NO314184B1 - Substituert benzensulfonamid derivater, fremgangsmåte for fremstilling av samme, farmasöytisk sammensetning innbefattende samme og anvendelseav samme forfremstilling av medikament - Google Patents
Substituert benzensulfonamid derivater, fremgangsmåte for fremstilling av samme, farmasöytisk sammensetning innbefattende samme og anvendelseav samme forfremstilling av medikament Download PDFInfo
- Publication number
- NO314184B1 NO314184B1 NO19984727A NO984727A NO314184B1 NO 314184 B1 NO314184 B1 NO 314184B1 NO 19984727 A NO19984727 A NO 19984727A NO 984727 A NO984727 A NO 984727A NO 314184 B1 NO314184 B1 NO 314184B1
- Authority
- NO
- Norway
- Prior art keywords
- phenyl
- sulfonyl
- methyl
- phenylisoxazol
- acetamide
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 69
- 238000002360 preparation method Methods 0.000 title claims description 35
- 230000008569 process Effects 0.000 title claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 11
- 239000003814 drug Substances 0.000 title claims description 6
- 229940079593 drug Drugs 0.000 title description 3
- 150000008331 benzenesulfonamides Chemical class 0.000 title 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 191
- 159000000000 sodium salts Chemical class 0.000 claims description 154
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 149
- 150000001875 compounds Chemical class 0.000 claims description 133
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 128
- -1 methylcarbonyloxymethyl Chemical group 0.000 claims description 85
- 150000003254 radicals Chemical class 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 57
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 229940124530 sulfonamide Drugs 0.000 claims description 32
- 150000003456 sulfonamides Chemical class 0.000 claims description 30
- 238000011282 treatment Methods 0.000 claims description 30
- 239000002585 base Substances 0.000 claims description 28
- 239000002904 solvent Substances 0.000 claims description 28
- HJZVHUQSQGITAM-UHFFFAOYSA-N butanamide Chemical compound CC[CH]C(N)=O HJZVHUQSQGITAM-UHFFFAOYSA-N 0.000 claims description 25
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical group CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 24
- 125000001145 hydrido group Chemical group *[H] 0.000 claims description 24
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 17
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 claims description 17
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 16
- 125000002883 imidazolyl group Chemical group 0.000 claims description 16
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 16
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 15
- 206010061218 Inflammation Diseases 0.000 claims description 15
- 239000002253 acid Substances 0.000 claims description 15
- 125000002541 furyl group Chemical group 0.000 claims description 15
- 230000004054 inflammatory process Effects 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 15
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 14
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 14
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 14
- 125000002971 oxazolyl group Chemical group 0.000 claims description 14
- 125000004043 oxo group Chemical group O=* 0.000 claims description 14
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 claims description 14
- 125000004076 pyridyl group Chemical group 0.000 claims description 14
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- UMBILIGVYYXBRD-UHFFFAOYSA-N n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 UMBILIGVYYXBRD-UHFFFAOYSA-N 0.000 claims description 12
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 12
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 11
- BOVVAGCRFBVSMH-UHFFFAOYSA-N 2-[[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylamino]acetic acid Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(=O)(=O)NCC(O)=O)C=C1 BOVVAGCRFBVSMH-UHFFFAOYSA-N 0.000 claims description 11
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 150000002460 imidazoles Chemical class 0.000 claims description 10
- DABKXKAHZRINCJ-UHFFFAOYSA-N n-[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)imidazol-1-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1N1C(C=2C(=NC=CC=2)C)=NC(C(F)(F)F)=C1 DABKXKAHZRINCJ-UHFFFAOYSA-N 0.000 claims description 10
- XLANJOIUYYCBSJ-UHFFFAOYSA-N n-[4-[5-(hydroxymethyl)-3-phenyl-1,2-oxazol-4-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1C1=C(CO)ON=C1C1=CC=CC=C1 XLANJOIUYYCBSJ-UHFFFAOYSA-N 0.000 claims description 9
- 229910052708 sodium Inorganic materials 0.000 claims description 9
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 8
- 208000002193 Pain Diseases 0.000 claims description 8
- SEVVOVNLQZXWRO-UHFFFAOYSA-N [4-[4-(acetylsulfamoyl)phenyl]-3-phenyl-1,2-oxazol-5-yl]methyl acetate Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1C1=C(COC(C)=O)ON=C1C1=CC=CC=C1 SEVVOVNLQZXWRO-UHFFFAOYSA-N 0.000 claims description 8
- 150000008064 anhydrides Chemical group 0.000 claims description 8
- IVQPYWFNIZDTFB-UHFFFAOYSA-N n-[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)imidazol-1-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1N1C(C=2C=C(C)C=NC=2)=NC(C(F)(F)F)=C1 IVQPYWFNIZDTFB-UHFFFAOYSA-N 0.000 claims description 8
- 230000036407 pain Effects 0.000 claims description 8
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 7
- GXLPXTQMKIFHNL-UHFFFAOYSA-N 2-amino-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylacetamide Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(=O)(=O)NC(=O)CN)C=C1 GXLPXTQMKIFHNL-UHFFFAOYSA-N 0.000 claims description 7
- 208000035475 disorder Diseases 0.000 claims description 7
- AROIRVNGHKAPEJ-UHFFFAOYSA-N n-[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)imidazol-1-yl]phenyl]sulfonylbutanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CCC)=CC=C1N1C(C=2C=C(C)C=NC=2)=NC(C(F)(F)F)=C1 AROIRVNGHKAPEJ-UHFFFAOYSA-N 0.000 claims description 7
- RRPAVYZAEYJLIV-UHFFFAOYSA-N n-[4-[3-(3-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1C1=C(C)ON=C1C1=CC=CC(F)=C1 RRPAVYZAEYJLIV-UHFFFAOYSA-N 0.000 claims description 7
- SHEZNOJEXCHKRT-UHFFFAOYSA-N 2-methyl-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C(C)C)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 SHEZNOJEXCHKRT-UHFFFAOYSA-N 0.000 claims description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 6
- 150000002148 esters Chemical class 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- OBNHDXLHPUVWBZ-UHFFFAOYSA-N methyl 3-[[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylamino]-3-oxopropanoate Chemical compound C1=CC(S(=O)(=O)NC(=O)CC(=O)OC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 OBNHDXLHPUVWBZ-UHFFFAOYSA-N 0.000 claims description 6
- CQWCMDRFKCDDBE-UHFFFAOYSA-N n-[4-(4,5-dimethyl-2-phenylpyrazol-3-yl)phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)C(C)=NN1C1=CC=CC=C1 CQWCMDRFKCDDBE-UHFFFAOYSA-N 0.000 claims description 6
- HBJRELCEAUESDU-UHFFFAOYSA-N n-[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)imidazol-1-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1N1C(C=2C=C(Cl)C=C(C)C=2)=NC(C(F)(F)F)=C1 HBJRELCEAUESDU-UHFFFAOYSA-N 0.000 claims description 6
- UFLSIWXZTLGQBO-UHFFFAOYSA-N n-[4-[2-pyridin-3-yl-4-(trifluoromethyl)imidazol-1-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1N1C(C=2C=NC=CC=2)=NC(C(F)(F)F)=C1 UFLSIWXZTLGQBO-UHFFFAOYSA-N 0.000 claims description 6
- JEFLFHUNDHMHBS-UHFFFAOYSA-N n-[4-[5-(difluoromethyl)-3-phenyl-1,2-oxazol-4-yl]phenyl]sulfonylbutanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CCC)=CC=C1C1=C(C(F)F)ON=C1C1=CC=CC=C1 JEFLFHUNDHMHBS-UHFFFAOYSA-N 0.000 claims description 6
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims description 5
- FEAXYAGGPKJWNP-UHFFFAOYSA-N 2-acetamido-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CNC(=O)C)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 FEAXYAGGPKJWNP-UHFFFAOYSA-N 0.000 claims description 5
- VKAMRRXGHIGUOC-UHFFFAOYSA-N 3-methoxy-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CCOC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 VKAMRRXGHIGUOC-UHFFFAOYSA-N 0.000 claims description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 239000000460 chlorine Substances 0.000 claims description 5
- UUYJQYHQMGMJNE-UHFFFAOYSA-N n-[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)imidazol-1-yl]phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1N1C(C=2C(=NC=CC=2)C)=NC(C(F)(F)F)=C1 UUYJQYHQMGMJNE-UHFFFAOYSA-N 0.000 claims description 5
- RNIVHFUBFIQAKR-UHFFFAOYSA-N n-[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1N1C(C=2C=CC(Cl)=CC=2)=CC(C(F)(F)F)=N1 RNIVHFUBFIQAKR-UHFFFAOYSA-N 0.000 claims description 5
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 5
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 claims description 5
- QWTFAROZGRGVKP-UHFFFAOYSA-N tert-butyl n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylcarbamate Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(=O)(=O)NC(=O)OC(C)(C)C)C=C1 QWTFAROZGRGVKP-UHFFFAOYSA-N 0.000 claims description 5
- 150000003512 tertiary amines Chemical class 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- UOJZXAVHVOSLBY-UHFFFAOYSA-N 2,2-dimethyl-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylpropanamide Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(=O)(=O)NC(=O)C(C)(C)C)C=C1 UOJZXAVHVOSLBY-UHFFFAOYSA-N 0.000 claims description 4
- UPCOALQBVSRRJH-UHFFFAOYSA-N 2-ethoxy-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)COCC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 UPCOALQBVSRRJH-UHFFFAOYSA-N 0.000 claims description 4
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical group CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000012346 acetyl chloride Substances 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
- OEHMOWQXDQWJOK-UHFFFAOYSA-N methyl 4-[[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylamino]-4-oxobutanoate Chemical compound C1=CC(S(=O)(=O)NC(=O)CCC(=O)OC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 OEHMOWQXDQWJOK-UHFFFAOYSA-N 0.000 claims description 4
- XZOXXAKVMYDPGI-UHFFFAOYSA-N n-[4-(2-oxo-3-phenyl-3h-furan-4-yl)phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=COC(=O)C1C1=CC=CC=C1 XZOXXAKVMYDPGI-UHFFFAOYSA-N 0.000 claims description 4
- JEKRFLTZIYZCFN-UHFFFAOYSA-N n-[4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1C1=C(C=2C=C(Cl)C(F)=CC=2)CCC1 JEKRFLTZIYZCFN-UHFFFAOYSA-N 0.000 claims description 4
- QYTCSNACICVAQU-UHFFFAOYSA-N n-[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)pyrazol-1-yl]phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1N1C(C=2C=C(F)C(OC)=CC=2)=CC(C(F)F)=N1 QYTCSNACICVAQU-UHFFFAOYSA-N 0.000 claims description 4
- RYKTYZGWZMSGIT-UHFFFAOYSA-N n-[4-[5-(hydroxymethyl)-3-phenyl-1,2-oxazol-4-yl]phenyl]sulfonylpropanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(CO)ON=C1C1=CC=CC=C1 RYKTYZGWZMSGIT-UHFFFAOYSA-N 0.000 claims description 4
- IPWFJLQDVFKJDU-UHFFFAOYSA-N pentanamide Chemical compound CCCCC(N)=O IPWFJLQDVFKJDU-UHFFFAOYSA-N 0.000 claims description 4
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 4
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
- DLZQFPWULWNSFC-UHFFFAOYSA-N 2-[acetyl-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylamino]acetic acid Chemical compound C1=CC(S(=O)(=O)N(CC(O)=O)C(=O)C)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 DLZQFPWULWNSFC-UHFFFAOYSA-N 0.000 claims description 3
- WZCCGMXSPZYGDX-UHFFFAOYSA-N 2-methoxy-n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)COC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 WZCCGMXSPZYGDX-UHFFFAOYSA-N 0.000 claims description 3
- IJTOZRCITTULPA-UHFFFAOYSA-N 4-[2-(4-fluorophenyl)pyrrol-1-yl]-n-methylbenzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NC)=CC=C1N1C(C=2C=CC(F)=CC=2)=CC=C1 IJTOZRCITTULPA-UHFFFAOYSA-N 0.000 claims description 3
- DMYSIIFBWILMSH-UHFFFAOYSA-N 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)pyrazol-1-yl]-n-methylbenzenesulfonamide Chemical compound C1=CC(S(=O)(=O)NC)=CC=C1N1C(C=2C=CC(F)=CC=2)=CC(C(F)(F)F)=N1 DMYSIIFBWILMSH-UHFFFAOYSA-N 0.000 claims description 3
- KYFKXZLWTIWCBK-UHFFFAOYSA-N 4-[[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylamino]-4-oxobutanoic acid Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(=O)(=O)NC(=O)CCC(O)=O)C=C1 KYFKXZLWTIWCBK-UHFFFAOYSA-N 0.000 claims description 3
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 3
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims description 3
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 3
- 201000011510 cancer Diseases 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- CXDHGRAOXJEMOO-UHFFFAOYSA-N methyl 2-[[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylamino]-2-oxoacetate Chemical compound C1=CC(S(=O)(=O)NC(=O)C(=O)OC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 CXDHGRAOXJEMOO-UHFFFAOYSA-N 0.000 claims description 3
- IRIHYRQDKBVTRJ-UHFFFAOYSA-N n-[4-(2-methyl-4-phenyl-1,3-oxazol-5-yl)phenyl]sulfonylacetamide Chemical compound C1=CC(S(=O)(=O)NC(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)N=C(C)O1 IRIHYRQDKBVTRJ-UHFFFAOYSA-N 0.000 claims description 3
- WCNGJPSUNBDLGE-UHFFFAOYSA-N n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylhexanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CCCCC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 WCNGJPSUNBDLGE-UHFFFAOYSA-N 0.000 claims description 3
- LSFPSLNEPSCUPY-UHFFFAOYSA-N n-[4-(5-methyl-3-phenyl-1,2-oxazol-4-yl)phenyl]sulfonylpentanamide Chemical compound C1=CC(S(=O)(=O)NC(=O)CCCC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 LSFPSLNEPSCUPY-UHFFFAOYSA-N 0.000 claims description 3
- WTWBDSYHGPGDBG-UHFFFAOYSA-N n-[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)pyrazol-1-yl]phenyl]sulfonylacetamide Chemical compound C1=C(F)C(OC)=CC=C1C1=CC(C(F)F)=NN1C1=CC=C(S(=O)(=O)NC(C)=O)C=C1 WTWBDSYHGPGDBG-UHFFFAOYSA-N 0.000 claims description 3
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Description
Foreliggende oppfinnelse hører inn under feltet antiinflammatoriske farmasøytiske midler og vedrører spesifikt promedikamenter av forbindelser som selektivt inhiberer cyklooksygenase-2, fremgangsmåte for fremstilling av samme, farmasøytisk sammensetning innbefattende samme og anvendelse av samme for fremstilling av medikament.
Anvendelse av ikke-steroidale antiinflammatoriske medikamenter (NSAID) for behandling av smerte og svelling assosiert med inflammasjon danner også alvorlige bivirkninger, inkludert livstruende sår. Den nylige oppdagelsen av et induserbart enzym assosiert med inflammasjon ("prostaglandin G/H syntase II" eller "cyklooksygenase-2 (COX-2)") tilveiebringer et anvendbart mål for inhibisjon som mer effektivt reduserer inflammasjonen og produserer feber og mindre drastiske bivirkninger.
Forbindelser som selektivt inhiberer cyklooksygenase-2 er blitt beskrevet. US-PS 5.380.738 beskriver oksazoler som selektivt inhiberer cyklooksygenase-2. US-PS 5.344.991 beskriver cyklopentener som selektivt inhiberer cyklooksygenase-2. US-PS 5.393.790 beskriver spiro forbindelser som selektivt inhiberer cyklooksygenase-2. W094/15932 beskriver tiofen og furanderivater som selektivt inhiberer cykloksygenase-2. Wo94/27980 beskriver oksazoler som selektivt inhiberer cykIoksygenase-2. W094/13635 beskriver forbindelser som selektivt inhiberer cyklooksygenase-2. WO94/20480 beskriver forbindelser som selektivt inhiberer cyklooksygenase-2. W095/15316 beskriver pyrazolylsulfonamidderivater som selektivt inhiberer cyklooksygenase-2.1 noen tilfeller er promedikamenter av anti-inflammatoriske forbindelser fordelaktige, spesielt når promedikamentene har øket oppløselighet i vann eller forsinket begynnende virkning.
Substituerte sulfonamider er blitt beskrevet. Pyrazolyl-sulfonylureaer er blitt beskrevet å ha mulig hypoglycemisk aktivitet [H. Faid-Allah and H. Mokhtar, Ind. J. Chem. 27,245
(1988)]. JP 1.045.374 beskriver vannoppløselige tetrazoliumforbindelser som er nyttige
i analyser for å bestemme reduserende forbindelser. D. Mukerjee et al. [Acta. Pharma. Jugosl., 31,151 (1981)) beskriver tetrazoliumsulfonamider som antivirale midler. JP 4.277.724 beskriver trifenylpyrazoliner som ikke-lineært optisk materiale. JP 5.323.522 beskriver anvendelse av heterocykliske forbindelser i svart og hvitt fotografisk materiale. US-PS 5.389.635 beskriver substituerte imidazoler som angiotensin II antagonister. US-PS 5.387.592 beskriver substituerte benzimidazolderivater som angiotensin II antagonister. G. Dorofeenko et al [Khim. Farm. Zh., 16,920 (1982)] beskriver pyridiniumsalter som antivirale midler. US-PS 5.338.749 beskriver diaryl
substituerte heterocyklyl forbindelser som antiartritt midler. Wo94/26731 beskriver tiofen forbindelser som selektivt inhiberer cyklooksygenase-2. WO95/00501 beskriver forbindelser for selektivt inhiberer cyklooksygenase-2, og 3-(4-(trifluoracetylaminosulfonyl)fenyl)-2-(4-fluorfenyl)tiofen blir beskrevet. T. Ivanov [Mh. Chem., 97,1499 (1966)] beskriver fremstilling av diarylindonderivater som mulige indikatorer, og 2-(4-(N-metylaminosulfonyl)fenyl]-3-fenylindon er spesifikt beskrevet.
J. Larsen and H. Bundgaard [Int. J. Pharmaceutics, 37, 87 (1987)] beskriver vurdering av N-acylsulfonamider som potensielle promedikamentderivater. J. Larsen et al [Int. J. Pharmaceutics, 47,103 (1988)] beskriver vurdering av N-metylsulfonamider som potensielle promedikamentderivater.
Det eksisterer for tiden et behov for forbindelser egnede for injiserbare antiinflammatoriske sammensetninger. Forbindelsene ifølge foreliggende oppfinnelse kan anvendes som promedikamenter.
En klasse av substituerte sulfonamid forbindelser nyttige som promedikamenter er definert i formel I:
hvori A er en ringsubstituent utvalgt fra C4-Cg-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon ved et eller flere radikaler utvalgt fra Ci-Cio-alkyl, C\- Ce-haloalkyl, okso, Ci-Ce-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-C[0-alkyl;
hvori R<1> er et radikal utvalgt fra pyridyl og fenyl, hvori R<1> eventuelt er substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og C(-C6-alkoksy;
hvori R<2> er hydrido;
og hvori R<3> er et radikal utvalgt fra Ci-Cio-alkyl, Ci-Cio-karboksyalkyl, Ci-Cio-acyl, Ci-C6-alkoksykarbonyl, Ci-C6-alkoksykarbonyl-Ci-Cio-alkylkarbonyl, Ci-C6-alkoksykarbonylkarbonyl, d-Cjo-karboksyalkylkarbonyl, Ci-Cio-alkylkarbonylamino-Ci-Cio-alkylkarbonyl, Ci-Cio-aminoalkylkarbonyl og C|-C6-alkoksy-Ci-Cio-alkylkarbonyl;
eller et farmasøytisk akseptablet salt derav.
Forbindelser med formel I kan være nyttige for, men ikke begrenset til, behandling av betennelse hos et individ, og forbehandling av andre cyklooksygenase-2 medierte forstyrrelser, så som, et smertestillende middel for behandling av smerte og hodepine, eller som et antipyretisk middel for behandling av feber. For eksempel kan forbindelsene ifølge opprinnelsen være nyttige for behandling av artritt, inkludert, men ikke begrenset til leddgikt, spondyloartropatier, gouty artritt, osteoartritt, systemisk lupus erythematosus og juvenil artritt. Slike forbindelser ifølge oppfinnelsen kan være nyttige for behandling av astma, bronkitt, menstruelle kramper, prematurfødsel, tendinitt, bursitt, hud-relaterte tilstander så som psoriasis, eksem, brannsår og dermatitt, og fra post-operative betennelser inkludert fra oftalmisk kirurgi så som katarakt kirurgi og refraktiv kirurgi. Forbindelsene ifølge oppfinnelsen kan også være nyttige for behandling av mave-tarm tilstander så som inflammatorisk tarmsykdom, Crohns sykdom, gastritt, irritabel mavesyndrom og ulcerativ kolitt. Forbindelsene ifølge oppfinnelsen kan være nyttige for forhindring eller behandling av cancer, så som kolorektal cancer, og cancer i bryst, lunge, prostata, blære, cervix og hud. Forbindelsene ifølge oppfinnelsen kan være nyttige for behandling av inflammasjon i slike sykdommer som vaskulære sykdommer, migrene hodepine, periartritt nodosa, thyroiditt, aplastisk anemi, Hodgkins sykdom, sklerodoma, revmatisk feber, type I diabetes, neuromuskulær junction sykdom inkludert myasthenia gravis, white matter sykdom inkludert multippel sklerose, sarkoidose, nefrotisk syndrom, Behcets syndrom, polymyositt, gingivitt, nefritt, hypersensitivitet, svelling som oppstår etter skade, myokardial ischemi og lignende. Forbindelsene kan også være nyttige for behandling av oftalmiske sykdommer, så som retinitt, retinopatier, uveitis, okulær fotofobi og akutt skade på øyevev. Forbindelsene kan også være nyttige for behandling av lungebetennelse, så som del som er assosiert med virale infeksjoner og cystisk fibrose. Forbindelsene kan også være nyttige for behandling av visse sentralnervesystem forstyrrelser, så som kortikal dementias inkludert Alzheimers sykdom, og sentralnervesystemskade som er et resultat av slag, ischemi og traumer. Forbindelsene ifølge oppfinnelsen er nyttige som anti-inflammatoriske midler, så som for behandling av artritt, med den ytterligere fordelen å ha betydelige mindre skadelige bivirkninger. Disse forbindelsene kan også være nyttige for behandling av allergisk rinitis, respiratorisk distress syndrom, endotoksin sjokk syndrom og aterosklerose. Forbindelsene kan også være nyttige for behandling av smerte, men er ikke begrenset til postoperativ smerte, tannpine, muskulær smerte og smerter som er et resultat av cancer. Forbindelsene kan også være nyttige for forhindring av dementias, så som Alzheimers sykdom.
Bortsett fra å være nyttig for behandling av mennesker er disse forbindelsene også nyttige for veterinær behandling av kjæledyr, eksotiske dyr og gårdsdyr, inkludert pattedyr, gnagere og lignende. Mer foretrukne dyr innbefatter hester, hunder og katter.
Foreliggende forbindelser kan også bli anvendt i samterapier, delvis eller fullstendig, i stedenfor andre konvensjonelle anti-inflammatoriske midler, så som sammen med steroider, NSAJD, 5-lipoksygenase inhibitorer, LTB4 antagonister og LTA4 hydrolase inhibitorer.
Egnede LTB4 inhibitorer innbefatter blant andre ebselen, Bayer Bay-x-1005, Ciba-Geigy forbindelse CGS-25019C, Leo Denmark forbindelse ETH-615, Lilly forbindelse LY-293111, Ono forbindelse ONO-4057, Terumo forbindelse TMK-688, Lilly forbindelse LY-213024,264086 og 292728, ONO forbindelse ONO-LB457, Searle forbindelse SC-53228, calcitrol, Lilly forbindelse LY-210073, LY223982, LY233469, og LY255283, ONO forbindelse ONO-LB-448, Searle forbindelser SC-41930, SC-50605 og SC-51146, og SK&F forbindelse SKF-104493. Det er foretrukket at LTB4 inhibitorene blir valgt fra ebselen, Bayer Bay-x-1005, Ciba-Geigy forbindelse CGS-25019C, Leo Denmark forbindelse ETH-615, Lilly forbindelse LY-293111, Ono forbindelse ONO-4057 og Terumo forbindelse TMK-688.
