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WO2001066546A1 - Composes spiro, leur procede de preparation et leur utilisation comme medicaments - Google Patents

Composes spiro, leur procede de preparation et leur utilisation comme medicaments Download PDF

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Publication number
WO2001066546A1
WO2001066546A1 PCT/JP2001/001793 JP0101793W WO0166546A1 WO 2001066546 A1 WO2001066546 A1 WO 2001066546A1 JP 0101793 W JP0101793 W JP 0101793W WO 0166546 A1 WO0166546 A1 WO 0166546A1
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WO
WIPO (PCT)
Prior art keywords
octane
spiro
azabicyclo
reaction
oxazolidine
Prior art date
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PCT/JP2001/001793
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English (en)
Japanese (ja)
Inventor
Masakazu Fujio
Kenji Hashimoto
Jiro Katayama
Atsushi Numata
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Mitsubishi Pharma Corporation
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Priority to AU2001241056A priority Critical patent/AU2001241056A1/en
Publication of WO2001066546A1 publication Critical patent/WO2001066546A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/20—Spiro-condensed systems
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/20—Spiro-condensed systems

Definitions

  • the present invention relates to a novel compound for providing a medicament useful for diseases of the central nervous system.
  • the nicotine receptor is known to have a number of subtypes, and to date at least 11 subtypes have been identified (Trends in Pharmacological). Sciences, 12: 34-40, 1991; Progress in Neurobiology, 53: 199-237, 1997).
  • the nicotine receptor exists as a pentamer of these subtypes, forms an ion channel, and is known to take in calcium ions and the like into cells. It is known that there are two main types of subtypes in the brain (4 ⁇ 2 and spike 7). As a hetero-oligomer, the nicotine receptor is formed as a homo-oligomer of the 7 subunit.
  • these subtypes (spike 452 nicotine receptor and spike 7 nicotine receptor) are distributed in a wide range of regions in the brain (cerebral cortex, hippocampus, etc.).
  • Nicotine receptors in the central nervous system (4-4-2 nicotine receptor and 7-nicotine receptor) are involved in various physiological functions such as neural development, differentiation, formation of learning and memory, and reward.
  • Basynaptic nicotine receptors are known to play an important role in the release of various neurotransmitters (acetylcholine, dopamine, glutamate, etc.) (Trends in
  • the amount of mRNA for nicotine receptor 7 in lymphocytes of Alzheimer's disease patients is significantly increased compared to the amount of mRNA for ⁇ 7 nicotine receptor 7 in lymphocytes of normal subjects.
  • Agonists of the nicotine receptor activate the reduced neurotransmitter of gluminic acid by releasing gluminic acid from presynapses, resulting in symptoms seen in schizophrenic patients. Positive symptoms, negative symptoms, cognitive impairment, etc.). Thus, it is highly likely that the nicotine receptor is involved in the site of action of the drug for the treatment of schizophrenia.
  • dementia eg, Alzheimer's disease
  • cognitive dysfunction eg, cognitive dysfunction and schizophrenia
  • attention deficit disorder anxiety, depression, epilepsy, pain, Tourette syndrome, Parkinson's disease, Huntington's disease, etc.
  • nicotine receptors are also associated with the disease.
  • nicotine receptor agonists or nicotine receptor partial agonists are useful for dementia (eg, Alzheimer's disease), cognitive dysfunction, attention deficit disorder, anxiety, depression, schizophrenia, It is useful as a remedy or prophylactic for epilepsy, pain, Torayt syndrome, Parkinson's disease, Huntington's disease, etc. Since this drug has a neuroprotective effect, it is also useful as a therapeutic or preventive drug for neurodegenerative diseases in which cholinergic neurotransmission is abnormal. In addition, smoking control Can be used to prompt.
  • WO 96/06098 states that spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxoxazolidine-1'-one] and 3'-methylspiro [1- Azabicyclo [2.2.2] octane-1,5 5 -oxazolidine-1 2'-one] has been disclosed, but the nicotinic receptor is not as highly potent.
  • 92/01690 spiro as Mus force phosphoric acetylcholine receptor antagonist [1- Azabishikuro [2.2.2] octane one 3, 5 5 one isoxazolidine one 3 '- one] c that derivative is disclosed
  • W095 / 03303 discloses a spiro-1-azabicyclo [2.2.2] octane derivative as a muscarinic acetylcholine receptor antagonist. However, all of these are ⁇ : 7 nicotine receptor agonists It is not intended.
  • An object of the present invention is to have a strong nicotine receptor agonistic action or a partial nicotine receptor agonistic action, and to have dementia (eg, Alzheimer's disease), cognitive dysfunction, attention deficit disorder, anxiety, depression For illness, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, etc., or for neurodegenerative diseases in which cholinergic neurotransmission is abnormal. Is prohibited
  • An object of the present invention is to provide a novel compound useful as a pharmacological agent.
  • the novel spirocyclic compound represented by (I), the optically active form thereof or a pharmaceutically acceptable salt thereof is selectively and potently capable of agonizing the nicotine receptor or partially agonizing the nicotine receptor.
  • the compound of the present invention is useful for treating dementia (eg, Alzheimer's disease), cognitive impairment, attention deficit disorder, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, etc. It may be useful as a therapeutic or prophylactic agent, a therapeutic or prophylactic agent for neurodegenerative diseases in which cholinergic neurotransmission is abnormal, and as a smoking cessation drug.
  • the present invention is as follows.
  • X represents an oxygen atom, a sulfur atom or —CH 2 —.
