HRP20041147A2 - Calcitonin gene related peptide receptor antagonists - Google Patents
Calcitonin gene related peptide receptor antagonistsInfo
- Publication number
- HRP20041147A2 HRP20041147A2 HR20041147A HRP20041147A HRP20041147A2 HR P20041147 A2 HRP20041147 A2 HR P20041147A2 HR 20041147 A HR20041147 A HR 20041147A HR P20041147 A HRP20041147 A HR P20041147A HR P20041147 A2 HRP20041147 A2 HR P20041147A2
- Authority
- HR
- Croatia
- Prior art keywords
- oxo
- dihydro
- quinazolin
- piperidine
- indazol
- Prior art date
Links
- 239000003735 calcitonin gene related peptide receptor antagonist Substances 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims description 351
- -1 morpholino, thiamorpholino Chemical group 0.000 claims description 183
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 97
- 229910052757 nitrogen Inorganic materials 0.000 claims description 73
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 claims description 66
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 56
- 150000004702 methyl esters Chemical class 0.000 claims description 54
- 125000003386 piperidinyl group Chemical group 0.000 claims description 52
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 51
- 125000000623 heterocyclic group Chemical group 0.000 claims description 50
- 108010078311 Calcitonin Gene-Related Peptide Receptors Proteins 0.000 claims description 49
- 230000017531 blood circulation Effects 0.000 claims description 46
- 102000008323 calcitonin gene-related peptide receptor activity proteins Human genes 0.000 claims description 44
- 229910052799 carbon Inorganic materials 0.000 claims description 41
- 150000001721 carbon Chemical group 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 38
- 125000004193 piperazinyl group Chemical group 0.000 claims description 36
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 34
- 241000124008 Mammalia Species 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 31
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 30
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 30
- 125000002755 pyrazolinyl group Chemical group 0.000 claims description 30
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 30
- 125000001422 pyrrolinyl group Chemical group 0.000 claims description 29
- 101000584583 Homo sapiens Receptor activity-modifying protein 1 Proteins 0.000 claims description 28
- 102100030697 Receptor activity-modifying protein 1 Human genes 0.000 claims description 28
- 125000002636 imidazolinyl group Chemical group 0.000 claims description 28
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 28
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 27
- 125000005879 dioxolanyl group Chemical group 0.000 claims description 27
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 26
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 25
- 125000002393 azetidinyl group Chemical group 0.000 claims description 25
- 229910052760 oxygen Inorganic materials 0.000 claims description 24
- 125000004076 pyridyl group Chemical group 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 23
- 125000005842 heteroatom Chemical group 0.000 claims description 23
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 23
- 125000002541 furyl group Chemical group 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 21
- 125000002883 imidazolyl group Chemical group 0.000 claims description 21
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
- 238000012360 testing method Methods 0.000 claims description 21
- 125000006661 (C4-C6) heterocyclic group Chemical group 0.000 claims description 19
- 208000019695 Migraine disease Diseases 0.000 claims description 19
- 206010027599 migraine Diseases 0.000 claims description 19
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 18
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 238000001727 in vivo Methods 0.000 claims description 18