Egnede 5-LO inhibitorer innbefatter, blant andre, masoproeol, tenidap, zileuton, pranlukast, tepoksalin, rilopiroks, flezelastin hydroklorid, enazadremfosfat og bunaprolast.
Foreliggende forbindelser kan også bli anvendt i kombinasjonsterapi med opioider og andre smertestillende midler, så som morfin, meperidin eller kodein.
Betegnelsen "cyklooksygenase-2 inhibitor" omfatter forbindelser som selektivt inhiberer cyklooksygenase-2 over cyklooksygenase-1. Det er foretrukket at forbindelsene har en cykloksygenase-2 IC50 som er mindre enn omtrent 0,5 um, og også har et selektivt Forhold av cyklooksygenase-2 inhibisjon i forhold til cyklooksygenase-1 inhibisjon på minst 50, og mer foretrukket minst 100. Det er mer foretrukket at forbindelsene har en cyklooksygenase-1 ICso som er høyere enn omtrent 1 nm, hvor det er mer foretrukket at den er høyere enn 20 um. En slik foretrukket selektivitet kan indikere en evne til å redusere forekomsten av vanlige NSAID-induserte bivirkninger.
Angivelsen "terapeutisk-effektive" skal omfatte mengden av hvert middel som kan anvendes i kombinasjonsterapi og som vil oppnå målene som omfatter forbedring av alvorligheten og frekvensen av forekomsten ved behandling av hvert middel alene, med unngåelse av negative bivirkninger som vanligvis er assosiert med alternative terapier.
Angivelsen "kombinasjonsterapi" (eller "ko-terapi"), ved definiering av anvendelsen av et cyklooksygenase-2 inhibitor middel og et annet middel, skal omfatte administrasjon av hvert middel på en sekvensiell måte i et regime som vil tilveiebringe fordelaktige effekter med medikamentkombinasjon, og skal også omfatte koadministrering av disse midlene på en vesentlig samtidig måte, så som i en enkelt kapsel som har et bestemt forhold av disse aktive midlene eller i flere, separate kapsler for hvert middel.
Betegnelsen "promedikament" refererer til forbindelser som er medikamentforløpere som, etter administrering til et individ og påfølgende absorpsjon, blir omdannet til en aktiv form in vivo via en viss prosess, så som en metabolsk prosess. Andre produkter fra omdanningsprosessen blir lett fjernet fra kroppen. Mer foretrukne promedikamenter produserer produkter fra omdanningsprosessen som generelt blir akseptert å være trygge.
En annen klasse forbindelser ifølge oppfinnelsen angår forbindelser med formel II
hvori A er en ringsubstituent utvalgt fra Q-Cg-cykloalkenyl, furyl, imidazolyl, isoksazoiyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en
substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, C1-C6-haloalkyl, okso, Ci-C6-hydroksyalkyl ogCi-Cio-alkylkarbonyloksy-Ci-Cjo-alkyl;
hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Ci-Ce-alkoksy;
og hvori R<5> er et radikal utvalgt fra hydrido, Ci-Qo-alkyl, Ci-C6-alkoksy, Ci-Ce-alkoksy-Ci-Cio-alkyl, fenyl, Ci-Cio-karboksyalkyl, Ci-Ce-alkoksykarbonyl-Ci-C^-alkyl, Ci-C6-alkoksykarbonyl, Ci-Cio-aminoalkyl og Ci-Cio-alkylkarbonylamino-Ci-C6-alkyl; eller et farmasøytisk akseptabelt salt derav.
En tredje klasse forbindelser ifølge oppfinnelsen angår forbindelser med formel HJ:
hvori R<6> er et radikal utvalgt fra Ci-C6-alkyI, Ci-C6-haloalkyl og Ci-C6-hydroksyalkyl;
hvori R<7> er et radikal utvalgt fra hydrido, Q-Ce-alkyl, halo og Q-Ce-alkoksy;
og hvori R<8> er et radikal utvalgt fra hydrido, Ci-C6-alkyl, Ci-C6-alkoksy, Ci-C6-alkoksy-Ci-C6-alkyl, fenyl, Ci-C6-karboksyalkyl, Ci-C6-alkoksykarbonyl-Ci-C6-alkyl, C1-C6-alkoksykarbonyl, Ci-Ce-aminoalkyl og Ci-Ce-alkylkarbonylamino-Ci-Ce-alkyl; eller et farmasøytisk akseptabelt salt derav.
En familie av spesifikke forbindelser av spesiell interesse i formlene I-UJ består av forbindelser og farmasøytiske akseptable salter derav som følger: N-[[4-[2-(2-metylpyrichn-6-yl)-4-(trifluormetyl)-lH-imidazol-l-yl] fenyl] sulfonyl ] acetamid; N-[[4-[2-(2-metyIp<y>ridin-6-yI)-4-(trifluormetyI)-IH-imidazoI-l-yl]fenyl]sulfonyl]propanamid;
N-[[4-[2-(2-metyltiazol-4-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl]fenyl]sulfonyl]acetamid;
N-[[4-[2-(2-metyltiazol-4-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]propanamid;
N-[[4-[2-(4-metyltiazol-2-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid;
N-[[4-[2-(4-metyltiazol-2-yl)-4-(trifluonnetyl)-1 H-imidazol-1 - yl]fenyl]sulfonyl]propanamid;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl]fenyl]sulfonyl]acetamid;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl] fenyl] sulfonyl] acetamid;
N-[[4-[2-(3-pyridinyl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyI]ace N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyI]acetamid;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl] fenyl] sulfonyl] acetamid;
N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl]fenyl]sulfonyl]butanamid;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butanamid;
N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid;
N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl] fenyl]sulfonyl]propanamid;
N-[[4-[3-(difIuormeryl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]butanamid;
N-[[4-[ 1 s5-dimetyl)-3-fenyl-1 H-pyrazol-4-yl]fenyl]sulfonyl]acetamid; 2-hydroksy-3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-3-oksopropanoisk syre;
2-hydroksy-3-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfo^ a-hydroksy-N[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]benzenetanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]benzenetanamid; N-[[4-[3-(3-fluorfenyl)-5-metylisoksazol-4-yl]fenyl]sulfonyl]acetamid; 2- metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[[4-(5-mety1-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]benzamid; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanarnid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]butanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]pentanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]heksanamid; 3- metoksy-N-[[4-(5-metyl-3-feriylisoksa2ol-4-yl)fenyl]sulfonyl]propanaiTiid; 2-etoksy-N-[[4-(5-metyl-3-fenylisoksazo1-4-yl)fenyl]sulfonyl]acetarnid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid;
N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-1 H-pyrazol-1 -yl]fenyl]sulfonyl]propanamid; N-[[4-[5-(4-klorfenyl)-3-(tirfluormetyl)-lH-pyrazol-1 -yl] fenyl]sulfonyl]butanamid; N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-1 H-pyrazol-1 -yl] fenyl]sulfonyl]acetamid; N-[[4-[3-(dilfuoimetyl)-6-fluor-l,5-dihydro-7-meto^ 1 -yl]fenyl]sulfonyl]acetamid; N-[[4-[6-lfuor-l,5-dihydro-7-metoksy-3-(trifluonrietyl)-[2]benzotiopyrano[4,3-c]pyrazol-1-yl] fenyl]sulfonyl]acetamid; N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-1 H-pyrazol-1 -yl] fenyl]sulfonyl]acetamid;
N-[[4-(2-metyl-4-fenyloksazol-5-yl)fenyl]sulfonyl]acetamid;
met<y>l[[[4-(5-met<y>l-3-fen<y>lisoksazol-4-yl)fen<y>l]sulfon<y>l]arnino]oksoacetat; 2-metoksy.N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fcnyl]sulfonyl]acetamid; N-[[4-[5-(difluonnetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]porpanamid; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid; 4- [[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoisk syre; N-[[4-[5-(metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]formarnid;
1,1 -dimetyletyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat; N- [ [4-(5 -metyl-3 -fenyli soksazol -4-yl) fenyl ] sul fonyl] glycin;
2-amino-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; 2-(acetylamino)-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid;
metyl 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoat; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat;
N-acetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin, etylester;
4~ [ [[4-(5 -metyl-3 - fenylisoksazol-4-yl)fenyl] sulfonyl] amino] -4-oksobutanoisk syre; N- [ [4-[5 -(4-metylfenyl)-3 -(tri fluormetyl)-1 H-pyrazol-1 -yl] fenyl] sulfonyl] acetamid; metyl 3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-3-oksopropanoat; 4-[5-(3-brom-5-fluor-4-metoksyfenyl)-2-(trifluormetyl)oksazol-4-yl]-N-metylbenzensulfonamid;
N-(l,l-dimetyletyI)-4-(5-metyI-3-fenyIisoksazol-4-yl)benzensuIfonamid; 4-[5-(4-lfuorfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]-N-metylbenzensulfonamid; N-metyl-4-(5-metyl-3-fenylisaoksazol-4'yl)benzensulfonamid; N-[[4-[5-(hydroksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid; N-[[4-[5-(acetoksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid; l,l-<iimetyletyl-N-[2-[[[.4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-2-oksoetyl]karbamat; N-[[4-[2-(3-klor-4-fluorfenyl)cyklopenten-l-yl]fenyl]sulfonyl]acetamid; 4-[2-(4-fluorfenyl)-1 H-pyrrol-1 -yl]-N-metylbenzensulfonamid; 4-[2-(4-fluorfenyl)-cyklopenten-1 -yl]-N-metylbenzensulfonamid; N-[[4-[3-(4-fluorfenyl)-2)3-dihydro-2-oksofuran-4-yl]fenyl]sulfonyl]acetamid; N-[[4-[3-fenyl-2,3-dihydro-2-oksofuran-4-yI]fenyl]sulfonyl]acetamid; N-[[4-[3,4-dimetyl-l-fenyl-lH-pyrazol-5-yl]fenyl]sulfonyl]propanamid; N-[[4-[2-(2-metylpyridin-3-yl)-4-trifluormetylimidazol-l-yl]fenyl]sulfonyl]propanamid; N-[[4-[3-(4-fluorfenyl)-2,3-dihydro-2-oksofuran-4-yl]fenyl]sulfonyl]propanamid; og N-[[4-[3-fenyl-2,3-dihydro-2-oksofuran-4-yl]fenyl]sulfonyl]propanamid.
En foretrukket familie av spesifikke forbindelser som er av spesiell interesse innenfor formlene I-IJJ består av følgende forbindelser: N-[[4-[2-(2-metylpyridin-6-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl] fenyl] sulfonyl] acetamid, natriumsalt; N-[[4-[2-(2-metylpyridin-6-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-[2-(2-metyltiazol-4-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[2-(2-metyltiazol-4-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]propanamid, natriumsalt;
N-[[4-[2-(4-metyltiazol-2-yl)-4-(trifluormetyl)-1 H-imidazol-1 -
yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-[2-(4-metyltiazol-2-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]propanamid, natriumsalt;
N- [ [4- [2-(3 -pyrimnyl)-4-(trifluormety])-1 H-imidazol-1 -yl] fenyl] sul fonyl] acetamid, natriumsalt;
N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl] fenyl] sulfonyl] acetamid, natriumsalt;
N-[ [4- [2-(5-metylpyridin-3 -yl)-4-(trifluormetyi)-1 H-imidazol-1 - yl]fenyl]sulfonyI]butanamid, natriumsalt;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluonnetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butanamid, natriumsalt;
N-[[4-[2-(3-klor-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]propanamid, natriumsalt;
N- [ [4- [3 -(difluormetyl)-5-(3 - fluor-4-metoksyfenyl)-1 H-pyrazol-1 - yl]fenyl]sulfonyl]butanamid, natriumsalt;
N-[[4-[l,5-dimetyl)-3-fenyl-lH-pyrazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; 2-hydroksy-3-[[[4-(5-metyI-3-fenyiisoksazoI-4-yI)fenyI]sulfonyI]amino]-3-oksopropanoat, natriumsalt;
2-hydroksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt;
a-hydroksy-N-[[4-(5-metyl-2-fenylisoksazol-4-yl)fenyl]sulfonyl]benzenetanamid, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]benzenetanamid, natriumsalt; N-[[4-[3-(3-fiuorfenyl)-5-metylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; 2- metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl)sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]benzamid, natriumsalt; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]pentanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]heksanamid, natriumsalt; 3- metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt;
2-etoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyI]acetamid, kaliumsalt;
N-[[4-[5-(4-kIorfenyl)-3-(trilfuormetyI)- lH-pyrazoI-1 -yl]fenyl]sulfonyl]propanamid, natriumsalt;
N-[[4-[5-(4-klorfenyl)-3-(trilfuormetyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]butanamids natriumsalt;
N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-lH^ natriumsalt;
N-[[4-[3-(difluormetyl)-6-fluor-l,5-dihydro-7-metoksy-[2]benzotiopyrano[4,3-c]pyrazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-[6-fluor-l,5-dihydro-7-metoksy-3-(trifluormetyl)-[2]benzotiopyrano[4,3-cjpyrazol-1 -yl]fenyl]sulfonyl] acetamid, natriumsalt;
N-[ [4- [3-(difluormetyl)-5-(3 -fluor-4-metoksyfenyk)-1 H-pyrazol-1 - yl]]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-(2-metyl-4-fenyloksozoI-5-yl)fenyl]sulfonyl]acetamid, natriumsalt;
metyl [[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]oksoacetat, natriumsalt; 2-metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; natriumsalt; N- [ [4-[5 -(difluormetyl)-3 -fenyli soksazol-4-yl] fenyl] sulfonyl]propanamid, natriumsalt; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid, natriumsalt; 4- [ [ [4-(5-metyl-3-fenyli soksazol-4-yl) fenyl] sul fonyl] amino] -4-oksobutanoisk syre, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyI]sulfonyl]formamid, natriumsalt; 1,1-dimetyletyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl] sulfonyl]glycin, natriumsalt; 2-amino-N-[[-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt; 2-(acetylamino)-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt;
metyl 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoat, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl] fenyl] sulfonyl]karbamat, natriumsalt; 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]amino]-4-oksobutanoisk syre, natriumsalt; N-[[4-[5-(4-metylfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt;
metyl 3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-3-oksopropanoat, natriumsalt;
N-[[4-(5-(hydroksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-(5-(acetoksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt;
' j
1,1 -dimetyletyl-N-[2-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]am oksoetyl]karbamat, natriumsalt;
N-[[4-[2-klor-4-lfuorfenyl)cyklopenten-1 -yl] fenyl]sulfonyl]acetamid, natriumsalt; og N-[[4-[3-(4-fluorfenyl)-2,3-dihydro-2-oksomran-4-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N- [ [4-(3 -fenyl-2m3 -dihydro-2-okso furan-4-yl) fenyl] sulfonyl] acetamid, natriumsalt; N-[[4-[3,4-dimetyl-l-fenyl-lH-pyrazol-5-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-[2-(2-metylpyridin-3-yl)^-trifluormetylimidazol-l-yl]fenyl]sulfonyl]propanamid, natriumsalt;
N-[[4-[3-(4-fluorfenyl)-2,3-dihydn)-2-oksofuran-4-yl]fenyl]sulfonyl]propanamid, natriumsalt; og
N-[[4-(3-fenyl-2,3-dihydro-2-oksofuran-4~yl)fenyl]sulfonyl]propanamid, natriumsalt.
Betegnelsen "hydrido" angir et enkelt hydrogenatom (H). Denne hydridoresten kan bli koblet, for eksempel til et oksygenatom for å danne en hydroksylrest eller to hydridorester kan bli koblet til et karbonatom for å danne en metylen (-CH2-) rest. Hvor anvendt, enten alene eller innenfor andre betegnelser så som "haloalkyl", "alkylsulfonyl", "alkoksyalkyl" og "hydroksyalkyl", omfatter betegnelsen "alkyl" lineære eller forgrenede rester.
Foreliggende oppfinnelse omfatter en farmasøytisk sammensetning omfattende en terapeutisk-effektiv mengde av en forbindelse med formel I i assosiasjon med minst en farmasøytisk akseptabel bærer, adjuvans eller fortynningsmiddel.
Anvendelse av en forbindelse ifølge oppfinnelsen, inkludert de hvor A er tetrazolium eller pyridinium; eller indanon når R3 er alkyl eller karboksyalkyl, for fremstilling av et medikament for behandling av inflammasjon eller inflammasjons-assosiert forstyrrelse.
Oppfinnelsen angår også en fremgangsmåte for fremstilling av en forbindelse med formel II
hvor A er en ringsubstituent utvalgt fra C4-Cg-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Cj-Cio-alkyl, Ci-Ce-haloalkyl, okso, Ci-C6-hydroksyalkyI og Ci-Cio-alkylkarbonyloksy-Ci-Cio-alkyl; hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Cj-Cio-alkyl, halo og C\~ C6-alkoksy; og hvori R<5> er et radikal utvalgt fra hydrido, Ci-Cio-alkyl, O-Ce-alkoksy, C1-C6-alkoksy-CrCio-alkyl, fenyl, Ci-Cio-karboksyalkyl, Ci-C6-alkoksykarbonyl-Ci-Cio-alkyl, Ci-Ce-alkoksykarbonyl, Ci-Cio-aminoalkyl og Ci-Cio-alkylkarbonylamino-Ci-Cg-alkyl; eller et farmasøytisk akseptabelt salt derav; kjennetegnet ved at fremgangsmåten innbefatter behandling av et usubstituert sulfonamid med et acyleringsmiddel under nærvær av en base og et løsemiddel. Forbindelsen angår i tillegg en fremgangsmåte for fremstilling av en forbindelse med formel Ul hvori R<6> er et radikal utvalgt fra C|-C6-alkyl, Ci-Ce-haloalkyl og Ci-Ce-hydroksyalkyl; hvori R er et radikal utvalgt fra hydndo, Ci-C6-alkyl, halo og Cj-Ce-alkoksy; og hvori R<8> er et radikal utvalgt fra hydrido, Ci-Ce-alkyl, Ci-Ce-alkoksy, Ci-C6-alkoksy-Ci-Ce-alkyl, fenyl, Ci-C6-karboksyalkyl, Ci-Ce-alkoksykarbonyl-Ci-Ce-alkyl, Ci-Ce-alkoksykarbonyl, Ci-Ce-aminoalkyl og Ci-Ce-alkylkarbonylarnino-Ci-Ce-alkyl; eller et farmasøytisk akseptabelt salt derav; kjennetegnet ved at fremgangsmåten innbefatter behandling av et usubstituert isoksazolyl-benzensulfonamid med et acyleringsmiddel under nærvær av en base og et løsemiddel. Oppfinnelsen angår videre en fremgangsmåte for fremstilling av en forbindelse med formel II hvori A er en ringsubstituent utvalgt fra C4-Cs-cykIoaIkenyI, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, C|-C6-haloalkyl, okso, d-C6-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-Cio-alkyl; hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Cr Ce-alkoksy; og hvori R<5> er et radikal utvalgt fra hydrido, Ct-Cjo-alkyl, Ci-Ce-alkoksy, Ci-Ce-alkoksy-Ci-Cio-alkyl, fenyl, CrCio-karboksyalkyl, Ci-Ce-alkoksykarbonyl-Ci-Cio-alkyl, Ci-Cc-alkoksykarbonyl, C]-C]o-aminoalkyl og Ci-Cio-alkylkarbonylamino-Ci-C6-alkyl; eller et farmasøytisk akseptabelt salt derav; kjennetegnet ved at fremgangsmåten innbefatter å danne et bis(N-acetylert)sulfonamid ved behandling av et usubstituert sulfonamid med overskudd av et anhydrid, syreklorid eller karbamylklorid, under nærvær av en tertiær aminbase, og behandle nevnte bis(N-acetylert)sulfonamid med ca. to ekvivalenter av en sterk base for å tilveiebringe saltet. Oppfinnelsen angår ytterligere en fremgangsmåte for fremstilling av en forbindelse med formel II
hvori A er en ringsubstituent utvalgt fra Cij-Cg-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazoly] og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, Ci-Ce-haloalkyl, okso, Ci-C6-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-Cio-alkyl;
hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Cj-Ce-alkoksy;
og hvori R<5> er et radikal utvalgt fra hydrido, Cj-Cio-alkyl, Ci-Ce-alkoksy, Cj-Ce-alkoksy-Ci-Cio-alkyl, fenyl, Ci-Cio-karboksyalkyl, Ci-C6-alkoksykarbonyl-Ci-Cio-alkyl, Ci-C6-alkoksykarbonyl, Ci-Cio-aminoalkyl og Ct-Cio-alkylkarbonylamino-Ci-C6-alkyl; eller et farmasøytisk akseptabelt salt derav;
kjennetegnet ved at fremgangsmåten innbefatter behandling av et usubstituert sulfonamid med et acyleringsmiddel under nærvær av syre.
Også innbefattet i familien av forbindelser med formel I er farmasøytiske-akseptable salter derav. Betegnelsen "farmasøytiske-akseptable salter" omfatter salter som vanligvis blir anvendt for å danne alkalimetallsalter og å danne addisjonssalter av frie syrer eller frie baser. Naturen til saltet er ikke kritisk, forutsatt at den er farmasøytisk akseptabel. Egnede farmasøytiske-akseptable syreaddisjonssalter av forbindelsene med formel I kan bli fremstilt fra en uorganisk syre eller fra en organisk syre. Eksempler på slike uorganiske syrer er saltsyre, hydrobromsyre, hydrojodsyre, salpetersyre, karbonsyre, svovelsyre og fosforsyre. Hensiktsmessige organiske syrer kan bli valgt fra alifatiske, cykloalifatiske, aromatiske, aralifatisk, heteocyklyl, karboksylsyre og sylfonsyreklasser av organiske syrer, for eksempel som maursyre, eddiksyre, propionsyre, ravsyre, glykolsyre, glukonsyre, melkesyre, maleinsyre, vinsyre, sitronsyre, askorbinsyre, glukuronsyre, maleinsyre, fumarsyre, pyruvatsyre, asparaginsyre, glutaminsyre, benzosyre, anthranilinsyre, mesylinsyre, stearinsyre, salicylsyre, p-hydroksybenzosyre, fenyleddiksyre, mandelsyre, embonisk syre (pamoisk) syre, metansulfonsyre, etansulfonsyre, benzensulfonsyre, pantotensyre, toluensulfonsyre, 2-hydroksyetansulfonsyre, sulfanilinsyre, cykoheksylaminosulfonsyre, algensyre, B-hydroksysmørsyre, galaktarisksyre og galakturonsyre. Egnede farmasøytiske akseptable baseaddisjonssalter av forbindelser med formel I innbefatter metalliske salter og organiske salter. Mer foretrukne metalliske salter innbefatter, men er ikke begrenset til, hensiktsmessig alkalimetall (gruppe Ia) salter, alkaliske jordmetall (gruppe Ila) salter og andre fysiologiske akseptable metaller. Slike salter kan bli fremstilt fra aluminium, kalsium, litium, magnesium, kalium, natrium og sink. Foretrukne organiske salter kan bli fremstilt fra tertiære aminer og kvaternære ammoniumsalter, inkludert delvis, trometamin, dietylamin, N,N'-dibenzyletylendiamin, klorprocain, cholin, dietanolamin, etylendiamin, meglumin, (N-metylglukamin) og procain. Alle disse saltene kan bli fremstilt ved konvensjonelle midler fra tilsvarende forbindelse med formlene I-UI, ved omsetning, for eksempel, av hensiktsmessig syre eller base med forbindelsen med formlene Mil.
Cykloksygenase-2 inhibitor promedikamentene ifølge oppfinnelsen kan bli syntetisert ifølge følgende fremgangsmåter ifølge skjemaene I-XVII, hvor R'-R<8> substituentene er som definert for formlene l-m ovenfor, unntatt når annet er angitt.
