Phosphinolactone derivatives and pharmaceutical uses thereof

Patent metadata

Field	Value
Publication number	US-10947260-B2
Application number	US-201716097914-A
Country	US
Kind code	B2
Filing date	Apr 27, 2017
Priority date	May 2, 2016
Publication date	Mar 16, 2021
Grant date	Mar 16, 2021

Abstract

A compound of following formula (I):

where:
X is O or S; A is an aromatic (hetero)cycle having 5 to 10 atoms selected from among carbon and nitrogen atoms, optionally being substituted; R′ is H or (C 1 -C 6 )alkyl group; R 1 , R 2 , R 3 , R 4 and R 5 , the same or different, are selected from the group formed by: H, (C 1 -C 6 )alkyl groups and (C 6 -C 10 )aryl groups.

The compound is for the treatment of neurodegenerative diseases.

First claim

The invention claimed is:

1. A method of treating a neurodegenerative disease, comprising administering to a subject in need thereof an effective a compound of following formula (I):

where:
X is O or S;
A is selected from the group formed by:
(C 6 -C 10 ) aryl groups,
heteroaryl groups having 5 to 10 atoms, and
heterocycloalkyls having 5 to 10 atoms,

said aryl, heteroaryl and heterocycloalkyl groups optionally being substituted by at least one substituent selected from the group formed by halogen atoms, OR a , SR a , NO 2 , NR a R b , N(R a )COOR c , R′ a and OR′ a ;
R a and R b , the same or different, being H or (C 1 -C 6 ) alkyl group;
R c being a —(C 1 -C 6 ) alkylene-(C 6 -C 10 ) aryl radical, in particular a —CH 2 — (C 6 -C 10 ) aryl radical;
R′ a being selected from the groups CF 3 , CHF 2 and CH 2 F
R′ is H or (C 1 -C 6 )alkyl group;
R 1 , R 2 , R 3 , R 4 and R 5 , the same or different, are selected from the group formed by:
H,
(C 1 -C 6 )alkyl groups, and
(C 6 -C 10 ) aryl groups,

R 1 and R 2 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms, and/or
R 3 and R 4 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms.

2. The method according claim 1 , wherein R′ is H.

3. The method according to claim 1 , wherein R 1 , R 2 , R 3 and R 4 , the same or different, are (C 1 -C 6 )alkyl groups and R 5 is H.

4. The method according to claim 1 , wherein X is O.

5. The method according to claim 1 , wherein A is an optionally substituted phenyl group.

6. The method according to claim 1 , wherein A is a heteroaryl having 6 atoms of which at least one is a nitrogen atom.

7. The method according to claim 6 , wherein A is selected from the group formed by 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, 2-pyrimidinyl and 5-pyrimidinyl groups.

8. Compound of following formula (I-1):

where:
R′ 1 , R′ 2 and R′ 3 , the same or different, are (C 1 -C 6 ) alkyl groups or (C 6 -C 10 )aryl groups, R′ 1 , R′ 2 and R′ 3 preferably being methyl groups;
R 4 and R 5 , the same or different, are selected from the group formed by:
H,
(C 1 -C 6 )alkyl groups, and
(C 6 -C 10 ) aryl groups,

R′ 1 and R′ 2 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms, and/or
R′ 3 and R 4 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms;
is selected from the group formed by:
(C 6 -C 10 ) aryl groups,
heteroaryl groups having 5 to 10 atoms, and
heterocycloalkyls having 5 to 10 atoms,

said aryl, heteroaryl and heterocycloalkyl groups optionally being substituted by at least one substituent selected from the group formed by halogen atoms, OR a , SR a , NO 2 , NR a R b , N(R a )COOR c , R′ a and OR′ a ;
R a and R b , the same or different, being H or (C 1 -C 6 ) alkyl group;
R c being a —(C 1 -C 6 ) alkylene-(C 6 -C 10 ) aryl radical, in particular a —CH 2 — (C 6 -C 10 ) aryl radical;
R′ a being selected from among the groups CF 3 , CHF 2 and CH 2 F;
and, when R′ 1 ═R′ 2 ═R′ 3 =Me, R 4 =Me or H and R 5 ═H, A differs from the following groups:

9. The compound according to claim 8 , wherein A is an aromatic ring having 6 atoms, at least one of which is a nitrogen atom, or A is selected from among the following groups:

10. Compound of following formula (1-2):

where:
A is selected from the group formed by:
(C 6 -C 10 ) aryl groups,
heteroaryl groups having 5 to 10 atoms, and,
heterocycloalkyls having 5 to 10 atoms,

said aryl, heteroaryl and heterocycloalkyl groups optionally being substituted by at least one substituent selected from the group formed by halogen atoms, OR a , SR a , NO 2 , NR a R b , N(R a )COOR c , R′ a and OR′ a ;
R a and R b , the same or different, being H or (C 1 -C 6 ) alkyl group;
R c being a —(C 1 -C 6 ) alkylene-(C 6 -C 10 ) aryl radical, in particular a —CH 2 — (C 6 -C 10 ) aryl radical;
R′ a being selected from the groups CF 3 , CHF 2 and CH 2 F;
R′ is H or (C 1 -C 6 )alkyl group;
R 1 , R 2 , R 3 , R 4 and R 5 , the same or different, are selected from the group formed by:
H,
(C 1 -C 6 )alky groups, and
(C 6 -C 10 ) aryl groups,

R 1 and R 2 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms, and/or
R 3 and R 4 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms.

11. Compound of following formula (1-3):

where:
X is O or S;
A is selected from the group formed by:
(C 6 -C 10 ) aryl groups,
heteroaryl groups having 5 to 10 atoms, and
heterocycloalkyls having 5 to 10 atoms,

said aryl, heteroaryl and heterocycloalkyl groups optionally being substituted by at least one substituent selected from the group formed by halogen atoms, OR a , SR a , NO 2 , NR a R b , N(R a )COOR c , R′ a and OR′ a ;
R a and R b , the same or different, being H or (C 1 -C 6 ) alkyl group;
R c being a —(C 1 -C 6 ) alkylene-(C 6 -C 10 ) aryl radical, in particular a —CH 2 — (C 6 -C 10 ) aryl radical;
R′ a being selected from the groups CF 3 , CHF 2 and CH 2 F;
R″ is a (C 1 -C 6 ) alkyl group;
R 1 , R 2 , R 3 , R 4 and R 5 , the same or different, are selected from the group formed by:
H,
(C 1 -C 6 )alky groups, and
(C 6 -C 10 ) aryl groups,

R 1 and R 2 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms, and/or
R 3 and R 4 , together with their carrier carbon atom, able to form a spiran ring having 3 to 6 carbon atoms.

12. Pharmaceutical composition comprising at least one compound according to claim 8 , in association with at least one pharmaceutically acceptable vehicle.

13. A pharmaceutical composition comprising at least one compound according to claim 9 , in association with at least one pharmaceutically acceptable vehicle.

14. A pharmaceutical composition comprising at least one compound according to claim 10 , in association with at least one pharmaceutically acceptable vehicle.

15. A pharmaceutical composition comprising at least one compound according to claim 11 , in association with at least one pharmaceutically acceptable vehicle.

Assignees

• Inst Nat Sante Rech Med
• Ecole Pratique Des Hautes Etudes
• Enscm
• Centre Nat Rech Scient
• Univ Montpellier

Inventors

• Maurice Tangui
• Volle Jean-Noël
• Virieux David
• Pirat Jean-Luc
• Laborde Coralie

Classifications

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07F9/6584 Primary

  having one phosphorus atom as ring hetero atom · CPC title