CA2249733A1 - Inhibiteurs de l'integrine spirocycle - Google Patents
Inhibiteurs de l'integrine spirocycle Download PDFInfo
- Publication number
- CA2249733A1 CA2249733A1 CA002249733A CA2249733A CA2249733A1 CA 2249733 A1 CA2249733 A1 CA 2249733A1 CA 002249733 A CA002249733 A CA 002249733A CA 2249733 A CA2249733 A CA 2249733A CA 2249733 A1 CA2249733 A1 CA 2249733A1
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- aryl
- aminomethyl
- oxa
- carbonylamino
- 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.)
- Abandoned
Links
- 108010044426 integrins Proteins 0.000 title abstract description 30
- 102000006495 integrins Human genes 0.000 title abstract description 30
- 239000003112 inhibitor Substances 0.000 title description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims abstract description 130
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims abstract description 67
- 235000019260 propionic acid Nutrition 0.000 claims abstract description 64
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims abstract description 64
- 238000000034 method Methods 0.000 claims abstract description 54
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 15
- 208000037803 restenosis Diseases 0.000 claims abstract description 14
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 13
- 206010027476 Metastases Diseases 0.000 claims abstract description 11
- 206010012689 Diabetic retinopathy Diseases 0.000 claims abstract description 10
- 201000011510 cancer Diseases 0.000 claims abstract description 9
- 230000009401 metastasis Effects 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 7
- -1 cyano, amino Chemical group 0.000 claims description 1091
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 436
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 385
- 125000003118 aryl group Chemical group 0.000 claims description 217
- 125000001072 heteroaryl group Chemical group 0.000 claims description 87
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 67
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 65
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 57
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 56
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 48
- 239000000203 mixture Substances 0.000 claims description 47
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 39
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 38
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 34
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- 150000003839 salts Chemical group 0.000 claims description 30
- 125000003342 alkenyl group Chemical group 0.000 claims description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 28
- 125000003545 alkoxy group Chemical group 0.000 claims description 25
- 229910052757 nitrogen Inorganic materials 0.000 claims description 22
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000004429 atom Chemical group 0.000 claims description 19
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 16
- 239000002253 acid Substances 0.000 claims description 16
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 12
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 12
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 11
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 9
- 229910006069 SO3H Inorganic materials 0.000 claims description 8
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 8
- 125000005418 aryl aryl group Chemical group 0.000 claims description 8
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 8
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 8
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 7
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000002837 carbocyclic group Chemical group 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 claims description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 4
- 229910004727 OSO3H Inorganic materials 0.000 claims description 4
- 208000001132 Osteoporosis Diseases 0.000 claims description 4
- 229910018830 PO3H Inorganic materials 0.000 claims description 4
