CA2915470A1 - Antagonists of prostaglandin ep3 receptor - Google Patents
Antagonists of prostaglandin ep3 receptor Download PDFInfo
- Publication number
- CA2915470A1 CA2915470A1 CA2915470A CA2915470A CA2915470A1 CA 2915470 A1 CA2915470 A1 CA 2915470A1 CA 2915470 A CA2915470 A CA 2915470A CA 2915470 A CA2915470 A CA 2915470A CA 2915470 A1 CA2915470 A1 CA 2915470A1
- Authority
- CA
- Canada
- Prior art keywords
- compound
- salt
- refers
- pharmaceutically acceptable
- solvate
- 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
- 101150053131 PTGER3 gene Proteins 0.000 title abstract description 6
- 150000003180 prostaglandins Chemical class 0.000 title abstract description 3
- 239000005557 antagonist Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 191
- 150000003839 salts Chemical class 0.000 claims abstract description 101
- 239000012453 solvate Substances 0.000 claims abstract description 48
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 64
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 16
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 150000004682 monohydrates Chemical class 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 6
- 101100495923 Schizosaccharomyces pombe (strain 972 / ATCC 24843) chr2 gene Proteins 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 2
- OJVNYQOKTZLPPX-OAQYLSRUSA-N 3-[(3R)-3-methyl-2-oxopiperidin-3-yl]-6-(5-methylquinolin-3-yl)-1H-pyridin-2-one Chemical compound C[C@]1(C(NCCC1)=O)C=1C(NC(=CC=1)C=1C=NC2=CC=CC(=C2C=1)C)=O OJVNYQOKTZLPPX-OAQYLSRUSA-N 0.000 claims 2
- QEUAUMWHNLVMDZ-HXUWFJFHSA-N 6-(5-fluoroquinolin-7-yl)-3-[(3R)-3-methyl-2-oxopiperidin-3-yl]-1H-pyridin-2-one Chemical compound FC1=C2C=CC=NC2=CC(=C1)C1=CC=C(C(N1)=O)[C@@]1(C(NCCC1)=O)C QEUAUMWHNLVMDZ-HXUWFJFHSA-N 0.000 claims 2
- ZUCVEFCHDRKBHT-MYKUNDNFSA-N Cc1cccc2ncc(cc12)C1CCC(C(=O)N1)[C@@]1(C)CCCNC1=O Chemical compound Cc1cccc2ncc(cc12)C1CCC(C(=O)N1)[C@@]1(C)CCCNC1=O ZUCVEFCHDRKBHT-MYKUNDNFSA-N 0.000 claims 2
- URFCQPHIMBZYON-OAQYLSRUSA-N 3-[(3R)-3-methyl-2-oxopiperidin-3-yl]-6-(5-methylquinolin-7-yl)-1H-pyridin-2-one Chemical compound C[C@]1(C(NCCC1)=O)C=1C(NC(=CC=1)C1=CC(=C2C=CC=NC2=C1)C)=O URFCQPHIMBZYON-OAQYLSRUSA-N 0.000 claims 1
- NYMPHOZUBJYHBQ-HXUWFJFHSA-N 3-[(3R)-3-methyl-2-oxopyrrolidin-3-yl]-6-(5-methylquinolin-3-yl)-1H-pyridin-2-one Chemical compound C[C@]1(C(NCC1)=O)C=1C(NC(=CC=1)C=1C=NC2=CC=CC(=C2C=1)C)=O NYMPHOZUBJYHBQ-HXUWFJFHSA-N 0.000 claims 1
- ALGSMAYBBGCDSR-HXUWFJFHSA-N 6-(5-chloroquinolin-7-yl)-3-[(3R)-3-methyl-2-oxopiperidin-3-yl]-1H-pyridin-2-one Chemical compound ClC1=C2C=CC=NC2=CC(=C1)C1=CC=C(C(N1)=O)[C@@]1(C(NCCC1)=O)C ALGSMAYBBGCDSR-HXUWFJFHSA-N 0.000 claims 1
- JXKXDDNPECXKSM-HSZRJFAPSA-N 6-(5-cyclopropylquinolin-7-yl)-3-[(3R)-3-methyl-2-oxopiperidin-3-yl]-1H-pyridin-2-one Chemical compound C1(CC1)C1=C2C=CC=NC2=CC(=C1)C1=CC=C(C(N1)=O)[C@@]1(C(NCCC1)=O)C JXKXDDNPECXKSM-HSZRJFAPSA-N 0.000 claims 1
- KPRFPENKXRBQRF-JOCHJYFZSA-N 6-(5-ethylquinolin-7-yl)-3-[(3R)-3-methyl-2-oxopiperidin-3-yl]-1H-pyridin-2-one Chemical compound C(C)C1=C2C=CC=NC2=CC(=C1)C1=CC=C(C(N1)=O)[C@@]1(C(NCCC1)=O)C KPRFPENKXRBQRF-JOCHJYFZSA-N 0.000 claims 1
- ICRVRXNPWUOCMP-IVAFLUGOSA-N CCc1cc(cc2ncccc12)C1=NC(=O)C(C=C1)[C@@]1(C)CCCNC1=O Chemical compound CCc1cc(cc2ncccc12)C1=NC(=O)C(C=C1)[C@@]1(C)CCCNC1=O ICRVRXNPWUOCMP-IVAFLUGOSA-N 0.000 claims 1
- ZTBLZTHRYZXYNZ-WBPHRXDCSA-N C[C@@]1(CCCNC1=O)C1C=CC(=NC1=O)c1cc(C2CC2)c2cccnc2c1 Chemical compound C[C@@]1(CCCNC1=O)C1C=CC(=NC1=O)c1cc(C2CC2)c2cccnc2c1 ZTBLZTHRYZXYNZ-WBPHRXDCSA-N 0.000 claims 1
- SGMZEERLWJABMZ-YBMSBYLISA-N C[C@@]1(CCCNC1=O)C1C=CC(=NC1=O)c1cc(Cl)c2cccnc2c1 Chemical compound C[C@@]1(CCCNC1=O)C1C=CC(=NC1=O)c1cc(Cl)c2cccnc2c1 SGMZEERLWJABMZ-YBMSBYLISA-N 0.000 claims 1
- SSQLJNRCSCKPFA-MYKUNDNFSA-N Cc1cc(cc2ncccc12)C1CCC(C(=O)N1)[C@@]1(C)CCCNC1=O Chemical compound Cc1cc(cc2ncccc12)C1CCC(C(=O)N1)[C@@]1(C)CCCNC1=O SSQLJNRCSCKPFA-MYKUNDNFSA-N 0.000 claims 1
