ZA200006772B - Biphenyl sulfonamides as dual angiotensin endothelin receptor antagonists. - Google Patents

Info

Publication number

ZA200006772B

ZA200006772B ZA200006772A ZA200006772A ZA200006772B ZA 200006772 B ZA200006772 B ZA 200006772B ZA 200006772 A ZA200006772 A ZA 200006772A ZA 200006772 A ZA200006772 A ZA 200006772A ZA 200006772 B ZA200006772 B ZA 200006772B

Authority

ZA

South Africa

Prior art keywords

dimethyl

biphenyl

methyl

isoxazolyl

sulfonamide

Prior art date

1998-07-06

Links

• Espacenet
• Global Dossier
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• SBXDENYROQKXBE-UHFFFAOYSA-N 2-phenylbenzenesulfonamide Chemical class NS(=O)(=O)C1=CC=CC=C1C1=CC=CC=C1 SBXDENYROQKXBE-UHFFFAOYSA-N 0.000 title claims description 142
• 229940118365 Endothelin receptor antagonist Drugs 0.000 title description 6
• 108010064733 Angiotensins Proteins 0.000 title description 5
• 102000015427 Angiotensins Human genes 0.000 title description 5
• 239000002308 endothelin receptor antagonist Substances 0.000 title description 5
• 230000009977 dual effect Effects 0.000 title description 4
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 487
• -1 cyano, hydroxy Chemical group 0.000 claims description 446
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 348
• 150000001875 compounds Chemical class 0.000 claims description 335
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 250
• 235000010290 biphenyl Nutrition 0.000 claims description 183
• 125000000217 alkyl group Chemical group 0.000 claims description 99
• 229940124530 sulfonamide Drugs 0.000 claims description 96
• 239000000203 mixture Substances 0.000 claims description 92
• 238000011282 treatment Methods 0.000 claims description 72
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 71
• 238000000034 method Methods 0.000 claims description 71
• 239000001257 hydrogen Substances 0.000 claims description 64
• 229910052739 hydrogen Inorganic materials 0.000 claims description 64
• 239000000126 substance Substances 0.000 claims description 63
• 239000004305 biphenyl Substances 0.000 claims description 61
• 150000002431 hydrogen Chemical class 0.000 claims description 53
• 125000003545 alkoxy group Chemical group 0.000 claims description 36
• 229910052736 halogen Inorganic materials 0.000 claims description 35
• 150000002367 halogens Chemical class 0.000 claims description 35
• QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 34
• 150000003839 salts Chemical class 0.000 claims description 30
• 239000003814 drug Substances 0.000 claims description 28
• 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 25
• 125000001188 haloalkyl group Chemical group 0.000 claims description 25
• 125000000623 heterocyclic group Chemical group 0.000 claims description 24
• 238000004519 manufacturing process Methods 0.000 claims description 21
• 239000002253 acid Substances 0.000 claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
• 230000001419 dependent effect Effects 0.000 claims description 16
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 14
• QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 13
• 208000035475 disorder Diseases 0.000 claims description 13
• ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 claims description 13
• 238000002360 preparation method Methods 0.000 claims description 13
• 239000003795 chemical substances by application Substances 0.000 claims description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 229950006323 angiotensin ii Drugs 0.000 claims description 11
• 125000004994 halo alkoxy alkyl group Chemical group 0.000 claims description 11
• 125000001072 heteroaryl group Chemical group 0.000 claims description 11
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 11
• 125000001424 substituent group Chemical group 0.000 claims description 11
• 206010020772 Hypertension Diseases 0.000 claims description 10
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 10
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 10
• 150000002148 esters Chemical class 0.000 claims description 10
• 102000005862 Angiotensin II Human genes 0.000 claims description 9
• 101800000733 Angiotensin-2 Proteins 0.000 claims description 9
• 108050009340 Endothelin Proteins 0.000 claims description 9
• 102000002045 Endothelin Human genes 0.000 claims description 9
• CZGUSIXMZVURDU-JZXHSEFVSA-N Ile(5)-angiotensin II Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC=1C=CC=CC=1)C([O-])=O)NC(=O)[C@@H](NC(=O)[C@H](CCCNC(N)=[NH2+])NC(=O)[C@@H]([NH3+])CC([O-])=O)C(C)C)C1=CC=C(O)C=C1 CZGUSIXMZVURDU-JZXHSEFVSA-N 0.000 claims description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 8
• 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
• 238000006073 displacement reaction Methods 0.000 claims description 8
• 229910052760 oxygen Inorganic materials 0.000 claims description 8
