Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders Number:7,160,920 from the United States Patent and Trademark Office (PTO) owispatent Disclosed are (i) compounds of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO.sub.2 group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, .beta.-agonists, anticholinergics, mast cell stabilizers and PDE inhibitors, which can optionally be substituted with at least one NO or NO.sub.2 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.sup.+) or nitroxyl (NO.sup.-), 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.<H compositions, nitrosylated, Nitrosated, and, , 7160920.html, Patent, pto, 7160920

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

Abstract: Disclosed are (i) compounds of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO.sub.2 group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, .beta.-agonists, anticholinergics, mast cell stabilizers and PDE inhibitors, which can optionally be substituted with at least one NO or NO.sub.2 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.sup.+) or nitroxyl (NO.sup.-), 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.

Patent Number: 7,160,920 Issued on 01/09/2007 to Garvey, et al.

Inventors: Garvey; David S. (Waltham, MA), Letts; L. Gordon (Dover, MA), Renfroe; H. Burt (Wellesley, MA), Richardson; Stewart K. (Ashford, CT)
Assignee: NitroMed, Inc. (Lexington, MA)

Appl. No.: 10/428,936

Filed: May 5, 2003

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
09689851	Oct., 2000	6579863
09157242	Sep., 1998	6197762
08620882	Mar., 1996	5824669
PCT/US97/04319	Mar., 1997

Current U.S. Class: 514/506 ; 514/509; 546/273.1; 546/334; 558/483; 558/488

Current International Class: A61K 31/21 (20060101); C07C 203/00 (20060101); C07D 401/00 (20060101)

Field of Search: 514/506,509 558/483,488 546/273.1,334

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Primary Examiner: Badio; Barbara P.
Attorney, Agent or Firm: Wilmer Cutler Pickering Hale and Dorr LLP

Parent Case Text

RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No. 09/689,851, filed Oct. 13, 2000, issued as U.S. Pat. No. 6,579,863, which is a divisional of U.S. application Ser. No. 09/157,242, filed Sep. 18, 1998, issued as U.S. Pat. No. 6,197,762, which is a divisional of U.S. application Ser. No. 08/620,882 filed Mar. 22, 1996, issued as U.S. Pat. No. 5,824,669, and RE 037611; and is a continuation of PCT Application No. PCT/US 97/04319 filed Mar. 19, 1997.

Claims

What is claimed is:

1. A .beta.-agonist compound of Formula (II): ##STR00013## wherein, E is nitrogen or C--R.sub.7; R.sub.7 is hydrogen, halogen, --CH.sub.2O--R.sub.j, or --O--R.sub.j; R.sub.j is hydrogen, D or M; D is (i) hydrogen (ii) --NO (iii) --NO.sub.2 (iv) --CH(R.sub.d)--O--C(O)--Y--(C(R.sub.e)(R.sub.f)).sub.p-T-Q; (v) --C(O)-T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.2-Q; or (vi) --C(O)-T-(C(R.sub.y)(R.sub.z)).sub.p; R.sub.d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl; Y is oxygen, sulfur or NR.sub.i; R.sub.i is hydrogen, lower alkyl, lower haloalkyl or heteroaryl; R.sub.e and R.sub.f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R.sub.e and R.sub.f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; p is an integer from 1 to 6; T, T.sup.1 and T.sup.2 are each independently a covalent bond, oxygen, sulfur or nitrogen; Q is --NO or --NO.sub.2; with the proviso that in "T-Q" and "T.sup.2-Q", T and T.sup.2 cannot be a covalent bond; R.sub.y and R.sub.z are each independently -T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.- 2-Q; G is a covalent bond, -T-C(O)--, --C(O)-T or Y; wherein R.sub.d, R.sub.e, R.sub.f, p, Q, T, T.sup.1, T.sup.2 and Y are as defined herein; M is (i) --C(O)-T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).sub- .p--N(N--(O.sup.-).N.dbd.O)--R.sub.i or (ii) --CH(R.sub.d)--O--C(O)-T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.- f)).sub.p--N(N--(O.sup.-).N .dbd.O)--R.sub.i; wherein T, R.sub.e, R.sub.f, p, G, R.sub.i, and R.sub.d are as defined herein; R.sub.8 and R.sub.9 are each independently amino, hydrogen, --CH.sub.2O--R.sub.j, or --O--R.sub.k; R.sub.k is --C(O)--R.sub.d or R.sub.j; wherein R.sub.d and R.sub.j are as defined herein; S.sub.1 is: (1) --CH.sub.2--N(Z)--R.sub.10; wherein Z is hydrogen, --(N(O.sup.-)N.dbd.O), or M; wherein M is as defined herein; R.sub.10 is: (i) lower alkyl (ii) --(CH.sub.2).sub.p--O--(CH.sub.2).sub.a--C.sub.6H.sub.5; wherein a is an integer from 1 to 4 and p is defined herein; ##STR00014## wherein Z is as defined herein; R.sub.11 is hydrogen, D, or M; with the proviso that R.sub.11 must be D or M if neither R.sub.8 or R.sub.9 include D or M and Z is a hydrogen; and with the proviso that the compounds of Formula (II) must contain at least one --NO group or at least one --NO.sub.2 group, and wherein the at least one --NO group or the at least one --NO.sub.2 group is linked to the compounds of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom.