- RXTUYFXTGPOYIV-ALLBUHFWSA-N Cc1cccc2ncc(cc12)C1CCC(C(=O)N1)[C@@]1(C)CCNC1=O Chemical compound Cc1cccc2ncc(cc12)C1CCC(C(=O)N1)[C@@]1(C)CCNC1=O RXTUYFXTGPOYIV-ALLBUHFWSA-N 0.000 claims 1
- 239000002089 prostaglandin antagonist Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 74
- 230000008569 process Effects 0.000 abstract description 5
- 239000000543 intermediate Substances 0.000 description 132
- 239000000203 mixture Substances 0.000 description 100
- 238000006243 chemical reaction Methods 0.000 description 79
- 239000007787 solid Substances 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 229910001868 water Inorganic materials 0.000 description 58
- 239000000243 solution Substances 0.000 description 55
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical class CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 44
- 239000011541 reaction mixture Substances 0.000 description 39
- -1 dulaglitide Chemical compound 0.000 description 37
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 33
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 32
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 28
- 238000005160 1H NMR spectroscopy Methods 0.000 description 26
- 239000002585 base Substances 0.000 description 26
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
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- 239000000460 chlorine Substances 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 23
- 229910052938 sodium sulfate Inorganic materials 0.000 description 23
- 235000011152 sodium sulphate Nutrition 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- 238000003756 stirring Methods 0.000 description 23
- 239000007832 Na2SO4 Substances 0.000 description 22
- 125000006239 protecting group Chemical group 0.000 description 22
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 20
- 229910052782 aluminium Inorganic materials 0.000 description 20
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 20
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 20
- 238000001816 cooling Methods 0.000 description 19
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- 230000002829 reductive effect Effects 0.000 description 17
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- 239000012065 filter cake Substances 0.000 description 14
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- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 11
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| US5612359A (en) | 1994-08-26 | 1997-03-18 | Bristol-Myers Squibb Company | Substituted biphenyl isoxazole sulfonamides |
| TW536540B (en) | 1997-01-30 | 2003-06-11 | Bristol Myers Squibb Co | Endothelin antagonists: N-[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]-N,3,3-trimethylbutanamide and N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[1,1'-biphe |
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-
2015
- 2015-12-11 EP EP15821169.8A patent/EP3237401B1/en not_active Not-in-force
- 2015-12-11 WO PCT/IB2015/059548 patent/WO2016103097A1/en not_active Ceased
- 2015-12-11 JP JP2017533416A patent/JP2017538769A/ja not_active Withdrawn
- 2015-12-16 US US14/970,930 patent/US9738626B2/en not_active Expired - Fee Related
- 2015-12-17 TW TW104142513A patent/TW201632513A/zh unknown
- 2015-12-17 CA CA2915470A patent/CA2915470A1/en not_active Abandoned
- 2015-12-18 UY UY0001036455A patent/UY36455A/es not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116106398A (zh) * | 2022-08-03 | 2023-05-12 | 南方医科大学珠江医院 | 用于诊断ckd的标志物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP3237401B1 (en) | 2019-03-06 |
| TW201632513A (zh) | 2016-09-16 |
| UY36455A (es) | 2016-07-29 |
| EP3237401A1 (en) | 2017-11-01 |
| WO2016103097A1 (en) | 2016-06-30 |
| US20160176851A1 (en) | 2016-06-23 |
| US9738626B2 (en) | 2017-08-22 |
| JP2017538769A (ja) | 2017-12-28 |
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