JP2019532052A5 - - Google Patents
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- Publication number
- JP2019532052A5 JP2019532052A5 JP2019515428A JP2019515428A JP2019532052A5 JP 2019532052 A5 JP2019532052 A5 JP 2019532052A5 JP 2019515428 A JP2019515428 A JP 2019515428A JP 2019515428 A JP2019515428 A JP 2019515428A JP 2019532052 A5 JP2019532052 A5 JP 2019532052A5
- Authority
- JP
- Japan
- Prior art keywords
- sulfonyl
- pyrrolidine
- hydroxymethyl
- hydroxy
- chloro
- 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.)
- Granted
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- 125000000217 alkyl group Chemical group 0.000 claims description 76
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 39
- 125000001153 fluoro group Chemical group F* 0.000 claims description 31
- -1 -OH Chemical group 0.000 claims description 30
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 150000001875 compounds Chemical class 0.000 claims description 25
- 150000003839 salts Chemical class 0.000 claims description 23
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 22
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 19
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
- 125000001424 substituent group Chemical group 0.000 claims description 16
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 14
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical group C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims description 8
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 8
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 7
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 6
- 125000002757 morpholinyl group Chemical group 0.000 claims description 6
- 150000003222 pyridines Chemical class 0.000 claims description 6
- 239000002464 receptor antagonist Substances 0.000 claims description 6
- 229940044551 receptor antagonist Drugs 0.000 claims description 6
- 229940079593 drug Drugs 0.000 claims description 5
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical group C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 4
- 229940125715 antihistaminic agent Drugs 0.000 claims description 4
- 239000000739 antihistaminic agent Substances 0.000 claims description 4
- 239000003112 inhibitor Substances 0.000 claims description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 4
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 4
- 108090000312 Calcium Channels Proteins 0.000 claims description 3
- 102000003922 Calcium Channels Human genes 0.000 claims description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 3
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims description 3
- 239000000674 adrenergic antagonist Substances 0.000 claims description 3
- 239000002170 aldosterone antagonist Substances 0.000 claims description 3
- 229940083712 aldosterone antagonist Drugs 0.000 claims description 3
- 239000002876 beta blocker Substances 0.000 claims description 3
- 229940097320 beta blocking agent Drugs 0.000 claims description 3
- 229940082638 cardiac stimulant phosphodiesterase inhibitors Drugs 0.000 claims description 3
- 239000000496 cardiotonic agent Substances 0.000 claims description 3
- 230000003177 cardiotonic effect Effects 0.000 claims description 3
- 239000002934 diuretic Substances 0.000 claims description 3
- 229940030606 diuretics Drugs 0.000 claims description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims description 3
- 239000003149 muscarinic antagonist Substances 0.000 claims description 3
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 claims description 3
- 239000002571 phosphodiesterase inhibitor Substances 0.000 claims description 3
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 3
- 239000002461 renin inhibitor Substances 0.000 claims description 3
- 229940086526 renin-inhibitors Drugs 0.000 claims description 3
- 230000003637 steroidlike Effects 0.000 claims description 3
