Compounds

Patent metadata

Field	Value
Publication number	US-9834560-B2
Application number	US-201615086120-A
Country	US
Kind code	B2
Filing date	Mar 31, 2016
Priority date	Oct 19, 2009
Publication date	Dec 5, 2017
Grant date	Dec 5, 2017

Abstract

The present invention relates to compounds of formula (I)

and to compositions comprising the same and to the use of the compounds and their compositions in treatment, for example in the treatment of inflammatory diseases, in particular respiratory inflammatory disease. The invention also extends to methods of making said compounds.

First claim

The invention claimed is:

1. A dry powder formulation comprising a compound of formula (I)

wherein
R 1 is selected from the group consisting of hydrogen, and a saturated or unsaturated, branched or unbranched C 1-15 alkyl chain, wherein optionally one or more carbons is/are replaced by a heteroatom selected from the group consisting of O, OH, N, NH, NH 2 , and S(O) p , wherein said chain is optionally substituted by one or more groups independently selected from the group consisting of oxo, halogen, aryl, heteroaryl, carbocyclyl and heterocyclyl,
each aryl, heteroaryl, carbocyclyl or heterocyclyl group bearing:
0 to 3 substituents selected from the group consisting of halogen, -hydroxyl, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 2-3 alkylOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 1-6 haloalkyl, amino, —C 1-4 mono or —C 2-8 di-alkyl amino, —C 1-4 mono or —C 2-8 di-acyl amino, —C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OC 0-6 alkyl, —NR 8 C 0-6 alkylC(O)NR 6 R 7 —NR 8 C 0-6 alkylC(O)C 0-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 , and —C 0-6 alkylC(O)C 1-6 alkyl; and/or one aryl, heterocyclyl or carbocyclyl;

X is C 6-10 aryl or a C 5-9 heteroaryl each independently substituted by R 2a and by R 2b wherein R 2a is selected from the group consisting of hydrogen, —C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 2-3 alkylOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 0-6 alkylS(O) q C 1-3 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OH, —C 0-6 alkylC(O)OC 1-6 alkyl, —NR 8 C 0-6 alkylC(O)NR 6 R 7 , —NR 8 C 0-6 alkylC(O)C 1-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 and —C 0-6 alkylC(O)C 1-6 alkyl;
R 2b is selected from the group consisting of hydrogen, C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, and —C 0-6 alkylS(O) q C 1-3 alkyl;
R 3a is hydroxyl;
R 3b is selected from the group consisting of hydrogen, hydroxyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 hydroxyalkyl, —C 1-3 alkoxy, and —S(O) q C 1-3 alkyl;
R 4 is hydrogen or —C 1-3 alkyl;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is hydrogen or —C 1-6 alkyl;
R 7 is hydrogen or —C 1-6 alkyl;
R 8 is hydrogen or —C 1-6 alkyl;
p is 0, 1 or 2; and
q is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof, wherein the compound of formula (I) is in finely divided form.

2. A dry powder formulation according to claim 1 wherein:
R 1 is selected from the group consisting of hydrogen, and a saturated or unsaturated, branched or unbranched C 1-10 alkyl chain, wherein optionally one or more carbons is/are replaced by a heteroatom selected from the group consisting of O, OH, N, NH, NH 2 , S(O) p , wherein said chain is optionally substituted by one or more groups independently selected from thr group consisting of oxo, halogen, aryl, heteroaryl group, carbocyclyl and heterocyclyl,
each aryl, heteroaryl, carbocyclyl or heterocyclyl group bearing:
0 to 3 substituents selected from the group consisting of halogen, —C 1-6 alkyl, —C 1-6 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 1-6 haloalkyl, amino, —C 1-4 mono or —C 2-8 di-alkyl amino, —C 1-4 mono or —C 2-8 di-acyl amino, —C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OC 0-6 alkyl, —NC 0-6 alkylC(O)NR 6 R 7 —NC 0-6 alkylC(O)C 0-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 , and —C 0-6 alkylC(O)C 1-6 alkyl; and/or one aryl, heterocyclyl or carbocyclyl;

