HRP980036A2 - Sulfamide-metalloprotease inhibitors - Google Patents

Info

Publication number

HRP980036A2

HRP980036A2 HR60/062,209A HRP980036A HRP980036A2 HR P980036 A2 HRP980036 A2 HR P980036A2 HR P980036 A HRP980036 A HR P980036A HR P980036 A2 HRP980036 A2 HR P980036A2

Authority

HR

Croatia

Prior art keywords

alkyl

hydrogen

compound according

group

sulfonyl

Prior art date

1997-01-23

Links

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• 239000003475 metalloproteinase inhibitor Substances 0.000 title description 3
• -1 amino, monosubstituted amino Chemical group 0.000 claims description 504
• 150000001875 compounds Chemical class 0.000 claims description 250
• 239000001257 hydrogen Substances 0.000 claims description 219
• 229910052739 hydrogen Inorganic materials 0.000 claims description 219
• 125000000217 alkyl group Chemical group 0.000 claims description 199
• 125000003118 aryl group Chemical group 0.000 claims description 126
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 124
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 121
• 125000001072 heteroaryl group Chemical group 0.000 claims description 109
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 100
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 91
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 91
• 238000000034 method Methods 0.000 claims description 85
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 68
• 125000001188 haloalkyl group Chemical group 0.000 claims description 63
• 229910052757 nitrogen Inorganic materials 0.000 claims description 62
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 56
• 125000001424 substituent group Chemical group 0.000 claims description 52
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 51
• 125000004404 heteroalkyl group Chemical group 0.000 claims description 46
• 238000006243 chemical reaction Methods 0.000 claims description 45
• 239000000203 mixture Substances 0.000 claims description 43
• 125000003342 alkenyl group Chemical group 0.000 claims description 42
• 125000004476 heterocycloamino group Chemical group 0.000 claims description 42
• 125000004429 atom Chemical group 0.000 claims description 40
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 30
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 28
• 125000004193 piperazinyl group Chemical group 0.000 claims description 25
• 125000002252 acyl group Chemical group 0.000 claims description 24
• 125000002947 alkylene group Chemical group 0.000 claims description 24
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 229910052799 carbon Inorganic materials 0.000 claims description 22
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 19
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 17
• 150000001721 carbon Chemical group 0.000 claims description 17
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
• 201000010099 disease Diseases 0.000 claims description 16
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
• 150000003839 salts Chemical class 0.000 claims description 16
• FTAHXMZRJCZXDL-UHFFFAOYSA-N 3-piperideine Chemical group C1CC=CCN1 FTAHXMZRJCZXDL-UHFFFAOYSA-N 0.000 claims description 15
• 239000002253 acid Substances 0.000 claims description 15
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 14
• 229910020008 S(O) Inorganic materials 0.000 claims description 13
• 239000008194 pharmaceutical composition Substances 0.000 claims description 11
• 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 10
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 10
• 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
• 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 10
• 239000003814 drug Substances 0.000 claims description 10
• 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 10
• 125000003545 alkoxy group Chemical group 0.000 claims description 9
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 9
• 125000004104 aryloxy group Chemical group 0.000 claims description 9
• 125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 9
• 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 9
• 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 9
• 229940002612 prodrug Drugs 0.000 claims description 9
• 239000000651 prodrug Substances 0.000 claims description 9
• 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
