Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivatives having both β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activities

Patent metadata

Field	Value
Publication number	US-9562039-B2
Application number	US-201414770206-A
Country	US
Kind code	B2
Filing date	Feb 27, 2014
Priority date	Feb 27, 2013
Publication date	Feb 7, 2017
Grant date	Feb 7, 2017

Abstract

The present invention is directed to crystalline addition salts of (i) 8-hydroxyquinolin-2(1H)-one derivatives and (ii) a hydroxycarboxylic acid, a sulfonic acid or a sulfimide, or a pharmaceutically acceptable solvates thereof.

First claim

The invention claimed is:

1. A pharmaceutically acceptable crystalline addition salt of (i) a sulfonic, a hydroxycarboxylic acid, a sulfimide derivative, or a pharmaceutically acceptable solvate thereof and (ii) a 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivative of formula (I), or pharmaceutically acceptable solvates thereof,

wherein:
R 1 is a methyl group,
R 2 is a methoxy group, and R 3 is a chlorine atom,
A is an ethylene group,
L is chosen from —NH(CO)—, or —NH(CO)O— group, wherein when L is —NH(CO)O—, the nitrogen atom is bound to the phenylene substituent and the oxygen atom is bound to the A substituent.

2. The salt according to claim 1 , chosen from:
trans-4-((3-(2-chloro-4-(((2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)methyl)-5-methoxyphenylamino)-3-oxopropyl)(methyl)amino)-cyclohexyl hydroxy(di-2-thienyl)acetate ethanedisulfonate,
trans-4-((2-(2-chloro-4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)-cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate disaccharinate,
L-tartrate salt of trans-4-((2-(2-chloro-4-(((R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino)-methyl)-5-methoxyphenylcarbamoyloxy)ethyl)-(methyl)amino)cyclohexyl 2-hydroxy-2,2-di(thiophen-2-yl)acetate,
or a pharmaceutically acceptable solvate thereof.

3. A pharmaceutical composition comprising a therapeutically effective amount of the salt according to claim 1 and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3 , wherein the composition is formulated for administration by inhalation as a dry powder.

5. The pharmaceutical composition according to claim 3 , further comprising a therapeutically effective amount of at least one additional therapeutic agent.

6. The pharmaceutical composition according to claim 5 , wherein the at least one additional therapeutic agent is chosen from:
(a) corticosteroids, or glucocorticoids,
(b) antihistamines,
(c) chemokine receptor antagonists,
(e) CRth2 antagonists,
(f) leukotriene receptor antagonists,
(g) JAK inhibitors,
(h) Syk inhibitors,
(i) phosdiesterase IV inhibitors,
(j) p38 Inhibitors,
(k) PKC inhibitors,
(l) 5-lipoxygenase activating protein inhibitors,
(m) 5-lipoxygenase inhibitors,
(n) CYSLTR1 antagonists,
(o) CYSLTR2 antagonists,
(p) BLT1 antagonists,
(q) BLT2 antagonists,
(r) thromboxane A2 antagonists,
(s) DP1 receptor antagonists,
(t) DP1 receptor agonists,
(u) IP receptor agonists,
(v) Anti-IgE,
(w) IL5 antibody,
(x) leukotriene formation inhibitors,
(y) decongestants,
(z) mucolytics,
(aa) antitussives,
(bb) analgesics, or
(cc) expectorants.

7. The combination comprising a salt according to claim 1 and at least one additional therapeutic agent chosen from:
(a) corticosteroids, or glucocorticoids,
(b) antihistamines,
(c) chemokine receptor antagonists,
(e) CRth2 antagonists,
(f) leukotriene receptor antagonists,
(g) JAK inhibitors,
(h) Syk inhibitors,
(i) phosdiesterase IV inhibitors,
(j) p38 Inhibitors,
(k) PKC inhibitors,
(l) 5-lipoxygenase activating protein inhibitors,
(m) 5-lipoxygenase inhibitors,
(n) CYSLTR1 antagonists,
(o) CYSLTR2 antagonists,
(p) BLT1 antagonists,
(q) BLT2 antagonists,
(r) thromboxane A2 antagonists,
(s) DP1 receptor antagonists,
(t) DP1 receptor agonists,
(u) IP receptor agonists,
(v) Anti-IgE,
(w) IL5 antibody,
(x) leukotriene formation inhibitors,
(y) decongestants,
(z) mucolytics,
(aa) antitussives,
(bb) analgesics, or
(cc) expectorants.

8. A method of treating a pathological condition or disease associated with both β2 adrenergic receptor agonist and M3 antimuscarinic activities, wherein the pathological condition or disease is chosen from asthma or chronic obstructive pulmonary disease, the method comprising administering to a patient in need thereof the salt according to claims 1 and 2 .

9. The pharmaceutical composition according to claim 4 , further comprising a therapeutically effective amount of at least one additional therapeutic agent.

10. A method of treating a pathological condition or disease associated with both β2 adrenergic receptor agonist and M3 antimuscarinic activities, wherein the pathological condition or disease is chosen from asthma or chronic obstructive pulmonary disease, the method comprising administering to a patient in need thereof the pharmaceutical composition according to claim 3 .

11. A method of treating a pathological condition or disease associated with both β2 adrenergic receptor agonist and M3 antimuscarinic activities, wherein the pathological condition or disease is chosen from asthma or chronic obstructive pulmonary disease, the method comprising administering to a patient in need thereof the combination according to claim 7 .

Assignees

• Almirall Sa

Inventors

• Julia Jane Montserrat
• Carrera Carrera Francesc
• Prat Quiñones Maria
• Puig Duran Carlos
• Pajuelo Lorenzo Francesca
• Perez Andres Juan Antonio

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/08

  Bronchodilators · CPC title

• C07D275/06

  with hetero atoms directly attached to the ring sulfur atom · CPC title

• C07C59/255

  Tartaric acid · CPC title