JP2002505332A - Glycine transport inhibitor - Google Patents

Glycine transport inhibitor

Info

Publication number
JP2002505332A
JP2002505332A JP2000534553A JP2000534553A JP2002505332A JP 2002505332 A JP2002505332 A JP 2002505332A JP 2000534553 A JP2000534553 A JP 2000534553A JP 2000534553 A JP2000534553 A JP 2000534553A JP 2002505332 A JP2002505332 A JP 2002505332A
Authority
JP
Japan
Prior art keywords
formula
hydrogen
alkyl
aryl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
JP2000534553A
Other languages
Japanese (ja)
Inventor
ルイテン，ワルター・ヘルマン・マリア・ルイ
ジヤンセン，フラン・エドウアール
ケニス，ルド・エドモンド・ジヨセフイーヌ
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Janssen Pharmaceutica NV
Original Assignee
Janssen Pharmaceutica NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Janssen Pharmaceutica NV filed Critical Janssen Pharmaceutica NV
Publication of JP2002505332A publication Critical patent/JP2002505332A/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
    • C07D211/86—Oxygen atoms
    • C07D211/88—Oxygen atoms attached in positions 2 and 6, e.g. glutarimide
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/10—Radicals substituted by halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • C07D513/02—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 two hetero rings
    • C07D513/04—Ortho-condensed systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

(57)【要約】 本発明は、中枢および末梢神経系の障害、とりわけ精神病、痛み、癲癇、神経変性性疾患（アルツハイマー病）、卒中、頭部外傷、多発性硬化症などを治療するための医薬の製造のためのグリシン輸送を阻害するα，α−ジフェニル−１−ピペリジンブタンアミドの使用に関する。本発明はさらに、新規化合物、それらの製造法およびそれらの製薬学的形態を含んで成る。   (57) [Summary] The present invention relates to the manufacture of a medicament for the treatment of disorders of the central and peripheral nervous system, in particular psychosis, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. It relates to the use of α, α-diphenyl-1-piperidinebutanamide which inhibits glycine transport. The invention further comprises the novel compounds, their preparation and their pharmaceutical forms.

Description

【発明の詳細な説明】DETAILED DESCRIPTION OF THE INVENTION

【０００１】 本発明は、中枢および末梢神経系の障害、とりわけ精神病、痛み、癲癇、神経
変性性疾患（アルツハイマー病）、卒中、頭部外傷、多発性硬化症などを治療す
るための医薬の製造のためのグリシン輸送を阻害するα，α−ジフェニル−１−
ピペリジンブタンアミドの使用に関する。本発明は、さらに、新規化合物、それ
らの製造法およびそれらの製薬学的形態を含んで成る。The present invention relates to the manufacture of a medicament for treating disorders of the central and peripheral nervous system, in particular mental illness, pain, epilepsy, neurodegenerative diseases (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. , Α-Diphenyl-1-inhibiting glycine transport for
It relates to the use of piperidine butanamide. The invention further comprises the novel compounds, their preparation and their pharmaceutical forms.

【０００２】 ４−（４−クロロフェニル）−４−ヒドロキシ−Ｎ，Ｎ−ジメチル−α，α−
ジフェニル−１−ピペリジンブタンアミド（ロペラミド、イモジウム［Ｉｍｏｄ
ｉｕｍ］（商標））のようなＮ，Ｎ−ジメチル−α，α−ジフェニル−１−ピペ
リジンブタンアミドは公知の抗下痢生成物である。これらの化合物、それらの活
性および製造法は最初に米国特許第３，７１４，１５９号に開示された。[0002] 4- (4-chlorophenyl) -4-hydroxy-N, N-dimethyl-α, α-
Diphenyl-1-piperidinebutanamide (loperamide, imodi [Imod
N, N-Dimethyl-α, α-diphenyl-1-piperidinebutanamide, such as [Ium] ™), is a known anti-diarrheal product. These compounds, their activities and their preparation were first disclosed in U.S. Pat. No. 3,714,159.

【０００３】 本発明は、中枢および末梢神経系の障害を治療するための医薬の製造のための
グリシン輸送阻害化合物［前記化合物は、式[0003] The present invention relates to a glycine transport inhibiting compound for the manufacture of a medicament for treating disorders of the central and peripheral nervous system, wherein said compound has the formula

【０００４】[0004]

【化８】 Embedded image

【０００５】 を有する］、 そのＮ−オキシド、立体異性体および製薬学的に許容できる付加塩の使用に関し
、上式中、 Ｒ1およびＲ2はそれぞれ独立に水素もしくはＣ1-4アルキルを表わす； Ｘは、式[0005] With regard to the use of its N-oxides, stereoisomers and pharmaceutically acceptable addition salts, wherein R 1 and R 2 each independently represent hydrogen or C 1-4 alkyl. X is the formula

【０００６】[0006]

【化９】 Embedded image

【０００７】 上式中、点線は任意の結合を表わす；Wherein the dotted line represents any bond;

【０００８】[0008]

【化１０】 Embedded image

【０００９】 は、式Is the equation

【００１０】[0010]

【化１１】 Embedded image

【００１１】 上式中、Ｒ6およびＲ7はそれぞれ水素を表わすか、もしくは、双方はそれらが結
合される２個の炭素原子と一緒になってフェニル環を形成しうる； Ｒ8は水素もしくはハロを表わす； ｎは１もしくは２である、 の基を表わす； Ｒ4は、水素、ヒドロキシ、Ｃ1-4アルキルオキシ、Ｃ1-4アルキルオキシＣ1-4ア
ルキルもしくはアリールＣ1-4アルキルオキシを表わす； Ｒ5は、ジアリールメチルオキシＣ1-4アルキル、もしくは式Wherein R 6 and R 7 each represent hydrogen, or both may form a phenyl ring together with the two carbon atoms to which they are attached; R 8 is hydrogen or N represents 1 or 2; n represents 1 or 2; R 4 represents hydrogen, hydroxy, C 1-4 alkyloxy, C 1-4 alkyloxy C 1-4 alkyl or aryl C 1-4 alkyl; R 5 represents diarylmethyloxy C 1-4 alkyl, or a compound of the formula

【００１２】[0012]

【化１２】 Embedded image

【００１３】 上式中、Ｂ1は−ＣＨ2、−ＣＨ（ＯＨ）−、−ＮＨ−、−ＣＨ2−ＮＨ−もしく は直接結合を表わす； Ｂ2は、−ＮＨ−、−ＣＨ2−もしくは直接結合を表わす； Ｂ3は、−ＮＲ12−、−ＣＨ2−、−Ｃ（＝Ｏ）−もしくは直接結合を表わす； Ｂ7は、−Ｃ1-4アルカンジイル−ＮＨ−もしくは−ＮＨ−Ｃ1-4アルキル−を表 わす； Ｂ8は、−ＮＲ19−、−ＣＨ2−もしくは−ＣＨ（アリール）−を表わす； 各Ｙは独立にＯもしくはＳを表わす； −ａ1＝ａ2−ａ3＝ａ4−は、式 −ＣＨ＝ＣＨ−ＣＨ＝ＣＨ− （ｂ−１−ａ）もしくは −Ｎ＝ＣＨ−Ｎ＝ＣＨ− （ｂ−１−ｂ）； 上式中、基（ｂ−１−ａ）中の水素原子はヒドロキシにより置換されうる、 の二価の基を表わす； Ｒ9は、Ｃ1-4アルキル；または、アリール、チエニル、フラニル、ヒドロキシＣ 1-4 アルキルで置換されるフラニル、もしくはチアゾリルで置換されるＣ1-4アル
キルを表わす； Ｒ10は、アリール、アリールアミノ、Ｃ1-4アルキルアミノ、Ｃ1-4アルキルチオ
を表わす； Ｒ11は、水素、Ｃ1-4アルキル、ハロもしくはトリフルオロメチルを表わす； Ｒ12は水素もしくはＣ1-4アルキルカルボニルを表わす； Ｒ13は、水素、Ｃ1-4アルキルもしくはアリールを表わす； Ｒ14は水素もしくはハロを表わす； Ｒ15およびＲ16はそれぞれ独立に水素もしくはアリールを表わす； Ｒ17は水素もしくはＣ1-4アルキルを表わす； Ｒ18は、アリール、１０，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｆ］アゼピン
−５−イル、またはＣ3-7シクロアルキルおよびアリールからそれぞれ独立に選 択される１もしくは２個の置換基で場合によっては置換されるＣ1-4アルキルを 表わす； Ｒ19は、水素、Ｃ1-4アルキルカルボニルもしくはジアリールＣ1-4アルキルを表
わす； Ｒ20、Ｒ21、Ｒ22およびＲ23はそれぞれ独立に水素、Ｃ1-4アルキルもしくはア リールを表わす； Ｒ24は水素もしくはトリフルオロメチルを表わす； Ｒ25は水素もしくはハロを表わす、 の基を表わす；そして Ｒ5が式（ｂ−３）の基を表わす場合には、Ｒ4はフェニルＣ1-4アルキルアミノ カルボニルでもまたありうる；そして Ｒ4およびＲ5は一緒になって式In the above formula, B1Is -CHTwo, -CH (OH)-, -NH-, -CHTwo-NH- or a direct bond; BTwoIs -NH-, -CHTwo-Or represents a direct bond; BThreeIs -NR12-, -CHTwo-, -C (= O)-or a direct bond; B7Is -C1-4Alkanediyl-NH- or -NH-C1-4Represents alkyl-; B8Is -NR19-, -CHTwo— Or —CH (aryl) —; each Y independently represents O or S;1= ATwo-AThree= AFour-Represents a group represented by the formula -CH = CH-CH = CH- (b-1-a) or -N = CH-N = CH- (b-1-b); A hydrogen atom in represents a divalent group of which may be replaced by hydroxy;9Is C1-4Alkyl; or aryl, thienyl, furanyl, hydroxy C 1-4 Furanyl substituted with alkyl, or C substituted with thiazolyl1-4Al
Represents a kill; RTenIs aryl, arylamino, C1-4Alkylamino, C1-4Alkylthio
R;11Is hydrogen, C1-4Represents alkyl, halo or trifluoromethyl; R12Is hydrogen or C1-4Represents an alkylcarbonyl; R13Is hydrogen, C1-4Represents alkyl or aryl; R14Represents hydrogen or halo; RFifteenAnd R16Each independently represents hydrogen or aryl; R17Is hydrogen or C1-4Represents alkyl; R18Is aryl, 10,11-dihydro-5H-dibenz [b, f] azepine
-5-yl or C3-7C optionally substituted with one or two substituents each independently selected from cycloalkyl and aryl1-4Represents alkyl; R19Is hydrogen, C1-4Alkylcarbonyl or diaryl C1-4Table showing alkyl
Forget; R20, Rtwenty one, Rtwenty twoAnd Rtwenty threeIs independently hydrogen, C1-4Represents alkyl or aryl; Rtwenty fourRepresents hydrogen or trifluoromethyl; Rtwenty fiveRepresents hydrogen or halo, represents a group of the formula:FiveRepresents a group of the formula (b-3),FourIs phenyl C1-4It can also be an alkylaminocarbonyl; and RFourAnd RFiveIs the expression

【００１４】[0014]

【化１３】 Embedded image

【００１５】 上式中、Ｒ26およびＲ27はそれぞれ独立に水素、Ｃ1-4アルキル、アリールもし くはアリールＣ1-4アルキルを表わす、 のスピロ基を形成しうる； アリールは、フェニル、またはＣ1-4アルキル、ハロ、トリフルオロメチル、ヒ ドロキシおよびＣ1-4アルキルオキシから独立に選択される１もしくは２個の置 換基で置換されるフェニルを表わす、 の基を表わす。Wherein R 26 and R 27 each independently represent hydrogen, C 1-4 alkyl, aryl or aryl C 1-4 alkyl, which may form a spiro group of the formula: Or a phenyl substituted with one or two substituents independently selected from C 1-4 alkyl, halo, trifluoromethyl, hydroxy and C 1-4 alkyloxy.

【００１６】 本発明はまた、中枢および末梢神経系の障害、とりわけ精神病、痛み、癲癇、
神経変性性疾患（アルツハイマー病）、卒中、頭部外傷、多発性硬化症などに罹
っている温血動物の治療方法にも関する。前記方法は、製薬学的担体との混合状
態にある治療上有効な量の式（Ｉ）の化合物あるいはそのＮ−オキシドの形態、
製薬学的に許容できる酸もしくは塩基付加塩または立体異性体の投与を含んで成
る。The invention also relates to disorders of the central and peripheral nervous system, in particular psychosis, pain, epilepsy,
It also relates to a method for treating a warm-blooded animal suffering from a neurodegenerative disease (Alzheimer's disease), stroke, head trauma, multiple sclerosis and the like. The method comprises treating a therapeutically effective amount of a compound of formula (I) or an N-oxide form thereof in admixture with a pharmaceutical carrier;
Comprising administering a pharmaceutically acceptable acid or base addition salt or stereoisomer.