• 230000010933 acylation Effects 0.000 claims description 7
• 238000005917 acylation reaction Methods 0.000 claims description 7
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 7
• ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 7
• 230000008878 coupling Effects 0.000 claims description 7
• 238000010168 coupling process Methods 0.000 claims description 7
• 238000005859 coupling reaction Methods 0.000 claims description 7
• 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 7
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
• 239000003085 diluting agent Substances 0.000 claims description 7
• 239000001301 oxygen Substances 0.000 claims description 7
• 150000001412 amines Chemical class 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 238000006268 reductive amination reaction Methods 0.000 claims description 6
• 150000003456 sulfonamides Chemical class 0.000 claims description 6
• 238000002560 therapeutic procedure Methods 0.000 claims description 6
• 238000006751 Mitsunobu reaction Methods 0.000 claims description 5
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 5
• 150000001408 amides Chemical class 0.000 claims description 5
• 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 5
• 125000000842 isoxazolyl group Chemical group 0.000 claims description 5
• 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 5
• 125000001715 oxadiazolyl group Chemical group 0.000 claims description 5
• 239000008194 pharmaceutical composition Substances 0.000 claims description 5
• 230000008569 process Effects 0.000 claims description 5
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 5
• 125000001425 triazolyl group Chemical group 0.000 claims description 5
• 206010019280 Heart failures Diseases 0.000 claims description 4
• 206010028980 Neoplasm Diseases 0.000 claims description 4
• 125000003342 alkenyl group Chemical group 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 230000001434 glomerular Effects 0.000 claims description 4
• 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 3
• 208000037487 Endotoxemia Diseases 0.000 claims description 3
• 208000010228 Erectile Dysfunction Diseases 0.000 claims description 3
• 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 claims description 3
• 208000019695 Migraine disease Diseases 0.000 claims description 3
• 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 3
• 206010064911 Pulmonary arterial hypertension Diseases 0.000 claims description 3
• 108090000783 Renin Proteins 0.000 claims description 3
• 102100028255 Renin Human genes 0.000 claims description 3
• 208000032851 Subarachnoid Hemorrhage Diseases 0.000 claims description 3
• 230000003213 activating effect Effects 0.000 claims description 3
• 230000001154 acute effect Effects 0.000 claims description 3
• 125000000304 alkynyl group Chemical group 0.000 claims description 3
• 201000011510 cancer Diseases 0.000 claims description 3
• 210000003904 glomerular cell Anatomy 0.000 claims description 3
• 201000001881 impotence Diseases 0.000 claims description 3
• 210000003584 mesangial cell Anatomy 0.000 claims description 3
• 206010027599 migraine Diseases 0.000 claims description 3
• 201000008312 primary pulmonary hypertension Diseases 0.000 claims description 3
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 3
• 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
• 125000004076 pyridyl group Chemical group 0.000 claims description 3
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 3
• 208000037803 restenosis Diseases 0.000 claims description 3
• KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical class [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 claims description 3
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 3
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 3
• 125000006350 alkyl thio alkyl group Chemical group 0.000 claims description 2
• 150000001450 anions Chemical class 0.000 claims description 2
• 125000004104 aryloxy group Chemical group 0.000 claims description 2
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
• 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 2
• 125000002524 organometallic group Chemical group 0.000 claims description 2
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• 125000006308 propyl amino group Chemical group 0.000 claims description 2
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims 165
• 125000004284 isoxazol-3-yl group Chemical group [H]C1=C([H])C(*)=NO1 0.000 claims 7
• 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 6
• 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims 5
• UENGBOCGGKLVJJ-UHFFFAOYSA-N 2-chloro-1-(2,4-difluorophenyl)ethanone Chemical compound FC1=CC=C(C(=O)CCl)C(F)=C1 UENGBOCGGKLVJJ-UHFFFAOYSA-N 0.000 claims 4
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims 4
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 3