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: ##STR00015## wherein, E is nitrogen or C--R.sub.7; R.sub.7 is hydrogen, halogen, --CH.sub.2O--R.sub.j, or O--R.sub.j; R.sub.j is hydrogen, D or M; D is (i) hydrogen (ii) --NO (iii) --NO.sub.2 (iv) --CH(R.sub.d)--O--C(O)--Y--(C(R.sub.e)(R.sub.f)).sub.p-T-Q; (v) --C(O)-T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.2-Q; or (vi) --C(O)-T-(C(R.sub.y)(R.sub.z)).sub.p; R.sub.d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl; Y is oxygen, sulfur or NR.sub.i; R.sub.i is hydrogen, lower alkyl, lower haloalkyl or heteroaryl; R.sub.e and R.sub.f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R.sub.e and R.sub.f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; p is an integer from 1 to 6; T, T.sup.1 and T.sup.2 are each independently a covalent bond, oxygen, sulfur or nitrogen; Q is --NO or --NO.sub.2; with the proviso that in "T-Q" and "T.sup.2-Q", T and T.sup.2 cannot be a covalent bond; R.sub.y and R.sub.z are each independently -T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.- 2-Q; G is a covalent bond, -T-C(O)--, --C(O)-T or Y; wherein R.sub.d, R.sub.e, R.sub.f, p, Q, T, T.sup.1, T.sup.2 and Y are as defined herein; M is: (i) --C(O)-T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).su- b.p--N(N--(O.sup.-).N.dbd.O)--R.sub.i or (ii) --CH(R.sub.d)--O--C(O)-T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.- f)).sub.p--N(N--(O.sup.-).N .dbd.O)--R.sub.i; wherein T, R.sub.e, R.sub.f, p, G, R.sub.i, and R.sub.d are as defined herein; R.sub.8 and R.sub.9 are each independently amino, hydrogen, --CH.sub.2O--R.sub.j, or --O--R.sub.k; R.sub.k is --C(O)--R.sub.d or R.sub.j; wherein R.sub.d and R.sub.j are as defined herein; S.sub.1 is: (1) --CH.sub.2--N(Z)--R.sub.10; wherein Z is hydrogen, --(N(O.sup.-)N.dbd.O), or M; wherein M is as defined herein; R.sub.10 is: (i) lower alkyl (ii) --(CH.sub.2).sub.p--O--(CH.sub.2).sub.a--C.sub.6H.sub.5; wherein a is an integer from 1 to 4 and p is defined herein; ##STR00016## wherein Z is as defined herein; R.sub.11 is hydrogen, D, or M; with the proviso that R.sub.11 must be D or M if neither R.sub.8 or R.sub.9 include D or M and Z is a hydrogen; and with the proviso that the compounds of Formula (II) must contain at least one --NO group or at least one --NO.sub.2 group, and wherein the at least one --NO group or the at least one --NO.sub.2 group is linked to the compounds of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom.

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) CH.sub.3(C(R.sub.e)(R.sub.f)).sub.xSNO; (ii) HS(C(R.sub.e)(R.sub.f)).sub.xSNO; (iii) ONS(C(R.sub.e)(R.sub.f)).sub.xB; or (iv) H.sub.2N--CH(CO.sub.2H)--(CH.sub.2).sub.x--C(O)NH--CH(CH.sub.2SNO- )--C(O)NH--CH.sub.2--CO.sub.2H; wherein x is 2 to 20; R.sub.e and R.sub.f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R.sub.e and R.sub.f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; and B is fluoro, C.sub.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 O.sub.2N--O--,O.sub.2N--N-- or O.sub.2N--S-- group; (iii) a compound of the structure (R).sub.u-A-M-(NO).sub.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 R.sub.61R.sub.62N--N(O--M.sup.+)--NO, wherein R.sub.61 and R.sub.62 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.sup.+ 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 O.sub.2N--O--,O.sub.2N--N-- or O.sub.2N--S-- group is an O.sub.2N--O--polypeptide, an O.sub.2N--N--polypeptide, an O.sub.2N--S--polypeptide, an O.sub.2N--O--amino acid, an O.sub.2N--N--amino acid, an O.sub.2N--S--amino acid, an O.sub.2N--O-- sugar, an O.sub.2N--N-- sugar, an O.sub.2N--S-- sugar, an O.sub.2N--O-oligonucleotide, an O.sub.2N--N--oligonucleotide, an O.sub.2N--S--oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O.sub.2N--O--hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O.sub.2N--N-hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O.sub.2N--S--hydrocarbon, an O.sub.2N--O--heterocyclic compound, an O.sub.2N--N--heterocyclic compound or an O.sub.2N--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.