【００１７】 前述の定義および以下で使用されるところのハロはフルオロ、クロロ、ブロモ
およびヨードに包括的なものであり；Ｃ3-7シクロアルキルはシクロプロピル、 シクロブチル、シクロペンチル、シクロヘキシルおよびシクロヘプチルに包括的
なものであり；Ｃ1-4アルキルは、例えばメチル、エチル、プロピル、ブチル、 １−メチルエチル、２−メチルプロピル、２，２−ジメチルエチルなどのような
１から４個までの炭素原子を有する直鎖および分枝状鎖の飽和炭化水素基を定義
し；Ｃ1-4アルカンジイルは、例えば１，１−メタンジイル、１，２−エタンジ イル、１，３−プロパンジイル、１，４−ブタンジイル、１，２−プロパンジイ
ル、２，３−ブタンジイルなどのような１から４個までの炭素原子を有する二価
の直鎖および分枝状鎖の飽和炭化水素基を定義する。Halo as defined above and as used hereinafter is generic to fluoro, chloro, bromo and iodo; C 3-7 cycloalkyl is to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. C 1-4 alkyl is a radical of 1 to 4 carbons such as, for example, methyl, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylethyl and the like. Straight and branched chain saturated hydrocarbon radicals having atoms; C 1-4 alkanediyl is, for example, 1,1-methanediyl, 1,2-ethanediyl, 1,3-propanediyl, Divalent linear chains having from 1 to 4 carbon atoms, such as 4-butanediyl, 1,2-propanediyl, 2,3-butanediyl and the like; And branched saturated hydrocarbon groups.

【００１８】 上述のような製薬学的に許容できる付加塩は、式（Ｉ）の化合物が形成するこ
とが可能である治療上有効な非毒性の塩基および酸付加塩の形態を含んで成るこ
とを意味される。塩基としてその遊離の形態で存在する式（Ｉ）の化合物の酸付
加塩の形態は、前記遊離塩基の形態を、無機酸、例えばハロ水素酸、例えば塩酸
もしくは臭化水素酸、硫酸、硝酸、リン酸など；または例えば酢酸、ヒドロキシ
酢酸、プロパン酸、乳酸、ピルビン酸、シュウ酸、マロン酸、コハク酸、マレイ
ン酸、フマル酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスル
ホン酸、ベンゼンスルホン酸、ｐ−トルエンスルホン酸、シクラミン酸、サリチ
ル酸、ｐ−アミノサリチル酸、パモン酸などのような有機酸のような適切な酸で
処理することにより得られることができる。A pharmaceutically acceptable addition salt as described above comprises the non-toxic, therapeutically effective non-toxic base and acid addition salt forms which the compounds of formula (I) can form. Is meant. The acid addition salts of the compounds of the formula (I) which are in their free forms as bases are obtained by converting the free base form into an inorganic acid such as a halohydroic acid such as hydrochloric or hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid and the like; or for example, acetic acid, hydroxyacetic acid, propanoic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, It can be obtained by treating with an appropriate acid such as an organic acid such as benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, and pamoic acid.

【００１９】 酸性プロトンを含有する式（Ｉ）の化合物は、適切な有機および無機塩基での
処理によりそれらの治療上有効な非毒性の塩基、すなわち金属もしくはアミン付
加塩の形態に転化されうる。適切な塩基塩の形態は、例えば、アンモニウム塩、
アルカリおよびアルカリ土類金属塩、例えばリチウム、ナトリウム、カリウム、
マグネシウム、カルシウム塩など、有機塩基との塩、例えばベンザチン、Ｎ−メ
チル−Ｄ−グルカミン、ヒドラバミン塩、ならびに例えばアルギニン、リシンな
どのようなアミノ酸との塩を含んで成る。Compounds of formula (I) containing acidic protons can be converted to their therapeutically effective non-toxic base, ie, metal or amine addition salt form, by treatment with appropriate organic and inorganic bases. Suitable base salt forms include, for example, ammonium salts,
Alkali and alkaline earth metal salts such as lithium, sodium, potassium,
It comprises salts with organic bases, such as magnesium and calcium salts, for example benzathine, N-methyl-D-glucamine, hydravamin salts, and salts with amino acids such as, for example, arginine, lysine and the like.

【００２０】 逆に、前記塩の形態は、適切な塩基もしくは酸での処理により遊離の形態に転
化され得る。Conversely, said salt forms may be converted to the free form by treatment with a suitable base or acid.

【００２１】 上で使用されるところの付加塩という用語はまた、式（Ｉ）の化合物ならびに
それらの塩が形成することが可能である溶媒和物も含んで成る。こうした溶媒和
物は、例えば、水和物、アルコール和物などである。The term addition salt as used above also comprises solvates which the compounds of the formula (I) can form, as well as their salts. Such solvates are, for example, hydrates, alcoholates and the like.

【００２２】 式（Ｉ）の化合物のＮ−オキシドの形態は、ピペリジンの窒素原子がＮ−オキ
シドに酸化される式（Ｉ）の化合物を含んで成ることを意味される。The N-oxide form of the compound of formula (I) is meant to comprise a compound of formula (I) in which the nitrogen atom of piperidine is oxidized to the N-oxide.

【００２３】 本明細書で使用されるところの「立体異性体」という用語は、式（Ｉ）の化合
物の全部の可能な立体異性体を定義する。別に挙げられないもしくは示されない
限り、化合物の化学的呼称は全部の可能な立体異性体の混合物、およびとりわけ
ラセミ混合物を示し、前記混合物は基本的分子構造の全部のジアステレオマーお
よび鏡像異性体を含有する。式（Ｉ）の化合物の立体異性体およびこうした形態
の混合物は、明らかに、式（Ｉ）により包含されることを意図される。The term “stereoisomers” as used herein defines all possible stereoisomers of the compounds of formula (I). Unless otherwise stated or indicated, chemical designations of compounds refer to mixtures of all possible stereoisomers, and especially racemic mixtures, which mixtures include all diastereomers and enantiomers of the basic molecular structure. contains. Stereoisomers of the compounds of formula (I) and mixtures of such forms are clearly intended to be encompassed by formula (I).

【００２４】 とりわけ、式（Ｉ）の化合物およびそれらの中間体のいくつかは、それらの構
造中に最低１個のステレオジェン中心を有する。このステレオジェン中心はＲも
しくはＳ配置で存在することができ、前記ＲおよびＳ表示はＰｕｒｅ Ａｐｐｌ
．Ｃｈｅｍ．、１９７６、４５、１１−３０に記述される規則に一致して使用さ
れる。In particular, some of the compounds of formula (I) and their intermediates have at least one stereogenic center in their structure. This stereogenic center can be in the R or S configuration, the R and S notation being Pure Appl.
. Chem. , 1976, 45, 11-30.

【００２５】 式（Ｉ）の化合物のいくつかはそれらの互変異性体でもまた存在しうる。こう
した形態は上の式において明確に示されないとは言え本発明の範囲内に包含され
ることを意図される。Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms, although not explicitly indicated in the above formula, are intended to be included within the scope of the present invention.

【００２６】 以下で使用される場合はいつでも、式（Ｉ）の化合物という用語は、Ｎ−オキ
シド、製薬学的に許容できる付加塩および全部の立体異性体もまた包含すること
を意味される。Whenever used below, the term compound of formula (I) is meant to also include N-oxides, pharmaceutically acceptable addition salts and all stereoisomers.

【００２７】 式（Ｉ）の本化合物は新規と思われるが、ただし、Ｒ4が水素でありそしてＲ5 がＢ1が−ＣＨ2−でありかつＲ9が４−フルオロベンジルである式（ｂ−１）の 基である場合には、−ａ1＝ａ2−ａ3＝ａ4−は−ＣＨ＝ＣＨ−ＣＨ＝ＣＨ−以外
である；また、Ｒ4が水素でありそしてＲ5がＢ1が−ＮＨ−でありかつＲ9が４−
メトキシベンジルである式（ｂ−１）の基である場合には、−ａ1＝ａ2−ａ3＝ ａ4−は−ＣＨ＝Ｎ−ＣＨ＝Ｎ−以外である。本発明はまた、医薬としての使用 のための式（Ｉ）の前記新規化合物にも関する。The compounds of formula (I) are believed to be novel, provided that R 4 is hydrogen and R 5 is B 1 is —CH 2 — and R 9 is 4-fluorobenzyl When b-1) is a group, -a 1 = a 2 -a 3 = a 4 -is other than -CH = CH-CH = CH-; also, R 4 is hydrogen and R 5 Is B 1 is —NH— and R 9 is 4-
When it is a group of the formula (b-1) which is methoxybenzyl, -a 1 = a 2 -a 3 = a 4 -is other than -CH = N-CH = N-. The invention also relates to said novel compounds of formula (I) for use as a medicament.

【００２８】 適しては、Ｒ5は、ジアリールメチルオキシＣ1-4アルキルまたは式（ｂ−２）
、（ｂ−３）、（ｂ−４）、（ｂ−５）、（ｂ−６）、（ｂ−７）、（ｂ−８）
、（ｂ−９）、（ｂ−１０）、（ｂ−１１）、（ｂ−１２）もしくは（ｂ−１３
）の基であるか；あるいは、Ｒ5はＲ4と一緒になって式（ｂ−１４）のスピロ基
を形成しうる。Suitably, R 5 is diarylmethyloxy C 1-4 alkyl or formula (b-2)
, (B-3), (b-4), (b-5), (b-6), (b-7), (b-8)
, (B-9), (b-10), (b-11), (b-12) or (b-13)
Or R 5 may together with R 4 form a spiro group of formula (b-14).

【００２９】 化合物の興味深い一群は、Ｒ1およびＲ2がメチルである式（Ｉ）の化合物であ
る。An interesting group of compounds are those compounds of formula (I) wherein R 1 and R 2 are methyl.

【００３０】 特定の化合物は、Ｘが式（ａ）の基、より具体的にはＲ6およびＲ7がそれらが
結合される２個の炭素原子と一緒になってフェニル環を形成する式（ａ）の基を
表わす、式（Ｉ）の化合物である。Certain compounds are of the formula (X) wherein X is a group of formula (a), more particularly R 6 and R 7 together with the two carbon atoms to which they are attached form a phenyl ring A compound of the formula (I) which represents the group of a).

【００３１】 他の特定の化合物は、ＸがＲ5が式（ｂ−１）の基でありかつ好ましくはＲ9が
アリールで置換されたＣ1-4アルキルを表わし、とりわけＲ9が４−フルオロベン
ジルである式（ｂ）の基を表わす、式（Ｉ）の化合物である。Other particular compounds are those wherein X represents C 1-4 alkyl wherein R 5 is a group of formula (b-1) and R 9 is preferably substituted with aryl, especially where R 9 is 4- A compound of formula (I) representing a group of formula (b) that is fluorobenzyl.

【００３２】 なお他の特定の化合物は、ＸがＲ5が式（ｂ−２）の基でありかつ好ましくは ＹがＳである式（ｂ）の基を表わす、式（Ｉ）の化合物である。Still other specific compounds are compounds of formula (I) wherein X represents a group of formula (b) wherein R 5 is a group of formula (b-2) and preferably Y is S. is there.

【００３３】 好ましい化合物は： ４−（１１，１２−ジヒドロ−６Ｈ−ベンズイミダゾ［２，１−ｂ］［３］ベン
ズアゼピン−６−イル）−Ｎ，Ｎ−ジメチル−α，α−ジフェニル−１−ピペリ
ジンブタンアミド； ４−［［１−［（４−フルオロフェニル）メチル］−１Ｈ−ベンズイミダゾル−
２−イル］ヒドロキシメチル］−Ｎ，Ｎ−ジメチル−α，α−ジフェニル−１−
ピペリジンブタンアミド；それらのＮ−オキシド、立体異性体および製薬学的に
許容できる付加塩 である。A preferred compound is: 4- (11,12-dihydro-6H-benzimidazo [2,1-b] [3] benzazepin-6-yl) -N, N-dimethyl-α, α-diphenyl-1 -Piperidinebutanamide; 4-[[1-[(4-fluorophenyl) methyl] -1H-benzimidazole-
2-yl] hydroxymethyl] -N, N-dimethyl-α, α-diphenyl-1-
Piperidine butanamide; their N-oxides, stereoisomers and pharmaceutically acceptable addition salts.

