Compounds

Patent metadata

Field	Value
Publication number	US-9862706-B2
Application number	US-201715606064-A
Country	US
Kind code	B2
Filing date	May 26, 2017
Priority date	May 31, 2016
Publication date	Jan 9, 2018
Grant date	Jan 9, 2018

Abstract

Imidazolone and pyrazolone derivatives of formula (I) described herein exhibit human neutrophil elastase inhibitory properties and are useful for the therapy of diseases and conditions in which HNE is implicated.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
X is —C or —N;
Y is C or N, wherein X and Y are not simultaneously C or simultaneously N;
R 1 is linear or branched —(C 1 -C 6 )alkyl, —(C 3 -C 6 )cycloalkyl, —(C 3 -C 6 )heterocycloalkyl, or aryl(C 1 -C 6 )alkylene-, wherein any of said —(C 3 -C 6 )cycloalkyl, —(C 3 -C 6 )heterocycloalkyl, and aryl(C 1 -C 6 )alkylene- may be optionally substituted by linear or branched —(C 1 -C 6 )haloalkyl-C(O)—, —(C 1 -C 6 )alkylsulfonyl, or aryl(C 1 -C 6 )alkylene-OC(O)—;
A is a group of one of the following formulae:

wherein
Q is —CH or N;
R 2 is —(C 1 -C 6 )alkyl, aryl(C 1 -C 6 )alkylene-, or heteroaryl(C 1 -C 6 )alkylene-;
R 3 is —(C 1 -C 6 )alkyleneN + R a R b R c or heteroaryl(C 1 -C 6 )alkylene;
R a is —(C 1 -C 6 )alkyl;
R b is —(C 1 -C 6 )alkyl;
R c is —(C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkylene, or heteroaryl(C 1 -C 6 )alkylene- or R a and R b together may form an heterocycloalkyl with the N + atom, wherein such heterocycloalkyl and heteroaryl may be optionally substituted by one or more (C 1 -C 6 )alkyl;

wherein the nitrogen atom in the heterocycloalkyl and heteroaryl groups may be quaternized; and
wherein the dotted lines connecting X to the carbon atom in position 4 and Y, indicate that when X is N, then the double bond is in 4-5 position, and when Y is N, then the double bond is in 3-4 position,
or a pharmaceutically acceptable salt thereof.

2. A compound or salt according to claim 1 , wherein X is C and Y is N.

3. A compound or salt according to claim 1 , wherein X is N and Y is C.

4. A compound or salt according to claim 1 , wherein A is

wherein Q is CH or N, and R 2 is —(C 1 -C 6 )alkyl or aryl(C 1 -C 6 )alkylene-.

5. A compound or salt according to claim 1 , wherein A is

wherein R 3 is —(C 1 -C 6 )alkyleneN + R a R b R c , R a and R b are each independently —(C 1 -C 6 )alkyl; and R c is —(C 1 -C 6 )alkyl, aryl-(C 1 -C 6 )alkylene-, or heteroaryl(C 1 -C 6 )alkylene-.

6. A compound which is selected from the group consisting of:
1-(4-cyanophenyl)-2-{3-(cyclopentylcarbamoyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-methyl-1H-imidazol-3-ium benzene sulfonate;
1-(4-cyanophenyl)-2-{3-(cyclopentylcarbamoyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-benzyl-1H-imidazol-3-ium bromide;
1-(4-cyanophenyl)-2-{3-(cyclobutylcarbamoyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-methyl-1H-imidazol-3-ium benzene sulfonate;
1-(4-cyanophenyl)-2-{3-[1-(2,2,2-trifluoro-acetyl)-piperidin-4-ylcarbamoyl]-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-methyl-1H-imidazol-3-ium benzene sulfonate;
1-(4-cyanophenyl)-2-{3-(4-methanesulfonyl-benzylcarbamoyl)-5-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1H-imidazol-4-yl}-3-methyl-1H-imidazol-3-ium benzene sulfonate;
1-(4-cyano-phenyl)-5-[3-cyclopentylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-4-methyl-1H-[1,2,4]triazol-4-ium benzene sulfonate;
3-(4-cyano-phenyl)-2-[4-cyclopentylcarbamoyl-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H-pyrazol-3-yl]-1-methyl-3H-imidazol-1-ium benzenesulfonate;
1-(4-cyano-phenyl)-5-[4-cyclopentylcarbamoyl-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H-pyrazol-3-yl]-4-methyl-1H-[1,2,4]triazol-4-ium benzenesulfonate;
[2-(5-cyano-2-{5-[3-cyclopentylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-phenyl)-ethyl]-trimethyl-ammonium benzene sulfonate;
benzyl-[2-(5-cyano-2-{5-[3-cyclopentylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-phenyl)-ethyl]-dimethyl-ammonium bromide;
[2-(5-cyano-2-{5-[3-cyclohexylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-phenyl)-ethyl]-trimethyl-ammonium benzene sulphonate;
[2-(5-cyano-2-{5-[3-cyclopropylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-phenyl)-ethyl]-trimethyl-ammonium benzene sulphonate;
[2-(5-cyano-2-{5-[3-ethylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-phenyl)-ethyl]-trimethyl-ammonium benzene sulphonate;
[2-(5-cyano-2-{5-[3-isopropylcarbamoyl-5-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-imidazol-4-yl]-pyrazol-1-yl}-phenyl)-ethyl]-trimethyl-ammonium benzene sulphonate;
(2-{5-cyano-2-[4′-cyclopentylcarbamoyl-2′-methyl-5′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,5′-dihydro-1′H-[3,3′]bipyrazolyl-2-yl]-phenyl}-ethyl)-trimethyl-ammonium benzene sulfonate;
benzyl-(2-{5-cyano-2-[4′-cyclopentylcarbamoyl-2′-methyl-5′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,5′-dihydro-1′H-[3,3′]bipyrazolyl-2-yl]-phenyl}-ethyl)-dimethyl-ammonium bromide; and
(2-{5-cyano-2-[4′-cyclohexylcarbamoyl-2′-methyl-5′-oxo-1′-(3-trifluoromethyl-phenyl)-2′,5′-dihydro-1′H-[3,3′]bipyrazolyl-2-yl]-phenyl}-ethyl)-trimethyl-ammonium benzene sulfonate,
or a pharmaceutically acceptable salt of said compound.

7. A pharmaceutical composition, comprising a compound or salt according to claim 1 and a pharmaceutically acceptable carrier or excipient.

8. A pharmaceutical composition according to claim 7 which is in a form suitable for oral administration or administration by the pulmonary route.

9. A method for the treatment of a disease or condition in which HNE is implicated, comprising administering an effective amount of a compound or salt according to claim 1 to a subject in need thereof.

10. A method according to claim 9 , wherein the disease or condition is chronic obstructive pulmonary disease, bronchiectasis, chronic bronchitis, lung fibrosis, pneumonia, acute respiratory distress syndrome, pulmonary emphysema, smoking-induced emphysema, or cystic fibrosis.

11. A method according to claim 9 , wherein the disease or condition is asthma, rhinitis, psoriasis, atopic dermatitis, non-atopic dermatitis, Crohn's disease, ulcerative colitis, or irritable bowel disease.

Assignees

• Chiesi Farm Spa

Inventors

• Capaldi Carmelida
• Armani Elisabetta
• Jennings Andrew Stephen Robert

Classifications

• A61P17/00

  Drugs for dermatological disorders · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D233/86

  Oxygen and sulfur atoms, e.g. thiohydantoin · CPC title

• C07D231/22

  with aryl radicals attached to ring nitrogen atoms · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title