Patent EA-004735-B1 (EA)
Title: Sulfonamides and derivatives thereof that modulate the activity of endothelin
Inventor: WU CHENGDE
IPC: A61P9/08
Filed: 2000-12-29
Abstract: 1. A compound of formulae: or pharmaceutically acceptable derivatives thereof, wherein: X is S; R<1> is C1-C6 alkyl; R<2> is C1-C6 alkyl; R<3> and R<4> are each hydrogen; R<5> is C1-C6 alkyl or -(CH2)xC(O)(CH2)yCH3; R<6> is C1-C6 alkyl or -(CH2)xC(O)(CH2)yCH3, or 5-membered heteroaryl comprising from 1 to 2 heteroatoms selected from O and N; R<7> is hydrogen, hydroxy, alkoxy, C1-C6 alkyl, S(O)2NHR<50> and OS(O)2NR<38>R<39>; where R<38> and R<39> are each independently selected from hydrogen, C1-C6 alkyl; x and y are each independently 0 to 14; R<50> is hydrogen, C1-C6 alkyl; Y is O; R<8> is CONR<38>R<39>, CN, 5-membered heteroaryl, comprising from 1 to 2 heteroatoms selected from O and N; R<9> is H; Y<1> and Y<2> are each independently carbon or nitrogen; a is 1 if Y<2> is carbon; a is 0 if Y<2> is nitrogen; b is 1 if Y<1> is carbon; b is 0 if Y<1> is nitrogen; and W is NH. 2. The compound of claim 1, wherein: X is S; R<3> and R<4> are each H; Y<1> and Y<2> are each carbon; and a and b are each 1. 3. The compound of claim 1, wherein the compound has the formula IV: and pharmaceutically acceptable derivatives thereof, wherein: X is S; R<1> is C1-C6 alkyl; R<2> is C1-C6 alkyl; R<3> and R<4> are each hydrogen; R<5> is C1-C6 alkyl or -(CH2)xC(O)(CH2)yCH3; R<6> is C1-C6 alkyl or -(CH2)xC(O)(CH2)yCH3, or 5-membered heteroaryl comprising from 1 to 2 heteroatoms selected from O and N; R<7> is hydrogen, hydroxy, alkoxy, C1-C6 alkyl, S(O)2NHR<50> and OS(O)2NR<38>R<39>; where R<38> and R<39> are each independently selected from hydrogen, C1-C6 alkyl; x and y are each independently 0 to 14; R<50> is hydrogen, C1-C6 alkyl; Y is O; R<8> is CONR<38>R<39>, CN, 5-membered heteroaryl, comprising from 1 to 2 heteroatoms selected from O and N; R<9> is H; Y<1> and Y<2> are each independently carbon or nitrogen; a is 1 if Y<2> is carbon; a is 0 if Y<2> is nitrogen; b is 1 if Y<1> is carbon; b is 0 if Y<1> is nitrogen; and W is NH. 4. The compound of claim 3, wherein R<1> is Me; and R<2> is Me. 5. The compound of claim 3, wherein: R<5> is Me or acetyl; R<6> is Me, acetyl or 2-oxazolyl; R<7> is H, Me, OSO2NMe2, OCH2-cyclopropyl, hydroxy or SO2NH-(4-chloro-3-methyl-5-isoxazolyl); Y is O; and R<8> is C(O)CH2SO2CH3, CN, C(O)N(Me)(CH2-t-Bu), SO2Me, 2-oxazolyl, SO2-isopropyl, SO2-n-propyl, CH(OH)Me, C(O)NMe2, C(=N-OMe)Me, or Cl; or Y and R<8> are together form hydrogen or nitrogen; R<9> is H; Y<1> and Y<2> are each independently carbon or nitrogen; a is 1 if Y<2> is carbon; a is 0 if Y<2> is nitrogen; b is 1 if Y<1> is carbon; b is 0 if Y<1> is nitrogen; and W is NH. 6. The compound of claim 3, wherein: X is S; R<1> is Me; R<2> is Me; R<3>, R<4> and R<9> are H; Y is O; W is NH; and Y<1> and Y<2> are each carbon. 7. The compound of claim 6, wherein the compound has the formula VI: or pharmaceutically acceptable derivatives thereof, wherein: R<1> is Me; R<5> is Me or acetyl; R<6> is Me, acetyl or 2-oxazolyl; R<7> is H, Me, OSO2NMe2, OCH2-cyclopropyl, hydroxy or SO2NH-(4-chloro-3-methyl-5-isoxazolyl); and R<8> is C(O)CH2SO2CH3, CN, C(O)N(Me)(CH2-t-Bu), SO2Me, 2-oxazolyl, SO2-isopropyl, SO2-n-propyl, CH(OH)Me, C(O)NMe2, C(=N-OMe)Me or Cl. 8. The compound of claim 7, wherein R<1>, R<5> and R<6> are Me; and R<7> is hydrogen. 9. The compound of claim 1 that is selected from the group consisting of N-(2-cyano-3,4,6-trimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide or pharmaceutically acceptable derivatives thereof. 10. The compound of claim 1, wherein Y<1> and Y<2> are each nitrogen. 11. The compound of claim 10, wherein a and b are each 0. 12. The compound of claim 10, wherein R<5> and R<6> are alkyl; Y is O; and W is NH. 13. A pharmaceutically acceptable salt of the compound of claim 1. 14. The salt of claim 13 that is a sodium salt. 15. A pharmaceutical composition, comprising an effective amount of a compound of claim 1 or pharmaceutically acceptable derivatives thereof in a pharmaceutically acceptable carrier, wherein the amount is effective for ameliorating the symptoms of an endothelin mediated disease. 16. The composition of claim 15 that is formulated for single or multiple dosage administration. 