TW580491B - Aryl-S(O)n-substituted hydroxamic acids, and their preparation and use - Google Patents

Info

Publication number

TW580491B

TW580491B TW86102686A TW86102686A TW580491B TW 580491 B TW580491 B TW 580491B TW 86102686 A TW86102686 A TW 86102686A TW 86102686 A TW86102686 A TW 86102686A TW 580491 B TW580491 B TW 580491B

Authority

TW

Taiwan

Prior art keywords

formula

compound

phenyl

hydrogen

scope

Prior art date

1995-12-20

Links

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• Global Dossier
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• 238000002360 preparation method Methods 0.000 title description 130
• NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical class C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 548
• -1 arylheteroalkyl Chemical group 0.000 claims abstract description 517
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 183
• 239000001257 hydrogen Substances 0.000 claims abstract description 183
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 81
• 229910052799 carbon Inorganic materials 0.000 claims abstract description 55
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 47
• 150000003839 salts Chemical class 0.000 claims abstract description 30
• 150000002148 esters Chemical class 0.000 claims abstract description 13
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 9
• 238000000034 method Methods 0.000 claims description 120
• 150000002431 hydrogen Chemical group 0.000 claims description 90
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 57
• 125000004432 carbon atom Chemical group C* 0.000 claims description 54
• 230000002829 reductive effect Effects 0.000 claims description 44
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 31
• 201000010099 disease Diseases 0.000 claims description 29
• QDKWLJJOYIFEBS-UHFFFAOYSA-N 1-fluoro-4-$l^{1}-oxidanylbenzene Chemical group [O]C1=CC=C(F)C=C1 QDKWLJJOYIFEBS-UHFFFAOYSA-N 0.000 claims description 26
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 claims description 25
• USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Natural products C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 claims description 22
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 21
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 21
• 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 17
• 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 17
• 239000004305 biphenyl Substances 0.000 claims description 14
• 239000008194 pharmaceutical composition Substances 0.000 claims description 12
• QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 12
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 11
• 239000000460 chlorine Substances 0.000 claims description 10
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 10
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 230000002401 inhibitory effect Effects 0.000 claims description 9
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
• KDGKTJGPFXIBEB-UHFFFAOYSA-N n-hydroxyformamide Chemical compound ONC=O KDGKTJGPFXIBEB-UHFFFAOYSA-N 0.000 claims description 8
• 239000007800 oxidant agent Substances 0.000 claims description 8
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000006267 biphenyl group Chemical group 0.000 claims description 6
• 201000006417 multiple sclerosis Diseases 0.000 claims description 6
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
• 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 230000004044 response Effects 0.000 claims description 5
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 5
• 238000002054 transplantation Methods 0.000 claims description 5
• 206010061218 Inflammation Diseases 0.000 claims description 4
• 206010027476 Metastases Diseases 0.000 claims description 4
• 230000015572 biosynthetic process Effects 0.000 claims description 4
• 235000010290 biphenyl Nutrition 0.000 claims description 4
• 201000007717 corneal ulcer Diseases 0.000 claims description 4
• 230000004054 inflammatory process Effects 0.000 claims description 4
• 239000012528 membrane Substances 0.000 claims description 4
• 230000009401 metastasis Effects 0.000 claims description 4
• 230000001590 oxidative effect Effects 0.000 claims description 4
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 3
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
• 206010028980 Neoplasm Diseases 0.000 claims description 3
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• 229960001171 acetohydroxamic acid Drugs 0.000 claims description 3
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• 230000000740 bleeding effect Effects 0.000 claims description 3
• 210000000988 bone and bone Anatomy 0.000 claims description 3
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
• 239000011737 fluorine Substances 0.000 claims description 3
• 229910052731 fluorine Inorganic materials 0.000 claims description 3
• 231100000252 nontoxic Toxicity 0.000 claims description 3
• 230000003000 nontoxic effect Effects 0.000 claims description 3
• 230000003239 periodontal effect Effects 0.000 claims description 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
• YXQKTWBASYSHQQ-UHFFFAOYSA-N 2-(4-phenoxyphenyl)sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)C(C(N)=O)C)=CC=C1OC1=CC=CC=C1 YXQKTWBASYSHQQ-UHFFFAOYSA-N 0.000 claims description 2
• 206010064996 Ulcerative keratitis Diseases 0.000 claims description 2
• SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
• 235000013336 milk Nutrition 0.000 claims description 2
