SK7232003A3 - Benzodiazepine derivatives as GABA A receptor modulators - Google Patents

Benzodiazepine derivatives as GABA A receptor modulators Download PDF

Info

Publication number: SK7232003A3
Authority: SK; Slovakia
Prior art keywords: benzodiazepine; triazolo; imidazo; ethyl; carboxylate
Prior art date: 2000-11-16

Application number

SK723-2003A

Other languages

English (en)

Slovak (sk)

Inventor

Raffaello Masciadri

Andrew William Thomas

Juergen Wichmann

Original Assignee

Hoffmann La Roche

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.)

2000-11-16

Filing date

2001-11-08

Publication date

2004-03-02

2001-11-08 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

2004-03-02 Publication of SK7232003A3 publication Critical patent/SK7232003A3/sk

Links

102000004300 GABA-A Receptors Human genes 0.000 title description 16
108090000839 GABA-A Receptors Proteins 0.000 title description 16
229940053197 benzodiazepine derivative antiepileptics Drugs 0.000 title description 2
125000003310 benzodiazepinyl group Chemical class N1N=C(C=CC2=C1C=CC=C2)* 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 145
-1 -SO2CH3 Chemical group 0.000 claims abstract description 113
BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 claims abstract description 22
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 21
239000001257 hydrogen Substances 0.000 claims abstract description 21
150000003839 salts Chemical class 0.000 claims abstract description 18
125000000217 alkyl group Chemical group 0.000 claims abstract description 17
229910052736 halogen Inorganic materials 0.000 claims abstract description 15
150000002367 halogens Chemical class 0.000 claims abstract description 14
229960003692 gamma aminobutyric acid Drugs 0.000 claims abstract description 12
239000002253 acid Substances 0.000 claims abstract description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 9
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 9
201000010099 disease Diseases 0.000 claims abstract description 7
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 7
125000001424 substituent group Chemical group 0.000 claims abstract description 7
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 6
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 6
125000001766 1,2,4-oxadiazol-3-yl group Chemical group [H]C1=NC(*)=NO1 0.000 claims abstract description 4
125000004505 1,2,4-oxadiazol-5-yl group Chemical group O1N=CN=C1* 0.000 claims abstract description 4
125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 4
125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 3
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 3
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 101
NZTCFMPWFGWRBN-UHFFFAOYSA-N 3H-[1,2,4]triazolo[4,3-d][1,4]benzodiazepine-10-carboxylic acid Chemical compound N1=NCN2C=CN=C3C(=C21)C=C(C=C3)C(=O)O NZTCFMPWFGWRBN-UHFFFAOYSA-N 0.000 claims description 56
238000000034 method Methods 0.000 claims description 33
NKWDDGCMDWGDLU-UHFFFAOYSA-N 3H-[1,2,4]triazolo[4,3-d][1,4]benzodiazepine Chemical compound N1=NCN2C=CN=C3C(=C21)C=CC=C3 NKWDDGCMDWGDLU-UHFFFAOYSA-N 0.000 claims description 20
GUJAGMICFDYKNR-UHFFFAOYSA-N 1,4-benzodiazepine Chemical compound N1C=CN=CC2=CC=CC=C12 GUJAGMICFDYKNR-UHFFFAOYSA-N 0.000 claims description 15
SFPHNARDXIEZPB-UHFFFAOYSA-N C1=NNN2C=CN=C3C(=C21)C=C(C=C3)C(=O)O Chemical compound C1=NNN2C=CN=C3C(=C21)C=C(C=C3)C(=O)O SFPHNARDXIEZPB-UHFFFAOYSA-N 0.000 claims description 13
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238000002360 preparation method Methods 0.000 claims description 11
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125000006302 indol-3-yl methyl group Chemical group [H]N1C([H])=C(C2=C([H])C([H])=C([H])C([H])=C12)C([H])([H])* 0.000 claims 1
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229930006000 Sucrose Natural products 0.000 description 1
240000008042 Zea mays Species 0.000 description 1
235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
235000002017 Zea mays subsp mays Nutrition 0.000 description 1
150000001242 acetic acid derivatives Chemical class 0.000 description 1
ZMQBBPRAZLACCW-UHFFFAOYSA-N acetic acid;dichloromethane Chemical compound ClCCl.CC(O)=O ZMQBBPRAZLACCW-UHFFFAOYSA-N 0.000 description 1
OFLXLNCGODUUOT-UHFFFAOYSA-N acetohydrazide Chemical compound C\C(O)=N\N OFLXLNCGODUUOT-UHFFFAOYSA-N 0.000 description 1
238000005054 agglomeration Methods 0.000 description 1
230000002776 aggregation Effects 0.000 description 1