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: ##STR00017## wherein, E is nitrogen or C--R.sub.7; R.sub.7 is hydrogen, halogen, --CH.sub.2O--R.sub.j, or --O--R.sub.j; R.sub.j is hydrogen, D or M; D is (i) hydrogen (ii) --NO (iii) --NO.sub.2 (iv) --CH(R.sub.d)--O--C(O)--Y--(C(R.sub.e)(R.sub.f)).sub.p-T-Q; (v) --C(O)-T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.2-Q; or (vi) --C(O)-T-(C(R.sub.y)(R.sub.z)).sub.p; R.sub.d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl; Y is oxygen, sulfur or NR.sub.i; R.sub.i is hydrogen, lower alkyl, lower haloalkyl or heteroaryl; R.sub.e and R.sub.f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R.sub.e and R.sub.f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; p is an integer from 1 to 6; T, T.sup.1 and T.sup.2 are each independently a covalent bond, oxygen, sulfur or nitrogen; Q is --NO or --NO.sub.2; with the proviso that in "T-Q" and "T.sup.2-Q", T and T.sup.2 cannot be a covalent bond; R.sub.y and R.sub.z are each independently -T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.- 2-Q; G is a covalent bond, -T-C(O)--, --C(O)-T or Y; wherein R.sub.d, R.sub.e, R.sub.f, p, Q, T, T.sup.1, T.sup.2 and Y are as defined herein; M is: (i) --C(O)-T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).su- b.p--N(N--(O.sup.-).N.dbd.O)--R.sub.i or (ii) --CH(R.sub.d)--O--C(O)-T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.- f)).sub.p--N(N--(O.sup.-).N.dbd.O)--R.sub.i; wherein T, R.sub.e, R.sub.f, p, G, R.sub.i, and R.sub.d are as defined herein; R.sub.8 and R.sub.9 are each independently amino, hydrogen, --CH.sub.2O--R.sub.j, or --O--R.sub.k; R.sub.k is --C(O)--R.sub.d or R.sub.j; wherein R.sub.d and R.sub.j are as defined herein; S.sub.1 is: (1) --CH.sub.2--N(Z)--R.sub.10; wherein Z is hydrogen, --(N(O.sup.-)N.dbd.O), or M; wherein M is as defined herein; R.sub.10 is: (i) lower alkyl (ii) --(CH.sub.2).sub.p--O--(CH.sub.2).sub.a--C.sub.6H.sub.5; wherein a is an integer from 1 to 4 and p is as defined herein; ##STR00018## wherein Z is as defined herein; R.sub.11 is hydrogen, D, or M; with the proviso that R.sub.11 must be D or M if neither R.sub.8 or R.sub.9 include D or M and Z is a hydrogen; and with the proviso that the compounds of Formula (II) must contain at least one --NO group or at least one --NO.sub.2 group, and wherein the at least one --NO group or the at least one --NO.sub.2 group is linked to the compounds of Formula (II) through an oxygen atom, a nitrogen atom or a sulfur atom.

