Pyrimidinone compounds as human neutrophil elastase inhibitors

Patent metadata

Field	Value
Publication number	US-9365577-B2
Application number	US-201314108904-A
Country	US
Kind code	B2
Filing date	Dec 17, 2013
Priority date	Dec 18, 2012
Publication date	Jun 14, 2016
Grant date	Jun 14, 2016

Abstract

Pyrimidinone compounds defined herein exhibit human neutrophil elastase inhibitory properties and are useful for treating diseases and conditions in which HINE is implicated.

First claim

The invention claimed is:

1. A compound of formula (I):

wherein
A is CH;
B is CH;
D is CH;
R 1 is:
hydrogen;
(C 1 -C 6 )alkyl;
NR 7 R 8 (C 1 -C 6 )alkyl;
(C 1 -C 4 )alkenyl;
phenyl(C 1 -C 6 )alkyl wherein said phenyl ring is optionally substituted by a NR 15 R 16 (C 1 -C 6 )alkyl or by N + R 15 R 16 R 17 (C 1 -C 6 )alkyl;
a group —CH 2 (CH 2 ) n OH;
a group —(CH 2 ) n CONR 5 R 6 ;
a group —(CH 2 ) n SO 2 NR 5 R 6 ;
a group —CH 2 —(CH 2 ) n NR 5 SO 2 R 6 ;
a group —(CH 2 ) t —(C 6 H 4 )—SO 2 (C 1 -C 4 )alkyl;
group —(CH 2 ) r SO 2 (C 1 -C 4 )alkyl wherein the (C 1 -C 4 )alkyl is optionally substituted by —NR 15 R 16 or —N + R 15 R 16 R 17 ;
a group —SO 2 -phenyl wherein the phenyl ring is optionally substituted by NR 7 R 8 (C 1 -C 6 )alkyl; or
a group —(CH 2 ) n —W wherein W is a 5-6-membered heteroaryl ring which is optionally substituted by —SO 2 (C 1 -C 4 )alkyl;
n is 1, 2 or 3;
t is zero, 1, 2 or 3;
r is zero, 1, 2 , 3 or 4;
R 5 is: hydrogen, (C 1 -C 6 )alkyl, NR 16 R 15 (C 1 -C 6 )alkyl or
N + R 17 R 15 R 16 (C 1 -C 6 )alkyl;
R 6 is hydrogen or (C 1 -C 6 )alkyl;
R 7 is: hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkylcarbonyl, —S 0 2 (C 1 -C 4 )alkyl, or NR 16 R 15 (C 1 -C 6 )alkyl;
R 8 is hydrogen or (C 1 -C 6 )alkyl; alternatively, R 7 and R 8 may form, together with the nitrogen atom to which they are attached, a (C 5 -C 7 )heterocycloalkyl ring system which is optionally substituted by one or more (C 1 -C 6 ) alkyl groups or oxo;
R 16 is hydrogen or (C 1 -C 6 )alkyl;
R 15 is hydrogen or (C 1 -C 6 )alkyl;
R 17 is hydrogen or (C 1 -C 6 )alkyl;
R 3 is —C(O)—XR 4 ;
X is: —O—;
R 4 is:
hydrogen; or
(C 1 -C 6 )alkyl;
R 2 is:
NR 18 R 19 (C 1 -C 6 )alkyl;
—CONR 21 R 20 ;
C 2 -C 6 -alkenyl which is substituted by —OH or —NR 18 R 19 ;
C 2 -C 6 -alkynyl which is substituted by —OH or —NR 18 R 19 ; or
a group —[CH 2 ] y -G-[CH 2 ] j —CH 2 —N + R 22 R 23 R 24
or R 2 is a group:

or R 2 is a group:

