Respiratory formulations and compounds for use therein

Patent metadata

Field	Value
Publication number	US-2018201611-A1
Application number	US-201415530681-A
Country	US
Kind code	A1
Filing date	Dec 5, 2014
Priority date	Jun 17, 2010
Publication date	Jul 19, 2018
Grant date	—

Abstract

The present invention relates to respiratory formulations comprising a compound of formula (I):

and use of said compounds and compositions in treatment, for example in the treatment of an inflammatory disease or a respiratory disorder, in particular an inflammatory mediated and/or virally mediated respiratory disorder such as asthma and COPD or the treatment or prevention of viral infection, for example infection by influenza virus, rhinovirus or RSV. The invention also extends to certain novel compounds of formula (I).

First claim

1 . A pharmaceutical formulation for topical administration by inhalation comprising a population of particles comprising a compound of formula (I):

J represents:

Q is N or —CH—;
X is O or O—CH 2 —;
Y is —CH═ or N;
Z is O, NR 4 , —CR 4a ═N— or —N═CR 4a — whereby the latter two groups, together with the atoms to which they are attached, form a 6 membered ring;
R 1 is C 1-6 alkyl, branched or unbranched, or C 3-6 cycloalkyl, each optionally substituted by a hydroxyl group;
R 2a is H, halo, saturated or unsaturated branched or unbranched C 1-8 alkylene chain, wherein one or more carbons (for example 1 to 3, such as 1, 2 or 3 carbons) are optionally replaced by a heteroatom(s) independently selected from —O—, —N— and/or S(O) m and the chain is optionally substituted by one or more halogen atoms (for example 1 to 6);
R 2b is H, halo, C 1-6 alkoxy or C 1-6 alkyl optionally substituted by OH;
R 2 and R 3 each independently represent H, C 1-4 alkyl, halogen; C 1-4 haloalkyl, O(C 1-4 alkyl), O(C 1-4 haloalkyl), CN, SO 2 R 5 , C(O)OR 6 with the proviso that R 2 and R 3 do not both represent H concomitantly, or
R 2 and R 3 together with the carbons to which they are attached form a six membered aromatic ring or a heteroaromatic ring comprising a nitrogen atom;
R 4 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 6 aryl, a 5 or 6 membered heteroaryl or a 5 or 6 membered heterocyclic group, wherein said aryl, heteroaryl or heterocyclic group is substituted with 0 to 3 substituents selected from halogen, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, amino, C 1-4 mono or di-alkyl amino, C 1-4 mono or di-acyl amino, S(O) q C 1-6 alkyl, C 0-6 alkylC(O)C 1-6 alkyl or C 0-6 alkylC(O)C 1-6 heteroalkyl;
R 4a is H or C 1-3 alkyl;
R 5 is H or C 1-4 alkyl;
R 6 is H or C 1-4 alkyl;
m is 0, 1 or 2;
q is 0, 1 or 2;
a pharmaceutically acceptable salt thereof, including all stereoisomers, tautomers and isotopic derivatives thereof in particulate form, wherein the mass mean aerodynamic diameter (MMAD) of the population of particles is in the range 1 to 20 microns, for example 1 to 10 microns, such as 1 to 4 microns.

2 . A formulation according to claim 1 wherein Z in compounds of formula (I) is —N═CR 4a , NH or O.

3 - 4 . (canceled)

5 . A formulation according to claim 1 , wherein J in compounds of formula (I) represents phenyl substituted by R 2a and R 2b .

6 . A formulation according to claim 1 , wherein J in compounds of formula (I) represents pyridinyl substituted by R 2a and R 2b .

7 . A formulation according to claim 1 , wherein J in compounds of formula (I) represents thienyl substituted by R 2a .

8 . A formulation according to claim 1 comprising a compound of formula (II):

wherein R 1 , R 2 , R 2a , R 3 and X are as defined above for compounds of formula (I) and Z represents NH.

9 . A formulation according to claim 1 comprising a compound of formula (IIIa):

wherein R 1 , R 2 , R 2a , R 3 , R 4a and X are as defined above for compounds of formula (I).

10 . A formulation according to claim 1 , wherein R 1 is tert-butyl.

11 - 19 . (canceled)

20 . A formulation according to claim 1 comprising a compound selected from
1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea;
1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea;
1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(4-(2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea;
1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea;
1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-(1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)naphthalen-1-yl)urea;
1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(8-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)quinolin-5-yl)urea;
1-(3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(8-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yloxy)quinolin-5-yl)urea;
1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)-3-(4-((2-methyl-3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-methyl-3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((1-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((1-ethyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((1-isopropyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(2,3-dichloro-4-((1-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yl)oxy)phenyl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(8-((2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yl)oxy)quinolin-5-yl)urea;
1-(3-(tert-Butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((8-oxo-8,9-dihydro-7H-purin-6-yl)oxy) naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-hydroxyphenyl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-(hydroxymethyl)phenyl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-(hydroxymethyl)-3-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(2,3-dichloro-4-((3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yl)oxy)phenyl)urea;
1-(3-(tert-Butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(5-methylthiophen-2-yl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-Butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((7-oxo-7,8-dihydropteridin-4-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-butyl)-1-(6-methoxypyridin-3-yl)-1H-pyrazol-5-yl)-3-(4-((1-methyl-2-oxo-2,3-dihydro-1H-imidazo [4,5-b]pyridin-7-yl)oxy)naphthalen-1-yl)urea;
1-(3-(tert-butyl)-1-(4-methoxyphenyl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)urea;
1-(4-(3-(tert-butyl)-5-(3-(4-((3-oxo-3,4-dihydropyrido [2,3-b]pyrazin-8-yl)oxy)naphthalen-1-yl)ureido)-1H-pyrazol-1-yl)phenyl)-N-methylmethanesulfonamide;
1-(3-(tert-butyl)-1-(4-chlorophenyl)-1H-pyrazol-5-yl)-3-(4-((3-oxo-3,4-dihydropyrido [2,3-b

Assignees

• Respivert Ltd

Inventors

• Murray Peter John
• Onions Stuart Thomas
• Williams Jonathan Gareth
• Joly Kevin

Classifications

• A61P37/08

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

• A61P43/00

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

• A61P31/12

  Antivirals · CPC title

• A61P29/00

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

• A61P31/16

  for influenza or rhinoviruses · CPC title