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 17
- 125000005843 halogen group Chemical group 0.000 claims description 17
- 230000002460 anti-migrenic effect Effects 0.000 claims description 16
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 14
- MNYOCYLUYZYUHD-UHFFFAOYSA-N 3-(7-methyl-1h-indazol-5-yl)-2-[[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carbonyl]amino]propanoic acid Chemical compound C1C2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)NC(C(O)=O)CC(C=C1C)=CC2=C1NN=C2 MNYOCYLUYZYUHD-UHFFFAOYSA-N 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000001544 thienyl group Chemical group 0.000 claims description 14
- 239000000018 receptor agonist Substances 0.000 claims description 13
- 229940044601 receptor agonist Drugs 0.000 claims description 13
- VIXLINDIDYPMME-UHFFFAOYSA-N 3-(7-chloro-1h-indazol-5-yl)-2-[[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carbonyl]amino]propanoic acid Chemical compound C1C2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)NC(C(=O)O)CC1=CC(Cl)=C(NN=C2)C2=C1 VIXLINDIDYPMME-UHFFFAOYSA-N 0.000 claims description 12
- JECMGRSNYXYSNO-UHFFFAOYSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1N1C(=O)NC2=CC=CC=C2C1 JECMGRSNYXYSNO-UHFFFAOYSA-N 0.000 claims description 12
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 12
- JHKXJGMNFAJQSK-UHFFFAOYSA-N 3-(7-ethyl-1h-indazol-5-yl)-2-[[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carbonyl]amino]propanoic acid Chemical compound C1C2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)NC(C(O)=O)CC(C=C1CC)=CC2=C1NN=C2 JHKXJGMNFAJQSK-UHFFFAOYSA-N 0.000 claims description 11
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 11
- 125000003367 polycyclic group Chemical group 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 125000000335 thiazolyl group Chemical group 0.000 claims description 11
- 230000009261 transgenic effect Effects 0.000 claims description 11
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 10
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 10
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 10
- 125000004306 triazinyl group Chemical group 0.000 claims description 10
- 210000001367 artery Anatomy 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 9
- 230000002093 peripheral effect Effects 0.000 claims description 9
- OYMBDCCMCHDGNO-UHFFFAOYSA-N 4-(2-oxo-3h-benzimidazol-1-yl)piperidine-1-carboxylic acid Chemical compound C1CN(C(=O)O)CCC1N1C(=O)NC2=CC=CC=C21 OYMBDCCMCHDGNO-UHFFFAOYSA-N 0.000 claims description 8
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 8
- 125000002785 azepinyl group Chemical group 0.000 claims description 8
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 claims description 8
- 125000002576 diazepinyl group Chemical group N1N=C(C=CC=C1)* 0.000 claims description 8
- 125000005435 dihydrobenzoxazolyl group Chemical group O1C(NC2=C1C=CC=C2)* 0.000 claims description 8
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 125000001715 oxadiazolyl group Chemical group 0.000 claims description 8
- 125000002971 oxazolyl group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 claims description 8
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 claims description 8
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 8
- 125000005958 tetrahydrothienyl group Chemical group 0.000 claims description 8
- 125000001113 thiadiazolyl group Chemical group 0.000 claims description 8
- 125000001425 triazolyl group Chemical group 0.000 claims description 8
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 7
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 7
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 239000000460 chlorine Chemical class 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical class [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- 125000005434 dihydrobenzoxazinyl group Chemical group O1N(CCC2=C1C=CC=C2)* 0.000 claims description 6
