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

• US 5,824,669 A
• Filed: 03/22/1996
• Issued: 10/20/1998
• Est. Priority Date: 03/22/1996
• Status: Expired due to Term

• Current Assignee: Healthcare Ventures III L.P., Healthcare Ventures VI, L.P., Nicox SA
• Original Assignee: Nitromed, Inc. (Arbor Pharmaceuticals LLC)
• Inventors: Letts, L. Gordon, Garvey, David S., Richardson, Stewart K., Renfroe, H. Burt
• Primary Examiner(s): Rotman, Alan L.
• Application Number:
  US08/620,882
• Time in Patent Office: 942 Days
• Field of Search: 552/572, 552/573, 552/575, 552/565, 552/566, 540/63, 540/66, 514/174, 514/178, 514/179
• US Class Current: 514/174
• 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 compound having the structure:

##STR13## wherein A is selected from --CH═

CH-- or --CH₂ --CH₂ --;

R₁ is selected from hydrogen or --C(O)CH₂ --B--D, wherein B is oxygen or sulfur and D is selected from (i) hydrogen, (ii) --NO and (iii) --NO₂, with the provision that when B is oxygen then D is H or --NO;

R₂ and R₃ are independently selected from hydrogen, hydroxyl, lower alkyl, --O(O)C--R_i, or --S--R_i wherein R_i is hydrogen, lower alkyl or lower haloalkyl, or when taken together are;

##STR14## wherein R_i¹ and R_i² are independently selected from R_i wherein R_i is defined as above;

R₄ and R₅ are independently selected from hydrogen or halogen;

R₆ is selected from hydrogen, --NO, --NO₂ and --C(O)CH₂ --B--D, wherein B is oxygen or sulfur and D is selected from hydrogen, --NO and --NO₂, with the provision when R₁ is hydrogen, or the D group of R₁ is hydrogen or --NO, with the B group being oxygen then R₆ is selected from the group consisting of --NO and --C(O)CH₂ --B--D, wherein B is oxygen or sulfur and D is --NO or --NO₂ ;

or an ester or thioester of said compound.

2. A compound according to claim 1, wherein A is --CH═

CH--.

3. A compound according to claim 1, wherein A is --CH₂ --CH₂ --.

4. A compound according to claim 2, wherein B is oxygen.

5. A compound according to claim 4, wherein R₂ and R₃ taken together are:

##STR15## wherein R_i¹ and R_i² are independently hydrogen or lower alkyl.

6. A compound according to claim 5, wherein R_i¹ and R_i² are each methyl.

7. A compound according to claim 4, wherein R₄ and/or R₅ are independently selected from hydrogen, a chloro group or a fluoro group.

8. A compound according to claim 7, wherein R₂ is hydroxy, R₃ is methyl, R₄ is a chloro group and R₅ is hydrogen.

9. A compound according to claim 7, wherein R₂ is hydroxy, R₃ is hydroxy, R₄ is a fluoro group and R₅ is hydrogen.

10. A compound according to claim 1, wherein R₁ is hydrogen, or the D group of R₁ is hydrogen or --NO, and R₆ is selected from the group consisting of --NO and --C(O)CH₂ --B--D, wherein B is oxygen or sulfur and D is --NO or --NO₂.

11. A compound according to claim 1, wherein the D group of R₁ is --NO, and R₆ is selected from the group consisting of hydrogen and --C(O)CH₂ --B--D, wherein B is oxygen or sulfur and D is hydrogen.

12. A composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable excipient or carrier.

13. A composition comprising a therapeutically effective amount of a compound according to claim 2 and a pharmaceutically acceptable excipient or carrier.

14. A composition comprising a therapeutically effective amount of a compound according to claim 5 and a pharmaceutically acceptable excipient or carrier.

15. A composition comprising a therapeutically effective amount of a compound according to claim 7 and a pharmaceutically acceptable excipient or carrier.

16. A composition comprising a therapeutically effective amount of a compound according to claim 11 and a pharmaceutically acceptable excipient or carrier.

17. A method for treating a respiratory disorder in an individual comprising administering an therapeutically effective amount of a compound according to claims 1.

18. A method for treating asthma in an individual comprising administering an therapeutically effective amount of a compound according to claims 1.

19. A method for treating a respiratory disorder in an individual comprising administering an therapeutically effective amount of a compound according to claims 5.