SK25099A3 - Substituted cyclic amine metalloprotease inhibitors - Google Patents

Info

Publication number

SK25099A3

SK25099A3 SK250-99A SK25099A SK25099A3 SK 25099 A3 SK25099 A3 SK 25099A3 SK 25099 A SK25099 A SK 25099A SK 25099 A3 SK25099 A3 SK 25099A3

Authority

SK

Slovakia

Prior art keywords

mmol

hydroxycarboxamido

methoxyphenylsulfonyl

alkyl

etoac

Prior art date

1996-08-28

Links

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• -1 cyclic amine Chemical class 0.000 title claims description 71
• 239000003475 metalloproteinase inhibitor Substances 0.000 title claims description 8
• 150000001875 compounds Chemical class 0.000 claims abstract description 140
• 102000005741 Metalloproteases Human genes 0.000 claims abstract description 75
• 108010006035 Metalloproteases Proteins 0.000 claims abstract description 75
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 58
• 238000000034 method Methods 0.000 claims abstract description 49
• 230000000694 effects Effects 0.000 claims abstract description 39
• 201000010099 disease Diseases 0.000 claims abstract description 35
• RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 72
• 125000000217 alkyl group Chemical group 0.000 claims description 60
• 125000003118 aryl group Chemical group 0.000 claims description 51
• 125000001072 heteroaryl group Chemical group 0.000 claims description 41
• 239000001257 hydrogen Substances 0.000 claims description 38
• 229910052739 hydrogen Inorganic materials 0.000 claims description 38
• 150000002148 esters Chemical class 0.000 claims description 29
• 150000002431 hydrogen Chemical class 0.000 claims description 28
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 27
• 238000002360 preparation method Methods 0.000 claims description 23
• 125000003545 alkoxy group Chemical group 0.000 claims description 21
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
• 150000003839 salts Chemical class 0.000 claims description 14
• 125000003282 alkyl amino group Chemical group 0.000 claims description 13
• 125000001769 aryl amino group Chemical group 0.000 claims description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
• 125000004947 alkyl aryl amino group Chemical group 0.000 claims description 12
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000003277 amino group Chemical group 0.000 claims description 8
• FUTBJBSRCVJYCQ-UHFFFAOYSA-N n-hexylpyrrolidin-1-amine Chemical compound CCCCCCNN1CCCC1 FUTBJBSRCVJYCQ-UHFFFAOYSA-N 0.000 claims description 8
• 230000003287 optical effect Effects 0.000 claims description 8
• 125000004104 aryloxy group Chemical group 0.000 claims description 7
• 125000004986 diarylamino group Chemical group 0.000 claims description 7
• CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 6
• 125000002947 alkylene group Chemical group 0.000 claims description 5
• 125000004474 heteroalkylene group Chemical group 0.000 claims description 5
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 5
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 4
• 150000001408 amides Chemical class 0.000 claims description 4
• 101000998548 Yersinia ruckeri Alkaline proteinase inhibitor Proteins 0.000 claims description 3
• 229910052736 halogen Chemical group 0.000 claims description 3
• 150000002367 halogens Chemical group 0.000 claims description 3
• 150000003949 imides Chemical class 0.000 claims description 3
• AUSRRRUBMHIEJD-UHFFFAOYSA-N 1-phenoxypyrrolidine Chemical compound C1CCCN1OC1=CC=CC=C1 AUSRRRUBMHIEJD-UHFFFAOYSA-N 0.000 claims description 2
• 206010006895 Cachexia Diseases 0.000 claims description 2
• UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 2
• CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 claims 1
• 208000023178 Musculoskeletal disease Diseases 0.000 claims 1
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
• 239000000825 pharmaceutical preparation Substances 0.000 claims 1
• 239000003112 inhibitor Substances 0.000 abstract description 20
• 102000004190 Enzymes Human genes 0.000 abstract description 13
• 108090000790 Enzymes Proteins 0.000 abstract description 13
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 6
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 501
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 414
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 297
• 235000019439 ethyl acetate Nutrition 0.000 description 204
• 239000000203 mixture Substances 0.000 description 204
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 201
• 239000000243 solution Substances 0.000 description 167
• 239000000047 product Substances 0.000 description 146
• 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 99
• 239000000741 silica gel Substances 0.000 description 84
• 229910002027 silica gel Inorganic materials 0.000 description 84
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• 150000004702 methyl esters Chemical class 0.000 description 53
• 238000011282 treatment Methods 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 46
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• 239000011734 sodium Substances 0.000 description 45
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 44
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 37
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 36
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
• 239000012074 organic phase Substances 0.000 description 34
• 239000000460 chlorine Substances 0.000 description 33
• 238000004587 chromatography analysis Methods 0.000 description 30
• 239000012267 brine Substances 0.000 description 28
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
• 238000006243 chemical reaction Methods 0.000 description 23
• 208000035475 disorder Diseases 0.000 description 23
• 238000000262 chemical ionisation mass spectrometry Methods 0.000 description 22
• NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 22
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 21
• 239000002904 solvent Substances 0.000 description 21
• 210000001519 tissue Anatomy 0.000 description 21
• FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 20
• FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 20
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 19
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• 235000019198 oils Nutrition 0.000 description 19
• 239000011541 reaction mixture Substances 0.000 description 19
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
• 241000282414 Homo sapiens Species 0.000 description 18
• 239000002253 acid Substances 0.000 description 18
• 239000012043 crude product Substances 0.000 description 18
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• 239000003937 drug carrier Substances 0.000 description 16
• 150000001412 amines Chemical class 0.000 description 15
• 125000004432 carbon atom Chemical group C* 0.000 description 15
• 239000000843 powder Substances 0.000 description 15
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
• 238000009472 formulation Methods 0.000 description 14
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 13
• 238000010438 heat treatment Methods 0.000 description 13
• DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 12
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
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• 230000006378 damage Effects 0.000 description 12
• 229940088598 enzyme Drugs 0.000 description 12
• 239000012071 phase Substances 0.000 description 12
• 150000003141 primary amines Chemical class 0.000 description 12
• 239000011780 sodium chloride Substances 0.000 description 12
• 229940050176 methyl chloride Drugs 0.000 description 11
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
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• 241001465754 Metazoa Species 0.000 description 10
• 125000004429 atom Chemical group 0.000 description 10
• 125000005842 heteroatom Chemical group 0.000 description 10
• 238000000746 purification Methods 0.000 description 10
• 125000001424 substituent group Chemical group 0.000 description 10
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
• FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 9
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• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 9
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• YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 8
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
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