【００３４】 一般に、式（Ｉ）の化合物は、米国特許第３，７１４，１５９号、米国特許第
４，６９５，５７５号および米国特許第５，００８，２６８号に記述される反応
手順に従って、より具体的には、Ｗ-が例えばハロゲンもしくはその機能的誘導 体のような適切な対イオンである式（ＩＩ）の中間体を式（ＩＩＩ）の中間体と
反応させることにより製造され得る。In general, the compounds of formula (I) are prepared according to the reaction procedures described in US Pat. Nos. 3,714,159, 4,695,575 and 5,008,268. More specifically, it can be prepared by reacting an intermediate of formula (II), wherein W - is a suitable counter ion, such as, for example, a halogen or a functional derivative thereof, with an intermediate of formula (III).

【００３５】[0035]

【化１４】 Embedded image

【００３６】 前記反応は、例えば、メチルイソブチルケトン、Ｎ，Ｎ−ジメチルアセトアミ
ドもしくはＮ，Ｎ−ジメチルホルムアミドのような反応不活性溶媒中、例えば炭
酸ナトリウム、重炭酸ナトリウムもしくはトリエチルアミンのような適する塩基
の存在下、そして場合によってはヨウ化カリウムの存在下で実施されうる。The reaction is carried out in a reaction inert solvent such as, for example, methyl isobutyl ketone, N, N-dimethylacetamide or N, N-dimethylformamide, for example with a suitable base such as sodium carbonate, sodium bicarbonate or triethylamine. It can be carried out in the presence, and optionally in the presence of potassium iodide.

【００３７】 これおよび以下の製造法において、反応生成物は反応媒体から単離されること
ができ、そして、必要な場合は、例えば抽出、結晶化、蒸留、摩砕およびクロマ
トグラフィーのような当該技術分野で公知の方法論に従ってさらに精製してもよ
い。In this and the following preparation methods, the reaction products can be isolated from the reaction medium and, if necessary, the state of the art, such as, for example, extraction, crystallization, distillation, trituration and chromatography. It may be further purified according to methodology known in the art.

【００３８】 式（Ｉ）の化合物はまた官能基転換の技術既知の手順に従って相互に転化され
ることもできる。Compounds of formula (I) may also be converted into each other according to procedures known in the art for functional group conversion.

【００３９】 式（Ｉ）の化合物はまた、三価の窒素をそのＮ−オキシドの形態に転化するた
めの技術既知の手順に従って対応するＮ−オキシドの形態に転化してもよい。前
記Ｎ−酸化反応は、一般に、式（Ｉ）の出発原料を３−フェニル−２−（フェニ
ルスルホニル）オキサジリジンまたは適切な有機もしくは無機過酸化物と反応さ
せることにより実施してよい。適切な無機過酸化物は、例えば、過酸化水素、ア
ルカリ金属もしくはアルカリ土類金属過酸化物、例えば過酸化ナトリウム、過酸
化カリウムを含んで成り；適切な有機過酸化物は、例えばベンゼンカルボペルオ
キシ酸もしくはハロ置換ベンゼンカルボペルオキシ酸、例えば３−クロロベンゼ
ンカルボペルオキシ酸、ペルオキソアルカン酸、例えばペルオキソ酢酸、アルキ
ルヒドロペルオキシド、例えばｔ−ブチルヒドロペルオキシドのような過酸を含
んでよい。適する溶媒は、例えば、水、低級アルカノール、例えばエタノールな
ど、炭化水素、例えばトルエン、ケトン、例えば２−ブタノン、ハロゲン化炭化
水素、例えばジクロロメタン、およびこうした溶媒の混合物である。The compounds of formula (I) may also be converted to the corresponding N-oxide form according to procedures known in the art for converting a trivalent nitrogen to its N-oxide form. The N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with 3-phenyl-2- (phenylsulfonyl) oxaziridine or a suitable organic or inorganic peroxide. Suitable inorganic peroxides include, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide; suitable organic peroxides include, for example, benzenecarboperoxy Acids or halo-substituted benzenecarboperoxy acids, such as 3-chlorobenzenecarboperoxyacid, peroxoalkanoic acids, such as peroxoacetic acid, alkyl hydroperoxides, and peracids such as t-butyl hydroperoxide may be included. Suitable solvents are, for example, water, lower alkanols, such as ethanol, hydrocarbons, such as toluene, ketones, such as 2-butanone, halogenated hydrocarbons, such as dichloromethane, and mixtures of such solvents.

【００４０】 式（Ｉ）の化合物のいくつかおよび本発明の中間体のいくつかは不斉炭素原子
を含有することができる。前記化合物および前記中間体の純粋な立体異性体は技
術既知の手順の応用により得ることができる。例えば、ジアステレオマーは、選
択的結晶化もしくはクロマトグラフィー技術、例えば向流分配、液体クロマトグ
ラフィーなどの方法のような物理的方法により分離し得る。鏡像異性体は、最初
にラセミ混合物を例えばキラルな酸のような適する分割剤を用いてジアステレオ
マー塩もしくは化合物の混合物に転化すること；その後ジアステレオマー塩もし
くは化合物の前記混合物を例えば選択的結晶化もしくはクロマトグラフィー技術
、例えば液体クロマトグラフィーなどの方法により物理的に分離すること；そし
て最後に前記分離されたジアステレオマー塩もしくは化合物を対応する鏡像異性
体に転化することにより、前記ラセミ混合物から得ることができる。純粋な立体
異性体はまた適切な中間体および出発原料の純粋な立体異性体からも得ることが
できるが、ただし、介在する反応が立体特異的に起こることが前提である。Some of the compounds of formula (I) and some of the intermediates of the invention may contain asymmetric carbon atoms. Pure stereoisomers of the compounds and the intermediates may be obtained by the application of art-known procedures. For example, diastereomers may be separated by physical methods, such as selective crystallization or chromatography techniques, such as countercurrent distribution, liquid chromatography, and the like. Enantiomers are first converted from a racemic mixture to a mixture of diastereomeric salts or compounds using a suitable resolving agent such as, for example, a chiral acid; The racemic mixture by physical separation by methods such as crystallization or chromatography techniques, such as liquid chromatography; and finally by converting the separated diastereomeric salt or compound to the corresponding enantiomer. Can be obtained from Pure stereoisomers can also be obtained from the appropriate intermediates and the pure stereoisomer of the starting material, provided that the intervening reaction occurs stereospecifically.

【００４１】 式（Ｉ）の化合物および中間体の鏡像異性体を分割する代替の一様式は液体ク
ロマトグラフィー、とりわけキラルな固定相を使用する液体クロマトグラフィー
を必要とする。An alternative mode of resolving the enantiomers of the compounds of formula (I) and intermediates requires liquid chromatography, especially using a chiral stationary phase.

【００４２】 中間体および出発原料のいくつかは既知化合物であり、そして商業的に入手可
能であることができるか、もしくは技術既知の手順に従って製造してもよい。Some of the intermediates and starting materials are known compounds and may be commercially available or may be prepared according to art-known procedures.

【００４３】 グリシンは阻害および興奮双方のシナプスでの中枢および末梢神経系中のアミ
ノ酸神経伝達物質である。グリシンのこれらの別個の機能は２種の型のレセプタ
ーにより媒介され、そのそれぞれは異なる分類のグリシン輸送体と関連する。グ
リシンの阻害作用は痙攣性アルカロイドストリキニーネに感受性であるグリシン
レセプターにより媒介され、そして従って「ストリキニーネ感受性」と称される
。ストリキニーネ感受性のグリシンレセプターは脊髄および脳幹中で主に見出さ
れる。Glycine is an amino acid neurotransmitter in the central and peripheral nervous system at both inhibitory and excitatory synapses. These distinct functions of glycine are mediated by two types of receptors, each of which is associated with a different class of glycine transporter. The inhibitory effect of glycine is mediated by the glycine receptor, which is sensitive to the spastic alkaloid strychnine, and is therefore termed "strychnine sensitive". Strychnine-sensitive glycine receptors are found predominantly in the spinal cord and brain stem.

【００４４】 グリシンは、神経系中の主要な興奮性神経伝達物質グルタミン酸の作用を調節
することにより興奮性伝達で機能する（ジョンソン（Ｊｏｈｎｓｏｎ）とアッシ
ャー（Ａｓｃｈｅｒ）、Ｎａｔｕｒｅ、３２５、５２９−５３１（１９８７）；
フレッチャー（Ｆｌｅｔｃｈｅｒ）ら、Ｇｌｙｃｉｎｅ Ｔｒａｎｓｍｉｓｓｉ ｏｎ 、（オターソン（Ｏｔｔｅｒｓｏｎ）とシュトルム・マティセン（Ｓｔｏｒ
ｍ−Ｍａｔｈｉｓｅｎ）編、１９９０）、ｐｐ．１９３−２１９）。とりわけ、
グリシンは、Ｎ−メチル−Ｄ−アスパラギン酸（ＮＭＤＡ）レセプターと命名さ
れるグルタミン酸レセプターの分類での必須の補助アゴニスト(co-agonist)であ
る。ＮＭＤＡレセプターは、脳全体に、大脳皮質および海馬構成体でとりわけ高
密度で、広範に分布する。Glycine functions in excitatory transmission by regulating the action of the major excitatory neurotransmitter glutamate in the nervous system (Johnson and Ascher, Nature, 325, 529-531 ( 1987);
Fletcher (Fletcher), et al., Glycine Transmissi on, (Otason (Otterson) and Sturm-Matisen (Stor
m-Mathisen), ed., 1990) pp. 193-219). Above all,
Glycine is an essential co-agonist in the class of glutamate receptors, termed N-methyl-D-aspartate (NMDA) receptor. NMDA receptors are particularly dense and widely distributed throughout the brain in the cerebral cortex and hippocampal constructs.

【００４５】 輸送体は神経伝達物質をシナプスから取り込み、それによりシナプス中での神
経伝達物質の濃度および期限（一緒にシナプス伝達の大きさを決定する）を調節
する。近接するシナプスへの神経伝達物質の広がりを予防することにより、輸送
体はシナプス伝達の忠実を維持する。最後に、放出された伝達物質のシナプス前
終末への再取り込みにより、輸送体は伝達物質の再利用を見込む。神経伝達物質
輸送体は細胞外ナトリウムおよび膜を横切る電位の差異に依存性である。特定の
条件下、例えば発作の間に、輸送体は逆に機能し得、カルシウム非依存的な非エ
キソサイトーシスの様式で神経伝達物質を放出する（アットウェル（Ａｔｔｗｅ
ｌｌ）ら、Ｎｅｕｒｏｎ、１１、４０１−４０７（１９９３））。神経伝達物質
輸送体の調節は従ってシナプス活性を調節するための手段を提供し、これは中枢
および末梢神経系の障害の治療のための有用な療法を提供する。Transporters take up neurotransmitters from synapses and thereby regulate neurotransmitter concentrations and time limits in synapses, which together determine the magnitude of synaptic transmission. By preventing the spread of neurotransmitters to nearby synapses, transporters maintain fidelity of synaptic transmission. Finally, the transporter expects to re-use the transmitter by reuptake of the released transmitter into the presynaptic terminal. Neurotransmitter transporters are dependent on extracellular sodium and differences in potential across the membrane. Under certain conditions, such as during a seizure, the transporter may function in reverse, releasing neurotransmitters in a calcium-independent, non-exocytic manner (Atwell
11 ) et al., Neuron , 11 , 401-407 (1993)). Modulation of neurotransmitter transporters thus provides a means for modulating synaptic activity, which provides a useful therapy for the treatment of disorders of the central and peripheral nervous system.

