Pyrazolone compounds having human neutrophil elastase inhibitory properties

Patent metadata

Field	Value
Publication number	US-10172830-B2
Application number	US-201715606154-A
Country	US
Kind code	B2
Filing date	May 26, 2017
Priority date	May 31, 2016
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

Pyrazolone derivatives of formula (I) defined herein exhibit human neutrophil elastase inhibitory properties and are useful for the treatment of diseases or conditions in which HNE is implicated.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
Z is —O— or —NH;
W is —H or (C 1 -C 4 )alkyl;
A is:

X is —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkylene-NR d R e , linear or branched —(C 1 -C 4 )alkylene-aryl, linear or branched —(C 2 -C 4 )alkylene-heteroaryl,

R 1 is:

n is an integer from 1 to 4;
m is an integer from 1 to 4;
t is 0 or an integer from 1 to 4;
y is an integer from 1 to 4;
w is an integer from 1 to 4;
R 2 is —H or linear or branched —(C 1 -C 4 )alkyl;
R 3 is —H, linear or branched —(C 1 -C 4 )alkyl; or
R 2 and R 3 may form together a —(C 3 -C 6 )cycloalkyl;
R 4 is heteroaryl, -arylene-(C 1 -C 4 )alkylene-NR d R e , heteroarylene-(C 1 -C 4 )alkylene-NR d R e , or

R 5 is —H, —(CH 2 ) t -heteroaryl, aryl-(C 1 -C 4 )alkyleneoxy-, linear or branched (C 1 -C 4 )alkyl-OC(O)—NH—, —(CH 2 ) t —NR d R e , —C(O)—N(R 10 )(C 1 -C 4 )alkylene-NR d R e , —C(O)O(C 1 -C 4 )alkylene-NR d R e , —O—C(O)—(C 1 -C 4 )alkylene-NR d R e , —(CH 2 ) t NHC(O)—(C 1 -C 4 )alkylene-NR d R e , or

R 6 is —H, —(C 1 -C 4 )alkyl, aryl-(C 1 -C 4 )alkylene-OC(O)—, CF 3 C(O)—, aryl-(C 1 -C 4 )alkylene-, linear or branched (C 1 -C 4 )alkyl-OC(O)—, —C(O)—(C 1 -C 4 )alkylene-NR d R e , —C(O)-heterocycloalkyl, —C(O)O—(C 1 -C 4 )alkylene-NR d R e , or —C(O)—N(R 10 )(C 1 -C 4 )alkylene-NR d R e ;
R d is —H or —(C 1 -C 4 )alkyl;
R e is —H or —(C 1 -C 4 )alkyl;
R 7 is —H or —(C 1 -C 4 )alkyl;
R 8 is —H or —(C 1 -C 4 )alkyl;
R 9 is -heterocycloalkyl, heterocycloalkyl-(C 1 -C 4 )alkylene-, or (C 1 -C 4 )alkylene-NR d R e ;
R 10 is —H or —(C 1 -C 4 )alkyl;
wherein any of such heterocycloalkyl, aryl, heteroaryl, heterocycloalkyl-(C 1 -C 4 )alkylene- and aryl-(C 1 -C 4 )alkylene may be optionally substituted by one or more groups independently selected from the group consisting of —(C 1 -C 4 )alkyl and —OR 7 , and
wherein * and # indicate the points of attachment for the radical groups to the rest of the molecule,
or a pharmaceutically acceptable salt thereof.

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

R 6 is —H, —(C 1 -C 4 )alkyl, —C(O)—(C 1 -C 4 )alkylene-NR d R e , or —C(O)-heterocycloalkyl, wherein the heterocycloalkyl may be optionally substituted by one or more —(C 1 -C 4 )alkyl groups; R d and R e are independently —H or —(C 1 -C 4 )alkyl; n is 2; m is 2; and R 7 is —H or —(C 1 -C 4 )alkyl.

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

R 2 and R 3 are independently —H or linear or branched —(C 1 -C 4 )alkyl; R 4 is heteroaryl optionally substituted by one or more —(C 1 -C 4 )alkyl.

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

R 2 and R 3 are independently —H or linear or branched —(C 1 -C 4 )alkyl; R 4 is -heteroarylene-(C 1 -C 4 )alkylene-NR d R e ; R d and R e are independently —H or —(C 1 -C 4 )alkyl.

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

R 2 is —H or linear or branched —(C 1 -C 4 )alkyl; R 3 is —H; R 1 is

R 7 is —H or —(C 1 -C 4 )alkyl; t is 0; n is 2; and m is 2.

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

R 10 is —H or —(C 1 -C 4 )alkyl; n is 1 or 2; m is 1 or 2; and R 7 is —H.

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

t is 0 or 1, n is 2, m is 2, and R 7 is —H.

8. A compound as claimed in claim 1 , wherein X is

n is 1 or 2, m is 1 or 2, R 7 is —H, and R d and R e are each independently —(C 1 -C 4 )alkyl.

9. A compound which is selected from the group consisting of
2′-(4-cyano-phenyl)-2-methyl-5-oxo- 1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid ethyl ester;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3 -trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H- [3,3′]bipyrazolyl-4-carboxylic acid (1-methyl-piperidin-4-yl)-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid ethylamide;
(3aS,5R,6aR)-5- {[2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carbonyl]-amino}-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2H-[3,3′bipyrazolyl-4-carboxylic acid [(S)-1-(5-dimethylaminomethyl-oxazol-2-yl)-ethyl]-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-{3,3′bipyrazolyl-4-carboxylic acid [1-(2-dimethylamino-acetyl)-piperidin-4-yl]-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid {(S)-1-[methyl-(1-methyl-piperidin-4-ylmethyl)-carbamoyl]-ethyl}-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid [(S)-1-(5-dimethylaminomethyl-[1,3,4]oxadiazol-2-yl)-ethyl]-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid {1-methyl-1-[methyl-(1-methyl-piperidin-4-ylmethyl)-carbamoyl]-ethyl}-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid [(S)-1-(5-dimethylaminomethyl-oxazol-2-yl)-2-methyl-ethyl]-amide;
2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid [(S)-1-(5-dimethylaminomethyl-oxazol-2-yl)-2-methyl-propyl]-amide;
2′-(trans-4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid [4-(1-methyl-piperidin-4-ylcarbamoyl)-cyclohexyl]-amide;
trans-4-{[2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carbonyl]-amino}-cyclohexanecarboxylic acid 1-methyl-piperidin-4-yl ester
2′-(trans-4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-carboxylic acid [4-(4-dimethylamino-piperidine-1-carbonyl)-cyclohexyl]-amide;
trans-4-{[2′-(4-cyano-phenyl)-2-methyl-5-oxo-1-(3-trifluoromethyl-phenyl)-2,5-dihydro-1H,2′H-[3,3′]bipyrazolyl-4-ca

Assignees

• Chiesi Farm Spa

Inventors

• Sutton Jonathan Mark
• Heald Robert Andrew
• Jennings Andrew Stephen Robert
• Capaldi Carmelida
• Armani Elisabetta

Classifications

• A61P11/06

  Antiasthmatics · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• A61K31/4152 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone · CPC title

• C07D249/08

  1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles · CPC title