Syntese skjema I viser fremstilling av cyklooksygenase-2 inhibitor forbindelser, som beskrevet i W095/15316, som er innkorporert heri som referanse. I trinn I blir keton 1 behandlet med en base, fortrinnsvis NaOMe eller NaH og en ester, eller esterekvivalent, for å danne mellomliggende diketon 2 (i enol form) som blir anvendt uten ytterligere rensning. I trinn 2 er diketon 2 et vannfritt protisk oppløsningsmiddel, så som absolutt etanol eller eddiksyre, blir behandlet med hydrokloridsaltet eller den frie basen til en substituert hydrazin ved tilbakestrømning for å tilveiebringe en blanding av pyrazolene 3 og 4. Omkrystallisering eller kromatografi tilveiebringer 3 vanligvis som et fast stoff. Lignende pyrazoler kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 5.401.765,5.434.178, 4.146.721,5.051.518,5.134.142 og 4.914.121 som også er innkorporert heri som referanse.
Skjema II viser fire trinnsprosedyren for fremstilling av cyklooksygenase-2 inhibitor pyrazoler 8 som beskrevet i US-PS 5.486.534 (hvor Ra er hydrido eller alkyl) fra ketonene 5.1 trinn 1 blir keton 5 omsatt med en base, så som litiumbis(trimetylsilyl)amid eller litiumdiisopropyalamid (LDA) for å danne anionet. I trinn 2 blir anionet omsatt med et acetyleringsreagens for å tilveiebringe diketon 6.1 trinn 3 fører omsetning av diketon 6 med hydrazin eller en substituert hydrazin, til pyrazol 7.1 trinn 4 blir pyrazol 7 oksidert med et oksideringsreagens, så som okson®
(kaliumperoksymonosulfat), 3-klorperbenzosyre (MCPBA) eller hydrogenperoksid, for å tilveiebringe en blanding av ønsket 3-(alkylsulfonyl)fenyl-pyrazol 8 og 5-(alkylsulfonyl)fenyl-pyrazol isomer. Sulfonamidene 9 kan bli fremstilt som beskrevet av Huang method [Tet. lett., 35,7201-04 (1994)].
Alternativt kan diketon 6 bli dannet fra keton 5 ved behandling med en base, så som natriumhydrid, i et oppløsningsmiddel, så som dimetylformamid, og ytterligere omsetning med et nitril for å danne et aminoketon. Behandling av aminoketonet med syre danner diketon 6. Lignende pyrazoler kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 3.984.431 som er innkorporert heri som referanse.
Cykloksygenase II inhibitor diaryl/heteroaryl tiofener (hvor T er S, og Rb er alkyl) kan bli fremstilt ved fremgangsmåtene beskrevet i US-PS 4.427.693,4.302.461,4,381.311, 4.590.205 og 4.820.827 og PCT dokumentene WO95/00501 og W094/15932, som er innkorporert heri som referanse. Lignende pyroler (hvor T er N), furanoner og furaner (hvor T er O) kan bli fremstilt ifølge fremgangsmåtene beskrevet i PCT dokumentene WO 95/00501 og W094/15932.
Cyklooksygenase-2 inhibitor diaryl/heteroaryl oksazoler kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 5.380.738,3.743.656, 3.644.499 og 3.647.858 og PCT dokumenter WO95/00501 og WO94/27980, som er innkorporert heri som referanse.
Cyklooksygenase-2 inhibitor diaryl/heteroaryl isoksazoler kan bli fremstilt ifølge fremgangsmåtene beskrevet i PCT søknad Serial No. US96/01869, PCT dokumenter WO92/05162, og WO92/19604, og europeisk publikasjon EO 26928, som er innkorporert heri som referanse. Sulfonamider 27 kan bli dannet fra hydrert isooksazol 26 i en to-trinnsprosedyre. Først blir hydrert isooksazol 26 behandlet ved omtrent 0°C med 2 eller 3 ekvivalenter klorsulfonsyre for å danne tilsvarende sulfonylklorid. I trinn 2 blir sulfonylklorid dannet på denne måten behandlet med konsentrert ammoniakk for å tilveiebringe sulfonamid derivat 27.
Skjema VI viser en tre-trinns fremstilling av cyklooksygenase-2 inhibitor imidazoler 33. I trinn 1 fører omsetning av substituerte nitriler (R<1->VN) 28 med primære fenylaminer 28 i nærvær av alkylaluminiumreagenser så som trimetylaluminium, trietylaluminium, dimetylaluminiumklorid, dietylaluminiumklorid i nærvær av inerte oppløsningsmidler så som toluen, benzen og xylen, amidiner 30.1 trinn 2 fører omsetning av amidin 30 med 2-haloketoner (hvor X er Br eller Cl) i nærvær av baser, så som natriumbikarbonat, kaliumkarbonat, natriumkarbonat, kaliumbikarbonat eller hindrede tertiære aminer så somN,N'-diisopropyletylamin, til 4,5-dihydroimidazoler 31 (hvor R<b> er alkyl). Noen av de egnede oppløsningsmidlene i denne reaksjonen er isopropanol, aceton og dimetylformamid. Reaksjonen kan bli utført ved temperaturer på omtrent 20°C til omtrent 90°C. I trinn 3 kan 4,5-dihydroimidazoler 31 bli dehydrert i nærvær av en sur katalysator så som 4 toluensulfonsyre eller mineralsyre for å danne 1,2-disubstituerte imidazoler 32 ifølge oppfinnelsen. Egnede oppløsningsmidler for dette dehydreringstrinnet er for eksempel toluen, xylen og benzen. Trifluoreddiksyre kan bli anvendt som oppløsningsmiddel og katalysator i dette dehydreringstrinnet. Sulfonamider 33 kan bli fremstilt ved Huang metoden [Tet. Lett., 35,7201-04 (1994)].
I noen tilfeller (for eksempel hvor R=metyl eller fenyl) kan mellomproduktet 31 ikke lett isoleres. Reaksjonen under betingelsene beskrevet ovenfor forløper for å tilveiebringe målsøkte imidazoler direkte.
Likeledes kan imidazolene bli fremstilt med sulfonylfenyldelen koblet i posisjon 2 og R<1> koblet ved nitrogenatomet i posisjon 1. Diaryl/heteroarylimidazoler kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 4.822.805 og PCT dokumentene WO93/14082 og WO96/03388, som er innkorporert heri som referanse. Imidazol cyklooksygenase-2 inhibitor forbindelsene 41 kan bli fremstilt ifølge sekvensen beskrevet i skjema VII. Aldehyd 34 kan bli omdannet til beskyttet cyanohydrin 35 ved omsetning med et trialkylsilylcyanid, så som trimetylsilyl cyanid (TMSCN). I nærvær av en katalysator så som sinkiodid (Znl2) eller kaliumcyanid (KCN). Omsetning av cyanohydrin 35 med en sterk base etterfulgt av behandling med benzaldehyd 36 og anvendelse av både syre og basebehandlinger, i denne rekkefølgen, ved opparbeidning tilveiebringer benzoin 37. Eksempler på sterke baser egnede i denne reaksjonen er litiumdiisopropylamid (LDA) og litiumheksametyldisilazan. Benzoin 37 kan bli omdannet til benzil 38 ved omsetning med et egnet oksideringsmiddel, så som bismetoksid eller mangandioksid, eller ifølge en Swern oksidasjon ved anvendelse av dimetylsulfoksid (DMSO) og trifluoreddiksyreanhydrid. Benzil 38 kan bli oppnådd direkte ved omsetning av anionet til cyanohydrin 35 med et substituert benzosyrehalid. Hvilke som helst av forbindelsene 37 og 38 kan bli anvendt som mellomprodukter for omdanning til imidazoler 39 ifølge de kjemiske prosedyrene kjent av fagfolk innenfor dette området og beskrevet av M.R. Grimmett," Advance in Imidazole Chemistry" i Advance in Heterocyklic Chemistry, 12, 104 (1970). Omdanning av 38 til imidazoler 39 blir utført ved omsetning med ammoniumacetat og et hensiktsmessig aldehyd (RCHO) i eddiksyre. Benzoin 37 kan bli omdannet til imidazoler 39 ved omsetning med formamid. I tillegg kan benzoin 37 bli omdannet til imidazoler ved først acylering med en hensiktsmessig acylgruppe (RCO-) og deretter behandling med ammonium hydroksid. Fagfolk innenfor dette området vet at oksidasjon av sulfid til sulfon kan bli utført ved et hvilket som helst punkt på veien begynnende med forbindelsene 36, og inkludert oksidasjon av imidazoler 39, ved anvendelse for eksempel reagenser så som hydrogenperoksid i eddiksyre, m-klorperoksybenzosyre (MCPBA) og kaliumperoksymonosulfat (OXONE®). Sulfonamider 41 kan bli fremstilt ifølge metoden til Huang [Tet. Lett., 35, 7201-04 (1994)].
Diaryl/heteroaryl imidazoler kan bli fremstilt ifølge fremgangsmåtene bekrevet i US-PS 3.707.475,4.686.231,4.503.065, 4.472.422,4.372.964,4.576.958, 3.901.908, PCT søknad Serial No. US95/09505, europeisk publikasjon EP 372,445, og PCT dokument WO 95/00501, som er innkorporert heri som referanse.
Diaryl/heteroaryl cyklopentencyklooksygenase-2 inhibitorer kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 5.344.991 og PCT dokument WO95/00501, som er innkorporert heri som referanse.
Likeledes viser synteseskjema IX prosedyrer for fremstilling av 1,2-diarylbenzencyklooksygenase-2 inhibitor midler 51 fra 2-brom-bifenyl mellomproduktene 49 (fremstilt som beskrevet i synteseskjema VIII) og hensiktsmessige substituerte fenylborsyrer. Ved anvendelse av en koblingsprosedyre som ligner den som er blitt utviklet av Suzuki et al. [Synth. Commun., 11, 513 (1981)], blir mellomproduktene 49 omsatt med borsyre i toluen/etanol ved tilbakestrømning i nærvær av en Pd<0> katalysator, for eksempel tetrakis(trifenylfosfin)palladium (0) og 2M natriumkarbonat for å tilveiebringe tilsvarende 1,2-diaxylbenzen antiinflammatoriske midler 50 ifølge oppfinnelsen. Sulfonamider 51 kan bli fremstilt ifølge metoden til Huang [Tet. Lett., 35, 7201-04 (1994)]. Slike terfenylforbindelser kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-søknad serie nr. 08/346,433, som er innkorporert heri som referanse.
Diaryl/heteroaryl tiazol cyklooksygenase-2 inhibitorer kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 4.051.250,4.632.930, europeisk dokument EP 592,664, og PCT dokumenter WO96703392 og WO95/00501, som er innkorporert heri som referanse. Isotioazoler kan bli fremstilt som beskrevet i PCT dokument WO95/00501.
Diaryl/heteroaryl pyridylcyklooksygenase-2 inhibitorer kan bli fremstilt ifølge fremgangsmåtene beskrevet i US-PS 5.169.857,4.011.328,4.533.666, PCT søknad serie nr. US96/01110 og PCT søknad serie nr. US96/01111, som er innkorporert heri som referanse.
Syntese skjema XI illustrerer en fremgangsmåte for fremstilling av acylerte sulfonarnider 57. Fremgangsmåten innbefatter behandling av et usubstituert sulfonamid 56 med et egnet acyleringsmiddel så som anhydrid, syreklorid, acylimidazol eller aktiv ester, i nærvær av base og et egnet oppløsningsmiddel, så som tetrahydrofuran (THF), for å tilveiebringe acylert sulfonamid 57. Produktet 57 kan deretter bli isolert ved kromatografi eller ved krystallisering.
Syntese skjema XII viser fremgangsmåten for fremstilling av tilsvarende saltform ifølge 57. Behandling av 57 med en egnet sterk base så som natriumhydroksid, kaliumhydroksid, kalsiumhydroksid og lignende fremstiller tilsvarende saltform 58. En mengde oppløsningsmidler kan bli anvendt dersom de ikke reagerer med den tilsatte sterke basen, og slike oppløsningsmidler som metanol og tetrahydrofuran er foretrukket.
Syntese skjema XIII viser fremgangsmåten anvendt for fremstilling av substituerte sulfonamider 60. Trinnet innbefatter behandling av et egnet sulfonylklorid 59 med et amin for å fremstille substituert sulfonamid 59. Aminet kan være enten et primært amin (R 3 NH2) eller et sekundært amin (R 3 R 2NH). Omsetningen blir generelt utført i nærvær av tilsatt base. Reaksjonen kan også bli utført i nærvær av amin i overskudd. Under betingelser med amin i overskudd virker aminet som både nukleofil og base.
Syntese skjema XIV viser fremgangsmåten anvendt for syntetisering av N-substituerte acylsulfonamider 61. Prosedyren innbefatter behandling av saltet av et acylert sulfonamid 58 med et alkylhalid (R<2->X) for å fremstille tilsvarende N-alkylert acylsulfonamid 61. Denne fremgangsmåten kan bli utført i en mengde oppløsningsmidler med en mengde elektrofiler.
Syntese skjema XV illustrerer fremgangsmåten anvendt for fremstilling av visse N-acylerte sulfonamider 57. Fremgangsmåten innbefatter behandling av sulfonamid 56 med et overskudd anhydrid, syreklorid eller karbamylklori i nærvær av en tertiær aminbase for å tilveiebringe tilsvarende bis(N-acylert)sulfonamid 62. bis(N-acylert)sulfonamid 62 blir deretter behandlet med to ekvivalenter av en sterk base så som natriumhydroksid for å tilveiebringe natriumsalt 58.
Syntese skjema XVI illustrerer fremgangsmåten anvendt for fremstilling av visse N-alkylerte pyrrolsulfonamider. Alkohol 65 blir fremstilt ved følgende litteraturprosedyre (J. Org. Chem. 57. 2195, 1992). Alkohol 65 blir oksidert ved behandling med oksalylklorid i et hensiktsmessig oppløsningsmiddel, så som metylenklorid eller DMSO. Tilsetning, så som ved Grignard reagenser, danner alkohol 67. Oksidasjon med pyrimniumklorkromat produserer ketoner 68. Kondensasjon med et [(N-substituert amino)sulfonyl]benzenamin i nærvær av p-toluensulfonsyre (produserer substituert pyrrolsulfonamid 69.
Syntese skjema XVII illustrerer fremgangsmåte for fremstilling av acylerte isoksazolsulfonamider 71. Trinnet innbefatter behandling av et usubstituert sulfonamid 70 med et egnet acyleringsmiddel så som et anhydrid, syreklorid, acylimidazol eller aktiv ester for å tilveiebringe acylert sulfonamid 71. Produkt 71 kan bli isolert ved kromatografi eller ved krystallisasjon.
Følgende eksempler inneholder detaljerte beskrivelser av fremgangsmåter for fremstilling av forbindelsene med formlene I-III. Disse detaljerte beskrivelsene hører inn under rammen og eksemplifiserer ovenfor angitte generelle synteseprosedyrer som danner en del av oppfinnelsen. Alle deler i vekt og temperaturer er i grader Celsius dersom ikke annet er angitt. Alle forbindelsene viste NMR spektere som er i samsvar med angitte strukturer.
Følgende forkortelser blir anvendt:
HC1 - saltsyre
DMSO - dimetylsulfoksid
DMSOd6 - deuterert dimetylsulfoksid
CDCI3 - deuterert kloroform
MgS04 - magnesiumsulfat NaHC03 - natriumbikarbonat
KHSO4 - kaliumhydrogensulfat
DMF - dimetylformamid NaOH - natriumhydroksid
BOC - tert-butyloksykarbonyl
CD3OD - deuterert metanol
EtOH - etanol
LiOH - litiumhydroksid
CH2C12 - metylenklorid
h - time
hr - time
min - minutter
THF - teti^ydrofuran
TLC - tynnsjiktskromatografi
Et30 - trietylamin
DBU - l,8-diazabicyklo[5.4.0]undek-7-ene DMAP - 4-dimetylaminopyridin
EKSEMPEL 1
N-n4-[2-(3-pyridin<y>l)-4-<trifluonnetyl)-lH-imidazol-l-yI]fenyl]sulfonyl]acetamid
En blanding av 4-[2-(pyridin-3-yl)-4-(trifluormctyl)-1 H-imidazol-1 - yljbenzensulfonamid (0,5 g, 1,36 mmol), eddiksyreanhydrid (0,42 g, 4,1 mmol), 4-dimetylaminopyridin (DMAP) (0,083 g, 0,68 mmol) og trietylamin (0,17 g, 1,6 mmol) ble omrørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 50 ml vann og ekstrahert med etylacetat. Det organiske laget ble vasket med vann, saltvann, tørket over magnesiumsulfat og filtrert. Filtratet ble konsentrert under vakuum og resten ble omkrystallisert fra etylacetat og heksan for tilveiebringing av 0,5 g (90%) N-[[4-[2-(3-pyridinyl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid som et farveløst fast stoff: smp. (DSC): 244.246°C. Anal. beregnet for C17Hi3F3N403S: C, 49,76; H, 3,19; N, 13,65; S, 7,81. Funnet: C, 49,66; H, 3,06; N, 13,53; S, 8,11.
EKSEMPEL 2
N-[[4-[2-(3-pyridinyl)-4-(rrilfuormetyl)-lH-imidazol-l-yl]-fenyl] sulfonyl] acetamid, natriumsalt
Til en suspensjon av N-[[4-[2-(3-pyirdinyl)-4-(tirfluonnetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid (eksempel 1) (0,41 g, 1,0 mmol) i 10 ml absolutt etanol ble det tilsatt en oppløsning av natriumhydroksid (0,04 g, 1,0 mmol) i 0,4 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 min. Oppløsningsmiddelet ble avdampet i vakuum og resten ble tørket ved høyt vakuum for å tilveiebringe 0,33 g (76%) N-[[4-[2-(3-pyridmyl)-4-(trifluonnetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt som et hvitt pulver: smp. (DSC): 291°C (dek.). Anal. beregnet for Ci7H12F3N4O3SNa 0,5 H20: C, 46,26; H, 2,97; N, 12,69; S, 7,26. Funnet: C, 45,88; H, 3,02; N, 11,69; S, 7,13.
EKSEMPEL 3
N-[[4-[2-(5-metylpyridin-3-yI)-4-(trifluormetyl)-lH-imidazol-l-yljfenyllsulfonylfacetamid
En blanding av 4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]benzensulfonamid (0,5 g, 1,3 mmol), eddiksyreanhydrid (0,40 g, 3,9 mmol), DMAP (0,09 g, 0,7 mmol) og trietylamin (0,16 g, 1,6 mmol) ble omrørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 50 ml vann og ekstrahert med etylacetat. Det organiske laget ble vasket med vann, saltvann, tørket over magnesiumsulfat og filtrert. Filtratet ble konsentrert under vakuum og resten ble omkrystallisert fra etylacetat og heksan for tilveiebringing av 0,4 g (72%) N-[[4-[2-(5-mety]pyridin-3-yl)-4-(trifluormet<y>l)-l H-imidazol-1-yl]fenyl]sulfonyI]acetamid som et farveløst fast stoff: smp. (DSC) 268-270°C. Anal. beregnet for C18Hi5F3N403S: C, 50,94; H, 3,56; N, 13,20; S, 7,56. Funnet: C, 50,68; H, 3,47; N, 12,53; S, 7,43.
EKSEMPEL 4
N- [ [4- [2-(5-metylpy ridin-3-y l)-4-(trifluormety l)-lH-imidazol-l-y I ] fenyl] sulfonyl] acetamid, natriu msalt
Til en suspensjon av N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid (eksempel 3) (0,25 g, 0,6 mmol) i 5 ml absolutt etanol ble det tilsatt en oppløsning av natriumhydroksid (0,024 g, 0,6 mmol) i 0,4 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 min. Oppløsningsmiddelet ble avdampet i vakuum og resten ble tørket ved høyt vakuum for å tilveiebringe 0,25 g (95%) N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-m^ natriumsalt som et hvitt pulver: smp. (DSC) 278-281°C. Anal. beregnet for C18H14F3N403SNa 1,0 H20: C, 46,55; H, 3,47; N, 12,06; S, 6,90. Funnet: C, 46,35; H, 3,19; N, 11,79; S, 6,52.
EKSEMPEL 5
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluornietyl)-lH-imidazol-l-y 1] fenyl] sulfonyl] acetamid
En blanding av 4-[2-(2-merylpyridin-3-yl)-4-(trifluormetyl)-l H-imidazol-1-yl]benzensulfonamid (0,5 g, 1,3 mmol), eddiksyreanhydrid (0,40 g, 3,9 mmol), DMAP (0,09 g, 0,7 mmol) og trietylamin (0,16 g, 1,6 mmol) ble omrørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 50 ml vann og ekstrahert med etylacetat. Det organiske laget ble vasket med vann, saltvann, tørket over magnesiumsulfat og filtrert. Filtratet ble konsentrert under vakuum og resten ble omkrystallisert fra etylacetat og heksan for å tilveiebringe 0,55 g (99%) N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid som et farveløst fast stoff: smp. (DSC) 243-245°C. Anal. beregnet for C^H^^C-jS: C, 50,94; H, 3,56; N, 13,20; s, 7,56. Funnet: C, 50,64; H, 3,43; N, 12,64; S, 7,37.
EKSEMPEL 6
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormeryl)-lH-imidazoH-yl]fenyl]sulfonyl]acetamid, natriumsalt
Til en suspensjon av N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-l H-imidazol-1-yl]fenyl]sulfonyl]acetamid (eksempel 5) (0,35 g, 0,83 mmol) i 7,5 ml absolutt etanol ble det tilsatt en oppløsning av natriumhydroksid (0,033 g, 0,83 mmol) i 0,83 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 min. Oppløsningsmiddelet ble avdampet i vakuum og resten ble tørket ved høyt vakuum for å tilveiebringe 0,37 g (99%) N-[[4-[2-(2-metylpyridin-3-yl)-4-(tirfluormety0 natriumsalt som et hvitt pulver: smp. (DSC) 313°C (dek.) Anal. beregnet for C18H14F3N4O3SNa0,75 H20: C, 47,01; H, 3,40; N, 12,18; S, 6,97. Funnet: C, 47,51; H, 3,71; N, 11,79; S, 6,51.
EKSEMPEL 7
N- [ [4- [2-(5-mety lpy ridin-3-y l)-4-(trifluormetyl)-1 H-imidazol-1-yl]fenyl] sulfonyl] butanamid
En blanding av 4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-l H-imidazol-1-yl]fenyl]benzensulfonamid (0,5 g, 1,3 mmol), smørsyreanhydrid (0,62 g, 3,9 mmol), DM AP (0,09 g, 0,7 mmol) og trietylamin (0,16 g, 1,6 mmol) ble omrørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 50 ml vann og ekstrahert med etylacetat. Det organiske laget ble vasket med vann, saltvann, tørket over magnesiumsulfat og filtrert. Filtratet ble konsentrert under vakuum og resten ble omkrystallisert fra etylacetat og heksan for tilveiebringing av 0,50 g (85%) N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-l H-imidazol-l-yl]fenyl]sulfonyl]butanamid som et farveløst fast stoff: smp. (DSC) 203-204°C. Anal. beregnet for C2oH19F3N403S: C, 53,09; H, 4,23; N, 12,38; S, 7,09. Funnet: C, 52,73; H, 4,21; N, 11,79; S, 7,00.
EKSEMPEL 8
N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluornieryl)-lH-iniidazol-l-yl]fenyljsulfbnyl]butanamid, natriumsalt
Til en suspensjon av N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imida2ol-l-yl]fenyl]sulfonyl]butanamid (eksempel 7) (0,31 g, 0,68 mmol) absolutt etanol ble det tilsatt en oppløsning av natriumhydroksid (0,028 g, 0,68 mmol) i 0,68 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 min. Oppløsningsmiddelet ble avdampet i vakuum og resten ble tørket ved høyt vakuum for å tilveiebringe 0,28 g (87%) N-[[4-[2-(5-metylpyridin-3-yl)-4-(trilfuormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butanamid, natriumsalt som et hvitt pulver: smp. (DSC) 303°C. (dek.). Anal. beregnet for C20H18F3N4O3SNa: 1,0 H20: C, 48,78; H, 4,09; N, 11,38; S, 6,51. Funnet: C, 47,90; H, 3,67; N, 11,38; S,6,06.