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 .beta.-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 .beta.-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) CH.sub.3(C(R.sub.e)(R.sub.f)).sub.xSNO; (ii) HS(C(R.sub.e)(R.sub.f)).sub.xSNO; (iii) ONS(C(R.sub.e)(R.sub.f)).sub.xB; or (iv) H.sub.2N--CH(CO.sub.2H)--(CH.sub.2).sub.x--C(O)NH--CH(CH.sub.2SNO- )--C(O)NH--CH.sub.2--CO.sub.2H; wherein x is 2 to 20; R.sub.e and R.sub.f are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R.sub.e and R.sub.f taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; and B is fluoro, C.sub.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 O.sub.2N--O--,O.sub.2N--N-- or O.sub.2N--S-- group; (iii) a compound of the structure (R).sub.u-A-M-(NO).sub.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 R.sub.61R.sub.62N--N(O-M.sup.+)--NO, wherein R.sub.61 and R.sub.62 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.sup.+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 O.sub.2N--O--,O.sub.2N--N-- or O.sub.2N--S-- group is an O.sub.2N--O--polypeptide, an O.sub.2N--N-polypeptide, an O.sub.2N-Sp polypeptide, an O.sub.2N--O--amino acid, an O.sub.2N--N--amino acid, an O.sub.2N--S--amino acid, an O.sub.2N--O-- sugar, an O.sub.2N--N-- sugar, an O.sub.2N--S-- sugar, an O.sub.2N--O-oligonucleotide an O.sub.2N--N-oligonucleotide, an O.sub.2N--S-oligonucleotide, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O.sub.2N--O--hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O.sub.2N--N--hydrocarbon, a straight or branched, saturated or unsaturated, aliphatic or aromatic, substituted or unsubstituted O.sub.2N--S-hydrocarbon, an O.sub.2N--O--heterocyclic compound, an O.sub.2N--N-heterocyclic compound or an O.sub.2N--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.

55. A kit comprising a .beta.-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 .beta.-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.

57. The composition of claim 23, wherein the compound comprising at least one O.sub.2N--O--, O.sub.2N--N-- or O.sub.2N--S-- group is isosorbide dinitrate and isosorbide mononitrate.

58. The composition of claim 44, wherein the compound comprising at least one O.sub.2N--O--, O.sub.2N--N-- or O.sub.2N--S-- group is isosorbide dinitrate and isosorbide mononitrate.

Description

BACKGROUND OF THE INVENTION

The present invention relates to the field of compounds, compositions and uses therefore, in oral and/or nasal administration prophylaxis and/or treatment of respiratory disorders. More particularly the invention relates to nitrosated and nitrosylated compounds, compositions comprising such compounds, which can optionally be unsubstituted or substituted with at least one NO or NO.sub.2 moiety, 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.); and uses for each of them.

A broad spectrum of respiratory diseases and disorders have been recognized, many of which have overlapping and interacting etiologies. One of the most widespread and prevalent of these diseases in western populations is the chronic disease referred to as "asthma". Other such disorders are also characterized by acute pulmonary vasoconstriction such as may result from 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, post-cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, herapin-protamine reactions, sepsis, status asthmaticus or hypoxia (including iatrogenic hypoxia) and other forms of reversible pulmonary vasoconstriction. Such pulmonary disorders also are also characterized by inflammation of the lung including those associated with the migration into the lung of nonresident cell types including the various leucocyte subclasses. Also included in the respiratory disorders contemplated are cystic fibrosis and other diseases which are characterized by excess mucosal secretion. Other physiological events which are contemplated to be controlled include platelet activation in the lung.

Asthma is a major and disabling obstructive respiratory disease associated with significant morbidity and mortality. The term "asthma" has been used to describe a condition which is characterized by widespread fluctuations in the diameter or caliber of bronchial airways over short periods of time resulting in changes in lung function. The resulting increased resistance to air flow produces symptoms including breathlessness (dyspnea), chest constriction or "tightness" and wheeze. The term as used is not currently limited to a disorder or disease resulting from any specific cause or causes, rather it is characterized by its clinical manifestation. A true immunological mechanism may or may not be a factor in the etiology of an individual asthmatic condition. Further, characteristic wheezing may not be present in particularly severe attacks where transport of air is completely obstructed. Regardless of the cause, asthma in all sufferers is characterized by reversible hyperresponsiveness of tracheal bronchial smooth muscle resulting in its contraction and interference with normal respiration. The lungs of patients who die of asthma are usually pale pink, hyperinflated, and fail to collapse after their removal from the chest. Many of the airways throughout the bronchial tree are occluded by thick mucus plugs which are infiltrated with various types of leukocytes, including mast cells. The smooth muscle of the airways is hypertrophied. The bronchoconstriction or bronchospasm characterized by asthmatic attacks causes obstruction to air flow which necessitates a forced exhalation and maintenance of artificially elevated functional air reserve capacity to keep the airways open. The resultant lung hyperinflation places a significant stress on the cardiovascular system (particularly the right ventricle) which can lead to a consequent cardiovascular event. One possible result is a progressive decrease in cardiac output referred to as "cardiopulmonary tamponade". Most deaths resulting from asthma are caused by a condition referred to as "status asthmaticus," which is essentially an intensely severe and bronchospasm that is unresponsive to treatment.

