Sulfonamides and derivatives thereof that modulate the activity of endothelin

• US 6,686,382 B2
• Filed: 12/29/2000
• Issued: 02/03/2004
• Est. Priority Date: 12/31/1999
• Status: Expired due to Fees

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Holland, George W., Wu, Chengde, Blok, Natalie
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): TRUONG, TAMTHOM NGO
• Application Number:
  US09/751,825
• Publication Number:
  US 20010056183A1
• Time in Patent Office: 1,131 Days
• Field of Search: 514/258.1, 514/256, 514/307, 514/311, 514/317, 514/380, 544/333, 548/245, 546/272.1
• US Class Current: 514/380
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings

Abstract

Thienyl-, furyl-, pyrrolyl- and phenylsulfonamides, formulations of pharmaceutically-acceptable derivatives thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides, N-(isoxazolyl)pyrrolylsulfonamides and N-(isoxazolyl)phenylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or pharmaceutically acceptable derivatives thereof that inhibit the activity of endothelin are also provided.

Claims

1. A compound that has formula IV:

or pharmaceutically acceptable derivatives thereof, wherein;

X is S or —

C(R³)═

(C(R⁴)—

;

R¹ is lower alkyl;

R² is lower alkyl;

R³ and R⁴ are independently selected from among hydrogen, halo, cyano, cyanoalkyl, C(O)R⁴¹, alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene or alkenylene, where R⁴¹ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino;

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 or OS(O)₂NR³⁸R³⁹;

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;

R⁵⁰ is hydrogen, lower alkyl, lower alkoxy or heteroaryl;

Y and R⁸ are selected from (i) or (ii) as follows;

(i) Y is O; and

R⁸ is CONR³⁸R³⁹, CN, heteroaryl, alkylsulfonyl, halide, pseudohalide, hydroxyalkyl, C(O)(CH₂)_xS(O)₂(CH₂)_yCH₃ or C(═

N—

OR³⁸)(CH₂)_yCH₃;

or

(ii) Y and R⁸ together with the atoms to which they are attached, form a 3 to 16 membered unsubstituted or substituted cyclic or heterocyclic ring;

R⁹ is H;

Y¹ and Y² are each independently carbon;

a is 1;

b is 1; and

W is NH.

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:

and pharmaceutically acceptable derivatives thereof, wherein;

X is S or —

CH═

CH—

;

R¹ is lower alkyl;

R² is lower alkyl;

R³ and R⁴ are each hydrogen;

R⁵ is lower alkyl or —

(CH₂)_xC(O)(CH₂)_yCH₃;

R⁶ is lower alkyl, —

(CH₂)_xC(O)(CH₂)_yCH₃, or heteroaryl;

R⁷ is selected from the group consisting of hydrogen, hydroxy, alkoxy, lower alkyl, S(O)₂NHR⁵⁰ and OS(O)₂NR³⁸R³⁹;

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;

R⁵⁰ is hydrogen, lower alkyl, lower alkoxy or heteroaryl;

Y and R⁸ are selected from (i) or (ii) as follows;

(i) Y is O; and

R⁸ is CONR³⁸R³⁹, CN, heteroaryl, alkylsulfonyl, halide, pseudohalide, hydroxyalkyl, C(O)(CH₂)_xS(O)₂(CH₂)_yCH₃ or C(═

N—

OR³⁸)(CH₂)_yCH₃;

or

(ii) Y and R⁸ together with the atoms to which they are attached, form a 3 to 16 membered unsubstituted or substituted cyclic or heterocyclic ring;

R⁹ is H;

Y¹ and Y² are each independently carbon;

a is 1;

b is 1; and

W is NH.

4. The compound of claim 3, wherein R¹ is 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, 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, C(O)Et or Cl;

or

(ii) Y and R⁸ together form —

CO—

N═

or —

CO—

C(CN)═

;

R⁹ is H;

Y¹ and Y² are each independently carbon;

a is 1;

b is 1; and

W is NH.

6. The compound of claim 3, wherein:

X is S;

R¹ is 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:

or pharmaceutically acceptable derivatives thereof, wherein;

R¹ is Me;

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, 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, C(O)Et or Cl.