EKSEMPEL 9
N-[[4-[2-(2-metyIpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl] butanamid
En blanding av 4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]benzensulfonamid (0,5 g, 1,3 mmol), smørsyreanhyrdid (0,62 g, 3,9 mmol), DMAP (0,09 g, 0,7 mmol) og trietylamin (0,16 g, 1,6 mmol) ble omrørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 50 ml vann og ekstrahert med etylacetat. Det organiske laget ble vasket med vann, saltvann, tørket over magnesiumsulfat og filtrert. Filtratet ble konsentrert under vakuum og resten ble omkrystallisert fra etylacetat og heksan for tilveiebringing av 0,49 g (84%) N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-1 H-imidazol-1 -yl]fenyl]sulfonyl]butanamid som et farveløst fast stoff: smp. (DSC) 250-252°C. Anal. beregnet for C20H19F3N4O3S: C, 53.09; H, 4,23; N, 12,38; S, 7,09. Funnet: C, 52,97; H, 4,21; N, 11,07; S, 7,11.
EKSEMPEL 10
N-l[4-[2-(2-metyipyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butanamid, natriumsalt
Til en suspensjon av N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluonnetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butanamid (eksempel 9) (0,3 g, 0,66 mmol) i 5 ml absolutt etanol ble det tilsatt en oppløsning av natriumhydroksid (0,027 g, 0,66 mmol) i 0,66 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 min. Oppløsningsmiddelet ble avdampet i vakuum og resten ble tørket ved høyt vakuum for å tilveiebringe 0,26 g (83%) N-[[4-[2-(2-metylpyridm-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butana^ natriumsalt som av et hvitt pulver: smp. (DSC) 320°C (dek.). Anal. beregnet forC20H18F3N4O3SNa: C, 50,63; H, 3,82; N, 11,81; S, 6,76. Funnet: C, 49,85; H, 3,78; N, 11,51; S, 6,32.
EKSEMPEL 11
N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-y 1] fenyl] sulfonyl] acetamid Til en suspensjon av 4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]benzensulfonamid (0,30 g, 0,72 mmol) i 1,5 ml eddiksyre ble det tilsatt 1,5 ml acetylklorid ved romtemperatur. Blandingen ble oppvarmet ved tilbakeløp i 5 timer. Etter avkjøling ble reaksjonsblandingen konsentrert under vakuum og resten ble behandlet med eter for å tilveiebringe 0,23 g (70%) N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid som et hvitt fast stoff: smp. (DSC) 232-235°C. Anal. beregnet for C19H15C1F3N303S: C, 49,84; H, 3,30; N, 9,18; S, 7,00. Funnet: C, 49,72; H, 3,48; N, 8,81; S, 7,18. EKSEMPEL 12
N-[[4-[2-(3-klor-5-mct>'lfenyl)-4-(trifluormctyt)-lH-iriiidazo]-l-yljfenyljsulfonyljacetamid, natriumsalt
ril en suspensjon avN-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-iniidazol-l-yl]fenyl]sulfonyl]acetamid (eksempel 11) (0,1 g, 0,22 mol) i 3 ml absolutt etanol ble det tilsatt en oppløsning natriumhydroksid (0,0088 g, 0,22 mmol) i 2 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 min. Oppløsningsmiddelet ble avdampet i vakuum 3g resten ble tørket ved høyt vakuum for å tilveiebringe 0,09 g (85%) N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-1 H-imidazol-1 -yl]fenyl]sulfonyl]acetamid, natriumsalt som et hvitt pulver: smp. (DSC) 320°C (dek.). Anal. beregnet for C19H14ClF3N303SNa: C, 47,56; H, 2,94; N, 8,76; S, 6,68. Funnet: C, 46,89; H, 3,02; N, 8,27; S, 6,03.
EKSEMPEL 13
N-[[4-[3-(3-fluorfenyl)-5-meryIisoksazol-4-yl]fenyl]sulfonyl]aceteamid
Eddiksyreanhydrid (1,01 g, 9,39 mmol) og trietylamin (0,401 g, 3,97 mmol) ble tilsatt til en oppløsning av 4-[5-metyl-3-(fluorfenyl)isoksazol-4-yl]benzensulfonamid (1,10 g. 3,31 mmol) og N,N-dimetyIpyridin (0,202 g) i tørr tetrahydrofuran. Etter omrøring i 18 timer ved romtemperatur ble reaksjonsblandingen konsentrert. Resten ble oppløst i etylacetat, vasket suksessivt med IN saltsyre og saltvann, tørket over vannfri MgS04 og konsentrert for tilveiebringing av 1,0 g (81%) ønsket produkt som et krystallinsk produkt: smp. 144-145<>C. <!>H NMR (CDC13) 8,00 (d, 2H, J=7,3Hz), 7,30-7,27 (m, 4H), 7,10-7,06 (m,3H), 2,46 (s, 3H), 1,99 (s, 3H). Anal. beregnet for ClgHlsFN204S: C, 57,75; H, 4,04; N, 7,48. Funnet: C, 57,84; H, 4,06; N, 7,49.
EKSEMPEL 14
N-[[4-[3-(3-fluorfenyl)-5-metylisoksazol-4-yl]sulfonyl]acetamid, natriumsalt
En blanding av N-[[4-[3-(3-fluorfenyl)-5-metylisoksazol-4-yl]sulfonyl]acetamid (eksempel 13) (0,312 g, 0,83 mmol) og natriumhydroksid (0,33 ml, 2,5 N) i etanol ble konsentrert til tørrhet. Resten ble fortynnet med etanol og ble på ny konsentrert. Resten ble tørket i vakuum for tilveiebringing av 0,32 g (97%) av krystallinsk produkt: smp.
112-131°C. 'H NMR (D2O/300 MHz) 7,64 (d, 2H, J=8,3 Hz), 7,21-6,91 (m, 6H), 2,27 (s, 3H), 1,78 (s, 3H). Anal. beregnet for C18H14FN204SNa 0,5 H20: C, 53,28; H, 3,73; N, 6,80. Funnet: C, 53,57; H, 3,73; N, 6,80.
Følgende forbindelser (eksemplene 15-67) ble oppnådd ifølge fremgangsmåter som ligner de som er eksemplifisert i eksemplene 13-14, med substitusjon av hensiktsmessig sulfonamid og anhydrid.
EKSEMPEL 15
2-meryl-N- [ [4-(5-metyl-3-feny lisoksazol-4-y l)feny 1] sulfonyl] propanamid
Smp. 115,0-115,6°C. 'H NMR (CDCI3/300 MHz) 8,43 (brs, 1H), 8,04 (d, 2H, J=8,5Hz), 7,40-7,31 (m, 7H), 2,50 (s, 3H), 2,45 (sept, 1H, J = 6,9 Hz), 1,12 (d, 6H, J = 6,8 Hz), FABLRMS m/z 385 (M<+>H). FABHRMS m/z 385.1222 (M*H, C20H2IN2O4S beregnet 385.1245). Anal. beregnet for C2oH20N204S: C, 62,48; H, 5,24; N, 7,29. Funnet: C, 62,55; H, 5,24; N, 7,21.
EKSEMPEL 16
2-metyl-N-[[4-(5-meryl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]
propanamid, natriumsalt
mp >300°C. 'H NMR (DMSO-dg/300 MHz) 7,71 (d, 2H, J = 8,1 Hz), 7,43-7,24 (m, 5H), 7,19 (d, 2H, J=8,lHz), 2,44 (s, 3H), 2,15 (sept, 1H, J = 6,9Hz), 0,89 (d, 6H, J = 6,9 Hz). FABLRMS m/z 407 (M<+>H). FABHRMS m/z 407.1053 (M<+>H, C20H21N2O4SNa beregnet 407.1041). Anal. beregnet for C20H19H2O4SNa: C, 59,10; H, 4,71; N, 6,89. Funnet: C, 58,98; H, 4,68; N, 6,94.
EKSEMPEL 17
N-[[4-(5-meryl-3-fenylisoksazol-4-ylJfenyl]sulfonyl] propanamid
smp. 148,9-151,0°C. <*>H NMR (CDC13/300 MHz) 8,60 (brs, 1H), 8,04 (d, 2H, J = 8,7 Hz), 7,38-7,31 (m, 7H), 2,50 (s, 3H), 2,32 (q, 2H, J=7,2 Hz), 1,10 (t, 3H, J = 7,2 Hz). FABLRMS m/z 371 (M<+>H). FABHRMS m/z 371.1049 (M<+>H), beregnet 371.1066. Analyse beregnet for C19HlgN204S: C, 61,61; H, 4,90; N, 7,56. Funnet: C, 61,52; H, 4,92; N, 7,53.
EKSEMPEL 18
N- [ [4-(5-metyl-3-fény lisoksazol-4-y 1] fenyl] sulfonyl]
-propanamid, natriumsalt
Smp. 271,5-272,7°C. <!>H NMR (D2O/300 MHz) 7,57 (d, 2H, J = 8,4 Hz), 7,30-6,90 (m, 7H), 2,12 (s, 3H), 2,00 (q, 2H, J=7,8Hz), 0,83 (t, 3H, J=7,8 Hz). FABLRMS m/z 393 (M<+>H). Anal. beregnet for C19H,7N204SNa: C, 58,61; H, 4,37; N, 7,14. Funnet: C, 57,92; H, 4,53; N, 6,95.
EKSEMPEL 19
N- [ [4-(5-metyl-3-feny lisoksazol-4-yl] fenyl] sulfonyl] benzamid
Smp. 208,8-210,2°C. 'H NMR (CDCl3/300 MHz) 9,05 (brs, 1H), 8,14 (d, 2H, J = 8,5 Hz), 7,82 (d, 2H, J = 7,5 Hz), 7,59 (dd, 1H, J=7,3, 7,5 Hz), 7,49-7,30 (m, 9H), 2,50 (s, 3H). FABLRMS m/z 419 (M^H). FABHRMS m/z 419,1083 (M<+>H), beregnet for 419.1066). Analyse beregnet for C23H,8N204S: C, 66,02; H, 4,34; N, 6,69. Funnet: C, 65,95; H, 4,40; N, 6,69.
EKSEMPEL 20
N-[[4-(5-meryl-3-fenylisoksazol-4-yl]fenylJsuIfonyl]
benzamid, natriumsalt
Smp. 288,2-291,2°C. <l>H NMR (DMSO-d6/300 MHz) 7,90 (d, 2H, J=8,l Hz), 7,83 (s, 2H, J=8,4 Hz), 7,44-7,23 (m, 8H), 7,22 (s, 2H, J=8,4 Hz), 2,44 (s, 3H), FABLRMS m/z 441 (M<+>H). FABHRMS m/z 441.0898 (M<+>H, beregnet 441.0885). Analyse beregnet for C^HpNASNa: C, 62,72; H, 3,89; N, 6,36. Funnet: C, 62,52; H, 4,06; N, 6,17.
EKSEMPEL 21
2^2-dimeryI-N-[[4-(5-metyI-3-fenylisoksazoI-4-yl).
fenyl]sulfonyl]propanamid
Smp. 190,5-191,1°C. <!>H NMR (CDCl3/300 MHz) 8,20 (brs, 1H), 8,04 (d, 2H, J=8,5Hz), 7,39-7,30 (m, 7H), 2,51 (s, 3H), 1,10 (s, 9H). FABLRMS m/z 399 (M<+>H). FABHRMS m/z 399.1388 (M<+>H, beregnet 399.1379). Analyse beregnet for C2IH22N204S: C, 63,30; H, 5,56; N, 7,03. Funnet; C, 63,45; H, 5,53; N, 7,08.
EKSEMPEL 22
2,2-dimetyl-N-[[4-(5-metyI-3-fenylisoksazol-4-yi).
fenyl]sulfonyl]propanamid, natriumsalt
Smp. >300°C. <*>H NMR (DMSO-6V300 MHz) 7,68 (d, 2H, J=8,l Hz), 7,42-7,31 (m, 5H), 7,18 (d, 2H, J = 8,1 Hz), 2,44 (s, 3H), 0,96 (s, 9H). FABLRMS m/z 421 (M<+>H). FABHRMS m/z 421.1196 (M<+>H, beregnet 421.1198). Analyse beregnet for C21H21N204SNa: C, 59,99; H, 5,03; N, 6,66. Funnet; C,59,83; H, 5,08; N, 6,58.
EKSEMPEL 23
Metyl 4-[ [ [4-(5-mety 1-3-feny lisoksazol-4-y 1] -
s ulfonyl] amin o] -4-oksobu tan oat
Smp. 114,9-117,7°C. <]>H NMR (CDCl3/300 MHz) 8,70 (brs, 1H), 8,04 (d, 2H, J = 8,4 Hz), 7,38-7,26 (m, 7H), 3,66 (s, 3H), 2,67-2,57 (m, 4H), 2,50 (s, 3H), 1,10 (s, 9H). FABLRMS m/z 429 (M<+>H). FABHRMS m/z 429.1102 (M<+>H, beregnet 429.1120). Anal. beregnet for C21H20N2O6S: C, 58,87; H, 4,70; N, 6,54. Funnet: C, 58,61; H, 4,77; N, 6,44.
EKSEMPEL 24
N-[[4-(5-metyl-3-fenylisoksazol-4-yl]-fenyl]suIfonyl[butanamid
Smp. 173,2°C. 'HNMR (CDCl3/300MHz) 8,55 (brs, 1H), 8,05 (d, 2H, J = 8,7 Hz), 7,40-7,29 (m, 7H), 2,50 (s, 3H), 2,86 (t, 2H, J = 7,2), 1,61 (sext, 2H, J = 7,2 Hz), 0,88 (t„ 3H J = 7,2 Hz). FABLRMS m/z 391 (M<+>Li). FABHRMS m/z 385.1224 (M<+>H, beregnet 385.1222). Anal. beregnet for C2(tH20N2O4S: C, 62,48; H, 5,24; N, 7,29. Funnet: C, 62,37; H, 5,28; N, 7,22.
EKSEMPEL 25
N-([4-(5-raetyl-3-fenylisoksazol-4-yl)-fenyl]
sulfonyl]butanamid, natriumsalt
Smp. 273,5-277,7°C. 'H NMR (D2O/300 MHz) 7,54 (d, 2H, J = 8,4 Hz), 7,13-6,73 (m, 7H), 2,06 (s, 3H), 1,94 (t, 2H, J = 7,2 Hz), 1,27 (sext, 2H, J = 7,2 Hz), 0,55 (t, 3H, J = 7,2 Hz). FABLRMS m/z 407 (M<+>H). FABHRMS m/z 407.1065 (M<+>H, beregnet 407.1041). Anal. beregnet for C20H19N2O4SNa: C, 59,10; H, 4,71; N, 6,89. Funnet C, 58,91; H, 4,77; N, 6,80.
EKSEMPEL 26
N-[[4-(5-metyI-3-fenylisoksazol-4-yl)fenyl $ulfonyl]pentanamid
Smp. 134,1-136,5°C. <!>H NMR (CDCl3/300 MHz) 8,58 (brs, 1H), 8,04 (d, 2H, J = 8,6 Hz), 7,40-7,31 (m, 7H), 2,50 (s, 3H), 2,28 (t, 2H, J = 7,5 Hz), 1,56 (pent, 2H, J = 7,5 Hz), 1,27 (sext, 2H, J = 7,5 Hz), 0,85 (t, 3H, J = 7,5 Hz). FABLRMS m/z 399 (M<+>H). FABHRMS m/z 399.1286 (M, beregnet 399.1300). Anal. beregnet forC21H22N204S: C, 63,30; H, 5,56; N, 7,03. Funnet C, 63,25; H, 5,63; N, 9,59.
EKSEMPEL 27
N-[(4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]
sulfonyljpentanamid, natriumsalt
Smp. 264,7°C. <*>H NMR (DMSO-d</300 MHz), 7,71 (d, 2H, J = 8,1 Hz), 7,43-7,32 (m, 5H), 7,18 (d, 2H, J = 8,1 Hz), 2,43 (s, 3H), 1,90 (t, 2H, J = 7,5 Hz), 1,35 (pent, 2H, J=7,5 Hz), 1,17 (sext, 2H, J = 7,5 Hz), 0,78 (t, 3H, J = 7,5 Hz). FABLRMS m/z 421 (M<+>H). Anal. beregnet for C21H2iN204SNa: C, 59,99; H, 5,03; N, 6,66. Funnet: C, 59,85; H, 5,08; N, 6,62.
EKSEMPEL 28
N-[[4-(5-meryl-3-fenyusoksazol-4-yI)fenyl]-sulfonyJJheksanamid
'H NMR (CDCV300 MHz) 8,50 (brs, 1H), 8,04 (d, 2H, J = 8,4 Hz), 7,40-7,30 (m, 7H), 2,50 (s, 3H), 2,27 (t, 2H, J = 7,2 Hz), 1,58 (pent, 2H, J = 7,2 Hz), 1,27-1,19 (m, 4H), 0,84 (t, 3H, J = 7,2 Hz). FABLRMS m/z 413 (M<+>H). FABHRMS m/z 413.1517 (M<+>H, beregnet 413.1535). Anal. beregnet for C^H^NAS: C, 64,06; H, 5,86; N, 6,79. Funnet: C, 64,04; H, 5,85; N, 6,70.
EKSEMPEL 29
3-metoksy-N-[[4-(5-meryl-3-fenylisoksazol-4-yl)-fenyl]sulfonyl]propanamid
Smp. 139,7-140,9°C. 'HNMR (CDCl3/300 MHz) 9,34 (brs, 1H), 8,05 (d, 2H, J= 8,5 Hz), 7,37 (m, 7H), 3,62 (t, 2H, J = 5,5 Hz), 3,43 (s, 3H), 2,54 (t, 2H, J = 5,5 Hz), 2,51 (s, 3H). FABHRMS m/z 400.1071 (M<+>, C20H20N2O5S beregnet 400.1093).
EKSEMPEL 30
3-metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]-sulfonyl]propanamid, natriumsalt
Smp. 240,7-243,2°C. 'H NMR (D2O/300MHz) 7,63 (d, 2H, J = 8,5 Hz), 7,33 (m, 1H), 7,20 (m, 4H), 7,16 (d, 2H, J = 8,5 Hz), 3,49 (t, 2H, J = 6,2 Hz), 3,11 (s, 3H), 2,29 (s og t overlappet, 5H, J = 6,2 Hz). FABHRMS m/z 429.1074 (M<+>Li), C20H19N2O5SNaLi beregnet 429.1072).
EKSEMPEL 31
2-etoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl-sulfonyljacetamid
Smp. 131,3-132,2°C. 'H NMR (CDCI3/3OO MHz) 8,98 (brs, 1H), 8,08 (d, 2H, J = 8,7 Hz), 7,37 (m, 7H), 3,95 (s, 2H), 3,58 (q, 2H, J = 7,0 Hz), 2,51 (s, 3H), 1,26 (t, 3H, J = 7,0 Hz). FABHRMS m/z 400.1093 (M+).
EKSEMPEL 32
2-etoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)-sulfonyl] acetamid, natriumsalt
Smp. 207,2-210,0°C. LH NMR (D2O/300 MHz) 7,67 (d, 2H, J = 8,5 Hz), 7,33 (m, 1H), 7,26-7,18 (m, 6H), 3,80 (s, 2H), 3,36 (q, 2H, J = 7,1 Hz), 2,33 (s, 3H), 1,00 (t, 3H, J = 7,1 Hz). FABHRMS m/z 423.0992 (M<+>H), C2oH20N205SNa beregnet 423.0991).
EKSEMPEL 33
N-[[4-[5-klorfenyl)-3-(trilfuormetyl)-lH-pyrazol-l-yl]-fenyl-l-yl]sulfonyl]propanamid
Smp. 77,9-85,l°C. Anal. beregnet for CuHuClFjNjC^S: C, 49,84; H, 3,30; N, 9,18. Funnet: C, 49,83; H, 3,35; N, 9,10.
EKSEMPEL 34
N-I[4-[5-(4-klorfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]
fenyl]sulfonyl]propanamid, natriumsalt
Smp. >300°C. Anal. beregnet for C^^ClFjNaOaSNa: C, 47,56; H, 2,94, N, 8,76. Funnet: C, 47,51; H, 3,02; N, 8,72.
EKSEMPEL 35
N-[{4-[5-(4-klorfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]butanamid
'H NMR (CDCl3/300 MHz) 8,1 (d, 2H, J = 8,7 Hz), 7,94 (brs, 1H), 7,5 (d, 2H, J ? 8,7 Hz), 7,37 (d, 2H, J = 8,4 Hz), 7,17 (d, 2H, J = 8,4 Hz), 6,79 (s, 1H), 2,24 (t, 2H, J = 7,5 Hz), 1,62 (m, 2H), 0,9 (t, 3H, J = 7,5 Hz). FABLRMS m/z 494 (M<+>H).
EKSEMPEL 36
N-[[4-[5-(4-klorfenyl)-3-(trilfuormet>l)-l H-pyrazol-1-yl]-fenyl]sulfonyl]butanamid, natriumsalt
Smp. 285,4-286,5°C.1 H NMR (CD3OD/300MHz) 7,95 (d, 2H, J = 8,7 Hz), 7,37 (m, 4H), 7,27 (d, 2H, J = 9,0 Hz), 6,96 (S, 1H), 2,1 (t, 2H, 6,9 Hz), 1,55 (m, 2H), 0,84 (t, 3H, J = 7,2 Hz).
EKSEMPEL 37
N-[[4-[5-(4-klorfenyl)-3-{trilfuormetyl)-lH-pyrazol-l-yl]-fenyI]sulfonyI]acetamid
Smp. 161,9-162,7°C. <l>H NMR (CDC13/300 MHz) 8,6 (brs, 1H), 8,07 (d, 2H, J = 6,9Hz), 7,5 (d, 2H, J = 6,9 Hz), 7,38 (d, 2H, J = 6,9 Hz), 7,18 (d, 2H, J = 6,9 Hz), 6,79 (s, 1H), 2,07 (s, 3H).
EKSEMPEL 38
N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-lH-pyrazol-l-y]]fenyl]sulfonyl]acetamid, natriumsalt
Smp. 269,8-272°C. <!>H NMR (D2O/300 MHz) 7,73 (d, 2H, J = 8,7 Hz), 7,3 (d, 2H, J = 8,7 Hz), 7,23 (d, 2H, J = 8,4 Hz), 7,06 (d, 2H, J = 8,4 Hz), 6,87 (s, 1H), 1,8 (s, 3H).
EKSEMPEL 39
N-[[4-[5-meryl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid
Smp. 169,3-170,6°C. Anal. beregnet for C^H^NjCvS: C, 60,66; H 4,53; N, 7,86. Funnet C, 60,57; H 4,59; N, 7,81.
EKSEMPEL 40
N-[[4-(5-meryl-3-fenylisoksazol-4-yl]fenyl]-sulfonyl]acetamid, narri rumsalt
Smp. 245,6-247°C. Anal. beregnet for C^H^N^SNa.rLO: C, 54,54; H, 4,32; N, 7,07. Funnet C, 54,47; H 4,34; N, 7,07.
EKSEMPEL 41
N-[[4-[5-metyl-3-fenylisoksazol-4-yl]-fenyl]sulfonyl] acetamid, katiumsalt
Smp. 279,7-283,7°C. 'H NMR (D2O/300 MHz) 7,62 (d, 2H, J = 8,4 Hz), 7,2 (m, 7H), 2,27 (s, 3H), 1,77 (s, 3H).
EKSEMPEL 42
N-[[4-[3-(difluormetyl)-6-fluor-l,5-dihydro-7-metoksy- [2] benzotiopyrano [4,3-c] pyrazol- 1-yl] fenyl] sulfonyl] acetamid
'H NMR (300 MHz/CDCl3) 8,1 (d, 2H, J = 6,9 Hz), 7,61 (d, 2H, J = 6,9 Hz), 6,69 (m, 3H), 4,0 (s, 2H), 3,82 (s, 3H), 1,96 (s, 3H). FABLRMS m/z 484 (M<+>H).