Various categories of drugs are known to be useful in the inhalation of treatment of asthma. These include .beta..sub.2 agonists (such as salmeterol, albuterol, metaproternol, terbutaline, pirbuterol, rimiterol, clenbuterol, bitolterol and repreterol, adrenalin, isoproterenol, ephedrine, orciprenlaine, fenoterol and isoetharine); anticholinergic agents (such as atropine, ipratropium, flutropium, tiotropium and rispenzepine) and mast cell stabilizers (chromolyn and nedocromil). Selective .beta. agonists have recently been developed with fewer cardiotonic side effects than those previously employed and are now considered suitable therapeutics for management of bronchitis and, particularly, emphysema, for which there previously had not been a suitable effective form of therapy.

Although corticosteroids are not generally indicated for routine use in the treatment of asthma, whether acute or chronic, they are used in large doses in the treatment of status asthmaticus. Nonetheless, the use of inhaled corticosteroids for the treatment of bronchial asthma has increased in recent years. Most frequently beclomethasone dipropionate, triamcinolone acetonide or flunisolide can be used to reduce or replace oral corticosteroid therapy, particularly in the treatment of children. This avoids or reduces bronchial reactivity and behavioral toxicity. See Cott and Cherniack, Steroids and "Steroid-sparing Agents in Asthma", New Engl. J. Med., 318:634 636, 1988.

Cystic fibrosis is a multi-organ disorder of the exocrine glands which is congenital, lethal and affects all populations, particularly European and North American populations. Primary effects of cystic fibrosis are in the secretory glands, particularly mucous secretion. One of the organ systems most effected by cystic fibrosis is the lungs and respiratory tract. Therapy is as yet only symptomatic as the underlying genetic defect has yet to be characterized.

SUMMARY OF THE INVENTION

The present invention is based on the discovery by the inventors that it is possible to directly or indirectly link an NO or NO.sub.2 group or a group which stimulates the endogenous production of NO or endothelium-derived relaxing factor (EDRF) in vivo, to a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a phosphodiesterase (PDE) inhibitor and that the resulting compound has beneficial therapeutic effects of both a steroid, a .beta.-agonist, an anticholinergic, a mast cell stablizer, or PDE inhibitor and an NO donor or stimulator.

Therefore, one aspect of the invention provides a compound comprising a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor to which is directly or indirectly linked at least one NO or NO.sub.2 group or a group which stimulates the endogenous production of NO or EDRF in vivo. The groups can be linked through sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation), carbon and nitrogen.

The invention is further based on the discovery by the inventors that it is possible to co-administer a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor with a compound that donates, transfers or releases nitric oxide and/or a compound that stimulates endogenous production of NO or EDRF in vivo. A nitric oxide donor is a compound that contains a nitric oxide moiety and which releases or chemically transfers nitric oxide to another molecule. Nitric oxide donors include but are not limited to S-nitrosothiols, nitrites, 2-hydroxy-2-nitrosohydrazines, and substrates of various forms of nitric oxide synthase. Compounds that stimulate endogenous production of nitric oxide or EDRF in vivo include L-arginine, the substrate for nitric oxide synthase, cytokines, adenosine, bradykinin, calreticulin, bisacodyl, phenolphthalein, and endothelein.

Therefore, another aspect of the invention provides a composition comprising (i) a therapeutically effective amount of a a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer and/or a PDE inhibitor in combination with (ii) a compound that donates, transfers or releases nitric oxide and/or a compound that stimulates endogenous production of NO or EDRF in vivo.

In another aspect the invention provides a composition comprising (i) a therapeutically effective amount of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor to which is directly or indirectly linked at least one NO or NO.sub.2 group or a group that stimulates endogenous production of NO or EDRF in vivo, and (ii) a compound that donates, transfers or releases nitric oxide and/or a compound that stimulates endogenous production of NO or EDRF in vivo. The invention also provides such compositions in a pharmaceutically acceptable carrier.

In another aspect the invention provides a method for treating respiratory disorders, such as asthma, in an individual in need thereof which comprises administering to the individual a therapeutically effective amount of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor to which is directly or indirectly linked at least one NO or NO.sub.2 group and/or a group that stimulates endogenous production of NO or EDRF in vivo.

In another aspect the invention provides a method of treating respiratory disorders, such as asthma, in an individual in need thereof which comprises administering to the individual (i) a therapeutically effective amount of a steroid, a .beta.-agonist, an anticholinergic, a mast cell stabilizer or a PDE inhibitor, which optionally may be substituted with at least one NO or NO.sub.2 group or a group that stimulates endogenous production of NO or EDRF in vivo, and (ii) a compound that donates, transfers or releases nitric oxide, and/or a group that stimulates production of NO or EDRF in vivo.

