JP5486602B2 - ベンゾオキサゾール化合物および使用方法 - Google Patents
ベンゾオキサゾール化合物および使用方法 Download PDFInfo
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- JP5486602B2 JP5486602B2 JP2011529267A JP2011529267A JP5486602B2 JP 5486602 B2 JP5486602 B2 JP 5486602B2 JP 2011529267 A JP2011529267 A JP 2011529267A JP 2011529267 A JP2011529267 A JP 2011529267A JP 5486602 B2 JP5486602 B2 JP 5486602B2
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- 238000000034 method Methods 0.000 title claims description 42
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical class C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 162
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 claims description 49
- 229940125833 compound 23 Drugs 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 31
- 238000011282 treatment Methods 0.000 claims description 29
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims description 27
- 206010025135 lupus erythematosus Diseases 0.000 claims description 23
- 239000003814 drug Substances 0.000 claims description 22
- 206010040047 Sepsis Diseases 0.000 claims description 18
- 229940079593 drug Drugs 0.000 claims description 18
- 208000026278 immune system disease Diseases 0.000 claims description 17
- 201000006417 multiple sclerosis Diseases 0.000 claims description 16
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 claims description 12
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- 241000282414 Homo sapiens Species 0.000 claims description 11
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 claims description 10
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims description 9
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 claims description 9
- 229940126142 compound 16 Drugs 0.000 claims description 9
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- 229940125851 compound 27 Drugs 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 claims description 8
- 229940126208 compound 22 Drugs 0.000 claims description 8
- 229940125904 compound 1 Drugs 0.000 claims description 6
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims description 4
- 229940126543 compound 14 Drugs 0.000 claims description 4
- 229940125810 compound 20 Drugs 0.000 claims description 4
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 claims description 4
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims description 3
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims description 3