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 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 X is —

C(R³)═

C(R⁴)—

.

23. A pharmaceutically acceptable salt of the compound of claim 1.

24. The salt of claim 23 that is a sodium salt.

25. A pharmaceutical composition, comprising and 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.

27. The composition of claim 25 that is formulated for single or multiple dosage administration.

29. 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 μ

M, 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.

31. 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.

33. The method of claim 31, 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, endotoxic 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, 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.

35. The method of claim 33, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

36. The method of claim 33, wherein the disease is glaucoma.

39. A method for inhibiting the binding of an endothelin peptide to an endothelin_A (ET_A) or endothelin_B (ET_B) 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 endothelin peptide.

41. A method for altering endothelin receptor-mediated activity, comprising contacting an endothelin receptor with a compound of claim 1, or a pharmaceutically acceptable derivative thereof.

43. The pharmaceutical composition of claim 25, wherein the pharmaceutically acceptable carrier comprises a sodium phosphate buffer solution containing a sugar.

44. The pharmaceutical formulation of claim 43, wherein the compound is a pharmaceutically-acceptable alkali metal salt.

45. A lyophilized powder, comprising a salt of the compound of claim 1.

46. The lyophilized powder of claim 45 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.

47. The powder of claim 46, wherein the sugar or carbohydrate contains dextrose.

48. An article of manufacture, comprising packaging material and the powder of claim 45, 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 μ

M, 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.

49. A combination comprising:

a sterile vial containing the pharmaceutical formulation of claim 45.

50. The combination of claim 49, wherein the sterile vial contains an amount of the powder that is for single dose administration.

51. The combination of claim 49, 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.

52. The pharmaceutical composition of claim 25 that is formulated as a tablet or capsule.

53. The composition of claim 52, further comprising an enteric coating.

54. The composition of claim 53, 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.

11. A compound that has formula VII:

and pharmaceutically acceptable derivatives thereof, where R¹ and R² are either (i), (ii) or (iii) as follows;

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, except that R² is not halide or pseudohalide;

or,

(ii) R¹ and R² together form —

(CH₂)_n—

, where n is 3 to 6;

or,

(iii) R¹ and R² together form 1,3-butadienyl (—

CH═

CH—

CH═

CH—

);

W is O, NH or (CH₂)_z wherein z is 0 to 6; and

Y is O, S, or, together with R⁸ and the atoms to which they are attached, form a 3 to 16 membered unsubstituted or substituted cyclic or heterocyclic ring;

R³ and R⁴ are independently selected from among hydrogen, halo, cyano, cyanoalkyl, C(O)R⁴¹, alkyl, alkenyl, cycloalkyl and aryl, or together form alkylene or alkenylene, where R⁴¹ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonylamino, arylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylarylamino, arylsulfonylalkylamino or arylsulfonylarylamino;

Y¹ and Y² are each independently carbon;

a and b are each independently 1;

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from (i) or (ii) as follows;

(i) R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from among H, NHR³⁸, CONR³⁸R³⁹, NO₂, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkoxyalkoxy, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, —

(CH₂)_xC(O)(CH₂)_yCH₃, —

(CH₂)_xCH₃, (CH₂)_xNH-lower alkyl, —

(CH₂)_{1 to 14}C(O)NH₂, a primary or secondary amide, —

(CH₂)_xCOOH, —

(CH₂)_xCH(COOH)(CH₂)_yCH₃, C(O)(CH₂)_xS(O)₂(CH₂)_yCH₃, C(═

N—

OR³⁸)(CH₂)_yCH₃, —

C(O)C(O)(CH₂)_yCH₃, —

(CH₂)_xN(CH₃)₂, S(O)₂NHR⁵⁰, OS(O)₂NR³⁸R³⁹, alkylaryl, alkylheteroaryl, —

C(O)NH-heteroaryl and —

C(O)N(H)N(H)R⁵⁰;

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;

R⁵⁰ is a substituent such as hydrogen, lower alkyl, lower alkoxy or heteroaryl;

or

(ii) at least two of R⁵, R⁶, R⁷, R⁸ and R⁹, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo lower alkyl, and the others of R⁵, R⁶, R⁷, R⁸ and R⁹ are selected as in (i).

