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WO2006062110A1 - Derive de la piperazine - Google Patents

Derive de la piperazine Download PDF

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Publication number
WO2006062110A1
WO2006062110A1 PCT/JP2005/022408 JP2005022408W WO2006062110A1 WO 2006062110 A1 WO2006062110 A1 WO 2006062110A1 JP 2005022408 W JP2005022408 W JP 2005022408W WO 2006062110 A1 WO2006062110 A1 WO 2006062110A1
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WO
WIPO (PCT)
Prior art keywords
group
tert
piperazine
compound
butoxycarbonyl
Prior art date
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PCT/JP2005/022408
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English (en)
Japanese (ja)
Inventor
Atsushi Satoh
Yasushi Nagatomi
Toshifumi Kimura
Gentaroh Suzuki
Akio Sato
Hisashi Ohta
Original Assignee
Banyu Pharmaceutical Co., Ltd.
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Application filed by Banyu Pharmaceutical Co., Ltd. filed Critical Banyu Pharmaceutical Co., Ltd.
Publication of WO2006062110A1 publication Critical patent/WO2006062110A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/02—Antidotes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members 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
    • C07D309/10—Oxygen atoms
    • C07D309/12—Oxygen atoms only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings

Definitions

  • the present invention relates to a piperazine derivative useful in the field of medicine.
  • This compound acts as an inhibitor of metapotropic glutamate receptor 1 and is used for cerebral disorders such as convulsions, acute pain, inflammatory pain, chronic pain, cerebral infarction or transient ischemic attack, schizophrenia, etc. It is useful as a therapeutic and / or prophylactic agent for diseases such as mental dysfunction, anxiety and drug dependence.
  • Glutamate is a transductor that mediates excitatory transmission in the central nervous system. Glutamate is responsible for many important brain functions such as neuronal survival and death, differentiation and proliferation, neuronal and glial development, and plastic changes in neurotransmission efficiency in the mature or developing brain, in addition to various neurotransmitter effects. (E.g., Annuanore Review OB Biophysics and Biomolecular Str. (See 1994).
  • mammalian central nervous system glutamate receptors are classified into two types: ion channel glutamate receptors and metabotropic glutamate receptors (hereinafter referred to as “mG l uR”).
  • the ion channel type glutamate receptor is a complex of different subunit proteins, and is an ion channel that is opened and closed by the binding of a ligand.
  • mG 1 uR is conjugated to GTP binding protein and acts by regulating intracellular second messenger production or ion channel activity via GTP binding protein (for example, Brain Research Reviews (B rain Research Re vi ews), 26, 230 (1998)).
  • mG 1 uR exists as eight different subtypes of mG 1 uR 1-8. These are divided into three subgroups according to amino acid sequence homology, signal transduction, and pharmacological properties.
  • Group I mG l uRl and 5
  • Group II mG 1 uR2 and 3
  • Group III mG 1 uR4, 6, 7, and 8 adenylate.
  • cAMP cyclic adenosine monophosphate
  • Group II is also selectively activated by LY354740 as described in, for example, Journal of Medical Chemistry, 42 ⁇ , page 1027 (1999). 4 activates selectively.
  • various receptors are expressed in a wide range of brain and nervous systems, except for mG 1 uR6, which exists specifically in the retina, and each of them has a characteristic brain distribution, and each receptor has a different physiological are thought to play a role (for example, neuro-chemistry one International (N eurochemistry I nternationa 1), 24 Certificates, 439 (1994) ⁇ Pi ® bite Lesbian journal O blanking off Ryoichi Mako ports for 1 to (Eu ropean J ournalof Ph a rma cology, ⁇ / 5 ⁇ , page 277 (1999)).
  • DHPG 5-Dihydroxyphe ny glycine
  • AI DA has a dose-dependent anticonvulsant effect (see, for example, Neuro ph armaco 1 ogy), 37 ⁇ , 1465 (1998)) Exhibits inhibitory effects on sound-induced convulsions in sexually active mice and rats (for example, Eu ropean Journal of Pharmacology, Volume 368, 17 (1999)) See).
  • Non-Patent Document 16 which is a mG luR1 selective antagonist, suppresses brain self-stimulation promoted by MK-801, an NMDA receptor antagonist.
  • MK-801 an NMDA receptor antagonist.
  • this test system is considered to be a model that reflects part of the dependence due to MK-801. . Therefore, the above-described paper suggests that selective antagonists of the mG 1 u R 1 receptor may be drug-dependent therapeutic agents.
  • mG l uRl or mG l u R 5 activates the hypothalamic nucleus. It is well known that the excitation of the subthalamic nucleus is characteristic of Parkinson's disease. Therefore, a mG 1 u R 1 selective antagonist may be useful as a therapeutic agent for Parkinson's disease.
  • An object of the present invention is to provide a novel piperazine derivative having mG l uRl inhibitory action.
  • the present inventors have intensively studied to develop a compound having an mG 1 uR 1 inhibitory action, and found that the compound according to the present invention is effective as a compound having an mG 1 uR 1 inhibitory action. Based on V, the present invention has been completed.
