IL263235B - Pyrazole derivatives as plasma kallikrein inhibitors - Google Patents

Info

Publication number

IL263235B

IL263235B IL263235A IL26323518A IL263235B IL 263235 B IL263235 B IL 263235B IL 263235 A IL263235 A IL 263235A IL 26323518 A IL26323518 A IL 26323518A IL 263235 B IL263235 B IL 263235B

Authority

IL

Israel

Prior art keywords

methyl

phenyl

pyrazole

carboxamide

methoxymethyl

Prior art date

2016-05-31

Links

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• Global Dossier
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• 108090000113 Plasma Kallikrein Proteins 0.000 title claims description 73
• 102000003827 Plasma Kallikrein Human genes 0.000 title claims description 68
• 229940127379 Kallikrein Inhibitors Drugs 0.000 title description 13
• 150000003217 pyrazoles Chemical class 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims description 140
• 150000003839 salts Chemical class 0.000 claims description 48
• 239000012453 solvate Substances 0.000 claims description 34
• 238000000034 method Methods 0.000 claims description 31
• 230000000694 effects Effects 0.000 claims description 22
• 238000011282 treatment Methods 0.000 claims description 21
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 17
• 239000003814 drug Substances 0.000 claims description 17
• 206010012688 Diabetic retinal oedema Diseases 0.000 claims description 15
• 201000011190 diabetic macular edema Diseases 0.000 claims description 15
• 201000010099 disease Diseases 0.000 claims description 15
• 230000000740 bleeding effect Effects 0.000 claims description 11
• 206010012689 Diabetic retinopathy Diseases 0.000 claims description 10
• 208000032843 Hemorrhage Diseases 0.000 claims description 10
• 230000023555 blood coagulation Effects 0.000 claims description 10
• 238000001356 surgical procedure Methods 0.000 claims description 10
• 230000008728 vascular permeability Effects 0.000 claims description 10
• 206010019860 Hereditary angioedema Diseases 0.000 claims description 9
• 230000002207 retinal effect Effects 0.000 claims description 9
• 206010008111 Cerebral haemorrhage Diseases 0.000 claims description 8
• 206010012601 diabetes mellitus Diseases 0.000 claims description 8
• 208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 7
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
• 230000001404 mediated effect Effects 0.000 claims description 6
• 239000008194 pharmaceutical composition Substances 0.000 claims description 6
• 206010061218 Inflammation Diseases 0.000 claims description 5
• 230000002612 cardiopulmonary effect Effects 0.000 claims description 5
• 230000004054 inflammatory process Effects 0.000 claims description 5
• 230000002980 postoperative effect Effects 0.000 claims description 5
• 208000031229 Cardiomyopathies Diseases 0.000 claims description 4
• 206010033645 Pancreatitis Diseases 0.000 claims description 4
• 208000017169 kidney disease Diseases 0.000 claims description 4
• 201000001119 neuropathy Diseases 0.000 claims description 4
• 230000007823 neuropathy Effects 0.000 claims description 4
• 208000033808 peripheral neuropathy Diseases 0.000 claims description 4
• 230000002265 prevention Effects 0.000 claims description 4
• 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 3
• 208000001953 Hypotension Diseases 0.000 claims description 3
• 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 3
• 206010028980 Neoplasm Diseases 0.000 claims description 3
• 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims description 3
• 206010040070 Septic Shock Diseases 0.000 claims description 3
• 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims description 3
• 201000000028 adult respiratory distress syndrome Diseases 0.000 claims description 3
• 206010003246 arthritis Diseases 0.000 claims description 3
• 201000011510 cancer Diseases 0.000 claims description 3
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• 230000001771 impaired effect Effects 0.000 claims description 3
• 208000004644 retinal vein occlusion Diseases 0.000 claims description 3
• 230000036303 septic shock Effects 0.000 claims description 3
• 230000004304 visual acuity Effects 0.000 claims description 3
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 492
• ZVXKYWHJBYIYNI-UHFFFAOYSA-N 1h-pyrazole-4-carboxamide Chemical compound NC(=O)C=1C=NNC=1 ZVXKYWHJBYIYNI-UHFFFAOYSA-N 0.000 description 320
• -1 indole amides Chemical class 0.000 description 231
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 188
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 100
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 95
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 64
• 239000011541 reaction mixture Substances 0.000 description 58
• 239000007787 solid Substances 0.000 description 57
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 50
• 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 49
• 239000000243 solution Substances 0.000 description 48
• 235000019439 ethyl acetate Nutrition 0.000 description 47
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 45
• 239000012267 brine Substances 0.000 description 38
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 38
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 33
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• AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 22
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• IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
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• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 21
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• 125000003118 aryl group Chemical group 0.000 description 19
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• 125000001072 heteroaryl group Chemical group 0.000 description 13
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• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 13
• 238000003756 stirring Methods 0.000 description 13
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• 241000700159 Rattus Species 0.000 description 12
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
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• 229940088598 enzyme Drugs 0.000 description 11
• 125000005843 halogen group Chemical group 0.000 description 11
• WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Inorganic materials [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
• 125000006239 protecting group Chemical group 0.000 description 11
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 10
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
• 239000008280 blood Substances 0.000 description 10
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• 229940079593 drug Drugs 0.000 description 10
• 230000002401 inhibitory effect Effects 0.000 description 10
• 229940126155 plasma kallikrein inhibitor Drugs 0.000 description 10
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
• 230000004913 activation Effects 0.000 description 9
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• 239000012279 sodium borohydride Substances 0.000 description 9
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• DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
• 101100453988 Homo sapiens KLK1 gene Proteins 0.000 description 7
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• 229960004592 isopropanol Drugs 0.000 description 6
• VBGWSQKGUZHFPS-VGMMZINCSA-N kalbitor Chemical compound C([C@H]1C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]2C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=3C=CC=CC=3)C(=O)N[C@H](C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)NCC(=O)NCC(=O)N[C@H]3CSSC[C@H](NC(=O)[C@@H]4CCCN4C(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CO)NC(=O)[C@H](CC=4NC=NC=4)NC(=O)[C@H](CCSC)NC(=O)[C@H](C)NC(=O)[C@@H](N)CCC(O)=O)CSSC[C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC3=O)CSSC2)C(=O)N[C@@H]([C@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=2NC=NC=2)C(=O)N2CCC[C@H]2C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N1)[C@@H](C)CC)[C@H](C)O)=O)[C@@H](C)CC)C1=CC=CC=C1 VBGWSQKGUZHFPS-VGMMZINCSA-N 0.000 description 6
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