DE69628740T2 - Thienyl-, furyl-, pyrrolyl- und biphenylsulfonamide und derivate zur modulation der endothelin-aktivität - Google Patents

Info

Publication number

DE69628740T2

DE69628740T2 DE69628740T DE69628740T DE69628740T2 DE 69628740 T2 DE69628740 T2 DE 69628740T2 DE 69628740 T DE69628740 T DE 69628740T DE 69628740 T DE69628740 T DE 69628740T DE 69628740 T2 DE69628740 T2 DE 69628740T2

Authority

DE

Germany

Prior art keywords

thiophene

isoxazolyl

methyl

sulfonamide

chloro

Prior art date

1995-04-04

Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)

Expired - Lifetime

Links

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• 229940124530 sulfonamide Drugs 0.000 title claims abstract description 62
• 230000000694 effects Effects 0.000 title claims abstract description 59
• -1 PYRROLYL Chemical class 0.000 title claims description 483
• 235000010290 biphenyl Nutrition 0.000 title 1
• 239000004305 biphenyl Substances 0.000 title 1
• ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 title 1
• 108050009340 Endothelin Proteins 0.000 claims abstract description 226
• 102000002045 Endothelin Human genes 0.000 claims abstract description 204
• 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 abstract description 192
• 102000005962 receptors Human genes 0.000 claims abstract description 82
• 108020003175 receptors Proteins 0.000 claims abstract description 82
• 150000003839 salts Chemical class 0.000 claims abstract description 66
• 239000002253 acid Substances 0.000 claims abstract description 52
• 150000002148 esters Chemical class 0.000 claims abstract description 52
• 150000003456 sulfonamides Chemical class 0.000 claims abstract description 45
• 230000027455 binding Effects 0.000 claims abstract description 31
• 102000010180 Endothelin receptor Human genes 0.000 claims abstract description 23
• 108050001739 Endothelin receptor Proteins 0.000 claims abstract description 23
• 230000002401 inhibitory effect Effects 0.000 claims abstract description 10
• 150000001875 compounds Chemical class 0.000 claims description 178
• BWJZHYWAXLWLTB-UHFFFAOYSA-N thiophene-3-sulfonamide Chemical compound NS(=O)(=O)C=1C=CSC=1 BWJZHYWAXLWLTB-UHFFFAOYSA-N 0.000 claims description 133
• 125000000217 alkyl group Chemical group 0.000 claims description 67
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 53
• 230000001404 mediated effect Effects 0.000 claims description 41
• 208000035475 disorder Diseases 0.000 claims description 28
• 201000010099 disease Diseases 0.000 claims description 25
• 238000011282 treatment Methods 0.000 claims description 23
• 206010047139 Vasoconstriction Diseases 0.000 claims description 19
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 19
• 230000025033 vasoconstriction Effects 0.000 claims description 19
• 208000024891 symptom Diseases 0.000 claims description 18
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
• 239000003814 drug Substances 0.000 claims description 16
• 239000001257 hydrogen Substances 0.000 claims description 16
• 229910052739 hydrogen Inorganic materials 0.000 claims description 16
• 206010020772 Hypertension Diseases 0.000 claims description 15
• KTFDYVNEGTXQCV-UHFFFAOYSA-N 2-Thiophenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CS1 KTFDYVNEGTXQCV-UHFFFAOYSA-N 0.000 claims description 13
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 125000003545 alkoxy group Chemical group 0.000 claims description 11
• 208000006673 asthma Diseases 0.000 claims description 11
• 150000004820 halides Chemical class 0.000 claims description 11
• 208000001647 Renal Insufficiency Diseases 0.000 claims description 10
• 201000006370 kidney failure Diseases 0.000 claims description 10
• 239000005022 packaging material Substances 0.000 claims description 10
• 239000008194 pharmaceutical composition Substances 0.000 claims description 9
• 239000003937 drug carrier Substances 0.000 claims description 8
• 150000002431 hydrogen Chemical class 0.000 claims description 8
• 238000004519 manufacturing process Methods 0.000 claims description 8
• 208000002815 pulmonary hypertension Diseases 0.000 claims description 8
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
• 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 6
• 208000024172 Cardiovascular disease Diseases 0.000 claims description 6
• 206010040070 Septic Shock Diseases 0.000 claims description 6
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
• 125000005605 benzo group Chemical group 0.000 claims description 6
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
• 208000027866 inflammatory disease Diseases 0.000 claims description 6
• 206010002199 Anaphylactic shock Diseases 0.000 claims description 5