  • R 1 represents a branched alkyl group having 3 to 9 carbon atoms
  • a linear or branched alkyl group having 2 to 9 carbon atoms which may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group (in the case of a branched alkyl group)
  • the branched alkyl groups may be bonded to each other to form a cycloalkyl group, and the carbon atom constituting the cycloalkyl group is substituted with 1 or 2 oxygen atoms.
  • (d) represents a bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms
  • X represents an oxygen atom, CH 2 or a single bond.
  • R 1 is a tert-butyl group
  • R 2 is a 2-methylpropyl group, a phenyl group, a tert-butyl group, a benzyl group or a cyclohexyl group
  • X is When it is an oxygen atom, except that R 1 is a tert-butyl group, R 2 is an adamantyl group, neopentyl group or cyclohexyl ether group, and R 3 is a single bond) Acceptable salt,
  • R 1 represents a branched alkyl group having 3 to 9 carbon atoms
  • (a) may be substituted with a group selected from the group consisting of a halogen atom, a hydroxy group, an alkoxy group and an alkoxycarbonyl group! /, a linear or branched alkyl group having 2 to 9 carbon atoms (branched alkyl group)
  • branched alkyl groups may be bonded to each other to form a cycloalkyl group, and the carbon atoms constituting the cycloalkyl group are 1 or 2 oxygen atoms. May be replaced),
  • (d) represents a bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms
  • X represents an oxygen atom, CH 2 or a single bond.
  • An mG 1 uR 1 antagonist comprising as an active ingredient a compound represented by the formula:
  • an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R 1 is a tert-butyl group or a 2,2-dimethylpropyl group,
  • mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom
  • an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein X is a single bond
  • an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R 2 is a linear or branched alkyl group having 2 to 9 carbon atoms;
  • an mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R 2 is an alkenyl group,
  • An mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R 2 is an aralkyl group,
  • An mG 1 uR 1 antagonist comprising, as an active ingredient, the compound according to (11) or a pharmaceutically acceptable salt thereof, wherein R 2 is an aryl group;
  • Infarction or epilepsy relates to therapeutic and / or preventive agents for brain disorders such as transient cerebral ischemic attacks, mental dysfunctions such as schizophrenia, anxiety, drug dependence and / or Parkinson's disease.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • ⁇ 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 ptyl group, an isobutyl group, and a sec_ptyl 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 Xyl 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 Group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1-eth -2-methylpropyl group and the Ru mentioned.
  • the “lower alkoxy group” means a group in which a hydrogen atom of a hydroxy group is substituted with the lower alkyl group.
  • Examples of the branched alkyl group having 3 to 9 carbon atoms represented by R 1 include isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isoamyl group, neopentyl group, isopentyl group, 1,1-dimethylpropyl group.
  • the group is preferably a 3,3-dimethylpropyl group, more preferably a tert-butyl group or a 2,2-dimethylpropyl group.
  • the linear or branched alkyl group having 2 to 9 carbon atoms represented by R 2 includes a cycloalkyl group having 3 to 9 carbon atoms or a cycloalkylalkyl group formed by bonding branched lower alkyl groups to each other. It is.
  • the carbon atoms constituting the cycloalkynole group having 3 to 9 carbon atoms or the cycloalkylalkyl group in the cycloalkylalkyl group may be substituted with 1 or 2 oxygen atoms.
  • linear or branched alkyl group having 2 to 9 carbon atoms represented by R 2 include, for example, an ethyl group, an isopropyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, an isoamyl group, and a neopentyl group.
  • Tyl group isopentyl group, 1,1-dimethylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group Group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-Ethylptyl group, 2-Ethylbutyl group, 1,2,2_trimethylpropyl group, 1-Ethyl-2-methylpropyl group, Cyclopropyl group, Cyclobutyl group, Cyclopentyl group , Cyclohexyl group, 2, 2, 3, 3-tetramethyl monocyclopropyl group, cyclopentylethyl group, cyclohexylethy
  • the linear or branched alkyl group having 3 to 9 carbon atoms may be substituted 1 to 3 with a group selected from the group consisting of a halogen atom, a lower alkoxy group and an alkoxycarbonyl group.
  • Examples of the halogen atom of the substituent include the same groups as the halogen atom defined above.
  • Examples of the lower alkoxy group for the substituent include the same groups as the lower alkoxy group defined above.
  • the alkoxycarbonyl group of the substituent means a group in which an alkoxy group as defined above and a force group are bonded.
  • a methoxycarbonyl group, an ethoxycarbonyl group, an isopropoxycarbonyl group, a propoxy group examples thereof include a carbonyl group and a tert-butoxycarbonyl group.
  • the alkenyl group represented by R 2 means a linear or branched alkenyl group having 2 to 9 carbon atoms.
  • the branched alkenyl group includes a case where branched alkyl groups on the alkenyl group are bonded to each other to form an alkyl group.
  • alkenyl group represented by R 2 include, for example, a butyl group, a allyl group, a 1-butenyl group, a 2-butenyl group, a 1-pentul group, a 3,3-dimethyl-1-butyr group, and a 2-cyclo group. And hexylvinyl group.
