Disubstituted trifluoromethyl pyrimidinones and their use

Patent metadata

Field	Value
Publication number	US-2016221965-A1
Application number	US-201415021372-A
Country	US
Kind code	A1
Filing date	Sep 12, 2014
Priority date	Sep 16, 2013
Publication date	Aug 4, 2016
Grant date	—

Abstract

The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.

First claim

1 . A compound of the formula (I)

in which
A represents C—H, C—F or N,
E represents CH 2 , CH(CH 3 ), 0, S, S(═O) or S(═O) 2 ,
R 1 and R 2 , independent of one another represent hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy,
where at least one of the two radicals R 1 and R 2 represents fluorine, chlorine, trifluoromethyl or trifluoromethoxy, and
R 3 represents (C 1 -C 4 )-alkyl which may be substituted by hydroxy, represents cyclopropyl or cyclobutyl or represents a group of the formula —NR 4A R 4B , —NH—C(═O)—R 5 , —NH—C(═O)—NH 2 or —CH 2 —C(═O)—NH 2 in which R 4A , R 4B and R 5 , independent of one another, represent hydrogen or (C 1 -C 4 )-alkyl, and their salts, solvates and solvates of the salts.

2 . The compound of the formula (I) according to claim 1 in which
A represents C—H, C—F or N,
E represents CH 2 , O or S,
R 1 and R 2 , independent of one another, represent hydrogen, fluorine, chlorine, methyl or trifluoromethyl, where at least one of the two radicals R 1 and R 2 represents fluorine, chlorine or trifluoromethyl, and
R 3 represents (C 1 -C 4 )-alkyl, which may be substituted by hydroxy, represents cyclopropyl or cyclobutyl or represents a group of the formula —NR 4A R 4B , —NH—C(═O)—R 5 , —NH—C(═O)—NH 2 or —CH 2 —C(═O)—NH 2 in which R 4A , R 4B and R 5 , independent of one another, represent hydrogen or (C 1 -C 4 )-alkyl, and their salts, solvates and solvates of the salts.

3 . The compound of the formula (I) according to claim claim 1 in which
A represents C—H or C—F,
E represents CH 2 , O or S,
R 1 represents fluorine, chlorine or trifluoromethyl,
R 2 represents hydrogen, fluorine, chlorine, methyl or trifluoromethyl and
R 3 represents (C 1 -C 4 )-alkyl which may be substituted by hydroxy, represents cyclopropyl or represents a group of the formula —NR 4A R 4B or —CH 2 —C(═O)—NH 2 in which R 4A and R 4B independently of one another represent hydrogen, methyl or ethyl, and their salts, solvates and solvates of the salts.

4 . The compound of the formula (I) according to claim claim 1 in which
A represents C—H,
E represents CH 2 or O,
R 1 represents fluorine, chlorine or trifluoromethyl,
R 2 represents fluorine or chlorine and
R 3 represents methyl, hydroxymethyl, ethyl, n-propyl, cyclopropyl or a group of the formula —NR 4A R 4B or —CH 2 —C(═O)—NH 2 in which R 4A and R 4B both represent hydrogen, and their salts, solvates and solvates of the salts.

5 . A process for preparing a compound of the formula (I) as defined in claim 1 , characterized in that
[A] a compound of the formula (II)

in which A, R 1 and R 2 have the meanings given in claim 1 ,
E 1 represents CH 2 or O and
T 1 represents methyl, ethyl, n-propyl or n-butyl, is condensed with a compound of the formula (III)

in which R 3 has the meaning given in claim 1 , or a salt thereof to give a compound of the formula (I-A)

in which A, E 1 , R 1 , R 2 and R 3 have the meanings given above, or

[B] a compound of the formula (IV)

in which A, R 1 and R 2 have the meanings given in claim 1 , and
E 2 represents O or S, is reacted in the form of an alkali metal salt or in the presence of a base with a compound of the formula (V)

in which R 3 has the meaning given in claim 1 to give a compound of the formula (I-B)

in which A, E 2 , R 1 , R 2 and R 3 have the meanings given above, and the resulting compounds of the formulae (I-A) and (I-B) are optionally converted with the appropriate (i) solvents and/or (ii) acids into their solvates, salts and/or solvates of the salts.

6 . The compound as defined in claim 1 for treatment and/or prevention of diseases.

7 . The compound as defined in claim 1 for use in a method for the treatment and/or prevention of acute coronary syndrome, myocardial infarction, acute and chronic heart failure, acute and chronic kidney failure and acute lung damage.

8 . Use of a compound as defined in claim 1 for preparing a medicament for the treatment and/or prevention of acute coronary syndrome, myocardial infarction, acute and chronic heart failure, acute and chronic kidney failure and acute lung damage.

9 . A medicament comprising a compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

10 . A medicament comprising a compound as defined in claim 1 in combination with one or more further active compounds selected from the group of the antihyperglycaemic agents (antidiabetics), the hypotensive agents, the platelet aggregation inhibitors, the anticoagulants and the HMG-CoA reductase inhibitors (statins).

11 . A medicament according to claim 9 for the treatment and/or prevention of acute coronary syndrome, myocardial infarction, acute and chronic heart failure, acute and chronic kidney failure and acute lung damage.

12 . A method for treatment and/or prevention of acute coronary syndrome, myocardial infarction, acute and chronic heart failure, acute and chronic kidney failure and acute lung damage in humans and animals by administration of an effective amount of at least one compound as defined in any of claim 1 .

13 . A method for treatment and/or prevention of acute coronary syndrome, myocardial infarction, acute and chronic heart failure, acute and chronic kidney failure and acute lung damage in humans and animals by administration of an effective amount of a medicament as defined in claim 9 .

Assignees

• Bayer Pharma AG

Inventors

• Straub Alexander
• Collin Marie-Pierre
• Koch Michael
• Meyer Jutta
• Schlemmer Karl-Heinz
• Nising Carl Friedrich
• Biber Nicole
• Anlauf Sonja
• Wittwer Matthias Beat

Classifications

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P29/00

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

• C07D239/545

  with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms · CPC title