The steroid, .beta.-agonist, anticholinergic, mast cell stabilizer or PDE inhibitor and the compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of NO or EDRF in vivo can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

BRIEF DESCRIPTION OF THE FIGURES

The following drawings are illustrative of embodiments of the invention and do not limit the scope of the invention as defined by the claims.

FIG. 1 illustrates a synthetic pathway for the preparation of nitrite containing steriod derivatives.

FIG. 2 illustrates a synthetic pathway for the preparation of nitrosothiol containing steriod derivatives.

FIG. 3 illustrates a synthetic pathway for the preparation of nitrate containing steriod derivatives.

FIG. 4 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing steriod derivatives.

FIG. 5 illustrates a synthetic pathway for the preparation of nitrite containing .beta.-agonist derivatives.

FIG. 6 illustrates a synthetic pathway for the preparation of nitrosothiol containing .beta.-agonist derivatives.

FIG. 7 illustrates a synthetic pathway for the preparation of nitrate containing .beta.-agonist derivatives.

FIG. 8 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing .beta.-agonist derivatives.

FIG. 9 illustrates a synthetic pathway for the preparation of nitrite containing anticholinergic derivatives.

FIG. 10 illustrates a synthetic pathway for the preparation of nitrosothiol containing anticholinergic derivatives.

FIG. 11 illustrates a synthetic pathway for the preparation of nitrate containing anticholinergic derivatives.

FIG. 12 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing anticholinergic derivatives.

FIG. 13 illustrates a synthetic pathway for the preparation of nitrite containing rispenzepine derivatives.

FIG. 14 illustrates a synthetic pathway for the preparation of nitrosothiol containing rispenzepine derivatives.

FIG. 15 illustrates a synthetic pathway for the preparation of nitrate containing rispenzepine derivatives.

FIG. 16 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing rispenzepine derivatives.

FIG. 17 illustrates a synthetic pathway for the preparation of nitrite containing rispenzepine derivatives.

FIG. 18 illustrates a synthetic pathway for the preparation of nitrosothiol containing rispenzepine derivatives.

FIG. 19 illustrates a synthetic pathway for the preparation of nitrate containing rispenzepine derivatives.

FIG. 20 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing rispenzepine derivatives.

FIG. 21 illustrates a synthetic pathway for the preparation of nitrite containing mast cell stablizer derivatives.

FIG. 22 illustrates a synthetic pathway for the preparation of nitrosothiol containing mast cell stablizer derivatives.

FIG. 23 illustrates a synthetic pathway for the preparation of nitrate containing mast cell stablizer derivatives.

FIG. 24 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing mast cell stablizer derivatives.

FIG. 25 illustrates a synthetic pathway for the preparation of sidnonimine containing mast cell stablizer derivatives.

FIG. 26 illustrates a synthetic pathway for the preparation of nitrite containing phosphodiesterase inhibitor derivatives.

FIG. 27 illustrates a synthetic pathway for the preparation of nitrosothiol containing phosphodiesterase inhibitor derivatives.

FIG. 28 illustrates a synthetic pathway for the preparation of nitrate containing phosphodiesterase inhibitor derivatives.

FIG. 29 illustrates a synthetic pathway for the preparation of 2-hydroxy-2-nitrosohydrazine containing phosphodiesterase inhibitor derivatives.

DETAILED DESCRIPTION OF THE INVENTION

The following illustrative elucidations are provided to facilitate understanding of certain terms used frequently herein, particularly in the examples. The elucidations are provided as a convenience and are not limitative of the invention.

The term "lower alkyl" as used herein refers to branched or straight chain alkyl groups comprising one to ten carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, neopentyl and the like.

The term "alkoxy" as used herein refers to R.sub.50O-wherein R.sub.50 is lower alkyl as defined above. Representative examples of alkoxy groups include methoxy, ethoxy, t-butoxy and the like.

The term "alkoxyalkyl" as used herein refers to an alkoxy group as previously defined appended to an alkyl group as previously defined. Examples of alkoxyalkyl include, but are not limited to, methoxymethyl, methoxyethyl, isopropoxymethyl and the like.

The term "hydroxy" as used herein refers to --OH.

The term "hydroxyalkyl" as used herein refers to a hydroxy group as previously defined appended to a lower alkyl group as previously defined.

The term "alkenyl" as used herein refers to a branched or straight chain C.sub.2 C.sub.10 hydrocarbon which also comprises one or more carbon-carbon double bonds.