  • Examples of the aralkyl group represented by R 2 include a phenylmethyl group and a phenylethyl group.
  • Examples of the aryl group represented by R 2 include a phenyl group and a naphthyl group.
  • R 2 is an aralkyl group or an aryl group
  • a substituent selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, and a hydroxy group is substituted with 1 to 3 in the aralkyl group or aryl group. 3 may be present, and when it has 2 or 3 substituents, these may be the same or different.
  • Examples of the halogen atom of the substituent include the same groups as the halogen atom defined above.
  • Examples of the lower alkyl tomb of the substituent include the same groups as the lower alkyl group defined above.
  • Examples of the lower alkoxy group of the substituent include the same groups as the lower alkoxy group defined above.
  • Examples of the bicyclic to tricyclic hydrocarbon group having 7 to 10 carbon atoms represented by R 2 include an adamantyl group, a noradamantyl group, and a norbornyl group.
  • Preferable embodiments of the compound (I) according to the present invention include, for example, the case where R 1 is a tert-butyl group or a 2,2-dimethylpropinole group and X is an oxygen atom.
  • a preferred embodiment of the compound (I) according to the present invention includes, for example, a case where R 1 is a tert-butyl group or a 2,2-dimethylpropyl group, and X is CH 2 .
  • R 1 is a tert-butyl group or a 2,2-dimethylpropyl group
  • R 2 is a straight chain or branched carbon number 2 Or an alkyl group of 9 to 9.
  • preferred embodiments of the compound (I) according to the present invention include, for example, the case where R 1 is a tert-butyl group or a 2,2-dimethylpropyl group, and R 2 is an aralkyl group. .
  • a preferred embodiment of the compound (I) according to the present invention includes a case where R 1 is a tert-butyl group or a 2,2-dimethylpropyl group, and R 2 is an aryl group.
  • 1-neopentinoreoxycanololebonyl-4 (2: 2, 2,2-trifluoro-1,1-dimethyl monoethyloxycarbonyl) monopiperazine
  • This step is a method for producing the compound (I 1 1) according to the present invention by reacting 1-Boc-piperazine (1) with the compound (2).
  • amide-forming reagents include thionyl chloride, chlorohydryl, N, N-dicyclohexylenocarposimide, 1_methyl-2-promopyridinium iodide, N, N, -carbonyldiimidazole.
  • Examples of the base used include trimethylamine, triethylamine, N, N-diisopropinoleethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylmethylaniline, 1,8-diazabicyclo [5 4.0 0] tertiary aliphatic amines such as Wundeker 7-Yen (DBU), 1, 5—azabicyclo [4. 3. 0] Nona 5-Yen (DBN); Examples thereof include aromatic amines such as 4-dimethylaminopyridine, picoline, noretidine, quinoline, and isoquinoline. Among them, tertiary aliphatic amines are preferable, and particularly, for example, triethylamine, N, N-diisopropylethylamine. Min or pyridine is preferred.
  • condensation aid used examples include N-hydroxybenzotriazol hydrate, N-hydroxysuccinimide, N-hydroxy_5-norbornene-2,3-dicarboxyimide, or 3-hydroxysilane. , 4-dihydro-1,4-oxo-1,2,3-benzotriazole and the like, and for example, N-hydroxybenzotriazole and the like are preferable.
  • the amount of compound (2) or its 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 equivalent to 1 equivalent of compound (1) 2 to 10 equivalents.
  • Examples of the compound (2) used include 3-cyclohexylpropionic acid, 3-cyclopentenorepropionic acid, 3-noradamantanecarboxylic acid, 2,2,3,3-tetramethylcyclopropanecarboxylic acid, Examples include 4-methylpentanoic acid, cinnamic acid, cyclohexylcarboxylic acid, 3,3-dimethylbutyric acid, 4,4-dimethylpentanoic acid, and the like.
  • Compound (2) can also be produced by a force using a commercially available product, or a method well known to those skilled in the art using a commercially available product as a raw material, or a method analogous thereto.
  • the amount of the amide-forming reagent used varies depending on the type of compound and solvent used and other reaction conditions. Usually 1 to 50 equivalents, preferably 2 to 10 equivalents, relative to 1 equivalent of normal compound (1) 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 (1). is there.
  • the amount of base used varies depending on the type of compound and solvent used and other reaction conditions.
  • Normal compound (1) 1 to 50 equivalents, preferably 2 to 5 equivalents per 1 equivalent .
  • the reaction solvent used in this step is not particularly limited. Specifically, for example, black mouth form, chlorohymethylene, pyridine, THF, jetyl ether, DMF, NMP, dioxane, toluene, benzene or Xylene and the like can be mentioned, and among these, pyridine, black mouth form, and THF are preferred.
  • the reaction temperature in this step is usually from 1 78 ° C to 1550 ° C, preferably from 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 base, amide formation reagent, and condensation aid used in this step can be used alone or in combination.