- ANMOCXJIWTUCIZ-DZGCQCFKSA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]sulfonylpyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C=1C=NC(=NC=1)C(F)(F)F)(O)CO ANMOCXJIWTUCIZ-DZGCQCFKSA-N 0.000 claims description 2
- QPAMCINKTNHHRX-GOEBONIOSA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)-4-[5-(trifluoromethyl)pyridin-2-yl]sulfonylpyrrolidin-3-ol Chemical compound ClC1=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=NC=C(C(F)(F)F)C=C2)C=CC(Cl)=C1 QPAMCINKTNHHRX-GOEBONIOSA-N 0.000 claims description 2
- REZAGHQSTJAQBB-JKSUJKDBSA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(O)CO REZAGHQSTJAQBB-JKSUJKDBSA-N 0.000 claims description 2
- JNLWUMKYPBFKIY-DLBZAZTESA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(3,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)(O)CO JNLWUMKYPBFKIY-DLBZAZTESA-N 0.000 claims description 2
- KIHLXIWRTRLYFG-DLBZAZTESA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(3,4-difluorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)F)F)(O)CO KIHLXIWRTRLYFG-DLBZAZTESA-N 0.000 claims description 2
- XSNUTFHJGMIWAF-DLBZAZTESA-N (3R,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(4-fluorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=CC=C(F)C=C2)C=CC(Cl)=C1 XSNUTFHJGMIWAF-DLBZAZTESA-N 0.000 claims description 2
- PTLVPDPCSNZKNX-FUHWJXTLSA-N (3R,4S)-1-[2-chloro-4-(difluoromethyl)phenyl]sulfonyl-4-(4-chlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)C(F)F)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO PTLVPDPCSNZKNX-FUHWJXTLSA-N 0.000 claims description 2
- STAOPFDANLGETD-ZWKOTPCHSA-N (3R,4S)-1-[2-chloro-4-(fluoromethyl)phenyl]sulfonyl-4-(4-chlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)CF)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO STAOPFDANLGETD-ZWKOTPCHSA-N 0.000 claims description 2
- OBUCPEQOUPIOSM-FUHWJXTLSA-N (3R,4S)-1-[4-chloro-2-(difluoromethyl)phenyl]sulfonyl-4-(4-chlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=CC(=C(C=C1)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO)C(F)F OBUCPEQOUPIOSM-FUHWJXTLSA-N 0.000 claims description 2
- GSTYRNAIWRLWND-DLBZAZTESA-N (3R,4S)-4-(4-chloro-3-fluorophenyl)sulfonyl-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl)(O)CO)F GSTYRNAIWRLWND-DLBZAZTESA-N 0.000 claims description 2
- OKXWVBCXBOPICS-DLBZAZTESA-N (3R,4S)-4-(4-chlorophenyl)sulfonyl-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl)(O)CO OKXWVBCXBOPICS-DLBZAZTESA-N 0.000 claims description 2
- CQBTVINTBADUGP-WMLDXEAASA-N (3R,4S)-4-(4-chlorophenyl)sulfonyl-1-[2-(difluoromethoxy)pyridin-3-yl]sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@](CN(C1)S(=O)(=O)C=1C(=NC=CC=1)OC(F)F)(O)CO CQBTVINTBADUGP-WMLDXEAASA-N 0.000 claims description 2
- AEIKJQLTWFSJIE-DLBZAZTESA-N (3R,4S)-4-(4-chlorophenyl)sulfonyl-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)C(F)(F)F)S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(O)CO AEIKJQLTWFSJIE-DLBZAZTESA-N 0.000 claims description 2
- JNLWUMKYPBFKIY-IRXDYDNUSA-N (3S,4S)-1-(2,4-dichlorophenyl)sulfonyl-4-(3,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=CC(=C1)Cl)S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)Cl)Cl)(O)CO JNLWUMKYPBFKIY-IRXDYDNUSA-N 0.000 claims description 2
- GSTYRNAIWRLWND-IRXDYDNUSA-N (3S,4S)-4-(4-chloro-3-fluorophenyl)sulfonyl-1-(2,4-dichlorophenyl)sulfonyl-3-(hydroxymethyl)pyrrolidin-3-ol Chemical compound ClC1=C(C=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl)(O)CO)F GSTYRNAIWRLWND-IRXDYDNUSA-N 0.000 claims description 2
- SOZGHDCEWOLLHV-UHFFFAOYSA-N 2-(trifluoromethyl)benzonitrile Chemical compound FC(F)(F)C1=CC=CC=C1C#N SOZGHDCEWOLLHV-UHFFFAOYSA-N 0.000 claims description 2
- UWTJDYHOXXQPKF-ZWKOTPCHSA-N 2-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound O[C@]1(CN(C[C@@H]1S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)S(=O)(=O)C1=C(C#N)C=CC=C1)CO UWTJDYHOXXQPKF-ZWKOTPCHSA-N 0.000 claims description 2
