Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders

• US 20050228184A1
• Filed: 04/15/2003
• Published: 10/13/2005
• Est. Priority Date: 04/19/2002
• Status: Active Grant

• Current Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Haj-Yehia, Abdullah Ibrahim
• Granted Patent: US 7,378,438 B2
• Time in Patent Office: Days
• US Class Current: 546/199
• CPC Class Codes: A61K 31/385 having two or more sulfur atoms in the same ring
• CPC Class Codes: A61K 31/4035 Isoindoles, e.g. phthalimide
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/44 Iso-indoles; Hydrogenated iso-indoles
• CPC Class Codes: C07D 339/04 having the hetero atoms in positions 1 and 2, e.g. lipoic acid
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to multifunctional β-agonist compounds comprising a reactive oxygen species scavenger group and a nitric oxide donor, and their use for the treatment of respiratory diseases involving airway obstruction, such as asthma and chronic bronchitis. The invention further relates to methods and devices for administering the compounds.

Claims

1. A multifunctional β

-agonist compound being ROS scavenger and NO donor of Formula 1;

2. A β

-agonist compound according to claim 1, wherein said saturated heterocycle is selected from the group consisting of pyrrolidine, oxazolidine, thiazolidine, tetrahydro 1,3-oxazine, 1,3-dioxane, piperidine, 3-thiapiperidine, and 1,3-thiazine.

3. A β

-agonist compound according to claim 1, wherein said saturated heterocycle comprises a substituted nitroxide free radical.

4. A β

-agonist compound according to claim 1, wherein the nitroxide free radical is a heterocyclyl moiety having the nitrogen atom within a 5-, 6- or 7-membered ring which optionally contains another heteroatom selected from oxygen and sulfur at position beta to the nitrogen, and which is substituted with methyl or ethyl at positions alpha to the nitrogen.

5. The β

-agonist compound of claim 4, wherein said heterocyclyl moiety is linked to the β

-agonist moiety via sharing of 1 to 2 atoms, or via a linker.

6. A β

-agonist compound according to any one of claims 1 to 5, wherein said ROS scavenger is selected from the group consisting of the following moieties;

7. A β

-agonist compound according to claim 1, wherein R² is selected from the following structures;

9. A multifunctional β

-agonist compound according to claim 1 having one of the following structures;

15. A multifunctional β

-agonist compound of any one of claims 1 to 9 for use as a medicament.

16. A method of treating a respiratory disorder in a mammal in need thereof comprising administering to said mammal an effective amount of a multifunctional β

-agonist compound of any one of claims 1 to 9.

17. A method according to claim 16, wherein said disorder is selected from asthma, chronic bronchitis, bronchictiasis and emphysema, chronic obstructive pulmonary disease, chronic obstructive airway disease, and restrictive diseases of the lungs.

18. A method according to claim 16, comprising symptoms selected from recurrent obstruction to air flow within the lung, increased resistance to air flow, narrowing or restriction of an airway, inflammation, bronchial hyperreactivity, airway hyperresponsiveness, mucosal edema, mucus plugging and hypersecretion, and reduced expansion of respiratory parenchyma.

19. A method according to claim 17, wherein asthma is extrinsic or intrinsic.

20. A method according to claim 17, wherein asthma is atopic.

21. A method according to claim 16, wherein said multifunctional β

-agonist compound is used in the treatment or prophylaxis of respiratory conditions selected from chronic obstructive pulmonary or airways disease, chronic bronchitis, emphysema, acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) in child or adult, pneumonia, pneumonitis, bronchial hyperreactivity, bronchiectasis, and airway hyperresponsiveness.

22. A method of any one of claims 16 to 21, wherein said administration or treatment is systemic.

23. A method of any one of claims 16 to 21, wherein said administration or treatment is topical

24. A method of claim 16, wherein said β

-agonist compound is administered by a route selected from oral, parenteral, intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, implant, buccal, inhalation spray, nasal, vaginal, rectal, and sublingual.

25. A method of claim 16, wherein said mammal is human.

26. A pharmaceutical composition comprising a β

-agonist compound of any one of claims 1 to 9.

27. A pharmaceutical composition according to claim 26 comprising salts, solvates, or optical isomers of said compound.

28. A pharmaceutical composition according to claim 26, further comprising carriers, adjuvants, and excipients.

29. A pharmaceutical composition according to any one of claims 26 to 28, further comprising an active agent selected from mucolytic, bronchodilator, muscle relaxant, decongestant, respiratory stimulant, vasodilator, β

-agonist, antiallergic, antiasthmatics, analgesic, anti-inflammatory, antibiotic, antifungal, antiprotozoal and antiviral agent.

30. A pharmaceutical composition according to any one of claims 26 to 29, for use as a medicament in treating a disorder selected from asthma, chronic bronchitis, bronchiectasis, emphysema, chronic obstructive pulmonary or airways disease, acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) in child or adult, pneumonia, pneumonitis, bronchial hyperreactivity, and airway hyperresponsiveness

31. Use of a β

-agonist compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, solvate thereof, or an optical isomer thereof, in the preparation of a medicament for treating or preventing a respiratory disorder, substantially as described in the specification.

32. Use according to claim 31, wherein said disorders is selected from the group comprising asthma, chronic bronchitis, bronchiectasis, emphysema, chronic obstructive pulmonary or airways disease, acute respiratory distress syndrome (ARDS) or severe acute respiratory syndrome (SARS) in child or adult, pneumonia, pneumonitis, bronchial hyperreactivity, and airway hyperresponsiveness

33. Use according to claim 31, wherein said disorder comprises symptoms selected from recurrent obstruction to air flow within the lung, increased resistance to air flow, narrowing or restriction of an airway, inflammation, bronchial hyperreactivity, airway hyperresponsiveness, mucosal edema, mucus plugging and hypersecretion, and reduced expansion of respiratory parenchyma.

34. A β

-agonist compound of any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, for use as a medicament for treating or preventing a respiratory disorder.

35. A method of claim 24, wherein said administration or treatment is via an inhalation device.

36. The method of claim 35 wherein said inhalation device for administering the multifunctional β

-agonist compounds, comprises an element selected from metered dose inhaler, liquid nebulizer, dry powder inhaler, sprayer, and thermal vaporizer.

38. A kit comprising an inhalation device, a multifunctional β

-agonist of claim 1 in the form of fine power or solution or suspension, wherein said powder or solution or suspension optionally contains other components selected from bulking agent, buffer, carrier, excipient, additive, antioxidant, stabilizer, surfactant, odorant, and a second pharmaceutically active agent.

8. A β

-agonist compound having the formula;

10. A process of preparing a compound of Formula 1:

11. A process according to claim 10, wherein said epoxide is prepared from diprotected salicylic acid or salicyl alcohol.

14. A process according to claims 10 or 12, further comprising converting —

SH groups to —

SNO groups in the presence of HCl and NaNO₂.

12. A process of preparing a compound of the formula:

13. A process according to claim 12, wherein said epoxide is prepared from N-benzylphthalimide.

37. An inhalation device for administering a multifunctional β

-agonist compound being ROS scavenger and NO donor of Formula 1;