• 239000008267 milk Substances 0.000 claims description 2
• 210000004080 milk Anatomy 0.000 claims description 2
• 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims description 2
• 230000001105 regulatory effect Effects 0.000 claims description 2
• 229910052717 sulfur Inorganic materials 0.000 claims description 2
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims 2
• BBEAQIROQSPTKN-UHFFFAOYSA-N pyrene Chemical compound C1=CC=C2C=CC3=CC=CC4=CC=C1C2=C43 BBEAQIROQSPTKN-UHFFFAOYSA-N 0.000 claims 2
• 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims 1
• PKRSYEPBQPFNRB-UHFFFAOYSA-N 2-phenoxybenzoic acid Chemical compound OC(=O)C1=CC=CC=C1OC1=CC=CC=C1 PKRSYEPBQPFNRB-UHFFFAOYSA-N 0.000 claims 1
• 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
• 208000023275 Autoimmune disease Diseases 0.000 claims 1
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
• 241001529936 Murinae Species 0.000 claims 1
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims 1
• RRUDCFGSUDOHDG-UHFFFAOYSA-N acetohydroxamic acid Chemical compound CC(O)=NO RRUDCFGSUDOHDG-UHFFFAOYSA-N 0.000 claims 1
• 210000004204 blood vessel Anatomy 0.000 claims 1
• 125000006011 chloroethoxy group Chemical group 0.000 claims 1
• GVEPBJHOBDJJJI-UHFFFAOYSA-N fluoranthrene Natural products C1=CC(C2=CC=CC=C22)=C3C2=CC=CC3=C1 GVEPBJHOBDJJJI-UHFFFAOYSA-N 0.000 claims 1
• 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 claims 1
• 239000003771 matrix metalloproteinase inhibitor Substances 0.000 claims 1
• ATDOYFPHCIRHKH-UHFFFAOYSA-N n-hydroxy-2,2-dimethylpropanamide Chemical compound CC(C)(C)C(=O)NO ATDOYFPHCIRHKH-UHFFFAOYSA-N 0.000 claims 1
• 125000003884 phenylalkyl group Chemical group 0.000 claims 1
• 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 claims 1
• 125000001544 thienyl group Chemical group 0.000 claims 1
• 229930192474 thiophene Natural products 0.000 claims 1
• 102000003390 tumor necrosis factor Human genes 0.000 claims 1
• 150000001721 carbon Chemical group 0.000 abstract description 38
• 125000000753 cycloalkyl group Chemical group 0.000 abstract description 38
• 125000003118 aryl group Chemical group 0.000 abstract description 31
• 125000001072 heteroaryl group Chemical group 0.000 abstract description 27
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 abstract description 23
• 229910052757 nitrogen Inorganic materials 0.000 abstract description 23
• 125000003710 aryl alkyl group Chemical group 0.000 abstract description 21
• 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 17
• 125000004475 heteroaralkyl group Chemical group 0.000 abstract description 15
• 125000004404 heteroalkyl group Chemical group 0.000 abstract description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 abstract description 7
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 abstract description 5
• 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 abstract description 4
• 239000011159 matrix material Substances 0.000 abstract description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 3
• 108030004510 Interstitial collagenases Proteins 0.000 abstract description 2
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 abstract description 2
• 239000003475 metalloproteinase inhibitor Substances 0.000 abstract 1
• 230000000144 pharmacologic effect Effects 0.000 abstract 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 228
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 158
• 239000000203 mixture Substances 0.000 description 158
• 238000011049 filling Methods 0.000 description 141
• 238000006243 chemical reaction Methods 0.000 description 127
• 239000000243 solution Substances 0.000 description 116
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 109
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 76
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 75
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 73
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 73
• 230000002079 cooperative effect Effects 0.000 description 72
• 239000002253 acid Substances 0.000 description 70
• WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 69
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 67
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 66
• 238000005481 NMR spectroscopy Methods 0.000 description 65
• 238000004364 calculation method Methods 0.000 description 64
• 238000004458 analytical method Methods 0.000 description 60
• 238000002844 melting Methods 0.000 description 60
• 230000008018 melting Effects 0.000 description 60
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 56
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 52
• 238000002474 experimental method Methods 0.000 description 52
• 101150041968 CDC13 gene Proteins 0.000 description 46
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• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 36
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• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 33
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• 235000019341 magnesium sulphate Nutrition 0.000 description 33
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• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 29
• 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 28
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• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 22
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• 239000000047 product Substances 0.000 description 21
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