239000000556 agonist Substances 0.000 description 1
150000001298 alcohols Chemical class 0.000 description 1
229910000147 aluminium phosphate Inorganic materials 0.000 description 1
125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
239000003963 antioxidant agent Substances 0.000 description 1
230000000949 anxiolytic effect Effects 0.000 description 1
239000007864 aqueous solution Substances 0.000 description 1
239000012131 assay buffer Substances 0.000 description 1
239000000759 benzodiazepine receptor stimulating agent Substances 0.000 description 1
150000001557 benzodiazepines Chemical class 0.000 description 1
QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 1
KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
239000007963 capsule composition Substances 0.000 description 1
239000003054 catalyst Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
229910052801 chlorine Inorganic materials 0.000 description 1
150000001860 citric acid derivatives Chemical class 0.000 description 1
239000003086 colorant Substances 0.000 description 1
230000002920 convulsive effect Effects 0.000 description 1
235000005822 corn Nutrition 0.000 description 1
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 1
125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
AAOVKJBEBIDNHE-UHFFFAOYSA-N diazepam Chemical compound N=1CC(=O)N(C)C2=CC=C(Cl)C=C2C=1C1=CC=CC=C1 AAOVKJBEBIDNHE-UHFFFAOYSA-N 0.000 description 1
229960003529 diazepam Drugs 0.000 description 1
ZGLDQGIONSGJCN-UHFFFAOYSA-N diazepin-5-one Chemical compound O=C1C=CN=NC=C1 ZGLDQGIONSGJCN-UHFFFAOYSA-N 0.000 description 1
238000010790 dilution Methods 0.000 description 1
239000012895 dilution Substances 0.000 description 1
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238000006073 displacement reaction Methods 0.000 description 1
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238000001035 drying Methods 0.000 description 1
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239000000839 emulsion Substances 0.000 description 1
PUSKHXMZPOMNTQ-UHFFFAOYSA-N ethyl 2,1,3-benzoselenadiazole-5-carboxylate Chemical compound CCOC(=O)C1=CC=C2N=[Se]=NC2=C1 PUSKHXMZPOMNTQ-UHFFFAOYSA-N 0.000 description 1
KLMCGBQPWCZXOH-UHFFFAOYSA-N ethyl 5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-8-propan-2-yl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(C=C2C2=O)C(C)C)C=1CN2CC1=CC=C(OC)C=C1OC KLMCGBQPWCZXOH-UHFFFAOYSA-N 0.000 description 1
NCJFITZMCOZJJG-UHFFFAOYSA-N ethyl 5-[(2,4-dimethoxyphenyl)methyl]-8-methoxy-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(OC)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC NCJFITZMCOZJJG-UHFFFAOYSA-N 0.000 description 1
YNNJJFCTTLDJPE-UHFFFAOYSA-N ethyl 5-[(2,4-dimethoxyphenyl)methyl]-8-methyl-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(C)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC YNNJJFCTTLDJPE-UHFFFAOYSA-N 0.000 description 1
RRUMLROPBAZIDM-UHFFFAOYSA-N ethyl 6,8-dibromo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Br)C2=CC(Br)=CC=C2N2C=NC(C(=O)OCC)=C21 RRUMLROPBAZIDM-UHFFFAOYSA-N 0.000 description 1
JGYPIGSWFPYDMC-UHFFFAOYSA-N ethyl 6-chloro-8-methoxy-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Cl)C2=CC(OC)=CC=C2N2C=NC(C(=O)OCC)=C21 JGYPIGSWFPYDMC-UHFFFAOYSA-N 0.000 description 1
BDXRIFYLHNNJNV-UHFFFAOYSA-N ethyl 6-chloro-8-methyl-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound C1N=C(Cl)C2=CC(C)=CC=C2N2C=NC(C(=O)OCC)=C21 BDXRIFYLHNNJNV-UHFFFAOYSA-N 0.000 description 1
HTXJCRJDWIIMRE-UHFFFAOYSA-N ethyl 8-[tert-butyl(diphenyl)silyl]oxy-5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(O[Si](C=3C=CC=CC=3)(C=3C=CC=CC=3)C(C)(C)C)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC HTXJCRJDWIIMRE-UHFFFAOYSA-N 0.000 description 1
LYUSPSRNFOTMMP-UHFFFAOYSA-N ethyl 8-[tert-butyl(diphenyl)silyl]oxy-6-chloro-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=3)C=1CN=C(Cl)C2=CC=3O[Si](C(C)(C)C)(C=1C=CC=CC=1)C1=CC=CC=C1 LYUSPSRNFOTMMP-UHFFFAOYSA-N 0.000 description 1
MDMOGZSWJAFOBB-UHFFFAOYSA-N ethyl 8-bromo-5-[(2,4-dimethoxyphenyl)methyl]-6-oxo-4h-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate Chemical compound CCOC(=O)C=1N=CN(C2=CC=C(Br)C=C2C2=O)C=1CN2CC1=CC=C(OC)C=C1OC MDMOGZSWJAFOBB-UHFFFAOYSA-N 0.000 description 1
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238000003818 flash chromatography Methods 0.000 description 1
229960004381 flumazenil Drugs 0.000 description 1
239000011737 fluorine Substances 0.000 description 1
