1 00—250me sh or 200—350me s manufactured by Fuji Silicon Chemical Co., Ltd. h) was used.
  • Mass spectra were measured by electrospray ionization (ESI) or atmospheric pressure chemical ionization (APC I) using microsass ZQ manufactured by Watters.
  • the NMR spectrum uses dimethyl sulfoxide as an internal standard when measuring with deuterated dimethyl sulfoxide solution, and Gemini-200 (20 OMH z;
  • V a r i a n Gem i n i—300 (30 OMH z; V r i a n), Mer c u r y 400 (400 MHz; V a r i a n) or I n o v a 400 (400
  • n -P r n-propyl group
  • Example 1 Using the compound of Example 1 according to the present invention, mG 1 u R 1 inhibitory action was measured.
  • CHO cells expressing mG 1 uR 1 a are 10% dialyzed fetal bovine clot, 1% proline, 100 units / m 1 penici 1 1 in s 0.1 mg / m 1 strept omy cinsulfate, 2 mM The cells were cultured in a DMEM medium containing glutamine.
  • Example 1 As a result, with respect to mG 1 u R 1, the compound according to the present invention described in Example 1 below did not show agonism until 10; uM. 10 ⁇ glutamic acid The increase in calcium was suppressed in a dose-dependent manner. Its IC 50 value was 38 ⁇ .
  • a novel substance having an mG 1 uR l inhibitory action is provided.
  • the dialyl-substituted hetero 5-membered ring derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof provided by the present invention has a potent mG lUR l inhibitory action, convulsions, acute pain, It is useful for the prevention or treatment of inflammatory pain, chronic pain, cerebral infarction or transient ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence, Parkinson's disease or gastrointestinal disorders.

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Abstract

Composé représenté par la formule (I) (dans laquelle R1 représente un alcoxy inférieur linéaire ou ramifié, etc. ; R2 représente un halogéno, un alkyle inférieur, un cyano, un nitro, un alcoxy, etc. ; R3 représente un hydrogène, un halogéno ou un alkyle inférieur ; et X1 représente un phényle, un hétéroaryle à 6 chaînons ayant un ou deux atomes d'azote dans le cycle, etc.) ou sel acceptable du point de vue pharmaceutique du composé. Le composé et le sel ont une activité d'inhibition du mGluR1 et sont utiles pour le traitement et/ou la prévention de convulsions, de douleurs aiguës, de troubles du cerveau tels que l'infarctus cérébral ou l'accident ischémique cérébral transitoire, de troubles des fonctions mentales tels que la schizophrénie, l'anxiété, la pharmacodépendance ou la maladie de Parkinson.
PCT/JP2005/012874 2004-07-09 2005-07-06 Derivé d'oxopipérazine WO2006006610A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2013544836A (ja) * 2010-12-02 2013-12-19 イーライ リリー アンド カンパニー ３−置換−６−（ピリジニルメトキシ）−ピロロピリジン化合物
JP2015157827A (ja) * 2008-02-07 2015-09-03 マーケット ユニバーシティー 統合失調症を治療するため及び薬物渇望を低減するためのシステイン及びシスチンプロドラッグ

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025789A1 (fr) * 1998-10-29 2000-05-11 Merck & Co., Inc. Procede pour traiter l'endometriose
WO2001051494A1 (fr) * 2000-01-12 2001-07-19 Merck & Co., Inc. Inhibiteurs de prenyle-proteine transferase
WO2001060368A1 (fr) * 2000-02-18 2001-08-23 Merck & Co., Inc. Inhibiteurs de la prenyle proteine transferase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000025789A1 (fr) * 1998-10-29 2000-05-11 Merck & Co., Inc. Procede pour traiter l'endometriose
WO2001051494A1 (fr) * 2000-01-12 2001-07-19 Merck & Co., Inc. Inhibiteurs de prenyle-proteine transferase
WO2001060368A1 (fr) * 2000-02-18 2001-08-23 Merck & Co., Inc. Inhibiteurs de la prenyle proteine transferase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015157827A (ja) * 2008-02-07 2015-09-03 マーケット ユニバーシティー 統合失調症を治療するため及び薬物渇望を低減するためのシステイン及びシスチンプロドラッグ
JP2013544836A (ja) * 2010-12-02 2013-12-19 イーライ リリー アンド カンパニー ３−置換−６−（ピリジニルメトキシ）−ピロロピリジン化合物

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