- 125000005059 halophenyl group Chemical group 0.000 claims description 6
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 claims description 6
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 claims description 6
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 5
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 5
- GCFAUZGWPDYAJN-UHFFFAOYSA-N cyclohexyl 3-phenylprop-2-enoate Chemical compound C=1C=CC=CC=1C=CC(=O)OC1CCCCC1 GCFAUZGWPDYAJN-UHFFFAOYSA-N 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- YWBFPKPWMSWWEA-UHFFFAOYSA-O triazolopyrimidine Chemical compound BrC1=CC=CC(C=2N=C3N=CN[N+]3=C(NCC=3C=CN=CC=3)C=2)=C1 YWBFPKPWMSWWEA-UHFFFAOYSA-O 0.000 claims description 5
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 4
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical class ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 4
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- FSTHECKIDGHTCR-UHFFFAOYSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)-n-[1-oxo-3-(2-oxo-4-phenylmethoxypyridin-1-yl)-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]piperidine-1-carboxamide Chemical compound C1CC(N2C(NC3=CC=CC=C3C2)=O)CCN1C(=O)NC(C(=O)N1CCC(CC1)N1CCCCC1)CN(C(C=1)=O)C=CC=1OCC1=CC=CC=C1 FSTHECKIDGHTCR-UHFFFAOYSA-N 0.000 claims description 3
- ZYODBVFKHMXORT-UHFFFAOYSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)-n-[1-oxo-3-(6-phenylmethoxypyridin-3-yl)-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]piperidine-1-carboxamide Chemical compound C1CC(N2C(NC3=CC=CC=C3C2)=O)CCN1C(=O)NC(C(=O)N1CCC(CC1)N1CCCCC1)CC(C=N1)=CC=C1OCC1=CC=CC=C1 ZYODBVFKHMXORT-UHFFFAOYSA-N 0.000 claims description 3
- 125000003342 alkenyl group Chemical group 0.000 claims description 3
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 claims description 3
- UVTONKGVDVAMRC-UHFFFAOYSA-N n-[3-(4-hydroxypiperidin-1-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide Chemical compound C1CC(O)CCN1CC(C(=O)N1CCC(CC1)N1CCCCC1)NC(=O)N1CCC(N2C(NC3=CC=CC=C3C2)=O)CC1 UVTONKGVDVAMRC-UHFFFAOYSA-N 0.000 claims description 3
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 3
- FWYCCWWQAGZHGM-NDEPHWFRSA-N (2s)-2-(1h-imidazol-5-ylmethylamino)-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound N([C@@H](CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N1CCC(CC1)N1CCCCC1)CC1=CN=CN1 FWYCCWWQAGZHGM-NDEPHWFRSA-N 0.000 claims description 2
- DDSWPUURUBKZEZ-LJAQVGFWSA-N (2s)-2-(5-chloro-2-nitroanilino)-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound [O-][N+](=O)C1=CC=C(Cl)C=C1N[C@H](C(=O)N1CCC(CC1)N1CCCCC1)CC(=O)N1CCC(N2C(NC3=CC=CC=C3C2)=O)CC1 DDSWPUURUBKZEZ-LJAQVGFWSA-N 0.000 claims description 2
- LGPAPWQZBAAEIC-VWLOTQADSA-N (2s)-2-[(2-chloro-7h-purin-6-yl)amino]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)NC=1N=C(N=C2N=CNC2=1)Cl)N(CC1)CCC1N1CCCCC1 LGPAPWQZBAAEIC-VWLOTQADSA-N 0.000 claims description 2
- CSTQCURFLGWKDV-SANMLTNESA-N (2s)-2-[(4,5-diamino-6-methylpyrimidin-2-yl)amino]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound NC1=C(N)C(C)=NC(N[C@@H](CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3C2)=O)C(=O)N2CCC(CC2)N2CCCCC2)=N1 CSTQCURFLGWKDV-SANMLTNESA-N 0.000 claims description 2
- UFUJOVPUOUSFQQ-SANMLTNESA-N (2s)-2-[(4-amino-6-methyl-5-nitropyrimidin-2-yl)amino]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound NC1=C([N+]([O-])=O)C(C)=NC(N[C@@H](CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3C2)=O)C(=O)N2CCC(CC2)N2CCCCC2)=N1 UFUJOVPUOUSFQQ-SANMLTNESA-N 0.000 claims description 2
- AYLBMSKJSZBJAD-HMNPYRHBSA-N (2s)-2-[(4-hydroxycyclohexyl)amino]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C1CC(O)CCC1N[C@H](C(=O)N1CCC(CC1)N1CCCCC1)CC(=O)N1CCC(N2C(NC3=CC=CC=C3C2)=O)CC1 AYLBMSKJSZBJAD-HMNPYRHBSA-N 0.000 claims description 2