229910052731 fluorine Inorganic materials 0.000 description 1
239000011888 foil Substances 0.000 description 1
235000003599 food sweetener Nutrition 0.000 description 1
235000019253 formic acid Nutrition 0.000 description 1
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230000006870 function Effects 0.000 description 1
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239000011521 glass Substances 0.000 description 1
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150000003840 hydrochlorides Chemical class 0.000 description 1
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230000002401 inhibitory effect Effects 0.000 description 1
239000008011 inorganic excipient Substances 0.000 description 1
229940125425 inverse agonist Drugs 0.000 description 1
229960004903 invert sugar Drugs 0.000 description 1
PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
238000002955 isolation Methods 0.000 description 1
125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
230000000670 limiting effect Effects 0.000 description 1
239000000395 magnesium oxide Substances 0.000 description 1
CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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150000002688 maleic acid derivatives Chemical class 0.000 description 1
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239000002184 metal Substances 0.000 description 1
AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
229940098779 methanesulfonic acid Drugs 0.000 description 1
ZSRCGGBALFGALF-VOTSOKGWSA-N methyl (e)-3-[4-(bromomethyl)phenyl]prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC=C(CBr)C=C1 ZSRCGGBALFGALF-VOTSOKGWSA-N 0.000 description 1
235000019813 microcrystalline cellulose Nutrition 0.000 description 1
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229940016286 microcrystalline cellulose Drugs 0.000 description 1
230000003278 mimic effect Effects 0.000 description 1
239000012452 mother liquor Substances 0.000 description 1
KIHLTOMYTLZHOE-UHFFFAOYSA-N n,n-diethyl-2-hydrazinyl-2-oxoacetamide Chemical compound CCN(CC)C(=O)C(=O)NN KIHLTOMYTLZHOE-UHFFFAOYSA-N 0.000 description 1
DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 1
DSWNRHCOGVRDOE-UHFFFAOYSA-N n,n-dimethylmethanimidamide Chemical compound CN(C)C=N DSWNRHCOGVRDOE-UHFFFAOYSA-N 0.000 description 1
125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
239000002858 neurotransmitter agent Substances 0.000 description 1
150000002823 nitrates Chemical class 0.000 description 1
229910017604 nitric acid Inorganic materials 0.000 description 1
230000009871 nonspecific binding Effects 0.000 description 1
QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
239000003921 oil Substances 0.000 description 1
235000019198 oils Nutrition 0.000 description 1
239000008012 organic excipient Substances 0.000 description 1
230000003204 osmotic effect Effects 0.000 description 1
125000004430 oxygen atom Chemical group O* 0.000 description 1
XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 1
229920000642 polymer Polymers 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
239000003755 preservative agent Substances 0.000 description 1
BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
238000000746 purification Methods 0.000 description 1
238000003653 radioligand binding assay Methods 0.000 description 1
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239000000018 receptor agonist Substances 0.000 description 1
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229920006395 saturated elastomer Polymers 0.000 description 1
238000010898 silica gel chromatography Methods 0.000 description 1
239000003381 stabilizer Substances 0.000 description 1
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239000010959 steel Substances 0.000 description 1
150000003890 succinate salts Chemical class 0.000 description 1
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239000003765 sweetening agent Substances 0.000 description 1
239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
MHYGQXWCZAYSLJ-UHFFFAOYSA-N tert-butyl-chloro-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C(C)(C)C)C1=CC=CC=C1 MHYGQXWCZAYSLJ-UHFFFAOYSA-N 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
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239000011534 wash buffer Substances 0.000 description 1
239000000080 wetting agent Substances 0.000 description 1
239000008096 xylene Substances 0.000 description 1