12. The compound of claim 11, wherein R³, R⁴ and R⁹ are H;

Y is O; and

W is NH.

13. The compound of claim 11, 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.

14. The compound of claim 11, wherein R¹ is lower alkyl or halide;

and R² is lower alkyl.

15. The compound of claim 11, wherein the compound has formula VIII:

or pharmaceutically acceptable derivatives thereof, wherein;

R¹ is lower alkyl or halide;

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 or OS(O)₂NR³⁸R³⁹; and

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.

16. The compound of claim 15, 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.

17. The compound of claim 15, wherein R⁵ and R⁶ are Me;

R⁷ is H; and

R⁸ is C(O)Me.

18. The compound of claim 15 that is N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2acetyl-4,6-dimethylphenylaminocarbonyl)benzenesulfonamide.

26. A pharmaceutical composition, comprising an effective amount of a compound of claim 11 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.

28. The composition of claim 26 that is formulated for single or multiple dosage administration.

30. An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable derivative thereof of claim 11 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 μ

M, 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.

32. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount of a compound of claim 11, or a pharmaceutically acceptable derivative thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

34. The method of claim 32, 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, endotoxic 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, 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.

37. The method of claim 34, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

38. The method of claim 34, wherein the disease is glaucoma.

40. A method for inhibiting the binding of an endothelin peptide to an endothelin_A (ET_A) or endothelin_B (ET_B) receptor, comprising contacting the receptor with a compound of claim 11, 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.

42. A method for altering endothelin receptor-mediated activity, comprising contacting an endothelin receptor with a compound of claim 11, or a pharmaceutically acceptable derivative thereof.

55. The pharmaceutical composition of claim 26, wherein the pharmaceutically acceptable carrier comprises a sodium phosphate buffer solution containing a sugar.

56. The pharmaceutical formulation of claim 55, wherein the compound is a pharmaceutically-acceptable alkali metal salt.

57. A lyophilized powder, comprising a salt of the compound of claim 11.

58. The lyophilized powder of claim 57 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.

59. The powder of claim 58, wherein the sugar or carbohydrate contains dextrose.

60. An article of manufacture, comprising packaging material and the powder of claim 57, 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 μ

M, 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.

61. A combination comprising:

a sterile vial containing the pharmaceutical formulation of claim 57.

62. The combination of claim 61, wherein the sterile vial contains an amount of the powder that is for single dose administration.

63. The combination of claim 61, 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.

64. The pharmaceutical composition of claim 26 that is formulated as a tablet or capsule.

65. The composition of claim 64, further comprising an enteric coating.

66. The composition of claim 65, 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.

19. A compound that has formula X:

or pharmaceutically acceptable derivatives thereof, where R¹ and R² are either (i), (ii) or (iii) as follows;

(i) R¹ and R² are each independently selected from H, NH₂, NO₂, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, aryloxy, arylamino, arylthio, arylsulfinyl, arylsulfonyl, haloaryl, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl, formyl, substituted or unsubstituted amido, and substituted or unsubstituted ureido, in which the alkyl, alkenyl and alkynyl portions contain from 1 up to about 14 carbon atoms and are either straight or branched chains or cyclic, and the aryl portions contain from about 4 to about 16 carbons, except that R² is not halide or pseudohalide;

or,

(ii) R¹ and R² together form —

(CH₂)_n—

, where n is 3 to 6;

or,

(iii) R¹ and R² together form 1,3-butadienyl (—

CH═

CH—

CH═

CH—

);

Y¹ and Y² are each independently carbon or nitrogen;

a and b are each independently 0 or 1;

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from (i) or (ii) as follows;