- WSLYBDGLOOWRKV-ZWKOTPCHSA-N 2-[(3R,4S)-4-(3,4-difluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-5-(trifluoromethyl)benzonitrile Chemical compound FC=1C=C(C=CC=1F)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C#N)C=C(C=C1)C(F)(F)F)(CO)O WSLYBDGLOOWRKV-ZWKOTPCHSA-N 0.000 claims description 2
- NYSOYBHHKXZKAL-ZWKOTPCHSA-N 2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonyl-5-(trifluoromethyl)benzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C#N)C=C(C=C1)C(F)(F)F)(CO)O NYSOYBHHKXZKAL-ZWKOTPCHSA-N 0.000 claims description 2
- FIUMIWMDAREBLP-ZWKOTPCHSA-N 2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C1=C(C#N)C=CC=C1)(CO)O FIUMIWMDAREBLP-ZWKOTPCHSA-N 0.000 claims description 2
- DPLMOBXRUYGQCI-RBUKOAKNSA-N 2-[5-chloro-2-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylphenyl]acetonitrile Chemical compound C1(CC#N)=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=CC=C(Cl)C=C2)C=CC(Cl)=C1 DPLMOBXRUYGQCI-RBUKOAKNSA-N 0.000 claims description 2
- LLOZHKBBVRPYFI-ZWKOTPCHSA-N 2-chloro-4-[(3S,4R)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C#N)C=CC(=C1)S(=O)(=O)[C@H]1CN(C[C@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)Cl LLOZHKBBVRPYFI-ZWKOTPCHSA-N 0.000 claims description 2
- LLOZHKBBVRPYFI-ROUUACIJSA-N 2-chloro-4-[(3S,4S)-1-[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C#N)C=CC(=C1)S(=O)(=O)[C@H]1CN(C[C@@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)Cl LLOZHKBBVRPYFI-ROUUACIJSA-N 0.000 claims description 2
- FSNDSLDYIRAFSN-ZWKOTPCHSA-N 2-chloro-5-[(3S,4R)-1-(2,4-dichlorophenyl)sulfonyl-4-hydroxy-4-(hydroxymethyl)pyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound ClC1=C(C#N)C=C(C=C1)S(=O)(=O)[C@H]1CN(C[C@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)Cl)Cl FSNDSLDYIRAFSN-ZWKOTPCHSA-N 0.000 claims description 2
- SFFRVAPGBGVILI-RBUKOAKNSA-N 2-fluoro-4-[(3S,4R)-4-hydroxy-4-(hydroxymethyl)-1-[2-methyl-4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-3-yl]sulfonylbenzonitrile Chemical compound FC1=C(C#N)C=CC(=C1)S(=O)(=O)[C@H]1CN(C[C@]1(CO)O)S(=O)(=O)C1=C(C=C(C=C1)C(F)(F)F)C SFFRVAPGBGVILI-RBUKOAKNSA-N 0.000 claims description 2
- JAIRADVACRBDQL-PKOBYXMFSA-N 3-(difluoromethyl)-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound FC(C=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)(CO)O)F JAIRADVACRBDQL-PKOBYXMFSA-N 0.000 claims description 2
- VQECCCDKLOYTPX-DLBZAZTESA-N 3-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylpyridine-2-carbonitrile Chemical compound ClC1=CC=C(C=C1)S(=O)(=O)[C@@H]1[C@@](CN(C1)S(=O)(=O)C=1C(=NC=CC=1)C#N)(CO)O VQECCCDKLOYTPX-DLBZAZTESA-N 0.000 claims description 2
- LPRYGAJXDSKREY-DLBZAZTESA-N 3-bromo-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound BrC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(CO)O LPRYGAJXDSKREY-DLBZAZTESA-N 0.000 claims description 2
- QFSCTDUWWDFTPR-ZWKOTPCHSA-N 3-bromo-4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound BrC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CO)O QFSCTDUWWDFTPR-ZWKOTPCHSA-N 0.000 claims description 2
- CBMYAGOITHXBFI-DZGCQCFKSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(1,3-thiazol-2-ylsulfonyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1SC=CN=1)(CO)O CBMYAGOITHXBFI-DZGCQCFKSA-N 0.000 claims description 2
- JZGRQLRHWWZWLY-LEWJYISDSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(4-propan-2-ylphenyl)sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(C)C)(CO)O JZGRQLRHWWZWLY-LEWJYISDSA-N 0.000 claims description 2
- DTDUDPJQNDVLRF-LEWJYISDSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-(4-propylphenyl)sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)CCC)(CO)O DTDUDPJQNDVLRF-LEWJYISDSA-N 0.000 claims description 2
- IVGDETGKDIXXTN-GOEBONIOSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[2-(trifluoromethyl)pyrimidin-5-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=NC=1)C(F)(F)F)(CO)O IVGDETGKDIXXTN-GOEBONIOSA-N 0.000 claims description 2
- HTTGTURMCLWJTN-ZWKOTPCHSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[4-(trifluoromethyl)phenyl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)(CO)O HTTGTURMCLWJTN-ZWKOTPCHSA-N 0.000 claims description 2