【００４６】 分子クローニングが、ＧｌｙＴ−１およびＧｌｙＴ−２と命名された２種の分
類のグリシン輸送体の存在を示した。ＧｌｙＴ−１は主として前脳中で見出され
、そしてその分布はグルタミン作動性経路およびＮＭＤＡレセプターのものに対
応する（スミス（Ｓｍｉｔｈ）ら、Ｎｅｕｒｏｎ．８、９２７−９３５（１９９
２））。ＧｌｙＴ−１の少なくとも３種のスプライス変異体すなわちＧｌｙＴ−
１ａ、ＧｌｙＴ−１ｂおよびＧｌｙＴ−１ｃが既知であり（キム（Ｋｉｍ）ら、 Ｍｏｌｅｃｕｌａｒ Ｐｈａｒｍａｃｏｌｏｇｙ 、４５、６０８−６１７（１９
９４））、それらのそれぞれは脳および末梢組織中で独特の分布を示す。Ｇｌｙ
Ｔ−２は、対照的に、主として脳幹および脊髄中で見出され、そしてその分布は
ストリキニーネ感受性のグリシンレセプターのものに緊密に対応する（リウ（Ｌ
ｉｕ）ら、Ｊ Ｂｉｏｌｏｇｉｃａｌ Ｃｈｅｍｉｓｔｒｙ．、２６８、２２８
０２−２２８０８（１９９３）；ジャースキ（Ｊｕｒｓｋｙ）とネルソン（Ｎｅ
ｌｓｏｎ）、Ｎｅｕｒｏｃｈｅｍｉｓｔｒｙ、６４、１０２６１０３３（１９９
５））。従って、グリシンのシナプスでのレベルを調節することによりＧｌｙＴ
−１およびＧｌｙＴ−２はそれぞれＮＭＤＡレセプターおよびストリキニーネ感
受性グリシンレセプターの活性を選択的に調節することを予期することができる
。[0046] Molecular cloning was performed on two separate components, designated GlyT-1 and GlyT-2.
Glycine transporter. GlyT-1 is found mainly in the forebrain
And its distribution is relative to that of the glutaminergic pathway and the NMDA receptor.
Respond (Smith et al.,Neuron.8, 927-935 (199).
2)). At least three splice variants of GlyT-1, ie, GlyT-
1a, GlyT-1b and GlyT-1c are known (Kim et al., Molecular Pharmacology ,45, 608-617 (19)
94)), each of which shows a unique distribution in brain and peripheral tissues. Gly
T-2, in contrast, is found primarily in the brain stem and spinal cord, and its distribution is
It closely corresponds to that of strychnine-sensitive glycine receptors (Liu (L
iu) et al.J Biological Chemistry.,268, 228
02-22808 (1993); Jursky and Nelson (Ne)
lson),Neurochemistry,64, 10261033 (199
5)). Therefore, by regulating synaptic levels of glycine, GlyT
-1 and GlyT-2 are NMDA receptor and strychnine sensation, respectively.
Can be expected to selectively modulate the activity of acceptor glycine receptors
.

【００４７】 グリシン輸送体を阻害もしくは活性化する化合物は、従ってレセプター機能を
変えそして多様な疾患状態において治療上の恩恵を提供することが予期されるで
あろう。従って、ＧｌｙＴ−２の阻害は、グリシンのシナプスでのレベルを増大
させることを介してストリキニーネ感受性のグリシンレセプターを有するニュー
ロンの活動を消失させ、そうして脊髄における痛みに関する（すなわち侵害受容
）情報の伝達（これらのレセプターにより媒介されることが示されている）を消
失させるのに使用し得る。ヤクシュ（Ｙａｋｓｈ）、Ｐａｉｎ、３７、１１１−
１２３（１９８９）。加えて、脊髄中のストリキニーネ感受性のグリシンレセプ
ターを通じて阻害性のグリシン作動性伝達を高めることを、筋の機能亢進を減少
させるのに使用することができ、これは痙縮、ミオクロヌスおよび癲癇のような
増大された筋収縮を伴う疾患もしくは状態の治療で有用である（トゥロング（Ｔ
ｒｕｏｎｇ）ら、Ｍｏｖｅｍｅｎｔ Ｄｉｓｏｒｄｅｒｓ、３、７７−８７（１
９８８）；ベッカー（Ｂｅｃｋｅｒ）、ＦＡＳＥＢ Ｊ、４ ２７６７−２７７
４（１９９０））。グリシンレセプターの調節を介して治療され得る痙縮は、癲
癇、卒中、頭部外傷、多発性硬化症、脊髄傷害、ジストニア、ならびに神経系の
疾病および傷害の他の状態に関連する。Compounds that inhibit or activate glycine transporters would therefore be expected to alter receptor function and provide therapeutic benefit in a variety of disease states. Thus, inhibition of GIyT-2 abolishes the activity of neurons with strychnine-sensitive glycine receptors through increasing synaptic levels of glycine, thus providing information on pain in the spinal cord (ie, nociception). It can be used to abolish transmission, which has been shown to be mediated by these receptors. Yaksh, Pain , 37 , 111-
123 (1989). In addition, increasing inhibitory glycinergic transmission through strychnine-sensitive glycine receptors in the spinal cord can be used to reduce muscle hyperactivity, which can increase augmentation such as spasticity, myoclonus and epilepsy (Tourong (T
Ruong) et al., Movement Disorders , 3 , 77-87 (1
988); Becker, FASEB J , 4 2767-277.
4 (1990)). Spasms that can be treated via modulation of the glycine receptor are associated with epilepsy, stroke, head trauma, multiple sclerosis, spinal cord injury, dystonia, and other conditions of the nervous system diseases and injuries.

【００４８】 ＮＭＤＡレセプターは記憶および学習に関与し（ライソン（Ｒｉｓｏｎ）とス
タントン（Ｓｔａｎｔｏｎ）、Ｎｅｕｒｏｓｃｉ．Ｂｉｏｂｅｈａｖ．Ｒｅｖ． 、１９、５３３ ５５２（１９９５）；ダニズ（Ｄａｎｙｓｚ）ら、Ｂｅｈａｖ ｉｏｒａｌ Ｐｈａｒｍａｃｏｌ． 、６、４５５−４７４（１９９５））；また
、ＮＭＤＡ媒介性の神経伝達の低下された機能は精神***病の症状に寄与するよ
うである（オルネイ（Ｏｌｎｅｙ）とファーバー（Ｆａｒｂｅｒ）、Ａｒｃｈｉ ｖｅｓ Ｇｅｎｅｒａｌ Ｐｓｙｃｈｉａｔｒｙ 、５２、９９８−１００７（１
９９６））。従って、ＧｌｙＴ−１を阻害しそしてそれによりＮＭＤＡレセプタ
ーのグリシン活性化を増大させる作用物質を、新規抗精神病薬および抗痴呆薬と
して、ならびに多動症候群および器質性脳症候群のような認識過程が損なわれる
他の疾患を治療するために使用し得る。逆に、ＮＭＤＡレセプターの過剰活性化
は、多数の疾患状態、とりわけ卒中、頭部外傷、および、おそらくアルツハイマ
ー病、多発脳梗塞性痴呆、ＡＩＤＳ痴呆、ハンチントン病、パーキンソン病、筋
萎縮性側索硬化症もしくはニューロン細胞死が起こる他の状態のような神経変性
性疾患に関連するニューロン死に関係している。コイル（Ｃｏｙｌｅ）とプット
ファルケン（Ｐｕｔｔｆａｒｃｋｅｎ）、Ｓｃｉｅｎｃｅ、２６２、６８９−６
９５（１９９３）；リプトン（Ｌｉｐｔｏｎ）とローゼンバーグ（Ｒｏｓｅｎｂ
ｅｒｇ）、Ｎｅｗ Ｅｎｇｌ．Ｊ．ｏｆ Ｍｅｄｉｃｉｎｅ、３３０、６１３−
６２２（１９９３）；チョイ（Ｃｈｏｉ）、Ｎｅｕｒｏｎ １、６２３−６３４
（１９８８）。従って、ＧｌｙＴ−１の活性を増大させる薬理学的作用物質はＮ
ＭＤＡレセプターでグリシン活性化の低下をもたらすことができ、その活性をこ
れらおよび関連疾患状態を治療するのに使用し得る。同様に、ＮＭＤＡレセプタ
ー上のグリシン部位を直接封鎖する薬物をこれらおよび関連疾患状態を治療する
のに使用し得る。[0048] NMDA receptors are involved in memory and learning (Raison (Rison) and Stanton (Stanton), Neurosci.Biobehav.Rev, 19, 533 552 (1995);.. Danizu (Danysz) et al, Behav ioral Pharmacol, 6 , 455-474 (1995)); and, decreased functionality of NMDA-mediated neurotransmission appears to contribute to the symptoms of schizophrenia (Olney (Olney) and Farber (Farber), Archi ves General Psychiatry, 52 , 998-1007 (1
996)). Thus, agents that inhibit GlyT-1 and thereby increase glycine activation of the NMDA receptor are identified as novel antipsychotics and anti-dementia agents and impair cognitive processes such as hyperactivity syndrome and organic brain syndrome. Can be used to treat other diseases. Conversely, NMDA receptor overactivation is associated with a number of disease states, notably stroke, head trauma, and possibly Alzheimer's disease, multiple cerebral infarction dementia, AIDS dementia, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis It has been implicated in neuronal death associated with neurodegenerative diseases such as disease or other conditions in which neuronal cell death occurs. Coyle and Putfalken, Science , 262 , 689-6.
95 (1993); Lipton and Rosenberg.
erg), New Engl. J. of Medicine , 330 , 613-
622 (1993); Choi, Neuron 1 , 623-634.
(1988). Therefore, pharmacological agents that increase the activity of GlyT-1 are N
The glycine activation at the MDA receptor can be reduced, and its activity can be used to treat these and related disease states. Similarly, drugs that directly block the glycine site on the NMDA receptor may be used to treat these and related disease states.

【００４９】 投与の目的上、主題の化合物を、製薬学的に許容できる担体および有効成分と
して治療上有効な量の式（Ｉ）の新規化合物を含んで成る多様な製薬学的組成物
に処方することができる。本発明の製薬学的組成物を製造するために、有効成分
としての付加塩または遊離の酸もしくは塩基の形態の有効量の特定の化合物が、
製薬学的に許容できる担体と緊密な混合状態で組み合わせられ、それは投与に所
望される製剤の形態に依存して広範な形態をとってよい。これらの製薬学的組成
物は、望ましくは、好ましくは経口で、経皮でもしくは非経口注入による投与に
適する単位投与剤形にある。例えば、経口投薬形態の組成物の製造においては、
懸濁剤、シロップ剤、エリキシル剤および溶液のような経口の液体製剤の場合に
は例えば水、グリコール、油、アルコールなどのような通常の製薬学的媒体のい
ずれか；もしくは散剤、丸剤、カプセル剤および錠剤の場合にはデンプン、糖類
、カオリン、滑沢剤、結合剤、崩壊剤などのような固体の担体を使用してよい。
投与におけるそれらの容易さのため、錠剤およびカプセル剤が最も有利な経口の
投薬単位形態を代表し、この場合固体の製薬学的担体が明らかに使用される。非
経口組成物については、担体は通常少なくとも大きな部分で滅菌水を含んで成る
ことができるが、とは言え例えば溶解を図るための他の成分を包含してよい。例
えば、担体が生理的食塩水溶液、ブドウ糖溶液もしくは生理的食塩水およびブド
ウ糖溶液の混合物を含んで成る注入可能な溶液を製造することができる。式（Ｉ
）の化合物を含有する注入可能な溶液は持続性作用のために油中で処方されてよ
い。この目的上適切な油は、例えば、ラッカセイ油、ゴマ油、綿実油、トウモロ
コシ油、大豆油、長鎖脂肪酸の合成グリセロールエステル、ならびにこれらおよ
び他の油の混合物である。注入可能な懸濁剤もまた製造することができ、その場
合、適切な液体担体、沈殿防止剤などを使用してよい。経皮投与に適する組成物
において、担体は、場合によっては、小さい比率でいずれかの性質の適する添加
物と場合によっては組み合わせられる浸透増強剤および／もしくは適する湿潤剤
を含んで成り、これら添加物は皮膚上でいかなる有意の有害な影響も引き起こさ
ない。前記添加物は皮膚への投与を助長することができ、そして／もしくは所望
の組成物の製造に役立つことができる。これらの組成物は多様な様式で、例えば
経皮貼付物、スポット・オン(spot-on)もしくは軟膏として投与されてよい。（ Ｉ）の付加塩は、対応する遊離塩基もしくは遊離酸の形態を上回るそれらの増大
された水溶性により、明らかに水性組成物の製造でより適する。For administration purposes, the subject compounds are formulated into a variety of pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a novel compound of formula (I) as an active ingredient. can do. To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound in the form of an addition salt or free acid or base as an active ingredient is
It is combined with a pharmaceutically acceptable carrier in intimate admixture, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unit dosage form suitable, preferably, for administration orally, transdermally, or by parenteral injection. For example, in the manufacture of compositions in oral dosage form,
In the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, any of the usual pharmaceutical media such as, for example, water, glycols, oils, alcohols and the like; or powders, pills, In the case of capsules and tablets, solid carriers such as starch, sugars, kaolin, lubricants, binders, disintegrants and the like may be used.
Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier may usually comprise at least a large portion of sterile water, but may include other ingredients, for example, for dissolution. For example, an injectable solution can be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Formula (I
An injectable solution containing the compound of the above) may be formulated in an oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids, and mixtures of these and other oils. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be used. In compositions suitable for transdermal administration, the carrier optionally comprises a penetration enhancer and / or a suitable humectant, optionally in small proportions, optionally combined with suitable additives of any nature. Does not cause any significant adverse effects on the skin. Said additives may facilitate the administration to the skin and / or may help in the manufacture of the desired composition. These compositions may be administered in various ways, eg, as a transdermal patch, spot-on or ointment. The addition salts of (I) are clearly more suitable for the preparation of aqueous compositions due to their increased water solubility over the corresponding free base or free acid forms.

