1-pyrazolyl-3- (4- ((2 -anilinopyrimidin- 4 - yl) oxy) napththalen- i - yl) ureas as p38 mapkinase inhibitors

Patent metadata

Field	Value
Publication number	US-2016009695-A1
Application number	US-201514795957-A
Country	US
Kind code	A1
Filing date	Jul 10, 2015
Priority date	Oct 3, 2011
Publication date	Jan 14, 2016
Grant date	—

Abstract

There is provided a compound of formula (I) which is an inhibitor of the family of p38 mitogen-activated protein kinase enzymes, and to its use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, such as asthma and COPD.

First claim

1 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.

2 . A compound according to claim 1 , as the free base.

3 . A compound according to claim 2 , as the anhydrous free base in solid crystalline form.

4 . A compound according to claim 3 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having the X-ray powder diffraction pattern substantially as shown in FIG. 1 (Form A).

5 . A compound according to claim 3 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having an X-ray powder diffraction pattern containing one, two, three, four, five, six or seven peaks selected from (±0.2) 10.3, 15.2, 17.5, 23.1, 24.6, 26.7 and 27.4 degrees 2-theta.

6 . A compound according to claim 3 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having the X-ray powder diffraction pattern substantially as shown in FIG. 2 (Form B).

7 . A compound according to claim 3 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having an X-ray powder diffraction pattern containing one, two, three, four, five, six, seven or all eight peaks selected from (±0.2) 3.9, 6.1, 11.8, 14.3, 16.7, 18.3, 18.7 and 28.9 degrees 2-theta.

8 . A pharmaceutical composition comprising a compound according to claim 1 , in combination with one or more pharmaceutically acceptable diluents or carriers.

9 . A compound of formula (I) according to claim 1 for use as a medicament.

10 . A compound of formula (I) according to claim 1 or a pharmaceutical composition according to claim 8 for use in the treatment or prevention of exacerbations in patients which chronic respiratory disease, such as COPD (including chronic bronchitis and emphysema), asthma, paediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis.

11 . A compound of formula (I) according to claim 1 or a pharmaceutical composition according to claim 8 for use in the treatment or prevention of a condition selected from: COPD (including chronic bronchitis and emphysema), asthma, paediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis, allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis, inflamed joints secondary to rheumatoid arthritis or osteoarthritis, rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growth and metastasis of tumours including non-small cell lung carcinoma, breast carcinoma, gastric carcinoma, colorectal carcinomas and malignant melanoma.

12 . Use of a compound of formula (I) according to claim 1 or a pharmaceutical composition according to claim 8 for the manufacture of a medicament for the treatment or prevention of a condition selected from: COPD (including chronic bronchitis and emphysema), asthma, paediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, pulmonary hypertension, allergic conjunctivitis, conjunctivitis, allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis, inflamed joints secondary to rheumatoid arthritis or osteoarthritis, rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growth and metastasis of tumours including non-small cell lung carcinoma, breast carcinoma, gastric carcinoma, colorectal carcinomas and malignant melanoma.

13 . A method of treatment of a condition selected from COPD (including chronic bronchitis and emphysema), asthma, paediatric asthma, cystic fibrosis, sarcoidosis, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, sinusitis, allergic conjunctivitis, conjunctivitis, allergic dermatitis, contact dermatitis, psoriasis, ulcerative colitis, inflamed joints secondary to rheumatoid arthritis or osteoarthritis, rheumatoid arthritis, pancreatitis, cachexia, inhibition of the growth and metastasis of tumours including non-small cell lung carcinoma, breast carcinoma, gastric carcinoma, colorectal carcinomas and malignant melanoma which comprises administering to a subject an effective amount of a compound of formula (I) according to claim 1 or a pharmaceutical composition according to claim 8 .

14 . A compound of formula (I) according to claim 1 or a pharmaceutical composition according to claim 8 for use as in the treatment or prevention of respiratory viral infections in patients with chronic conditions such as congestive heart failure, diabetes, cancer, or in immunosuppressed patients, for example post-organ transplant.

15 . A compound of formula (I) according to claim 1 or a pharmaceutical composition according to claim 8 in combination with anti-viral therapy such as zanamivir or oseltamivir (for example oseltamivir phosphate), for use in the treatment or prevention of respiratory viral infections in patients with chronic conditions such as congestive heart failure, diabetes, cancer, or in immunosuppressed patients, for example post-organ transplant.

16 . A combination product comprising:
(A) a compound of formula (I) according to claim 1 ; and (B) another therapeutic agent;
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable diluent or carrier;
wherein said combination product may be either a single pharmaceutical formulation or a kit-of-parts.

17 . A method for sensitizing a subject suffering from COPD or asthma to treatment with a corticosteroid, where the subject has previously become refractory to treatment with a corticosteroid, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I)

or a pharmaceutically acceptable salt thereof, including all stereoisomers and tautomers thereof.

18 . The method of claim 17 , wherein the compound of Formula (I) is a free base.

19 . The method of claim 17 , wherein the compound of Formula (I) is anhydrous free base in solid crystalline form.

20 . The method of claim 17 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having the X-ray powder diffraction pattern substantially as shown in FIG. 1 (Form A).

21 . The method of claim 17 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having an X-ray powder diffraction pattern containing one, two, three, four, five, six or seven peaks selected from (±0.2) 10.3, 15.2, 17.5, 23.1, 24.6, 26.7 and 27.4 degrees 2-theta.

22 . The method of claim 17 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having the X-ray powder diffraction pattern substantially as shown in FIG. 2 (Form B).

23 . The method of claim 17 , wherein the compound of formula (I) as the anhydrous free base is in solid crystalline form having an X-ray powder diffraction pattern containing one, two, three, four, five, six, seven or all eight peaks selected from (±0.2) 3.9, 6.1, 11.8, 14.3, 16.7, 18.3, 18.7 and 28.9 degrees 2-theta.

Assignees

• Respivert Ltd

Inventors

• Ito Kazuhiro
• Charron Catherine Elisabeth
• King-Underwood John
• Onions Stuart Thomas
• Longshaw Alistair Ian
• Broeckx Rudy
• Filliers Walter
• Copmans Alex

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title