(i) R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from among H, NHR³⁸, CONR³⁸R³⁹, NO₂, cyano, halide, pseudohalide, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, alkoxy, alkylamino, alkylthio, haloalkyl, alkylsulfinyl, alkylsulfonyl, alkoxycarbonyl, alkylcarbonyl, alkenylthio, alkenylamino, alkenyloxy, alkenylsulfinyl, alkenylsulfonyl, arylaminocarbonyl, alkylaminocarbonyl, aminocarbonyl, (alkyl-aminocarbonyl)alkyl, acetoxy, hydroxyl, carboxyl, carboxyalkyl, carboxyalkenyl, alkylsulfonylaminoalkyl, cyanoalkyl, acetyl, acetoxyalkyl, hydroxyalkyl, alkoxyalkoxy, (acetoxy)alkoxy, (hydroxy)alkoxy, formyl, sulfonyl chlorides, amino acids, hexoses, O-glycosides, riboses, —

(CH₂)_xC(O)(CH₂)_yCH₃, —

(CH₂)_xCH₃, (CH₂)_xNH-lower alkyl, —

(CH₂)_{1 to 14}C(O)NH₂, a primary or secondary amide, —

(CH₂)_xCOOH, —

(CH₂)_xCH(COOH)(CH₂)_yCH₃, C(O)(CH₂)_xS(O)₂(CH₂)_yCH₃, C(═

N—

OR³⁸)(CH₂)_yCH₃, —

C(O)C(O)(CH₂)_yCH₃, —

(CH₂)_xN(CH₃)₂, S(O)₂NHR⁵⁰, OS(O)₂NR³⁸R³⁹, alkylaryl, alkylheteroaryl, —

C(O)NH-heteroaryl and —

C(O)N(H)N(H)R⁵⁰;

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;

R⁵⁰ is a substituent such as hydrogen, lower alkyl, lower alkoxy or heteroaryl;

or

(ii) at least two of R⁵, R⁶, R⁷, R⁸ and R⁹, which substitute adjacent carbons on the ring, together form alkylenedioxy, alkylenethioxyoxy or alkylenedithioxy which is unsubstituted or substituted by replacing one or more hydrogens with halide, lower alkyl, lower alkoxy or halo lower alkyl, and the others of R⁵, R⁶, R⁷, R⁸ and R⁹ are selected as in (i).

20. The compound of claim 19, 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, alkylsultonyl, (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;

a is 1; and

b is 1.

21. The compound of claim 20, 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.

22. The compound of claim 19 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.

67. A pharmaceutical composition, comprising an effective amount of a compound of claim 19 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.

68. The composition of claim 67 that is formulated for single or multiple dosage administration.

69. An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable derivative thereof of claim 19 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 μ

M, 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.

70. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount of a compound of claim 19, or a pharmaceutically acceptable derivative thereof, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

71. The method of claim 70, 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, endotoxic 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, 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.

72. The method of claim 71, wherein the disease is selected from the group consisting of asthma and inflammatory diseases.

73. The method of claim 71, wherein the disease is glaucoma.

74. A method for inhibiting the binding of an endothelin peptide to an endothelin_A (ET_A) or endothelin_B (ET_B) receptor, comprising contacting the receptor with a compound of claim 19, or a pharmaceutically acceptable derivative thereof, wherein:

the contacting is effected prior to, simultaneously with or subsequent to contacting the receptor with the endothelin peptide.

75. A method for altering endothelin receptor-mediated activity, comprising contacting an endothelin receptor with a compound of claim 19, or a pharmaceutially acceptable derivative thereof.

76. The pharmaceutical composition of claim 67, wherein the pharmaceutically acceptable carrier comprises a sodium phosphate buffer solution containing a sugar.

77. The pharmaceutical formulation of claim 76, wherein the compound is a pharmaceutically-acceptable alkali metal salt.

78. A lyophilized powder, comprising a salt of the compound of claim 19.

79. The lyophilized powder of claim 78 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.

80. The powder of claim 79, wherein the sugar or carobohydrate contains dextrose.

81. An article of manufacture, comprising packaging material and the powder of claim 78, 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 μ

M, 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.

82. A combination comprising:

a sterile vial containing the pharmaceutical formulation of claim 78.

83. The combination of claim 82, wherein the sterile vial contains an amount of the powder that is for single dose administration.

84. The combination of claim 82, 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.

85. The pharmaceutical composition of claim 67 that is formulated as a tablet or capsule.

86. The composition of claim 85, further comprising an enteric coating.

87. The composition of claim 86, 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.