EKSEMPEL 43
N-ll4-|3-(difluormer>l)-6-fluor-l,5-dihydro-7-metoksy-|2]-benzotiopyrano[43-c]pyrazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt
Smp. >300°C. <l>H NMR (CD3OD/300 MHz) 8,04 (d, 2H, J = 6,6 Hz), 7,6 (d, 2H, J = 6,6 Hz), 6,82 (m, 3H), 4,08 (s, 2H), 3,85 (s, 3H), 1,90 (s, 3H).
EKSEMPEL 44
N-[[4-[6-fluor-l,5-dihydro-7-metoksy-3-(trifluormetyl)-[2] benzotiopy rano [4,3-c ] py razol- 1-y 1] fenyl] sulfonyl] acetamid
'H NMR (CDCl3/300 MHz) 8,06 (d, 2H, J = 8,4 Hz), 7,6 (d, 2H, J = 8,4 Hz), 6,68 (d, 2H, J = 8,7 Hz), 6,50 (d, 2H, J = 8,7 Hz), 3,97 (s, 2H), 3,79 (s, 3H), 1,92 (s, 3H). FABLRMS m/z 502 (M<+>H).
EKSEMPEL 45
N-[[4-[6-fluor-l,5-dihydro-7-metoksy-3-(tirfluormetyl)-[2]benzotiopyrano[4,3-c]pyrazoM-yl]fenyl]sulfonylacetamid, natriumsalt Smp. 183-191,1°C. 'H NMR (CD3OD/300 MHz) 8,06 (d, 2H, J = 8,7 Hz), 7,62 (d, 2H, J = 8,7 Hz), 6,9 (d, 2H, J = 8,7 Hz), 6,6 (d, 2H, J = 8,7 Hz), 4,11 (s, 2H), 3,85 (s, 3H), 1,90 (s, 3H).
EKSEMPEL 46
N-[[4-[3-(dilfuormetyl)-5-<3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]acetamid
Smp. 173-175°C. <J>H NMR (aceton-dV300 MHz) 8,1 (d, 2H, J = 8,9 Hz), 7,6 (d, 2H, J = 8,9 Hz), 7,2-6,8 (m, 6H), 3,9 (s, 3H). Anal. beregnet for C19H16N3F304S: C, 51,94; H, 3,67; N, 9,56. Funnet: C, 51,80; H, 3,72; N, 9,47.
EKSEMPEL 47
N-[[4-|3-(dilfuormety])-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]acetamid, natrimsalt
Smp. 140,1-146,0°C. <!>H NMR (D2O/300 MHz) 7,7 (d, 2H, J = 8,4 Hz), 7,2 (d, 2H, J = 8,4 Hz), 6,9-6,6 (m, 5H), 3,6 (s, 3H), 1,8 (s, 3H). Anal. beregnet for CI9H,sN3F304SNa + 3,06% H20; C, 47,95; H, 3,52; N, 8,83. Funnet: C, 47,94; H, 3,42; N, 8,78.
EKSEMPEL 48
N- [ [4-{2-mery 1-4-feny loksazol-5-yl)feny 1] sulfonyl] acetamid
Smp. 220,7-221,0°C. <!>H NMR (aceton-dV300 MHz) 8,0 (d, 2H, J = 8,7 Hz), 7,8 (d, 2H, J = 9,0 Hz), 7,6 (m, 2H), 7,4 (m, 3H), 2,5 (s, 3H), 2,0 (s, 3H). Anal. Beregnet for Ci8H16N204S: C, 60,66; H, 4,53; N, 7,86. Funnet: C, 50,54; H, 4,56; N, 7,90.
EKSEMPEL 49
N-[[4-(2-metyI-4-fenyloksazol-5-yl)fenyl]sulfonyl]acetamid, natriumsalt
Smp. 259,9-260,0°C. <*>H NMR (D2O/300 MHz) 7,6 (d, 2H, J = 8,4 Hz), 7,4 (d, 2H, J = 8,4 Hz), 7,3 (m, 5H), 2,3 (s, 3H), 1,8 (s, 3H). Anal. beregnet for ClgHI5N204SNa <+ >5,94% H20: C, 53,74; H, 4,42; N, 6,96. Funnet: C, 53,73; H, 4,28; N, 6,94.
EKSEMPEL 50
Metyl [ [ [4-(5-metyl-3-fenylisoksazol-4-yi)fenyl]
-sulfonyl]amino]oksoacetat
Smp. 171,1-172,3°C. <!>H NMR (CDC1/300 MHz) 9,4 (bs, 1H), 8,1 (d, 2H, J = 8,7 Hz), 7,4-7,2 (m, 7H), 7,6 (m, 2H), 3,9 (s, 3H), 2,5 (s, 3H). Anla. beregnet for C19H,6N206S: C, 56,99; H, 4,03; N, 7,00. Funnet C, 56,74; H, 3,96; N, 6,94.
EKSEMPEL 51
Metyl [[[4-(5-mety 1-3-fenylisoksazol-4-yl)feny 1]-sulfonyl]amino]oksoacetat, natriumsalt
Smp. 146,0-151,8°C. <J>H NMR (DMSO-dgÆOO MHz) 7,8-7,7 (m, 2H), 7,5-7,2 (m, 7H), 3,5 (s, 3H), 2,5 (s, 3H). Anal. beregnet for C,9H15N206SNa + 3,22% H20: C, 52,29; H, 3,82; N, 6,42. Funnet: C, 52,28; H, 3, 66; N, 6,44.
EKSEMPEL 52
2-metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]-sulfonyljacetamid
Smp. 123,9-125,3°C. <*>H NMR (aceton-d6/300 MHz) 8,0 (d, 2H, J = 8,7 Hz), 7,5 (d, 2H, J = 8,7 Hz), 7,5-7,4 (m, 5H), 4,0 (s, 2H), 3,4 (s, 3H), 2,5 (s, 3H). Anal. beregnet for C19H,8N205S: C, 59,06; H, 4,70; N, 7,25. Funnet: C, 59,14; H, 4,73; N, 725.
EKSEMPEL 53
2-metoksy-N-[[4-(5-meryl-3-fenylisoksazo]-4-yl)
fenyl]sulfonyl]acetamid, natriumsalt
Smp. 276,9-277,9°C. <!>H NMR (DMSO-dV300 MHz) 7,7 (d, 2H, J = 8,4 Hz), 7,5-7,3 (m, 5H), 7,2 (d, J = 8,4 Hz, 2H), 3,6 (s, 2H), 3,2 (s, 3H), 2,4 (s, 3H). FABHRMS m/z 409.0848 (M<+>H, beregnet 409.0851).
EKSEMPEL 54
N-I[4-[5-(dilfuormetyl)-3-fenylisoksazol-4-yl]fenyll-sulfonyljpropanamid
Smp. 136,9-141,0°C. <*>H NMR (aceton-d6/300 MHz) 10,7 (bs, 1H), 8,1 (d, 2H, J = 8,4 Hz), 7,6 (d, 2H, J = 8,4 Hz), 7,6-7,4 (m, 5H), 7,2 (t, 1H, J = 52,2 Hz), 2,4 (t, 2H, J = 7,5 Hz), 1,0 (t, 3H, J = 7,5 Hz). Anal. beregnet for C19H16F2N204S: C, 56,15; H, 3,97; N, 6,89. Funnet: C, 56,10; H, 3,93; N, 6,81.
EKSEMPEL 55
N-([4-t5-(dilfuormetyl)-3-fenylisoksazol-4-yl]fenyl]-sulfonyl]propanamid, natriumsalt
Smp. 287,8-293,6°C. 'H NMR (DMSO-dV300 MHz) 7,7 (d, 2H, J = 8,1 Hz), 7,5-7,1 (m, 8H), 1,9 (dd, 2H, J = 7,5 Hz), 0,8 (t, 3H, J = 7,5 Hz): Anal. beregnet for Ci9H,5N2F2Na04S + 2,04% H20: C, 52,17; H, 3,63; N, 6,45. Funnet: C, 52,18; H, 3,69; N,6,41.
EKSEMPEL 56
N-[I4-[5-(dilfuormetyl)-3-fenylisoksazol-4-yl]fenyl]-sulfonyl]butanamid
Smp. 154,9-155,9°C. <*>H NMR (aceton-dy300 MHz) 10,7 (bs, 1H), 8,1 (d, 2H, J = 8,4 Hz), 7,6 (d, 2H, J = 8,4 Hz), 7,6-7,4 (m, 5H), 7,2 (t, 1H, J = 51,9 Hz), 2,3 (dd, 2H, J = 7,2 Hz), 1,6 (m, 2H), 0,8 (t, 3H, J = 7,2 Hz). Anal. beregnet for C20H18F2N2O4S: C, 57,14; H, 4,32; N, 6,66. Funnet: C, 57,18; H, 4,37; N, 6,65.
EKSEMPEL 57
N-[[4-[5-(dilfuormetyl)-3-fenylisoksazol-4-yl]fenyI]-sulfonyljbutanamid, natriumsalt
Smp. 281,7-286,3°C. <!>H NMR (DMSO-d6/300 MHz) 7,7 (d, 2H, J = 8,1 Hz), 7,6-7,1 (m, 8H), 1,9 (dd, 2H, J = 7,2 Hz), 1,4 (m, 2H), 0,7 (t, 3H, J = 7,5 Hz). Anal. beregnet for C20H17N2F2NaO4S + 2,25% H20: C, 53,07; H, 3,96; N, 6,17. Funnet: C, 53,08; H, 4,04; N, 6,19.
EKSEMPEL 58
4-[[[4-(5-tnetyl-3-fenylisoksazoM-yl)fenyl]sulfonyl]amino]-4-oksobutanoisk syre
Smp. 158,4-165,4°C. <*>H NMR (CDCl3/300 MHz) 8,04 (m, 2H, J = 8,7 Hz), 7,45-7,25 (m 7H), 2,75-2,65 (m, 2H), 2,65-2,53 (m, 2H), 2,51 (s, 3H). FABLRMS m/z 414
(M<+>H). FABHRMS m/z 415.0958 (M<+>H, beregnet 415.0964). Anal. beregnet for C20HlgN2O6S: C, 57,96; H, 4,38; N, 6,76. Funnet: C, 57,71; H, 4,81; N, 6,67.
EKSEMPEL 59
4-[[[4-(5-meryl-3-fenylisoksazol-4-yl)fenyl] sulfonyl]amino]-4-oksobiitanoisk syre, dinatriumsalt
Smp. > 300°C. 'H NMR (D2O/300 MHz) 7,68 (d, 2H, J = 8,5 Hz), 7,39-7,20 (m, 7H), 2,34 (s, 3H), 2,33-2,15 (m, 4H). Anal. beregnet for C20H16N2O6SNa2. 0,95 H20: C, 50,53; H, 3,79; N, 5,89. Funnet: C, 50,52; H, 3,82; N, 5,89.
EKSEMPEL 60
N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyI]-sulfonyljformamid
Smp. 111-122°C. <*>H NMR (CDCl3/300 MHz) 8,69 (br s, 1H), 7,92 (d, 2H, J = 8,5 Hz), 7,48-7,31 (m, 7H), 2,52 (s, 3H). FABLRMS m/z 343 (M<+>H). FABHRMS m/z 343.0753
(M<+>H, beregnet 343.0753). Anal. beregnet for C17H14N204S: C, 59,64; H, 4,12; N, 8,18; Funnet C, 59,59; H, 4,17; N, 8,07.
EKSEMPEL 61
N- [ [4-(5-mety 1-3-fény loksazol-4-y l)feny I] -
sulfonyljformamid, natriumsalt
Smp. 198-204°C. <[>H NMR (D2O/300 MHz) 8,57 (s, 1H), 7,64 (d, 2H, J = 8,3 Hz), 7,38-7,13 (m, 7H), 2,31 (s, 3H). FABLRMS m/z 365 (M<+>H). FABHRMS m/z 365.0565 (M<+>H, beregnet 365.0572). Anal. beregnet for C17H13N204SNa. 0,73 EtOH 0,51 H20: C, 54,46; H, 4,55; N, 6,88; funnet C, 54,46; H, 4,44; N, 6,74.
EKSEMPEL 62
1,1-dimetyletyl N-[[4-(5-inetyl-3-fenylisoksazol-4-yl)fenyl]
sulfonyljkarbamat
Smp. 168-171°C. <*>H NMR (CDCI3/3OO MHz) 8,01 (d, 2H, J = 8,7 Hz), 7,51 (s, 1H), 7,46-7,30 (m, 7H), 2,50 (s, 3H), 1,40 (s, 9H). FABLRMS m/z 415 (M<+>H). FABHRMS m/z 415.1337 (M<+>H, beregnet 415.1328). Anal. beregnet for C21H22N205S: C, 60,86; H, 5,35; N, 6,76. Funnet C, 60,79; H, 5,40; N, 6,75.
EKSEMPEL 63
l,l-dimetyIetylN-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]
sulfonyl] karbamat, natriumsalt
Smp. 241-243°C. 'H NMR (D2O/300 MHz) 7,67 (d, 2H, J = 8,3 Hz), 7,42-7,17 (m, 7H), 2,35 (s, 3H), 1,11 (s, 9H). FABLRMS (M<+>H) m/z 437. FABHRMS m/z 437.1171 (M<+>H, beregnet 437.1147). Anal. beregnet for C2,H21N205SNa. 0,96 H20: C, 55,52; H, 5,10; N, 6,17; funnet C, 55,50; H, 5,06; N, 6,29.
EKSEMPEL 64
4-[2-(4-fluorfeny])cylopenten-l-ylJ-N-merylbeiizensuJfonamid
Smp. 121-122°C. 'H NMR (CDC13) 8 2,08 (p, J = 9 Hz, 2H), 2,67 (s, 3H), 2,91 (t, J = 9 Hz, 4H), 4,24 (br s, 1H), 6,92 (d, J = 9 Hz, 2H), 7,07-7,13 (m, 2H), 7,28 (d, J = 9 Hz, 2H), 7,67 (d, J = 9 Hz, 2H). MS (FAB) m/z 332 (M+H)<+.> Anal. beregnet for C18H18N02SF: C, 65,24; H, 5,47; N, 4,23. Funnet: C, 65,02; H, 5,69; N, 4,20.
EKSEMPEL 65
N-[[4-[2-(3-klor-4-fluorfenyl)cyklopenten-l-yl]-feny 1] sulfonyl] acetamid
Smp. 127-129°C. 'H NMR (CDC13) 8 2,03-2,14 (m, 5H), 2,84-2,95 (m, 4H), 6,92-7,00 (m, 2H), 7,18 (dd, J = 2,8 Hz, 1H), 7,29 (d, J = 9 Hz, 2H), 7,88 (d, J = 9 Hz, 2H), 8,20 (br s, IH). MS (FAB) m/z 394 (M+H)<+>. HRMS beregnet for (M+H) 394.0680. Funnet 394.0630. Anal. beregnet for C19H17NCIF03S & 0,49 H20): C, 56,68; H, 4,50; N, 3,48. Funnet: C, 56,65; H, 4,39; N, 3,74.
EKSEMPEL 66
N-[|4-|2-(3-klor-3-fluorfenyl)cyklopenten-l-yl]fenyl]-suIfonyl]acetamid, natriumsalt
Smp. > 180°C. 'H NMR (D20) 8 1,77 (s, 3H), 1,90 (p, J = 8 Hz, 2H), 2,67-2,78 (m, 4H), 6,94 (d, J = 8 Hz, 2H), 7,13 (s, 1H), 7,17 (d, J = 8 Hz, 2H), 7,53 (d, J = 8 Hz, 2H). Anal. beregnet for (C,9H16NClF03SNa & 0,15 NaOH & 0,85 H20): C, 52,21; H, 4,12; N, 3,20; Na, 6,03. Funnet: C, 52,20; H, 4,02; N, 3,22; Na, 6,02.
EKSEMPEL 67
metyl 3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]-suIfonyl]amino]-3-oksopropanoat
'H NMR (aceton-dg/300 MHz) 8,04 (d, J = 8,5 Hz, 2H), 7,49 (d, J = 8,5 Hz, 2H), 7,40-7,39 (m, 5H), 3,64 (s, 3H), 3,47 (s, 2H), 2,53 (s, 3H). FABLRMS m/z 415 (M<+>H).
EKSEMPEL 68
N-t[4-[3,4-dimetyI-l-fenyl-lH-pyrazol-5-yl]-fenyl] sulfonyl] prop anamid
Smp. 187,4-188,7 °C. *H NMR (aceton oV300 MHz) 8,0 (d, 2H, J = 8,5 Hz), 7,43 (d, 2H, J = 8,5 Hz), 7,23 (m, 5H), 2,27 (s, 3H), 2,05 (s, 3H). Anal. beregnet for CjoH^OjS: C, 62,64; H, 5,52; N, 10,96. Funnet: C, 62,83; H 5,61; N, 10,90.
EKSEMPEL 69
N-[[4-[3,4-dimetyl-l-fenyl-lH-pyrazol-5-yl]fenyl]-sulfonyl] propanamid, natriumsalt
Smp. 264,0-267,6°C. 1H NMR (DMSO d6/300 MHz) 7,68 (d, 2H, J = 8,4 Hz), 7,25 (m,3H), 7,11 (m, 4H), 2,19 (s, 3H), 1,94 (s, 3H).
EKSEMPEL 70
N-[[4-[5-(4-metylfenyl)-3-(trifluormetyl)-lH-pyrazoI-1 -y ljfeny 1] sulfonyl] acetamid
4-[5-(4-metyIfenyI)-3-(trifIuormetyl)-IH-pyra2»I-l-yl]berizensuifonamid (0,60 g, 1,57 mmol) ble oppvarmet i 2 ml acetylklorid og 2 ml eddiksyre ved tilbakestrømning i 2 timer. Ytterligere 2 ml acetylklorid ble tilsatt og blandingen ble oppvarmet ved tilbakeløp i ytterligere 5 timer. Blandingen ble avkjølt og konsentrert. Omkrystallisering fra eter/heksan tilveiebrakte produktet som et hvitt fast stoff: anal. beregnet for C19H16N303SF3: C, 53,90; H, 3,81; N, 9,92; S, 7,57. Funnet: C, 54,04; H, 3,80; N, 9,93; S, 7,66.
EKSEMPEL 71
N-[[4-[5-(4-met>lfenyl)-3-(rirfluormet>l)-l H-pyrazol-1-yl]
-fenyl] sulfonyl] acetamid, natriumsalt
Til 300 mg (0,71 mmol) N-[[4-[5-(4-metylfenyl)-3-(trifluormetyl)-lH-pyrazoM-yl]fenyI]sulfonyl]acetamid (eksempel 70) i 4 ml EtOH ble det tilsatt 40 ul 50% NaOH (0,76 mmol) og blandingen ble omrørt ved romtemperatur i 1 time. Konsentrering tilveiebrakte natriumsaltet som et hvitt fast stoff.
EKSEMPEL 72
Metyl N-[[4-(5-nietyl-3-fenylisoksazol-4-yl)fenyl]-sulfonyl]karbamat, natriumsalt
Til en oppløsning av 4-[5-metyl-3-(fenyl)isoksazol-4-yl]benzensulfonamid (1.920 g, 6,11 mmol) i 40 ml THF ble behandlet med metylklorformat (1,16 ml, 1,38 g, 14,60 mmol) og deretter l,8-diazabicyklo[5.4.0]undek-7-ene (DBU) (2,80 ml, 2,79 g, 18,33 mmol) ved romtemperatur. Etter 48 timer ble den resulterende blandingen fordelt mellom etylacetat og KHS04 oppløsningen. Den organiske fasen ble vasket med saltvann, tørket over MgS04, filtrert og konsentrert i vakuum for tilveiebringing av en svak gul klar olje. Denne oljen ble renset ved å kjøre to flarnmekromatografikolonner (første eiueringsmiddel 1:1, heksan: etylacetat; andre elueringsmiddel CH2Cl2 med THF) som tilveiebringer råforbindelsen som var egnet for anvendelse uten ytterligere rensing. Råforbindelsen ble oppløst i 8 ml kloroform og behandlet med 2 ml mettet vandig NaHC03. Produktet ble separert som et krystallinsk fast stoff og ble samlet ved filtrering for tilveiebringing av rent salt som hvite nåler (0,607 g, 25%): smp. 267,4-275,0°C. 'H NMR (D2O/300 MHz) 7,68 (d, 2H, J = 8,5 Hz), 7,39-7,12 (m, 7H), 3,37 (s, 3H), 2,34 (s, 3H). FABLRMS m/z 401 (M+Li). FABHRMS m/z 395.0675 (M<+>H, beregnet 395.0678). Anal. beregnet for C18H15N205SNa. 3,66 H20: C, 46,96; H, 4,89, N, 6,09; funnet: C, 46,91; H, 4,40; N, 6,00.
EKSEMPEL 73
N-[[4-[5-acetoksymeryl-3-fenylisoksazol-4-yl]-fenyl]sulfonyl]acetamid
En suspensjon av 4-[5-hydroksymetyl-3-(fenyl)isoksazol-4-yl)benzensulfonamid (1,51 g, 4,56 mmol) i 60 ml diklormetan ble behandlet med eddiksyreanhydrid (1,30 ml, 1,40 g, 13,69 mmol), trietylamin (1,90 ml, 1,40 g, 13,70 mmol) og dimetylaminopyridin (0,056 g, 0,46 mmol). I løpet av 5 minutter ble blandingen homogen og omrøringen ble fortsatt i 40 timer. Reakjonsblandingen ble fortynnet med etylacetat og vasket med N-[[4-[5-acetoksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid (1,67 g, 88%): smp. 137-139°C. 'H NMR (CDCl3/300 MHz) 8,58 (brs, 1H), 8,06 (d, 2H, J = 8,47 Hz), 7,47-7,34 (m, 7H), 5,17 (s, 2H), 2,12 (s, 3H), 2,10 (s, 3H). FABLRMS m/z 421 (M+Li). FABHRMS m/z 415.0953 (M+H, C20H19N2O6S beregnet 415.0964).
EKSEMPEL 74
N-[[4-[5-hydroksymetyl-3-fenylisoksazol-4-yl]-fenyl]sulfonyl]acetamid
En oppløsning av N-[[4-[5-acetoksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid (eksempel 73) (0,867 g, 2,09 mmol) i metanol ble behandlet med natiiumhydroksid. Reaksjonen ble konsentrert i vakuum, oppløst i vann og sakte surgjort med IN HC1 for å tilveiebringe et fast stoff. Det faste stoffet ble oppløst i etylacetat, vasket med saltvann, tørket over MgS04, filtrert og konsentrert i vakuum for tilveiebringing av N-[[4-[5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid som et gult skum, (0,513 g, 66%) med egnet renhet for anvendelse uten ytterligere rensing: smp. 94-103°C. 'H NMR (CDCl3/300 MHz) 8,18 (brs, 1H), 7,09 (d, 2H, J = 10,08 Hz), 7,47-7,35 (m, 7H), 4,78 (s, 2H), 2,23 (brs, 1H), 2,11 (s, 3H). FABLRMS m/z 373 (M+H). FABHRMS m/z 373.0876 (M+H, beregnet 373.0858). Anal. beregnet for.C^H^NjOsS,: C, 58,06; H, 4,33, N, 7,52. Funnet C, 57,73, H, 4,70, N, 7,07.
EKSEMPEL 75
N-[[4-[5-hydroksymeryI-3-fenyIisoksazol-4-yI]fenyI]-sulfonyI]acetamid, natriumsalt
En oppløsning av N-[[4-[5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid (eksempel 74) (0,468 g, 1,26 mmol) i metanol ble behandlet med NaOH oppløsning, 1,26 mmol). Etter 5 minutter ble oppløsningen konsentrert i vakuum for tilveiebringing av N-[[4-[5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt (0,462 g, 93%) som et brunt skum. <]>H NMR (D2O/300 MHz) 7,68 (d, 2H, J = 8,46 Hz), 7,39-7,23 (m, 7H), 4,60 (s, 2H), 1,79 (s, 3H). FABLRMS m/z 395 (M+Na).