R 14 is hydrogen or (C 1 -C 6 )alkyl which may be optionally substituted by a (C 1 -C 4 )alkoxyl group;
R 18 is hydrogen or (C 1 -C 6 )alkyl;
R 19 is hydrogen or (C 1 -C 6 )alkyl;
R 20 is: hydrogen, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylNR 18 R 19 ;
R 21 is hydrogen or (C 1 -C 6 )alkyl;
j is an integer ranging from zero to 4;
y is an integer ranging from zero to 4;
G is a divalent linker selected from the group consisting of: —O—, —(SO 2 )—, NR 25 , a bond, C 2 -C 6 -alkenylene, C 2 -C 6 -alkynylene, (C 3 -C 6 )cycloalkylene, monocyclic heterocycloalkylene, bicyclic heterocycloalkylene, —[CONR 25 ]— and —[NR 25 CO]—;
R 25 is hydrogen or (C 1 -C 6 )alkyl;
R 22 is: (C 1 -C 6 )alkyl, which is optionally substituted by one or more of
(C 3 -C 6 )cycloalkyl, phenyl, benzyl, CN, —OR 26 , —SO 2 R 26 , —CO 2 R 26 , —CONR 26 R 27 or —SO 2 NR 26 R 27 ; (C 3 -C 10 )cycloalkyl which is optionally substituted by one or more of —OR 26 , —SO 2 R 26 , —CO 2 R 26 , —CONR 26 R 27 or —SO 2 NR 26 R 27 ; or
(C 4 -C 7 )heterocycloalkyl which is optionally substituted by one or more of —OR 26 ,
—SO 2 R 26 , —CO 2 R 26 , —CONR 26 R 27 or —SO 2 NR 26 R 27 ;
R 26 is hydrogen or (C 1 -C 6 )alkyl;
R 27 is hydrogen or (C 1 -C 6 )alkyl;
R 23 is hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted by one or more of —OR 29 , —SO 2 R 29 , —CO 2 R 29 , —CONR 29 R 30 or
—SO 2 NR 29 R 30 ;
R 24 is hydrogen or (C 1 -C 6 )alkyl, which (C 1 -C 6 )alkyl is optionally substituted by one or more of —OR 31 , —SO 2 R 31 , —CO 2 R 31 , —CONR 31 R 32 or
—SO 2 NR 31 R 32 ;
alternatively, R 23 and R 24 may form, together with the nitrogen atom to which they are attached, a 5-11-membered saturated monocyclic or bicyclic heterocyclic ring system which is optionally substituted by one or more of —OR 28 , halo, C 1 -C 6 alkyl, —SO 2 R 33 , —CO 2 R 33 , —CONR 33 R 34 or —SO 2 NR 33 R 34 ; and which 5-11-membered saturated monocyclic or bicyclic ring optionally contains a further heteroatom which is oxygen or nitrogen or a —SO 2 — group;
or R 22 together with R 23 , R 24 and the nitrogen atom to which they are attached, may form a bridged bicyclic heterocyclic ring;
R 28 is hydrogen or (C 1 -C 6 )alkyl;
R 29 is hydrogen or (C 1 -C 6 )alkyl;
R 30 is hydrogen or (C 1 -C 6 )alkyl;
R 31 is hydrogen or (C 1 -C 6 )alkyl;
R 32 is hydrogen or (C 1 -C 6 )alkyl;
R 33 is hydrogen or (C 1 -C 6 )alkyl;
R 34 is hydrogen or (C 1 -C 6 )alkyl;
R 38 represents one or two optional substituents at each occurrence independently selected from the group consisting of: (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxyl, hydroxyl, hydroxyl-C 1 -C 6 -alkyl, halo, trifluoromethyl, and trifluoromethoxy;
wherein if one or more groups N + R 11 R 12 R 13 — or N + R 15 R 16 R 17 — are present, they form a quaternary salt with a pharmaceutically acceptable counter ion;
and wherein groups R 5 to R 38 , and n may have the same or different meanings at each occurrence, if present in more than one group,
or a pharmaceutically acceptable salt thereof.

2. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 2 is —[CH 2 ] y -G-[CH 2 ] j —CH 2 —N + R 22 R 23 R 24 .

3. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 4 is (C 1 -C 6 )alkyl.

4. The compound or pharmaceutically acceptable salt according to claim 1 , wherein R 1 is hydrogen or —(CH 2 ),SO 2 (C 1 -C 4 )alkyl.

5. A compound which is selected from the group consisting of:
5-[4-cyano-2-(4-hydroxy-but-1-ynyl)-phenyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester;
5-[4-cyano-2-(3-dimethylamino-prop-1-ynyl)-phenyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester;
5-[4-cyano-2-(3-dimethylamino-prop-1-ynyl)-phenyl]-2-(3-methanesulfonyl-propyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester;
(3-{5-cyano-2-[2-(3-methanesulfonyl-propyl)-6-methoxycarbonyl-7-methyl-3-oxo-8-m-tolyl-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-phenyl}-prop-2-ynyl)-trimethyl-ammonium formate;
5-[4-cyano-2-(3-dimethylamino-propyl)-phenyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester;
5-(4-cyano-2-dimethylaminomethyl-phenyl)-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidine-6-carboxylic acid methyl ester;
{5-cyano-2-[6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-benzyl}-trimethyl-ammonium bromide;
(2-{5-cyano-2-[6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-benzoylamino}-ethyl)-trimethyl-ammonium chloride;
{5-cyano-2-[(R)-6-methoxycarbonyl-7-methyl-3-oxo-8-(3-trifluoromethyl-phenyl)-2,3,5,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrimidin-5-yl]-benzyl}-trimethyl-ammonium formate;
(R)-5-[4-cyano-2-(3-dimethylamino-propyl)-phenyl]-7-methyl-3-oxo-8-(3-trifluoromethyl-phe

Assignees

• Chiesi Farma Spa

Inventors

• Alcaraz Lilian
• Heald Robert Andrew
• Sutton Jonathan Mark
• Armani Elisabetta
• Capaldi Carmelida

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P29/00

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title