- MBFCRDYWDVDSTF-SANMLTNESA-N (2s)-2-[(7-methyl-2h-triazolo[4,5-d]pyrimidin-5-yl)amino]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound O=C([C@H](CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)NC=1N=C(C=2NN=NC=2N=1)C)N(CC1)CCC1N1CCCCC1 MBFCRDYWDVDSTF-SANMLTNESA-N 0.000 claims description 2
- HBQDMNWZCXPWMC-MHZLTWQESA-N (2s)-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)-2-(pyrimidin-4-ylamino)butane-1,4-dione Chemical compound N([C@@H](CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N1CCC(CC1)N1CCCCC1)C1=CC=NC=N1 HBQDMNWZCXPWMC-MHZLTWQESA-N 0.000 claims description 2
- 125000006545 (C1-C9) alkyl group Chemical group 0.000 claims description 2
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 2
- LIIIFFYJOZKOQS-UHFFFAOYSA-N 1-(2,6-dimethylmorpholin-4-yl)-2-[(7-methyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1C(C)OC(C)CN1C(=O)C(CC=1C=C2C=NNC2=C(C)C=1)CC(=O)N1CCC(N2C(NC3=CC=CC=C3C2)=O)CC1 LIIIFFYJOZKOQS-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- XJVKFXVDJQRGOY-UHFFFAOYSA-N 2-(1h-indazol-5-ylmethyl)-n,n-dimethyl-4-oxo-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]butanamide Chemical compound C1=C2NN=CC2=CC(CC(CC(=O)N2CCC(CC2)N2C(NC3=CC=CC=C3C2)=O)C(=O)N(C)C)=C1 XJVKFXVDJQRGOY-UHFFFAOYSA-N 0.000 claims description 2
- LGPJPEYOSHPRNS-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-1-(4-methylpiperidin-1-yl)-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C1CC(C)CCN1C(=O)C(CC=1C=C2C=NNC2=C(C)C=1)CC(=O)N1CCC(N2C(NC3=CC=CC=C3C2)=O)CC1 LGPJPEYOSHPRNS-UHFFFAOYSA-N 0.000 claims description 2
- RZFGZHGHBZUOHP-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-1-morpholin-4-yl-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N1CCOCC1 RZFGZHGHBZUOHP-UHFFFAOYSA-N 0.000 claims description 2
- BIXIUWBEHSVRHZ-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(CC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N(CC1)CCC1N1CCCCC1 BIXIUWBEHSVRHZ-UHFFFAOYSA-N 0.000 claims description 2
- UYSNZQZJQYYIEV-UHFFFAOYSA-N 2-[(7-methyl-1h-indazol-5-yl)methyl]-4-oxo-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-n-prop-2-ynylbutanamide Chemical class C1C2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)CC(C(=O)NCC#C)CC(C=C1C)=CC2=C1NN=C2 UYSNZQZJQYYIEV-UHFFFAOYSA-N 0.000 claims description 2
- ARYQPYFEMJGFLN-UHFFFAOYSA-N 2-amino-3-(7-methyl-1H-indazol-5-yl)-1-(4-piperidin-1-ylpiperidin-1-yl)propan-1-one Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(N)C(=O)N(CC1)CCC1N1CCCCC1 ARYQPYFEMJGFLN-UHFFFAOYSA-N 0.000 claims description 2
- WJOBOUQJRVIDTN-UHFFFAOYSA-N 2-amino-3-(7-methyl-1H-indazol-5-yl)-1-(4-pyridin-4-ylpiperazin-1-yl)propan-1-one Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(N)C(=O)N(CC1)CCN1C1=CC=NC=C1 WJOBOUQJRVIDTN-UHFFFAOYSA-N 0.000 claims description 2
- JVODHUCPEOKAHT-UHFFFAOYSA-N 2-amino-3-(7-methyl-1H-indazol-5-yl)-1-piperidin-1-ylpropan-1-one Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(N)C(=O)N1CCCCC1 JVODHUCPEOKAHT-UHFFFAOYSA-N 0.000 claims description 2
- YXWMLHQAWAZSMG-UHFFFAOYSA-N 2-amino-3-(7-methyl-1H-indazol-5-yl)-N-(pyridin-4-ylmethyl)propanamide Chemical compound C=1C=2C=NNC=2C(C)=CC=1CC(N)C(=O)NCC1=CC=NC=C1 YXWMLHQAWAZSMG-UHFFFAOYSA-N 0.000 claims description 2
- 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 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- ZNQNPOJBQVXQDS-UHFFFAOYSA-N 3-(1h-indazol-5-yl)-2-[[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carbonyl]amino]propanoic acid Chemical compound C1C2=CC=CC=C2NC(=O)N1C(CC1)CCN1C(=O)NC(C(=O)O)CC1=CC=C(NN=C2)C2=C1 ZNQNPOJBQVXQDS-UHFFFAOYSA-N 0.000 claims description 2
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- JWHJIIANXOMUPH-WJOKGBTCSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)-n-[(2r)-1-oxo-3-(2-oxo-1,3-dihydroindol-5-yl)-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]piperidine-1-carboxamide Chemical compound O=C([C@@H](CC=1C=C2CC(=O)NC2=CC=1)NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)N(CC1)CCC1N1CCCCC1 JWHJIIANXOMUPH-WJOKGBTCSA-N 0.000 claims description 2