EKSEMPEL 76
N-[[4-(5-hydroksymetyI-3-fenylisoksa2ol-4-yl]fenyl]sulfonyl]-propanamid, natriumsalt
Trinn 1: fremstilling av N-[[4-f5-propoksvmetvl-3-fenvlisoksa2X)l-4-yl]sulfonvl1propanamid
En suspensjon av 4-[5-hydroksymetyl-3-(fenyl)isoksazol-4-yl]benzensulfonamid (0,314 g, 0,947 mmol) i THF ble behandlet med propionsyreanhydrid (0,36 ml, 0,37 g, 2,846 mmol), trietylamin (0,40 ml, 0,29 g, 2,85 mmol) og dimetylaminopyridin (0,025 g, 0,205 mmol). Den resulterende oppløsningen ble omrørt i 24 timer. Råreaksjonen ble fortynnet med etylacetat og vasket med KHS04, saltvann, tørket over MgS04, filtrert og konsentrert i vakuum. Det resulterende produktet ble renset ved flammekromatografi ved anvendelse som elueringsmiddel heksan/etylacetat (1:1). Konsentrasjon av hensiktsmessige fraksjoner tilveiebrakte N-[[4-(5-propoksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid (0,33 g, 79%) som en klar brun olje med egnet renhet som kan bli anvendt i neste trinn.
Trinn 2: fremstilling av N-f[4-f5-hvdroksvmetvl-3-fenvlisoksazol-4-yl]fenyl]$ulfopyl]propanamid
N-[[4-(5-propoksymetyl-3-fenylisoksazol-4-yl[fenyl]sulfonyl]propanamid (trinn 1) ble løst opp i metanol og NaOH oppløsning (0,89 ml 2,5 N, 2,24 mmol) ble tilsatt med omrøring. Etter 12 timer ble reaksjonen surgjort med IN HC1 oppløsning og ekstrahert med en blanding av diklormetan og etylacetat. Kombinerte organiske faser ble tørket over MgS04, filtrert og konsentrert i vakuum for tilveiebringing av N-[[4-(5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid (0,238 g, 83%) med tilstrekkelig renhet for å bli anvendt i neste trinn.
Trinn 3: fremstilling avN-[[4-f5-hvdroksvmetvl-3-fenvlisoksazol-4-yl] fenvl] sulfonvl1propanamid. natriumsalt
N-[[4-(5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid (trinn 2) ble oppløst i metanol og behandlet medNaOH oppløsning (1,23 ml 0,50 N, 0,62 mmol). Den resulterende oppløsningen ble konsentrert i vakuum. Den resulterende oljen ble fortynnet med vann og konsentrert ved høyt vakuum for tilveiebringing av N-[[4-(5-hydroksymety 1-3 -feny lisoksazol-4-yl]fenyi]sulfony ljpropanamid, natriumsal7 (0,195 mg, 64%) som et brunt skum: smp. 153,5-157,1°C, 'H NMR (D2O/300 MHz) 7,68 (d, 2H, J = 8,46 Hz), 7,39-7,15 (m, 7H), 4,59 (s, 2H), 2,04 (q, 2H, J = 7,66 Hz), 0,86 (t, 3H, J = 7,66 Hz).
EKSEMPEL 77
4-[5-(4-fluorfenyl)-3-trifluormetyI-lH-pyrazol-l-yl]-N-metylbenzensulfonamid
Til en oppløsning av 4-[5-(4-fluorfenyl)-3-trifluormetyl-lH-pyrazol-l-yl]benzensulfonamid (100 mg, 0,26 mmol) i DMSO (2 ml) ble det tilsatt natriumhydrid (6 mg, 0,26 mmol). Reaksjonsblandingen ble omrørt ved romtemperatur i 1,5 time. Til denne blandingen ble det tilsatt metyliodid (0,025 ml, 0,4 mmol). Blandingen ble omrørt ved romtemperatur i 16 timer. Blandingen ble fortynnet med etylacetat (15 ml) og vasket med vann (3x10 ml). Den organiske oppløsningen ble samlet, tørket (Na2S04) og konsentrert. Resten ble kromatografert (3:1 heksametylacetat) for tilveiebringing av monometylsulfonamid (22 mg, 21%) som en gummi. Nøyaktig masse beregnet for C17HI3F4N302S: 399.0664. Funnet 399.0662.
EKSEMPEL 78
4-[2-(4-lfuorfenyl)-lH-pyrroH-yl]-N-metylbenzensulfonamid Trinn 1: fremstilling av 5.5-dimetvl-1.3-dioksan-2-propanol 5)5-dimetyl-l,3-dioksan-2-propanol ble syntetisert ved å følge litteraturprosedyren (J. Org. Chem. 57, 2195,1992).
Trinn 2: fremstilling av 5.5-dimetvl-1.3-dioksan-2-propanol
DMSO (10,2 ml, 0,14 mol) ble tilsatt til en oppløsning av oksalylklorid (5,5 ml, 63,2 mmol) i metylenklorid (25 ml) ved -78°C. Etter omrøring i 15 min. ble oppløsningen av 5,5-dimetyi-l,3-dioksan-2-propanol (trinn 1) (10 g, 57,5 mmol) i metylenklorid (100 ml) tilsatt iløpet av 10 min. Reaksjonen ble omrørt i 1 time og trietylamin (40 ml, 0,2 mol) ble tilsatt. Etter omrøring ved -78°C i l time ble reaksjonsblandingen oppvarmet ved romtemperatur og omrørt i 2 timer. Reaksjonen ble stoppet med vann og ekstrahert med metylenklorid. Organiske fraksjoner ble vasket med vandig natriumbikarbonat og saltvann. Etter tørking (Na2S04), filtrering og konsentrering ble rå forbindelse kromatografert (silikagel, heksan/etylacetat 7/3) for å tilveiebringe 5,5-dimetyl-l ,3-dioksan-2-propanal (6,1 g, 61%) som en farveløs væske: analyse beregnet for C9Hl603 0,2 H20: C, 61,48; H, 9,40. Funnet: C, 61,46; H, 9,24.
Trinn 3: Fremstilling av C: tt-f4-fluorfenvlV5.5-dimetvl-1.3-dioksan-2-propanol 4-fluorfenylmagnesiumbromid (8,7 ml, 2M oppløsning i eter, 17,44 mmol) ble tilsatt til en oppløsning av 5,5-dimetyl-l,3-dioksan-2-propanal (2 g, 11,62 mmol) (trinn 2) i THF
(50 ml) ved -70°C. Etter omrøring ved -70°C i 2 timer ble reaksjonsblandingen varmet til romtemperatur og omrørt over natt. Reaksjonen ble stoppet med vann og ekstrahert med etylacetat. Organiske fraksjoner ble kombinert og vasket suksessivt med vann og saltvann. Etter tørking (MgS04), filtrering og konsentrering ble råforbindelsen (3,5 g) kromatografert for å tilveiebringe a-(4-fluorfenyl)-5,5-dimetyl-l,3-dioksan-2-propanol (2,73 g) som et hvitt fast stoff: smp. (DSC) 84°C. Anal beregnet for C15H21F03: C, 67,14; H, 7,89. Funnet: C, 67,18; H, 7,98.
Trinn 4: Fremstilling av 3-f5.5-dimetvl-1.3-dioksan-2-vn-l-f4-fluorfenvnpropan-l-one Til en oppløsning av a-(4-fluorfenyl)-5,5-dimetyl-l,3-dioksan-2-propanol (trinn 3) (2,6 g, 10,7 mmol) i metylenklorid (100 ml), pyridiniumklorkromat (3,5 g, 16,05 mmol) tilsatt. Etter omrøring ved romtemperatur i 3 timer ble reaksjonsblandingen fortynnet med eter og filtrert gjennom en kort silikagelkolonne. Kolonne ble eluert med eter og fraksjoner inneholdende 3-(5,5-dimetyl-l,3-dioksan-2-yl)-l-(4-fluorfenyl)propan-l-one ble kombinert og konsentrert (2,2 g, 85%): smp. (DSC) 65°C. Anal beregnet for C15H,9F03: C, 67,65; H, 7,19. Funnet: C, 67,21; H, 7,43.
Trinn 5: Fremstilling a vN- metyl- 4-nitrobenzensulfonamid
Til en suspensjon av 4-nitrobenzensulfonylklorid (5 g, 22,56 mmol) i eter (250 ml), metylamin (5 ml, 40% ak. oppløsning, 56,4 mmol) ble tilsatt, og blandingen ble omrørt ved romtemperatur. Etter 16 timer ble reaksjonsblandingen konsentrert for å fjerne oppløsningsmiddel og resten ble resuspendert i metylenklorid. Etter vasking med 2N HC1 og saltvann ble de organiske fraksjonene tørket (MgS04), filtrert og konsentrert for tilveiebringing av N-metyl-4-nitrobenzensulfonamid (4,8 g, 98%): smp. (DSC) 109°C. Anal. beregnet for C7HgN204S: C, 38,89; H, 3,73; N, 12,96. Funnet: C, 38,83; H, 3,72; N, 12,96.
Trinn 6: Fremstilling av 4-[( N- metylamino) sulfonyl] anilin
Til en oppløsning av N-metyl-4-nitrobenzensulfonamid (trinn 5) (4,8 g, 22,2 mmol) i metanol (100 ml) i en Parr flaske ble det tilsatt Raney-nikkel i metanol. Reaksjonsblandingen ble skylt med nitrogen og hydrogen flere ganger og opprettholdt under hydrogen ved leveringstrykk på 5 psi. Etter omrøring ved 25°C i omtrent 20 timer ble reaksjonen ventilert og spylt med nitrogen. Innholdet av reaksjonen ble filtrert og konsentrert for å fjerne oppløsningsmiddelet. 4-[(N-metylamino)sulfonyl]anilin ble oppnådd som et hvitt fast stoff (4,1 g, 100%) ble anvendt i det neste trinnet uten ytterligere rensning: smp (DSC) 138°C. Anal beregnet for C7H10N2O2S: C, 44,08; H, 5,55; N, 14,69. Funnet: C, 43,83; H, 5,39; N, 14,81.
Trinn 7: fremstilling av 4-[ 2- f4- fluorfenv1VlH^ En blanding av 3-(5,5-dimetyl-l,3-dioksan-2-yl)-l-(4-fluorfenyl)propan-l-one (trinn 4)
(400 mg, 1,5 mmol), 4-[(N-metylamino)sulfonyl]anilin (trinn 6) (308 mg, 1,65 mmol) og p-toluensulfonsyre (40 mg) i toluen (80 ml) ble oppvarmet til tilbakeløp i 48 timer. Reaksjonsblandingen ble avkjølt, filtrert og konsentrert. Rå gulaktig fast stoff (760 mg) ble kromatografert (silikagel, heksan/etylacetat 7/3) for å tilveiebringe 4-[2-(4-fluorfenyI)-lH-pyrrol-l-yl]-N-metylbenzensulfonamid (198 mg, 40%) som et hvitt fast stoff: smp. (DSC) 174°C. Anal beregnet for CI7HISN2F02S 0,25 H20: C, 60,97; H, 4,67; N, 8,37. Funnet: C, 60,86; H, 4,56; N, 8,01.
EKSEMPEL 79
N-f[4-(5-meryI-3-fenylisoksazoI-4-yI)fenyI]suIfonyiJgIycin
Trinn 1: fremstilling av N- acetyl- N-[[ 4- f5- metyl- 3- fenylisoksazol- 4-vnfenvl]sulfonvl]glvcin. etvlester
Til enn omrørt oppløsning av N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid (eksempel 39) (0.612 g, 1,72 mmol) i diklormetan ble behandlet med etylbromacetat (0,20 ml, 0,29 g, 1,72 mmol) og Et3N (0,26 ml, 0,19 g, 1,89 mmol). Etter 7 dager var reaksjonen fortsatt ufullstendig ifølge TLC. Ytterligere etylbromacetat (0,20 ml, 0,29 g, 1,72 mmol) og Et3N (0,26 ml, 0,19 g, 1,89 mmol) ble tilsatt og reaksjonen ble omrørt i ytterligere 6 dager. Reaksjonen ble fortynnet med diklormetan og vasket med KHS04 oppløsning, NaHC03 oppløsning og saltvann, tørket over MgS04, filtrert og konsentrert i vakuum for å tilveiebringe en klar olje. Denne oljen ble renset ved flammekromatografi for tilveiebringing av N-acetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin, etylester (0,243 g, 32%) som en klar farveløs olje med egnet renhet for anvendelse i neste trinn: <*>H NMR (CDCl3/300 MHz) 8,03 (d, 2H, J = 8,7 Hz, 7,47-7,27 (m, 9H), 4,61 (s, 2H), 4,21 (q, 2H, J = 7,1 Hz), 2,51 (s, 3H), 2,33 (s, 3H), 1,28 (t, 3H, J = 7,1 Hz). FABLRMS m/z 443 (M+H). FABHRMS m/z 442.1201 (M<+>, C^H^NjOgS beregnet 442.1199).
Trinn 2: fremstilling av N-[[ 4-( 5- metyl- 3- fenylisoksazol- 4- ynfenyl] sulfonyl] glycin Til en omrørt oppløsning av N-acetyI-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulofnyl]glycin, etylester (trinn 1) (0,24 g, 0,54 mmol) i metanol ble det tilsatt LiOH H20 (0,06 g, 1,36 mmol) i vann. Etter 5 dager var reaksjonen fullført og oppløsningsmidlene ble fjernet i vakuum. Det resulterende halv-faste stoffet ble fordelt mellom etylacetat og IN KHS04 oppløsning. Etylacetatfasen ble tørket over MgS04, filtrert og konsentrert i vakuum for tilveiebringing av N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin (0,139 g, 69%) som et hvitt pulver: smp. 242-248°C. <[>H NMR (CDCl3/300 MHz med DMSO-d^) 7,76 (d, 2H, J = 8,5 Hz), 7,33-7,22 (m, 5H), 7,19 (d, 2H, J = 8,5 Hz), 6,35 (t, 1H, J = 5,4 Hz), 3,63 (d, 2H, J = 5,4 Hz), 2,39 (s, 3H). FABLRMS m/z 373 (M<+>H). FABHRMS m/z 372.0786 (M+, beregnet 372.0780). Anal beregnet for C18H16N205S: C, 58,06; H, 4,33; N, 7,52; funnet C, 58,09; H, 4,44; N, 7,45.
EKSEMPEL 80
N-[[4-(5-metyl-3-fenylisoksazol-4-yl)-fenyl]sulfonyl]glycin, natriumsalt
Til en oppløsning av N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin (eksempel 79) (0,095 g, 0,255 mmol) i EtOH ble det tilsatt 0.5022N NaOH (0,58 ml, 0,29 mmol). Oppløsningen ble konsentrert i vakuum for tilveiebringing av ønsket salt (1,100 g, 100%) som et hvitt pulver: smp. 216°C (dek.). <!>H NMR (D2O/300 MHz) 7,66 (d, 2H, J = 8,1 Hz), 7,42-7,15 (m, 7H), 3,36 (s, 2H), 2,32 (s, 3H). FABLRMS m/z 395 (M<+>H). FABHRMS m/z 395.0707 (M<+>H, beregnet 395.0678). Anal. beregnet for CigHlsN205SNa. 1,55 H20: C, 51,19; H, 4,32; N, 6,63. Funnet C, 51,18; H, 4,20; N, 6,56.
EKSEMPEL 81
2-amino-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)-feny 1] sulfonyl] acetamid
Trinn 1: fremstilling av 1. 1- dimetyletyl N-[ 2-[[[ 4-( 5- metyl- 3- fenylisoksazol- 4-vnfenvl]sulfonvl1amino]-2-oksoetyl]karbamat
En blanding av 4-[5-metyl-3-(fenyl)isoksazol-4-yl]benzensulfonamid (15,0 g, 47,7 mmol), N-t-boc-glycinN-hydroksysuksinimidester (13,0 g, 47,7 mmol) og 1,8-diazobicyklo[4.3.0]undek-7-ene (14,5 g, 95,4 mmol) ble blandet sammen i
tetrahydrofuran i 1 time ved romtemperatur. Ytterligere N-t-boc-glycin N-
i hydroksysuksinimidester (1,3 g, 4,7 mmol) ble tilsatt og oppløsningen ble omrørt i ytterligere 2 timer. Oppløsningsmiddelet ble fjernet ved redusert trykk og resten ble tatt opp i etylacetat. Etylacetat ble vasket med 10% vandig HC1, met. aq. NaHC03, tørket over vannfri Na2S04, filtrert og konsentrert i vakuum for tilveiebringing av ønsket amid
som et klart glassaktig fast stoff (6,5 g, 75%): smp. 160,2-162,0°C. <!>H NMR (CDCl3/300 MHz) 8,04 (d, 2H, J = 8,4 Hz), 7,44-7,33 (m, 5H), 7,28 (d, 2H, J = 8,4 Hz).
5,24 (brs, 1H), 3,85 (m, 2H), 2,50 (s, 3H), 1,43 (s, 9H). FABLRMS m/z (M+H). Anal.
beregnet for C^HjsNaOjS. 0,18 H20: C, 58,19, H, 5,38; N, 8,85. Funnet: C, 58,22; H, 5,73; N, 8,92.
Trinn 2: fremstilling av 2-amino-N-[[4-(5-metvl-3-fenv1isoksazol-4-yl)fen<y>l]sulfonvl]acetamid
Amidet fra trinn 1 (16,2 g, 34,3 mmol) ble oppløst i diklormetan. Vannfri HC1 ble boblet gjennom oppløsning i 30 min. ved romtemperatur. Oppløsningen ble blandet i 1 time og oppløsningsmiddelet ble fjernet ved redusert trykk. Den resulterende resten ble oppløst i vann og krystallene begynte å bli dannet. Oppløsningen ble omrørt i 3 timer og krystallene samlet ved vakuumfiltrering. Produktet ble tørket til en konstantvekt under vakuum (25°C ved 15 mm Hg, 4 dager) (9,4 g, 73%): smp. 230.7-234,7°C. <!>H NMR
(DMSO-da/300 MHz) 7,84 (d, 2H, J = 8,4 Hz); 7,70-7,60 (brs, 3H), 7,45-7,30 (m, 5H), 7,23 (d, 2H, J = 8,4 Hz), 3,24 (m, 2H), 2,43 (s, 3H). FABLRMS m/z 372 (M+H). Anal. beregnet for C,8H17N304S . 0,30 H20: C, 57,37; H, 4,71; N, 11,15, funnet: C, 57,37; H, 4,70; N, 11,12.
EKSEMPEL 82
2-(acerylamino)-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)
fenyl] sulfonyl] acetam id
2-amino-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid (eksempel 81)
(4.08 g, 10,9 mmol) ble blandet i acetonitril ved romtemperatur. Trietylamin (3,03 g, 30,0 mmol) og eddiksyreanhydrid (1,23 g, 12,1 mmol) ble tilsatt og den heterogene oppløsningen ble omrørt i 2 timer. Oppløsningen ble vakuumfiltrert gjennom et stykke diatomejord og oppløsningsmiddelet ble fjernet ved redusert trykk. Vann ble tilsatt og
oppløsningen ble omrørt i 30 minutter. Hvite krystaller ble dannet, samlet ved vakuumfiltrering og tørket for tilveiebringing av ønsket produkt som et hvitt fast stoff (3,25 g, 78%): smp. 218,2-219,3°C. <*>H NMR (CD3OD/300 MHz) 8,01 (d, 2H, J = 8,2 Hz), 7,42-7,36 (m, 7H), 3,85 (s, 2H), 2,50 (s, 3H), 1,95 (s, 3H). FABLRMS m/z 414 (M+H). Anal. beregnet for C20Hl9N3O5S: C, 58,10; H, 4,63; N,10,16. Funnet: C, 58,18; H, 4,66; N, 10,14.
EKSEMPEL 83
N-[[4-(3-fenyl-2,3-dihydro-2-oksofuran-4-yl)fenyl] sulfonyl] propan amid
Trinn 1: fremstilling av 3.4-difenyl-2-r5HVfuranoat
En oppløsning av fenacylbromid (16,540 g, 83,1 mmol) og fenyleddiksyre (11,612 g, 85,3 mmol) i acetonitril ble behandlet med trietylamin (9,23 g, 91,4 mmol) og oppløsningen ble omrørt ved romtemperatur i 1 time. Oppløsningen ble behandlet med 3N HC1 og ekstrahert med etylacetat. Det kombinerte ekstraktet ble vasket med 3N HC1, saltvann, tørket over vannfri MgS04, filtrert og konsentrert i vakuum for tilveiebringing av et fast stoff. Det faste stoffet ble krystallisert fra heksaner/etylacetat 1:1 for tilveiebringing av furanon (11,627 g, 59%): smp. 103,8-104,9°C. <*>H NMR (CDCl3/300 MHz) 7,45-7,25 (m, 10H), 5,18 (s, 2H). FABLRMS m/z 237 (M+H). Anal. beregnet for Ci6H1202. 0,83% H20: C, 80,66; H, 5,17. Funnet: C, 80,67; H, 5,29.
Trinn 2: fremstilling av 3-[r4-aminosulfonvnfenvn]-4-fenvl-2-f5H'i-ruranon.
Til 20 ml omrørende klorsulfonsyre avkjølt til -5°C ble det tilsatt 3,4-difenyl-2-(5H)-furanon (trinn 1) (3,160 g, 13,4 mmol) i porsjoner over 30 minutter. Oppløsningen ble varmet til romtemperatur og opprettholdt ved den temperaturen i 16 timer. Reaksjonsblandingen ble fortynnet med diklormetan og stoppet i isvann. Fasene ble separert og den vandige fasen ekstrahert med diklormetan, kombinert diklormetanekstrakt ble tørket over varinfri MgS04, filtrert og konsentrert i vakuum. Resten ble fortynnet med diklormetan og tilsatt til overskudd konsentrert MH4OH. Blandingen ble omrørt i 1 time. Fasen ble separert og den vandige fasen ble ekstrahert med diklormetan. Det organiske ekstraktet ble tørket over vannfri MgS04, filtrert og konsentrert i vakuum for tilveiebringing av et hvitt fast stoff som ble krystallisert fra vandig etanol for tilveiebringing av ren 3-[(4-aminosulfonyl)fenyl)]-4-fenyl-2-(5H)-furanon (2,110 g, 50%): smp. 225,5-226,5°C. <!>H NMR (CDCl3/300 MHz) 7,79 (s, 2H, J = 8,4 Hz), 7,41 (d, 2H, J = 8,4 Hz), 6,38 (brs, 2H), 5,09 (s, 2H). FABLRMS m/z 316 (m+H). Anal. beregnet for Ci6H13N04S: C, 60,94; H, 4,16; N, 4,44. Funnet: C,60,86; H, 4,18; N, 4,40.
Trinn 3. Fremstilling avN-f[4-r3-fenvl-2.3-dihvdro-2-oksofuran-4-yl) fenyl] sulfonyl] propanamid
En oppløsning av 3-[(4-aminosulfonyl)fenyl)]-4-fenyl-2-(5H)-furanon (trinn 2) (209 mg, 0,663 mmol), trietylamin (134 mg, 1,33 mmol), N,N-dimetylaminopyridin (58 mg, 0,475 mmol) i THF ble behandlet med propionsyreanhydrid (129 mg, 0,994 mmol) ved romtemperatur i 45 minutter. Oppløsningen ble fortynnet med 3N HC1 og ekstrahert med etylacetat. Etylacetatoppløsningen ble vasket med saltvann, tørket over vannfri MgS04, filtrert og konsentrert for å tilveiebringe en olje som ble krystallisert fra etylacetat/heksaner for tilveiebringing av acylert sulfonamid som et hvitt fast stoff (179 mg, 73%): smp. 182,3-183,4°C. 'HNMR (CDCl3/300 MHz) 8,56 (s, 1H), 8,06 (d, 2H, J = 8,7 Hz), 7,62 (d, 2H, J = 8,7 Hz), 7,44-7,22 (m, 5H), 5,23 (s, 2H), 2,30 (q, 2H, J = 7,5 Hz), 1,08 (t, 3H, J = 7,5 Hz). FABLERMS m/z 372 (M+H). Anal. beregnet for C,9H,7N05S: C, 61,44; H, 4,61; N, 3,77. Funnet: C, 61,26; H, 4,64; N, 3,71.
