SK9532002A3 - Sulfonamides and derivatives thereof that modulate the activity of endothelin - Google Patents

Info

Publication number

SK9532002A3

SK9532002A3 SK953-2002A SK9532002A SK9532002A3 SK 9532002 A3 SK9532002 A3 SK 9532002A3 SK 9532002 A SK9532002 A SK 9532002A SK 9532002 A3 SK9532002 A3 SK 9532002A3

Authority

SK

Slovakia

Prior art keywords

group

endothelin

compound

hydrogen

methyl

Prior art date

1999-12-31

Links

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• 108050009340 Endothelin Proteins 0.000 title claims abstract description 244
• 102000002045 Endothelin Human genes 0.000 title claims abstract description 217
• 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 title claims abstract description 207
• 230000000694 effects Effects 0.000 title claims abstract description 71
• 229940124530 sulfonamide Drugs 0.000 title claims abstract description 67
• 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 43
• 239000000203 mixture Substances 0.000 claims abstract description 144
• 238000000034 method Methods 0.000 claims abstract description 89
• 102000005962 receptors Human genes 0.000 claims abstract description 75
• 108020003175 receptors Proteins 0.000 claims abstract description 75
• 238000009472 formulation Methods 0.000 claims abstract description 67
• 230000001404 mediated effect Effects 0.000 claims abstract description 47
• 230000027455 binding Effects 0.000 claims abstract description 34
• 102000010180 Endothelin receptor Human genes 0.000 claims abstract description 33
• 108050001739 Endothelin receptor Proteins 0.000 claims abstract description 33
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 15
• 150000001875 compounds Chemical class 0.000 claims description 283
• -1 2-oxazolyl Chemical group 0.000 claims description 264
• 125000000217 alkyl group Chemical group 0.000 claims description 246
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 123
• 125000003545 alkoxy group Chemical group 0.000 claims description 102
• 125000003118 aryl group Chemical group 0.000 claims description 102
• 239000001257 hydrogen Substances 0.000 claims description 99
• 229910052739 hydrogen Inorganic materials 0.000 claims description 99
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 93
• 239000000243 solution Substances 0.000 claims description 83
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 77
• 125000003342 alkenyl group Chemical group 0.000 claims description 72
• 125000001072 heteroaryl group Chemical group 0.000 claims description 71
• 125000000304 alkynyl group Chemical group 0.000 claims description 62
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 62
• 150000003839 salts Chemical class 0.000 claims description 58
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 57
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 56
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 54
• 125000000623 heterocyclic group Chemical group 0.000 claims description 52
• 201000010099 disease Diseases 0.000 claims description 49
• 159000000000 sodium salts Chemical class 0.000 claims description 49
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 48
• 125000001188 haloalkyl group Chemical group 0.000 claims description 45
• 208000035475 disorder Diseases 0.000 claims description 44
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 44
• 125000004432 carbon atom Chemical group C* 0.000 claims description 43
• 229910052736 halogen Inorganic materials 0.000 claims description 43
• 150000002367 halogens Chemical class 0.000 claims description 42
• 125000002877 alkyl aryl group Chemical group 0.000 claims description 40
• 125000002577 pseudohalo group Chemical group 0.000 claims description 40
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 39
• 229910052757 nitrogen Inorganic materials 0.000 claims description 36
• 125000000392 cycloalkenyl group Chemical group 0.000 claims description 35
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 35
• 229910052799 carbon Inorganic materials 0.000 claims description 34
• 125000005843 halogen group Chemical group 0.000 claims description 34
• 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 34
• 125000001424 substituent group Chemical group 0.000 claims description 33
• 125000004122 cyclic group Chemical group 0.000 claims description 32
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 31
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
• 229910052717 sulfur Inorganic materials 0.000 claims description 26
• 208000024891 symptom Diseases 0.000 claims description 25
• 206010020772 Hypertension Diseases 0.000 claims description 24
• 150000001413 amino acids Chemical class 0.000 claims description 24
• 239000002775 capsule Substances 0.000 claims description 24
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 24
• 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 23
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 22
• 125000003282 alkyl amino group Chemical group 0.000 claims description 21
• 125000004104 aryloxy group Chemical group 0.000 claims description 21
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 21
• 239000003937 drug carrier Substances 0.000 claims description 20