The term "amino" as used herein refers to --NH.sub.2.

The term "carboxy" as used herein refers to --C(O)O--

The term "nitrate" as used herein refers to --O--NO.sub.2.

The term "alkylamino" as used herein refers to R.sub.51NH-wherein R.sub.51 is a lower alkyl group as defined above, for example, methylamino, ethylamino, butylamino, and the like.

The term "dialkylamino" as used herein refers to R.sub.52R.sub.53N-wherein R.sub.52 and R.sub.53 are independently selected from lower alkyl groups as defined above, for example dimethylamino, diethylamino, methyl propylamino and the like.

The term "nitro" as used herein refers to the group --NO.sub.2 and "nitrosated" refers to compounds that have been substituted therewith.

The term "nitroso" as used herein refers to the group --NO and "nitrosylated" refers to compounds that have been substituted therewith.

The term "aryl" as used herein refers to a mono- or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like. Aryl groups (including bicyclic aryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo, and nitro. In addition, substituted aryl groups include tetrafluorophenyl and pentafluorophenyl.

The term "arylalkyl" as used herein refers to a lower alkyl radical to which is appended an aryl group. Representative arylalkyl groups include benzyl, phenylethyl, hydroxybenzyl, fluorobenzyl, fluorophenylethyl and the like.

The term "arylalkoxy" as used herein refers to an alkoxy radical to which is appended an aryl group. Representative arylalkoxy groups include benzyloxy, phenylethoxy, chlorophenylethoxy and the like.

The term "cycloalkyl" as used herein refers to an alicyclic group comprising from 3 to 7 carbon atoms including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

The term "bridged cycloalkyl" herein refers to two or more cycloalkyl radicals fused via adjacent or non-adjacent carbon atoms, including but not limited to adamantyl and decahydronapthyl.

The term "cycloalkoxy" as used herin refers to R.sub.54O-- wherein R.sub.54 is cycloalkyl as defined above. Representative examples of alkoxy groups include cyclopropoxy, cyclopentyloxy, and cyclohexyloxy and the like.

The term "arylthio" herein refers to R.sub.55S-- wherein R.sub.55 is an aryl group.

The term "alkylsulfinyl" herein refers to R.sub.55--S(O).sub.2-- wherein R.sub.55 is as previously defined.

The term "carboxamido" herein refers to --C(O)NH.sub.2.

The term "carbamoyl" herein refers to --O--C(O)NH.sub.2.

The term "carboxyl" herein refers to --CO.sub.2H.

The term "halogen" or "halo" as used herein refers to I, Br, Cl, or F. The term "haloalkyl" as used herein refers to a lower alkyl radical, as defined above, bearing at least one halogen substituent, for example, chloromethyl, fluoroethyl or trifluoromethyl and the like.

The term "haloalkyl" as used herein refers to a lower alkyl radical to which is appended one or more halogens. Representative examples of a haloalkyl group include trifluoromethyl, chloromethyl, 2-bromobutyl, 1-bromo-2-chloro-pentyl and the like.

The term "haloalkoxy" as used herin refers to a haloalkyl radical to which is appended an alkoxy group. Representative examples of haloalkoxy groups incluse fluoromethoxy, 1,1,1-trichloroethoxy, 2-bromobutoxy and the like.

The term "heteroaryl" as used herein refers to a mono- or bi-cyclic ring system containing one or two aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring. Heteroaryl groups (including bicyclic heteroaryl groups) can be unsubstituted or substituted with one, two or three substituents independently selected from lower alkyl, haloalkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, halo and nitro. Examples of heteroaryl groups include but are not limited to pyridine, pyrazine, pyrimidine, pyridazine, pyrazole, triazole, thiazole, isothiazole, benzothiazole, benzoxazole, thiadiazole, oxazole, pyrrole, imidazole and isoxazole.

The term "heterocyclic ring" refers to any 3-, 4-, 5-, 6-, or 7-membered nonaromatic ring containing at least one nitrogen atom, oxygen, or sulfur.

The term "arylheterocyclic ring" as used herein refers to a bi- or tricyclic ring comprised of an aryl ring as previously defined appended via two adjacent carbons of the aryl group to a heterocyclic ring as previously defined.

The term "heterocyclic compounds" herein refers to mono and polycyclic compounds containing at least one heteroaryl or heterocyclic ring.

