Hydroxyalkyl-substituted heteroaryltriazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-10526314-B2
Application number	US-201716098202-A
Country	US
Kind code	B2
Filing date	May 2, 2017
Priority date	May 3, 2016
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

Abstract

The present invention relates to novel 5-(hydroxyalkyl)-1-heteroaryl-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 renal and cardiovascular diseases.

First claim

The invention claimed is:

1. A compound of formula (I):

in which
R 1 represents a group selected from a hydrogen atom and methyl,
Ar represents a 5- or 6-membered heteroaryl group attached via a ring carbon atom having one or two ring heteroatoms selected from a nitrogen atom and a sulfur atom,
wherein any 5- or 6-membered heteroaryl group are each optionally substituted, identically or differently, with one or two groups selected from a halogen atom, nitro, cyano, (C 1 -C 4 )-alkyl, (C 1 -C 4 )-alkoxy, (C 1 -C 4 )-alkylsulfanyl, (C 1 -C 4 )-alkoxycarbonyl, aminocarbonyl and —S(═O) 2 NH 2 ,
wherein said (C 1 -C 4 )-alkyl group, said (C 1 -C 4 )-alkoxy group and said (C 1 -C 4 ) -alkylsulfanyl group are each optionally substituted with up to three fluorine atoms,

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

2. A compound of formula (I) according to claim 1 , wherein
R 1 represents a methyl group,
Ar represents a group selected from pyridine, pyrazine, pyridazine, 1-methylimidazole, 1,3-thiazole,
wherein any pyridine group is each optionally substituted, identically or differently, with one or two groups selected from a fluorine atom, a chlorine atom, methoxy, trifluoromethyl and trifluoromethoxy,
wherein any pyrazine group is optionally substituted with methoxy,

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

3. A compound of formula (I) according to claim 1 , wherein
R 1 represents a methyl group,
Ar represents a group of the formula

in which
# 1 represents the point of attachment to the nitrogen atom,
R 2 A represents a group selected from a hydrogen atom, a chlorine atom, trifluoromethyl and trifluoromethoxy,
R 2B represents a group selected from a hydrogen atom and a chlorine atom
R 2C represents a chlorine atom,

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

4. A method of preparing a compound of formula (I) of claim 1 , said method comprising the step
[A] of allowing an intermediate compound of formula (II):

in which
R 3 represents a (C 1 -C 4 )-alkyl group, to react in a first step in the presence of an at least stoichiometric amount of a base with a compound of formula (III):

in which
R 1 is as defined for the compound of formula (I) according to claim 1 ,
PG represents a suitable alcohol protecting group,

to give an intermediate compound, which is then allowed to react in a second step with a hydrazine compound of formula (IV) or a respective salt thereof

in which
Ar is as defined for the compound of formula (I) according to claim 1 ,

thereby giving an intermediate compound of formula (V):

in which
R 1 Ar are as defined for the compound of formula (I) according to claim 1 ,
PG represents a suitable alcohol protecting group,

followed by alcohol deprotection of (V) with a suitable deprotection agent thereby giving a compound of formula (I) in which
R 1 and Ar are as defined for the compound of formula (I) according to claim 1 ,

or
[B] allowing an intermediate compound of formula (VI):

in which,
R 1 is as defined for the compound of formula (I) according to claim 1 ,
and/or a tautomer thereof to react with a compound of formula (VII):

in which
Ar is as defined for the compound of general formula (I) according to claim 1 , and
R XA and R XB represent, independently from each other, a hydrogen atom, or
R XA and R XB together form a —CH 2 CH 2 —or —C(CH 3 ) 2 C(CH 3 ) 2 — bridge,

in the presence of a copper catalyst and an amine base thereby giving a compound of general formula (I) in which
R 1 and Ar are as defined for the compound of general formula (I) according to claim 1 ,

each [A] and [B] optionally followed, where appropriate, by (i) separating the compounds of formula (I) thus obtained into their respective diastereomers, and/or (ii) converting the compounds of formula (I) into their respective hydrates, solvates, salts and/or hydrates or solvates of the salts by treatment with the corresponding solvents and/or acids or bases.

5. A pharmaceutical composition comprising a compound as defined in claim 1 and one or more pharmaceutically acceptable excipients.

6. The pharmaceutical composition of claim 5 further comprising one or more first active ingredients selected from the group consisting of:
a diuretic,
an angiotensin AII antagonist,
an ACE inhibitor,
a beta-receptor blocker,
a mineralocorticoid receptor antagonist,
an antidiabetic,
an organic nitrate,
a NO donor,
an activator and stimulator of the soluble guanylate cyclase (sGC),
an antiinflammatory agent,
an immunosuppressive agent,
a phosphate binder and
a compound which modulate vitamin D metabolism.

Assignees

• Bayer Ag
• Bayer Pharma AG

Inventors

• Collin-Kröpelin Marie-Pierre
• Kolkhof Peter
• Neubauer Thomas
• Fürstner Chantal
• Pook Elisabeth
• Wittwer Matthias Beat
• Schmeck Carsten
• Wasnaire Pierre
• Tinel Hanna
• Schirmer Heiko

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61K31/497

  containing further heterocyclic rings · 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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title