EKSEMPEL 84
N-[[4-[2-(2-metylpyridin-3-yl)-4-trifIuormetylimidazol-l-yl]fenyl]sulfonyl] propanamid
En blanding av 4- [2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-l H-imidazol-1-yl]benzensulfonamid (2,0 g, 5,2 mmol), propionsyreanhydrid (2,03 g, 15,6 mmol) DMAP (0,38 g, 2,6 mmol) og trietylamin (0,65 g, 6,4 mmol) i 80 ml THF ble omrørt ved romtemperatur i 16 timer. Reaksjonsblandingen ble fortynnet med 200 ml vann og ekstrahert med etylacetat. Det organiske laget ble vasket med vann, saltvann, tørket over MgS04 og filtrert. Filtratet ble konsentrert under vakuum og resten ble omkrystallisert fra etylacetat og heksan for tilveiebringing av 1,95 g av ønsket produkt som et farveløst fast stoff (87%): smp. (DSC): 217-218°C. Anal. beregnet for C19H17F3N403S: C, 52,05; H, 3,91; N, 12,98; S, 7,31. Funnet: C, 51,87; H, 3,84; N, 12,67; S, 7,63.
EKSEMPEL 85
N-[[4- [2-(2-mety lpy ridin-3-y l)-4-trifluormetyIimidazol-1 -
yl] fenyl] sulfonyl] propanamid, natriumsalt
Til en suspensjon av N-[[4-(2-metylpyridin-3-yl)-4-trifluormetylimidazol-l-yl]fenyl]sulfonyl]propanamid (eksempel 84) (1,1 g, 2,5 mmol) i 20 ml absolutt etanol ble det tilsatt en oppløsning av natriumhydroksid (0,1 g, 2,5 mmol) i 1,0 ml etanol. Blandingen ble omrørt ved romtemperatur i 10 minutter. Oppløsningsmiddelet ble avdampet i vakuum og resten ble tørket ved høyt vakuum for å tilveiebringe 1,15 g av forbindelsen som et hvitt pulver (99%): smp. (DSC): 298°C (dek.). Anal. beregnet for C19H17F3N403SNa. 1,0 H20: C, 47,70; H, 3,79; N. 11,71; S, 6,70. Funnet: C, 47,37; H, 4,03; N, 11,32; S, 6,32.
EKSEMPEL 87
En sammensetning blir fremstilt ved følgende komponenter:
Mannitol (40 mg) blir tilsatt til fosfatbuffer oppløsningen (2 ml). N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt blir tilsatt og den resulterende oppløsningen lyofilisert.
BIOLOGISK VURDERING
Rotte carrageenan fotblad ødem test
Carrageenan fotbladødemtest ble utført med materialer, reagenser og prosedyrer vesentlig som beskrevet av Winter, et al., (Proe. Soc. Exp. Biol. Med., 111, 544
(1962)]. Hann Sprague-Dawley rotter ble valgt i hver gruppe slik at gjennomsnittlig kroppsvekt var så nær som mulig. Rottene ble fastet med fri adgang til vann i over 16 timer før testen. Rottene ble dosert oralt (1 ml) med forbindelser suspendert i bærer inneholdende 0,5% metylcellulose og 0,025% overflateaktivt middel eller med kun bærer. En time senere ble en subplantar injeksjon av 0,1 ml 1% oppløsning av carrageenan/sterilt 0,9% saltvann administrer og volumet til injisert fot ble målt med et erstatnings plethysmometer koblet til en trykkoverfører med en digital indikator. 3 timer etter injeksjon av carrageenan ble volumet til foten på ny målt. Gjennomsnittlig svelling av foten i en gruppe på medikamentbehandlede dyr ble sammenlignet med den til gruppen av placebo-behandlede dyr og prosentandel inhibisjon av ødem ble bestemt (Otterness and Bliven, Laboratory Models for Testing NSAID, in Non-steroidal Anti-Inflammatory Drugs, (J. Lombardino, ed., 1985)). Prosent inhibisjon viser prosent reduksjon fra kontrollpotevolumet bestemt i denne prosedyren og data for valgte forbindelser i oppfinnelsen som oppsummert i tabell I.
Rotte Carrageenan-indusert analgesi test
Rotte carrageenan analgesi test ble utført med materialer, reagenser og prosedyrer vesentlig som beskrevet av Hargreaves, et al., (Pain, 32,77 (1988)). Hann Sprague-
Dawley rotter ble behandlet som tidligere beskrevet for carrageen fotbladødemtest. 3 timer etter injeksjon av carrageenan ble rottene plassert i spesial pleksiglassbeholdere med et gjennomsiktig gulv som har en høy intensitetslampe som utstrålende varmekilde som kan plassereres under gulvet. Etter en innledende 20 min. lang periode ble termisk stimulering påbegynt på enten injisert fot eller på kontralateral uinjisert fot. En fotoelektrisk celle slukket lampen og tidsinstilleren når lyset ble avbrutt ved tilbaketrekning av poten. Tidspunktet helt til rotten fjerner foten ble deretter målt. Tilbaketrekningslatensen i sekunder ble bestemt for kontroll og medikament behandlede grupper, og prosent inhibisjon av hyperalgesisk fot tilbaketrekning ble bestemt. Resultatene er vist i tabell I.
In vitro omdanning av promedikamenter
Omdanning av promedikamenter til S9 leverfraksjoner ble bestemt ifølge den følgende fremgangsmåten. S9 leverfraksjonssuspensjon (HAM) ble tint og suspensjonen ble omrørt ved vortex behandling. Suspensjonen ble blandet med 12M urea ved 1:7, v:v, (som tilveiebringe 10,5 M urea sluttkonsentrasjon) og ble ytterligere omrørt ved vortex behandling. S9 suspensjonsoppløsningen ble delvis renset ved fast fase ekstrahering (Vac-Elut apparatus:Cjg kolonner (Varian #1210-2001)) eluerende med acetonnitril. Fraksjonene ble blandet ved vortex behandling og konsentrert til tørrhet under nitrogen (uten varme). Fraksjonene ble resuspendert i 100 ul acetonitril:fosfatbuffer (8,3 mM, pH 7,2) (20:80).
Forbindelsene ble oppløst i vann (0,2 ml, 10 ug/ml) og inkubert ved 37°C (pH 7,2,90 minutter) med rensede S9 fraksjoner (0,2 ml, 3 mg/ml). Omdanning av promedikamentet til aktiv COX-2 inhibitor ble fulgt ved HPLC (Beckmann System Gold, Novapak C,8 kolonne (3,9 x 150 mm), acetomtril:fosfatbuffer (8,3 mM, pH 7,2)
(20:80 - 40:60), UV deteksjon 240nm). Kvantifisering av omdanning av promedikament ble bestemt ved måling av integrert HPLC toppområde. Resultatene til analysene er innbefattet i tabell II:
Også omfattet av oppfinnelsen er en klasse farmasøytiske sammensetninger som omfatter de aktive forbindelsene ifølge denne kombinasjonsterapien i assosiasjonen med en eller flere ikke-toksiske, farmasøytiske akseptable bærere og/eller fortynningsmidler og/eller adj uvanter (kollektivt referert til heri som "bærer" materialer) og, om ønskelig, andre aktive ingredienser. De aktive forbindelsene ifølge foreliggende oppfinnelse kan bli administrert ifølge en hvilken som helst egnet vei, fortrinnsvis i form av en farmasøytisk sammensetning tilpasset til en slik vei, og på en dose effektiv for behandling. De aktive forbindelsene og sammensetningen kan for eksempel bli administrert oralt, intravaskulært (IV), intrapeirtonealt, subkutan, intramuskulært (IM) eller topisk.
For oral administrering kan den farmasøytiske sammensetningen være i form av for eksempel en tabelett, hard eller bløt kapsel, pastiller, dispergerbare pulvere, suspensjon eller væske. Den farmasøytiske sammensetningn blir fortrinnsvis fremstilt i form av en doseringsenhet inneholdende en bestemt mengde aktiv ingrediens. Eksempler på slike doseringsenheter er tabletter eller kapsler.
Det aktive ingredienset kan også bli administrert ved injeksjon (IV, IM, subkutan eller jet) som en sammensetning hvori for eksempel saltvann, dekstrose eller vann kan bli anvendt som en egnet bærer. pH til sammensetningen kan bli jusert om nødvendig med egnet syre, base eller buffer. Egnet bulking, dispergerings-, fukte- eller suspenderings-midler, innbefatter mannitol og PEG 400, kan også bli innbefattet i sammensetningen. En egnet parenteral sammensetning kan også innbefatte en forbindelse formulert som en steril fast forbindelse, inkludert lyofilisert pulver, i injeksjonsbeholdere. Den vandige oppløsningen kan bli tilsatt for å oppløse forbindelsen før injeksjon.
Mengden av terapeutiske aktive forbindelser som blir administrert og doseringsregime for behandling av en sykdomstilstand med forbindelsene og/eller sammensetningene ifølge oppfinnelsen avhenger av forskjellige faktorer, inkludert alder, vekt, kjønn og medisinsk tilstand til individet, hvor alvorlig betennelsen eller den betennelsesrelaterte forstyrrelsen er, vei og frekvens til administreringen, og den spesielle forbindelsen som blir anvendt, og kan følgelig variere meget. Promedikamentsammensetningene bør innbefatte lignende doseringer som opphavsforbindelsene. Farmasøytiske sammensetninger kan inneholde aktive ingredienser i området på omtrent 0,1 til 1000 mg, fortrinnsvis i området på omtrent 0,5 til 250 mg og fortrinnsvis mellom omtrent 1 og 60 mg. En daglig dose på omtrent 0,01 til 100 mg/kg kroppsvekt, fortrinnsvis mellom omtrent 0,5 og omtrent 25 g/kg kroppsvekt og fortrinnsvis mellom omtrent 0,1 til 10 mg/kg kroppsvekt, kan være hensiktsmessig. Den daglige dosen kan bli administrert i 1 til 4 doser pr dag.
Når det gjelder hudtilstandene kan det være foretrukket å påføre et topisk preparat av forbindelsene ifølge oppfinnelsen til påvirket område 2 til 4 ganger pr dag.
For forstyrrelser i øyet eller andre ytre vev, for eksempel, munn og hud, blir formuleringene fortrinnsvis påført som en topisk gel, en spray, en salve eller en krem, eller som en suppositorie, inneholdende de aktive ingrediensene i en totalmengde på for eksempel 0,075 til 30% w/w, fortrinnsvis 0,2 til 20% w/w og mest foretrukket 0,4 til 15% w/w. Når formulering i en salve kan de aktive ingrediensene bli anvendt med enten parafin eller en vann-blandbar salvebase. Alternativt kan de aktive ingrediensene bli formulert i en krem med en olje-is-vann krembase. Om ønskelig kan den vandige fasen av krembasen innbefatte for eksempel minst 30% w/w av en polyhydrisk alkohol så som propylenglykol, butan-1,3-diol, mannitol, sorbitol, glycerol, polyetylenglykol og blandinger derav. Den topiske formuleringen kan om ønskelig innbefatte en forbindelse som forsterker absorpsjonen eller penetreringen av det aktive ingredienset gjennom huden eller andre påvirkede områder. Eksempler på slike dermale penetreringsforsterkningsmidler innbefatter dimetylsulfoksid og beslektede analoger. Forbindelsene ifølge oppfinnelsen kan bli administrert i en transdermal innretning. Det er foretrukket at den topiske administrering blir oppnådd ved anvendelse av et stykke enten av reservoar eller porøs membrantype eller av en fast matrisevariant. I et hvert tilfelle blir det aktive middelet levert samtidig fra reservoaret og mikrokapsler gjennom en membran inn i aktivt middel permeabel adhesiv, som er i kontakt med huden eller slimhinnen til mottakeren. Dersom det aktive middelet blir absorbert gjennom huden blir en kontrollert og forutbestemt strømning av det aktive middelet administrert til mottageren. Når det gjelder mikrokapsler kan innkapslingsmiddelet også virke som membran. Det transdermale stykket kan innbefatte forbindelsen i et egnet oppløsningsmiddelsystem med et adhesivt system, så som en akrylisk emulsjon, og et polyesterstykke.
Den oljeholdige fasen til emulsjonene ifølge oppfinnelsen kan bli dannet fra kjente ingredienser på kjent måte. Fasen kan omfatte bare et emulgeringsmiddel, og kan omfatte en blanding av minst et emulgeringsmiddel med et fettstoff eller en olje eller med både et fettstoff og en olje. Det er foretrukket at et hydrofilt emulgeringsmiddel blri innbefattet sammen med et lipofilt emulgeringsmiddel som virker som et stabiliseirngsmiddel. Det er også foretrukket å innbefatte både en olje og et fettstoff. Sammen utgjør emulgeringsmiddelet med eller uten stabilisatorer den såkalte emulgeringsvoksen, og voksen sammen med oljen og fettet utgjør såkalte emulgeringssalvebasen som danner oljedispergeringsfasen til kremformuleringene. Emulgeringsmidler og emulsjonsstabilisatorer egnet for anvendelse i formuleringer ifølge foreliggende oppfinnelse innbefatter Tween 60, Span 80, cetostearyl alkohol, myristylalkohol, glycryl monostearat og natriumlaurylsulfat, blant andre.
Valg av egnede oljer eller fettstoffer for formulering er basert på oppnåelse av ønskede kosmetiske egenskaper på grunn av oppløseligheten til den aktive forbindelsen i de fleste oljene som sannsynligvis blir anvendt i farmasøytiske emulsjonsformuleringer er meget lav. Kremen bør følgelig fortrinnsvis vare en ikke-fettholdig, ikke-farvende og et vaskbart produkt med egnet konsistens for å unngå lekkasje fra rør eller andre beholdere. Lineær eller forgrenet kjede, mono- eller dibasiske alkylestere så som di-isoadipat, isocetyl stearat, propylenglykoldiester av kokosnøttfettsyrer, isopropylmyristat, decyloleat, isopropylpalmitat, butylstearat, 2-etylheksylpalmitat eller en blanding av forgrenet kjedeestere kan bli anvendt. Disse kan bli anvendt alene eller i kombinasjon avhengig av egenskaper som er påkrevd. Alternativt kan lipider med høyt smeltepunkt så som hvit bløt parafin og/eller flytende parafin eller andre mineraloljer bli anvendt.
Formuleringer egnede for topisk administrering til øyet innbefatter også øyedråper hvor de aktive ingrediensene blir oppløst eller suspendert i egnede bærere, spesielt et vandig oppløsningsmiddel for aktive ingredienser. Antiinflammatoriske aktive ingredienser er for tiden tilstede i slike formuleringer i en konsentrasjon på 0,5 til 20%, fortrinnsvis 0,5 til 10% og spesielt omtrent 1,5% w/w.
For terapeutiske formål blir de aktive forbindelsene ifølge denne kombinasjonen opprinnelig kombinert med en eller flere adj uvants som er hensiktsmessig for den indikerte administrasjonsveien. Dersom administrert per os kan forbindelsene bli blandet sammen med laktose, sukrose, stivelsespulver, celluloseestere av alkansyrer, cellulosealkylestere, talk, stearinsyre, magnesiumstearat, magnesiumoksid, natrium og kalsiumsalter av fosfor og svovelsyrer, gelatin, akasia gummi, natrium alginat, polyvinylpyrrolidon og/eller polyvinylalkohol, og deretter blir det dannet tabletter eller innkapslet for hensiktsmessig administrering. Slike kapsler eller tabletter kan inneholde en formulering med kontrollert frigjøring tilveiebrakt i en dispersjon av aktiv forbindelse i hydroksypropylmetylcellulose. Formuleringer for parenteral administrering kan være i form av vandige og/eller ikke-vandige isotoniske sterile injeksjonsoppløsninger eller suspensjoner. Disse oppløsningene og suspensjonene kan bli fremstilt fra sterile pulvere eller granuler med en eller flere bærere eller fortynningsmidler nevnt for anvendelse i formuleringer for oral administrering. Forbindelsene kan bli oppløst i vann, polyetylenglykol, propylenglykol, etanol, maisolje, bomullsfrøolje, peanøttolje, sesamolje, benzylalkohol, natriumklorid og/eller forskjellige buffere. Andre adj uvants og administrasjonsmetoder er kjent innenfor det farmasøytiske området.
Claims (45)
1.
Forbindelse, karakterisert ved formelen I
hvori A er en ringsubstituent utvalgt fra C4-Cg-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon ved et eller flere radikaler utvalgt fra Ci-Cio-alkyl, Ci-Cg-haloalkyl, okso, Ci-C6-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-Cjo-alkyl;
hvori R<1> er et radikal utvalgt fra pyridyl og fenyl, hvori R<1> eventuelt er substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Ci-C6-alkoksy;
hvori R er hydrido;
og hvori R er et radikal utvalgt fra Ci-Cio-alkyl, Ci-Cio-karboksyalkyl, C|-Cio-acyl, d-C6-alkoksykarbonyl, C i -C6-alkoksykarbonyl-C i -C i o-alkylkarbonyl, C i -C6-alkoksykarbonylkarbonyl, C]-C]o-karboksyalkylkarbonyl, Ci-Cio-alkylkarbonylamino-C|-Cio-alkylkarbonyl, Ci-Cio-aminoalkylkarbonyl og Ct-Ce-alkoksy-Ci-Cio-alkylkarbonyl;
eller et farmasøytisk akseptablet salt derav.
2.
Forbindelse ifølge krav 1, karakterisert ved at A er en ringsubstituent utvalgt fra cyklopentenyl, furyl, imidazolyl, isoksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-C6-alkyl, Ci-Ce-haloalkyl, okso, Ci-C6-hydroksyalkyl og Ci-Ce-alkylkarbonyloksy-Ci-Ce-alkyl; hvori R<1> er et radikal utvalgt fra pyridyl og fenyl, hvori R<1> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Ce-alkyl, halo og C|-C6-alkoksy; hvori R<2> er hydrido; og hvori R<3> er et radikal utvalgt fra Ci-Ce-alkyi, Ci-C6-karboksyaIkyl, Ci-Ce-acyl, Ci-Ce-alkoksykarbonyl C1-C6-alkoksykarbony 1-C i -Ce-alkylkarbonyl, C i -C6-alkoksykarbonylkarbony 1, C i - Cg-karboksyalkylkarbonyl, Ci-C6-alkylkarbonylamino-Ci -C6-alkylkarbonyl, Ci -Ce-aminoalkylkarbonyl og Ci-Ce-alkoksy-Ci-Ce-alkylkarbonyl; eller et farmasøytisk akseptabelt salt derav.
3.
Forbindelse ifølge krav 2, karakterisert ved at A er en ringsubstituent utvalgt fra cyklopentenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra metyl, difluormetyl, trifluormetyl, okso, metylkarbonyloksymetyl og hydroksymetyl; hvori R1 er et radikal utvalgt fra pyridyl og fenyl, hvori R<1> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra metyl, fluor, klor og metoksy; hvori R<2> er hydrido; og hvori R<3> er et radikal utvalgt fra metyl, karboksymetyl, formyl, metylkarbonyl, etylkarbonyl, propylkarbonyl, isopropylkarbonyl, butylkarbonyl, tørt-butylkarbonyl, pentylkarbonyl, fenylkarbonyl, metoksykarbonyl, ferr-butoksykarbonyl, metoksymetylkarbonyl, aminometylkarbonyl, karboksyetylkarbonyl, metoksyetylkarbonyl, etoksymetylkarbonyl, metoksykarbonylmetylkarbonyl, metoksykarbonyletylkarbonyl, metoksykarbonylkarbonyl og metylkarbonylaminometylkarbonyl; eller et farmasøytisk akseptabelt salt derav.
4.
Forbindelse ifølge krav 3, karakterisert ved at den blir valgt fra forbindelser og deres farmasøytiske aksepable salter, fra gruppen bestående av
N-[t4-[3-difluormetyl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]propanamid; N- [ [4- [3 -di fluorm etyl) - 5 -(3 - fl uor-4-metoksyfenyl)-1 H-pyrazo 1-1 - yl]fenyl]sulfonyl]butanamid; N-[[4-[l,5-dimetyl)-3-fenyl-lH-pyrazol-4-yl]fenyl]sulfonyl]acetamid; N-[[4-[2-(pyridinyl)-4-(trifluormetyl) 1 H-imidazol-1 -yl] fenyl]sulfonyl]acetamid; N-[[4-[2-(5-metyIpyridin-3-yl)-4-(trilfuormetyl)-1 H-imidazol-1 - yl] fenyl] sulfonyl] acetamid;
N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)-1 H-imidazol-1-yl] fenyl] sulfonyl] acetamid; N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-l H-imidazol-1 - yl]fenyl]sulfonyl]butanamid; N-[[4-[2-(2-metyIpyrimn-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]butanamid; N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-1 H-imidazol-1-yl] fenyl]sulfonyl]acetamid; N-[[4-[3-(3-fluorfenyl)-5-metylisoksazol-4-yl]fenyl]sulfonyl]acetamid;
2- metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[ [4-(5 -metyl-3 -fenylisoksazol-4-yl] fenyl] sulfonyl]propanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]benzamid; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[[4~(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]butanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]pentanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyI]sulfonyl]heksanamid;
3- metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; 2-etoksy-N-[[4-(5-metyl-3-fenyIisoksazol-4-yl)fenyl]sulfonyI]acetamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]propanamid; N-[[4-[5-(4-klorfenyl)-3-(trifluonnetyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]acetamid; N-[[4-[3-(difluormetyl)-6-fluor-l,5-dmydro-7-metoksy[2]benzotiopyrano[4,3-c]pyrazol-1 -yl] fenyl]sulfonyl]acetamid; N-[[4-[6-lfuor-l,5-dihydro-7-metoksy-3-(trifluoiinetyl)-[2]berizotiopyrani[4,3-c]pyrazo 1-1 -yl] fenyl] sul fonyl ] acetamid; N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl]-lH-pyrazol-l-yl] fenyl] sulfonyl] acetamid; N-[[4-(2-metyl-4-fenyloksazol-5-yl)fenyl]sulfonyl]acetamid;
metyl [[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]oksoacetat; 2-metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; N-[[4-[5-(diflurmetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid; N-[[4-[5-(diflurmetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid; N-[[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]amino]-4-oksobutanoisk syre; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]formamid;
1,1 -dimetyletyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin; 2-amino-N-[[4-(5-metyl-2-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid;
2-(acetylamino)-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid;
metyl 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino-4-oksobutanoat; metyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat; N-acetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin, etylester; N-[[4-[5-(4-metylfenyl)-3-(trilfuormetyl)-l H-pyrazol-1 -yl]fenyl]sulfonyl]acetamid; metyl 3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-3-oksopropanoat; 4-[5-(3-brom-5-fluor-4-metoksyfenyl]-2-(trilfuormetyl)oksazol-4-yl]-N-metylbenzensulfonamid; N-( 1,1 -dimetyletyl)-4-(5-metyl-3-fenylisoksazol-4-yl)benzensulfonamid;
4-[ 5 -(4-lfuor fenyl)-3 -(tri fluormety 1)- lH-pyrazol-l-yl]-N-metylbenzensulfonamid; N-metyl-4-(5-metyl-3-fenyIisoksazol-4-yl)benzensulfonamid; N-[[4-[5-(hydroksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid; N- [ [4-[5 -(acetoksymetyl)-3-fenylisoksazol-4-yl] fenyl] sul fonyl] acetamid;
1,1 -dimetyletyl-N-[2-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-2-oksoetyl] karbamat;
N-[[4-[2-(3-klor-3-fluorfenyl)cyklopenten-1 -yl] fenyl]sulfonyl]acetamid; 4-[2-(4-fluorfenyl)-1 H-pyrrol-1 -yl]-N-metylbenzensulfonamid; N-[[4-[3,4-dimetyl-1 -fenyl 1 H-pyrazol-5-yl]fenyl]sulfonyl]propanamid; N-[[4-[2-(2-metylpyridin-3-yl)-4-trifluormetylimidazol-l-yl]fenyl]sulfonyl]propanamid; 4-[2-(4-fluorfenyl)cyklopenten-1 -yI]-N-metylbenzensulfonamid; og N-[[4-(3-fenyl-2,3-dihydro-2-oksofuran-4-yl)fenyl]sulfonyI]propanamid.