- 229910018828 PO3H2 Inorganic materials 0.000 claims description 4
- 125000000278 alkyl amino alkyl group Chemical group 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
- 125000004104 aryloxy group Chemical group 0.000 claims description 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 claims description 4
- 125000004122 cyclic group Chemical group 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 4
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 4
- 125000005143 heteroarylsulfonyl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
- 125000006574 non-aromatic ring group Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 229930194542 Keto Natural products 0.000 claims description 3
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 claims description 3
- 125000000468 ketone group Chemical group 0.000 claims description 3
- 201000003142 neovascular glaucoma Diseases 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- YIMZCGXFBFESRO-FHGPBERCSA-N (2S)-3-[[8-[(1H-imidazol-2-ylamino)methyl]-7-phenylmethoxycarbonyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]-2-(phenylmethoxycarbonylamino)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NC=CN1 YIMZCGXFBFESRO-FHGPBERCSA-N 0.000 claims description 2
- SZHLTXNLZWMMQI-FOCKTWCOSA-N (2s)-2-(benzenesulfonamido)-3-[[8-[(4,5-dihydro-1h-imidazol-2-ylamino)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 SZHLTXNLZWMMQI-FOCKTWCOSA-N 0.000 claims description 2
- WPXAXCKNHWGIDZ-CBTZJSNWSA-N (2s)-2-(benzenesulfonamido)-3-[[8-[(4,5-dihydro-1h-imidazol-2-ylamino)methyl]-7-phenylmethoxycarbonyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NCCN1 WPXAXCKNHWGIDZ-CBTZJSNWSA-N 0.000 claims description 2
- WYWJHGWUIYPPQB-XGRGOYMPSA-N (2s)-2-[(2,6-dichlorophenyl)sulfonylamino]-3-[[8-[(4,5-dihydro-1h-imidazol-2-ylamino)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1Cl)Cl)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 WYWJHGWUIYPPQB-XGRGOYMPSA-N 0.000 claims description 2
- IXOAWYBDWBVEOT-PAUKFODVSA-N (2s)-2-[(2,6-dichlorophenyl)sulfonylamino]-3-[[8-[(4,5-dihydro-1h-imidazol-2-ylamino)methyl]-7-phenylmethoxycarbonyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]propanoic acid Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1Cl)Cl)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NCCN1 IXOAWYBDWBVEOT-PAUKFODVSA-N 0.000 claims description 2
- IBXMYCNAAVLIET-FTGMFABGSA-N (2s)-3-[[7-phenylmethoxycarbonyl-8-[(pyridin-2-ylamino)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]-2-[(2,4,6-trimethylphenyl)sulfonylamino]propanoic acid Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CN(C(=O)OCC=2C=CC=CC=2)C(CNC=2N=CC=CC=2)C1 IBXMYCNAAVLIET-FTGMFABGSA-N 0.000 claims description 2
- OKIZXTUJHVIZQG-FHGPBERCSA-N (2s)-3-[[8-[(4,5-dihydro-1h-imidazol-2-ylamino)methyl]-7-phenylmethoxycarbonyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]-2-[(2,6-dimethylphenyl)sulfonylamino]propanoic acid Chemical compound CC1=CC=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CN(C(=O)OCC=2C=CC=CC=2)C(CNC=2NCCN=2)C1 OKIZXTUJHVIZQG-FHGPBERCSA-N 0.000 claims description 2
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 2
- ABQBPZCCFCKJPM-FHGPBERCSA-N C(C1=CC=CC=C1)OC(=O)N[C@H](C(=O)O)CNC(=O)C1=NOC2(C1)CN(C(C2)CNC=2NCCN2)C(=O)OCC2=CC=CC=C2 Chemical compound C(C1=CC=CC=C1)OC(=O)N[C@H](C(=O)O)CNC(=O)C1=NOC2(C1)CN(C(C2)CNC=2NCCN2)C(=O)OCC2=CC=CC=C2 ABQBPZCCFCKJPM-FHGPBERCSA-N 0.000 claims description 2
- VMECWTYFQOKYRD-YSJWXEPDSA-N C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NC=CN1 Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NC=CN1 VMECWTYFQOKYRD-YSJWXEPDSA-N 0.000 claims description 2
- AKLDLKLUKAWTQS-VUXSYYGTSA-N C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=CC=CC=N1 Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=CC=CC=N1 AKLDLKLUKAWTQS-VUXSYYGTSA-N 0.000 claims description 2
- YBKRCPSZUZWWEI-WYBLULDQSA-N C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 YBKRCPSZUZWWEI-WYBLULDQSA-N 0.000 claims description 2
