Claims
- 1. A compound that has formula IV:
- 2. The compound of claim 1, wherein:
X is S; R3 and R4 are each H; Y1 and Y2 are each carbon; and a and b are each 1.
- 3. The compound of claim 1, wherein the compound has formula V:
- 4. The compound of claim 3, wherein R1 is Cl or Me; and R2 is Me.
- 5. The compound of claim 3, wherein:
R5 is Me or acetyl; R6 is Me, acetyl or 2-oxazolyl; R7 is H, Me, OSO2NMe2, OCH2-cyclopropyl, hydroxy or SO2NH—(4-chloro-3-methyl-5-isoxazolyl); Y and R8 are selected from (i) or (ii), as follows: (i) Y is O; and R8 is C(O)CH2SO2CH3, C(O)Me, 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, Me, C(O)Et, Cl, n-propyl or ethyl; or (ii) Y and R8 together form —CO—N═ or —CO—C(CN)═; R9 is H; Y1 and Y2 are each independently carbon or nitrogen; a is 1 if Y2 is carbon; a is 0 if Y2 is nitrogen; b is 1 if Y1 is carbon; b is 0 if Y1 is nitrogen; and W is NH.
- 6. The compound of claim 3, wherein:
X is S; R1 is Cl or Me; R2 is Me; R3, R4 and R9 are H; Y is O; W is NH; and Y1 and Y2 are each carbon.
- 7. The compound of claim 6, wherein the compound has the formula VI:
- 8. The compound of claim 7, wherein R1, R5 and R6 are Me; and R7 is hydrogen.
- 9. The compound of claim 1 that is selected from the group consisting of N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide, N-(2-cyano-3,4,6-trimethylphenyl)-3-{[(3,4-dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(3,4,6-trimethyl-2-propanoylphenyl)-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-[2-(1-hydroxyethyl)-4,6-dimethylphenyl]-2-thiophene carboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-{2-[(dimethylamino)carbonyl]-4,6-dimethylphenyl)-2-thiophene carboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-{2,4-dimethyl-6-[(methyloxy)ethanimidoyl]phenyl}-2-thiophene carboxamide, 3-{[(3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenyl)-carbonyl]amino}-2,4,6-trimethylphenyl-N,N-dimethylsulfamate, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-{3-[(cyclopropylmethyl)-oxy]-2,4,6-trimethylphenyl}-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2,4,6-trimethyl-5-pyrimidinyl)-2-thiophenecarboxamide, N-(2-acetyl-3,4,6-trimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2-cyano-3,4,6-trimethylphenyl)-2-thiophenecarboxamide, N-(2-chloro-4,6-dimethylphenyl)-3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(4,6-diacetyl-3-hydroxy-2-propylphenyl-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2,4-dimethyl-6-[2-(methylsulfonyl)acetyl]-phenyl}-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)-amino]sulfonyl}-N-(2,4-dimethyl-6-{[methyl(2,2-dimethylpropyl)amino]-carbonyl}phenyl)-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]-sulfonyl)-N-[2,4-dimethyl-6-(methylsulfonyl)phenyl]-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]-sulfonyl}-N-[2,4-dimethyl-6-(1 ,3-oxazol-2-yl)phenyl]-2-thiophenecarboxamide, 3-{[(4-chloro-5-isoxazolyl)amino]sulfonyl}-N-[2-(2-propylsulfonyl)-4,6-dimethylphenyl]-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl)-N-[2,4-dimethyl-6-(propylsulfonyl)phenyl]-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]-sulfonyl}-N-(2-ethyl-4,6-dimethylphenyl)-2-thiophenecarboxamide, 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-[2,6-dimethyl-4-(1,3-oxazol-2-yl)phenyl]-2-thiophenecarboxamide, N-(4-chloro-3-methyl-5-isoxazolyl)-2-(6,8-dimethyl-4-hydroxy-2-benzopyrimidinyl)thiophene-3-sulfonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-cyano-4-hydroxy-6,8-dimethylbenzo[b]pyridin-2-yl)thiophene-3-sulfonamide, or a pharmaceutically acceptable derivative thereof.
- 10. The compound of claim 1 that is N-(2-acetyl-4,6-dimethylphenyl)-3-{[(3,4 dimethyl-5-isoxazolyl)amino]sulfonyl}-2-thiophenecarboxamide, or a pharmaceutically acceptable derivative thereof.
- 11. A pharmaceutically acceptable salt comprising the compound of claim 10.
- 12. The salt of claim 11 that is a sodium salt.