  • the compound (1-1) thus obtained can be isolated and purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • each symbol is the same as described above] includes, for example, that it can be produced by the following method. [Where each symbol is the same as above]
  • This step is a method for producing the compound (1-2) according to the present invention by reacting the compound (1) with the compound (3).
  • Examples of the compound (3) used in this process include 2,2-dimethylpropyl chloroformate, 2,2,2-trichloroethyl chloroformate, pentyl chloroformate, and 2-methinoreprovir.
  • Examples include chloroformate, 2-ethylhexylchloroformate, and butylchloroformate.
  • Compound (3) can be produced by using a commercially available product or by a method well known to those skilled in the art using a commercially available product as a raw material.
  • the amount of compound (3) used is usually 1 to 10 equivalents, preferably 1 to 5 equivalents, relative to 1 equivalent of compound (1).
  • the reaction in this step may be performed in the presence of a base.
  • bases examples include trimethylenoamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylenorealin, 1,8-diazabixic mouth [5. 4. 0] Wundeker 7-Yen (DBU), 1, 5 — Azabicyclo [4. 3.
  • Tertiary aliphatic amines such as Nona 5-Yen (DBN); for example, pyridine, 4 -Aromatic amines such as dimethylaminopyridine, picoline, lutidine, quinoline or isoquinoline, etc., among which pyridine or triethylamine are preferred.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • black mouth form methylene chloride, pyridine, acetonitrile, THF, jetyl ether, DMF, NMP, dioxane, toluene, benzene or Xylene and the like. Among these, black mouth form is preferable.
  • the reaction temperature is usually -78 ° C to 150 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 30 minutes to 48 hours, preferably 6 hours to 24 hours.
  • the compound (1-2) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography and the like.
  • Compound (1-2) can also be produced, for example, by the following method.
  • Step 3 is a method for producing compound (5) by reacting compound (4) with carbonyldiimidazole (hereinafter abbreviated as “CD I”).
  • the amount of CD I used is usually 1 to 2 equivalents, preferably 1.1 to 1.3 equivalents, relative to 1 equivalent of compound (4).
  • Examples of the compound (4) to be used include (1-methylcyclopentyl) methanol, cyclopentenolemethanol, (1-methinorecyclohexenole) methanol, cyclohexenolemethanol, 3,3-dimethylbutane-2-ol.
  • the reaction in this step may be performed in the presence of a base.
  • Examples of the base to be used include trimethylamine, triethylamine, N, N-diisopropylenoethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylaniline, 1,8-diazabicycle mouth [ 5. 4. 0] Wundeker 7-Yen (DBU), 1,5-azabicyclo [4. 3.
  • Nona 5-Yen (DBN) and other tertiary aliphatic amines for example, pyridine, 4-dimethyl
  • aromatic amines such as aminopyridine, picoline, lutidine, quinoline and isoquinoline, and among these, pyridine and triethylamine are preferable.
  • the amount of the base to be used is generally 0.1 to 10 equivalents, preferably 0.1 to 2 equivalents, relative to 1 equivalent of compound (4).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • chlorophonolem methyl chloride, pyridine, acetonitrile, THF, jeti ac-ter, DMF, NMP, dioxane, toluene, benzene, xylene, etc.
  • black mouth form or acetonitrile is preferred.
  • the reaction temperature is usually _78 ° C to 150 ° (: preferably 0 ° C to 50 ° C).
  • the reaction time is usually 1 hour to 48 hours, preferably 3 hours to 6 hours.
  • the compound (5) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography, etc., or without isolation. It can be attached to the process.
  • Step 4 This step is a method for producing compound (6) by reacting compound (5) obtained in step 3 with methyl iodide.
  • the amount of methyl iodide used in this step is usually 1 equivalent to 1 equivalent to 1 equivalent of compound (5).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include black mouth form, salt methylene chloride, acetonitrile, THF, DMF, NMP, dioxane, etc. Among these, acetonitrile Is preferred.
  • the reaction temperature is usually 0 ° C to 50 ° C, preferably 0 ° C to 30 ° C.
  • the reaction time is usually 1 to 12 hours, preferably 3 to 6 hours.
  • the compound (6) thus obtained can be isolated or purified by a known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography or the like without isolation. It can be attached to the process.
  • Step 5 This step is performed according to the present invention by reacting the compound (6) obtained in the above step (4) with 1-Boc-piperazine (1) in the presence of a base.
  • This is a method for producing a compound (1-2).
  • the amount of compound (6) used is usually 1 to 3 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (1).
  • the amount of the base used is usually 1 to 10 equivalents, preferably 1 to 3 equivalents, relative to 1 equivalent of compound (1).
  • base to be used examples include triethylamine, pyridine, 4-dimethylaminoviridine and the like.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include black mouth form, methylene chloride, acetonitrinol, THF, DMF, NMP, dioxane, and the like. Mouth form is preferred.
  • the reaction temperature is usually 0 ° C to 50 ° C, preferably 10 ° C to 30 ° C.
  • the reaction time is usually 1 hour to 24 hours, preferably 5 hours to 10 hours.
