Amide-substituted pyridinyltriazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-9988367-B2
Application number	US-201715581064-A
Country	US
Kind code	B2
Filing date	Apr 28, 2017
Priority date	May 3, 2016
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention relates to novel 5-(carboxamide)-1-pyridinyl-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 general formula (I)

in which
R 1 represents a group of the formula

in which
# 1 represents the point of attachment to the nitrogen atom,

Ar represents a group of the formula

in which
# 2 represents the point of attachment to the nitrogen atom,
R 2A represents a group selected from the group consisting of a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl, and —C(═O)NH 2 ,
R 2B represents a group selected from the group consisting of a chlorine atom, trifluoromethyl, and ethoxycarbonyl;

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

2. A compound of general formula (I) according to claim 1 , wherein
R 1 represents a group of the formula

in which
# 1 represents the point of attachment to the nitrogen atom,

Ar represents a group of the formula

in which
# 2 represents the point of attachment to the nitrogen atom,
R 2A represents a group selected from the group consisting of a chlorine atom, a bromine atom, trifluoromethyl, trifluoromethoxy, ethoxycarbonyl, and —C(═O)NH 2;

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

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

in which
# 1 represents the point of attachment to the nitrogen atom,

Ar represents a group of the formula

in which
# 2 represents the point of attachment to the nitrogen atom,
R 2A represents a group selected from the group consisting of a chlorine atom, trifluoromethyl, and trifluoromethoxy;

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

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

in which R 1 is as defined for the compound of general formula (I),
R 3 represents a (C 1 -C 4 )-alkyl group, to react in a first step in the presence of a base, and optionally a copper salt, with a compound of general formula (III):

in which
R 4 represents a (C 1 -C 4 )-alkyl group, to give an intermediate compound, which is then allowed to react in the presence of a base in a second step with a hydrazine compound of general formula (IV) or a respective salt thereof

in which Ar is as defined for the compound of general formula (I), thereby giving a compound of general formula (V):

in which R 1 and Ar are as defined for the compound of general formula (I),
R 4 represents a (C 1 -C 4 )-alkyl group, followed by a subsequent step

[B] allowing the compound of general formula (V) obtained in step [A] to react with ammonia thereby giving a compound of general formula (I):

in which R 1 and Ar are as defined for the compound of general formula (I), optionally followed by step

[C] converting alcohol of general formula (I-A):

in which Ar is as defined for the compound of general formula (I), to ketone of general formula (I-B):

in which Ar is as defined for the compound of general formula (I), by oxidation,

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

5. Compound as defined in claim 1 , for use in a method for the treatment of acute kidney disease, chronic kidney disease, acute heart failure, chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome and dysmenorrhea.

6. Pharmaceutical composition comprising a compound as defined in claim 1 , and one or more pharmaceutically acceptable excipients.

7. Pharmaceutical composition of claim 6 , comprising one or more first active ingredients, which are compounds of general formula (I), and one or more further active ingredients, which are one or more additional therapeutic agents selected from the group consisting of diuretics, angiotensin AII antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, antidiabetics, organic nitrates and NO donors, activators and stimulators of the soluble guanylate cyclase (sGC), antiinflammatory agents, immunosuppressive agents, phosphate binders, and/or compounds which modulate vitamin D metabolism.

8. The pharmaceutical composition as defined in claim 6 , for the treatment of acute kidney disease, chronic kidney disease, acute heart failure, chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, and dysmenorrhea.

9. A method for treatment of at least one of the group consisting of acute kidney disease, chronic kidney disease, acute heart failure, chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, and dysmenorrhea in a human or other mammal;
comprising administering to the human or other mammal in need thereof a therapeutically effective amount of one or more compounds as defined in claim 1 .

10. A method for treatment of at least one of the group consisting of acute kidney disease, chronic kidney disease, acute heart failure, chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, and dysmenorrhea in a human or other mammal; comprising administering to the human or other mammal in need thereof a therapeutically effective amount of a pharmaceutical composition comprising (i) one or more compounds as defined in claim 1 , and (ii) one or more pharmaceutically acceptable excipients.

Assignees

• Bayer Pharma AG

Inventors

• Collin Marie-Pierre
• Kolkhof Peter
• Neubauer Thomas
• Fürstner Chantal
• Pook Elisabeth
• Wittwer Matthias Beat
• Lustig Klemens
• Buchmüller Anja
• Tinel Hanna
• DRÖBNER Karoline
• Mondritzki Thomas
• Schirmer Heiko
• Kretschmer Axel
• Schmeck Carsten
• Wasnaire Pierre
• Cernecka Hana

Classifications

• A61K31/4439 Primary

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

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61P9/04

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