- HJHJQIYYTRHNDA-AHRXXFTPSA-N C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=CC=CC=N1 Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=CC=CC=N1 HJHJQIYYTRHNDA-AHRXXFTPSA-N 0.000 claims description 2
- AQPCAEUXJFJVRD-KASSKGRBSA-N C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NC=CN1 Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1)C=1C=CC=CC=1)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NC=CN1 AQPCAEUXJFJVRD-KASSKGRBSA-N 0.000 claims description 2
- DMPSQMFYRUBFGN-XGRGOYMPSA-N C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1Cl)Cl)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NC=CN1 Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1Cl)Cl)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NC=CN1 DMPSQMFYRUBFGN-XGRGOYMPSA-N 0.000 claims description 2
- ZJBCMGXLRDOQRU-PAUKFODVSA-N C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1Cl)Cl)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NC=CN1 Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C(=CC=CC=1Cl)Cl)NC(=O)C(C1)=NOC1(CN1C(=O)OCC=2C=CC=CC=2)CC1CNC1=NC=CN1 ZJBCMGXLRDOQRU-PAUKFODVSA-N 0.000 claims description 2
- UPROCOPQHWKHSX-QOALBKQRSA-N C([C@@H](C(=O)O)NS(=O)(=O)C=1C=C2C=CC=CC2=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 Chemical compound C([C@@H](C(=O)O)NS(=O)(=O)C=1C=C2C=CC=CC2=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 UPROCOPQHWKHSX-QOALBKQRSA-N 0.000 claims description 2
- SNPPRMWJZFCLGO-KRXIBUGQSA-N C1=C(C=CC2=CC=CC=C12)S(=O)(=O)N[C@H](C(=O)O)CNC(=O)C1=NOC2(C1)CN(C(C2)CNC=2NCCN2)C(=O)OCC2=CC=CC=C2 Chemical compound C1=C(C=CC2=CC=CC=C12)S(=O)(=O)N[C@H](C(=O)O)CNC(=O)C1=NOC2(C1)CN(C(C2)CNC=2NCCN2)C(=O)OCC2=CC=CC=C2 SNPPRMWJZFCLGO-KRXIBUGQSA-N 0.000 claims description 2
- JQJWOIRZBCYRDZ-HRZDDSQGSA-N CC1=C(C(=CC(=C1)C)C)S(=O)(=O)N[C@H](C(=O)O)CNC(=O)C1=NOC2(C1)CNC(C2)CNC=2NCCN2 Chemical compound CC1=C(C(=CC(=C1)C)C)S(=O)(=O)N[C@H](C(=O)O)CNC(=O)C1=NOC2(C1)CNC(C2)CNC=2NCCN2 JQJWOIRZBCYRDZ-HRZDDSQGSA-N 0.000 claims description 2
- FFZRIJWHHIJYHI-HRZDDSQGSA-N CC1=CC(C)=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CC(CNC=2NC=CN=2)NC1 Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CC(CNC=2NC=CN=2)NC1 FFZRIJWHHIJYHI-HRZDDSQGSA-N 0.000 claims description 2
- JVLWRELAKZFJMW-WWYNCQBJSA-N CC1=CC(C)=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CN(C(=O)OCC=2C=CC=CC=2)C(CNC=2NCCN=2)C1 Chemical compound CC1=CC(C)=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CN(C(=O)OCC=2C=CC=CC=2)C(CNC=2NCCN=2)C1 JVLWRELAKZFJMW-WWYNCQBJSA-N 0.000 claims description 2
- OEXNDXKHXSFKOG-YSJWXEPDSA-N CC1=CC=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CC(CNC=2NC=CN=2)NC1 Chemical compound CC1=CC=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CC(CNC=2NC=CN=2)NC1 OEXNDXKHXSFKOG-YSJWXEPDSA-N 0.000 claims description 2
- QHOPVCIDGNOSKQ-YSJWXEPDSA-N CC1=CC=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CC(CNC=2NCCN=2)NC1 Chemical compound CC1=CC=CC(C)=C1S(=O)(=O)N[C@H](C(O)=O)CNC(=O)C(C1)=NOC11CC(CNC=2NCCN=2)NC1 QHOPVCIDGNOSKQ-YSJWXEPDSA-N 0.000 claims description 2
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 12
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- 125000000027 (C1-C10) alkoxy group Chemical group 0.000 claims 2
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims 2
- 125000006725 C1-C10 alkenyl group Chemical group 0.000 claims 2
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 2
- 125000005865 C2-C10alkynyl group Chemical group 0.000 claims 2
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- BNHWTPGWPDELPS-HXBUSHRASA-N (2s)-3-[[7-[(6-aminopyridin-2-yl)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3-carbonyl]amino]-2-(benzenesulfonamido)propanoic acid Chemical compound NC1=CC=CC(CN2CC3(CC2)ON=C(C3)C(=O)NC[C@H](NS(=O)(=O)C=2C=CC=CC=2)C(O)=O)=N1 BNHWTPGWPDELPS-HXBUSHRASA-N 0.000 claims 1
- LZSOIKDDPZARNK-YSJWXEPDSA-N C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 Chemical compound C([C@@H](C(=O)O)NC(=O)OCC=1C=CC=CC=1)NC(=O)C(C1)=NOC1(C1)CNC1CNC1=NCCN1 LZSOIKDDPZARNK-YSJWXEPDSA-N 0.000 claims 1
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- 238000010189 synthetic method Methods 0.000 description 1
