Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders

• US 7,160,920 B2
• Filed: 05/05/2003
• Issued: 01/09/2007
• Est. Priority Date: 03/22/1996
• Status: Expired due to Fees

• Current Assignee: Arbor Pharmaceuticals LLC
• Original Assignee: Nitromed, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Letts, L. Gordon, Renfroe, H. Burt, Garvey, David S., Richardson, Stewart K.
• Primary Examiner(s): Badio; Barbara P.
• Application Number:
  US10/428,936
• Publication Number:
  US 20030199529A1
• Time in Patent Office: 1,345 Days
• Field of Search: 514/506, 514/509, 558/483, 558/488, 546/273.1, 546/334
• US Class Current: 514/506
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: C07C 313/36 having nitrogen atoms of sulfenamide groups further bound to other hetero atoms
• CPC Class Codes: C07D 311/22 with oxygen or sulfur atoms directly attached in position 4
• CPC Class Codes: C07D 451/06 Oxygen atoms
• CPC Class Codes: C07D 451/10 acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07J 31/00 Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
• CPC Class Codes: C07J 5/00 Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
• CPC Class Codes: C07J 7/00 Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of two carbon atoms C07J5/00 takes precedence
• CPC Class Codes: C07J 71/00 Steroids in which the cyclopenta(a)hydrophenanthrene skeleton is condensed with a heterocyclic ring spiro-condensed heterocyclic rings C07J21/00, C07J33/00, C07J43/00
• CPC Class Codes: C07J 71/0031 at positions 16, 17

Abstract

Disclosed are (i) compounds of a steroid, a β-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO₂ group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, β-agonists, anticholinergics, mast cell stabilizers and PDE inhibitors, which can optionally be substituted with at least one NO or NO₂ moiety or a group which stimulates endogenous production of NO or EDRF in vivo, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO⁺) or nitroxyl (NO⁻), or as the neutral species, nitric oxide (NO.) or that stimulates endogenous production of NO or EDRF in vivo; and (iii) uses for them in preventing and/or treating respiratory disorders.

Claims

1. A β

-agonist compound of Formula (II);

2. The compound of claim 1, wherein the compound of Formula (II) is a nitrosated salmeterol, a nitrosylated salmeterol, a nitrosated and nitrosylated salmeterol, a nitrosated albuterol, a nitrosylated albuterol, a nitrosated and nitrosylated albuterol, a nitrosated metaproternol, a nitrosylated metaproternol, a nitrosated and nitrosylated metaproternol, a nitrosated terbutalin, a nitrosylated terbutalin, a nitrosated and nitrosylated terbutaline, a nitrosated pirbuterol, a nitrosylated pirbuterol, a nitrosated and nitrosylated pirbuterol, a nitrosated rimiterol, a nitrosylated rimiterol, a nitrosated and nitrosylated rimiterol, a nitrosated clenbuterol, a nitrosylated clenbuterol, a nitrosated and nitrosylated clenbuterol, a nitrosated bitolterol, a nitrosylated bitolterol, a nitrosated and nitrosylated bitolterol, a nitrosated reproterol, a nitrosylated reproterol or a nitrosated and nitrosylated reproterol.

3. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

4. The composition of claim 3, wherein the composition is in a form that can be administered by oral inhalation, nasal inhalation or intranasal mucosal administration.

5. The composition of claim 3, wherein the composition is in a form that can be administered orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously or subcutaneously.

6. The composition of claim 3, wherein the composition is in form that can be administered as an aerosol.

7. A method for treating asthma in an individual comprising administering a therapeutically effective amount of the composition of claim 3.

8. A method for treating a respiratory disorder in an individual comprising administering a therapeutically effective amount of the composition of claim 3.

9. The method of claim 8, wherein the respiratory disorder is acute pulmonary vasoconstriction, pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, asthma, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthmaticus, hypoxia, chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension or chronic hypoxia.

10. A method of treating cystic fibrosis in an individual comprising administering a therapeutically effective amount of the composition of claim 3.

11. The method of claim 7, 8 or 10, comprising administering a therapeutically effective amount of the composition by oral inhalation, by nasal inhalation, or by intranasal mucosal administration.

12. The method of claim 7, 8 or 10, comprising administering a therapeutically effective amount of the composition as an aerosol.

13. The method of claim 7, 8 or 10, comprising administering a therapeutically effective amount of the composition orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously, or subcutaneously.