- IUSARDYWEPUTPN-OZBXUNDUSA-N (2r)-n-[(2s,3r)-4-[[(4s)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxy-1-[3-(1,3-thiazol-2-yl)phenyl]butan-2-yl]-2-methoxypropanamide Chemical compound C([C@H](NC(=O)[C@@H](C)OC)[C@H](O)CN[C@@H]1C2=CC(CC(C)(C)C)=CN=C2OC2(CCC2)C1)C(C=1)=CC=CC=1C1=NC=CS1 IUSARDYWEPUTPN-OZBXUNDUSA-N 0.000 claims description 3
- STBLNCCBQMHSRC-BATDWUPUSA-N (2s)-n-[(3s,4s)-5-acetyl-7-cyano-4-methyl-1-[(2-methylnaphthalen-1-yl)methyl]-2-oxo-3,4-dihydro-1,5-benzodiazepin-3-yl]-2-(methylamino)propanamide Chemical compound O=C1[C@@H](NC(=O)[C@H](C)NC)[C@H](C)N(C(C)=O)C2=CC(C#N)=CC=C2N1CC1=C(C)C=CC2=CC=CC=C12 STBLNCCBQMHSRC-BATDWUPUSA-N 0.000 claims description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 3
- 229940126657 Compound 17 Drugs 0.000 claims description 3
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 claims description 3
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- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 3
- PIDFDZJZLOTZTM-KHVQSSSXSA-N ombitasvir Chemical compound COC(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@H]1C(=O)NC1=CC=C([C@H]2N([C@@H](CC2)C=2C=CC(NC(=O)[C@H]3N(CCC3)C(=O)[C@@H](NC(=O)OC)C(C)C)=CC=2)C=2C=CC(=CC=2)C(C)(C)C)C=C1 PIDFDZJZLOTZTM-KHVQSSSXSA-N 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims 6
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 claims 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims 2
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 claims 2
- NPRYCHLHHVWLQZ-TURQNECASA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynylpurin-8-one Chemical compound NC1=NC=C2N(C(N(C2=N1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C NPRYCHLHHVWLQZ-TURQNECASA-N 0.000 claims 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims 2
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- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims 2
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P25/00—Drugs for disorders of the nervous system
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- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- 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
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- Plural Heterocyclic Compounds (AREA)
Description
式中、R5、R6、またはR7のうちの1つが、式(a):
iおよびjは同一であって、かつ0、1、2、3または4であり、
R1およびR4は同一であって、かつH、CH3およびCH2CH3からなる群から選択され、
R2はCH3であり、R3は(CH2)hN(CH3)2(hが2、3または4である)および(CH2)2O(CH2)2O(CH2)2N(CH3)2からなる群から選択されるか、若しくは、
R2およびR3は同一であって、かつ
(CH2)kCH3(式中、kは0、1または2である)、
(CH2)mN(CH2CH3)2(式中、mは2または3である)、
(CH2)nN(CH3)2(式中、nは2、3または4である)、
