Sulfonamides and derivatives thereof that modulate the activity of endothelin

• US 20030208084A1
• Filed: 05/28/2003
• Published: 11/06/2003
• Est. Priority Date: 09/27/1996
• Status: Abandoned Application

• Current Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Original Assignee: Encysive Pharmaceuticals Incorporated (Pfizer Inc.)
• Inventors: Wu, Chengde, Kogan, Timothy, Blok, Natalie, Raju, Bore Gowda, Woodard, Patricia
• Application Number:
  US10/447,763
• Publication Number:
  US 20030208084A1
• Time in Patent Office: Days
• US Class Current: 548/534
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• 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 27/02 Ophthalmic agents
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• 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 409/12 linked by a chain containing hetero atoms as chain links
• 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
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Thienyl-, furyl- and pyrrolyl-sulfonamides, formulations of pharmaceutically-acceptable salts 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 and N-(isoxazolyl)pyrrolylsulfonamides, 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 prodrugs thereof that inhibit the activity of endothelin are also provided.

Claims

1. A sulfonamide compound of formula (A):

2. A compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein M is

3. A compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein M is C(O)CH₂, C(O)NH, —

CH═

CH—

, CH₂CH₂C(O)(CH)₂ or CH₂CHC(O)CH₂.

4. A compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein M is selected from among:

5. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1 that has formula (I):

6. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein the compounds of formula (A) are of formula (II):

7. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 6, wherein R⁷, R⁸ and R¹⁰ are alkyl, haloalkyl, polyhaloalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl.

8. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 7, wherein R⁷, R⁸ and R¹⁰ are lower alkyl, lower alkenyl, lower alkynyl, or aryl.

9. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 8, wherein R⁷, R⁸ and R¹⁰ are methyl.

10. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 6, wherein R⁷, R⁸, R⁹ and R¹⁰ do not contain cyano groups, and W is not —

CH₂—

.

11. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 6, wherein:

W is —

NH—

, ═

NCO₂R¹⁶, or is —

CH₂—

when R⁹ is hydroxyl;

R⁷, R⁸ and R¹⁰ are methyl; and

R⁹ is selected from the group consisting of Z-substituted and unsubstituted alkyl, hydroxyl, substituted and unsubstituted alkoxy, OC(O)R¹⁶, OCO₂R¹⁶, NR¹²R¹⁶ and S(O)_nR¹⁶ in which n is 0-2.

12. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 11, wherein R⁹ is selected from the group consisting of methoxy, methoxycarbonylmethoxy, 2-(2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxy, hydroxy, cyanomethyl, acetoxymethyl, hydroxymethyl, carboxylmethyl, methanesulfonylamino, N,N-dimethylaminomethyl, SO₂NH₂, and methoxycarbonylmethyl.

13. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 11, wherein R⁹ does not contain a cyano group.

14. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 11, wherein R⁹ is selected from the group consisting of methoxy, methoxycarbonylmethoxy, 2-(2-methoxyethoxy)ethoxyacetoxy, 2-hydroxyethoxy, N,N-dimethylthiocarbonyloxy, N,N-dimethylthiocarbonyloxymethyl, dimethylamino, pyrrolidinyl, acetoxymethyl, methoxycarbonylmethyl, hydroxy and acetoxy.

15. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1 that is a thiophene-3-sulfonamide.

16. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 6 that is a thiophene-3-sulfonamide.

17. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1 that has formula III:

18. The sulfonamides of claim 17, wherein Ar¹ is a phenyl group.

19. The sulfonamides of claim 17, wherein:

R, G and R′

are selected where the amino acid is L-Asp or L-Glu;

the hexose is D-mannose, the heteroaryl is triazolyl, and X is S.

20. The sulfonamides of claim 17, wherein:

W is ═

CH₂, ═

NH, ═

NCH₃, ═

NCH₂CH₃, ═

C(CH₃)₂ or CF₂; and

G is —

CH₃, —

CN, —

COCH₃, —

CH₂CH₃, —

(CH₂)_xCO₂H.