14. A kit comprising the composition of claim 3.

15. A composition comprising a compound of Formula (II) and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase,

wherein the compound of Formula (II) is:

16. The composition of claim 15 further comprising a pharmaceutically acceptable carrier or excipient.

17. The composition of claim 15, wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is an S-nitrosothiol.

18. The composition of claim 17, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine, or S-nitroso-glutathione.

19. The composition of claim 17, wherein the S-nitrosothiol is

(i) CH₃(C(R_e)(R_f))_xSNO;

(ii) HS(C(R_e)(R_f))_xSNO;

(iii) ONS(C(R_e)(R_f))_xB;

or

(iv) H₂N—

CH(CO₂H)—

(CH₂)_x—

C(O)NH—

CH(CH₂SNO)—

C(O)NH—

CH₂—

CO₂H;

wherein x is 2 to 20;

R_e and R_f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R_e and R_f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; and

B is fluoro, C_1-6 alkoxy, cyano, carboxamido, cycloalkyl, arylalkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, carboxyl, hydrogen, nitro or aryl.

20. The composition of claim 15, wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is L-arginine.

21. The composition of claim 15, wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is:

(i) a compound comprising at least one ON—

N—

or ON—

O—

group;

(ii) a compound comprising at least one O₂N—

O—

,O₂N—

N—

or O₂N—

S—

group;

(iii) a compound of the structure (R)_u-A-M-(NO)_v, wherein R is a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aromatic or aliphatic hydrocarbon, or a heterocyclic group;

u and v are each independently an integer of 1, 2 or 3;

A is sulfur, oxygen or nitrogen, and M is a metal;

or

(iv) a compound of the structure R₆₁R₆₂N—

N(O—

M⁺)—

NO, wherein R₆₁ and R₆₂ are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aromatic or aliphatic hydrocarbon, or a heterocyclic group; and

M⁺ is a metal cation.

22. The composition of claim 21, wherein the compound comprising at least one ON—

N—

or ON—

O—

group is an ON—

N-polypeptide, an ON—

O-polypeptide, an ON—

N-amino acid, an ON—

O-amino acid, an ON—

N-sugar, an ON—

O-sugar, an ON—

N-oligonucleotide, an ON—

O-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted ON—

N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted ON—

O-hydrocarbon, an ON—

N-heterocyclic compound or an ON—

O-heterocyclic compound.

23. The composition of claim 21, wherein the compound comprising at least one O₂N—

O—

,O₂N—

N—

or O₂N—

S—

group is an O₂N—

O—

polypeptide, an O₂N—

N—

polypeptide, an O₂N—

S—

polypeptide, an O₂N—

O—

amino acid, an O₂N—

N—

amino acid, an O₂N—

S—

amino acid, an O₂N—

O—

sugar, an O₂N—

N—

sugar, an O₂N—

S—

sugar, an O₂N—

O-oligonucleotide, an O₂N—

N—

oligonucleotide, an O₂N—

S—

oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

O—

hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

S—

hydrocarbon, an O₂N—

O—

heterocyclic compound, an O₂N—

N—

heterocyclic compound or an O₂N—

S—

heterocyclic compound.

24. The composition of claim 15, wherein the composition is in a form that can be administered by oral inhalation, nasal inhalation or intranasal mucosal administration.

25. The composition of claim 15, wherein the composition is in a form that can be administered as an aerosol.

26. The composition of claim 15, wherein the composition is in a form that can be administered orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously or subcutaneously.

27. A method for treating asthma in an individual comprising administering a therapeutically effective amount of the composition of claim 15.

28. A method for treating a respiratory disorder in an individual comprising administering a therapeutically effective amount of the composition of claim 15.

29. The method of claim 28, wherein the respiratory disorder is acute pulmonary vasoconstriction, pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, asthma, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthmaticus, hypoxia, chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension or chronic hypoxia.

30. A method of treating cystic fibrosis in an individual comprising administering a therapeutically effective amount of the composition of claim 15.

31. The method of claim 27, 28 or 30, comprising administering a therapeutically effective amount of the composition by oral inhalation, by nasal inhalation, or by intranasal mucosal administration.

32. The method of claim 27, 28 or 30, comprising administering a therapeutically effective amount of the composition as an aerosol.

33. The method of claim 27, 28 or 30, comprising administering a therapeutically effective amount of the composition orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously, or subcutaneously.

57. The composition of claim 23, wherein the compound comprising at least one O₂N—

O—

, O₂N—

N—

or O₂N—

S—

group is isosorbide dinitrate and isosorbide mononitrate.

34. A kit comprising a compound of Formula (II) and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase,

wherein the compound of Formula (II) is:

35. The kit of claim 34, wherein the compound of Formula (II) and the a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are separate components in the kit or are in the form of a composition in the kit.

36. A composition comprising a therapeutically effective amount of a β

-agonist and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase, wherein the β

-agonist is salmeterol, albuterol, metaproternol, terbutaline, pirbuterol, rimiterol, bitolterol or reproterol.