(CH2)pO(CH2)qN(CH3)2(式中、pおよびqは同一であって、かつ2または3である)、
式(b):
式(c):
R1−N−R2およびR3−N−R4は同一であって、かつ
式(d):
式(e):
YはCHまたはNであり、
R8はH、CH3、CH(CH3)2、N(CH3)2、CH2OCH3または式(f):
R9はH、CH2OCH3または式(f)の基である)
の基からなる群から選択される。
「治療」、「治療する」、および「治療すること」とは、本明細書に記載される障害または疾患の進行を後退させること、軽減すること、または阻止することをさす。さらに、本明細書において用いられるように、被験体の「治療」とは、免疫学的障害を有するか、かかる免疫学的障害の症状を有するか、あるいはかかる免疫学的障害の危険性がある(または免疫学的障害に罹患しやすい)被験体への、前記障害、前記障害の症状、あるいは前記障害の危険性(または前記障害に対する易罹患性)を治す、癒す、軽減する、緩和する、変化させる、除去する、改善する、好転させる、または作用する目的での、本明細書に記載される本発明の化合物の被験体への適用または投与、あるいは被験体の細胞または組織への前記化合物の適用または投与が含まれる。用語「治療すること」とは、損傷、病変または状態の治療または改善の成功のいずれかの徴候をさし、それには、任意の客観的または主観的パラメーター、例えば、軽減、緩解、症状の減少あるいは損傷、病変または状態を被験体にとってより許容できるものにすること、変性または減退の速度を遅らせること、変性の最終状態の衰弱を抑えること、被験体の身体的または精神的健康を向上させること、あるいは、場合によっては、前記障害のより重症な型または症状の発症を予防することなど、が含まれる。症状の治療または改善は、身体検査、精神鑑定、または当分野で公知の診断検査の結果を含む客観的または主観的パラメーターに基づくことができる。
本明細書に記載される一部の化合物は、1以上の不斉中心を含んでよく、従ってそれらの化合物は、様々な異性体形、例えば立体異性体および/またはジアステレオマーとして存在することができる。キラル中心の周囲の結合の配向が式に明記されていない場合には、その式は、本発明の化合物の構造において起こり得る、不斉炭素に基づく幾何異性体、光学異性体、立体異性体および互変異性体などの考え得るあらゆる異性体を包含すると理解すべきである。
(CH2)kCH3(式中、kは0、1または2である)、
(CH2)mN(CH2CH3)2(式中、mは2または3である)、
本明細書で上述した式(b)の基、および
本明細書で上述した式(c)の基
からなる群から選択される。
式(g):
iおよびjは双方とも1であり、
R1およびR4は同一であって、かつHおよびCH3からなる群から選択され、
R2はCH3であり、R3は(CH2)2N(CH3)2および(CH2)2O(CH2)2O(CH2)2N(CH3)2からなる群から選択されるか、若しくは
R2およびR3は同一であって、かつ
a)(CH2)kCH3(式中、kは0、1または2である)、
b)(CH2)mN(CH2CH3)2(式中、mは2または3である)、
c)本明細書で上述した式(b)の基、および
d)本明細書で上述した式(c)の基
からなる群から選択されるか、又は、
R1−N−R2およびR3−N−R4は同一であって、かつ
式(g)の基、式(h)の基、式(i)の基、式(j)の基、式(k)の基、および式(m)の基からなる群から選択される(全ては本明細書で上述した記載の通りである)。
本明細書に記載される化合物は、一連の反応によって調製することができる。本発明の化合物を調製するための一般的方法を下に示す。実施例を記載するセクションにおいて下にさらに述べるように、ある特定の場合において例として特定の化合物を記載する。下に記述されている場合を除き、以下の方法では、R1、R2、R3、R4、i、およびjは、上の式Iにおいて定義されるものと同一である。
上に示した方法1の反応スキームにおいて、
n、i、およびjは同一であって、かつ0、1、2、3または4であり、
R1aおよびR4aは双方ともRxと同一であり、
R2aおよびR3aは双方ともRyと同一であり、
R1bおよびR4bは同一であり、
R2bおよびR3bは同一であり、
R1aおよびR4aが双方ともHである場合には、R1bおよびR4bは双方ともメチルであり、
R2aおよびR3aが双方ともHである場合には、R2bおよびR3bは双方ともメチルである。
上に示した方法2の反応スキームにおいて、
n、i、およびjは同一であって、かつ0、1、2、3または4であり、
R1aおよびR4aは双方ともRxと同一であり、
R2aおよびR3aは双方ともRyと同一であり、
R1bおよびR4bは同一であり、
R2bおよびR3bは同一であり、
R1aおよびR4aが双方ともHである場合には、R1bおよびR4bは双方ともメチルであり、
R2aおよびR3aが双方ともHである場合には、R2bおよびR3bは双方ともメチルである。
方法3の反応スキームにおいて、
R1およびR4は同一であって、かつHおよびCH3からなる群から選択され、
R2はCH3であり、R3は(CH2)2N(CHs)2および(CH2)2O(CH2)2O(CH2)2N(CH3)2からなる群から選択される。
一実施形態では、本発明は、化合物を含む医薬組成物である。もう1つの実施形態では、前記医薬組成物は医薬上許容される担体をさらに含む。本明細書において用いられる用語「医薬上許容される担体」とは、被験体への治療薬の送達のためのビヒクルとして用いられる、それ自体は治療薬でない、任意の物質をさす。