【００５０】 前述の製薬学的組成物を、投与の容易さおよび投薬量の均一性のために投薬単
位形態で処方することがとりわけ有利である。本明細書の明細および請求の範囲
で使用されるところの投薬単位形態は、単位投薬量として適する物理的に別個の
単位を指し、各単位は、必要とされる製薬学的担体と共同して所望の治療効果を
生じさせるよう算出された、予め決められた量の有効成分を含有する。こうした
投薬単位形態の例は、錠剤（割線をつけられたもしくはコーチングされた錠剤を
包含する）、カプセル剤、丸剤、散剤の包装(powder packet)、カシェ剤、注入 可能な溶液もしくは懸濁剤、茶さじ一杯、テーブルスプーン一杯など、およびそ
れらの分離された複数である。It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unit dosages, each unit associated with a required pharmaceutical carrier. It contains a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, cachets, injectable solutions or suspensions. , A teaspoon, a tablespoon, etc., and their separated plurals.

【００５１】 以下の実施例は本発明を具体的に説明することを意図される。The following examples are intended to illustrate the invention.

【００５２】 実験の部 実施例Ａ．１ 米国特許第３，７１４，１５９号に記述されるとおり製造された臭化ジメチル
（テトラヒドロ−３，３−ジフェニル−２−フリリデン）アンモニウム（０．０
１ｍｏｌ）、（±）−４−（１１，１２−ジヒドロ−６Ｈ−ベンズイミダゾ［２
，１−ｂ］［３］ベンズアゼピン−６−イル）ピペリジン（０．０１ｍｏｌ）、
Ｎａ2ＣＯ3（０．０１ｍｏｌ）およびＫＩ（１０ｍｇ）のメチルイソブチルケト
ン（２００ｍＬ）中混合物を一夜攪拌かつ還流した。溶媒を蒸発させそして残渣
を水／ＣＨ2Ｃｌ2に溶解した。有機層を分離し、そして水層をＣＨ2Ｃｌ2で再度
抽出した。合わせられた有機層を乾燥し、濾過し、そして溶媒を蒸発させた。残
渣をガラスフィルター上でシリカゲル（溶離液：ＣＨ2Ｃｌ2／ＣＨ3ＯＨ／ ９ ５／５ないし９０／１０）の上で精製した。純粋な画分を収集しかつ蒸発させた
。残渣をＣＨ3ＣＮから結晶化し、０．８８ｇ（１５％）の（±）−４−（１１ ，１２−ジヒドロ−６Ｈ−ベンズイミダゾ［２，１−ｂ］［３］ベンズアゼピン
−６−イル）−Ｎ，Ｎ−ジメチル−α，α−ジフェニル−１−ピペリジンブタン
アミド（化合物１；ｍｐ．２５５．３℃）を生じた。Experimental Section Example A. 1 Dimethyl (tetrahydro-3,3-diphenyl-2-furylidene) ammonium bromide (0.0) prepared as described in U.S. Patent 3,714,159.
1 mol), (±) -4- (11,12-dihydro-6H-benzimidazo [2
, 1-b] [3] benzazepin-6-yl) piperidine (0.01 mol),
A mixture of Na 2 CO 3 (0.01 mol) and KI (10 mg) in methyl isobutyl ketone (200 mL) was stirred and refluxed overnight. The solvent was evaporated and the residue was dissolved in water / CH 2 Cl 2. The organic layer was separated, and the aqueous layer was re-extracted with CH 2 Cl 2. The combined organic layers were dried, filtered, and the solvent was evaporated. The residue was purified on silica gel (eluent: CH 2 Cl 2 / CH 3 OH / 95/5 to 90/10) on a glass filter. Pure fractions were collected and evaporated. The residue was crystallized from CH 3 CN, 0.88g (15% ) of (±) -4- (11, 12- dihydro -6H- benzimidazo [2,1-b] [3] benzazepin-6-yl) This resulted in -N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide (Compound 1; mp. 255.3 ° C.).

【００５３】 実施例Ａ．２ ４−（３−ブロモ−２−オキソプロピル）−Ｎ，Ｎ−ジメチル−α，α−ジフ
ェニル−１−ピペリジンブタンアミドモノヒドロブロミド（１３ｇ）の攪拌され
たメタノール（８０ｍｌ）中混合物に７０℃で（２，６−ジメチルフェニル）チ
オ尿素（４．１ｇ）を添加した。攪拌を還流温度で１時間継続した。溶媒を蒸発
させそして残渣を水に溶解した。炭酸カリウムを約９のｐＨまで添加し、そして
混合物を酢酸エチルで抽出した。有機層を酸塩基抽出により精製し、乾燥し、濾
過しそして溶媒を蒸発させた。残渣をメタノールから結晶化した。沈殿を濾過分
離し、洗浄しかつ乾燥して、６．７ｇ（５２％）の４−［［２−［［２，６−ジ
メチルフェニル］アミノ］−４−チアゾリル］メチル］−Ｎ，Ｎ−ジメチル−α
，α−ジフェニル−１−ピペリジンブタンアミド（化合物４７；ｍｐ．２１０．
５℃）を生じた。Example A. To a mixture of 4- (3-bromo-2-oxopropyl) -N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide monohydrobromide (13 g) in stirred methanol (80 ml) at 70 ° C. Then, (2,6-dimethylphenyl) thiourea (4.1 g) was added. Stirring was continued at reflux temperature for 1 hour. The solvent was evaporated and the residue was dissolved in water. Potassium carbonate was added to a pH of about 9 and the mixture was extracted with ethyl acetate. The organic layer was purified by acid-base extraction, dried, filtered and the solvent was evaporated. The residue was crystallized from methanol. The precipitate was filtered off, washed and dried, and 6.7 g (52%) of 4-[[2-[[2,6-dimethylphenyl] amino] -4-thiazolyl] methyl] -N, N- Dimethyl-α
, Α-diphenyl-1-piperidinebutanamide (compound 47; mp. 210.
5 ° C).

【００５４】 類似の様式で、 ４−［［２−［［２，６−ジクロロフェニル］アミノ］−４−チアゾリル］メチ
ル］−Ｎ，Ｎ−ジメチル−α，α−ジフェニル−１−ピペリジンブタンアミド（
化合物４８；ｍｐ．２０７．０℃）； Ｎ，Ｎ−ジメチル−４−［［２−（メチルアミノ）−４−チアゾリル］メチル］
−α，α−ジフェニル−１−ピペリジンブタンアミド（化合物４９；ｍｐ．１８
８．３℃） を製造した。In a similar manner, 4-[[2-[[2,6-dichlorophenyl] amino] -4-thiazolyl] methyl] -N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide (
Compound 48; mp. N, N-dimethyl-4-[[2- (methylamino) -4-thiazolyl] methyl]
-Α, α-diphenyl-1-piperidinebutanamide (Compound 49; mp. 18
8.3 ° C).

【００５５】 実施例Ａ．３ ＮａＨ（７８％分散系；０．５５ｇ）の攪拌された１，４−ジオキサン（５０
ｍｌ）中混合物に１−（４−フルオロフェニル）−Ｎ，Ｎ−ジメチル−４−オキ
ソ−α，α−ジフェニル−１，３，８−トリアザスピロ［４，５］−デカン−８
−ブタンアミド（７．７ｇ）を添加した。室温で１時間攪拌した後に、混合物を
６０℃に加熱し、そして（クロロメチル）ベンゼン（２．３ｇ）を添加した。攪
拌を６０℃で一夜継続した。反応混合物を水上に注ぎ、そして混合物をＣＨＣｌ 3 で抽出した。抽出物を水で洗浄し、乾燥し、濾過し、そして溶媒を蒸発させた 。残渣を、溶離液として気体アンモニアで飽和されたＣＨＣｌ3および３％メタ ノールの混合物を使用するシリカゲルでのカラムクロマトグラフィーにより精製
した。純粋な画分を収集しそして溶媒を蒸発させた。残渣をｎ−ヘキサン中で摩
砕した。沈殿を濾過分離しかつ乾燥して、２ｇの１−（４−フルオロフェニル）
−Ｎ，Ｎ−ジメチル−４−オキソ−α，α−ジフェニル−３−フェニルメチル−
１，３，８−トリアザスピロ［４，５］デカン−８−ブタンアミド（化合物５０
；ｍｐ．１３９．８℃）を生じた。Example A. NaH (78% dispersion; 0.55 g) in stirred 1,4-dioxane (50
ml) in a mixture of 1- (4-fluorophenyl) -N, N-dimethyl-4-oxo.
So-α, α-diphenyl-1,3,8-triazaspiro [4,5] -decane-8
-Butanamide (7.7 g) was added. After stirring for 1 hour at room temperature, the mixture was
Heat to 60 ° C. and add (chloromethyl) benzene (2.3 g). Disturbance
Stirring was continued at 60 ° C. overnight. The reaction mixture is poured over water and the mixture is washed with CHCl Three Extracted. The extract was washed with water, dried, filtered, and the solvent was evaporated. The residue was washed with CHCl saturated with gaseous ammonia as eluentThreePurification by column chromatography on silica gel using a mixture of and 3% methanol
did. Pure fractions were collected and the solvent was evaporated. The residue was triturated in n-hexane.
Crushed. The precipitate is filtered off and dried, yielding 2 g of 1- (4-fluorophenyl)
-N, N-dimethyl-4-oxo-α, α-diphenyl-3-phenylmethyl-
1,3,8-Triazaspiro [4,5] decane-8-butanamide (compound 50
Mp. 139.8 ° C).

【００５６】 表１および２は実施例Ａ．１に従って製造した化合物を列挙する。いくつかの
化合物は実施例Ａ．１で使用されたものに関して異なる塩基および／もしくは溶
媒を使用して製造した。また、いくつかの化合物はＫＩを使用することなしに製
造した。反応条件を表１および２の「反応条件」の欄に挙げる。前記欄で、ＭＩ
Ｋはメチルイソブチルケトンを意味し、ＤＭＡはＮ，Ｎ−ジメチルアセトアミド
を意味し、そしてＤＭＦはＮ，Ｎ−ジメチルホルムアミドを意味する。Tables 1 and 2 show Example A. Compounds prepared according to 1 are listed. Some compounds are described in Example A. Prepared using different bases and / or solvents for those used in 1. Also, some compounds were prepared without using KI. The reaction conditions are listed in the columns of "Reaction conditions" in Tables 1 and 2. In the above column, MI
K means methyl isobutyl ketone, DMA means N, N-dimethylacetamide and DMF means N, N-dimethylformamide.

【００５７】[0057]

【表１】 [Table 1]

【００５８】[0058]

【表２】 [Table 2]

【００５９】[0059]

【表３】 [Table 3]

【００６０】[0060]

【表４】 [Table 4]

【００６１】[0061]

【表５】 [Table 5]

【００６２】[0062]

【表６】 [Table 6]

【００６３】 実施例Ａ．１に従って、しかしＫＩを使用することなく、１−（５−クロロ−
２−メチルフェニル）−Ｎ，Ｎ−ジメチル−４−オキソ−α，α−ジフェニル−
１，３，８−トリアザスピロ［４，５］デカン−８−ブタンアミド（化合物４６
；ｍｐ．１７５．７℃）も製造した。Example A. 1 but without using KI, 1- (5-chloro-
2-methylphenyl) -N, N-dimethyl-4-oxo-α, α-diphenyl-
1,3,8-Triazaspiro [4,5] decane-8-butanamide (compound 46
Mp. 175.7 ° C.).

【００６４】 薬理学的実施例 実施例Ｂ．１：ＧｌｙＴ１輸送体を介する輸送のアッセイ コンフルエント以下の(subconfluent)ＨＥＫ２９３−ＧｌｙＴ１細胞（すなわ
ちヒトグリシン輸送体１を安定に発現する細胞系）を、１００μｌのＤＭＥＭ培
地（１０％ウシ胎児血清、１ｍＭピルビン酸ナトリウム、２ｍＭグルタミン、１
００Ｕペニシリン／ｍｌおよび０．１ｍｇ／ｍｌのストレプトマイシンで補充さ
れたダルベッコの改変イーグル培地）中ウェルあたり細胞５０，０００個の濃度
でサイトスター（Ｃｙｔｏｓｔａｒ）−Ｔプレートに植え付けた。細胞を３７℃
、５％ＣＯ2、９５％湿度で４８時間インキュベーションした。Pharmacological Examples Example B. 1: Assay for transport through the GlyT1 transporter. Subconfluent HEK293-GlyT1 cells (ie, a cell line that stably expresses human glycine transporter 1) were treated with 100 μl of DMEM medium (10% fetal bovine serum, 1 mM pyrvin). Sodium acid, 2 mM glutamine, 1
Cytostar-T plates were seeded at a concentration of 50,000 cells per well in Dulbecco's modified Eagle's medium supplemented with 00U penicillin / ml and 0.1 mg / ml streptomycin. Cells at 37 ° C
Incubation for 48 hours at 5% CO 2 , 95% humidity.