37. The composition of claim 36, further comprising a pharmaceutically acceptable carrier or excipient.

38. The composition of claim 36, wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is an S-nitrosothiol.

39. The composition of claim 38, wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine, or S-nitroso-glutathione.

40. The composition of claim 38, wherein the S-nitrosothiol is

(i) CH₃(C(R_e)(R_f))_xSNO;

(ii) HS(C(R_e)(R_f))_xSNO;

(iii) ONS(C(R_e)(R_f))_xB;

or

(iv) H₂N—

CH(CO₂H)—

(CH₂)_x—

C(O)NH—

CH(CH₂SNO)—

C(O)NH—

CH₂—

CO₂H;

wherein x is 2 to 20;

R_e and R_f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R_e and R_f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; and

B is fluoro, C_1-6 alkoxy, cyano, carboxamido, cycloalkyl, arylalkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, carboxyl, hydrogen, nitro or aryl.

41. The composition of claim 36, wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is L-arginine.

42. The composition of claim 36, wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase:

(i) a compound comprising at least one ON—

N—

or ON—

O—

group;

(ii) a compound comprising at least one O₂N—

O—

,O₂N—

N—

or O₂N—

S—

group;

(iii) a compound of the structure (R)_u-A-M-(NO)_v, wherein R is a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aromatic or aliphatic hydrocarbon, or a heterocyclic group;

u and v are each independently an integer of 1, 2 or 3;

A is sulfur, oxygen or nitrogen, and M is a metal;

or

(iv) a compound of the structure R₆₁R₆₂N—

N(O-M⁺)—

NO, wherein R₆₁ and R₆₂ are each independently a polypeptide, an amino acid, a sugar, an oligonucleotide, a straight or branched, saturated or unsaturated, aromatic or aliphatic hydrocarbon, or a heterocyclic group; and

M⁺is a metal cation.

43. The composition of claim 42, wherein the compound comprising at least one ON—

N—

or ON—

O—

group is an ON—

N-polypeptide, an ON—

O-polypeptide, an ON—

N-amino acid, an ON—

O-amino acid, an ON—

N-sugar, an ON—

O-sugar, an ON—

N-oligonucleotide, an ON—

O-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted ON—

N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted ON—

O-hydrocarbon, an ON—

N-heterocyclic compound or an ON—

O-heterocyclic compound.

44. The composition of claim 42, wherein the compound comprising at least one O₂N—

O—

,O₂N—

N—

or O₂N—

S—

group is an O₂N—

O—

polypeptide, an O₂N—

N-polypeptide, an O₂N-Sp polypeptide, an O₂N—

O—

amino acid, an O₂N—

N—

amino acid, an O₂N—

S—

amino acid, an O₂N—

O—

sugar, an O₂N—

N—

sugar, an O₂N—

S—

sugar, an O₂N—

O-oligonucleotide an O₂N—

N-oligonucleotide, an O₂N—

S-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

O—

hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

N—

hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O₂N—

S-hydrocarbon, an O₂N—

O—

heterocyclic compound, an O₂N—

N-heterocyclic compound or an O₂N—

S—

heterocyclic compound.

45. The composition of claim 36 wherein the composition is in a form that can be administered by oral inhalation, nasal inhalation or intranasal mucosal administration.

46. The composition of claim 36, wherein the composition is in a form that can be administered as an aerosol.

47. The composition of claim 36, wherein the composition is in a form that can be administered orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously or subcutaneously.

48. A method for treating asthma in an individual comprising administering a therapeutically effective amount of the composition of claim 36.

49. A method for treating a respiratory disorder in an individual comprising administering a therapeutically effective amount of the composition of claim 36.

50. The method of claim 49, wherein the respiratory disorder is acute pulmonary vasoconstriction, pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, asthma, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthmaticus, hypoxia, chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension or chronic hypoxia.

51. A method of treating cystic fibrosis in an individual comprising administering a therapeutically effective amount of the composition of claim 36.

52. The method of claim 48, 49 or 51, comprising administering a therapeutically effective amount of the composition by oral inhalation, by nasal inhalation, or by intranasal mucosal administration.

53. The method of claim 48, 49 or 51, comprising administering a therapeutically effective amount of the composition as an aerosol.

54. The method of claim 48, 49 or 51, comprising administering a therapeutically effective amount of the composition orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously, or subcutaneously.

58. The composition of claim 44, wherein the compound comprising at least one O₂N—

O—

, O₂N—

N—

or O₂N—

S—

group is isosorbide dinitrate and isosorbide mononitrate.

55. A kit comprising a β

-agonist and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxidesynthase.

56. The kit of claim 55, wherein the compound of β

-agonist and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are separate components in the kit or are in the form of a composition in the kit.