  • the compound (1-2) thus obtained can be isolated and purified by known separation and purification means, for example, concentration, concentration under reduced pressure, reprecipitation, solvent extraction, crystallization, chromatography and the like.
  • the compound (1-3) according to the present invention can be produced, for example, by the following method.
  • Step 6 This step is a method for producing the compound (7-2) by removing the Boc group of the compound (7) using TFA (trifluoroacetic acid).
  • Compound (7) can be produced by the same method as in step 1 or 2, a method analogous thereto, or a combination of these with a conventional method.
  • the reaction in this step is carried out according to a method described in the literature (for example, Protecti V e Gr ou psin Organic Synthesis, TW G reen, 2nd edition, John Wile y & S ons, 1991, etc.), a method according to this method, or a combination of these and conventional methods.
  • the compound (7-2) thus obtained can be obtained by known separation and purification means such as concentration, concentration under reduced pressure, It can be isolated and purified by solvent extraction, solvent extraction, reprecipitation, chromatography, etc., or can be subjected to the next step without isolation and purification.
  • Step 7 is a method for producing the compound (1-3) according to the present invention by reacting the compound (7-2) obtained in the step 6 with the compound (3). .
  • reaction in this step may be performed in the presence of a base.
  • Examples of the base to be used include trimethylamine, triethylamine, N, N-diisopropylethylamine, N-methylmorpholine, N-methylpyrrolidine, N-methylbiperidine, N, N-dimethylenoreaniline, 1,8-diazabixic mouth [ 5. 4. 0] Wunde force 1—7-Yen (DBU), 1, 5-azabicyclo [4. 3.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include chloroform, chlorohimethylene, pyridine, acetonitrile, THF, jetyl ether, DMF, NMP, dioxane, toluene, benzene, and xylene. Of these, black mouth form is preferred.
  • the reaction temperature is usually from 78 ° C to 150 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 30 minutes to 48 hours, preferably 6 hours to 24 hours.
  • the compound (1-3) 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 and the like.
  • the compound (1-4) according to the present invention can be produced, for example, by the following method.
  • R 3 represents a linear or branched alkyl group having 1 to 7 carbon atoms.
  • Step 8 This step is a method for producing a compound (8-2) by reacting the compound (8) with triphenylphosphine in the presence of a base and then treating with a base.
  • triphenylphosphine used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of compound (8).
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction.
  • the reaction temperature is usually 50 ° C to 150 ° C, preferably 80 ° C to 120 ° C.
  • the reaction time is usually 1 hour to 24 hours, preferably 2 hours to 4 hours.
  • the compound thus obtained is isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc., or treated with a base without isolation and purification.
  • Examples of the base used in this step include aqueous solutions of sodium hydroxide, hydroxide power, hydrogen carbonate power, sodium carbonate, and the like.
  • the amount of the base used is usually 1 to 5 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (8).
  • the compound (8-2) thus obtained can be isolated or purified by a known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. It can be attached to the next process.
  • Step 9) This step is a method for producing the compound (1-4) according to the present invention by reacting the compound (8-2) obtained in the step 8 with the compound (9). .
  • the amount of the compound (9) used is usually 1 to 10 equivalents, preferably 1 to 2 equivalents, relative to 1 equivalent of the compound (8-2).
  • Examples of the compound (9) to be used include pivalaldehyde, cyclohexanecarbaldehyde, cyclopentanecarbaldehyde, 1-methylcyclohexanecarbaldehyde, 1-methinocyclic mouth pentanecarbaldehyde and the like. Of these, pivalaldehyde, 1-methylcyclohexane aldehyde, 1-methylcyclopentanecarbaldehyde, etc. are preferred.
  • the reaction solvent is not particularly limited as long as it does not interfere with the reaction, and examples thereof include chlorohonolem, salt methylene, pyridine, acetonitrile, THF, methanolol, ethanol, DMF, toluene, benzene, and xylene. Of these, THF is preferred.
  • the reaction temperature is generally 0 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time is usually 1 hour to 48 hours, preferably 5 hours to 20 hours.
  • the compound (26) thus obtained can be isolated or purified by known separation and purification means such as concentration, concentration under reduced pressure, crystallization, solvent extraction, reprecipitation, chromatography, etc. it can.
  • the piperazine compound according to the present invention can exist as a pharmaceutically acceptable salt, and the salt includes the above (1), (1-1), (1-2), (I_3) Or it can manufacture in accordance with a conventional method using the compound represented by (I-4).
  • the acid addition salt examples include hydrohalides such as hydrochloride, hydrofluoride, hydrobromide, hydroiodide; nitrate, perchlorate, sulfate, phosphate, Inorganic acid salts such as carbonates; lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, and ethane sulfonate; aryl sulfonic acids such as benzene sulfonate and p-toluene sulfonate Salts: Organic acid salts such as fumarate, succinate, tamate, tartrate, oxalate and maleate; and acid addition salts which are organic acids such as amino acids such as glutamate and aspartate Can be mentioned.
  • the corresponding pharmaceutical agent can also be obtained by treating the compound with a base.
  • a base can be converted to an acceptable salt.