【００６５】 第３日に、細胞を、取り込み緩衝液（２ＭトリスでｐＨ７．５に調節された、
２５ｍＭ Ｈｅｐｅｓ、５．４ｍＭグルコン酸カリウム、１．８ｍＭグルコン酸
カルシウム、０．８ｍＭ ＭｇＳＯ4、１４０ｍＭ ＮａＣｌ、５ｍＭブドウ糖 、５ｍＭアラニン）で同時にマイクロプレートの全９６個のウェルを洗浄するよ
う設計されたティーカン（Ｔｅｃａｎ）ＰＷ９６マイクロプロセッサ制御洗浄器
を使用して洗浄した。ティーカン（Ｔｅｃａｎ）ＰＷ９６を、各ウェル中に７５
μｌを残して細胞を５回洗浄するようプログラムした。試験化合物をＤＭＳＯ中
にマイクロモル濃度範囲で多様な濃度で溶解した。１μｌの試験溶液を各ウェル
に添加し、そして細胞を周囲温度で５分ないし１０分間インキュベーションした
。その後、２５μｌの取り込み緩衝液で希釈された３０μＭの［Ｕ14Ｃ］グリシ
ンを添加した。細胞を周囲温度で１時間インキュベーションした。プレートをそ
の後シールし、そして［Ｕ14Ｃ］グリシンの取り込みをパッカード（Ｐａｃｋａ
ｒｄ）マイクロプレートシンチレーション計数器（トップカウント（ＴｏｐＣｏ
ｕｎｔ））上で測定した。多様な濃度の各試験薬物について得られた結果から、
グリシン取り込みの５０％阻害を与える濃度（ＩＣ50）を算出した。本発明の試
験化合物についての算出されたデータをｐＩＣ50値（ＩＣ50の負の対数値）とし
て表３に示す。On the third day, cells were harvested in uptake buffer (pH 7.5 with 2 M Tris,
25 mM Hepes, potassium 5.4mM gluconate, 1.8 mM calcium gluconate, 0.8 mM MgSO 4, 140 mM NaCl, 5mM glucose, Tikan designed to wash all 96 wells of a microplate simultaneously with 5mM alanine) Washed using a (Tecan) PW96 microprocessor controlled washer. Tecan PW96 was added to each well at 75
Cells were programmed to wash 5 times, leaving μl. Test compounds were dissolved in DMSO at various concentrations in the micromolar range. 1 μl of test solution was added to each well and the cells were incubated for 5-10 minutes at ambient temperature. Thereafter, 30 μM [U 14 C] glycine diluted in 25 μl uptake buffer was added. Cells were incubated for 1 hour at ambient temperature. The plate is then sealed and [U 14 C] glycine incorporation is checked by Packard.
rd) Microplate scintillation counter (TopCount (TopCo
unt)). From the results obtained for various concentrations of each test drug,
The concentration giving 50% inhibition of glycine incorporation (IC 50 ) was calculated. The calculated data for the test compounds of the invention are shown in Table 3 as pIC 50 values (negative logarithms of IC 50 ).

【００６６】 米国特許第４，６９５，５７５号に開示されるような４−［［１−［（４−フ
ルオロフェニル）メチル］−１Ｈ−ベンズイミダゾル−２−イル］メチル］−Ｎ
，Ｎ−ジメチル−α，α−ジフェニル−１−ピペリジンブタンアミドである化合
物５１、および米国特許第５，００８，２６８号に開示されるような４−［［９
−［（４−メトキシフェニル）メチル］−９Ｈ−プリン−８−イル］アミノ］−
Ｎ，Ｎ−ジメチル−α，α−ジフェニル−１−ピペリジンブタンアミド（Ｅ）−
２−ブテンジオエート（２：５）である化合物５２もまた試験した。4-[[1-[(4-Fluorophenyl) methyl] -1H-benzimidazol-2-yl] methyl] -N as disclosed in US Pat. No. 4,695,575
, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide, and 4-[[9 as disclosed in US Pat. No. 5,008,268.
-[(4-methoxyphenyl) methyl] -9H-purin-8-yl] amino]-
N, N-dimethyl-α, α-diphenyl-1-piperidinebutanamide (E)-
Compound 52, which is 2-butenedioate (2: 5), was also tested.

【００６７】[0067]

【表７】 [Table 7]

【００６８】 Ｃ．組成物実施例 以下の処方は、本発明に従った動物およびヒト被験体への全身投与に適する典
型的な製薬学的組成物を例示する。「有効成分」（Ａ．Ｉ．）は式（Ｉ）の化合
物もしくはその製薬学的に許容できる付加塩に関する。C. Composition Examples The following formulations illustrate typical pharmaceutical compositions suitable for systemic administration to animal and human subjects according to the present invention. "Active ingredient" (AI) relates to a compound of formula (I) or a pharmaceutically acceptable addition salt thereof.

【００６９】 実施例Ｃ．１：フィルムコーチング錠 錠剤核の製造 １００ｇのＡ．Ｉ．、５７０ｇの乳糖および２００ｇのデンプン
の混合物を十分に混合し、そしてその後、５ｇのドデシル硫酸ナトリウムおよび
１０ｇのポリビニルピロリドンの約２００ｍｌ水溶液で湿らせた。湿潤粉末混合
物を篩過し、乾燥しそして再度篩過した。その後、１００ｇの微晶質セルロース
および１５ｇの水素化植物油を添加した。全体を十分に混合し、そして錠剤に圧
縮し、１０，０００個の錠剤を与え、それぞれは１０ｍｇの有効成分を含んだ。
コーチング １０ｇのメチルセルロースの７５ｍｌ変性エタノール溶液に、５ｇ
のエチルセルロースの１５０ｍｌジクロロメタン溶液を添加した。その後、７５
ｍｌのジクロロメタンおよび２．５ｍｌの１，２，３−プロパントリオールを添
加した。１０ｇのポリエチレングリコールを溶融し、そして７５ｍｌのジクロロ
メタンに溶解した。後者の溶液を前者に添加し、そしてその後２．５ｇのオクタ
デカン酸マグネシウム、５ｇのポリビニルピロリドンおよび３０ｍｌの濃縮色懸
濁液を添加し、そして全体を均質化した。錠剤核を、かように得られた混合物を
用いてコーチング装置中でコーチングした。Example C 1: Film Coated Tablet Preparation of Tablet Core 100 g of A. I. A mixture of 570 g of lactose and 200 g of starch was mixed well and then moistened with an approximately 200 ml aqueous solution of 5 g of sodium dodecyl sulfate and 10 g of polyvinylpyrrolidone. The wet powder mixture was sieved, dried and sieved again. Thereafter, 100 g of microcrystalline cellulose and 15 g of hydrogenated vegetable oil were added. The whole was mixed well and compressed into tablets, giving 10,000 tablets, each containing 10 mg of active ingredient.
Coating 10g of methylcellulose in 75ml denatured ethanol solution, 5g
Of ethylcellulose in 150 ml of dichloromethane was added. Then 75
ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. 10 g of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated color suspension were added and the whole was homogenized. The tablet core was coated in a coating machine with the mixture thus obtained.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.7 識別記号 ＦＩ テーマコート゛(参考） Ａ６１Ｋ 31/454 Ａ６１Ｋ 31/454 ４Ｃ０８６ 31/4545 31/4545 31/519 31/519 31/55 31/55 Ａ６１Ｐ 9/10 Ａ６１Ｐ 9/10 25/00 25/00 25/04 25/04 25/08 25/08 25/18 25/18 43/00 １１１ 43/00 １１１ Ｃ０７Ｄ 211/32 Ｃ０７Ｄ 211/32 211/34 211/34 211/48 211/48 211/50 211/50 211/58 211/58 211/62 211/62 401/04 401/04 401/06 401/06 401/12 401/12 405/06 405/06 405/14 405/14 409/14 409/14 413/12 413/12 417/04 417/04 417/06 417/06 417/14 417/14 471/04 １０５ 471/04 １０５Ｅ 487/04 １５２ 487/04 １５２ 513/04 ３５５ 513/04 ３５５ (81)指定国 ＥＰ(ＡＴ，ＢＥ，ＣＨ，ＣＹ， ＤＥ，ＤＫ，ＥＳ，ＦＩ，ＦＲ，ＧＢ，ＧＲ，ＩＥ，Ｉ Ｔ，ＬＵ，ＭＣ，ＮＬ，ＰＴ，ＳＥ)，ＯＡ(ＢＦ，ＢＪ ，ＣＦ，ＣＧ，ＣＩ，ＣＭ，ＧＡ，ＧＮ，ＧＷ，ＭＬ， ＭＲ，ＮＥ，ＳＮ，ＴＤ，ＴＧ)，ＡＰ(ＧＨ，ＧＭ，Ｋ Ｅ，ＬＳ，ＭＷ，ＳＤ，ＳＬ，ＳＺ，ＵＧ，ＺＷ)，Ｅ Ａ(ＡＭ，ＡＺ，ＢＹ，ＫＧ，ＫＺ，ＭＤ，ＲＵ，ＴＪ ，ＴＭ)，ＡＬ，ＡＭ，ＡＴ，ＡＵ，ＡＺ，ＢＡ，ＢＢ ，ＢＧ，ＢＲ，ＢＹ，ＣＡ，ＣＨ，ＣＮ，ＣＵ，ＣＺ， ＤＥ，ＤＫ，ＥＥ，ＥＳ，ＦＩ，ＧＢ，ＧＥ，ＧＨ，Ｇ Ｍ，ＨＲ，ＨＵ，ＩＤ，ＩＬ，ＩＮ，ＩＳ，ＪＰ，ＫＥ ，ＫＧ，ＫＰ，ＫＲ，ＫＺ，ＬＣ，ＬＫ，ＬＲ，ＬＳ， ＬＴ，ＬＵ，ＬＶ，ＭＤ，ＭＧ，ＭＫ，ＭＮ，ＭＷ，Ｍ Ｘ，ＮＯ，ＮＺ，ＰＬ，ＰＴ，ＲＯ，ＲＵ，ＳＤ，ＳＥ ，ＳＧ，ＳＩ，ＳＫ，ＳＬ，ＴＪ，ＴＭ，ＴＲ，ＴＴ， ＵＡ，ＵＧ，ＵＳ，ＵＺ，ＶＮ，ＹＵ，ＺＷ (72)発明者 ルイテン，ワルター・ヘルマン・マリア・ ルイ ベルギー・ビー−2340ビールセ・トウルン ホウトセベーク30・ジヤンセン・フアーマ シユーチカ・ナームローゼ・フエンノート シヤツプ (72)発明者 ジヤンセン，フラン・エドウアール ベルギー・ビー−2340ビールセ・トウルン ホウトセベーク30・ジヤンセン・フアーマ シユーチカ・ナームローゼ・フエンノート シヤツプ (72)発明者 ケニス，ルド・エドモンド・ジヨセフイー ヌ ベルギー・ビー−2340ビールセ・トウルン ホウトセベーク30・ジヤンセン・フアーマ シユーチカ・ナームローゼ・フエンノート シヤツプ Ｆターム(参考） 4C050 AA01 BB05 CC10 EE03 FF01 GG01 HH04 4C054 AA02 BB01 CC03 DD01 DD23 EE01 EE05 EE08 EE16 FF01 FF04 FF05 FF10 FF12 FF13 FF25 FF30 FF38 4C063 AA01 AA03 BB01 BB02 BB03 BB09 CC10 CC19 CC26 CC52 CC62 CC76 CC92 DD04 DD06 DD10 DD26 EE01 4C065 AA03 BB06 CC09 DD02 EE02 HH01 PP13 4C072 AA01 BB02 CC02 CC16 DD06 EE13 FF09 GG01 HH07 UU01 4C086 AA01 AA02 AA03 AA04 BC21 BC31 BC32 BC39 BC69 BC82 BC84 CB05 CB11 CB26 GA02 GA07 GA09 GA10 MA01 MA04 ZA02 ZA06 ZA08 ZA18 ZA20 ZC41 ──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. 7 Identification symbol FI Theme coat ゛ (Reference) A61K 31/454 A61K 31/454 4C086 31/4545 31/4545 31/519 31/519 31/55 31/55 A61P 9/10 A61P 9/10 25/00 25/00 25/04 25/04 25/08 25/08 25/18 25/18 43/00 111 43/00 111 C07D 211/32 C07D 211/32 211 / 34 211/34 211/48 211/48 211/50 211/50 211/58 211/58 211/62 211/62 401/04 401/04 401/06 401/06 401/12 401/12 405/06 405 / 06 405/14 405/14 409/14 409/14 413/12 413/12 417/04 417/04 417/06 417/06 417/14 417/14 471/04 105 471/04 105E 487/04 152 487/04 152 513/04 355 513/04 355 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD) , SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP , KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Ruiten, Walter Hermann Maria Louis Belgian Bee-2340 Beerse Touln Houtsebeek 30 Jyansen Fama Syutika Namurse Fennaught Shajap (72) Inventor Jyansen, Fran Edouard Belgian Bee-2340 Beerse・ Turun Houtsebeek 30 ・ Jyansen Huarma Syutika Nahmrose Fennoat Shyaupp (72) Inventor Kennis, Ludo Edmund Jyosefine Belgium ・ B-2340 Reference) 4C050 AA01 BB05 CC10 EE03 FF01 GG01 HH04 4C054 AA02 BB01 CC03 DD01 DD23 EE01 EE05 EE08 EE16 FF01 FF04 FF05 FF10 FF12 FF13 FF25 FF30 FF38 4C063 AA01 AA03 BB01 CC02 CC52 CC02 CC02 DD04 DD06 DD10 DD26 EE01 4C065 AA03 BB06 CC09 DD02 EE02 HH01 PP13 4C072 AA01 BB02 CC02 CC16 DD06 EE13 FF09 GG01 HH07 UU01 4C086 AA01 AA02 AA03 AA04 BC21 BC31 BC32 BC39 BC69 GA02 ZA02 Z02 ZC41