X is C 6-10 aryl or a C 5-9 heteroaryl each substituted by R 2a and optionally by R 2b wherein R 2a is selected from the group consisting of hydrogen, —C 1-3 alkyl, halo, hydroxyl, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy, —C 2-3 alkoxyOC 1-3 alkyl, —C 1-3 hydroxyalkyl, —C 0-6 alkylS(O) q C 1-3 alkyl, —C 0-6 alkylS(O) p NR 6 R 7 , —C 0-6 alkylNR 8 C 0-6 alkylS(O) p C 1-6 alkyl, —C 0-6 alkylC(O)OH, —C 0-6 alkylC(O)OC 1-6 alkyl, —NC 0-6 alkylC(O)NR 6 R 7 , —NR 8 C 0-6 alkylC(O)C 1-6 alkyl, —C 0-6 alkylC(O)NR 6 R 7 and —C 0-6 alkylC(O)C 1-6 alkyl;
R 2b is selected from the group consisting of hydrogen, C 1-3 alkyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 alkoxy and —C 0-6 alkylS(O) q C 1-3 alkyl;
R 3a is hydroxyl;
R 3b is selected from the group consisting of hydrogen, hydroxyl, halo, cyano, —C 1-3 haloalkyl, —C 1-3 hydroxy alkyl, —C 1-3 alkoxy, and —S(O) q C 1-3 alkyl;
R 4 is hydrogen or —C 1-3 alkyl;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is hydrogen or —C 1-6 alkyl;
R 7 is hydrogen or —C 1-6 alkyl;
R 8 is hydrogen or —C 16 alkyl;
p is 0 or an integer 1 or 2; and
q is 0 or an integer 1 or 2;
or a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof.

3. A dry powder formulation according to claim 1 , wherein R 1 is hydrogen.

4. A dry powder formulation according to claim 1 wherein R 1 is:

5. A dry powder formulation according to claim 1 wherein R 1 is —CH 2 CH 2 CH 2 C(O)OH.

6. A dry powder formulation according to claim 1 wherein R 1 is —CH 2 OCH 2 CH 2 OCH 2 CH 2 OCH 3 .

7. A dry powder formulation according to claim 1 , wherein R 2a is selected from the group comprising chloro, fluoro, cyano, methoxy, trifluoromethyl and SO 2 CH 3 .

8. A dry powder formulation according to claim 1 , wherein R 4 is hydrogen.

9. A dry powder formulation according to claim 1 , wherein R 5 is hydrogen.

10. A dry powder formulation according to claim 1 , wherein R 3a is in the meta position.

11. A dry powder formulation according to claim 1 , wherein R 3a is in the para position.

12. A dry powder formulation according to claim 1 , wherein carbocyclyl is a C 3-10 saturated or partially saturated carbocyclic ring systems.

13. A dry powder formulation according to claim 1 , wherein heteroaryl is a C 5-9 membered aromatic carbocylic ring or bicyclic ring system comprising one or more, heteroatoms independently selected from O, N and S.

14. A dry powder formulation according to claim 1 , wherein heterocyclic is a 5 to 10 membered ring system which is saturated or partially unsaturated and which is non-aromatic comprising one or more heteroatoms independently selected from O, N and S.

15. A dry powder formulation according to claim 1 , wherein aryl is C 6-14 mono or polycyclic groups having from 1 to 3 rings wherein at least one ring is aromatic.

16. A dry powder formulation according to claim 1 , wherein the compound of formula (I) is selected from:
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-ethynylquinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(3-(2-(2-methoxyethoxy)ethoxy)prop-1-yn-1-yl) quinazolin-4(3H)-one;
2-((4-Amino-3-(3-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-5-(6-morpholino-6-oxohex-1-yn-1-yl) quinazolin-4(3H)-one; 6-(2-((4-Amino-3-(4-hydroxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-3-(2-chlorobenzyl)-4-oxo-3,4-dihydroquinazolin-5-yl)hex-5-

Assignees

• Respivert Ltd
• Respivert Ltd

Inventors

• King-Underwood John
• Ito Kazuhiro
• Murray Peter John
• Hardy George
• Brookfield Frederick Arthur
• Brown Christopher John

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/08

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

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P27/02

  Ophthalmic agents · CPC title