- 13. The compound of claim 1, wherein Y1 and Y2 are each nitrogen.
- 14. The compound of claim 13, wherein a and b are each 0.
- 15. The compound of claim 13, wherein R5, R6 and R8 are alkyl; Y is O; and W is NH.
- 16. The compound of claim 13, wherein R3 and R4 are each H; and X is S.
- 17. The compound of claim 13 that is 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2,4,6-trimethyl-5-pyrimidinyl)-2-thiophenecarboxamide, or a pharmaceutically acceptable derivative thereof.
- 18. The compound of claim 1, wherein X is —C(R3)═C(R4)—.
- 19. The compound of claim 18 that has formula VII:
- 20. The compound of claim 19, wherein R3, R4 and R9 are H; Y is O; and W is NH.
- 21. The compound of claim 19, wherein R1 and R2 are each selected independently from among alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, halide, pseudohalide or H, except that R2 is not halide.
- 22. The compound of claim 19, wherein R1 is lower alkyl or halide; and R2 is lower alkyl.
- 23. The compound of claim 19, wherein the compound has formula VIII:
- 24. The compound of claim 23, wherein:
R5 is Me or acetyl; R6 is Me, acetyl or 2-oxazolyl; R7 is H, Me, OSO2NMe2, OCH2-cyclopropyl, hydroxy or SO2NH—(4-chloro-3-methyl-5-isoxazolyl); and R8 is C(O)CH2SO2CH3, C(O)Me, 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, Me, C(O)Et, Cl, n-propyl or ethyl.
- 25. The compound of claim 23, wherein R5 and R6 are Me; R7 is H; and R8 is C(O)Me.
- 26. The compound of claim 23 that is N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-acetyl-4,6-dimethylphenylaminocarbonyl)benzene-sulfonamide.
- 27. The compound of claim 1, wherein M is (CH2)z, where z is 0 to 6.
- 28. The compound of claim 27, wherein the compound has formula X:
- 29. The compound of claim 28, wherein:
R1 is halo or lower alkyl; R2 is lower alkyl; R5 is lower alkyl or —(CH2)xC(O)(CH2)yCH3; R6 is lower alkyl, —(CH2)xC(O)(CH2)yCH3, or heteroaryl; R7 is hydrogen, hydroxy, alkoxy, lower alkyl, S(O)2NHR50 and OS(O)2NR38R39; where R38 and R39 are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, haloalkyl, alkylaryl, heterocyclyl, arylalkyl, arylalkoxy, alkoxy, aryloxy, cycloalkyl, cycloalkenyl and cycloalkynyl; x and y are each independently 0 to 14; and R50 is hydrogen, lower alkyl, lower alkoxy or heteroaryl; R8 is CONR38R39, CN, heteroaryl, alkylsulfonyl, (CH2)xC(O)(CH2)yCH3, alkyl, halide, pseudohalide, hydroxyalkyl, C(O)(CH2)xS(O)2(CH2)yCH3 or C(═N—OR38)(CH2)yCH3; R9 is H; Y1 and Y2 are each independently carbon or nitrogen; a is 1 if Y2 is carbon; a is 0 if Y2 is nitrogen; b is 1 if Y1 is carbon; and b is 0 if Y1 is nitrogen.
- 30. The compound of claim 29, wherein Y1 and Y2 are carbon; a and b are each 1; R5, R6 and R8 are lower alkyl; and R7 is H or SO2NHR50, where R50 is heteroaryl.
- 31. The compound of claim 28 selected from the group consisting of N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2,4,6-trimethylbenzyl)benzo[b]thiophene-3-sulfonamide and N-(4-chloro-3-methyl-5-isoxazolyl)-2-(3-(4-chloro-3-methyl-5-isoxazolyl)aminosulfonyl-2,4,6-trimethylbenzyl)benzo[b]thiophene-3-sulfonamide.
- 32. A pharmaceutically acceptable salt of the compound of claim 1.
- 33. The salt of claim 32 that is a sodium salt.
- 34. A pharmaceutical composition, comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.
- 35. A pharmaceutical composition, comprising an effective amount of a compound of claim 10 or a pharmaceutically acceptable derivative thereof in a pharmaceutically acceptable carrier, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.
- 36. The composition of claim 34 that is formulated for single or multiple dosage administration.
- 37. The composition of claim 35 that is formulated for single or multiple dosage administration.
- 38. An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable derivative thereof of claim 1 contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC50 of less than about 10 μM, and the packaging material includes a label that indicates that the sulfonamide or derivative thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.