Claims (10)

【特許請求の範囲】[Claims] 【請求項１】 中枢および末梢神経系の障害を治療するための医薬の製造の
ためのグリシン輸送阻害化合物［前記化合物は、式 【化１】 を有する]、 そのＮ−オキシド、立体異性体もしくは製薬学的に許容できる付加塩の使用であ
って、上式中、 Ｒ1およびＲ2はそれぞれ独立に水素もしくはＣ1-4アルキルを表わす； Ｘは、式 【化２】 上式中、点線は任意の結合を表わす； 【化３】 は、式 【化４】 上式中、Ｒ6およびＲ7はそれぞれ水素を表わすか、もしくは、双方はそれらが結
合される２個の炭素原子と一緒になってフェニル環を形成しうる； Ｒ8は水素もしくはハロを表わす； ｎは１もしくは２である、 の基を表わす； Ｒ4は、水素、ヒドロキシ、Ｃ1-4アルキルオキシ、Ｃ1-4アルキルオキシＣ1-4ア
ルキルもしくはアリールＣ1-4アルキルオキシを表わす； Ｒ5は、ジアリールメチルオキシＣ1-4アルキル、もしくは式 【化５】 上式中、Ｂ1は−ＣＨ2、−ＣＨ（ＯＨ）−、−ＮＨ−、−ＣＨ2−ＮＨ−もしく は直接結合を表わす； Ｂ2は、−ＮＨ−、−ＣＨ2−もしくは直接結合を表わす； Ｂ3は、−ＮＲ12−、−ＣＨ2−、−Ｃ（＝Ｏ）−もしくは直接結合を表わす； Ｂ7は、−Ｃ1-4アルカンジイル−ＮＨ−もしくは−ＮＨ−Ｃ1-4アルキル−を表 わす； Ｂ8は、−ＮＲ19−、−ＣＨ2−もしくは−ＣＨ（アリール）−を表わす； 各Ｙは独立にＯもしくはＳを表わす； −ａ1＝ａ2−ａ3＝ａ4−は、式 −ＣＨ＝ＣＨ−ＣＨ＝ＣＨ− （ｂ−１−ａ）もしくは −Ｎ＝ＣＨ−Ｎ＝ＣＨ− （ｂ−１−ｂ）； 上式中、基（ｂ−１−ａ）中の水素原子はヒドロキシにより置換されうる、 の二価の基を表わす； Ｒ9は、Ｃ1-4アルキル；または、アリール、チエニル、フラニル、ヒドロキシＣ 1-4 アルキルで置換されるフラニル、もしくはチアゾリルで置換されるＣ1-4アル
キルを表わす； Ｒ10は、アリール、アリールアミノ、Ｃ1-4アルキルアミノ、Ｃ1-4アルキルチオ
を表わす； Ｒ11は、水素、Ｃ1-4アルキル、ハロもしくはトリフルオロメチルを表わす； Ｒ12は水素もしくはＣ1-4アルキルカルボニルを表わす； Ｒ13は、水素、Ｃ1-4アルキルもしくはアリールを表わす； Ｒ14は水素もしくはハロを表わす； Ｒ15およびＲ16はそれぞれ独立に水素もしくはアリールを表わす； Ｒ17は水素もしくはＣ1-4アルキルを表わす； Ｒ18は、アリール、１０，１１−ジヒドロ−５Ｈ−ジベンズ［ｂ，ｆ］アゼピン
−５−イル、またはＣ3-7シクロアルキルおよびアリールからそれぞれ独立に選 択される１もしくは２個の置換基で場合によっては置換されるＣ1-4アルキルを 表わす； Ｒ19は、水素、Ｃ1-4アルキルカルボニルもしくはジアリールＣ1-4アルキルを表
わす； Ｒ20、Ｒ21、Ｒ22およびＲ23はそれぞれ独立に水素、Ｃ1-4アルキルもしくはア リールを表わす； Ｒ24は水素もしくはトリフルオロメチルを表わす； Ｒ25は水素もしくはハロを表わす、 の基を表わす；そして Ｒ5が式（ｂ−３）の基を表わす場合には、Ｒ4はフェニルＣ1-4アルキルアミノ カルボニルでもまたありうる；そして Ｒ4およびＲ5は一緒になって式 【化６】 上式中、Ｒ26およびＲ27はそれぞれ独立に水素、Ｃ1-4アルキル、アリールもし くはアリールＣ1-4アルキルを表わす、 のスピロ基を形成しうる； アリールは、フェニル、またはＣ1-4アルキル、ハロ、トリフルオロメチル、ヒ ドロキシおよびＣ1-4アルキルオキシから独立に選択される１もしくは２個の置 換基で置換されるフェニルを表わす、 の基を表わす、使用。1. A method for the manufacture of a medicament for treating disorders of the central and peripheral nervous system.
A glycine transport inhibiting compound, wherein the compound has the formula:The use of N-oxides, stereoisomers or pharmaceutically acceptable addition salts thereof.
In the above formula, R1And RTwoIs independently hydrogen or C1-4X represents an alkyl;In the above formula, a dotted line represents an arbitrary bond;Is of the formulaIn the above formula, R6And R7Each represents hydrogen, or both represent
R can combine with the two carbon atoms to form a phenyl ring;8Represents hydrogen or halo; n is 1 or 2;FourIs hydrogen, hydroxy, C1-4Alkyloxy, C1-4Alkyloxy C1-4A
Lucyl or aryl C1-4Represents alkyloxy; RFiveIs diarylmethyloxy C1-4Alkyl or a compound of the formulaIn the above formula, B1Is -CHTwo, -CH (OH)-, -NH-, -CHTwo-NH- or a direct bond; BTwoIs -NH-, -CHTwo-Or represents a direct bond; BThreeIs -NR12-, -CHTwo-, -C (= O)-or a direct bond; B7Is -C1-4Alkanediyl-NH- or -NH-C1-4Represents alkyl-; B8Is -NR19-, -CHTwo— Or —CH (aryl) —; each Y independently represents O or S;1= ATwo-AThree= AFour-Represents a group represented by the formula -CH = CH-CH = CH- (b-1-a) or -N = CH-N = CH- (b-1-b); A hydrogen atom in represents a divalent group of which may be replaced by hydroxy;9Is C1-4Alkyl; or aryl, thienyl, furanyl, hydroxy C 1-4 Furanyl substituted with alkyl, or C substituted with thiazolyl1-4Al
Represents a kill; RTenIs aryl, arylamino, C1-4Alkylamino, C1-4Alkylthio
R;11Is hydrogen, C1-4Represents alkyl, halo or trifluoromethyl; R12Is hydrogen or C1-4Represents an alkylcarbonyl; R13Is hydrogen, C1-4Represents alkyl or aryl; R14Represents hydrogen or halo; RFifteenAnd R16Each independently represents hydrogen or aryl; R17Is hydrogen or C1-4Represents alkyl; R18Is aryl, 10,11-dihydro-5H-dibenz [b, f] azepine
-5-yl or C3-7C optionally substituted with one or two substituents each independently selected from cycloalkyl and aryl1-4Represents alkyl; R19Is hydrogen, C1-4Alkylcarbonyl or diaryl C1-4Table showing alkyl
Forget; R20, Rtwenty one, Rtwenty twoAnd Rtwenty threeIs independently hydrogen, C1-4Represents alkyl or aryl; Rtwenty fourRepresents hydrogen or trifluoromethyl; Rtwenty fiveRepresents hydrogen or halo, represents a group of the formula:FiveRepresents a group of the formula (b-3),FourIs phenyl C1-4It can also be an alkylaminocarbonyl; and RFourAnd RFiveTogether form the formulaIn the above formula, R26And R27Is independently hydrogen, C1-4Alkyl, aryl or aryl C1-4Aryl may form a spiro group of the formula: aryl is phenyl, or C1-4Alkyl, halo, trifluoromethyl, hydroxy and C1-4Represents a phenyl substituted by one or two substituents independently selected from alkyloxy; 【請求項２】 Ｒ1およびＲ2がメチルである、請求項１に記載の使用。2. Use according to claim 1, wherein R 1 and R 2 are methyl. 【請求項３】 Ｘが式（ａ）もしくは（ｂ）の基である、請求項１もしくは
２に記載の使用。3. Use according to claim 1, wherein X is a group of formula (a) or (b). 【請求項４】 障害が、精神病、痛み、癲癇、神経変性性疾患、卒中、頭部
外傷もしくは多発性硬化症である、請求項１に記載の使用。4. The use according to claim 1, wherein the disorder is psychosis, pain, epilepsy, neurodegenerative disease, stroke, head trauma or multiple sclerosis. 【請求項５】 請求項１ないし３のいずれか一で定義されるような式（Ｉ）
の化合物であるが、ただし、Ｒ4が水素でありそしてＲ5がＢ1が−ＣＨ2−であり
かつＲ9が４−フルオロベンジルである式（ｂ−１）の基である場合には、−ａ1 ＝ａ2−ａ3＝ａ4−は−ＣＨ＝ＣＨ−ＣＨ＝ＣＨ−以外である；また、Ｒ4が水素
でありそしてＲ5がＢ1が−ＮＨ−でありかつＲ9が４−メトキシベンジルである 式（ｂ−１）の基である場合には、−ａ1＝ａ2−ａ3＝ａ4−は−ＣＨ＝Ｎ−ＣＨ
＝Ｎ−以外である、化合物。5. A compound of the formula (I) as defined in claim 1
Provided that R 4 is hydrogen and R 5 is a group of formula (b-1) wherein B 1 is —CH 2 — and R 9 is 4-fluorobenzyl , -A 1 = a 2 -a 3 = a 4 -is other than -CH = CH-CH = CH-; also, R 4 is hydrogen and R 5 is B 1 -NH- and R When 9 is 4-methoxybenzyl, a group of the formula (b-1), -a 1 = a 2 -a 3 = a 4 -is -CH = N-CH
= A compound other than N-. 【請求項６】 Ｒ5が、ジアリールメチルオキシＣ1-4アルキルまたは式（ｂ
−２）、（ｂ−３）、（ｂ−４）、（ｂ−５）、（ｂ−６）、（ｂ−７）、（ｂ
−８）、（ｂ−９）、（ｂ−１０）、（ｂ−１１）、（ｂ−１２）もしくは（ｂ
−１３）の基であるか；あるいは、Ｒ5がＲ4と一緒になって式（ｂ−１４）のス
ピロ基を形成しうる、請求項５で記載されるような化合物。Wherein R 5 is, diaryl methyloxy C 1-4 alkyl or formula (b
-2), (b-3), (b-4), (b-5), (b-6), (b-7), (b
-8), (b-9), (b-10), (b-11), (b-12) or (b
Is a group -13); or, R 5 taken together with R 4 may form a spiro radical of formula (b-14), compounds as described in claim 5. 【請求項７】 製薬学的に許容できる担体および有効成分として治療上有効
な量の請求項５もしくは６に記述されるような化合物を含んで成る製薬学的組成
物。7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound as described in claim 5 or 6 as an active ingredient. 【請求項８】 治療上有効な量の請求項５もしくは６で請求されるような化
合物が製薬学的担体と緊密に混合されることを特徴とする、請求項７で請求され
るような製薬学的組成物の製造方法。8. A pharmaceutical as claimed in claim 7, characterized in that a therapeutically effective amount of the compound as claimed in claim 5 or 6 is intimately mixed with a pharmaceutical carrier. For producing a chemical composition. 【請求項９】 医薬としての使用のための請求項５もしくは６に記述される
ような化合物。9. A compound as described in claim 5 or 6 for use as a medicament. 【請求項１０】 Ｗ-が適切な対イオンもしくはその機能的誘導体である式 （ＩＩ）の中間体を、反応不活性溶媒中、適する塩基の存在下、かつ、場合によ
ってはヨウ化カリウムの存在下に式（ＩＩＩ）の中間体と反応させること； 【化７】 そして、所望の場合は、式（Ｉ）の化合物を、酸での処理により酸付加塩に、も
しくは塩基での処理により塩基付加塩に転化すること、または、逆に、アルカリ
での処理により酸付加塩の形態を遊離塩基に転化すること、もしくは酸での処理
により塩基付加塩を遊離酸に転化すること；そして、所望の場合はそのＮ−オキ
シドおよび／もしくは立体異性体を製造することを特徴とする、請求項５に記述
されるような化合物の製造方法。10. An intermediate of formula (II) wherein W - is a suitable counterion or a functional derivative thereof, is prepared by reacting the intermediate of formula (II) in a reaction inert solvent in the presence of a suitable base and, optionally, the presence of potassium iodide. Reacting with an intermediate of formula (III) below: Then, if desired, the compound of formula (I) is converted into an acid addition salt by treatment with an acid or to a base addition salt by treatment with a base, or conversely, by treatment with an alkali. Converting the addition salt form to the free base, or converting the base addition salt to the free acid by treatment with an acid; and, if desired, preparing its N-oxide and / or stereoisomer. A method for the preparation of a compound as described in claim 5, characterized in that:
JP2000534553A 1998-03-06 1999-02-26 Glycine transport inhibitor Withdrawn JP2002505332A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP98200700.7 1998-03-06
EP98200700 1998-03-06
PCT/EP1999/001308 WO1999045011A1 (en) 1998-03-06 1999-02-26 Glycine transport inhibitors