21. The sulfonamides of claim 18, wherein:

W is ═

CH₂, ═

NH, ═

NCH₃, ═

NCH₂CH₃, ═

C(CH₃)₂ or CF₂; and

G is —

CH₃, —

CN, —

COCH₃, —

CH₂CH₃, —

(CH₂)_xCO₂H.

22. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 17 that is a thiophene-3-sulfonamide.

23. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein the compounds of formula (A) are of formula (IV):

24. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 23, wherein:

R⁶ is H, or substituted or unsubstituted alkyl.

25. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 23, wherein R⁶ is methyl or carboxymethyl.

26. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 23 that is a thiophene-3-sulfonamide.

27. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein the compounds of formula (A) are of formula (V):

28. A sulfonamide compound or pharmaceutically acceptable salt, acid or ester thereof of claim 27 that is a thiophene-3-sulfonamide.

29. The compounds of claim 1 that are pharmaceutically acceptable sodium salts.

30. A pharmaceutical composition, comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, acid or ester thereof in a pharmaceutically acceptable carrier, wherein the amount is effective for ameliorating the symptoms of an endothelin-mediated disease.

31. The composition of claim 30 that is formulated for single or multiple dosage administration.

32. An article of manufacture, comprising packaging material and a compound or a pharmaceutically acceptable salt, acid or ester 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 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.

33. A method for the treatment of endothelin-mediated diseases, comprising administering to a subject an effective amount the pharmaceutical composition of claim 1, wherein the effective amount is sufficient to ameliorate one or more of the symptoms of the disease.

34. The method of claim 33, wherein the disease is selected from the group consisting of hypertension, cardiovascular disease, asthma, pulmonary hypertension, inflammatory diseases, ophthalmologic disease, menstrual disorders, obstetric conditions, wounds, gastroenteric disease, renal failure, immunosuppressant-mediated renal vasoconstriction, erythropoietin-mediated vasoconstriction endotoxin shock, pulmonary hypertension, anaphylactic shock and hemorrhagic shock.

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

36. A method for inhibiting the binding of an endothelin peptide to endothelin_A (ET_A) or endothelin_B (ET_B) receptors, comprising contacting the receptors an endothelin peptide and with a compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein:

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

37. A method for altering endothelin receptor-mediated activity, comprising contacting endothelin receptors with a compound or pharmaceutically acceptable salt, acid or ester thereof of claim 1.

38. The pharmaceutical composition of claim 30, that comprises a sodium phosphate buffer solution containing a sugar and the compound, or a pharmaceutically acceptable salt, acid or ester thereof, dissolved therein.

39. The pharmaceutical formulation of claim 38, wherein the sulfonamide is a pharmaceutically-acceptable salt that is an alkali metal.

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

41. The lyophilized powder of claim 40 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.

42. The powder of claim 41, wherein the sugar or carbohydrate is dextrose.

43. An article of manufacture, comprising packaging material and a the powder of claim 40, 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.

44. The combination comprising:

a sterile vial containing the pharmaceutical formulation of claim 40.

45. The combination of claim 44, wherein the sterile vial contains an amount of the powder that is for single dose administration.

46. The combination of claim 44, 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.

47. The pharmaceutical composition of claim 30 that is formulated as a tablet or capsule.

48. A composition of claim 47, further comprising an enteric coating.

49. The composition of claim 47, 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.

50. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein Ar¹ is phenyl.

51. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 6, wherein Ar¹ is phenyl.

52. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 1, wherein M is (CH₂)_mC(O)(CH₂)_r, (CH₂)_mC(O)NH(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, (CH₂)_mC(O)(CH₂)_sNH(CH₂)_r, (CH₂)_m(CH═

CH)(CH₂)_r, C═

N(OH)(CH₂)_r, CH(OH)(CH₂)_r, (CH₂)_r, (CH₂)_rO, (CH₂)S(O)_n, C(O)O.

53. A sulfonamide or pharmaceutically acceptable salt, acid or ester thereof of claim 27, wherein:

W is —

NH—

; and

R²⁰ is CONH², COOH, or phenyl.