  • Y represents an oxygen atom or a sulfur atom.
  • R 1 represents a hydrogen atom or an alkyl having 1 to 4 carbons.
  • n 2 or 3.
  • n 1 or 2.
  • Ar represents an aromatic heterocyclic residue which may have a substituent, a bicyclic hydrocarbon residue which may have a substituent, or a phenyl group having at least one substituent. . )
  • R 1 is a hydrogen atom
  • m is 2
  • Ar is a monocyclic aromatic heterocyclic residue which may have a substituent, a bicyclic aromatic heterocyclic residue which may have a substituent, or may have a substituent A good naphthyl group or a phenyl group having one or more substituents;
  • spirocyclic compound of the above an optical isomer or a pharmaceutically acceptable salt thereof.
  • X and Y are both oxygen atoms
  • R 1 is a hydrogen atom
  • Ar being the same or different and optionally having 1 to 3 substituents, 2-naphthyl selected from alkoxy having 1 to 4 carbons, halogen and alkyl having 1 to 4 carbons;
  • Benzo [b] thiophen-5-yl which may have the same or different 1 to 3 substituents selected from halogen and alkyl having 1 to 4 carbon atoms; halogen and 1 to 4 carbon atoms
  • Benzo [b] furan-5Tl which may have 1 to 3 identical or different substituents selected from 4 alkyls;
  • 2-Chenyl group which may have the same or different 1 to 3 substituents selected from halogen, alkyl having 1 to 4 carbon atoms, acyl, cyano and haloalkyl having 1 to 4 carbon atoms;
  • Benzo [b] thiophene-2-yl which may have the same or different 1 to 3 substituents selected from halogen and alkyl having 1 to 4 carbon atoms; halogen and having 1 to 4 carbon atoms 1,3-Penzodioxolan-5-yl which may have 1 to 3 identical or different substituents selected from alkyl; selected from halogen and alkyl having 1 to 4 carbon atoms 2,3-dihydro-1,4-benzodioxin-6-yl which may have 1 to 3 identical or different substituents; or
  • X and Y are both oxygen atoms
  • Ar is the same or different 1 to 3 selected from phenyl, naphthyl, benzo [b] thiophenyl; or a substituent selected from halogen, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, cyano and acyl.
  • a medicament comprising the spiro II compound of the above 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  • a pharmaceutical composition comprising the spirocyclic compound of 1 or 2 above, an optical isomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable additive.
  • a nicotine receptor agonist or a nicotine receptor partial agonist comprising the spirocyclic compound of 1 or 2 above, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  • An agent for improving cognitive dysfunction comprising the spirocyclic compound of the above 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof.
  • An anti-dementia drug comprising the spirocyclic compound of the above 1 or 2, its optical isomer or a pharmaceutically acceptable salt thereof.
  • a prophylactic or therapeutic agent for schizophrenia containing the spirocyclic compound of 1 or 2 above, an optical isomer thereof or a pharmaceutically acceptable salt thereof.
  • n 2 or 3.
  • n 1 or 2.
  • R 1 represents a hydrogen atom or an alkyl having 1 to 4 carbons.
  • Ar-NHCOOT (18) (wherein, T represents an alkyl group having 1 to 4 carbon atoms).
  • Ar represents an aromatic heterocyclic residue which may have a substituent, a bicyclic hydrocarbon residue which may have a substituent, or a phenyl group having at least one substituent .
  • the compound is represented by the general formula (19):
  • n 1 or 2.
  • R 1 represents a hydrogen atom or an alkyl having 1 to 4 carbons.
  • Ar represents an aromatic heterocyclic residue which may have a substituent, a bicyclic hydrocarbon residue which may have a substituent, or a phenyl group having at least one substituent .
  • the compound represented by the general formula (3) is subjected to a deborane reaction.
  • n, m, R 1 and Ar are as defined above.
  • the aromatic heterocyclic residue in Ar includes not only a monocyclic but also a bicyclic or higher aromatic heterocyclic residue, preferably a monocyclic aromatic heterocyclic residue, a bicyclic aromatic Tribe complex Ring residues.
  • the mono-aromatic heterocyclic residue is a 5-membered or 6-membered group having one or two identical or different hetero atoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring. And a membered ring, such as pyridyl, furyl, phenyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, and isothiazolyl.
  • a membered ring such as pyridyl, furyl, phenyl, pyrimidinyl, oxazolyl, thiazolyl, isoxazolyl, and isothiazolyl.
  • the aromatic heterocyclic ring referred to herein has, in the ring, 1 to 3 identical or different heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom, It represents a 5- or 6-membered aromatic residue, and a saturated heterocyclic ring is a heterocyclic ring which is saturated by adding hydrogen to the aromatic heterocyclic ring.
  • benzoxazole, benzothiazole, 1,2-benzisoxazole, 1,2-benzisothiazole, indole benzo [b] furan, benzo [b] thiophene, quinoline , Isoquinoline, quinazoline, cyclopentene [b] thiophene, 4,5,6,7-tetrahydrobenzo [b] thiophene, 1,3-benzodioxolan, 2,3-dihydrobenzo [b] furan 1,2,3-dihydro-1,4, -benzodioxin, indolin, benzoxazoline, 1,2,5,1-benzobenzodiazole, 1,3-dihydroisobenzobenzofuran (phthalane), 1,2,3,4 —Tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline, benzothiazoline and the like.
  • Ar can be bonded to a nitrogen atom on a 5-membered nitrogen-
  • Halogen fluorine, chlorine, bromine, iodine
  • linear or branched alkyl having 1 to 4 carbon atoms eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc.
