Salts of 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1h)-one derivatives having both muscarinic receptor antagonist and beta2 adrenergic receptor agonist activities

Patent metadata

Field	Value
Publication number	US-2016166566-A1
Application number	US-201414906991-A
Country	US
Kind code	A1
Filing date	Jul 24, 2014
Priority date	Jul 25, 2013
Publication date	Jun 16, 2016
Grant date	—

Abstract

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

First claim

1 . A pharmaceutically acceptable crystalline addition salt of (i) a 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivative and (ii) a dicarboxylic acid or a sulfimide derivative, or a pharmaceutically acceptable solvate thereof, wherein the 2-amino-1-hydroxyethyl-8-hydroxyquinolin-2(1H)-one derivative is a compound of formula (I):

wherein:
R 1 , R 2 and R 3 each are independently chosen from a hydrogen atom or a C 1-2 alkyl group,
R 4 is chosen from a hydrogen atom, a hydroxy group, a hydroxymethyl group or a linear or branched C 1-4 alkyl group,
R 5 and R 6 each are independently chosen from a thienyl group, a phenyl group, a benzyl group or a C 4-6 cycloalkyl group,
V and W each are independently chosen from a —N—, —S— or —C(O)— group,
n and m each are independently chosen from 0, 1, 2, 3, or 4.

2 . The salt according to claim 1 , wherein R 1 , R 2 and R 3 each are independently chosen from a hydrogen atom or a methyl group.

3 . The salt according to claim 1 , wherein V is chosen from a —N— or —S— group and W is chosen from —N— or —C(O)— group.

4 . The salt according to claim 1 , wherein n is chosen from 0 or 1, and m is chosen from 2 or 3.

5 . The salt according to claim 1 , wherein both R 1 and R 2 are a hydrogen atom, R 3 is a methyl group, V is chosen from a —N— or —S— group, W is chosen from —N— or —C(O)— group, n is 0 and m is 3.

6 . The salt according to claim 1 , wherein the dicarboxylic acid is fumaric acid or the sulfimide derivative is saccharin.

7 . The salt according to claim 1 , chosen from:
trans-4-[{3-[5-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-1H-1,2,3-benzotriazole-1-yl]propyl}(methyl)amino]cyclohexyl hydroxy(di-2-thienyl)acetate saccharinate, trans-4-[{3-[6-({[(2R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl]amino}methyl)-2-oxo-1,3-benzothiazole-3(2H)-yl]propyl}(methyl)-amino]cyclohexyl hydroxy(di-2-thienyl)acetate fumarate,
or a pharmaceutically acceptable solvate thereof.

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

9 . The pharmaceutical composition according to claim 8 , wherein the composition is formulated for administration by inhalation as a dry powder.

10 . The pharmaceutical composition according to claim 8 , further comprising a therapeutically effective amount of at least one additional therapeutic agent.

11 . The pharmaceutical composition according to claim 10 , wherein the at least one additional therapeutic agent is chosen from:
(a) corticosteroids, or gluococorticoids, (b) antihistamines, (c) chemokine receptor antagonists, (e) CRTH 2 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, and (cc) expectorants.

12 . A combination comprising a salt according to claim 1 and at least one additional therapeutic agent chosen from:
(a) corticosteroids, or gluococorticoids,
(b) antihistamines,
(c) chemokine receptor antagonists,
(e) CRTH 2 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,
IL5 antibody,
(x) leukotriene formation inhibitors,
(y) decongestants,
(z) mucolytics,
(aa) antitussives,
(bb) analgesics, and
(cc) expectorants.

13 . (canceled)

14 . A method for treating a subject afflicted with a pathological condition or disease associated with β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activity, comprising administering to the subject a therapeutically effective amount of the salt according to claim 1 .

15 . The method according to claim 14 , wherein the pathological condition or disease is chosen from asthma or chronic obstructive pulmonary disease.

16 . (canceled)

17 . A method for treating a subject afflicted with a pathological condition or disease associated with β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activity, comprising administering to the subject the pharmaceutical composition according to claim 8 .

18 . The salt according to claim 1 , wherein R 1 and R 2 are a hydrogen atom and R 3 is a methyl group.

19 . The salt according to claim 2 , wherein V is chosen from a —N— or —S— group and W is chosen from —N— or —C(O)— group.

20 . The salt according to claim 1 , wherein n is 0 and m is 3.

21 . A method for treating a subject afflicted with a pathological condition or disease associated with β2 adrenergic receptor agonist and M3 muscarinic receptor antagonist activity, comprising administering to the subject the combination according to claim 12 .

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

• A61P11/08

  Bronchodilators · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• C07C57/15

  Fumaric acid · CPC title