S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof

• US 5,574,068 A
• Filed: 11/14/1994
• Issued: 11/12/1996
• Est. Priority Date: 03/29/1991
• Status: Expired due to Term

• Current Assignee: Brigham and Women's Hospital Incorporated
• Original Assignee: Brigham and Women's Hospital Incorporated
• Inventors: Loscalzo, Joeseph, Stamler, Jonathan, Simon, Daniel, Brown, Robert, Slivka, Adam, Drazen, Jeffrey
• Primary Examiner(s): Lilling, Herbert J.
• Application Number:
  US08/338,893
• Time in Patent Office: 729 Days
• Field of Search: 514/562
• US Class Current: 514/562
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: C07C 381/00 Compounds containing carbon and sulfur and having functional groups not covered by groups C07C301/00 - C07C337/00
• CPC Class Codes: C07K 5/0215 containing natural amino acids, forming a peptide bond via their side chain functional group, e.g. epsilon-Lys, gamma-Glu

Abstract

S-nitrosothiols exert a potent relaxant effect, mediated both by guanylate cyclase, and a cGMP-independent mechanism, upon non-vascular smooth muscle. Such types of smooth muscle include airway, gastrointestinal, bladder, uterine and corpus cavernosal. Thus, S-nitrosothiols may be used for the treatment or prevention of disorders associated with relation of smooth muscle, such as airway obstruction, and other respiratory disorders, bladder dysfunction, premature labor and impotence. Additionally, S-nitrosothiols may be used to alleviate smooth muscle contraction and spasm, and thus facilitate procedures involving diagnostic instrumentation, such as endoscopy, bronchoscopy, laparoscopy and cystoscopy. S-nitrosothiols also increase the binding affinity between hemoglobin and oxygen, and therefore, may be used to improve hemoglobin-oxygen binding, and oxygen transport to bodily tissues.

Claims

1. A method of treating an individual to relax non-vascular smooth muscle which comprises treating an individual with S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to relax non-vascular smooth muscle by administering a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to their site of action in said individual.

2. The method of claim 1 wherein delivering nitric oxide comprises delivering a S-nitrosothiol compound having the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.

12. The method of claim 1 wherein the S-nitrosothiol delivers a negatively charged species.

13. The method of claim 12 wherein the negatively charged species is nitroxyl.

41. The method of claim 1 wherein said compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.

45. The method of claim 1 wherein the S-nitrosothiol delivers a positively charged species.

47. The method of claim 45 wherein the positively charged species is nitrosonium.

50. The method of claim 1 wherein treating the individual with a charged form of nitric oxide to relax non-vascular smooth-muscle comprises alleviating contraction or spasm of non-vascular smooth muscle associated with medical instrumentation procedures by administering to an individual in need thereof a contraction or spasm alleviating amount of a nitrosating agent which transfers substantially exclusively charged nitric oxide species to said non-vascular smooth muscle.

51. The method of claim 50 wherein the nitrosating agent is an S-nitrosothiol.

52. The method of claim 51 wherein the S-nitrosothiol is an S-nitroso-amino acid.

53. The method of claim 51 wherein the S-nitrosothiol is an S-nitroso-protein.

54. The method of claim 51 wherein the S-nitrosothiol is an S-nitroso-peptide.

55. The method of claim 50 wherein the nitrosating agent transfers substantially exclusively nitrosonium ions.

56. The method of claim 50 wherein the nitrosating agent transfers substantially exclusively nitroxyl ions.

57. The method of claim 50 wherein the procedure is selected from the group consisting of bronchoscopy, endoscopy, laparoscopy, cystoscopy, cannulation of the pancreatic duct and biliary tract, gall bladder cannulation, bile duct stone removal, stint replacement and cholecystectomy.

58. The method of claim 57 wherein the laparoscopy is a laparoscopic examination of the fallopian tubes.

59. The method of claim 57 wherein the laparoscopy is a fertilization procedure.

60. The method of claim 57 wherein the laparoscopy is a laparoscopic cholangiogram.

61. The method of claim 57 wherein the cystoscopy is a visualization of the interior of the urethra and bladder.

62. The method of claim 57 wherein the endoscopy procedure is selected from the group consisting of esophagogastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, colonoscopy and sigmoidoscopy.

3. A method of treating an individual to relax airway smooth muscle which comprises treating an individual with a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to relax airway smooth muscle by administering a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to their site of action in said individual.