  • haloalkyl having 1 to 4 carbon atoms in which the alkyl portion is linear or branched halogen has the same meaning as halogen in the above (1), preferably fluorine, and is substituted by 1 or 2 or more (E.g., fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, etc.)
  • Ra and Rb independently represent a straight-chain or branched-chain carbon number of 1-4, or form a ring by combining Ra and Rb with an adjacent nitrogen atom.
  • dialkylamino such as dimethylamino, getylamino, N-methyl-N-ethylamino; pyrrolidine-11-yl, piperidine-11-yl, etc.
  • a straight chain or branched chain alkyl having 1 to 4 carbon atoms and carbonyl eg, formyl, acetyl, propionyl, 2-methylpropionyl, butyryl, etc.
  • Esters composed of straight-chain or branched alkoxy having 1 to 4 carbon atoms and carbonyl for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tertiary Butoxycarbonyl
  • Alkylthio (eg, methylthio, ethylthio, propylthio, butylthio, etc.) composed of a linear or branched alkyl having 1 to 4 carbon atoms and a sulfur atom;
  • hydroxyalkyl (the alkyl portion is linear or branched, preferably has 1 to 4 carbon atoms, and the hydroxy group may be substituted at any position of the alkyl chain; for example, Hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl, and the like, with hydroxymethyl and 1-hydroxyethyl being preferred.)
  • Alkoxyalkyl (The alkoxy part is linear or branched, and preferably has 1 to 4 carbon atoms.
  • the alkyl part is linear or branched, and preferably has carbon atoms. 1-4, for example, methoxymethyl, ethoxymethyl, propoxymethyl, butoxymethyl and the like, and particularly preferred is methoxymethyl and ethoxymethyl),
  • the substituents in the monocyclic aromatic heterocyclic residue are preferably (1) to (4) ⁇ (8) to (10), (12), (21) and (22).
  • As the substituent in the bicyclic aromatic heterocyclic residue (1), (2) and (23) are preferable.
  • substituents (1) to (23) may be substituted on any one or more, preferably 1 to 3 carbon atoms of Ar.
  • ⁇ may be newly formed between the adjacent substituents.
  • the bicyclic hydrocarbon residue in Ar is, for example, naphthylene, Examples thereof include a 3,4-tetrahydro compound (tetralin) and indane, which may be substituted with the following substituents.
  • a linear or branched alkoxy having 1 to 4 carbon atoms for example, methoxy, ethoxy, propoxy, butoxy and the like, particularly preferably methoxy
  • a linear or branched alkoxy having 1 to 4 carbon atoms examples include branched alkyl (eg, methyl, ethyl, propyl, butyl, etc., and particularly preferably methyl), halogen, trifluoromethyl, hydroxy, nitro, amino, etc., and alkoxy (especially, methoxy). ), Alkyl (especially methyl) is preferred
  • Examples of the phenyl group having one or more substituents in Ar include a phenyl group substituted with one or more substituents described below.
  • alkyl having 1 to 4 carbons for example, methyl, ethyl, propyl, isopropyl, butyl and the like, and particularly preferably alkyl having 1 to 3 carbons
  • Halogen fluorine, chlorine, bromine, iodine
  • alkoxy having 1 to 4 carbon atoms for example, methoxy, ethoxy, propoxy, butoxy, etc.
  • acetyl for example, acetyl, propionyl, butyryl, etc., and acetyl is particularly preferable
  • haloalkyl having 1 to 4 carbon atoms (the halogen portion is as defined in (3) above, and the alkyl portion is linear or branched; for example, trifluoromethyl, 2,2: 2- Trifluroethyl, etc.),
  • linear or branched alkylthio having 1 to 4 carbon atoms eg, methylthio, ethylthio, propylthio, butylthio, etc.
  • the alkyl having 1 to 4 carbon atoms in R 1 is linear or branched and includes, for example, methyl, ethyl, propyl, isopropyl, butyl and the like, and methyl is preferable.
  • the compound of the present invention has the general formula (I)
  • X represents an oxygen atom, a sulfur atom or one CH 2 —).
  • Y represents an oxygen atom or a sulfur atom.
  • R 1 represents a hydrogen atom or an alkyl having 1 to 4 carbons.
  • n 2 or 3.
  • n 1 or 2.
  • Ar is an aromatic heterocyclic residue which may have a substituent, a dihydrocarbon residue which may have a substituent, or a phenyl group having at least one substituent Is shown.
  • optical isomer or a pharmaceutically acceptable salt thereof wherein ⁇ is preferred, wherein m and ⁇ are both 2.
