Patent EA-001367-B1 (EA)
Title: Pentafluorobenzenesulfonamides and analogs
Inventor: CLARK DAVID
IPC: C07D213/75
Filed: 1997-02-22
Abstract: 1. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula I   or a pharmaceutically acceptable salt thereof, wherein: Y is -S(O)- or -S(O)2-; and  Z is -NR<1>R<2> , wherein R<1> is selected from hydrogen, substituted or unsubstituted (C1-C10)alkyl, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C4)heteroalkyl and R<2> is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; wherein  R<1> and R<2> may be connected by a linking group E to give a substituent of the formula  2. The composition of claim 1, wherein R<1> is hydrogen or (C1-C6)alkyl, R<2> is optionally substituted phenyl and there is no linking group E between R<1> and R<2>. 3. The composition of claim 1, wherein R<1> is hydrogen or methyl and R<2> is substituted phenyl, having from one to four substituents, which are independently selected from (C1-C6)alkyl, hydroxy, (C1-C6) alkoxy, amino optionally substituted with one or two (C1-C6)alkyls, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted phenoxy, and halogen. 4. The composition of claim 1, wherein R<1> is hydrogen and R<2> is substituted phenyl, wherein the substituents on R<2> are independently chosen from amino, (C1-C6)alkylamino, and di((C1-C6)alkyl)amino, and are located at one or more of positions 3- and 4- of the phenyl ring, in relation to the sulfonamido group. 5. The composition of claim 4, wherein the compound is  4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene,  4-(N,N-Diethylamino)-1 -pentafluorophenylsulfonamidobenzene,  3-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzene,  4-Amino-1-pentafluorophenylsulfonamidobenzene, or  4-(N,N-Dimethylamino)-1-pentafluorophenylsulfonamidobenzenehydrochloride. 6. The composition of claim 1, wherein R<1> is hydrogen, and R<2> is phenyl substituted at positions 3- and 4-, in relation to the sulfonamido group, with a divalent moiety that forms a 5- or 6- membered ring together with carbons 3- and 4- of the phenyl ring. 7. The composition of claim 6, wherein the divalent moiety is: -OCH2CH2O-, -OCH2O-, -C=CNH-, or-C=NNH-. 8. The composition of claim 7, wherein the compound is  1,2-Ethylenedioxy-4-pentafluorophenylsulfonamidobenzene,  1,2-Methylenedioxy-4-pentafluorophenylsulfonamidobenzene,  5-Pentafluorophenylsulfonamidoindazole, or  5-Pentafluorophenylsulfonamidoindole. 9. The composition of claim 1, wherein R<1> is hydrogen, and the substituents on R<2> are independently selected from halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6) alkylamino, and di((C1-C6)alkyl)amino. 10. The composition of claim 9, wherein the substituents on R<2> are independently selected from bromo, chloro, fluoro, hydroxy, methoxy, ethoxy, amino, and dimethylamino. 11. The composition of claim 10, wherein the compound is  4-Methoxy-1-pentafluorophenylsulfonamidobenzene,  3-Hydroxy-1-pentafluorophenylsulfonamidobenzene,  4-Hydroxy-1-pentafluorophenylsulfonamidobenzene,  4-Ethoxy-1-pentafluorophenylsulfonamidobenzene,  3-Ethoxy-1-pentafluorophenylsulfonamidobenzene,  3-Phenoxy-1-pentafluorophenylsulfonamidobenzene,  3-Methoxy-1-pentafluorophenylsulfonamidobenzene, or  4-tert-Butoxy-1-pentafluorophenylsulfonamidobenzene. 12. The composition of claim 1, wherein the compound is  1,2-Dimethoxy-4-pentafluorophenylsulfonamidobenzene,  2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene,  2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, monosodium salt, and  2-Hydroxy-1-methoxy-4-pentafluorophenylsulfonamidobenzene, monopotassium salt. 13. The composition of claim 1, wherein the compound is  2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene,  2-Bromo-1-methoxy-4-pentafluorophenylsulfonamidobenzene,  2-Chloro-1-methoxy-4-pentafluorophenylsulfonamidobenzene,  2-Fluoro-1-methoxy-4-pentafluorophenylsulfonamidobenzene, sodium salt, and 2-Fluoro-methoxy-4-pentafluorophenylsulfonamidobenzene, potassium salt. 14. The composition of claim 1, wherein in the compound of formula I, Y is SO2, R<1> is hydrogen or (C1-C6)alkyl, and R<2> is an unsubstituted or optionally substituted naphthyl group. 15. The composition of claim 1, wherein R<2> is a phenyl ring substituted by a heterocyclic group at the 4- position, in relation to the sulfonamido group 16. The composition of claim 1, wherein R<1> and R<2> are covalently joined in a moi ety that forms a 5- or 6-membered heterocyclic ring with the nitrogen atom of NR<1>R<2>. 17. The composition of claim 16, wherein R<1> is a -CH=CH- group or -(CH2)3- group, linked to the 2-position of the R<2> phenyl group, in relation to the sulfonamido group. 18. The composition of claim 1, wherein R<1> is an optionally substituted (C2-C10) alkyl or optionally substituted (C3-C6)alkenyl. 