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-2016009698-A1
Application number	US-201414770206-A
Country	US
Kind code	A1
Filing date	Feb 27, 2014
Priority date	Feb 27, 2013
Publication date	Jan 14, 2016
Grant date	—

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

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 chosen from a hydrogen atom or a C 1-4 alkyl group,
R 2 and R 3 each independently are chosen from a hydrogen atom, a halogen atom, a C 1-4 alkyl group, a C 1-4 alkoxy group, or a cyano group,
A is a C 1-4 alkylene group unsubstituted or substituted with at least one C 1-2 alkyl group,
L is chosen from a direct bond, —NH(CO)—, —(CO)NH—, 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 , wherein R 1 is chosen from a hydrogen atom or a methyl group.

3 . The salt according to claim 1 , wherein R 2 and R 3 each independently are chosen from a halogen atom or a C 1-4 alkoxy group.

4 . The salt according to claim 3 , wherein R 2 and R 3 h independently are chosen from a chlorine atom or a methoxy group.

5 . The salt according to claim 1 , wherein A is a C 1-2 alkylene group unsubstituted or substituted with one or two methyl groups.

6 . The salt according to claim 5 , wherein A is an unsubstituted ethylene group.

7 . The salt according to claim 1 , wherein L is chosen from a —NH(CO)—, —(CO)NH—, or —NH(CO)O— group.

8 . The salt according to claim 1 , wherein R 1 is a methyl group, R 2 is a methoxy group, R 3 is a chlorine atom, A is an ethylene group, and L is chosen from a —NH(CO)— or —NH(CO)O— group.

9 . 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.

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

11 . The pharmaceutical composition according to claim 10 , wherein the composition is formulated for administration by inhalation as a dry powder.

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

13 . The pharmaceutical composition according to claim 12 , wherein the at least one additional therapeutic agent is chosen from:
(a) corticosteroids, or gluococorticoids, (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) DPI receptor antagonists, (t) DPI 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.

14 . The 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) 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) mucolytics,
(z) mucolytics,
(aa) antitussives,
(bb) analgesics, or
(cc) expectorants.

15 . A method of treating a pathological condition or disease associated with both β2 adrenergic receptor and M3 antimuscarinic activity, comprising administering to a patient in need thereof the salt according to claim 1 .

16 . The method according to claim 15 , wherein the pathological condition or disease is chosen from respiratory diseases.

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

18 . (canceled)

19 . (canceled)

20 . The salt according to claim 1 , wherein R 1 is a methyl group.

21 . The salt according to claim 1 , wherein R 2 and R 3 each independently are chosen from a halogen atom or a C 1-2 alkoxy group.

22 . The salt according to claim 3 , wherein R 2 is a methoxy group and R 3 is a chlorine atom.

23 . The salt according to claim 1 , wherein A is an ethylene group unsubstituted or substituted with a methyl group.

24 . The salt according to claim 1 , wherein L is chosen from a —NH(CO)— or —NH(CO)O— group.

25 . The pharmaceutical composition according to claim 11 , further comprising a therapeutically effective amount of at least one additional therapeutic agent.

26 . A method of treating a pathological condition or disease associated with both β2 adrenergic receptor and M3 antimuscarinic activity, comprising administering to a patient in need thereof the pharmaceutical composition according to claim 10 .

27 . A method of treating a pathological condition or disease associated with both β2 adrenergic receptor and M3 antimuscarinic activity, comprising administering to a patient in need thereof the combination according to claim 14 .

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

Assignees

• Almirall Sa

Inventors

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

Classifications

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K9/0075

  for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles · CPC title