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 20
• 239000008194 pharmaceutical composition Substances 0.000 claims description 20
• 125000001769 aryl amino group Chemical group 0.000 claims description 19
• 239000000843 powder Substances 0.000 claims description 19
• 125000004434 sulfur atom Chemical group 0.000 claims description 19
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
• WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 18
• 206010047139 Vasoconstriction Diseases 0.000 claims description 17
• 150000001721 carbon Chemical group 0.000 claims description 17
• 150000002402 hexoses Chemical class 0.000 claims description 17
• 230000025033 vasoconstriction Effects 0.000 claims description 17
• 125000005110 aryl thio group Chemical group 0.000 claims description 16
• 239000008176 lyophilized powder Substances 0.000 claims description 16
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 15
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
• 208000023504 respiratory system disease Diseases 0.000 claims description 15
• 229930182473 O-glycoside Natural products 0.000 claims description 14
• 150000008444 O-glycosides Chemical class 0.000 claims description 14
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 14
• 125000004414 alkyl thio group Chemical group 0.000 claims description 14
• 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 14
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 14
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical group ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 claims description 14
• HMFHBZSHGGEWLO-SOOFDHNKSA-N D-ribofuranose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H]1O HMFHBZSHGGEWLO-SOOFDHNKSA-N 0.000 claims description 13
• PYMYPHUHKUWMLA-LMVFSUKVSA-N Ribose Natural products OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PYMYPHUHKUWMLA-LMVFSUKVSA-N 0.000 claims description 13
• 125000005213 alkyl heteroaryl group Chemical group 0.000 claims description 13
• 125000005530 alkylenedioxy group Chemical group 0.000 claims description 13
• HMFHBZSHGGEWLO-UHFFFAOYSA-N alpha-D-Furanose-Ribose Natural products OCC1OC(O)C(O)C1O HMFHBZSHGGEWLO-UHFFFAOYSA-N 0.000 claims description 13
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 13
• 125000004966 cyanoalkyl group Chemical group 0.000 claims description 13
• MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 12
• NBVXSUQYWXRMNV-UHFFFAOYSA-N fluoromethane Chemical compound FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 claims description 12
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 12
• 229910052760 oxygen Inorganic materials 0.000 claims description 11
• 239000005022 packaging material Substances 0.000 claims description 11
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
• 208000001647 Renal Insufficiency Diseases 0.000 claims description 10
• 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 10
• 125000002947 alkylene group Chemical group 0.000 claims description 10
• 208000006673 asthma Diseases 0.000 claims description 10
• 125000004429 atom Chemical group 0.000 claims description 10
• 239000008121 dextrose Substances 0.000 claims description 10
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 10
• 201000006370 kidney failure Diseases 0.000 claims description 10
• 239000000463 material Substances 0.000 claims description 10
• 235000000346 sugar Nutrition 0.000 claims description 10
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 9
• 229910052801 chlorine Inorganic materials 0.000 claims description 9
• 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 8
• 125000006323 alkenyl amino group Chemical group 0.000 claims description 8
• 208000010125 myocardial infarction Diseases 0.000 claims description 8
• 208000010412 Glaucoma Diseases 0.000 claims description 7
• 229910052783 alkali metal Inorganic materials 0.000 claims description 7
• 125000005108 alkenylthio group Chemical group 0.000 claims description 7
• 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 7
• 125000005154 alkyl sulfonyl amino alkyl group Chemical group 0.000 claims description 7
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 7
• 125000005019 carboxyalkenyl group Chemical group 0.000 claims description 7
• 125000004181 carboxyalkyl group Chemical group 0.000 claims description 7
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000003106 haloaryl group Chemical group 0.000 claims description 7
• 125000004475 heteroaralkyl group Chemical group 0.000 claims description 7
• 229920001223 polyethylene glycol Polymers 0.000 claims description 7
• 150000003334 secondary amides Chemical class 0.000 claims description 7
• 239000012064 sodium phosphate buffer Substances 0.000 claims description 7
• 206010002199 Anaphylactic shock Diseases 0.000 claims description 6
• 208000029725 Metabolic bone disease Diseases 0.000 claims description 6
• 239000002202 Polyethylene glycol Substances 0.000 claims description 6
• 206010040070 Septic Shock Diseases 0.000 claims description 6
• 206010049771 Shock haemorrhagic Diseases 0.000 claims description 6
• 125000004450 alkenylene group Chemical group 0.000 claims description 6