  • the base addition salt include, for example, alkaline metal salts such as sodium and potassium, alkaline earth metal salts such as calcium and magnesium, ammonium salts, ammonium salts, guanidine, triethylamine, and dioxy hexylamine. Salt.
  • the compounds of the present invention may exist as any hydrate or solvate of the free ichthy compound or its salt.
  • conversion from a salt or ester to a free compound can also be performed according to a conventional method.
  • the compound according to the present invention may have a stereoisomer or a tautomer such as an optical isomer, a diastereoisomer, a multiple isomer, or the like 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 included in the compounds according to the present invention.
  • the compound according to the present invention the aromatic hydrogen in the compound tritium, a methyl group in 3 H 3 C, 1 4 CH 3, 1 1 CH 3, fluorine in 1 8 F, carbo - Le group It can also be used as a radiolabel by converting the carbon of isotopes such as 11 C.
  • Example 18 Using the compounds described in Example 4, Example 18, Example 20 and Example 27 according to the present invention, mG 1 u R 1 inhibitory action was measured.
  • cDNA of human metabotropic glutamate receptor 1 a (mG 1 uR 1 a) was transfected into CHO cells, and mG 1 uR 1 a A stable expression strain was obtained.
  • CHO cells expressing mG 1 uRla are 10% dialyzed fetal bovine serum, 1% proline, 100 un its / ml penicil 1 in ⁇ 0. lmg / ml strept omy cinsulfate, 2 mM glutamine in DMEM medium In culture.
  • Example 4 As a result of the above test, the compounds described in Example 4, Example 18, Example 20 and Example 27 with respect to mG 1 uR 1 were not observed to have agonist properties up to 10 / zM.
  • the calcium increase that was increased by 10 / xM glutamic acid was suppressed in a dose-dependent manner, and its I C 50 value is shown in Table 1 below.
  • Inhibitory effects of compounds on behavioral activity in mice increased by methamphetamine Using a male ICR (CD-I) mouse (20—40 g), the amount of activity was measured using a behavior amount measuring apparatus (manufactured by Neuroscience) that senses animal movement with an infrared sensor. A compound or an appropriate solvent was administered to mice, and the amount of behavior was measured for 60 minutes immediately after administration of physiological saline or methamphetamine 30 minutes later. During the measurement period, the difference between the behavior amount of the methamphetamine administration group and the behavior amount of the solvent administration group was defined as 100%, and the evaluation was expressed by% inhibition of the behavior amount of the test compound group.
  • a behavior amount measuring apparatus manufactured by Neuroscience
  • the amount of behavior during 60 minutes after administration was significantly increased by subcutaneous administration of methamphetamine (2 mg / kg).
  • the increase in the amount of behavior due to methamphetamine was clearly suppressed by the intraperitoneal administration of the compound (3 O mg / kg) having a harmful effect of m G 1 u R 1 PI according to the present invention 30 minutes before methamphetamine administration. .
  • the results are shown in Table 2.
  • the compound according to the present invention has an mG 1 u R 1 inhibitory action.
  • the “mG lu R l inhibitory action” may be any substance that inhibits the function of m G 1 u R 1, for example, MG 1 u R 1 antagonistic activity and non-antagonistic mG 1 u R 1 receptor antagonistic activity.
  • the compound represented by the general formula (I) can be administered orally or parenterally, and by formulating it into a form suitable for such administration, convulsions, acute pain, inflammation using the same Sexual pain, chronic pain, cerebral infarction or transient cerebral ischemic attack, mental dysfunction such as schizophrenia, anxiety, drug dependence, treatment and Z or preventive for Parkinson's disease.
  • additives that are usually used in the pharmaceutical field can be used as additives in such cases.
  • dosage forms formulated as a mixture with these additives include solid preparations such as tablets, capsules, granules, powders or suppositories; or liquid preparations such as syrups, elixirs or injections, etc. These can be prepared according to conventional methods in the pharmaceutical field. Liquid preparations may be dissolved or suspended in water or other suitable medium at the time of use. In particular, in the case of injections, they may be dissolved or suspended in physiological saline or puddle sugar solution as necessary, and buffering agents and preservatives may be added.
  • preparations can contain the compound of the present invention in an amount of 1.0 to 100% by weight, preferably 1.0 to 60% by weight. These preparations may also contain other therapeutically effective compounds.
  • the dose of the concomitant drug may be determined according to the dose used clinically, and can be appropriately selected depending on the administration subject, administration route, disease, combination and the like.
  • the administration form of the concomitant drug is not particularly limited, as long as the compound of the present invention and the concomitant drug are combined at the time of administration. Examples of such dosage forms include 1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and a concomitant drug, and 2) separate preparation of the compound of the present invention and the concomitant drug.
  • the dose and frequency of administration vary depending on the sex, age, body weight, symptom of the patient, and the type and range of the intended treatment effect, but generally administered orally.
  • 0.01 ⁇ : L 0 O mg Z kg preferably 0.03 ⁇ : 1 mg Z kg can be divided into 1 ⁇ several times, or in the case of parenteral administration 0.001 to 1 O mg / kg, preferably 0.0 1 to 0.1 mg / kg is preferably administered in 1 to several divided doses.