• 102000003951 Erythropoietin Human genes 0.000 claims description 5
• 108090000394 Erythropoietin Proteins 0.000 claims description 5
• 208000032456 Hemorrhagic Shock Diseases 0.000 claims description 5
• 206010049771 Shock haemorrhagic Diseases 0.000 claims description 5
• 208000003455 anaphylaxis Diseases 0.000 claims description 5
• 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 claims description 5
• 229940105423 erythropoietin Drugs 0.000 claims description 5
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 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
• BJVAENLIIOACPY-UHFFFAOYSA-N 1-benzothiophene-3-sulfonamide Chemical compound C1=CC=C2C(S(=O)(=O)N)=CSC2=C1 BJVAENLIIOACPY-UHFFFAOYSA-N 0.000 claims description 4
• KZOWNALBTMILAP-JBMRGDGGSA-N ancitabine hydrochloride Chemical compound Cl.N=C1C=CN2[C@@H]3O[C@H](CO)[C@@H](O)[C@@H]3OC2=N1 KZOWNALBTMILAP-JBMRGDGGSA-N 0.000 claims description 4
• 230000003042 antagnostic effect Effects 0.000 claims description 4
• AMZDQGOJRQATPU-UHFFFAOYSA-N n-(4-bromo-3-methyl-1,2-oxazol-5-yl)-2-[(3,4,5-trimethoxyphenyl)methyl]-1-benzothiophene-3-sulfonamide Chemical compound COC1=C(OC)C(OC)=CC(CC2=C(C3=CC=CC=C3S2)S(=O)(=O)NC2=C(C(C)=NO2)Br)=C1 AMZDQGOJRQATPU-UHFFFAOYSA-N 0.000 claims description 4
• LYXCSZFDWCMVQS-UHFFFAOYSA-N n-(4-bromo-3-methyl-1,2-oxazol-5-yl)-2-[(3,4-dimethoxyphenyl)methyl]-1-benzothiophene-3-sulfonamide Chemical compound C1=C(OC)C(OC)=CC=C1CC1=C(S(=O)(=O)NC2=C(C(C)=NO2)Br)C2=CC=CC=C2S1 LYXCSZFDWCMVQS-UHFFFAOYSA-N 0.000 claims description 4
• LFJWGKAUSUIRQH-UHFFFAOYSA-N 2-(1,3-benzodioxol-5-ylmethyl)-n-(4-bromo-3-methyl-1,2-oxazol-5-yl)-1-benzothiophene-3-sulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C=2C3=CC=CC=C3SC=2CC=2C=C3OCOC3=CC=2)=C1Br LFJWGKAUSUIRQH-UHFFFAOYSA-N 0.000 claims description 3
• 208000010412 Glaucoma Diseases 0.000 claims description 3
• 208000019255 Menstrual disease Diseases 0.000 claims description 3
• 229960003444 immunosuppressant agent Drugs 0.000 claims description 3
• 239000003018 immunosuppressive agent Substances 0.000 claims description 3
• 206010052428 Wound Diseases 0.000 claims description 2
• 208000027418 Wounds and injury Diseases 0.000 claims description 2
• 230000001861 immunosuppressant effect Effects 0.000 claims description 2
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims 9
• XRUNQUOBZSSTNJ-UHFFFAOYSA-N n-phenyl-3-sulfamoylthiophene-2-carboxamide Chemical compound C1=CSC(C(=O)NC=2C=CC=CC=2)=C1S(=O)(=O)N XRUNQUOBZSSTNJ-UHFFFAOYSA-N 0.000 claims 3
• 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims 2
• 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
• 125000005504 styryl group Chemical group 0.000 claims 2
• AEWDJTNFRJECRE-UHFFFAOYSA-N 2-phenyl-n-thiophen-2-ylsulfonylacetamide Chemical compound C=1C=CSC=1S(=O)(=O)NC(=O)CC1=CC=CC=C1 AEWDJTNFRJECRE-UHFFFAOYSA-N 0.000 claims 1
• DDLQURLFWCNWJP-UHFFFAOYSA-N 3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]-n-(2-cyano-4,5-dimethoxyphenyl)thiophene-2-carboxamide Chemical compound C1=C(OC)C(OC)=CC(NC(=O)C2=C(C=CS2)S(=O)(=O)NC2=C(C(C)=NO2)Cl)=C1C#N DDLQURLFWCNWJP-UHFFFAOYSA-N 0.000 claims 1
• UXNJXSWMWFYCEM-UHFFFAOYSA-N 3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]-n-[3-(hydroxymethyl)-2,4,6-trimethylphenyl]thiophene-2-carboxamide Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)NC=2C(=C(CO)C(C)=CC=2C)C)=C1Cl UXNJXSWMWFYCEM-UHFFFAOYSA-N 0.000 claims 1
• 208000018522 Gastrointestinal disease Diseases 0.000 claims 1
• 208000030533 eye disease Diseases 0.000 claims 1
• 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 1
• 239000003112 inhibitor Substances 0.000 claims 1
• GLFFKEDSTKDWRX-UHFFFAOYSA-N methyl 3-[[3-[(4-chloro-3-methyl-1,2-oxazol-5-yl)sulfamoyl]thiophene-2-carbonyl]amino]-2,4,6-trimethylbenzoate Chemical compound COC(=O)C1=C(C)C=C(C)C(NC(=O)C2=C(C=CS2)S(=O)(=O)NC2=C(C(C)=NO2)Cl)=C1C GLFFKEDSTKDWRX-UHFFFAOYSA-N 0.000 claims 1
• BHPQYINQHPDQAV-UHFFFAOYSA-N n-(4-chloro-3-methyl-1,2-oxazol-5-yl)-2-[2-(3-cyano-2,4,6-trimethylphenyl)acetyl]thiophene-3-sulfonamide Chemical compound CC1=NOC(NS(=O)(=O)C2=C(SC=C2)C(=O)CC=2C(=C(C#N)C(C)=CC=2C)C)=C1Cl BHPQYINQHPDQAV-UHFFFAOYSA-N 0.000 claims 1
• CXBLWIRXCMJQLI-UHFFFAOYSA-N n-phenoxythiophene-2-sulfonamide Chemical compound C=1C=CSC=1S(=O)(=O)NOC1=CC=CC=C1 CXBLWIRXCMJQLI-UHFFFAOYSA-N 0.000 claims 1
• 230000010807 negative regulation of binding Effects 0.000 claims 1
• 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 1
• 238000000034 method Methods 0.000 abstract description 99
• 108090000765 processed proteins & peptides Proteins 0.000 abstract description 14
• 102000004196 processed proteins & peptides Human genes 0.000 abstract description 10