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- KGGGMMJUCGLDSX-UHFFFAOYSA-N tert-butyl 3-amino-2-[(2,4,6-trimethylphenyl)sulfonylamino]propanoate Chemical compound CC1=CC(C)=C(S(=O)(=O)NC(CN)C(=O)OC(C)(C)C)C(C)=C1 KGGGMMJUCGLDSX-UHFFFAOYSA-N 0.000 description 1
- WZDMEUOIVUZTPB-UHFFFAOYSA-N tert-butyl n-(6-bromopyridin-2-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=CC(Br)=N1 WZDMEUOIVUZTPB-UHFFFAOYSA-N 0.000 description 1
- XBXCNNQPRYLIDE-UHFFFAOYSA-N tert-butylcarbamic acid Chemical compound CC(C)(C)NC(O)=O XBXCNNQPRYLIDE-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 1
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- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical class NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 1
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- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
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- 230000004614 tumor growth Effects 0.000 description 1
- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
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- 238000001262 western blot Methods 0.000 description 1
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- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
Classifications
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
- A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- 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
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- 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
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Rheumatology (AREA)
- Physical Education & Sports Medicine (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Cardiology (AREA)
- Oncology (AREA)
- Endocrinology (AREA)
- Ophthalmology & Optometry (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Cette invention concerne de nouveaux hétérocycles, comprenant l'acide (S)-2-phénylsulfonylamino-3[8-(2-pirydinilaminométhyl)-]-1-oxa-2-azaspiro-[4,5]-dec-2-en-3-yl]carbonylamino]propionique, qui sont utiles en tant qu'antagonistes de l'intégrine .alpha.¿v?.beta.¿3? et les récepteurs apparentés de protéines adhérant à la surface de cellules, l'invention concernant également des compositions pharmaceutiques contenant ces composés, des procédés de préparation de ces composés, ainsi que des méthodes d'utilisation de ces composés, seuls ou combinés à d'autres agents thérapeutiques pour empêcher l'adhésion cellulaire, le traitement de troubles angiogéniques, l'inflammation, la dégradation osseuse, les métastases de cancer, la rétinopathie diabétique, la thrombose, la resténose, la dégénération maculaire et d'autres états pathologiques induits par l'adhésion cellulaire et/ou la migration cellulaire et/ou l'angiogenèse.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1353996P | 1996-03-15 | 1996-03-15 | |
| US60/013,539 | 1996-03-15 | ||
| US64689696A | 1996-05-08 | 1996-05-08 | |
| US08/646,896 | 1996-05-08 | ||
| US08/816,580 US5760029A (en) | 1996-03-15 | 1997-03-14 | Spirocycle integrin inhibitors |
| US08/816,580 | 1997-03-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2249733A1 true CA2249733A1 (fr) | 1997-09-18 |
Family
ID=27359885
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002249733A Abandoned CA2249733A1 (fr) | 1996-03-15 | 1997-03-17 | Inhibiteurs de l'integrine spirocycle |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP0888344A1 (fr) |
| JP (1) | JP2001527513A (fr) |
| AU (1) | AU2421797A (fr) |
| CA (1) | CA2249733A1 (fr) |
| WO (1) | WO1997033887A1 (fr) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1998043962A1 (fr) * | 1997-03-28 | 1998-10-08 | Du Pont Pharmaceuticals Company | Promedicaments heterocycliques inhibiteurs d'integrine |
| ATE542797T1 (de) | 1998-04-09 | 2012-02-15 | Meiji Seika Pharma Co Ltd | Aminopiperidinderivate als integrin alpha v beta 3 antagonisten |
| CA2328414C (fr) * | 1998-05-08 | 2014-04-15 | The Regents Of The University Of California | Procedes de detection et d'inhibition de l'angiogenese |