- 39. An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable derivative thereof of claim 10 contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC50 of less than about 10 μM, and the packaging material includes a label that indicates that the sulfonamide or derivative thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.
- 40. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable derivative thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.
- 41. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount of a compound of claim 10, or a pharmaceutically acceptable derivative thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.
- 42. The method of claim 40, 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.
- 43. The method of claim 41, 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.
- 44. The method of claim 42, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.
- 45. The method of claim 42, wherein the disease is glaucoma.
- 46. The method of claim 43, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.
- 47. The method of claim 43, wherein the disease is glaucoma.
- 48. A method for inhibiting the binding of an endothelin peptide to an endothelinA (ETA) or endothelinB (ETB) receptor, comprising contacting the receptor with a compound of claim 1, or a pharmaceutially acceptable derivative thereof, wherein:
the contacting is effected prior to, simultaneously with or subsequent to contacting the receptor with the endothelin peptide.
- 49. A method for inhibiting the binding of an endothelin peptide to an endothelinA (ETA) or endothelinB (ETB) receptor, comprising contacting the receptor with a compound of claim 10, or a pharmaceutially acceptable derivative thereof, wherein:
the contacting is effected prior to, simultaneously with or subsequent to contacting the receptor with the endothelin peptide.
- 50. A method for altering endothelin receptor-mediated activity, comprising contacting an endothelin receptor with a compound of claim 1, or a pharmaceutially acceptable derivative thereof.
- 51. A method for altering endothelin receptor-mediated activity, comprising contacting an endothelin receptor with a compound of claim 10, or a pharmaceutially acceptable derivative thereof.
- 52. The pharmaceutical composition of claim 34, wherein the pharmaceutically acceptable carrier comprises a sodium phosphate buffer solution containing a sugar.
- 53. The pharmaceutical formulation of claim 52, wherein the compound is a pharmaceutically-acceptable alkali metal salt.
- 54. A lyophilized powder, comprising a salt of the compound of claim 1.
- 55. The lyophilized powder of claim 54 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.
- 56. The powder of claim 55, wherein the sugar or carobohydrate contains dextrose.
- 57. An article of manufacture, comprising packaging material and a the powder of claim 54, contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC50 of less than about 1 μM, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.
- 58. A combination comprising:
a sterile vial containing the pharmaceutical formulation of claim 54.
- 59. The combination of claim 58, wherein the sterile vial contains an amount of the powder that is for single dose administration.
- 60. The combination of claim 58, 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.
- 61. The pharmaceutical composition of claim 34 that is formulated as a tablet or capsule.
- 62. The composition of claim 61, further comprising an enteric coating.
- 63. The composition of claim 61, 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 carnuba wax.
- 64. The pharmaceutical composition of claim 35, wherein the pharmaceutically acceptable carrier comprises a sodium phosphate buffer solution containing a sugar.
- 65. The pharmaceutical formulation of claim 64, wherein the compound is a pharmaceutically-acceptable alkali metal salt.
- 66. A lyophilized powder, comprising a salt of the compound of claim 10.
- 67. The lyophilized powder of claim 66 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.
- 68. The powder of claim 67, wherein the sugar or carobohydrate contains dextrose.
- 69. An article of manufacture, comprising packaging material and a the powder of claim 66, contained within the packaging material, wherein the compound is effective for antagonizing the effects of endothelin, ameliorating the symptoms of an endothelin-mediated disorder, or inhibiting the binding of an endothelin peptide to an ET receptor with an IC50 of less than about 1 μM, and the packaging material includes a label that indicates that the sulfonamide or salt thereof is used for antagonizing the effects of endothelin, inhibiting the binding of endothelin to an endothelin receptor or treating an endothelin-mediated disorder.
- 70. A combination comprising:
a sterile vial containing the pharmaceutical formulation of claim 66.
- 71. The combination of claim 70, wherein the sterile vial contains an amount of the powder that is for single dose administration.
- 72. The combination of claim 70, 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.
- 73. The pharmaceutical composition of claim 35 that is formulated as a tablet or capsule.
- 74. The composition of claim 73, further comprising an enteric coating.
- 75. The composition of claim 73, 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 carnuba wax.
RELATED APPLICATIONS
[0001] Benefit of priority under 35 U.S.C. §119(e) is claimed to U.S. provisional application Serial No. 60/174,104 to Wu et al., filed Dec. 31, 1999, entitled “SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN”. The subject matter of the provisional application is incorporated herein in its entirety.
Provisional Applications (1)
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Number |
Date |
Country |
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60174104 |
Dec 1999 |
US |