  • R 1 is a hydrogen atom
  • Ar may be a monoaromatic heterocyclic residue which may have a substituent, a diaromatic heterocyclic residue which may have a substituent, or may have a substituent A good naphthyl group or a phenyl group having one or more substituents;
  • a spirocyclic compound of the above formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof is preferred,
  • X and Y are both oxygen atoms
  • R 1 is a hydrogen atom
  • A is an alkoxy having 1 to 4 carbon atoms, a halogen and an alkyl having 1 to 4 carbon atoms 2-naphthyl which may have 1 to 3 identical or different substituents selected from
  • Benzo [b] thiophen-5-yl which may have the same or different 1 to 3 substituents selected from halogen and alkyl having 1 to 4 carbon atoms; halogen and 1 to 4 carbon atoms
  • Benzo [b] furan-1-yl which may have 1 to 3 same or different substituent (s) selected from alkyl;
  • 2-Chenyl group which may have the same or different 1 to 3 substituents selected from halogen, alkyl having 1 to 4 carbon atoms, acyl, cyano and haloalkyl having 1 to 4 carbon atoms;
  • Benzo [b] thiophene-2-yl which may have the same or different 1 to 3 substituents selected from halogen and alkyl having 1 to 4 carbon atoms; halogen and 1 to 4 carbon atoms 1, 3-benzodioxolan-5-yls which may have the same or different 1 to 3 substituents selected from alkyl; from halogen and alkyl having 1 to 4 carbon atoms 2,3-dihydro-l, 4-l-benzodioxin-6-yl which may have 1 to 3 identical or different substituents selected; or
  • X and Y are both oxygen atoms
  • Ar is the same or different 1 to 4 selected from chenyl, naphthyl, benzo [b] thiophenyl; or a substituent selected from halogen, alkyl having 1 to 4 carbons, alkoxy having 1 to 4 carbons, cyano and acyl.
  • Pharmaceutically acceptable salts of the compound of general formula (I) include the compound and an inorganic acid (eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.) or an organic acid (acetic acid, propionic acid, succinic acid) Acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, and ascorbic acid).
  • an inorganic acid eg, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.
  • an organic acid acetic acid, propionic acid, succinic acid
  • Acid glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, maleic acid, fumaric acid, methanesulfonic acid,
  • the compound of the general formula (I) and a pharmaceutically acceptable salt thereof may exist in the form of a hydrate or a solvate. Hydrates, monohydrates, 3Z dihydrates, dihydrates, trihydrates, etc.) and solvates are also included in the present invention.
  • the compound of the general formula (I) has an asymmetric atom, at least two types of optical isomers exist. These optical isomers and their racemates Included in the present invention.
  • n, m, R 1 and Ar are as defined above, and J is chlorine, bromine, iodine, trifluoromethanesulfonyloxy, p-toluenesulfonyloxy, methyl sulfonyloxy, etc.
  • a suitable leaving group generally used in organic synthesis.
  • Compound of the general formula (1) (hereinafter also referred to as compound (1); Compound (1) wherein n and m are both 2 and H 1 is a hydrogen atom is disclosed in W096 / 06098 )
  • a compound of the general formula (2) (hereinafter also referred to as compound (2)) by a suitable base generally used in organic synthetic chemistry (for example, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, Sodium bicarbonate, sodium acetate, sodium acetate, sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium hydride, etc.
  • n, m, R ⁇ Ar and J are as defined above.
  • Compound (1) and compound (2) are combined with an appropriate base generally used in organic synthetic chemistry (for example, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, sodium , Potassium, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, sodium acetate, sodium acetate acetate, sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium butyl, butyllithium, etc.)
  • a suitable solvent for example, benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, N-methyl-1-pyrrolidone, or a mixed solvent thereof
  • n, m, R 1 and Ar are as defined above.
  • a compound of the general formula (4) (hereinafter also referred to as compound (4); And the compound (4) in which R 1 is a hydrogen atom is disclosed in Helvetica Chimica Acta, p. 1689, p. 1954, and a compound of the general formula (5) (hereinafter, compound ( 5)), a suitable solvent that does not inhibit the progress of the reaction
  • a suitable base that does not inhibit the progress of the reaction for example, triethylamine, pyridine, dimethylaminopyridine, diisopropylethylamine, potassium carbonate, etc.
  • a suitable base that does not inhibit the progress of the reaction for example, triethylamine, pyridine, dimethylaminopyridine, diisopropylethylamine, potassium carbonate, etc.
  • a suitable condensing agent eg, getyl cyanophosphate, benzotriazo-l-l-yloxysitol (dimethylamino)
  • Phosphonium ⁇
  • the fully O b phosphate (Bop reagent), 1 one Echiru one 3- (3 5 - Jimechirua Minopuropiru) Karupojiimido (WSCI), 1, 3-dicyclohexyl to Kishirukarubo diimide (DC CD), etc.) is added, 0.1 to 48
  • a compound of the general formula (6) hereinafter, also referred to as compound (6)
  • Compound (6) can be obtained by the following two methods other than this method.
  • Method 1 Compound (4) is converted to an appropriate solvent that does not inhibit the progress of the reaction (for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethyl acetate, dimethyl sulfoxide, N-methyl-1-pyrrolid). Don, salt ⁇ ! Methylene, black form, ethylene dichloride, or any mixed solvent of these) and a suitable base (triethylamine, pyridin, dimethyl) which does not inhibit the progress of the reaction.
  • an appropriate solvent that does not inhibit the progress of the reaction for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethyl acetate, dimethyl sulfoxide, N-methyl-1-pyrrolid.
  • Method 2 Suitable halogenating agent for compound (4) (for example, phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, phosphorus tribromide, phosphorus pentabromide, odor
  • a reactive intermediate is obtained using 1,1'-carbonylbis-1H-imidazole and the like, and the reactive intermediate is reacted with the compound (5) to give the compound (6).