- HBRMZOPADQKLOP-GDLZYMKVSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)-n-[(2r)-1-oxo-3-(2-oxo-3h-1,3-benzoxazol-6-yl)-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]piperidine-1-carboxamide Chemical compound O=C([C@@H](CC=1C=C2OC(=O)NC2=CC=1)NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)N(CC1)CCC1N1CCCCC1 HBRMZOPADQKLOP-GDLZYMKVSA-N 0.000 claims description 2
- SJKVRDVGZOWFJZ-UHFFFAOYSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)-n-[1-oxo-3-(2-oxo-3h-1,3-benzoxazol-6-yl)-1-(4-pyridin-4-ylpiperazin-1-yl)propan-2-yl]piperidine-1-carboxamide Chemical compound C1CC(N2C(NC3=CC=CC=C3C2)=O)CCN1C(=O)NC(CC=1C=C2OC(=O)NC2=CC=1)C(=O)N(CC1)CCN1C1=CC=NC=C1 SJKVRDVGZOWFJZ-UHFFFAOYSA-N 0.000 claims description 2
- CYZYQSICCRZIDS-UHFFFAOYSA-N 4-(2-oxo-1,4-dihydroquinazolin-3-yl)-n-[1-oxo-3-(2-oxo-3h-1,3-benzoxazol-6-yl)-1-piperidin-1-ylpropan-2-yl]piperidine-1-carboxamide Chemical compound C1CC(N2C(NC3=CC=CC=C3C2)=O)CCN1C(=O)NC(CC=1C=C2OC(=O)NC2=CC=1)C(=O)N1CCCCC1 CYZYQSICCRZIDS-UHFFFAOYSA-N 0.000 claims description 2
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- DTRBWJORPBTYLO-UHFFFAOYSA-N n-[3-(7,7-dimethyl-4,6-dihydro-1h-pyrazolo[4,3-c]pyridin-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide Chemical compound C1C=2C=NNC=2C(C)(C)CN1CC(NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N(CC1)CCC1N1CCCCC1 DTRBWJORPBTYLO-UHFFFAOYSA-N 0.000 claims description 2
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- TZDIWGLMNHGRDQ-UHFFFAOYSA-N n-[3-(7-ethyl-2-oxo-1,3-dihydrobenzimidazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide Chemical compound C=1C=2NC(=O)NC=2C(CC)=CC=1CC(NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N(CC1)CCC1N1CCCCC1 TZDIWGLMNHGRDQ-UHFFFAOYSA-N 0.000 claims description 2
- XZPPRPUYSDMMLA-UHFFFAOYSA-N n-[3-(7-ethyl-3-methyl-2-oxo-1h-benzimidazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide Chemical compound C=1C=2N(C)C(=O)NC=2C(CC)=CC=1CC(NC(=O)N1CCC(CC1)N1C(NC2=CC=CC=C2C1)=O)C(=O)N(CC1)CCC1N1CCCCC1 XZPPRPUYSDMMLA-UHFFFAOYSA-N 0.000 claims description 2
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- KHVVJLUZBVDCSE-UHFFFAOYSA-N methyl 2-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-(2-oxo-4-phenylmethoxypyridin-1-yl)propanoate Chemical compound O=C1N(CC(C(=O)OC)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C=CC(OCC=2C=CC=CC=2)=C1 KHVVJLUZBVDCSE-UHFFFAOYSA-N 0.000 description 2
- FUTIBRAHVIQLBH-UHFFFAOYSA-N methyl 2-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-(4-hydroxypiperidin-1-yl)propanoate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(C(=O)OC)CN1CCC(O)CC1 FUTIBRAHVIQLBH-UHFFFAOYSA-N 0.000 description 2
- WONWLNYQTGIDEV-UHFFFAOYSA-N methyl 2-[bis[(2-methylpropan-2-yl)oxycarbonyl]amino]-3-[(2-methylpropan-2-yl)oxycarbonyloxy]propanoate Chemical compound CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(C(=O)OC)COC(=O)OC(C)(C)C WONWLNYQTGIDEV-UHFFFAOYSA-N 0.000 description 2
- BCNULXAVPAFXEZ-UHFFFAOYSA-N methyl 2-amino-3-(1,4,6,7-tetrahydropyrazolo[4,3-c]pyridin-5-yl)propanoate Chemical compound C1N(CC(N)C(=O)OC)CCC2=C1C=NN2 BCNULXAVPAFXEZ-UHFFFAOYSA-N 0.000 description 2
- NNTXZUCCVNHSTI-UHFFFAOYSA-N methyl 2-amino-3-(7,7-dimethyl-4,6-dihydro-1h-pyrazolo[4,3-c]pyridin-5-yl)propanoate Chemical compound CC1(C)CN(CC(N)C(=O)OC)CC2=C1NN=C2 NNTXZUCCVNHSTI-UHFFFAOYSA-N 0.000 description 2
- BEUQXXJKIQGBQT-UHFFFAOYSA-N methyl 2-amino-3-(7-chloro-1h-indazol-5-yl)propanoate Chemical compound COC(=O)C(N)CC1=CC(Cl)=C2NN=CC2=C1 BEUQXXJKIQGBQT-UHFFFAOYSA-N 0.000 description 2
- XVBDOJTZMGJLDM-UHFFFAOYSA-N methyl 2-amino-3-(7-ethyl-1h-indazol-5-yl)propanoate Chemical compound CCC1=CC(CC(N)C(=O)OC)=CC2=C1NN=C2 XVBDOJTZMGJLDM-UHFFFAOYSA-N 0.000 description 2
