Substituted 2-imino-1,3-thiazolidin-4-ones as N-arachidonoylethanolamine cellular uptake inhibitors

Patent metadata

Field	Value
Publication number	US-10155754-B2
Application number	US-201515314067-A
Country	US
Kind code	B2
Filing date	May 28, 2015
Priority date	May 28, 2014
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

The invention relates to a compound comprising the following general formula (1):

and said compound for use as a medicament, in particular for use in the treatment psychiatric or neurological disorders and inflammation, in particular neuroinflammation: (formula 1) wherein each of R 1 , R 2 and R 3 are selected independently from each other from alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, or heteroaryl.

First claim

The invention claimed is:

1. A compound of formula (1):

wherein:
R 1 is selected from formula (2e) or formula (2e′):

wherein:
D is C 1 -C 4 -alkyl;
T is independently selected from —CH 2 —, —NH—, —S—, —O—, —CH(CH 3 )— or —C(CH 3 ) 2 —;
each Z 1 is independently selected from —F, —Cl, —Br, —I, —CN, —R a , —OR a , —(CH 2 ) r OR a , —SR a , —(CH 2 ) r SR a or —N(R a ) 2 ;
each R a is independently selected from H, an unsubstituted C 1 -C 8 -alkyl, an unsubstituted C 2 -C 8 -alkenyl or an unsubstituted C 2 -C 8 -alkynyl;
r is 1, 2, 3 or 4; and
n is 0, 1, 2 or 3;

R 2 is selected from an unsubstituted cycloalkyl, a substituted or unsubstituted aryl, an unsubstituted saturated heterocyclyl, or a substituted or unsubstituted heteroaryl;
wherein:
the substituted aryl or the substituted heteroaryl is substituted by at least one Z 2 ;
each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R b , —OR b , —(CH 2 ) r OR b , —SR b , —(CH 2 ) r SR b or —N(R b ) 2 ;
each R b is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
r is 1, 2, 3 or 4; or

R 2 is formula -L-Ar;
wherein:
L is an alkyl, an alkenyl or an alkynyl; and
Ar is a substituted or unsubstituted C 6 -aryl or a substituted or unsubstituted C 5 -C 6 -heteroaryl;
wherein:
the substituted C 6 -aryl or substituted C 5 -C 6 -heteroaryl is substituted by at least one Z 2 ;
each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R b , —OR b , —(CH 2 ) r OR b , —SR b , —(CH 2 ) r SR b or —N(R b ) 2 ;
each R b is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
r is 1, 2, 3 or 4; and

R 3 is selected from an unsubstituted alkyl, an unsubstituted alkoxy, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, an unsubstituted saturated heterocyclyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;
wherein:
the substituted aryl or substituted heteroaryl is substituted by at least one Z 3 ;
each Z 3 is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;
each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
r is 1, 2, 3 or 4; or

R 3 is formula -D-Ar;
wherein:
D is an alkyl, an alkenyl or an alkynyl; and
Ar is a substituted or unsubstituted C 6 -aryl or a substituted or unsubstituted C 5 -C 6 -heteroaryl;
wherein:
the substituted C 6 -aryl or substituted C 5 -C 6 -heteroaryl is substituted by at least one Z 3 ;
each Z 3 is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;
each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
r is 1, 2, 3 or 4.

2. The compound according to claim 1 , wherein each Z 1 is independently selected from —F, —Cl, —Br, —I, —CN, —R a , —OR a or —(CH 2 ) r OR a .

3. The compound according to claim 1 , wherein R 2 is formula -L-Ar.

4. The compound according to claim 1 , wherein R 2 is formula -L-Ar, wherein formula -L-Ar is formula (4a) or formula (4b):

wherein o is 0, 1, 2, 3, 4 or 5; or

wherein o is 1, 2, 3, 4 or 5.

5. The compound according to claim 4 , wherein each Z 2 is independently selected from —F, —Cl, —Br, —I, —CN, —R b , —OR b , —CH 2 OR b or —N(R b ) 2 .

6. The compound according to claim 1 , wherein:
R 3 is selected from an unsubstituted alkyl, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl; or
R 3 is formula -D-Ar.

7. The compound according to claim 1 , wherein:
R 3 is an unsubstituted C 3 -C 10 -cycloalkyl; or
R 3 is formula -D-Ar.

8. The compound according to claim 1 , wherein R 3 is formula -D-Ar, wherein formula -D-Ar is formula (5a) or formula (5b):

wherein p is 0, 1, 2, 3, 4 or 5; or

wherein p is 1, 2, 3, 4 or 5.

9. A method for inhibiting N-arachidonoylethanolamine uptake in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

10. The method according to claim 9 , wherein the subject has a disorder selected from the group consisting of a psychiatric disorder, a neurological disorder and neuroinflammation.

11. A compound of formula (1):

wherein:
R 1 is formula (6a):

wherein:
M is alkyl, alkenyl or alkynyl;
each Z 10 is independently selected from —CN, —OR e or —CH 2 OR e ;
each R e is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
l is 0, 1, 2 or 3; or

R 1 is formula (6b):

wherein:
each Z 10 is independently selected from —CN, —OR e or —CH 2 OR e ;
each R e is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
l is 1, 2 or 3; or

R 1 is selected from an unsubstituted saturated heterocyclyl or a substituted or unsubstituted heteroaryl;
wherein:
the substituted heteroaryl is substituted by at least one substituent;
each substituent is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;
each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
r is 1, 2, 3 or 4;

R 2 is an unsubstituted alkyl, an unsubstituted alkoxy, an unsubstituted alkenyl, an unsubstituted alkynyl, an unsubstituted cycloalkyl, an unsubstituted saturated heterocyclyl, a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl;
wherein:
the substituted aryl or substituted heteroaryl is substituted by at least one substituent;
each substituent is independently selected from —F, —Cl, —Br, —I, —CN, —R d , —OR d , —(CH 2 ) r OR d , —SR d , —(CH 2 ) r SR d or —N(R d ) 2 ;
each R d is independently selected from H, an unsubstituted C 1 -C 12 -alkyl, an unsubstituted C 2 -C 12 -alkenyl or an unsubstituted C 2 -C 12 -alkynyl; and
r is 1, 2, 3 or 4; or

Assignees

• Univ Bern

Inventors

• Reymond Jean-Louis
• Nicolussi Simon
• Gertsch Jurg

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D417/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D277/54 Primary

  Nitrogen and either oxygen or sulfur atoms · CPC title