5.
Forbindelse, karakterisert ved formel II
hvori A er en ringsubstituent utvalgt fra C4-C8-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, Ci-Ce-haloalkyl, okso, C]-C6-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Cj-Cio-alkyl;
hvori R4 er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Ci-Cs-alkoksy;
og hvori R<5> er et radikal utvalgt fra hydrido, Ci-Cio-alkyl, Ci-C6-alkoksy, Ci-Ce-alkoksy-C[-Cio-alkyl, fenyl, Ci-Cio-karboksyalkyl, Ci-C6-alkoksykarbonyl-C]-Cio-alkyl, C ] -Cg-alkoksykarbonyl, C i -C i o-aminoalkyl og C j -C j o-alkylkarbonylamino-C i -Ce-alkyl; eller et farmasøytisk akseptabelt salt derav.
6.
Forbindelse ifølge krav 5, karakterisert ved atAeren ringsubstituent utvalgt fra cyklopentenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Ce-alkyl, Ci-Cg-haloalkyl, okso, Ci-C6-hydroksyalkyl og Ci-Cé-alkylkarbonyloksy-Ci-Ce-alkyl; hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Ce-alkyl, halo og Ci-C6-alkoksy; og hvori R<5> er et radikal utvalgt fra hydrido, Ci-C6-alkyl, Ci-C6-alkoksy, Ci-Ce-alkoksy-Ci-Ce-alkyl, fenyl, C[-C6-karboksyalkyl, Ct-Ce-alkoksykarbonyl-Ci-Ce-alkyl, Ci-C6-alkoksykarbonyl, Ci-Ce-aminoalkyl og Ci-Ce-alkylkarbonylamino-Ci-Ce-alkyl; eller et farmasøytisk akseptabelt salt derav.
7.
Forbindelse ifølge krav 6, karakterisert ved atAeren ringsubstituent utvalgt fra cyklopentenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra metyl, difluormetyl, trifluormetyl, okso, hydroksymetyl og metylkarbonyloksymetyl; hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4 >er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra metyl, fluor, klor og metoksy; og hvori R<5> er et radikal utvalgt fra hydrido, metyl, etyl, propyl, isopropyl, butyl, tert-butyl, pentyl, metoksy, ferf-butoksy, metoksymetyl, metoksyetyl, etoksymetyl, fenyl, karboksyetyl, metoksykarbonylmetyl, metoksykarbonyletyl, metoksykarbonyl, aminometyl og metylkarbonylaminometyl; eller et farmasøytisk akseptabelt salt derav.
8.
Forbindelse ifølge krav 7, karakterisert ved at den blir valgt fra forbindelser og farmasøytiske akseptable salter derav, fra gruppen bestående av
N-[[4-[3-(difluoimetyl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl] fenyl] sul fonyl]propanamid; N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)- lH-pyrazol-1 - yl]fenyl]sulfonyl]butanamid;
N-[[4-[ l,5-dimetyl)-3-fenyl-l H-pyrazol-4-yl] fenyl] sulfonyl] acetamid; N- [ [4-[2-(3-pyridinyl)-4-(trifluormetyl)-1 H-imidazol-1 -yl] fenyl] sulfonyl] acetamid; N-[[4-[2-(5-metylpyridinyl-3-yl)-4-(trifluormetyl)-1 H-imidazol-1 - yl] fenyl] sulfonyl] acetamid; N-[[4-[2-(2-metylpyridinyl-3-yl)-4-(trifluormetyl)-l H-imidazol-1 - yl] fenyl]sulfonyl]acetamid; N-[[4-[2-(5-metylpyridinyl-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl] fenyl]sulfonyl]butanamid; N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluonnetyl)- lH-imidazol-1-yl]fenyl]sulfonyl]butanamid; N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-yl] fenyl]sulfonyl]acetamid; N-[[4-[3-(3-ftuorfenyl)-5-metylisoksazol-4-yl]fenyl]sulfonyl]acetamid;
2- metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]benzamid; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]pentanamid; N-[[4-(5-metyl-3-fenylisoksazol~4-yl]fenyl]sulfonyl]heksanamid;
3- metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; 2-etoksy-N-[[4(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; N-[[4-(5-metyl-3-fenylisoksazoI-4-yl]fenyl]sulfonyl]acetamid; N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]propanamid; N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-1 H-pyrazol-1 -yl] fenyl]sulfonyl]butanamid; N-[[4-[5-(4-klorfenyI)-3-(trifluormetyl)- lH-pyrazol-1 -yl] fenyl]sulfonyl]acetamid; N-[[4-[3-(difluormetyl)-6-fluor-l,5-dihydro-7-metoksy[2]benzotiopyrani[4,3-c]pyrazol-1 -yl] fenyl]sulfonyl]acetamid;
N- [ [4- [6-fluor-1,5-dihydro-7-metoksy-3-(trifluorm etyl)-[2]benzotiopyrano [4,3-c]pyrazol-l-yl]fenyl]sulfonyl]acetamid; N-[[4-[3-(difluorrnetyl)-5-(3-fluor-4-metoksyfenyl)-l H-pyrazol-1 - yl] fenyl] sulfonyl] acetamid; N-[[-(2-metyl-4-fenyloksazol-5-yl)fenyl]sulfonyl]acetamid;
metyl [[[4-(5-metyl-2-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]oksoacetat; 2-metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid; 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoisk syre; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]formamid;
1,1-dimetyletyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin; 2-amino-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; 2-(acetylamino)-N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid;
metyl 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoat; metyl 4-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat; N-[ [4-(5 -(4-metylfentyl)-3 -(tri fluormetyl) -1 H-pyrazol-1 -yl] fenyl] sul fonyl] acetamid;
metyl 3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-3-oksopropanoat; N-[[4-[5-(hydroksymetyl)-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid; N-[[4-[5-(acetoksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid; l,l-dimetyletyl-N-[2-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-2-oksoetyl]karbamat; N-[[4-[3,4-dimetyl-l-fenyl-lH-pyrazol-5-yl]fenyl]sulfonyl]propanamid; N-[[4-[2-(2-metylpyridin-3-yl)-4-trifluormetylimidazol-l-yl]fenyl]sulfonyl]propanamid; N-[[4-[2-(3-klor-4-fluorfenyl)cyklopenten-l-yl]fenyl]sulfonyl]acetamid; og N-[[4-(3-fenyl-2,3-dihy(lrdo-2-oksofuran-4-yl)fenyl]sulfonyl]propanamid.
9.
Forbindelse ifølge krav 5, karakterisert ved at de farmasøytiske akseptable saltene er metallsalter.
10.
Forbindelse ifølge krav 9, karakterisert ved at de farmasøytiske akseptable saltene blir valgt fra alkalimetallsalter og alkaliske jordmetallsalter.
11.
Forbindelse ifølge krav 10, karakterisert ved at de farmasøytiske akseptable saltene blir valgt fra natrium og kaliumsalter.
12.
Forbindelse ifølge krav 11, karakterisert ved at den blir valgt fra forbindelser og farmasøytiske akseptable salter derav, fra gruppen bestående av
N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-l H-pyrazol-1 - yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-lH-pyrazol-l-yl]fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-[l,5-dimetyl)-3-fenyl-lH-pyrazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[2-(3-pyridinyI)-4-(rrifluormetyl)-lH-imidazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-l-yl] fenyl] sulfonyl] acetamid, natriumsalt; N-[[4-[2-(2-metylpyridin-3-yl)-4-(trifluormetyl)- lH-imidazol-1 - yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[2-(5-metylpyridin-3-yl)-4-(trifluormetyl)-lH-imidazol-1 - yl]fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-[2-(3-klor-5-metylfenyl)-4-(trifluormetyl)-lH-imidazol-l-yl] fenyl] sulfonyl] acetamid, natriumsalt; N-[[4-[3-(3-fluorfenyl)-5-metylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt;
2- metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]benzamid, natriumsalt; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]pentanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]heksanamid, natriumsalt;
3- metoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt;
2-etoksy-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-(5-rnetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, kaliumsalt; N-[[4-[5-(4-klorfenyl)-3-(trifluormetyl)-l H-pyrazol-1 -yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-[5-(4-klorfenyl)-3-(trilfuormetyl)-1 H-pyrazol-1 -yl] fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-(5-(4-klorfenyl)-3-(trilfuormetyl)-1 H-pyrazol-1 -yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-(3-difluormetyl)-6-fluor-l,5-dihydVo-7-metoksy-[2]benzotiopyrano[4,3-c]pyrazol-1 -yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-(6-lfuor-l,5-dihydro-7-metoksy-3-(nifluormetyl)-[2]benzotiopyrano[4,3-c]pyrazol-l-yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[3-(difluormetyl)-5-(3-fluor-4-metoksyfenyl)-1 H-pyrazol-1 -yl]fenyl] sulfonyl]acetamid, natriumsalt; N-[[4-(2-metoksy-4-fenyloksazol-5-yl)fenyl]sulfonyl]acetamid, natriumsalt;
metyl [[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]oksoacetat, natriumsalt; 2-metoksy-N-[t4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid, natriumsalt; 4-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoisk syre, natrumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]formamid, natriumsalt;
1,1 -dimetyletyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]glycin, natriumsalt; 2-amino-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt; 2-(acetylamino)-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]acetamid, natriumsalt;
metyl 4-[[[4-(5-metyI-3-fenylisoksazoI-4-yl)fenyl]sulfonyl]amino]-4-oksobutanoat, natriumsalt;
metyl N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]karbamat, natriumsalt, N-[[4-(5-hydroksymetyl-3-fenyIisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[5-metylfenyl)-3-(trifluormetyl)-1 H-pyrazol-1 -yl] fenyl]sulfonyl]acetamid, natriumsalt;
metyl 3-[[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]amino]-3-oksopropanoat, natriumsalt;
N-[[4-(5-(hydroksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[5-(acetoksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt;
N-[[4-[3,4-dimetyl-1 -fenyl-1 H-pyrazol-5-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[ 4-[2 -(2 -metylpyri di n-3 -yl)-4-tri fluormetylimidazol-l-yl]fenyl]sulfonyl]propanamid3 natriumsalt;
N-[[4-[2-(3-klor-4-fluorfenyl)cyklopenten-l-yl]fenyl]sulfonyl]acetamid, natriumsalt; og N-[[4-(3-fenyl-2,3-dihydro-2-oksofuran-4-yl)fenyl]sulfonyl]propanamid, natriumsalt.
13.
Forbindelse, karakterisert ved formel III
hvori R<6> er et radikal utvalgt fra Ci-C6-alkyl, Ci-Ce-haloalkyl og Ci-Ce-hydroksyalkyl; hvori R<7> er et radikal utvalgt fra hydrido, Ci-C6-alkyl, halo og CpCe-alkoksy;
og hvori R<8> er et radikal utvalgt fra hydrido, Ci-C6-alkyl, CrC6-alkoksy, Ci-Ce-alkoksy-Ci-Cc-alkyl, fenyl, Ci-C6-karboksyalkyl, Ci-C6-alkoksykarbonyl-Ci-C6-alkyl, C1-C6-alkoksykarbonyl, Ci-C6-aminoalkyl og Ci-Ce-alkylkarbonylamino-Ci-Ce-alkyl; eller et farmasøytisk akseptabelt salt derav.
14.
Forbindelse ifølge krav 13, karakterisert ved at R<6 >blir valgt fra CrCio-alkyl, C]-C6-haloalkyl, og Ci-C6-hydroksyalkyl; hvor R7 er en eller flere rester valgt fra hydrido, Ci-Cio-alkyl, halo og Ci-C6-alkoksy; og hvor R<8> blir valgt fra Ci-Cio-alkyl, fenyl og amino-Ci-Cio-alkyl; eller et farmasøytisk akseptabelt salt derav.
15.
Forbindelse ifølge krav 13, karakterisert ved at R<6> er et radikal utvalgt fra metyl, difluormetyl og hydroksymetyl; hvori R<7> er et radikal utvalgt fra hydrido og fluor; og hvori R<8> er et radikal utvalgt fra hydrido, metyl, etyl, propyl, isopropyl, butyl, tert-butyl, pentyl, metoksy, førf-butoksy, metoksymetyl, metoksyetyl, etoksymetyl, fenyl, karboksyetyl, metoksykarbonylmetyl, metoksykarbonyletyl, metoksykarbonyl, aminometyl og metylkarbonylaminometyl; eller et farmasøytisk akseptabelt salt derav.
16.
Forbindelse ifølge krav 15, karakterisert ved at den blir valgt fra forbindelser og farmasøytiske akseptable salter derav, fra gruppen bestående av N-[ [4- [3-(3 -fluorfenyl)-5 -metylisoksazol-4-yl] fenyl] sulfonyl] acetamid;
2-metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[[4-(5-metyl-3-fenyIisoksazol-4-yI]fenyI]sulfonyI]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]benzamid; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid; N-[ [4-(5 -metyl-3 -fenyli soksazol-4-yl] fenyl] sulfonyl]butanamid;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]pentanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]heksanamid; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid; N-[[4-(5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid; N- [ [4-(5-(di fluormetyl)-3 -fenylisoksazol-4-yl] fenyl] sulfonyl]propanamid; N-[[4-(5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid; N- [ [4-(5 -metyl-3 -fenyli soksazol-4-yl] fenyl] sulfonyl] glycin; og N-[[4-[5-(hydroksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid.
17.
Forbindelse ifølge krav 13, karakterisert ved at farmasøytiske akseptable salter blir valgt fra alkalimetallsalter og alkaliske jordmetallsalter.
18.
Forbindelse ifølge krav 17, karakterisert ved at farmasøytiske akseptable salter blir valgt fra natrium og kaliumsalter.
19.
Forbindelse ifølge krav 18, karakterisert ved at den blir valgt fra forbindelser og farmasøytiske akseptable salter derav, fra gruppen bestående av
N-[[4-[5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, kaliumsalt; N-[[4-[3-(3-fluorfenyl)-5-metylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt; 2-metyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]benzamid, natriumsalt; 2,2-dimetyl-N-[[4-(5-metyl-3-fenylisoksazol-4-yl)fenyl]sulfonyl]propanamid, natriumsalt;
N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]suIfonyl]pentanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]heksanamid, natriumsalt; N-[[4-[2-metyl-4-fenylisoksazol-5-yl]fenyl]sulfonyl]acetamid, natriumsalt; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-[5-(difluormetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]butanamid, natriumsalt; N-[[4-(5-hydroksymetyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, natriumsalt; N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]glycin, natriumsalt; og N-[[4-[5-hydroksymetyl)-3-fenylisoksazol-4-yl]fenyl]sulfonyl]acetamid, natriumsalt.
20.
Farmasøytisk sammensetning, karakterisert ved at den omfatter en terapeutisk effektiv mengde av en forbindelse, i det nevnte forbindelse blir valgt fra en familie av forbindelser ifølge krav 1, inkludert de hvor A er tetrazolium eller A er indan når R<3> er alkyl eller cykloalkyl; eller ifølge et hvilket som helst av kravene 2-19.
21.
Fremgangsmåte for fremstilling av en forbindelse med formel II
hvor A er en ringsubstituent utvalgt fra Gt-Cs-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, C1-C6-haloalkyl, okso, Ci-Cé-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-Cio-alkyl;
hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Cr C6-alkoksy;
og hvori R<5> er et radikal utvalgt fra hydrido, Ci-Ci o-alkyl, Ci-C6-alkoksy, Ci-Ce-alkoksy-C 1 -C1 o-alkyl, fenyl, C1 -C1 o-karboksyalkyl, C1 -Gs-alkoksykarbonyl-C 1 -C1 o-alkyl, Ci-C6-alkoksykarbonyl, Ci-Ci0-aminoalkyl og Ci-Cio-alkylkarbonylamino-Ci-Ce-alkyl; eller et farmasøytisk akseptabelt salt derav;
karakterisert ved at
fremgangsmåten innbefatter behandling av et usubstituert sulfonamid med et acyleringsmiddel under nærvær av en base og et løsemiddel.
22.
Fremgangsmåte ifølge krav 21, karakterisert ved at acyleringsmiddelet velges fra anhydrider, syreklorider, acyl, imidazoler og aktive estere.
23.
Fremgangsmåte ifølge krav 22, karakterisert ved at acyleringsmiddelet velges fra eddiksyreanhydrid, propinsyreanhydrid og smørsyreanhydrid.
24.
Fremgangsmåte ifølge krav 21, karakterisert ved at oppløsningsmiddelet er tetrahydrofuran.
25.
Fremgangsmåte for fremstilling av en forbindelse med formel HI
hvori R<6> er et radikal utvalgt fra Ci-C6-alkyl, C]-C6-haloalkyl og Ci-C6-hydroksyalkyl; hvori R<7> er et radikal utvalgt fra hydrido, Ci-Ce-alkyl, halo og Cj-Ce-alkoksy,
og hvori R<8> er et radikal utvalgt fra hydrido, Ci-Cg-alkyl, Ci-C6-alkoksy, C]-C6-alkoksy-Ci-C6-alkyl, fenyl, Ci-Ce-karboksyalkyl, Ci-Ce-alkoksykarbonyl-Ci-Ce-alkyl, C1-C6-alkoksykarbonyl, Ci-Ce-aminoalkyl og Ci-Ce-alkylkarbonylamino-Ci-Ce-alkyl; eller et farmasøytisk akseptabelt salt derav;
karakterisert ved at
fremgangsmåten innbefatter behandling av et usubstituert isoksazolyl-benzensulfonamid med et acyleringsmiddel under nærvær av en base og et løsemiddel.
26.
Fremgangsmåte for fremstilling av en forbindelse med formel II hvori A er en ringsubstituent utvalgt fra Q-Cs-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, Cj-Ce-haloalkyl, okso, CrCg-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-Cio-alkyl;
hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra C|-Cio-alkyl, halo og C]-C6-alkoksy;
og hvori R<5> er et radikal utvalgt fra hydrido, Ci-Cio-alkyl, Cj-C6-alkoksy, Cj-Cé-alkoksy-Ci-Cio-alkyl, fenyl, Ci-Cio-karboksyalkyl, CrCe-alkoksykarbonyl-Ci-Cio-alkyl, Ci-Ce-alkoksykarbonyl, Ci-Cio-aminoalkyl og Ci-Cio-alkylkarbonylamino-Ci-C6-alkyl; eller et farmasøytisk akseptabelt salt derav;
karakterisert ved at fremgangsmåten innbefatter å danne et bis(N-acetylert)sulfonamid ved behandling av et usubstituert sulfonamid med overskudd av et anhydrid, syreklorid eller karbamylklorid, under nærvær av en tertiær aminbase, og behandle nevnte bis(N-acetylert)sulfonamid med ca. to ekvivalenter av en sterk base for å tilveiebringe saltet.
27.
Fremgangsmåte for fremstilling av en forbindelse med formel II hvori A er en ringsubstituent utvalgt fra C4-Cg-cykloalkenyl, furyl, imidazolyl, isoksazolyl, oksazolyl, pyrazolyl og pyrrolyl, hvori A er eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, Ci-Ce-haloalkyl, okso, CrCs-hydroksyalkyl og Ci-Cio-alkylkarbonyloksy-Ci-Cio-alkyl;
hvori R<4> er et radikal utvalgt fra pyridyl og fenyl, hvori R<4> eventuelt substituert i en substituerbar posisjon med et eller flere radikaler utvalgt fra Ci-Cio-alkyl, halo og Ci-Ce-alkoksy;
og hvori R<5> er et radikal utvalgt fra hydrido, Ci-Cio-alkyl, Ci-Ce-alkoksy, C1-C6-alkoksy-Ci-Cio-alkyl, fenyl, Ci-Cio-karboksyalkyl, Ci-Ce-alkoksykarbonyl-Ci-Cio-alkyl, Ci-C6-alkoksykarbonyl, Ci-Cio-aminoalkyl og Ci-Cio-alkylkarbonylamino-Ci-C6-alkyl; eller et farmasøytisk akseptabelt salt derav;
karakterisert ved at
fremgangsmåten innbefatter behandling av et usubstituert sulfonamid med et acyleringsmiddel under nærvær av syre.
28.
Fremgangsmåte ifølge krav 27, karakterisert ved at acyleringsmiddelet velges fra anhydrider og syreklorider.
29.
Fremgangsmåte ifølge krav 28, karakterisert ved at acyleringsmiddelet velges fra acetylklorid, eddiksyreanhydrid, propionsyreanhydrid og smørsyreanhydrid.
30.
Fremgangsmåte ifølge krav 27, karakterisert ved at A blir valgt fra oksazolyl, furyl, imidazolyl, isoksazolyl, pyrazolyl, cyklopentenyl og cyklopentadienyl.
31.
Fremgangsmåte ifølge krav 30, karakterisert ved at A blir valgt fra imidazolyl, isokszolyl og pyrazolyl.
32.
Anvendelse av en forbindelse ifølge krav 1, inkludert de hvor A er tetrazolium eller pyridinium; eller indanon når R<3> er alkyl eller karboksyalkyl; eller ifølge et hvilket som helst av kravene 1-19 for fremstilling av et medikament forbehandling av inflammasjon eller inflammasjons-assosiert forstyrrelse.
33.
Anvendelse ifølge krav 32, hvor tilstanden er en inflammasjon.
34.
Anvendelse ifølge krav 32, hvori tilstanden er en inflammasjonsassosiert forstyrrelse.
35.
Anvendelse ifølge krav 34, hvor den inflammasjons-assosierte forstyrrelsen er smerte.
36.
Anvendelse ifølge krav 35, hvor smerten er assosiert med cancer.
37.
Anvendelse ifølge krav 35, hvor smerten er tannpine.
38.
Anvendelse ifølge krav 35, hvor forbindelsen administreres intravenøst.
39.
Anvendelse ifølge krav 35, hvor forbindelsen administreres intramuskulært.
40.
Forbindelse ifølge krav 16, karakterisert ved at den er N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, eller et farmasøytisk akseptabelt salt derav.
41.
Forbindelse ifølge krav 19, karakterisert ved at den er N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, natriumsalt.
42.
Farmasøytisk sammensetning ifølge krav 20, karakterisert v e d at nevnte forbindelse er N-[[4-(5-metyl-3-fenylisoksazol-4-yl] fenyl]sulfonyl]propanamid, eller et farmasøytisk akseptabelt salt derav.
43.
Farmasøytisk sammensetning ifølge krav 20, karakterisert v e d at nevnte forbindelse er N-[[4-(5-metyl-3-fenylisoksazol-4-yl] fenyl] sulfonyl]propanamid, natriumsalt.
44.
Anvendelse ifølge krav 32, hvor nevnte forbindelse er N-[[4-(5-metyl-3-fenylisoksazol-4-yl]fenyl]sulfonyl]propanamid, eller et farmasøytisk akseptabelt salt derav.
45.
Anvendelse ifølge krav 32, hvor nevnte forbindelse er N-[[4-(5-metyl-3-fenylisoksazol-4-yI]fenyl]sulfonyl]propanamid, natriumsalt.
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US63151496A | 1996-04-12 | 1996-04-12 | |
PCT/US1997/005497 WO1997038986A1 (en) | 1996-04-12 | 1997-04-11 | Substituted benzenesulfonamide derivatives as prodrugs of cox-2 inhibitors |
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- 2002-09-04 JP JP2002258955A patent/JP4049307B2/ja not_active Expired - Lifetime
- 2002-12-30 IL IL15373802A patent/IL153738A0/xx active IP Right Grant
-
2004
- 2004-06-02 IS IS7292A patent/IS7292A/is unknown
- 2004-09-13 US US10/939,852 patent/US7420061B2/en not_active Expired - Fee Related
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MK1K | Patent expired |