Examples of contemplated steroids include beclamethasone, fluticasone, flunisolide, triamcinolone, butixocort, dexamethasone, fluocortin, budesonide, tixocortal, tipredane and mometasone. Examples of contemplated .beta.-agonists include salmeterol, albuterol, metaproterenol, terbutaline, pirbuterol, rimiterol, clenbuterol, bitoterol and reproterol. Examples of contemplated anticholinergics include ipratropium, flutropium, tiotropium and rispenzepine. Examples of contemplated mast cell stabilizers include cromalyn and nedocromil. Examples of contemplated PDE inhibitors include filaminast, denbufyllene piclamilast, zardaverine, and rolipram.

Sources of information for the above include Goodman and Gilman, The Pharmacological Basis of Therapeutics (8th Ed.), McGraw-Hill, Inc., 1993; the Physician's Desk Reference (49th Ed.), Medical Economics (1995); Drug Facts and Comparisons (1993 Ed), Facts and Comparisons (1993); and The Merck Index (11th Ed.), Merck & Co., Inc. (1989), all of which are incorporated herein by reference in their entirety.

A principal aspect of the invention relates to novel nitrosated and/or nitrosylated compounds.

One embodiment of this aspect provides compounds having the structure:

##STR00001## wherein

A is selected from --CH.dbd.CH-- or --CH.sub.2--CH.sub.2--;

R.sub.1 is selected from (1) --C(O)CH.sub.2-B-D wherein B is oxygen or sulfur; D is selected from (i) --NO; (ii) --NO.sub.2; (iii) --C(R.sub.d)--O--C(O)--Y--(C(R.sub.e)(R.sub.f)).sub.p-T-Q in which R.sub.d is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl, aryl or heteroaryl, Y is oxygen, sulfur, or NR.sub.i in which R.sub.i is hydrogen, lower alkyl, lower haloalkyl, or heteroaryl, R.sub.e and R.sub.f are independently selected from hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, carboxy, or taken together are carbonyl, cycloalkyl or bridged cycloalkyl, p is an integer from 1 to 6, T is a covalent bond, oxygen, sulfur or nitrogen and Q is selected from --NO or --NO.sub.2; (iv) --C(O)-T.sup.1(C(R.sub.e)(R.sub.f)).sub.p-T.sup.2-Q wherein T.sup.1 and T.sup.2 are independently selected from T and R.sub.e, R.sub.f, p, Q, and T are as defined above; (v) --C(O)-T(C(R.sub.y)(R.sub.z)).sub.p wherein R.sub.y and R.sub.z are independently selected from -T.sup.1-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).sub.p-T.sup.- 2-Q wherein G is (i) a covalent bond; (ii) -T-C(O)--; (iii) --C(O)-T, or (iv) Y, and wherein R.sub.d, R.sub.e, R.sub.f, p, Q, T, and Y are as defined above; (2) --C(O)--C(O)--O--R.sub.i wherein R.sub.i is as defined above; (3) --C(O)--B--R.sub.i wherein B and R.sub.i are as defined above; (4) --C(O)--CH.sub.2--B--C(O)--R.sub.i wherein B and R.sub.i are as defined above; (5) --C(O)--CH.sub.2--X wherein X is halogen; (6) --S--R.sub.i wherein R.sub.i is as defined above; (7) --C(O)CH.sub.2--B-M wherein M is selected from --C(O)T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)).sub.p--N(N--(- O.sup.-)N.dbd.O)--R.sub.i or --C(R.sub.d)--O--C(O)T-(C(R.sub.e)(R.sub.f)).sub.p-G-(C(R.sub.e)(R.sub.f)- ).sub.p--N(N--(O.sup.-)N.dbd.O)--R.sub.i, wherein R.sub.e, R.sub.f, R.sub.i, p, G and T are as defined above;

R.sub.2 and R.sub.3 are independently selected from hydrogen, hydroxyl, lower alkyl, --O(O)C--R.sub.i, or --S--R.sub.i wherein R.sub.i is as defined above or R.sub.2 and R.sub.3 when taken together are

##STR00002## wherein R.sup.1.sub.i and R.sup.2.sub.i are independently selected from R.sub.i wherein R.sub.i is as defined above;

R.sub.4 and R.sub.5 are independently selected from hydrogen or halogen;

R.sub.6 is selected from hydrogen, D, or M wherein D and M are as defined above with the provision that R.sub.6 must be D or M if the selection for R.sub.1 does not include D or M;

Another embodiment of this aspect provides compounds having the structure:

##STR00003##

wherein,

E is nitrogen or C--R.sub.7 wherein R.sub.7 is hydrogen, halogen, --CH.sub.2O--R.sub.j, or --O--R.sub.j wherein R.sub.j is hydrogen, D or M wherein D and M are defined as above;

R.sub.8 and R.sub.9