• 208000003455 anaphylaxis Diseases 0.000 claims description 6
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 6
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 6
• 239000000460 chlorine Substances 0.000 claims description 6
• 238000000576 coating method Methods 0.000 claims description 6
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 6
• 125000004986 diarylamino group Chemical group 0.000 claims description 6
• 238000001914 filtration Methods 0.000 claims description 6
• 208000019622 heart disease Diseases 0.000 claims description 6
• 208000027866 inflammatory disease Diseases 0.000 claims description 6
• IAYNHDZSSDUYHY-UHFFFAOYSA-N n-(2-acetyl-4,6-dimethylphenyl)-3-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxamide Chemical compound CC(=O)C1=CC(C)=CC(C)=C1NC(=O)C1=C(S(=O)(=O)NC2=C(C(C)=NO2)C)C=CS1 IAYNHDZSSDUYHY-UHFFFAOYSA-N 0.000 claims description 6
• ZQBAKBUEJOMQEX-UHFFFAOYSA-N phenyl salicylate Chemical compound OC1=CC=CC=C1C(=O)OC1=CC=CC=C1 ZQBAKBUEJOMQEX-UHFFFAOYSA-N 0.000 claims description 6
• 150000003140 primary amides Chemical class 0.000 claims description 6
• 206010006482 Bronchospasm Diseases 0.000 claims description 5
• 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 5
• 102000003951 Erythropoietin Human genes 0.000 claims description 5
• 108090000394 Erythropoietin Proteins 0.000 claims description 5
• 208000019255 Menstrual disease Diseases 0.000 claims description 5
• 230000002159 abnormal effect Effects 0.000 claims description 5
• 230000003042 antagnostic effect Effects 0.000 claims description 5
• 125000005100 aryl amino carbonyl group Chemical group 0.000 claims description 5
• 230000007885 bronchoconstriction Effects 0.000 claims description 5
• 150000001720 carbohydrates Chemical class 0.000 claims description 5
• 238000009505 enteric coating Methods 0.000 claims description 5
• 239000002702 enteric coating Substances 0.000 claims description 5
• 229940105423 erythropoietin Drugs 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 238000004519 manufacturing process Methods 0.000 claims description 5
• 230000002611 ovarian Effects 0.000 claims description 5
• 230000010412 perfusion Effects 0.000 claims description 5
• OXCMYAYHXIHQOA-UHFFFAOYSA-N potassium;[2-butyl-5-chloro-3-[[4-[2-(1,2,4-triaza-3-azanidacyclopenta-1,4-dien-5-yl)phenyl]phenyl]methyl]imidazol-4-yl]methanol Chemical compound [K+].CCCCC1=NC(Cl)=C(CO)N1CC1=CC=C(C=2C(=CC=CC=2)C2=N[N-]N=N2)C=C1 OXCMYAYHXIHQOA-UHFFFAOYSA-N 0.000 claims description 5
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• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
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• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
• YMSLHGRGMAOKEC-UHFFFAOYSA-N n-(2-cyano-3,4,6-trimethylphenyl)-3-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carboxamide Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)NC=2C(=C(C)C(C)=CC=2C)C#N)=C1C YMSLHGRGMAOKEC-UHFFFAOYSA-N 0.000 claims description 4
• 125000001749 primary amide group Chemical group 0.000 claims description 4
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• 239000003018 immunosuppressive agent Substances 0.000 claims description 3
• QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
• OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
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• 125000003368 amide group Chemical group 0.000 claims description 2
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• 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 8
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• ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims 2
• 229920001214 Polysorbate 60 Polymers 0.000 claims 2
• ULBTUVJTXULMLP-UHFFFAOYSA-N butyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCC ULBTUVJTXULMLP-UHFFFAOYSA-N 0.000 claims 2
• 239000004203 carnauba wax Substances 0.000 claims 2
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• ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims 2
• 229940125721 immunosuppressive agent Drugs 0.000 claims 2
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• 108090000765 processed proteins & peptides Proteins 0.000 abstract description 15
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• KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical class NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 abstract description 5
• 125000002541 furyl group Chemical group 0.000 abstract description 5
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• HLBCDKJOMBEQMZ-UHFFFAOYSA-N n-(1,2-oxazol-3-yl)-1h-pyrrole-2-sulfonamide Chemical class C=1C=CNC=1S(=O)(=O)NC=1C=CON=1 HLBCDKJOMBEQMZ-UHFFFAOYSA-N 0.000 abstract 1
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• 235000002639 sodium chloride Nutrition 0.000 description 70
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• 101800004490 Endothelin-1 Proteins 0.000 description 25
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• 239000000556 agonist Substances 0.000 description 12
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• 238000000338 in vitro Methods 0.000 description 12
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