もう1つの実施形態では、本発明は、被験体において免疫学的障害を予防または治療する方法であり、その方法は、本発明の化合物の治療上有効な量を被験体に投与することを含む。特定の実施形態では、本発明の方法による、免疫学的障害を予防または治療するために用いられる本発明の化合物は、化合物13、化合物16、化合物22、化合物23、化合物26、化合物27、化合物30、化合物34、および化合物35またはその医薬上許容される塩、からなる群から選択される式Iの化合物である。もう1つの実施形態では、前記化合物は、化合物23、化合物26、および化合物30またはその医薬上許容される塩からなる群から選択される。もう1つの実施形態では、前記化合物は、化合物23またはその医薬上許容される塩である。
(化合物40の合成)
(化合物23の合成)
(化合物30の合成)
(化合物51の合成)
(例となる化合物)
下の表1中の以下の類似体が調製された。これらの化合物は、表中に特定される対応するジクロロアルカンおよび側鎖アミンを用いて、化合物23(実施例4)および/または化合物30(実施例5)の調製のための手順に従って調製することができる。これらの化合物は、化合物51(実施例6)の調製のための手順に従っても調製することができる。
化合物1:1H NMR(400MHz,CD3OD)δ 8.14(d,J=8.8Hz,2H)、7.58(d,J=8.8Hz,1H)、7.33(d,J=2.4Hz,1H)、7.16(d,J=8.8Hz,2H)、7.06(dd,J=2.2,8.8Hz,1H)、4.28(m,4H)、3.10(m,4H)、2.68(s,6H)、2.57(s,6H)。
(化合物34の合成)
(インビトロ生物活性)
(A.一次アッセイ)
一次アッセイは、ヒト胚腎臓上皮(HEK)細胞にTLR9をトランスフェクトすることを伴う。より具体的には、pGL3−エンハンサーベクター(Promega Corp.Madison,WI)にクローニングされた、E−セレクチン−1プロモーターに含められた3つのNF−kB結合部位の制御下、HEK293線維芽細胞(ATCC番号 CRP−1573、American Type Culture Collection,Manassas,VA)を、ヒトTLR9をコードするpcDNA3.1D/V5−His−TOPO(登録商標)プラスミド(Invitrogen,Carlsbad,CA)およびホタルルシフェラーゼを用いてトランスフェクトした(Taqポリメラーゼ増幅PCR産物として直接挿入した)。このアッセイで試験された化合物を下の表1に記載する。各々の化合物は、30分細胞に添加された後、ヌクレオチド配列5’−TCG TCG TTT TGT CGT TTT GTC GTT−3’(配列番号1)とともに、合成ホスホロチオエートオリゴヌクレオチドであるオリゴCpG2006(Hartmann et al.,J Immunol 164:1617−24(2000))で刺激した。細胞を、37℃にて一晩インキュベートした。ルシフェラーゼ基質Steady−Glo(登録商標)(Promega)をウェルに添加し、発光を測定してTLR9に駆動される(TLR9−driven)遺伝子活性化の程度を決定した。発光データを用いて各々の試料についてのIC50を算出した。IC50は、化合物の不在下で、言い換えれば完全な刺激を伴って観察される発光の50%まで発光を抑制する化合物の濃度として定義される。このアッセイの結果を下の表2に示す。比較化合物のIC50は、0.16マイクロモルであることが見出された。化合物1のIC50は、0.06マイクロモルであることが見出され、残りの化合物のIC50は、0.04マイクロモル未満であった。
(1)HEK/TLR7活性化アッセイ:一次アッセイと同じ化合物を、以下の違いを伴って同じように試験した。HEK細胞株をトランスフェクトするために使用したプラスミドは、TLR9の代わりにヒトTLR7をコードし、オリゴCpG2006の代わりにR848を用いて細胞を刺激した。このアッセイの結果も表2に記載する。試験した各々の化合物について、上のHEK/TLR9活性化アッセイから得られるIC50は、HEK/TLR7アッセイから得られるIC50よりも有意に低く、TLR7に対するよりもTLR9に対する特異性が大きいことが示される。
(インビボ生物活性:短期CpG刺激)
短期CpG刺激アッセイ:上の実施例9に記載されるHEK/TLR9および脾細胞CpG1668アッセイにおいて効力を有すると特定された化合物を、インビボでの短期CpG刺激アッセイにおいて試験した。マウスに水中の化合物を経口投与し、90分以内に、30μgのオリゴCpG1668の皮下(s.c.)注射を投与した。2時間後、血清を採取し、ELISA分析を用いてIL−6についてアッセイした。このアッセイの結果を下の表3に示す。異なる日付に反復されたアッセイから得られる結果は、コンマで隔てられる複数の数字として示される。
(インビボ生物活性:リンパ節応答)
上の実施例10に記載されるアッセイされた2種類の化合物、化合物23および化合物30は、特に高レベルの抑制を示した。マウスにそれらの2種類の化合物の1種類またはヒドロキシクロロキン(「HCQ」)を、毎日20mg/kgかまたは60mg/kgで2週間経口投与した。インビボ投薬の後、リンパ節を取り出してインビトロで1μg/mlのCpG1668を用いて72時間刺激し、その後上清を取り出してELISAによりIL−6についてアッセイした。このアッセイの結果を図1に示す。投薬のレベルは図中に表示される各々の化合物名の後に示される。
(インビボ生物活性:自発的狼瘡モデル)
(A.MRL/MpJ−faslpr/J 実験1)