Classifications

- 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
- C07D487/12—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 three hetero rings
- C07D487/14—Ortho-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
General Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Life Sciences & Earth Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
Public Health (AREA)
Medicinal Chemistry (AREA)
Biomedical Technology (AREA)
Neurosurgery (AREA)
Neurology (AREA)
Hospice & Palliative Care (AREA)
Psychiatry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Plural Heterocyclic Compounds (AREA)

SK723-2003A 2000-11-16 2001-11-08 Benzodiazepine derivatives as GABA A receptor modulators SK7232003A3 (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
EP00124332		2000-11-16
PCT/EP2001/012887 WO2002040487A2 (en)	2000-11-16	2001-11-08	Benzodiazepine derivatives as gaba a receptor modulators

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Publication Number	Publication Date
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US (1)	US6743789B2 (es)
EP (1)	EP1337535B1 (es)
JP (1)	JP4088151B2 (es)
KR (1)	KR100504300B1 (es)
CN (1)	CN1191255C (es)
AR (1)	AR031345A1 (es)
AT (1)	ATE268776T1 (es)
AU (2)	AU1700702A (es)
BG (1)	BG107817A (es)
BR (1)	BR0115393A (es)
CA (1)	CA2427576C (es)
CZ (1)	CZ295256B6 (es)
DE (1)	DE60103776T2 (es)
DK (1)	DK1337535T3 (es)
EC (1)	ECSP034607A (es)
ES (1)	ES2220831T3 (es)
GC (1)	GC0000375A (es)
GT (1)	GT200100230A (es)
HR (1)	HRP20030360A2 (es)
HU (1)	HUP0303281A3 (es)
IL (1)	IL155813A0 (es)
JO (1)	JO2359B1 (es)
MA (1)	MA26962A1 (es)
MX (1)	MXPA03004251A (es)
MY (1)	MY141675A (es)
NO (1)	NO324706B1 (es)
NZ (1)	NZ525413A (es)
PA (1)	PA8532401A1 (es)
PE (1)	PE20020583A1 (es)
PL (1)	PL362925A1 (es)
PT (1)	PT1337535E (es)
RU (1)	RU2278865C2 (es)
SI (1)	SI1337535T1 (es)
SK (1)	SK7232003A3 (es)
TR (1)	TR200402073T4 (es)
TW (1)	TWI239333B (es)
UY (1)	UY27026A1 (es)
WO (1)	WO2002040487A2 (es)
YU (1)	YU35603A (es)
ZA (1)	ZA200303435B (es)

