RU96108920A - INDOLA DERIVATIVES - Google Patents

Claims (15)

1. The compound of formula I

where R is a group selected from halo, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO ₂ R ₂ or COR ₂ groups, where R ₂ is hydroxy, methoxy, amino, alkylamino or dialkylamino group; m is zero or an integer 1 or 2;
R ₁ is cycloalkyl, bridged cycloalkyl, heteroaryl, bridged heterocyclic or possibly substituted phenyl or fused bicyclic group: A denotes a C _1-4 alkylene chain or chain (CH ₂ ) _p Y (CH ₂ ) _q , where Y is O, S ( O) _n or NR ₃ , and these chains may be substituted by one or two groups selected from C _1-6 alkyls, optionally substituted by hydroxy, amino, alkylamino or dialkylamino group, or these chains may be substituted by = O;
R ₃ is a hydrogen, alkyl or nitrogen protecting group;
n is zero or an integer from 1 to 2;
p is zero or an integer from 1 to 3;
a is zero or an integer from 1 to 3, provided that the sum p + q = 1, 2 or 3,
or its salt is metabolically labile ether.  2. The compound according to claim 1, characterized in that m is 2, and R is chlorine in positions 4 and 6 in the indole core. 3. Connection on PP. 1 and 2, characterized in that A is a chain selected from - (CH ₂ ) ₂ , - (CH ₂ ) ₃ -, -CH ₂ CO-, CH ₂ NH-, CH ₂ NCH ₃ -, (CH ₂ ) ₂ NH-, NHCO- or CH ₂ O-. 4. Connection on PP. 1 - 3, characterized in that A is a chain CH ₂ NH-. 5. The compound according to claims 1-4, wherein R ₁ is a group selected from optionally substituted phenyl, 1-naphthyl, 2-pyridyl, 2-quinolinyl, cyclohexyl or 2-adamantyl. 6. The compound according to claims 1 - 5, characterized in that R ₁ is possibly substituted phenyl. 7. The compound according to claims 1 - 6, characterized in that R ₁ is phenyl.  8. The trans isomer of a compound according to claims 1-7.  9. The compound according to claim 1, characterized in that it is (E) -4,6-dichloro-3- (5-oxo-1-phenyl-pyrazolidin-4-ylidene) -1H-indole-2-carboxylic acid or its physiologically acceptable salts or metabolically labile esters. 10. Compounds according to claim 1, characterized in that they are:
(E) -4,6-dichloro-3- (2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid;
(E) -4,6-dichloro-3- (2-oxo-1-phenyl-piperidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid;
(E) -4,6-dichloro-3 - [(5-oxo-1- (4-aminophenyl)) aminophenyl-4-ylidene] -1H-indole-2-carboxylic acid;
(Z) -4,6-dichloro-3- (2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl) -1H-and -ddol-2-carboxylic acid;
(E) -4,6-dichloro-3- (2,5-dioxo-1-phenyl-imidazolidin-4-ylidenemethyl) -1H-and -ddol-2-carboxylic acid;
4,6-dichloro-3- [5-oxo-1- (4-acetylamino-phenyl) -pyrazolidin-4-ylidenemyl) -1H-indole-2-carboxylic acid;
4,6-dichloro-3- [5-oxo-1- (4-ureido-phenyl) -pyrazolidin-4-ylidene] -1H- -indole-2-carboxylic acid;
4,6-dichloro-3- [1- (4-methylsulfamidophenyl) -5-oxo-pyrazolidin-4-ylidenmethyl] -1H-indole-2-carboxylic acid;
4,6-dichloro-3- (3-oxo-2-phenyl-isoxazolidin-4-ylidenemethyl) -1H-indole-2-carboxylic acid;
(E) -4,6-dichloro-3 - [(5-oxo-1- (3-aminophenyl)) - pyrazolidin-4-ylidene]) -1H-indole-2-carboxylic acid;
(E) -4,6-dichloro-3- (2,5-dioxo-1-phenyl-pyrrolidin-3-ylidenemethyl) -1H-indole-2-carboxylic acid;
(E) -4,6-dichloro-3 - [(5-oxo-1- (1-naphthyl) pyrazolidin-4-ylidenemethyl) -1H-and -dol-2-carboxylic acid;
and their physiologically acceptable salts and metabolically labile esters.  11. Compounds according to claims 1 - 10, characterized in that they are intended for use in therapy.  12. A method of manufacturing a therapeutic agent for suppressing the effects of excitatory amino acids on the NMDA receptor complex, characterized in that in the manufacturing process using a compound according to claims 1 - 10.  13. Pharmaceutical composition, characterized in that it comprises a compound according to claims. 1 to 10 mixed with one or more physiologically acceptable carriers or excipients.  14. A method of treating mammals, including humans, in conditions where the suppression of the effects of excitatory amino acids on the NMDA receptor complex is therapeutically justified, characterized in that the body is affected by an effective amount of the compound according to claims 1 - 10. 15. The method of producing compounds according to claim 1, which includes:
a) a method of producing compounds of formula I, where chain A has the meanings defined in paragraph 1, provided that A is not NHCO-, which includes the interaction of aldehyde II

where R has the meanings given in formula I, or is their protected derivative, R ₄ is a carboxyl-protecting group, and R ₅ is a nitrogen-protecting group,
with cyclic amide of formula III
where R ₁ and A have the meanings given in formula I (provided that A is not —NHCO), or are protected derivatives thereof,
in the presence of a base;
b) a method of producing compounds of the formula I, where A is the chain -NHCO-, which includes the interaction of aldehyde III or its protected derivative with a derivative of glycine VIII

where R ₁ is a group as defined in claim 1, or a protected derivative thereof, and R ₆ and R ₇ are independently C _1-4 alkyl. C) the method of obtaining the compounds of formula I, where A is CH ₂ CO, through the interaction of aldehyde II or its protected derivative with a phosphoric derivative IX

wherein R ₁ is as defined in formula I, or is a protected derivative thereof, in the presence of a base;
d) a method for preparing compounds of the formula I, wherein the exocyclic bond is in the cis configuration, which comprises irradiating the corresponding trans isomer or its protected derivative with UV light;
and if necessary or desirable, the resulting compound is subjected to one or more of the following operations:
(I) removing one or more protecting groups;
(Ii) isolating compounds as its salt;
(III) the conversion of the compounds of formula I or its salt in its metabolically labile ether or
(Iv) converting a compound of formula I into its physiologically acceptable salt.