19. The composition of claim 18, wherein the compound is  2-Hydroxy-1-methoxy-4-[N-(5-hydroxypent-1-yl)pentafluorophenyl-sulfonamido]benzene,  4-Methoxy-1-[N-(2-propenyl)pentafluorophenylsulfonamido]benzene,  4-Methoxy-1-[N-(4-pentenyl)pentafluorophenylsulfonamido]benzene,  1-[N-(2,3-Dishydroxypropyl)pentafluorophenylsulfonamido]-4-methoxybenzene,  1-[N-(3,4-Dihydroxybutyl)pentafluorophenylsulfonamido]-4-methoxybenzene,  1-[N-(4,5-Dihydroxypentyl)pentafluorophenylsulfonamido]-4-methoxybenzene,  1-[N-(4-hydroxybutyl)pentafluorophenylsulfonamido]-4-methoxybenzene, and 4-Methoxy-1-[N-(5-hydroxypentyl)pentafluorophenylsulfonamido]benzene. 20. A method of treating or preventing a disease state characterized by abnormally high levels of low density lipoprotein particles or cholesterol in the blood, which method comprises administering to a mammalian subject in need thereof a therapeutically effective amount of a composition of claim 1. 21. The method of claim 20, wherein the desease is atherosclerosis. 22. The method of claim 20, wherein the desease is pancreatitis. 23. The method of claim 20, wherein the desease is hypercholesteremia. 24. The method of claim 20, wherein the desease is hyperlipoproteinemia. 25. The method of claim 20, wherein the composition is administered orally. 26. The method of claim 20, wherein the subject is human. 27. The method of claim 20, wherein the composition is administered in combination with a therapeutically effective amount of a hypolipemic agent or a hypocholesterolemic agent. 28. A compound of formula I   or a pharmaceutically acceptable salt thereof, wherein Y is -S(O)- or -S(O)2-;  Z is -NR<1>R<2>, where R<2> is an optionally substituted phehyl group and R<1> is selected from the group comprising hydrogen, substituted or unsubstituted (C1-C10)alkyl, substituted or unsubstituted (C3-C6)alkenyl, substituted or unsubstituted (C2-C6)heteroalkyl, substituted or unsubstituted (C3-C6)heteroalkenyl, substituted or unsubstituted (C3-C8)cycloalkyl, substituted or unsubstituted (C5-C7)cycloalkenyl, phenyl substituents, if any, are selected from the group comprising (C1-C6)alkyl, hydroxy, (C1-C6) alkoxy, amino optionally substituted with one or two (C1-C6)alkyls, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted phenoxy, and halogen; R<1> and R<2> may be connected by a linking group E to give a substituent of the formula    wherein E represents a bond, (C1-C4) alkylene, or (C1-C4) heteroalkylene, and th e ring formed by R<1>, E, R<2> and the nitrogen contains no more than 8 atoms; provided that: in the case that Y is -S(O2)-, and R<1> is hydrogen or methyl, then R<2> is substituted phenyl; in the case that Y is -S(O2)- and R<2> is phenyl, and R<1> is a propylene unit attaching the nitrogen of -NR<1>R<2>- to the 2- position of the phenyl ring in relation to the sulfonamido group to form a 1,2,3,4-tetrahydroquinoline system, and one or more of the remaining valences on the bicyclic system so formed is substituted with at least one substituent that is not hydrogen; in the case that Y is -S(O2)- and R<2> is phenyl substituted with 3-(1-hydroxyethyl) 3-dimethylamino, 4-dimethylamino, 4-phenyl, 3-hydroxy, 3-hydroxy-4-diethylaminom ethyl, 3,4-methylenedioxy, 3,4-ethylenedioxy, 2-(1-pyrrolyl), or 2-methoxy-4-(1-morphol ino), then either R<1> is not hydrogen or when R<1> is hydrogen, one or more of the remaining valences on the phenyl ring of R<2> is substituted with a substituent that is not hydrogen; wherein said compound has pharmacological activity. 29. The compound of claim 28, wherein R<1> is hydrogen or methyl and R<2> is substituted phenyl, wherein the substituents on R<2>, ranging in number from one to four, are independently selected from (C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, amino optionally s ubstituted with one or two (C1-C6)alkyls, optionally substituted arylamino, optionally substituted heteroarylamino, optionally substituted phenoxy, and halogen. 30. The compound of claim 29, wherein R<1> is hydrogen and R<2> is substituted phenyl, wherein the substituents on R<2> are independently chosen from amino, (C1-C6)alkyl amino, and di((C1-C6)alkyl)amino, and are located at one or more of positions 3- and 4- of th e phenyl ring, in relation to the sulfonamido group. 31. The compound of claim 30, wherein the compound is  4-(N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene,  4-Amino-1-pentafluorophenylsulfonamidobenzene and 4-(N-Diethylamino)-1-pentafluorophenylsulfonamidobenzene. 32. The compound of claim 28, wherein R<1> is hydrogen, and R<2> is phenyl substitut ed at positions 3- and 4-, in relation to the sulfonamido group, with a divalent moiety that forms a 5- or 6- membered ring together with carbons 3- and 4- of the phenyl ring. 33. The composition of claim 29, wherein R<1> is hydrogen, and the phenyl substituents are independently selected from halogen, hydroxy, (C1-C6)alkyl, (C1-C6)alkoxy, amino, (C1-C6) alkylamino, and di((C1-C6)alkyl)amino. 34. The composition of claim 9, wherein the phenyl substituents are independently selected from bromo, chloro, fluoro, hydroxy, methoxy, ethoxy,