• 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 3
• 125000004494 ethyl ester group Chemical group 0.000 claims 3
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims 3
• 230000017095 negative regulation of cell growth Effects 0.000 claims 3
• 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims 2
• 125000004793 2,2,2-trifluoroethoxy group Chemical group FC(CO*)(F)F 0.000 claims 2
• YWPABLWXCWUIIT-UHFFFAOYSA-N 2-(2-phenylphenyl)acetic acid Chemical compound OC(=O)CC1=CC=CC=C1C1=CC=CC=C1 YWPABLWXCWUIIT-UHFFFAOYSA-N 0.000 claims 2
• 125000004791 2-fluoroethoxy group Chemical group FCCO* 0.000 claims 2
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims 2
• 208000009304 Acute Kidney Injury Diseases 0.000 claims 2
• 201000001320 Atherosclerosis Diseases 0.000 claims 2
• 206010057671 Female sexual dysfunction Diseases 0.000 claims 2
• 206010057672 Male sexual dysfunction Diseases 0.000 claims 2
• 208000033626 Renal failure acute Diseases 0.000 claims 2
• 201000011040 acute kidney failure Diseases 0.000 claims 2
• 208000012998 acute renal failure Diseases 0.000 claims 2
• 208000006673 asthma Diseases 0.000 claims 2
• LDECUSDQMXVUMP-UHFFFAOYSA-N benzyl 3-[6-[[2-(butylamino)-1-[3-methoxycarbonyl-4-(2-methoxy-2-oxoethoxy)phenyl]-2-oxoethyl]-hexylamino]-6-oxohexyl]-4-methyl-2-oxo-6-(4-phenylphenyl)-1,6-dihydropyrimidine-5-carboxylate Chemical compound O=C1NC(C=2C=CC(=CC=2)C=2C=CC=CC=2)C(C(=O)OCC=2C=CC=CC=2)=C(C)N1CCCCCC(=O)N(CCCCCC)C(C(=O)NCCCC)C1=CC=C(OCC(=O)OC)C(C(=O)OC)=C1 LDECUSDQMXVUMP-UHFFFAOYSA-N 0.000 claims 2
• 150000003857 carboxamides Chemical class 0.000 claims 2
• 208000020832 chronic kidney disease Diseases 0.000 claims 2
• 208000022831 chronic renal failure syndrome Diseases 0.000 claims 2
• 208000028867 ischemia Diseases 0.000 claims 2
• 125000002510 isobutoxy group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])O* 0.000 claims 2
• 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims 2
• 239000011664 nicotinic acid Substances 0.000 claims 2
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• HLEKYJVHEBHTMR-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O.CCCCC(N)=O HLEKYJVHEBHTMR-UHFFFAOYSA-N 0.000 claims 2
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 2
• 229960005206 pyrazinamide Drugs 0.000 claims 2
• 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 2
• ABYZSYDGJGVCHS-ZETCQYMHSA-N (2s)-2-acetamido-n-(4-nitrophenyl)propanamide Chemical compound CC(=O)N[C@@H](C)C(=O)NC1=CC=C([N+]([O-])=O)C=C1 ABYZSYDGJGVCHS-ZETCQYMHSA-N 0.000 claims 1
• XDEHMKQLKPZERH-BYPYZUCNSA-N (2s)-2-amino-3-methylbutanamide Chemical compound CC(C)[C@H](N)C(N)=O XDEHMKQLKPZERH-BYPYZUCNSA-N 0.000 claims 1
• RTSUXCDLIDGDAG-UHFFFAOYSA-N 1-tert-butyl-1-methylurea Chemical compound NC(=O)N(C)C(C)(C)C RTSUXCDLIDGDAG-UHFFFAOYSA-N 0.000 claims 1
• ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 claims 1
• KMLXIQFZZZWADQ-UHFFFAOYSA-N 2-(2-fluorophenyl)-n-methylacetamide Chemical compound CNC(=O)CC1=CC=CC=C1F KMLXIQFZZZWADQ-UHFFFAOYSA-N 0.000 claims 1
• WLPDLZHYIZNBKB-UHFFFAOYSA-N 2-(3,4-dimethyl-1,2-oxazol-5-yl)-6-phenylbenzenesulfonamide Chemical compound CC1=NOC(C=2C(=C(C=3C=CC=CC=3)C=CC=2)S(N)(=O)=O)=C1C WLPDLZHYIZNBKB-UHFFFAOYSA-N 0.000 claims 1
• NTBOMZCMZSXPGB-UHFFFAOYSA-N 2-[4-[(2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl]-2-(1-hydroxyethyl)phenyl]-n-(4,5-dimethyl-1,2-oxazol-3-yl)benzenesulfonamide Chemical compound O=C1N(CC=2C=C(C(=CC=2)C=2C(=CC=CC=2)S(=O)(=O)NC=2C(=C(C)ON=2)C)C(C)O)C(CCCC)=NC21CCCC2 NTBOMZCMZSXPGB-UHFFFAOYSA-N 0.000 claims 1
• HZPYCAQIDLRKRU-UHFFFAOYSA-N 2-[4-[(2-butyl-4-oxoquinazolin-3-yl)methyl]phenyl]-n-(3,4-dimethyl-1,2-oxazol-5-yl)benzenesulfonamide Chemical compound CCCCC1=NC2=CC=CC=C2C(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1S(=O)(=O)NC=1ON=C(C)C=1C HZPYCAQIDLRKRU-UHFFFAOYSA-N 0.000 claims 1
• ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 claims 1
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• KSRWGFLROQLABM-UHFFFAOYSA-N 5-chloro-3-[[4-[2-[(4,5-dimethyl-1,2-oxazol-3-yl)sulfamoyl]phenyl]phenyl]methyl]-n,n-dimethyl-2-propylimidazole-4-carboxamide Chemical class CCCC1=NC(Cl)=C(C(=O)N(C)C)N1CC1=CC=C(C=2C(=CC=CC=2)S(=O)(=O)NC=2C(=C(C)ON=2)C)C=C1 KSRWGFLROQLABM-UHFFFAOYSA-N 0.000 claims 1
• 241000532370 Atla Species 0.000 claims 1
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• QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 claims 1
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• WAIWMLBJZHNEOY-UHFFFAOYSA-N n-(4,5-dimethyl-1,2-oxazol-3-yl)-2-[4-[(4-oxo-2-propyl-5,6,7,8-tetrahydrocyclohepta[d]imidazol-3-yl)methyl]-2-propylphenyl]benzenesulfonamide Chemical compound CCCC1=NC=2CCCCC(=O)C=2N1CC(C=C1CCC)=CC=C1C1=CC=CC=C1S(=O)(=O)NC1=NOC(C)=C1C WAIWMLBJZHNEOY-UHFFFAOYSA-N 0.000 claims 1
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