17. An article of manufacture, comprising packaging material and a compound or pharmaceutically acceptable derivatives thereof of claim 1 contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelia, ameliorating the symptoms of an endothelia-mediated disorder, or inhibiting the binding of an endothelia peptide to an ET receptor with an IC50 of less than about 10 muM, and the packaging material includes a label that indicates that the sulfonamide or derivative thereof is used for antagonizing the effects of endothelia, inhibiting the binding of endothelia to an endothelia receptor or treating an endothelia-mediated disorder. 18. A method for the treatment of endothelia-mediated diseases, comprising administering to a subject an effective amount of a compound of claim 1, or pharmaceutically acceptable derivatives thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease. 19. The method of claim 18, wherein the disease is selected from the group consisting of hypertension, cardiovascular diseases, cardiac diseases including myocardial infarction, pulmonary hypertension, neonatal pulmonary hypertension, erythropoietin-mediated hypertension, respiratory diseases and inflammatory diseases, including asthma, bronchoconstriction, ophthalmologic diseases including glaucoma and inadequate retinal perfusion, gastroenteric diseases, renal failure, endotoxin shock, menstrual disorders, obstetric conditions, wounds, laminitis, erectile dysfunction, menopause, osteoporosis and metabolic bone disorders, climacteric disorders including hot flushes, abnormal clotting patterns, urogenital discomfort and increased incidence of cardiovascular disease, and other disorders associated with the reduction in ovarian function in middle-aged women, pre-eclampsia, control and management of labor during pregnancy, nitric oxide attenuated disorders, anaphylactic shock, hemorrhagic shock and immunosuppressant-mediated renal vasoconstriction. 20. The method of claim 19, wherein the disease is selected from the group consisting of asthma and inflammatory diseases. 21. The method of claim 19, wherein the disease is glaucoma. 22. A method for inhibiting the binding of an endothelia peptide to an endothelin A (ETA) or endothelin B (ETB) receptor, comprising contacting the receptor with a compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein: the contacting is effected prior to, simultaneously with or subsequent to contacting the receptor with the endothelia peptide. 23. A method for altering endothelia receptor-mediated activity, comprising contacting an endothelia receptor with a compound of claim 1, or a pharmaceutically acceptable derivative thereof. 24. The pharmaceutical composition of claim 15, wherein the pharmaceutically acceptable carrier comprises a sodium phosphate buffer solution containing a sugar. 25. The pharmaceutical formulation of claim 24, wherein the compound is a pharmaceutically-acceptable alkali metal salt. 26. A lyophilized powder, comprising a salt of the compound of claim 1. 27. The lyophilized powder of claim 26 produced by a process, comprising: (a) dissolving a pharmaceutically-acceptable salt of the sulfonamide compound in a sodium phosphate buffer solution containing a sugar or carbohydrate; (b) sterile-filtering the resulting solution; and (c) lyophilizing the filtered solution under standard conditions to produce a sterile powder. 28. The powder of claim 27, wherein the sugar or carbohydrate contains dextrose. 29. An article of manufacture, comprising packaging material and a the powder of claim 26, contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelia, ameliorating the symptoms of an endothelia-mediated disorder, or inhibiting the binding of an endothelia peptide to an ET receptor with an IC50 of less than about 1 muM, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelia, inhibiting the binding of endothelia to an endothelia receptor or treating an endothelia-mediated disorder. 30. A combination comprising: a sterile vial containing the lyophilized powder of claim 26. 31. The combination of claim 30, wherein the sterile vial contains an amount of the powder that is for single dose administration. 32. The combination of claim 30, wherein the sterile vial also contains an amount of sterile water for injection; and the final concentration of the sulfonamide sodium salt is between about 1 and 250 mg/mL. 33. The pharmaceutical composition of claim 15 that is formulated as a tablet or capsule. 34. The composition of claim 33, further comprising an enteric coating. 35. The composition of claim 34, wherein the coating is selected from cellulose acetate phthalate, polyethylene glycol, polyoxyethylene sorbitan, castor oil, ethyl cellulose pseudolatex, phenyl salicylate, n-butyl stearate, stearic acid and camuba wax.