この実験では、Jackson Laboratoriesより入手したMRL/MpJ−faslpr/Jマウス(「MRL/lpr」)に、水中20または60mg/kgの化合物23を経口的に投薬した。MRL/lprマウスは、リンパ球死に欠陥を有し、ヒト全身性紅斑性狼瘡(SLE)に見出される抗核抗体を含む自己抗体を自発的に発生させる。投薬は、5週齢に開始して週に5回毎日行った。血液および尿試料を1日目の投薬前に採取し、以降3〜4週毎に採取した。ELISAアッセイを用いて投薬の7週前および7週後の血清抗dsDNAを測定した。マウス抗dsDNA全Ig定性ELISAキット(Alpha Diagnostic International.San Antonio,TX)を用いてアッセイを行った。結果を図2に示す。図2は、この自己抗体への用量設定効果を示し、ビヒクルを投与された動物に対して450nmでの平均光学濃度(Optical Density)(OD450)が統計上有意に抑制された。統計的有意差は投薬10週でなお観察されたが、その後化合物治療群は12週およびそれ以降に、経口によってdH2Oを投薬されたビヒクル治療動物に一層類似するようになった。全体的な様子または体重測定で判断して、投薬量に関連する毒性の根拠は見られなかった。
このSLE実験において、投薬群は、下の表4に記載される通りであった。化合物23の2種類の用量レベルをHCQおよびシクロホスファミド(Cytoxan(登録商標))と比較した。HCQおよびシクロホスファミドは、それぞれ、皮膚狼瘡および全身性狼瘡の治療に現在使用されている。シクロホスファミドは、一貫した血清抗dsDNAレベルの抑制を示した。この差は、ANOVAによりビヒクルに対して試験した場合に8週および12週の投薬時点で統計上有意であった。12週間の投薬前および投薬後の個々の動物血清について450ナノメートルでの光学濃度(OD450)のELISAアッセイから得られる結果を図4に示す。血清は、PBS中1:600希釈でアッセイした。(マウス抗dsDNA全Ig定性ELISAキット、Alpha Diagnostic International)。投薬は、経口(p.o.)かまたは腹腔内(i.p.)投与のいずれかにより行った。このアッセイから得られる個々のデータポイントを図4に図示する。図4は、12週で、ビヒクルと高用量の化合物23との間に平均dsDNAレベルの統計上の有意差があったことも示す。
(インビボ生物活性:NZBWF1/J自発的狼瘡モデル)
化合物23および化合物30のインビボ研究を、NZBWF1/Jマウスモデルで行った。マウスはJackson Laboratoriesより入手し、12の群に分け、水中の化合物を5ヶ月齢で開始し週に5日、経口的に投薬した。投薬の詳細を下の表5に提供する。
(インビボ生物活性:実験的自己免疫性脳炎 多発性硬化症モデル)
実験的自己免疫性脳炎(EAE)は、ヒト多発性硬化症を模倣する、マウスにおいて誘導される自己免疫であり、自己免疫には、自己抗体、および中枢神経系抗原に対して標的とされる細胞応答が含まれる。EAEを誘導するため、8頭の雄C57BL/6Jマウス(Jackson Laboratories)の群を、完全フロイントアジュバント(CFA)中200μg/マウスの用量で、アミノ酸配列MEVGWYRSPFSRVVHLYRNGK(配列番号4)とともに、合成ペプチドMOGp35−55(Becher et al.J.Clin.Invest.112:1186−1191(2003))で0日目に皮下に免疫化した。同時に、動物に百日咳毒素を腹腔内に30ng/マウスで投与した。2日目に、百日咳注射を繰り返した。7日目に、マウスを不完全フロイントアジュバント中200μg/マウスのMOGp35−55で追加免疫した。9日目から、20mg/kgまたは60mg/kgの水中の化合物23を用いて経口胃管栄養法により毎日投与した。尾および四肢の麻痺の程度および位置を観察することにより症状をスコア化し、各々の8頭のマウス群の平均スコアを示す。
(インビボ生物活性:コラーゲン誘発関節炎)
II型コラーゲン誘発関節炎モデルを、関節炎の治療のために化合物2をインビボで評価するために使用した。このモデルでは、関節炎を、完全フロイントアジュバントを用いて雄DBA/1J(Jackson Labs)マウスにおいて誘導した。最初のプライミング/免疫化用量の300μgの、等容積の完全フロイントアジュバントで乳化したウシII型コラーゲンを、尾の付け根から少なくとも5mmの皮下に(s.c.)注射する。
(インビボ生物活性:盲腸結紮穿刺術)
盲腸結紮穿刺(CLP)モデルは、腹部切開を行って盲腸(消化管の容易に単離される部分)を露出させ、盲腸の一部分を結紮する外科手技を伴う。次に、盲腸を穿刺し、少量の腸内容物を押し出す。切開を閉じ、動物に蘇生のための生理食塩水および抗生物質を与える。敗血症は、主に押し出された腸内容物からの殺菌に起因して発症し、疾患の発症は、盲腸の穿刺のサイズおよび数に依存する迅速性および重篤度とともに起こる。
ケタミン、キシラジンおよびアセプロマジンの組合せの腹腔内投与によりマウスにおいて麻酔を誘導する。動物の腹部領域は短く刈ってよく、体温を測定するためのトランスポンダを皮下に埋め込む。この手順は無菌生存手術に適した領域で行う。この手順の間中、動物は加温パッドの上に置く。腹部領域は、ポビドン/ヨードおよびアルコールで最低3回交互に拭いて準備する。
化合物は、手術の約1時間後に抗生物質注射の時に投与されるが、このタイミングは変動する可能性がある。化合物は、候補化合物の薬物動態特性に応じて1日に2回投与される。試験化合物の投与は、投与のために確立されたガイドラインに従って、次の経路:尾静脈からの経口、腹腔内、皮下、または静脈注射のいずれかによって行われる。
Claims (23)
- 式(I):
が(a)である場合、R5およびR7は双方ともHであり、R7が(a)である場合、R
5およびR6は双方ともHであり、
iおよびjは同一であって、かつ0、1、2、3または4であり、