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US6686352B2 (en) *	2001-05-18	2004-02-03	Hoffmann-La Roche Inc.	Substituted imidazo [1,5-a] pyrimido [5,4-d] [1] benzazepine derivatives
WO2004113321A1 (ja) *	2003-06-19	2004-12-29	Daiichi Pharmaceutical Co., Ltd.	選択的なアミノ置換基導入法
EP2343073A3 (en)	2003-12-11	2011-10-12	Sepracor Inc.	Combination of a sedative and a neurotransmitter modulator, and methods for improving sleep quality and treating depression
WO2006020959A2 (en)	2004-08-13	2006-02-23	Amgen Inc.	Substituted benzofused heterocycles
CN101039678B (zh) *	2004-10-12	2011-06-15	弗·哈夫曼-拉罗切有限公司	用于治疗认知障碍的咪唑并[1,5-a]三唑并[1,5-d]苯并二氮杂䓬衍生物
EP1805184B1 (en) *	2004-10-20	2013-01-09	F. Hoffmann-La Roche AG	Imidazo-benzodiazepine derivatives
NZ554556A (en) *	2004-10-20	2009-11-27	Hoffmann La Roche	Halogen substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepines
ATE396998T1 (de) *	2004-12-14	2008-06-15	Hoffmann La Roche	Tetrazyklische imidazobenzodiazepine als gaba- rezeptormodulatoren
EP2682481A3 (en) *	2005-08-03	2014-09-17	The Johns-Hopkins University	Methods for characterizing and treating cognitive impairment in aging and disease
US8510055B2 (en)	2005-08-03	2013-08-13	The Johns Hopkins University	Methods for characterizing and treating cognitive impairment in aging and disease
CN101287738B (zh) *	2005-10-11	2011-08-10	弗·哈夫曼-拉罗切有限公司	咪唑并苯并二氮杂*衍生物
US20070112017A1 (en) *	2005-10-31	2007-05-17	Braincells, Inc.	Gaba receptor mediated modulation of neurogenesis
WO2009139916A1 (en) *	2008-05-16	2009-11-19	Synta Pharmaceuticals Corp.	Tricyclic triazole compounds that modulate hsp90 activity
JP5384659B2 (ja) *	2008-11-18	2014-01-08	エフ．ホフマン−ラロシュアーゲー	ジヒドロテトラアザベンゾアズレンのアルキルシクロヘキシルエーテル
RU2507205C2 (ru) *	2008-11-28	2014-02-20	Ф. Хоффманн-Ля Рош Аг	Арилциклогексилэфиры дигидротетраазабензоазуленов для применения в качестве антагонистов рецептора вазопрессина v1a
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Publication number	Publication date
IL155813A0 (en)	2003-12-23
MY141675A (en)	2010-06-15
TWI239333B (en)	2005-09-11
NO20032208L (no)	2003-05-15
ZA200303435B (en)	2004-08-05
MXPA03004251A (es)	2003-09-22
NZ525413A (en)	2005-02-25
TR200402073T4 (tr)	2004-10-21
DE60103776T2 (de)	2005-07-14
UY27026A1 (es)	2002-06-20
PT1337535E (pt)	2004-09-30
SI1337535T1 (en)	2004-10-31
CA2427576A1 (en)	2002-05-23
DE60103776D1 (de)	2004-07-15
CN1474820A (zh)	2004-02-11
US6743789B2 (en)	2004-06-01
WO2002040487A3 (en)	2002-09-26
JP4088151B2 (ja)	2008-05-21
HRP20030360A2 (en)	2005-04-30
ECSP034607A (es)	2003-06-25
AU1700702A (en)	2002-05-27
GT200100230A (es)	2002-07-04
CZ20031597A3 (cs)	2003-11-12
NO20032208D0 (no)	2003-05-15
BR0115393A (pt)	2004-07-06
WO2002040487A2 (en)	2002-05-23
DK1337535T3 (da)	2004-10-25
CN1191255C (zh)	2005-03-02
ES2220831T3 (es)	2004-12-16
US20020103371A1 (en)	2002-08-01
JO2359B1 (en)	2006-12-12
NO324706B1 (no)	2007-12-03
EP1337535B1 (en)	2004-06-09
RU2003116895A (ru)	2005-02-20
BG107817A (bg)	2004-07-30
JP2004517070A (ja)	2004-06-10
HUP0303281A3 (en)	2005-05-30
CZ295256B6 (cs)	2005-06-15
KR20030045192A (ko)	2003-06-09
KR100504300B1 (ko)	2005-07-28
YU35603A (sh)	2006-05-25
AR031345A1 (es)	2003-09-17
HUP0303281A2 (hu)	2004-01-28
HK1062442A1 (en)	2004-11-05
ATE268776T1 (de)	2004-06-15
EP1337535A2 (en)	2003-08-27
GC0000375A (en)	2007-03-31
AU2002217007B2 (en)	2006-11-30
PE20020583A1 (es)	2002-07-06
RU2278865C2 (ru)	2006-06-27
PA8532401A1 (es)	2002-08-26
PL362925A1 (en)	2004-11-02
CA2427576C (en)	2007-11-06
MA26962A1 (fr)	2004-12-20

Publication	Publication Date	Title
SK7232003A3 (en)	2004-03-02	Benzodiazepine derivatives as GABA A receptor modulators
AU2002217007A1 (en)	2002-08-01	Benzodiazepine derivatives as GABA A receptor modulators
EP1399448B1 (en)	2004-12-01	Imidazo 1,5-a] pyrimido 5,4-d] benzazepine derivatives as gaba a receptor modulators
CZ185092A3 (en)	1993-12-15	Imidazodiazepines
RO117698B1 (ro)	2002-06-28	Derivaţi de imidazodiazepină şi procedee de preparare a acestora
ES2399439T3 (es)	2013-04-01	Derivados de imidazo-benzodiazepina
NZ554556A (en)	2009-11-27	Halogen substituted imidazo[1,5-a][1,2,4]triazolo[1,5-d][1,4]benzodiazepines
JP2002536449A (ja)	2002-10-29	Ｇａｂａレセプターに対するリガンドとしてのトリアゾロ−ピリダジン誘導体
KR20010041234A (ko)	2001-05-15	치환된 1,2,4-트리아졸로[3,4-ａ]피리다진

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