Patent EA-003924-B1 (EA)
Title: Arylsulfonanilide ureas
Inventor: HOUZE JONATHAN B
IPC: C07D249/14
Filed: 1999-09-21
Abstract: 1. A compound having the formula: wherein X is O; R<1> and R<2> are each members independently selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)heteroalkyl; R<3> is a substituent selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)heteroalkyl, or is combined with Y and the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered heterocyclic ring; R<4> is a substituent selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, -OR<11>, -SR<11> and -NR<11>R<12>, wherein R<11> and R<12> are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl and (C1-C8)heteroalkyl; Y is a substituent selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, or is optionally linked together with R<3> to form a 5-, 6- or 7-membered heterocyclic ring; wherein heteroalkyl is optionally substituted, saturated or unsaturated, linear or branched or cyclic hydrocarbon radical, or a combination thereof, consisting of said number of carbon atoms and 1-3 heteroatoms selected from the group consisting of O, N, Si and S; Ar is a substituent selected from the group consisting of: wherein X<1> and X<2> are each independently selected from the group consisting of F, Cl and Br; or a pharmaceutically acceptable salt thereof. 2. A compound of claim 1, wherein Y is (C1-C6)alkyl. 3. A compound of claim 1, wherein Y is hydrogen. 4. A compound of claim 1, wherein Y is optionally substituted, saturated or unsaturated, linear or branched or cyclic hydrocarbon radical, consisting of 1-8 carbon atoms and 1-3 heteroatoms selected from the group consisting of O, N, Si and S. 5. A compound of claim 1, wherein Y is combined with R<3> and the nitrogen atom to which each is attached to form a 5- or 6-membered heterocyclic ring. 6. A compound of claim 1, wherein Y is selected from the group consisting of 2thiazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, pyrazolyl, 1,2,3,4-tetrazolyl, imidazolyl, oxazolyl and 1,2,3-triazolyl. 7. A compound of claim 1, wherein R<1>, R<2>, R<3> and Y are each hydrogen. 8. A compound of claim 1, wherein R<4> is selected from the group consisting of hydrogen, (C1-C3)alkyl and (C1-C3)alkoxy. 9. A compound of claim 1, wherein R<1>, R<2> and R<3> are each hydrogen and R<4> is (C1-C3)alkoxy. 10. A compound of claim 1, wherein R<1> and R<2> are each hydrogen and Y is combined with R<3> and the nitrogen atom to which each is attached to form a 5or 6membered heterocyclic ring. 11. A compound of claim 1, wherein Ar is pentafluorophenyl. 12. A compound of claim 1, wherein Ar is 2,3,4,5-tetrafluorophenyl. 13. A compound of claim 1, wherein R<1>, R<2> and R<3> are hydrogen, R<4> is located in the para-position relative to the sulfonamide moiety and is selected from the group consisting of hydrogen, (C1-C3)alkyl, (C1-C3)alkoxy and (C1-C3)thioalkoxy, and Y is hydrogen or (C1-C3)alkyl. 14. A compound of claim 1, wherein Ar is pentafluorophenyl; R<1>, R<2> and R<3> are each hydrogen; R<4> is 4-methoxy; and Y is hydrogen or (C1-C3)alkyl. 15. A compound of claim 1, represented by the formula: 16. A compound of claim 1, represented by the formula: 17. A compound of claim 1, represented by the formula: 18. A compound of claim 1, represented by the formula: 19. A compound of claim 1, represented by the formula: 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, or by an abnormally high level of cell proliferation, which method comprises administering to a mammalian subject in need thereof a therapeutically effective amount of a composition comprising a compound of formula: wherein X is O; R<1> and R<2> are each members independently selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)heteroalkyl; R<3> is a substituent selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)heteroalkyl, or is combined with Y and the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered heterocyclic ring; R<4> is a substituent selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, -OR<11>, -SR<11> and -NR<11>R<12>, wherein R<11> and R<12> are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl and (C1-C8)heteroalkyl; Y is a substituent selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, or is optionally linked together with R<3> to form a 5-, 6- or 7-membered heterocyclic ring; wherein heteroalkyl is optionally substituted, saturated or unsaturated, linear or branched or cyclic hydrocarbon radical, or a combination thereof, consisting of said number of carbon atoms and 1-3 heteroatoms selected from the group consisting of O, N, Si and S; Ar is a substituent selected from the group consisting of: wherein X<1> and X<2> are each independently selected from the group consisting of F, Cl and Br; or a pharmaceutically acceptable salt thereof. 21. A method in accordance with claim 20, wherein the disease state is cancer or a cancerous condition. 22. A method in accordance with claim 20, wherein the proliferative disease state is infection by a microorganism. 23. A method in accordance with claim 20, wherein the proliferative disease state is psoriasis. 24. A method in accordance with claim 20, wherein the proliferative disease state is vascular restenosis. 25. A method in accordance with claim 20, wherein the disease state is hypercholesterolemia or another disease state associated with abnormally high levels of cholesterol or lipoproteins. 26. A method in accordance with claim 20, wherein the compound is administered orally. 27. A method in accordance with claim 20, wherein the compound is administered intravenously, intramuscularly, subcutaneously or intraduodenally. 28. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: wherein X is O; R<1> and R<2> are each members independently selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)heteroalkyl; R<3> is a substituent selected from the group consisting of hydrogen, (C1-C6)alkyl and (C1-C6)heteroalkyl, or is combined with Y and the nitrogen atom to which each is attached to form a 5-, 6- or 7-membered heterocyclic ring; R<4> is a substituent selected from the group consisting of hydrogen, halogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, -OR<11>, -SR<11> and -NR<11>R<12>, wherein R<11> and R<12> are each independently selected from the group consisting of hydrogen, (C1-C8)alkyl and (C1-C8)heteroalkyl; Y is a substituent selected from the group consisting of hydrogen, (C1-C8)alkyl, (C1-C8)heteroalkyl, aryl(C1-C4)alkyl, aryl(C1-C4)heteroalkyl, or is optionally linked together with R<3> to form a 5-, 6- or 7-membered heterocyclic ring; wherein heteroalkyl is optionally substituted, saturated or unsaturated, linear or branched or cyclic hydrocarbon radical, or a combination thereof, consisting of said number of carbon atoms and 1-3 heteroatoms selected from the group consisting of O, N, Si and S; Ar is a substituent selected from the group consisting of: wherein X<1> and X<2> are each independently selected from the group consisting of F, Cl and Br; or a pharmaceutically acceptable salt thereof. 29. A composition of claim 28, wherein Ar is selected from the group consisting of 30. A composition of claim 28, wherein Ar is pentafluorophenyl. 31. A composition of claim 28, wherein Ar is 2,3,4,5-tetrafluorophenyl. 32. A composition of claim 28, further comprising an antiproliferative agent selected from the group consisting of cyclophosphamide, methotrexate, adriamycin, cisplatin, daunomycin, vincristine, vinblastine, vinarelbine, paclitaxel, docetaxel, tamoxifen, flutamide, hydroxyurea, and mixtures thereof. 33. A composition of claim 28, further comprising a member selected from the group consisting of hypocholesterolemic and hypolipemic agents.