  • compound (6) is dissolved in a solvent that does not hinder the progress of the reaction (eg, tetrahydrofuran, dioxane, geethylether, diisopropyl ether, or any mixed solvent thereof) in an appropriate reducing agent (eg, Using borane, lithium aluminum hydride, diisobutylaluminum hydride, etc., at a temperature of 78 ° C to the reflux temperature of the solvent for 0.1 to 48 hours, the general formula (7) )
  • a solvent that does not hinder the progress of the reaction eg, tetrahydrofuran, dioxane, geethylether, diisopropyl ether, or any mixed solvent thereof
  • an appropriate reducing agent eg, Using borane, lithium aluminum hydride, diisobutylaluminum hydride, etc., at a temperature of 78 ° C to the reflux temperature of the solvent for 0.1 to 48 hours, the general formula (7)
  • Compound (7) is converted into a suitable solvent that does not hinder the progress of the reaction (for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, methylene chloride, Form, ethylene dichloride, tetrahydrofuran, dioxane, getyl ether, diisopropyl ether, methanol, ethanol, isopropanol, propanol, or any mixed solvent thereof).
  • a suitable solvent that does not hinder the progress of the reaction for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, methylene chloride, Form, ethylene dichloride, tetrahydrofuran, dioxane, getyl
  • n, m, R ⁇ Ar and J are as defined above.
  • Compound (1) is synthesized in an appropriate solvent that does not hinder the progress of the reaction (for example, benzene, toluene, xylene, dichloromethane, chloroform, ethylene dichloride, or any mixed solvent thereof).
  • an appropriate solvent for example, benzene, toluene, xylene, dichloromethane, chloroform, ethylene dichloride, or any mixed solvent thereof.
  • a suitable cationizing agent such as Lawesson's reagent
  • Compound (8) is a compound of the general formula (9) (hereinafter also referred to as compound (9); n and m are both 2, and: Compound (9) wherein R 1 is a hydrogen atom is Patent No. 5,137,895) is converted to a suitable solvent that does not hinder the progress of the reaction (for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylone).
  • a suitable solvent that does not hinder the progress of the reaction
  • Suitable bases that do not inhibit the progression of (e.g., triethylamine, pyridine, dimethylamino In the presence or absence of lysine, diisopropylethylamine, carbon dioxide lime, hydrogen carbonate lime, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, etc., a suitable thiocarbylating agent (eg, , Carbon disulfide, thiophosgene, etc.) and reacting under ice-cooling to the reflux temperature of the solvent for 0.1 to 48 hours.
  • a suitable thiocarbylating agent eg, Carbon disulfide, thiophosgene, etc.
  • Compound (8) and compound (2) are combined with a suitable base generally used in organic synthetic chemistry (for example, potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium acetate, water).
  • a suitable base generally used in organic synthetic chemistry
  • a suitable monovalent copper reagent eg, cuprous bromide, cuprous iodide, etc.
  • benzene, toluene, xylene, dimethylformamide, dimethylsulfoxide, N-methyl-2-pyrrolidone, or a mixed solvent thereof or in the absence of a solvent at room temperature to the reflux temperature of the solvent or the compound (2).
  • n, m, R Ar and J are as defined above.
  • n, m, R 1 and Ar are as defined above.
  • Compound (7) is converted to a suitable solvent that does not hinder the progress of the reaction (for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, In methylene chloride, chloroform, ethylene dichloride, tetrahydrofuran, dioxane, geethylether, diisopropyl ether, methanol, ethanol, isopropanol, propanol, or any mixed solvent thereof).
  • a suitable solvent that does not hinder the progress of the reaction for example, benzene, toluene, xylene, ethyl acetate, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, In methylene chloride, chloroform, ethylene dichloride, tetrahydrofuran, diox
  • n, m, R A r and Y are as defined above.
  • Compound of general formula (11) (hereinafter also referred to as compound (11); Compound (11) wherein n and m are both 2 and R 1 is a hydrogen atom is disclosed in JP-A-2-62883. )
  • a suitable solvent that does not hinder the progress of the reaction eg, methanol, ethanol, dimethylformamide, dimethylsulfoxide, water or any mixed solvent thereof.
  • a compound of the general formula (12) (hereinafter referred to as a compound) by reacting with an agent (eg, sodium cyanide, potassium cyanide, etc.) at 0 ° C. to the reflux temperature of the solvent for 0.1 to 48 hours.
  • Object (12) Compound (12) can also be obtained by reacting in dichloromethane in the presence of trimethylsilyl cyanide and aluminum chloride at 0 ° C to the reflux temperature of the solvent for 0.1 to 48 hours. Wear.
  • compound (12) is subjected to hydrolysis of nitrile, which is commonly used in organic synthetic chemistry (for example, in hydrochloric acid, sulfuric acid, acetic acid or a mixed solvent thereof at 0 ° C to 0 ° C). Reaction at reflux temperature for 0.1 to 48 hours, etc.)
  • a compound of the general formula (13) (hereinafter, also referred to as compound (13)) can be obtained.
  • the compound (13) is converted into a hydrazide reaction commonly used in organic synthetic chemistry (for example, known in organic synthetic chemistry using alcoholic sulfuric acid, alcoholic hydrochloric acid, alcoholic monochloride, etc.).
  • the compound (14) in which Y is S can be obtained by reacting the compound (14) with the above thionation reagent.
  • the compound of the general formula (15) (hereinafter referred to as “the compound”) is reacted under the generally used Curtius rearrangement conditions in organic synthetic chemistry (for example, reaction with sodium nitrite in an acidic aqueous solution).
  • Compound (15) can be obtained.
  • the compound of the general formula (16) (hereinafter also referred to as the compound (16)) can be obtained by reacting the compound (15) with the method described in the above synthesis method 1 or synthesis method 2.
  • Equation (19) consists of the following equations (19a) and (3))
  • T represents a linear or branched alkyl group having 1 to 4 carbon atoms, Q does not exist, or borane (BH 3 ) is shown.
