Heteroarylcarboxamide derivatives as plasma kallikrein inhibitors

Patent metadata

Field	Value
Publication number	US-10501440-B2
Application number	US-201815953523-A
Country	US
Kind code	B2
Filing date	Apr 16, 2018
Priority date	Apr 21, 2017
Publication date	Dec 10, 2019
Grant date	Dec 10, 2019

Abstract

Disclosed are heteroarylcarboxamides of formula (I),

and pharmaceutically acceptable salts thereof, wherein A, T, R 1 , R 2 and R 3 are as defined herein. Also disclosed are methods of using these compounds for the treatment of diseases which can be influenced by inhibition of plasma kallikrein.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein
A is selected from the group A-G1 consisting of N and CH;
T is selected from the group T-G1 consisting of N, C—H, C—C 1-4 -alkyl, C—CHF 2 , C—CF 3 and C—OCH 3 ;
R 1 is selected from the group R 1 -G1 consisting of C 1-3 -alkyl;
R 2 is selected from the group R 2 -G1 consisting of a fused or spiro bicyclic ring system consisting of 1 N atom and 5 to 6 C atoms as ring members, wherein the ring system is attached via the N atom to the monocyclic heteroaromatic ring in formula (I) and wherein the ring system is optionally substituted with one substituent selected from the group consisting of F, C 1-3 -alkyl, CF 3 , CN, HO—C 1-3 -alkyl- and C 1-3 -alkyloxy- and wherein the ring system is optionally additionally substituted with one substituent selected from the group consisting of F and CH 3 ; and
R 3 is selected from the group R 3 -G1 consisting of H, CH 3 , CHF 2 or CF 3 ,

or a salt thereof.

2. The compound according to claim 1 , wherein
A is CH,

or a salt thereof.

3. The compound according to claim 1 , wherein
A is N,

or a salt thereof.

4. The compound according to claim 1 , wherein
T is selected from the group T-G3 consisting of N, C—H, C—CH 3 , C—CH(CH 3 ) 2 , C—CHF 2 , C—CF 3 and C—OCH 3 ,

or a salt thereof.

5. The compound according to claim 1 , wherein
R 1 is CH 3 ,

or a salt thereof.

6. The compound according to claim 1 , wherein
R 2 is selected from the group R 2 -G4 consisting of

wherein, as indicated by the asterisk, the ring system is attached via the N atom to the monocyclic heteroaromatic ring in formula (I),
or a salt thereof.

7. The compound according to claim 1 , wherein
R 3 is selected from the group R 3 -G2 consisting of H and CH 3 ,

or a salt thereof.

8. The compound according to claim 1 , wherein the compound of formula (I) is selected from the group consisting of

or a salt thereof.

9. A pharmaceutically acceptable salt of a compound according to claim 1 .

10. A pharmaceutical composition comprising one or more compounds according to claim 1 , or pharmaceutically acceptable salts thereof, optionally together with one or more inert carriers and/or diluents.

11. A pharmaceutical composition comprising one or more compounds according to claim 1 , or pharmaceutically acceptable salts thereof, and one or more additional therapeutic agents, optionally together with one or more inert carriers and/or diluents.

12. The pharmaceutical composition according to claim 11 wherein the one or more additional therapeutic agents are selected from the group consisting of antidiabetic agents, agents for the treatment of overweight and/or obesity, agents for the treatment of high blood pressure, heart failure and/or atherosclerosis and agents for the treatment of ocular diseases.

13. A method for treatment of diabetic complications, in a patient in need thereof, the method comprising administering a compound according to claim 1 , or pharmaceutically acceptable salts thereof, to the patient.

14. The method according to claim 13 , wherein the diabetic complication is retinal vascular permeability associated with diabetic retinopathy or diabetic macular edema.

Assignees

• Boehringer Ingelheim Int

Inventors

• Frattini Sara
• Lingard Iain
• Hamprecht Dieter Wolfgang
• Bakker Remko Alexander
• Eckhardt Matthias
• Gollner Andreas
• Hehn Joerg P
• Langkopf Elke
• Wagner Holger
• Wellenzohn Bernd
• Wiedenmayer Dieter

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K45/06

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

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title