Hydroxyalkyl-substituted phenyltriazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9771352-B2
Application number	US-201514930157-A
Country	US
Kind code	B2
Filing date	Nov 2, 2015
Priority date	Nov 3, 2014
Publication date	Sep 26, 2017
Grant date	Sep 26, 2017

Abstract

The present invention relates to novel 5-(hydroxyalkyl)-1-phenyl-1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular and renal diseases.

First claim

We claim:

1. A compound of formula (I)

wherein
R 1 is hydrogen or methyl,
and
R 2A and R 2B are independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy and trifluoromethoxy,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

2. The compound of claim 1 , wherein
R 1 is hydrogen or methyl,
and
R 2A and R 2B are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl and methoxy, wherein at least one of R 2A and R 2B is other than hydrogen,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

3. The compound of claim 1 , wherein the compound is selected from the group consisting of
5-(4-chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]-methyl-}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]-methyl-}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5 -(4-chlorophenyl)-2-{[5 -(hydroxymethyl)-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl]-methyl-}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-({1-(2-chloro-4-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-5 -(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-{[1-(2-chloro-4-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1);
2-{[1-(2-chloro-4-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2);
2-({1-(2-chloro-5-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-{[1-(2-chloro-5-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1);
2-{[1-(2-chloro-5-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2);
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1R)- 1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
and
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

4. The compound of claim 1 , wherein the compound is selected from the group consisting of
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
and
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

5. 5-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, a compound having the following formula

or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.

6. The compound of claim 5 , wherein the compound is 5-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one having the following formula

7. A process for preparing a compound of claim 1 , comprising:
reacting a compound of formula (II)

is with hydrazine to give the hydrazide of formula (III)

condensing the hydrazide of formula (III) with an amidine of formula (IV)

or a salt thereof,
wherein R 1 has the meaning indicated in claim 1 ,
in the presence of a base to give a 1,2,4-triazole derivative of formula (V)

and/or a tautomer thereof,
wherein R 1 has the meaning indicated in claim 1 ,
and coupling the 1,2,4-triazole derivative of formula (V) and/or tautomer thereof with a phenylboronic acid of formula (VI)

wherein R 2A and R 2B have the meanings indicated in claim 1 ,
in the presence of a copper catalyst and an amine base to yield a compound of formula (I)

wherein R 1 , R 2A and R 2B have the meanings indicated in claim 1 , and
when more than one diastereomer, hydrate, solvate, salt, or h

Assignees

• Bayer Pharma AG

Inventors

• Schmeck Carsten
• Gerisch Michael
• Griebenow Nils
• Kolkhof Peter
• Kölling Florian
• Engelen Anna
• Kretschmer Axel
• Lang Dieter
• Lustig Klemens
• Mondritzki Thomas
• Pook Elisabeth
• Beck Hartmut
• Süβmeier Frank
• Vollmer Sonja
• Wasnaire Pierre

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

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

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title