  • Examples of the linear or branched alkyl group having 1 to 4 carbon atoms in T include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc. preferable.
  • the compound of the general formula (19) (hereinafter also referred to as compound (19); in the general formula (19), when Q does not exist, corresponds to the compound (3)) is a compound of the general formula (17)
  • a compound (hereinafter, also referred to as compound (17)) can be produced by reacting the compound with a compound of the general formula (18) (hereinafter, also referred to as compound (18)).
  • Compound (17) (compound (17) wherein both n and m are 2 and R 1 is a hydrogen atom is disclosed in JP-A-08-134067) and compound (18) Commonly used amines in synthetic chemistry (eg, triethylamine, diisopropylethylamine, 4-methylmorpholine, pyridine, etc.) or quaternary ammonium salts generally used in organic synthesis (eg, , Tet chloride Lamethylammonium, tetramethylammonium bromide, tetramethylammonium bromide, tetramethylammonium iodide, tetrabutylammonium salt, tetrabutylammonium fluoride, tetrabutylammonium bromide Butylammonium, tetrabutylammonium iodide, benzyltrimethylammonium chloride, benzyltrimethylammonium fluoride, benzyltrimethylam
  • the compound (19) (the compound represented by the above formula (19a)) in which Q is borane;
  • the compound (3) can be obtained by subjecting it to a deborane reaction.
  • Compound (19a) is dissolved in a suitable solvent that does not inhibit the progress of the reaction (for example, methanol, ethanol, propanol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylsulfoxide, acetone, water, or any of these).
  • a suitable solvent for example, methanol, ethanol, propanol, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylsulfoxide, acetone, water, or any of these.
  • an appropriate acid that is commonly used in organic synthetic chemistry
  • the compound (3) can be obtained by reacting for 0.1 to 24 hours.
  • the spiro II compound of the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method and a column chromatography method.
  • a conventional method such as a recrystallization method and a column chromatography method.
  • the obtained product is a racemic form, it is separated into the desired optically active form, for example, by fractional recrystallization of a salt with an optically active acid or by passing through a column packed with an optically active carrier.
  • Individual diastereomers can be separated by means such as fractional crystallization, chromatography and the like. These use optically active raw material compounds, etc. Can also be obtained.
  • Stereoisomers can be isolated by recrystallization, column chromatography, or the like.
  • the compound of the present invention is pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, Pharmaceutical compositions obtained by mixing with flavoring agents, emulsifiers, diluents, solubilizing agents, etc. as such or as pharmaceuticals (tablets, pills, capsules, granules, powders, syrups, emulsions, elixirs) , Suspensions, solutions, injections, infusions or suppositories) can be administered orally or parenterally.
  • the pharmaceutical composition can be formulated according to a usual method.
  • parenteral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, infusion and the like.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be prepared according to the known art using suitable dispersing or wetting agents and suspending agents.
  • Acceptable vehicles or solvents that can be used include water, Ringer's solution, isotonic saline and the like.
  • sterile, fixed oils can also be employed as conventional solvents or suspending solvents.
  • any non-volatile oil or fatty acid can be used, including natural, synthetic or semi-synthetic fatty oils or fatty acids, natural, synthetic or semi-synthetic mono, di- or triglycerides.
  • Suppositories for rectal administration consist of the drug and a suitable nonirritating excipient (for example, cocoa basin and polyethylene glycols which are solid at room temperature but liquid at intestinal temperature and And then release the drug).
  • a suitable nonirritating excipient for example, cocoa basin and polyethylene glycols which are solid at room temperature but liquid at intestinal temperature and And then release the drug.
  • the active ingredient compound may comprise at least one excipient, such as sucrose, lactose, cellulose sugar, corn starch, mannitol, maltitol, dextran, starches, agar, algine
  • Such dosage forms are as usual, further additives (e.g.
  • inert diluents lubricants such as magnesium stearate, talc, preservatives such as parabens, sorbins, ascorbic acid, antiacids such as tocopherol, cysteine
  • a disintegrant a disintegrant, a binder, a thickener, a buffer, a sweetening agent, a flavoring agent, a perfume agent, and the like. Tablets and pills can also be prepared by enteric coating.
  • Liquid preparations for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions, solutions and the like, which are inert diluents commonly used in the art, such as water. May be included.
  • Compounds of general formula (I), their optical isomers or pharmaceutically acceptable salts thereof have potent nicotine receptor agonism or partial nicotine receptor agonism and may have Alzheimer's disease, cognitive impairment, Remedies or prophylaxis for deficits, anxiety, depression, schizophrenia, epilepsy, pain, Tourette's syndrome, Parkinson's disease, Huntington's disease, etc., or for neurodegenerative diseases with abnormal cholinergic neurotransmission or It is effective as a prophylactic and even a smoking cessation drug.
  • Dosage may be or other depending on age, weight, general health, gender, diet, time of administration, mode of administration, excretion rate, drug combination, and the severity of the condition the patient is treating at the time. Is determined in consideration of the following factors.
  • the compound of the present invention, its optical isomer or pharmaceutically acceptable salt thereof can be used safely with low toxicity, and its daily dose depends on the condition and weight of the patient, the type of compound, the administration route, etc.
  • Raw material synthesis example 2 (compound (15)) Spiro [[1] azabicyclo [2.2.2] octane-1,2,1'-thiirane] and trimethylsilyl cyanide described in JP-A-2-62883 are dissolved in methylene chloride, aluminum chloride is added, and the mixture is heated to reflux. I do. After the completion of the reaction, the reaction solution is poured into an aqueous solution of potassium carbonate, extracted with chloroform, and dried over potassium carbonate. You. This was concentrated, and the obtained residue was subjected to silica gel column chromatography.