  • Example 2 The compound of Example 1 (10 parts), heavy magnesium oxide (15 parts) and lactose (75 parts) are uniformly mixed to obtain a powdery or finely divided powder of 3500 ⁇ m or less. This powder is put into a capsule container to make a force push agent.
  • Formulation Example 2 The compound of Example 1 (10 parts), heavy magnesium oxide (15 parts) and lactose (75 parts) are uniformly mixed to obtain a powdery or finely divided powder of 3500 ⁇ m or less. This powder is put into a capsule container to make a force push agent.
  • a granule is prepared in the same manner as in Formulation Example 2, and then 3 parts of calcium stearate is added to 96 parts of this granule, followed by compression molding to produce a tablet having a diameter of 1 O mm.
  • Formulation Example 4
  • a sugar-coated tablet is prepared by adding a mixed suspension of basic carbonated lucium.
  • silica gel column chromatography For the silica gel column chromatography of the examples, Wako Pure Chemical Industries, Ltd. Wakoge 1 (registered trademark) C-300 or Biotage KP-Si 1 (registered trademark) S i 1 ica prepacked column was used. For the preparative thin-layer chromatography, Kieselgel TM 60F 25 4 J Art. 57 44 manufactured by Merck & Co. was used. Basic silica gel column chromatography is manufactured by Fuji Silicon Chemical Co., Ltd.
  • n-P r n-propyl group
  • Boc-piperazine 4 Omg was dissolved in 1 ml of pyridine, and 0.02 ml of 2,2,2-trichloroethyl chloroformate was added and stirred at room temperature for 3 hours.
  • the reaction mixture was diluted with Jetylether, washed with 10% hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, and saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain 62 mg of the title compound as a colorless solid.
  • Cyclopentanemethanol 20 Omg was dissolved in black mouth form 2 ml, CD I 33 Omg was added, and the mixture was stirred at room temperature for 6 hours.
  • the reaction mixture was diluted with chloroform, washed with saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure, and the residue was dissolved in acetonitrile 4 ml 1, added with methyl methyl 500 1 and stirred at room temperature for 3 hours. After distilling off the solvent of the reaction solution under reduced pressure, the residue was dissolved in 4 ml of black form, 1_Boc-piperazine 19 Omg and triethylamine 420 / ⁇ 1 were added, and the mixture was stirred at room temperature for 2 hours.
  • the title compound was obtained as a colorless solid by the same method as in Example 6 using hexane hexanemethanol instead of cycline pentanemethanol.
  • the title compound was obtained as a colorless solid in the same manner as in Example 6 except that 1-methylcyclopropanemethanol was used instead of the cyclopentanemethanol.
  • the title compound was obtained as a colorless solid in the same manner as in Example 2, except that neopentyl chloroformate was used instead of 2,2,2-trichlorodiethyl chloroformate.
  • Example 9 1- (tert-top, toxicanoreponinole) -4--(neopentyloxycarbonyl) piperazine obtained in Example 9 was added to 5 .42 g of trifluoroacetic acid 10 ml, and then at room temperature for 30 minutes. Stir. Excess trifluoroacetic acid was distilled off under reduced pressure to obtain 4.48 g of the title compound as a colorless solid.
  • the title compound was obtained as a colorless solid in the same manner as in Example 6 except that 1-methylcyclohexane hexane methanol (Tetra rhedron Lett rs, 2000, 41, 2945) was used in place of the cyclopentane methanol.
  • the title compound was obtained as a colorless solid in the same manner as in Example 6 except that 33-dimethyl-1,2-ptanol was used instead of cyclopentanemethanol.
  • Example 6 using 1-methylcyclopentanemethanol prepared according to the method described in the literature instead of cyclopentanemethanol (Journal of American Chemical Society (JACS), 2002, Vol. 1, 24, 1 2106) The title compound was obtained as a colorless solid by the same method as described above.
  • the title compound was obtained as a colorless solid in the same manner as in Example 6 except that 5-hydroxymethyl-5-methyl-1,3-dioxane was used in place of the cyclopentanemethanol.
  • the title compound was obtained as a colorless solid by the same method as in Example 10 using isopropyl ethyl formate instead of ethyl ethyl formate.
  • 1-Boc-piperazine (265mg) is dissolved in 2m1 of pyridine, 0.26-ml of 3-cyclopentylpropionic acid and 462mg of 1-ethyl-1- (3-dimethylaminopropyl) carbodiimide hydrochloride are added, Stir at room temperature for 2 hours.
  • the title compound was obtained as a colorless solid in the same manner as in Example 22 except that 3-noradamantancanolevonic acid was used in place of 3-sucral pentylbropionic acid.
  • the title compound was obtained as a colorless solid in the same manner as in Example 22 except that tetramethylcyclopropanecarboxylic acid was used in place of 3-cyclopentylbropionic acid.
  • the title compound was obtained as a colorless solid in the same manner as in Example 22 except that 3-cyclohexylbropionic acid was used instead of 3-cyclopentylbropionic acid.