Publications (1)

Publication Number Publication Date
JP2002505332A true JP2002505332A (en) 2002-02-19

Family

ID=8233443

Family Applications (1)

Application Number Title Priority Date Filing Date
JP2000534553A Withdrawn JP2002505332A (en) 1998-03-06 1999-02-26 Glycine transport inhibitor

Country Status (17)

Country Link
EP (1) EP1058684A1 (en)
JP (1) JP2002505332A (en)
KR (1) KR20010032967A (en)
CN (1) CN1291984A (en)
AU (1) AU3254499A (en)
BG (1) BG104686A (en)
BR (1) BR9907953A (en)
CA (1) CA2322136A1 (en)
EE (1) EE200000483A (en)
HR (1) HRP20000524A2 (en)
HU (1) HUP0101281A3 (en)
IL (1) IL138227A0 (en)
NO (1) NO20004432L (en)
PL (1) PL342818A1 (en)
SK (1) SK13092000A3 (en)
TR (1) TR200002570T2 (en)
WO (1) WO1999045011A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003513063A (en) * 1999-11-01 2003-04-08 エヌピーエス アレリックス コーポレーション Diaryl-enines
JP2006516239A (en) * 2002-05-31 2006-06-29 ユーロ−セルティーク エス．エイ． Triazaspiro compounds useful for treating or preventing pain
JP2014520799A (en) * 2011-06-28 2014-08-25 ビボゾーン インコーポレイテッド Combinations of active substances that induce the synergistic effect of multiple targeting and their uses

Families Citing this family (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2001288896A1 (en) 2000-09-08 2002-03-22 Gliatech, Inc. Substituted hydrazine derivatives
EP1324986A1 (en) 2000-09-14 2003-07-09 Gliatech, Inc. Nitrogen-containing compounds and their use as glycine transport inhibitors
TW579375B (en) * 2000-10-12 2004-03-11 Ssp Co Ltd 2,2-Diphenylbutanamide derivatives and medicines containing the same
AR032653A1 (en) 2001-02-09 2003-11-19 Telik Inc HYPERCYCLIC INHIBITORS OF THE GLICINE TRANSPORTER 2 PHARMACEUTICAL COMPOSITIONS, USE AND METHODS.
WO2003082819A1 (en) * 2002-04-01 2003-10-09 Nippon Chemiphar Co.,Ltd. N-phenyl-n-(4-piperidinyl)amide derivative
FR2838739B1 (en) 2002-04-19 2004-05-28 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL) BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2842804B1 (en) * 2002-07-29 2004-09-03 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
FR2842805A1 (en) * 2002-07-29 2004-01-30 Sanofi Synthelabo N- [PHENYL (PIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND APPLICATION THERAPEUTICS
US7202259B2 (en) 2002-11-18 2007-04-10 Euro-Celtique S.A. Therapeutic agents useful for treating pain
RU2330842C2 (en) * 2003-02-17 2008-08-10 Ф.Хоффманн-Ля Рош Аг Piperidinbenzolsulfamide derivatives
EA009986B1 (en) 2003-08-11 2008-04-28 Ф. Хоффманн-Ля Рош Аг Piperazine with or-substituted phenyl group and their use as glyt1 inhibitors
FR2861071B1 (en) 2003-10-17 2006-01-06 Sanofi Synthelabo N- [PHENYL (ALKYLPIPERIDIN-2-YL) METHYL] BENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2861076B1 (en) 2003-10-17 2006-01-06 Sanofi Synthelabo N-HETEROCYCLYMETHYLBENZAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2861070B1 (en) * 2003-10-17 2006-01-06 Sanofi Synthelabo DERIVATIVES OF N- [PHENYL (PYRROLIDIN-2-YL) METHYL] BENZAMIDE AND N - [(AZEPAN-2-YL) PHENYLMETHYL] BENZAMIDE, THEIR PREPARATION AND THEIR THERAPEUTIC USE
WO2005058317A1 (en) * 2003-12-18 2005-06-30 Glaxo Group Limited Glycine transporter-1 inhibirors
BRPI0506548A (en) * 2004-01-30 2007-05-02 Euro Celtique Sa Methods for Making 4-Tetrazolyl-4-Phenylpiperidine Compounds
GB0408774D0 (en) * 2004-04-20 2004-05-26 Glaxo Group Ltd Compounds
ATE430142T1 (en) 2004-12-09 2009-05-15 Hoffmann La Roche PHENYLPIPERAZINE-METHANONE DERIVATIVES
NZ555476A (en) * 2004-12-15 2009-09-25 Hoffmann La Roche Bi- and tricyclic substituted phenyl methanones as glycine transporter I (GLYT-1) inhibitors for the treatment of alzheimerÆs disease
US7485637B2 (en) 2005-01-04 2009-02-03 Hoffmann-La Roche Inc. Benzoyl-tetrahydropiperidine derivatives
BRPI0519794A2 (en) 2005-01-07 2009-03-17 Hoffmann La Roche [4- (heteroaryl) piperazin-1-yl] - (2,5-substituted phenyl) methanone derivatives as glycine 1 (glyt-1) transporter inhibitors for the treatment of neurological and neuropsychiatric disorders
WO2006077026A1 (en) 2005-01-18 2006-07-27 F.Hoffmann-La Roche Ag 2, 5-disubstituted phenyl methanone derivatives as glycine transporter 1 (glyt-i) inhibitors for the treatment of neurological and neuropsychiatry disorders
RU2007126951A (en) 2005-01-26 2009-03-10 Ф.Хоффманн-Ля Рош Аг (Ch) Phenylmethanone derivatives and their use as glycine carrier inhibitors 1
CA2596636C (en) 2005-02-07 2016-04-12 F. Hoffmann-La Roche Ag Heterocyclyl substituted phenyl methanones as inhibitors of the glycine transporter 1
ES2520015T3 (en) 2005-04-08 2014-11-11 Pfizer Products Inc. [3.1.0] Bicyclic heteroaryl amides as type 1 glycine transport inhibitors
WO2009010479A2 (en) * 2007-07-13 2009-01-22 Euroscreen S.A. Heterocyclic methylene piperidine derivatives and their use
AU2009322420A1 (en) * 2008-12-04 2011-06-23 Sanofi Novel polymorphic forms of an azabicyclo-trifluoromethyl benzamide derivative
CN102766080B (en) * 2011-05-06 2015-09-23 上海医药工业研究院 One class pyrrolidin derivatives, its preparation method and application

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3714159A (en) * 1971-03-30 1973-01-30 Janssen Pharmaceutica Nv 2,2-diaryl-4-(4'-aryl-4'-hydroxy-piper-idino)-butyramides
US4695575A (en) * 1984-11-13 1987-09-22 Janssen Pharmaceutica, N.V. 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines
GB8515934D0 (en) * 1985-06-24 1985-07-24 Janssen Pharmaceutica Nv (4-piperidinomethyl and-hetero)purines
CA1332236C (en) * 1985-10-11 1994-10-04 Lourens Wals –,-–-diaryl-4-aryl-4-hydroxy-1-piperidinebutanamide, n-oxides
AU737095B2 (en) * 1996-05-31 2001-08-09 Nps Pharmaceuticals, Inc. Pharmaceutical for treating of neurological and neuropsychiatric disorders

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003513063A (en) * 1999-11-01 2003-04-08 エヌピーエス アレリックス コーポレーション Diaryl-enines
JP2006516239A (en) * 2002-05-31 2006-06-29 ユーロ−セルティーク エス．エイ． Triazaspiro compounds useful for treating or preventing pain
JP2011021021A (en) * 2002-05-31 2011-02-03 Euro-Celtique Sa Triazaspiro compound useful for treating or preventing pain
JP4658595B2 (en) * 2002-05-31 2011-03-23 ユーロ−セルティーク エス．エイ． Triazaspiro compounds useful for treating or preventing pain
JP2014520799A (en) * 2011-06-28 2014-08-25 ビボゾーン インコーポレイテッド Combinations of active substances that induce the synergistic effect of multiple targeting and their uses

Also Published As

Publication number Publication date
HUP0101281A2 (en) 2001-09-28
CA2322136A1 (en) 1999-09-10
SK13092000A3 (en) 2001-03-12
BR9907953A (en) 2000-10-24
HRP20000524A2 (en) 2001-02-28
WO1999045011A1 (en) 1999-09-10
PL342818A1 (en) 2001-07-02
BG104686A (en) 2001-04-30
AU3254499A (en) 1999-09-20
IL138227A0 (en) 2001-10-31
KR20010032967A (en) 2001-04-25
TR200002570T2 (en) 2000-12-21
EE200000483A (en) 2002-02-15
EP1058684A1 (en) 2000-12-13
NO20004432D0 (en) 2000-09-05
CN1291984A (en) 2001-04-18
HUP0101281A3 (en) 2001-11-28
NO20004432L (en) 2000-11-02
WO1999045011A8 (en) 1999-10-14

Similar Documents

Publication Publication Date Title
JP2002505332A (en) Glycine transport inhibitor
JP2002505277A (en) Glycine transport inhibitor
EP2643299B1 (en) Bipyridine sulfonamide derivatives for the treatment of neurodegenerative diseases or conditions
JP2000513717A (en) Carboline derivative
JP6285610B2 (en) Azetidinyloxyphenylpyrrolidine compound
JP2022508657A (en) Amino acid compounds and their usage
KR101021042B1 (en) Pharmaceutical compositions comprising sulfonylaminocarboxylic acid N-arylamides as guanylate cyclase activators
JP3032274B2 (en) Novel pyridone derivatives, their production and intermediates, their use as pharmaceuticals and compositions containing them
TWI659022B (en) Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors
JP6364545B2 (en) Crystalline (2S) -3-[(3S, 4S) -3-[(1R) -1-hydroxyethyl] -4- (4-methoxy-3-{[1- (5-methylpyridin-2-yl) ) Azetidin-3-yl] oxy} phenyl) -3-methylpyrrolidin-1-yl] -3-oxopropane-1,2-diol
RU2296757C2 (en) Derivatives of quinazoline
CA3082724C (en) Substituted azacycles as muscarinic m1 receptor positive allosteric modulators
MXPA00008692A (en) Glycine transport inhibitors
CZ20003146A3 (en) Inhibitors of glycine transfer
MXPA00008690A (en) Glycine transport inhibitors
CZ20003147A3 (en) Glycine transfer inhibitors
NZ751050B2 (en) Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors
JPH04270279A (en) Isomer of 1-azabicyclo (2.2.2) octo-3-yl- 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- 5-nitropyridine-3-carboxylate

Legal Events

Date Code Title Description
A300 Application deemed to be withdrawn because no request for examination was validly filed

Free format text: JAPANESE INTERMEDIATE CODE: A300

Effective date: 20060509