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 569
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 393
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 252
• 235000019439 ethyl acetate Nutrition 0.000 description 198
• 239000007787 solid Substances 0.000 description 172
• 239000000243 solution Substances 0.000 description 160
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 130
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 123
• 239000000203 mixture Substances 0.000 description 118
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
• 238000003818 flash chromatography Methods 0.000 description 77
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 75
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• XCYKKCVEVOZFIL-UHFFFAOYSA-N 4-bromo-3-methyl-1,2-oxazol-5-amine Chemical compound CC1=NOC(N)=C1Br XCYKKCVEVOZFIL-UHFFFAOYSA-N 0.000 description 68
• 238000001953 recrystallisation Methods 0.000 description 59
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• 229910000104 sodium hydride Inorganic materials 0.000 description 44
• 238000004128 high performance liquid chromatography Methods 0.000 description 42
• 238000003756 stirring Methods 0.000 description 41
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• 239000012043 crude product Substances 0.000 description 37
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 34
• 230000002829 reductive effect Effects 0.000 description 34
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 32
• YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 32
• FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 30
• UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 29
• 239000000843 powder Substances 0.000 description 27
• 101800004490 Endothelin-1 Proteins 0.000 description 26
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• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 26
• 239000000047 product Substances 0.000 description 26
• 102400000686 Endothelin-1 Human genes 0.000 description 25
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• 210000001519 tissue Anatomy 0.000 description 23
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• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
• 125000003118 aryl group Chemical group 0.000 description 21
• 229910052757 nitrogen Inorganic materials 0.000 description 21
• 239000003480 eluent Substances 0.000 description 20
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• 238000004140 cleaning Methods 0.000 description 19
• YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 18
• 238000001704 evaporation Methods 0.000 description 18
• 230000008020 evaporation Effects 0.000 description 18
• 238000001727 in vivo Methods 0.000 description 17
• NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 17
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 16
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• 239000012267 brine Substances 0.000 description 16
• 239000007788 liquid Substances 0.000 description 16
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 16
• AQRLNPVMDITEJU-UHFFFAOYSA-N triethylsilane Chemical compound CC[SiH](CC)CC AQRLNPVMDITEJU-UHFFFAOYSA-N 0.000 description 16
• XQULVCXDMBETEF-UHFFFAOYSA-N 1-(5-bromothiophen-2-yl)sulfonylpyrrole Chemical compound S1C(Br)=CC=C1S(=O)(=O)N1C=CC=C1 XQULVCXDMBETEF-UHFFFAOYSA-N 0.000 description 15
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
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• 239000005557 antagonist Substances 0.000 description 15
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• MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 14
• 239000000706 filtrate Substances 0.000 description 14
• 238000012360 testing method Methods 0.000 description 14
• 125000001544 thienyl group Chemical group 0.000 description 14
• PYNDWPFZDQONDV-UHFFFAOYSA-N 3,4-dimethyl-1,2-oxazol-5-amine Chemical compound CC1=NOC(N)=C1C PYNDWPFZDQONDV-UHFFFAOYSA-N 0.000 description 13
• 125000004122 cyclic group Chemical group 0.000 description 13
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• 229940002612 prodrug Drugs 0.000 description 10
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• UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 9
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• 239000004480 active ingredient Substances 0.000 description 9
• 150000001413 amino acids Chemical class 0.000 description 9
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• 230000004071 biological effect Effects 0.000 description 9
• 125000004432 carbon atom Chemical group C* 0.000 description 9
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