• 229940079593 drug Drugs 0.000 claims description 8
• 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
• 125000005843 halogen group Chemical group 0.000 claims description 8
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 8
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 claims description 8
• 201000006417 multiple sclerosis Diseases 0.000 claims description 7
• 238000002360 preparation method Methods 0.000 claims description 7
• 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
• 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 6
• VSWICNJIUPRZIK-UHFFFAOYSA-N 2-piperideine Chemical class C1CNC=CC1 VSWICNJIUPRZIK-UHFFFAOYSA-N 0.000 claims description 6
• AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 6
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 6
• 206010028980 Neoplasm Diseases 0.000 claims description 6
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
• ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical class C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 claims description 6
• 239000002585 base Substances 0.000 claims description 6
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 6
• WSZLRMUWTDAHFS-QGZVFWFLSA-N (2r)-4-(dimethylcarbamoyl)-1-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]piperazine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CC=C(C=2C=CC(F)=CC=2)CC1 WSZLRMUWTDAHFS-QGZVFWFLSA-N 0.000 claims description 5
• 206010027476 Metastases Diseases 0.000 claims description 5
• 208000001132 Osteoporosis Diseases 0.000 claims description 5
• GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 5
• 230000033115 angiogenesis Effects 0.000 claims description 5
• 230000009401 metastasis Effects 0.000 claims description 5
• 201000008482 osteoarthritis Diseases 0.000 claims description 5
• 208000028169 periodontal disease Diseases 0.000 claims description 5
• 150000004885 piperazines Chemical group 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 208000037803 restenosis Diseases 0.000 claims description 5
• PMBFZMBLMABGCK-QGZVFWFLSA-N (3r)-4-[4-(4-fluorophenyl)piperidin-1-yl]sulfonyl-3-n-hydroxy-1-n,1-n-dimethylpiperazine-1,3-dicarboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CCC(C=2C=CC(F)=CC=2)CC1 PMBFZMBLMABGCK-QGZVFWFLSA-N 0.000 claims description 4
• ZGTUJWFPJXGONO-QGZVFWFLSA-N (3r)-4-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]-3-n-hydroxy-1-n,1-n-dimethylpiperazine-1,3-dicarboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CC=C(C=2C=CC(F)=CC=2)CC1 ZGTUJWFPJXGONO-QGZVFWFLSA-N 0.000 claims description 4
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 4
• 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 4
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 4
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
• 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims description 4
• 230000001594 aberrant effect Effects 0.000 claims description 4
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
• SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 4
• QKIHQFCYDKNBDP-QGZVFWFLSA-N (2r)-4-(dimethylcarbamoyl)-1-[4-(4-fluorophenyl)piperidin-1-yl]sulfonylpiperazine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CCC(C=2C=CC(F)=CC=2)CC1 QKIHQFCYDKNBDP-QGZVFWFLSA-N 0.000 claims description 3
• ZUJIVHDUJHBQQG-CYBMUJFWSA-N (3r)-3-n-hydroxy-1-n,1-n-dimethyl-4-[4-(4,5,6,7-tetrafluoro-1h-indol-3-yl)piperidin-1-yl]sulfonylpiperazine-1,3-dicarboxamide Chemical compound ONC(=O)[C@H]1CN(C(=O)N(C)C)CCN1S(=O)(=O)N1CCC(C=2C3=C(F)C(F)=C(F)C(F)=C3NC=2)CC1 ZUJIVHDUJHBQQG-CYBMUJFWSA-N 0.000 claims description 3
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
• 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 claims description 3
• 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
• 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 3
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 3
• 125000004548 quinolin-3-yl group Chemical group N1=CC(=CC2=CC=CC=C12)* 0.000 claims description 3
• OOZZCPLUTVIMEI-JOCHJYFZSA-N (2r)-1-[4-(5-cyano-1h-indol-3-yl)piperidin-1-yl]sulfonyl-n-hydroxy-4-(morpholine-4-carbonyl)piperazine-2-carboxamide Chemical compound C([C@@H](N(CC1)S(=O)(=O)N2CCC(CC2)C=2C3=CC(=CC=C3NC=2)C#N)C(=O)NO)N1C(=O)N1CCOCC1 OOZZCPLUTVIMEI-JOCHJYFZSA-N 0.000 claims description 2
