Indolin-2-one pyridine derivatives, preparation and therapeutic use thereof
View Patent ↗The disclosure concerns indolin-2-one pyridine compounds of general formula (I): wherein R 0 , R 1 , R 2 , R 3 , R 4 , Z and B have the meanings given in the description, and pharmaceutically acceptable salts thereof; and also pharmaceutical compositions comprising, processes for making and methods of using said compounds.
1. A compound of formula (I):
wherein:
R 0 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 1 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 2 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 3 represents a hydrogen atom or a (C 1 -C 6 )alkyl group;
R 4 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
Z represents a tetrahydrofuranyl group or a tetrahydropyranyl group, said groups optionally being substituted by one or more (C 1 -C 3 )alkyl, hydroxyl or carboxyl groups or a —CH 2 OH group;
B represents a T-W group, in which:
T represents a —(CH 2 ) m — group, in which m is equal to 0 or 1;
W represents:
a —CONR 6 R 7 group, in which:
R 6 represents a hydrogen atom or a (C 1 -C 6 )alkyl group,
R 7 represents a (C 1 -C 6 )alkylene group;
or W represents an —NR 8 COR 9 group, in which:
R 8 represents a hydrogen atom or a (C 1 -C 6 )alkyl group,
R 9 represents a —(CH 2 ) n -group, in which n is a value selected from 0 to 3;
or a racemic mixture, enantiomer, or diastereoisomer of said compound, or a mixture thereof;
or a pharmaceutically acceptable salt thereof.
2. The compound of formula (I) as claimed in claim 1 , wherein:
R 0 represents a (C 1 -C 6 )alkoxy group;
R 1 represents a (C 1 -C 6 )alkoxy group;
R 2 , R 3 , R 4 , Z and B are as defined in claim 1 ;
or a racemic mixture, enantiomer, or diastereoisomer of said compound, or a mixture thereof;
or a pharmaceutically acceptable salt thereof.
3. The compound of formula (I) as claimed in claim 1 , wherein:
R 0 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 1 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 2 , R 3 , R 4 and B are as defined in claim 1 ;
Z represents an oxygen atom;
or a racemic mixture, enantiomer, or diastereoisomer of said compound, or a mixture thereof;
or a pharmaceutically acceptable salt thereof.
4. The compound of formula (I) as claimed in claim 1 , in which:
R 0 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 1 represents a hydrogen atom, a halogen atom, a (C 1 -C 6 )alkyl group or a (C 1 -C 6 )alkoxy group;
R 2 , R 3 , R 4 and B are as defined in claim 1 ;
Z represents a tetrahydrofuranyl group or a tetrahydropyranyl group, said groups optionally being substituted by one or more (C 1 -C 3 )alkyl groups, a hydroxyl or carboxyl group or a —CH 2 OH group;
or a racemic mixture, enantiomer, or diastereoisomer of said compound, or a mixture thereof;
or a pharmaceutically acceptable salt thereof.
5. The compound as claimed in claim 1 , selected from the group consisting of:
1-(β-D-glucopyranuronosyl)-3-[({4-chloro-3-[5-chloro-1-(2, 4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]benzoyl}(ethyl)amino)methyl]pyridinium chloride;
3-[({4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]benzoyl}(ethyl)amino)methyl]-1-(D-glucopyranosyl)pyridinium chloride; and
3-[({4-chloro-3-[5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-indol-3-yl]benzoyl}(ethyl)amino)methyl]-1-(D-galactopyranosyl)pyridinium chloride.
6. A process for the preparation of a compound of formula (I) as claimed in claim 1 , wherein the compound of formula (II):
in which R 0 , R 1 , R 2 , R 3 , R 4 and B are as defined in claim 1 , is reacted with a compound of formula Z-X, in which Z is as defined in claim 1 and X represents a leaving group.
7. A pharmaceutical composition comprising one or more compound according to claim 1 and a suitable excipient.
8. A pharmaceutical composition comprising one or more compound according to claim 2 and a suitable excipient.
9. A pharmaceutical composition comprising one or more compound according to claim 3 and a suitable excipient.
10. A pharmaceutical composition comprising one or more compound according to claim 4 and a suitable excipient.
11. A pharmaceutical composition comprising one or more compound according to claim 5 and a suitable excipient.