Adamantane and memantine derivatives as peripheral NMDA receptor antagonists

Patent metadata

Field	Value
Publication number	US-10538482-B2
Application number	US-201615747507-A
Country	US
Kind code	B2
Filing date	Jul 26, 2016
Priority date	Jul 28, 2015
Publication date	Jan 21, 2020
Grant date	Jan 21, 2020

Abstract

The present invention relates to cationic compounds of formula (I) for use as peripheral NMDA receptor antagonists.

First claim

The invention claimed is:

1. Cationic compound of formula (I):

wherein:
R 1 and R 2 represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl group;
the group —(CH 2 ) n -A is linked to the cycle in position (a) or (b);
n is 0, 1, 2 or 3;
A represents a —NR 3 R 4 group or a —N + R 3 R 4 R 5 group;
R 3 , R 4 and R 5 represent, independently of each other, a hydrogen atom, a (C 1 -C 10 )alkyl group, a (C 1 -C 10 )alkoxy group, a (C 1 -C 10 )alkyl-C(═NH)(—OH) group, a (C 3 -C 8 )cycloalkane group, a 6- to 10-membered aryl group or a 5- to 12-membered heteroaryl group; said alkyl or alkoxy groups being optionally substituted with one or more —NR 6 R 7 group, —N + R 6 R 7 R 8 group, (C 3 -C 8 )cycloalkane group, 6- to 10-membered aryl group or 5- to 12-membered heteroaryl group;

with R 6 , R 7 and R 8 represent, independently of each other, a hydrogen atom or a (C 1 -C 6 )alkyl; and
the compound of formula (I) contains at least one positive charged nitrogen atom;
provided that R 1 and R 2 are not both a hydrogen atom; and
provided that when R 1 and R 2 are a methyl group, the group —(CH 2 ) n -A is linked to the cycle in position (a), and n is 0, then A is not a group —N + H 3 .

2. Cationic compound according to claim 1 , wherein R 1 and R 2 are chosen among a hydrogen atom or a methyl group.

3. Cationic compound according to claim 1 , wherein the group —(CH 2 ) n -A is linked to the cycle in position (a).

4. Cationic compound according to claim 1 , wherein n is 0 or 1.

5. Cationic compound according to claim 1 , wherein said compound is of formula (Ia):

wherein R 1 , R 2 , R 3 , R 4 , R 5 and n are as defined in claim 1 .

6. Cationic compound according to claim 1 , wherein R 3 , R 4 and R 5 represent, independently of each other, a (C 1 -C 10 )alkyl group.

7. Cationic compound according to claim 1 , wherein at least one of R 3 , R 4 and R 5 represents a methyl group.

8. Cationic compound according to claim 1 , wherein R 3 , R 4 and R 5 are simultaneously a methyl group.

9. Cationic compound according to claim 1 , wherein R 3 and R 4 are a methyl group and R 5 represent a (C 1 -C 10 )alkyl group substituted with a (C 3 -C 8 )cycloalkane group.

10. Cationic compound according to claim 1 , chosen among:

11. Medicament comprising as pharmaceutical active agent at least one compound as defined in claim 1 .

12. A pharmaceutical composition comprising at least one compound as defined in claim 1 , and at least one pharmaceutically acceptable excipient.

13. A pharmaceutical composition as claimed in claim 12 , wherein said compound is in combination with at least one other therapeutic agent.

14. Cationic compound of formula (I) according to claim 1 for use as a peripheral NMDA receptor antagonist.

15. Cationic compound according to claim 1 , for use for treating a disease or a condition chosen among pulmonary hypertension, pulmonary diseases involving inflammation, fibrosis and remodeling, non-neuronal cancers, diabetes, atherosclerosis, sickle cell disease, diseases involving thrombosis, acute infections, chronic infectious diseases, inflammatory disease, autoimmune disease, heart failure, arrhythmias, renal disorders, pain, psoriasis, atopic dermatitis, and osteoporosis.

16. Cationic compound according to claim 15 , wherein the disease is pulmonary arterial hypertension.

Assignees

• Inst Nat Sante Rech Med
• Hopitaux Paris Assist Publique
• Centre Nat Rech Scient
• Univ Paris Sud

Inventors

• Humbert Marc
• Cohen-Kaminsky Sylvia
• Dumas Sébastien
• Bru-Mercier Gilles
• Alami Mouad
• Brion Jean-Daniel
• Messaoudi Samir
• Galvani Gilles

Classifications

• A61P9/12

  Antihypertensives · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C07C2601/02

  with a three-membered ring · CPC title

• C07C211/63

  having quaternised nitrogen atoms bound to acyclic carbon atoms · CPC title

• C07C215/08

  with only one hydroxy group and one amino group bound to the carbon skeleton · CPC title