  • 3-cyanomethyl-1-azabicyclo [2.2.2] octane-3-thiol is obtained.
  • This compound is dissolved in methanol, and hydrochloric acid gas is blown under ice cooling. After completion of the reaction, the mixture is concentrated to obtain 3-methoxycarbonylmethyl-11-azabicyclo [2.2.2] octane-13-thiol.
  • This compound is dissolved in methanol, hydrazine hydrate is added, and the mixture is heated under reflux. After completion of the reaction, the mixture is concentrated to obtain (3-thiohydroxy-1-azabicyclo [2.2.2] octane-3-yl) acetohydrazide.
  • This compound is dissolved in aqueous hydrochloric acid, heated with sodium nitrite. After completion of the reaction, the reaction solution is cooled to room temperature, adjusted to a liquid property by adding carbonated lime, and extracted with a mixed solution of chloroform and methanol. Dry with potassium carbonate and concentrate to obtain spiro [1-azabicyclo [2.2.2] octane-1,5'-thiazolidine-1'-one].
  • reaction solution is cooled to room temperature, potassium carbonate is added to adjust the solution to alkaline, and the mixture is extracted with a mixture of form and medium. Concentrated dried over potassium carbonate, to obtain spiro [[1] Azabishikuro [2.2.2] octane one 3, 5 5 one thiazolidine [2] thione.
  • This compound was dissolved in 100 ml of methanol, and 10 ml of concentrated sulfuric acid was added dropwise under ice cooling. The mixture was stirred overnight at room temperature, and the residue obtained by concentration was dissolved in chloroform and poured into aqueous potassium carbonate. Extract with black hole form, dry the organic layer with magnesium sulfate, concentrate and concentrate (5S) -2- (6-hydroxy-11-azabicyclo [3.2.1] oct-6-yl) methyl acetate The ester was obtained quantitatively as a solid. This compound was dissolved in methanol (200 ml), hydrazine monohydrate (50 ml) was added, and the mixture was heated under reflux for 3 hours.
  • Example 1 using (-)-(S) -spiro [1-azabicyclo [2.2.2] octane-1,5'-oxazolidine-1'-one] and 3-promo 5-isopropylthiophene the reaction was carried out in the same way, (R) -3, - ( 5- isopropyl one 3-thienyl) spiro [1 Azabishikuro [2.2.2] octane one 3, 5 5 one Okisazorijin one 2, one on Get.
  • reaction solution was cooled to room temperature, a 5% aqueous sodium thiosulfate solution, an aqueous potassium carbonate solution and ethyl acetate were added, and the precipitated crystals were removed by filtration.
  • the organic layer was taken, and further water was added. Washed with water. The residue obtained by drying with sodium sulfate and concentrating was subjected to silica gel column chromatography.
  • Example 1 using (1-)-(S) -spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxoxazolysine_2, one] and 2-promo 5-cyclofuran (R) -3,1- (5-Chloro-2-furanyl) spiro [1-azabicyclo [2.2.2] octane-1,5'-oxazolidin-1 2'-one ].
  • Example 64 (1) One (S) -spiro [1-azabicyclo [2.2.2] octane-1,5'-oxazolidin-1 2'-one] and 4-bromoisopropylbenzene in the same manner as in Example 1 the reaction carried out, (R) - get 3 one (4-isopropyl building Hue sulfonyl) spiro [on 1- Azabishikuro [2.2.2] octane one 3, 5 5 - - Okisazo lysine one 2 '].
  • Example 1 using (1-)-(S) -spiro [1-azabicyclo [2.2.2] octane-1,5'-oxazolidin-1 2'-one] and 3,4-difluorobromobenzene
  • the reaction is performed in the same manner as described above, and (R) —3 '-(3,4-difluorophenyl) spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxoxazolidine-1,2one] Get.
  • Example 1 using (1-)-1 (S) -spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxazolidine-1,2, one] and 2-chloro-4-1-bromotoluene
  • the reaction is carried out in the same manner to give (R) -3,1- (3-chloro-1--4-methylphenyl) spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxaxazolidine-1,2,1 On] get.
  • Example 86 (One) Single (S) Supiro [1- Azabishikuro [2.2.2] octane one 3, 5 5 one Okisazorijin one 2 '- On the same method as in Example 1 using 4 one promo acetophenone in carrying out the reaction, (R) -3, - obtaining - (4 one Asechirufuweniru) spin orifice [Okisazorijin one 2 5 one on 1 Azabishikuro [2.2.2] octane one 3, 5 J].
  • Example 93 (I) Example using (S) -spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxoxazolidine-12,1one] and 2-bromo-14-fluorothiophene The reaction is carried out in the same manner as in (1), and (R) — 3, — (4-fluoro-2-phenyl) spiro [1-azabicyclo [2.2.2] octane-1,3,5 '—oxazolidine-1 2' — On] get.
  • Example 1 using (-) 1- (S) -spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxazolidine-1 2'-one] and (5-promo-2-cenyl) methanol (R) — 3, — (5-Hydroxymethyl-1-2-enyl) spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxoxazolidine-12, oneone ].
  • Example 1 using (-) 1- (S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-thiazolidine-1 2'-one] and 2-promo 4-ethylthiophene The reaction is carried out in the same manner, and (R) — 3 '— (4-ethyl-2-enyl) spiro [1-azabicyclo [2.2.2] octane _ 3, 5, 1, thiazolidin-1, 2, 1 ].