4. The method of claim 3 wherein delivering nitric oxide comprises delivering a S-nitrosothiol compound having the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected front the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.

5. The method of claim 3 wherein treating said individual to relax airway smooth muscle comprises threating said individual for a respiratory disorder.

6. The method of claim 5 wherein said S-nitrosothiol compound has the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.

7. The method of claim 5 wherein said compound is administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.

14. The method of claim 3 wherein the S-nitrosothiol delivers a positively charged species.

15. The method of claim 14 wherein the positively charged species is nitrosonium.

16. The method of claim 3 wherein the S-nitrosothiol delivers a negatively charged species.

17. The method of claim 16 wherein the negatively charged species is nitroxyl.

18. The method of claim 5 wherein the S-nitrosothiol delivers a positively charged species.

19. The method of claim 18 wherein the positively charged species is nitrosonium.

20. The method of claim 5 wherein the S-nitrosothiol delivers a negatively charged species.

38. The method of claim 20 wherein the negatively charged species is nitroxyl.

43. The method of claim 3 wherein said compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.

8. A method of treating an individual to relax corpus cavernosum smooth muscle which comprises treating an individual with a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to relax corpus cavernosum smooth muscle by administering a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to their site of action in said individual.

11. The method of claim 8 wherein said compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.

26. The method of claim 8 wherein the S-nitrosothiol delivers a positively charged species.

27. The method of claim 26 wherein the positively charged species is nitrosonium.

28. The method of claim 8 wherein the S-nitrosothiol delivers a negatively charged species.

29. The method of claim 28 wherein the negatively charged species is nitroxyl.

42. The method of claim 8 wherein administering nitric oxide comprises administering a S-nitrosothiol compound having the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.

9. A method of treating an individual to relax bladder smooth muscle which comprises treating an individual with a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to relax bladder smooth muscle by administering an S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to their site of action in said individual.

30. The method of claim 9 wherein the S-nitrosothiol delivers a positively charged species.

31. The method of claim 30 wherein the positively charged species is nitrosonium.

32. The method of claim 9 wherein the S-nitrosothiol delivers a negatively charged species.

33. The method of claim 32 wherein the negatively charged species is nitroxyl.

44. The method of claim 9 wherein administering nitric oxide comprises administering a S-nitrosothiol compound having the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.

48. The method of claim 9 wherein said compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.

10. A method of treating an individual to relax uterine smooth muscle which comprises treating an individual with a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to relax uterine smooth muscle by administering a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to their site of action in said individual.

34. The method of claim 10 wherein the S-nitrosothiol delivers a positively charged species.

35. The method of claim 34 wherein the positively charged species is nitrosonium.

36. The method of claim 10 wherein the S-nitrosothiol delivers a negatively charged species.

37. The method of claim 36 wherein the negatively charged species is nitroxyl.

46. The method of claim 10 wherein administering nitric oxide comprises administering a S-nitrosothiol compound having the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.

49. The method of claim 10 wherein said compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.

21. A method of treating an individual to relax gastrointestinal smooth muscle which comprises treating an individual with a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to relax gastrointestinal smooth muscle by administering a S-nitrosothiol which transfers substantially exclusively charged nitric oxide species to their site of action in said individual.

22. The method of claim 21 wherein the S-nitrosothiol delivers a positively charged species.

23. The method of claim 22 wherein the positively charged species is nitrosonium.

24. The method of claim 21 wherein the S-nitrosothiol delivers a negatively charged species.

25. The method of claim 24 wherein the negatively charged species is nitroxyl.

39. The method of claim 21 wherein said compound is administered in a pharmaceutical composition which includes a pharmaceutically acceptable carrier.

40. The method of claim 21 wherein delivering nitric oxide comprises delivering a S-nitrosothiol compound having the formula:

space="preserve" listing-type="equation">ONS(CH.sub.2).sub.x Y

wherein;

X equals 2 to 20;

Y is selected from the group consisting of fluoro, C₁ -C₆ alkoxy, cyano, carboxamido, C₃ -C₆ cycloalkyl, aralkoxy, C₂ -C₆ alkylsulfinyl, arylthio, C₁ -C₆ alkylamino, C₂ -C₁₅ dialkylamino, hydroxy, carbamoyl, C₁ -C₆ N-alkylcarbamoyl, C₂ -C₁₅ N,N-dialkylcarbamoyl, amino, hydroxyl, carboxyl, hydrogen, nitro and aryl;

wherein aryl includes benzyl, naphthyl and anthracenyl groups.