  • the title compound was obtained as a colorless solid in the same manner as in Example 27 except that pivalaldehyde was used in place of hexane carbaldehyde.
  • the compound according to the present invention or a pharmaceutically acceptable salt thereof has a potent mG 1 uR 1 inhibitory action, and not only convulsions and acute pain but also inflammatory pain, chronic pain, cerebral infarction or transient It is useful for the treatment and / or prevention of brain disorders such as cerebral ischemic attacks, mental dysfunction such as schizophrenia, anxiety, drug dependence, and diseases such as Z or Parkinson's disease.

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Abstract

L’invention concerne un composé représenté par la formule (I) : [dans laquelle R1 représente un alkyle ramifié en C3-9 ; R2 représente p.ex. un alkyle linéaire ou ramifié en C2-9, facultativement substitué par halogène etc. ; et X représente de l’oxygène, etc.] (à condition que les cas suivants soient exclus : le cas où R1 est tert-butyle, R2 est 2-méthylpropyle, phényle, tert-butyle, benzyle ou cyclohexyle et X est oxygène ; et le cas où R1 est tert-butyle, R2 est catégoriquement néopentyle ou cyclohexyléthényle et R3 est une simple liaison) ; ou un sel pharmaceutiquement acceptable du composé. Le composé et le sel possèdent une activité inhibitrice vis-à-vis du récepteur 1 du glutamate métabotropique. Ils sont dès lors utiles dans le traitement de maladies telles que les convulsions, la douleur aiguë, la douleur inflammatoire, la douleur chronique, les troubles psychofonctionnels incluant la schizophrénie et l’anxiété.
PCT/JP2005/022408 2004-12-06 2005-11-30 Derive de la piperazine WO2006062110A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143404A1 (fr) * 2008-05-23 2009-11-26 Wyeth Pipérazine utilisée en tant que modulateurs allostériques négatifs agissant sur le récepteur métabotropique du glutamate de type 5 (mglur5)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1575589A (fr) * 1968-02-20 1969-07-25
JPH02262654A (ja) * 1988-12-06 1990-10-25 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料
WO1997018203A1 (fr) * 1995-11-14 1997-05-22 Merck Sharp & Dohme Limited Derives de la piperazine, de la piperidine et de la tetrahydropyridine
JP2000505795A (ja) * 1996-02-02 2000-05-16 ピエール、ファーブル、メディカマン 置換シクロアザンから誘導された新規芳香族ピペラジン、それらの調製法、医薬組成物、および薬剤としての使用
JP2002507992A (ja) * 1997-07-02 2002-03-12 スミスクライン・ビーチャム・コーポレイション 新規な置換イミダゾール化合物
JP2002518478A (ja) * 1998-06-25 2002-06-25 ブリストル−マイヤーズ スクイブ カンパニー アミジノおよびグアニジノアゼチジノントリプターゼ阻害剤
WO2003018538A1 (fr) * 2001-08-31 2003-03-06 Ajinomoto Co., Inc. Nouveaux derives de diarylalcene et nouveaux derives de diarylalcane
JP2004511544A (ja) * 2000-10-17 2004-04-15 グラクソ　グループ　リミテッド 化合物
JP2004519438A (ja) * 2000-12-15 2004-07-02 エフ．ホフマン−ラ　ロシュ　アーゲー ピペラジン誘導体

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR1575589A (fr) * 1968-02-20 1969-07-25
JPH02262654A (ja) * 1988-12-06 1990-10-25 Fuji Photo Film Co Ltd ハロゲン化銀カラー写真感光材料
WO1997018203A1 (fr) * 1995-11-14 1997-05-22 Merck Sharp & Dohme Limited Derives de la piperazine, de la piperidine et de la tetrahydropyridine
JP2000505795A (ja) * 1996-02-02 2000-05-16 ピエール、ファーブル、メディカマン 置換シクロアザンから誘導された新規芳香族ピペラジン、それらの調製法、医薬組成物、および薬剤としての使用
JP2002507992A (ja) * 1997-07-02 2002-03-12 スミスクライン・ビーチャム・コーポレイション 新規な置換イミダゾール化合物
JP2002518478A (ja) * 1998-06-25 2002-06-25 ブリストル−マイヤーズ スクイブ カンパニー アミジノおよびグアニジノアゼチジノントリプターゼ阻害剤
JP2004511544A (ja) * 2000-10-17 2004-04-15 グラクソ　グループ　リミテッド 化合物
JP2004519438A (ja) * 2000-12-15 2004-07-02 エフ．ホフマン−ラ　ロシュ　アーゲー ピペラジン誘導体
WO2003018538A1 (fr) * 2001-08-31 2003-03-06 Ajinomoto Co., Inc. Nouveaux derives de diarylalcene et nouveaux derives de diarylalcane

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009143404A1 (fr) * 2008-05-23 2009-11-26 Wyeth Pipérazine utilisée en tant que modulateurs allostériques négatifs agissant sur le récepteur métabotropique du glutamate de type 5 (mglur5)

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