| US6852318B1 (en) | 1998-05-08 | 2005-02-08 | The Regents Of The University Of California | Methods for detecting and inhibiting angiogenesis |
| US6833373B1 (en) | 1998-12-23 | 2004-12-21 | G.D. Searle & Co. | Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia |
| US6586187B1 (en) | 1999-04-14 | 2003-07-01 | Wyeth | Methods for solid phase combinatorial synthesis of integrin inhibitors |
| DE19921101A1 (de) * | 1999-05-03 | 2000-11-16 | Schering Ag | Neue spirocyclische Verbindungen, Verfahren zu deren Herstellung und deren Verwendung zur Behandlung hyperproliferativer Erkrankungen |
| EP1198231A1 (fr) | 1999-07-21 | 2002-04-24 | American Home Products Corporation | Antagonistes bicycliques selectifs contre l'integrine(alpha)v (beta)3 |
| AU6316900A (en) | 1999-08-05 | 2001-03-05 | Meiji Seika Kaisha Ltd. | Omega-amino-alpha-hydroxycarboxylic acid derivatives having integrin alphavbeta3antagonism |
| DE10130020A1 (de) * | 2001-06-25 | 2003-12-04 | Gruenenthal Gmbh | Substituierte 1-Oxa-2,8-diaza-spiro[4.5]dec-2-en-derivate |
| US7285268B2 (en) | 2002-11-26 | 2007-10-23 | Pdl Biopharma, Inc. | Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis |
| US7276589B2 (en) | 2002-11-26 | 2007-10-02 | Pdl Biopharma, Inc. | Chimeric and humanized antibodies to α5β1 integrin that modulate angiogenesis |
| KR20070009637A (ko) | 2004-03-24 | 2007-01-18 | 피디엘 바이오파르마 인코포레이티드 | 암 세포 증식을 억제하는 항α5β1 항체의 용도 |
| GB0412553D0 (en) * | 2004-06-04 | 2004-07-07 | Univ Aberdeen | Therapeutic agents for the treatment of bone conditions |
| DE102005044814A1 (de) * | 2005-05-19 | 2006-11-23 | Grünenthal GmbH | Substituierte Sprio-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln |
| DE102005023784A1 (de) * | 2005-05-19 | 2006-11-30 | Grünenthal GmbH | Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln |
| DE102005044813A1 (de) | 2005-05-19 | 2007-10-04 | Grünenthal GmbH | Substituierte Spiro-Verbindungen und deren Verwendung zur Herstellung von Arzneimitteln |
| EP1739078A1 (fr) | 2005-05-30 | 2007-01-03 | Jerini AG | Antagonistes du recepteur C5a |
| GB0705400D0 (en) | 2007-03-21 | 2007-05-02 | Univ Aberdeen | Therapeutic compounds andm their use |
| GB0817207D0 (en) | 2008-09-19 | 2008-10-29 | Pimco 2664 Ltd | therapeutic apsac compounds and their use |
| GB0817208D0 (en) | 2008-09-19 | 2008-10-29 | Pimco 2664 Ltd | Therapeutic apsap compounds and their use |
| GB201311361D0 (en) | 2013-06-26 | 2013-08-14 | Pimco 2664 Ltd | Compounds and their therapeutic use |
| JP6480653B2 (ja) * | 2013-09-26 | 2019-03-13 | 株式会社トーキン | 導電性高分子溶液 |
| SI3262028T1 (sl) | 2014-12-17 | 2022-02-28 | Pimco 2664 Limited | N-(4-hidroksi-4-metil-cikloheksil)-4-fenil-benzensulfonamidne in N-(-4hidroksi-4-metil-cikloheksil)-4-(2-piridil)-benzensulfonamidne spojine in njihova terapevtska uporaba |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU646966B2 (en) * | 1991-08-23 | 1994-03-10 | Takeda Chemical Industries Ltd. | 2-piperazinone compounds, their production and use |
| DE69411584T2 (de) * | 1993-11-24 | 1998-12-17 | The Du Pont Merck Pharmaceutical Co., Wilmington, Del. | Isoxazoline derivate anwendbar als fibrinogen rezeptor antagonisten |
| BR9408137A (pt) * | 1993-11-24 | 1997-08-12 | Du Pont Merck Pharma | Composto éster de prodroga método de tratamento composição farmacêutica e método de inibição |
| IL118325A0 (en) * | 1995-05-25 | 1996-10-31 | Pont Merck And Pharmaceutical | Integrin receptor antagonists and pharmaceutical compositions containing them |
-
1997
- 1997-03-17 JP JP53292497A patent/JP2001527513A/ja active Pending
- 1997-03-17 CA CA002249733A patent/CA2249733A1/fr not_active Abandoned
- 1997-03-17 EP EP97919892A patent/EP0888344A1/fr not_active Withdrawn
- 1997-03-17 WO PCT/US1997/004567 patent/WO1997033887A1/fr not_active Ceased
- 1997-03-17 AU AU24217/97A patent/AU2421797A/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| AU2421797A (en) | 1997-10-01 |
| JP2001527513A (ja) | 2001-12-25 |
| EP0888344A1 (fr) | 1999-01-07 |
| WO1997033887A1 (fr) | 1997-09-18 |
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