- ALDHNPXBSNOFKR-UHFFFAOYSA-N methyl 3-(3,4-dinitrophenyl)-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C=C([N+]([O-])=O)C([N+]([O-])=O)=CC=1C=C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 ALDHNPXBSNOFKR-UHFFFAOYSA-N 0.000 description 2
- OQEOZHLDJSIOQP-UHFFFAOYSA-N methyl 3-(6-methoxypyridin-3-yl)-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C=C(OC)N=CC=1C=C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 OQEOZHLDJSIOQP-UHFFFAOYSA-N 0.000 description 2
- HPOIXMWHYQEAET-UHFFFAOYSA-N methyl 3-(7-chloro-1h-indazol-5-yl)-2-(phenylmethoxycarbonylamino)prop-2-enoate Chemical compound C=1C(Cl)=C2NN=CC2=CC=1C=C(C(=O)OC)NC(=O)OCC1=CC=CC=C1 HPOIXMWHYQEAET-UHFFFAOYSA-N 0.000 description 2
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- A01K2207/00—Modified animals
- A01K2207/15—Humanized animals
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- A01K2217/00—Genetically modified animals
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K2227/10—Mammal
- A01K2227/106—Primate
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- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/0306—Animal model for genetic diseases
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2500/00—Screening for compounds of potential therapeutic value
- G01N2500/10—Screening for compounds of potential therapeutic value involving cells
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
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PCT/US2003/016576 WO2003104236A1 (en) | 2002-06-01 | 2003-05-27 | Calcitonin gene related peptide receptor antagonists |
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EP (1) | EP1539766B1 (pt) |
JP (1) | JP4490809B2 (pt) |
KR (2) | KR20050008790A (pt) |
CN (1) | CN100558728C (pt) |
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HR (1) | HRP20041147A2 (pt) |
HU (1) | HUE032132T2 (pt) |
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PT (1) | PT1539766T (pt) |
RS (1) | RS52552B (pt) |
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2003
- 2003-05-27 LT LTEP03736721.6T patent/LT1539766T/lt unknown
- 2003-05-27 KR KR10-2004-7019744A patent/KR20050008790A/ko active Application Filing
- 2003-05-27 ES ES03736721.6T patent/ES2616539T3/es not_active Expired - Lifetime
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- 2003-05-27 CN CNB038184753A patent/CN100558728C/zh not_active Expired - Lifetime
- 2003-05-27 WO PCT/US2003/016576 patent/WO2003104236A1/en active Application Filing
- 2003-05-27 KR KR1020117028478A patent/KR20120004541A/ko not_active Application Discontinuation
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- 2003-05-27 BR BRPI0311812A patent/BRPI0311812B8/pt active IP Right Grant
- 2003-05-27 HU HUE03736721A patent/HUE032132T2/en unknown
- 2003-05-27 PT PT37367216T patent/PT1539766T/pt unknown
- 2003-05-27 MX MXPA04011960A patent/MXPA04011960A/es active IP Right Grant
- 2003-05-27 DK DK03736721.6T patent/DK1539766T3/en active
- 2003-05-27 EP EP03736721.6A patent/EP1539766B1/en not_active Expired - Lifetime
- 2003-05-27 US US10/445,523 patent/US20040063735A1/en not_active Abandoned
- 2003-05-27 PL PL03374017A patent/PL374017A1/xx not_active Application Discontinuation
- 2003-05-27 AU AU2003237255A patent/AU2003237255B8/en not_active Expired
- 2003-05-27 RS YU104004A patent/RS52552B/en unknown
- 2003-05-27 JP JP2004511306A patent/JP4490809B2/ja not_active Expired - Lifetime
- 2003-06-03 TW TW092115067A patent/TWI308151B/zh not_active IP Right Cessation
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2004
- 2004-11-29 NO NO20045219A patent/NO332691B1/no not_active IP Right Cessation
- 2004-12-01 HR HR20041147A patent/HRP20041147A2/hr not_active Application Discontinuation
- 2004-12-03 IS IS7583A patent/IS7583A/is unknown
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2006
- 2006-12-19 US US11/641,974 patent/US20070148093A1/en not_active Abandoned
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2017
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