  • Example 1 using (1-)-(S) -spiro [1-azabicyclo [2.2.2] octane-1,5'-thiazolidine-1,2-one] and 2-promo 5-ethylthiophene
  • the reaction is performed in the same way, and (R) — 3 '— (5-ethyl-2 Yl) spiro [1 Azabishikuro [2.2.2] octane one 3, 5 3 one thiazol Jin one 2, one On obtained.
  • Example 121 (One) Single (S) - spiro [l- Azabishikuro [2.2.2] octane one 3, 5 5 - Okisazorijin one 2 '- thione] same manner as in Example 1 using 2-promoter 5-methylthiophene the reaction was carried out in the manner, (R) -3 '- ( 5- methyl-2-thienyl) spiro [1- Azabishikuro [2.2.2] octane one 3, 5 5 - O keys Sazorijin one 2 5 - thione] Get.
  • Example 1 using (-) 1- (S) -spiro [1-azabicyclo [2.2.2] octane-1,5'-oxazolidine-1 2'-thione] and 2-promo-1-5-ethylthiophene And (R) — 3 '— (5-ethyl-2-enyl) spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxosazolidine-1,2, thione ].
  • Example 1 using (-) 1- (S) -spiro [1-azabicyclo [2.2.2] octane-1,5'-oxazolidine-1 2'-one] and 2-promo 5- (trifluoromethyl) thiophene The reaction is carried out in the same manner, and (R) —3,-(5- (trifluoromethyl) thiophen-1-yl) spiro [1-azabicik mouth [2.2.2] octane-1, 3, 5 5 —Oxazolidine-one, one-one].
  • Example 133
  • Example 138 (1) Example using (S) -spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxoxazolidine_2, one] and 6-promo-2-methylbenzo [b] furan The reaction was carried out in the same manner as in 1, and (R) -3 '-(2-methylbenzo [b] furan-1-6-yl) spiro [1-azabicyclo [2.2.2] octane-1 3,5 5 1, oxazolidin-1,2, one].
  • the reaction was carried out in the same manner as in Example 38 using 0.8 g of hydroboron to give 3,-(2-bromobenzo '[b] thiophen-1-yl) spiro [1-azabicyclo [2.2.2] ] octane one 3, 5 5 - Okisazorijin one 2, - one] was obtained 0. 35 g.
  • Example 1 using (-)-(S) -spiro [1-azabicyclo [2.2.2] octane-3,5'-oxazolidin-1,2-one] and 6-bromobenzothiazol. the reaction was carried out in the same manner, (H) - 3, - (benzothiazole Ichiru one 6- I le) spiro [1 Azabishikuro [2.2.2] octane one 3, 5 three to Okisazori Jin one 2 '- one ].
  • Example 2 Same as Example 1 using 0.5 g of 4-methylspiro [1-azabicyclo [2.2.2] octane-1,5 5 -oxazolidine-1'-one] and 1.5 g of 2-bromonaphthylene of the reaction was carried out in the way, 4-methyl-3 - (2-naphthyl) spin port [1 Azabishikuro [2.2.2] octane one 3, 5 5 - Okisazorijin one 2, one on hydrochloride 0. 2 g I got
  • Example 19 1 (5 S) -3 '- (2-thienyl) spiro [1 Azabishikuro [3.2.1] octane one 6, 5 5 - Okisazorijin one 2' - On Example 3 9 with 0. 5 g The reaction is carried out in the same manner, and (5S) -3 '-(5-bromo-2-phenyl) spiro [1-azabicyclo [3.2.1] octane-1,6,5 5 -oxazolidine-2, -one 0.21 g of hydrochloride monohydrate was obtained.
  • Example 1 using (1-)-(S) -spiro [1-azabicyclo [2.2.2] octane-1,5,1-oxazolidine-12'-one] and 2-bromo-8-methylnaphthylene. the reaction was carried out in the same way, (R) - 3, - (8- Mechirunafutare down one 2-I le) spiro [1- Azabishikuro [2.2.2] octane one 3, 5, one Okisazorijin one 2 5 - On] get.
  • Example 1 using (-)-(S) -spiro [1-azabicyclo [2.2.2] octane-1,3,5, oxazolidine-12'-one] and 2-bromo-17-methylnaphthylene.
  • the reaction is carried out in the same manner, and (R) — 3 '— (7-methylnaphthalene-1-yl) spiro [1-azabicyclo [2.2.2] octane-1, 3,5, oxazolidin-1 2' — On] get.

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Abstract

L'invention concerne des composés spiro de formule générale (I), leurs isomères optiques, ou des sels de ces derniers pharmaceutiquement acceptables, qui présentent une affinité élevée pour le récepteur nicotinique α7 et qui peuvent, par conséquent, constituer des remèdes contre la démence (par exemple la maladie d'Alzheimer), la schizophrénie, les troubles cognitifs, etc., chaque symbole étant défini dans le descriptif.
PCT/JP2001/001793 2000-03-09 2001-03-07 Composes spiro, leur procede de preparation et leur utilisation comme medicaments WO2001066546A1 (fr)

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US8884017B2 (en) 2001-12-27 2014-11-11 Bayer Intellectual Property Gmbh 2-heteroarylcarboxylic acid amides
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JP4749715B2 (ja) * 2002-07-05 2011-08-17 ターガセプト，インコーポレイテッド Ｎ−アリールジアザスピロ環式化合物、並びにその製造及び使用方法
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