R1およびR4は同一であって、かつH、CH3およびCH2CH3からなる群から選
択され、
R2はCH3であり、R3は(CH2)hN(CH3)2(式中、hが2、3または4
である)および(CH2)2O(CH2)2O(CH2)2N(CH3)2からなる群か
ら選択されるか、若しくは、
R2およびR3は同一であって、かつ
(CH2)kCH3(式中、kは0、1または2である)、
(CH2)mN(CH2CH3)2(式中、mは2または3である)、
(CH2)nN(CH3)2(式中、nは2、3または4である)、
(CH2)pO(CH2)qN(CH3)2(式中、pおよびqは同一であって、かつ
2または3である)、
式(b):
式(c):
ある)の基からなる群から選択されるか、又は、
R1−N−R2およびR3−N−R4は同一であって、かつ
式(d):
式(e):
YはCHまたはNであり、
R8はH、CH3、CH(CH3)2、N(CH3)2、CH2OCH3または式(f
):
R9はH、CH2OCH3、または式(f)の基である)
の基からなる群から選択される)
の化合物またはその医薬上許容される塩。 - iおよびjが双方とも1である請求項1に記載の化合物。
- R2およびR3が同一であって、かつ
(CH2)kCH3(式中、kは0、1または2である)、
(CH2)mN(CH2CH3)2(式中、mは2または3である)、
式(b)の基、および
式(c)の基からなる群から選択される請求項1に記載の化合物。 - iおよびjが双方とも1であり、
R1およびR4が同一であって、かつHおよびCH3からなる群から選択され、
R2がCH3であり、R3が(CH2)2N(CH3)2および(CH2)2O(CH
2)2O(CH2)2N(CH3)2からなる群から選択されるか、若しくは
R2およびR3が、
a)(CH2)kCH3(式中、kは0、1または2である)、
b)(CH2)mN(CH2CH3)2(式中、mは2または3である)、
c)式(b)の基、および
d)式(c)の基からなる群から選択されるか、または
R1−N−R2およびR3−N−R4が同一であって、かつ式(g)の基、式(h)の
基、式(i)の基、式(j)の基、式(k)の基および式(m)の基からなる群から選択
される請求項1に記載の化合物。 - R5が式(a)の基であり、R6およびR7が各々Hである請求項1に記載の化合物。
- 本化合物が、
またはその医薬上許容される塩からなる群から選択される請求項1に記載の化合物。 - 式(I):
が(a)である場合、R5およびR7は双方ともHであり、R7が(a)である場合、R
5およびR6は双方ともHであり、
iおよびjは同一であって、かつ0、1、2、3または4であり、
R1およびR4は同一であって、かつH、CH3およびCH2CH3からなる群から選
択され、
R2はCH3であり、R3は(CH2)hN(CH3)2(hが2、3、または4であ
る)および(CH2)2O(CH2)2O(CH2)2N(CH3)2からなる群から選
択されるか、若しくは
R2およびR3は同一であって、かつ
(CH2)kCH3(式中、kは0、1または2である)、
(CH2)mN(CH2CH3)2(式中、mは2または3である)、
(CH2)nN(CH3)2(式中、nは2、3または4である)、
(CH2)pO(CH2)qN(CH3)2(式中、pおよびqは同一であって、かつ
2または3である)、
式(b):
式(c):
)の基からなる群から選択されるか、又は
R1−N−R2およびR3−N−R4は同一であって、かつ
式(d):
式(e):
YはCHまたはNであり、
R8はH、CH3、CH(CH3)2、N(CH3)2、CH2OCH3または式(f
):
R9はH、CH2OCH3または式(f)の基である)
の基からなる群から選択される)
の化合物またはその医薬上許容される塩を含む医薬組成物。 - 前記化合物が、
からなる群から選択される化合物またはその医薬上許容される塩である請求項10に記載
の医薬組成物。 - 前記被験体がヒトである請求項14に記載の薬物。
- 前記免疫障害が敗血症である請求項14に記載の薬物。
- 前記免疫障害が、狼瘡、関節リウマチおよび多発性硬化症からなる群から選択される請求項14に記載の薬物。
- 請求項8に記載の化合物を使用して、敗血症、狼瘡、関節リウマチおよび多発性硬化症からなる群から選択される免疫障害を治療するための薬物を製造する方法。
- 前記免疫障害が敗血症である請求項22に記載の方法。
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US10071079B2 (en) | 2016-06-29 | 2018-09-11 | Bristol-Myers Squibb Company | [1,2,4]triazolo[1,5-a]pyridinyl substituted indole compounds |
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US7045539B2 (en) * | 2000-12-22 | 2006-05-16 | Astrazeneca Ab | Therapeutic benzoxazole compounds |
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UA83620C2 (ru) | 2001-12-05 | 2008-08-11 | Уайт | Замещенные бензоксазолы и их аналоги как эстрогенные агенты |
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