• UZCHIJMNFOONOL-MRXNPFEDSA-N (2r)-1-[[4-(3-chloro-4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]piperidine-2-carboxylic acid Chemical compound OC(=O)[C@H]1CCCCN1S(=O)(=O)N1CC=C(C=2C=C(Cl)C(F)=CC=2)CC1 UZCHIJMNFOONOL-MRXNPFEDSA-N 0.000 claims description 2
• KRAGHFLTVIWIQP-QGZVFWFLSA-N (2r)-1-[[4-(4-fluoro-3-methylphenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]piperidine-2-carboxylic acid Chemical compound C1=C(F)C(C)=CC(C=2CCN(CC=2)S(=O)(=O)N2[C@H](CCCC2)C(O)=O)=C1 KRAGHFLTVIWIQP-QGZVFWFLSA-N 0.000 claims description 2
• KCRVQMUGCKXEME-MRXNPFEDSA-N (2r)-1-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]-n-hydroxypiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CC=C(C=2C=CC(F)=CC=2)CC1 KCRVQMUGCKXEME-MRXNPFEDSA-N 0.000 claims description 2
• WTECAOZWVGHXGI-GOSISDBHSA-N (2r)-2-(4-fluorophenyl)-2-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonylamino]-n-hydroxyacetamide Chemical compound N([C@@H](C(=O)NO)C=1C=CC(F)=CC=1)S(=O)(=O)N(CC=1)CCC=1C1=CC=C(F)C=C1 WTECAOZWVGHXGI-GOSISDBHSA-N 0.000 claims description 2
• LGARTHUDBLGZMM-OAHLLOKOSA-N (2r)-2-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonylamino]-3-methylbutanoic acid Chemical compound C1N(S(=O)(=O)N[C@H](C(C)C)C(O)=O)CCC(C=2C=CC(F)=CC=2)=C1 LGARTHUDBLGZMM-OAHLLOKOSA-N 0.000 claims description 2
• HNYFEXVRCNMJLW-QGZVFWFLSA-N (2r)-4-(dimethylsulfamoyl)-1-[[4-(4-fluorophenyl)-3,6-dihydro-2h-pyridin-1-yl]sulfonyl]-n-hydroxypiperazine-2-carboxamide Chemical compound ONC(=O)[C@H]1CN(S(=O)(=O)N(C)C)CCN1S(=O)(=O)N1CC=C(C=2C=CC(F)=CC=2)CC1 HNYFEXVRCNMJLW-QGZVFWFLSA-N 0.000 claims description 2
• AVQNLPBUKQGTIW-GFCCVEGCSA-N (2r)-n-hydroxy-1-[4-(4,5,6,7-tetrafluoro-1h-indol-3-yl)piperidin-1-yl]sulfonylpiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(C=2C3=C(F)C(F)=C(F)C(F)=C3NC=2)CC1 AVQNLPBUKQGTIW-GFCCVEGCSA-N 0.000 claims description 2
• 238000004519 manufacturing process Methods 0.000 claims description 2
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
• 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 claims description 2
• 150000002431 hydrogen Chemical class 0.000 claims 39
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• 206010064996 Ulcerative keratitis Diseases 0.000 claims 2
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• PJUKANOMPKVIBK-CQSZACIVSA-N (2r)-1-[4-(5-chloropyridin-2-yl)oxypiperidin-1-yl]sulfonyl-n-hydroxypiperidine-2-carboxamide Chemical compound ONC(=O)[C@H]1CCCCN1S(=O)(=O)N1CCC(OC=2N=CC(Cl)=CC=2)CC1 PJUKANOMPKVIBK-CQSZACIVSA-N 0.000 claims 1
• LIKMQTVZSHGANU-OAHLLOKOSA-N (2r)-2-[[4-(4-fluorophenyl)piperidin-1-yl]sulfonylamino]-3-methylbutanoic acid Chemical compound C1CN(S(=O)(=O)N[C@H](C(C)C)C(O)=O)CCC1C1=CC=C(F)C=C1 LIKMQTVZSHGANU-OAHLLOKOSA-N 0.000 claims 1
• KYFHBAUBKXBFKS-UHFFFAOYSA-N FC1=CC2=C(C=NCCN2)C=C1 Chemical compound FC1=CC2=C(C=NCCN2)C=C1 KYFHBAUBKXBFKS-UHFFFAOYSA-N 0.000 claims 1
• 239000012458 free base Substances 0.000 claims 1
• 229960002449 glycine Drugs 0.000 claims 1
• 235000013905 glycine and its sodium salt Nutrition 0.000 claims 1
• 125000003107 substituted aryl group Chemical group 0.000 claims 1
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• 239000011541 reaction mixture Substances 0.000 description 112
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 101
• 239000000243 solution Substances 0.000 description 101
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• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 87
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 82
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• 239000007787 solid Substances 0.000 description 48
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• 235000019341 magnesium sulphate Nutrition 0.000 description 41
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• 102000003390 tumor necrosis factor Human genes 0.000 description 22
• 125000004432 carbon atom Chemical group C* 0.000 description 21
• 125000003884 phenylalkyl group Chemical group 0.000 description 21
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• 230000005764 inhibitory process Effects 0.000 description 14
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• 150000003254 radicals Chemical class 0.000 description 13
• 238000012360 testing method Methods 0.000 description 13
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