- LVILWSRKTWZYMY-DOTOQJQBSA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[5-(trifluoromethyl)pyridin-2-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=NC=C(C=C1)C(F)(F)F)(CO)O LVILWSRKTWZYMY-DOTOQJQBSA-N 0.000 claims description 2
- NAZBDWWLJWHYMF-DLBZAZTESA-N 3-chloro-4-[(3R,4S)-3-hydroxy-3-(hydroxymethyl)-4-[6-(trifluoromethyl)pyridin-3-yl]sulfonylpyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C=1C=NC(=CC=1)C(F)(F)F)(CO)O NAZBDWWLJWHYMF-DLBZAZTESA-N 0.000 claims description 2
- FTRZGPXZCAQDIT-ZWKOTPCHSA-N 3-chloro-4-[(3R,4S)-4-(4-chloro-3-fluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC(=C(C=C1)Cl)F)(CO)O FTRZGPXZCAQDIT-ZWKOTPCHSA-N 0.000 claims description 2
- TUADROHZTJLERW-ZWKOTPCHSA-N 3-chloro-4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CO)O TUADROHZTJLERW-ZWKOTPCHSA-N 0.000 claims description 2
- OCGZBKOXQIVIBD-RBUKOAKNSA-N 3-chloro-4-[(3R,4S)-4-(4-chlorophenyl)sulfonyl-3-hydroxy-3-[(2,2,2-trifluoroethylamino)methyl]pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC=1C=C(C#N)C=CC=1S(=O)(=O)N1C[C@@]([C@H](C1)S(=O)(=O)C1=CC=C(C=C1)Cl)(CNCC(F)(F)F)O OCGZBKOXQIVIBD-RBUKOAKNSA-N 0.000 claims description 2
- SDNLCTDHVZERAD-RBUKOAKNSA-N 3-chloro-4-[(3R,4S)-4-(4-cyano-3-fluorophenyl)sulfonyl-3-hydroxy-3-(hydroxymethyl)pyrrolidin-1-yl]sulfonylbenzonitrile Chemical compound ClC1=C(S(=O)(=O)N2C[C@@H]([C@](O)(CO)C2)S(=O)(=O)C2=CC=C(C(=C2)F)C#N)C=CC(C#N)=C1 SDNLCTDHVZERAD-RBUKOAKNSA-N 0.000 claims description 2
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| US10590077B2 (en) | 2016-09-20 | 2020-03-17 | Glaxosmithkline Intellectual Property Development Limited | TRPV4 antagonists |
| TW201825458A (zh) | 2016-09-20 | 2018-07-16 | 英商葛蘭素史克智慧財產（第二）有限公司 | Ｔｒｐｖ４拮抗劑 |
| SG11202107260VA (en) | 2019-02-15 | 2021-08-30 | Novartis Ag | Methods for treating ocular surface pain |
| JP6994061B2 (ja) | 2019-02-15 | 2022-01-14 | ノバルティス アーゲー | ４－（７－ヒドロキシ－２－イソプロピル－４－オキソ－４ｈ－キナゾリン－３－イル）－ベンゾニトリルの製剤 |
| CN110407721A (zh) * | 2019-08-13 | 2019-11-05 | 上海毕得医药科技有限公司 | 一种4-氰基-3-(三氟甲基)苯-1-磺酰氯的合成方法 |
| WO2021221169A1 (en) | 2020-04-30 | 2021-11-04 | Raqualia Pharma Inc. | Pyrimidin-4(3h)-one derivatives as trpv4 antagonists |
| KR20230041680A (ko) | 2020-07-16 | 2023-03-24 | 라퀄리아 파마 인코포레이티드 | 안구 질환 치료제로서의 trpv4 억제제 |
| CN112500419A (zh) * | 2020-11-23 | 2021-03-16 | 浙大城市学院 | 一种环氧稠合的2-亚甲基吡咯烷类化合物及其制备方法 |
| CN114058694A (zh) * | 2021-11-29 | 2022-02-18 | 上海市普陀区中心医院 | Trpv1在筛选或制备预防、缓解和/或治疗肝脏疾病的药物中的应用 |
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| DK172541B1 (da) | 1982-10-08 | 1998-12-07 | Glaxo Group Ltd | Apparat til administrering af medikamenter til patienter og en medikamentpakning til brug i apparatet |
| GB2169265B (en) | 1982-10-08 | 1987-08-12 | Glaxo Group Ltd | Pack for medicament |
| US4778054A (en) | 1982-10-08 | 1988-10-18 | Glaxo Group Limited | Pack for administering medicaments to patients |
| DE3682457D1 (de) | 1985-07-30 | 1991-12-19 | Glaxo Group Ltd | Geraet zur verabreichung von medikamenten an patienten. |
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| DOP2006000010A (es) | 2005-01-10 | 2006-07-31 | Arena Pharm Inc | Procedimiento para preparar eteres aromáticos |
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-
2017
- 2017-09-20 CN CN201780057911.XA patent/CN109790116B/zh active Active
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- 2017-09-20 US US16/334,400 patent/US11260049B2/en active Active
- 2017-09-20 AU AU2017330620A patent/AU2017330620A1/en not_active Abandoned
- 2017-09-20 JP JP2019515428A patent/JP7106528B2/ja active Active
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- 2017-09-20 RU RU2019110821A patent/RU2019110821A/ru not_active Application Discontinuation
- 2017-09-20 KR KR1020197010953A patent/KR20190049865A/ko not_active Withdrawn
- 2017-09-20 WO PCT/IB2017/055702 patent/WO2018055526A1/en not_active Ceased
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