Patent EA-000308-B1 (EA)
Title: Indole derivatives as eaa antagonists
Inventor: CONTI NADIA
IPC: A61K31/403
Filed: 1996-03-01
Abstract: 1. A compound of formula (I)   or a salt, or metabolically labile ester thereof wherein m is 2, and R is chloro at the 4 and 6 position. A is an unsubstituted ethenyl group in the trans configuration. R1 represents hydrogen,C1-4alkyl optionally substituted by carboxyl, C3-6cycloalkyl, phenyl optionally substituted by methoxy, 3-pyridyl, 4-tetrahydro-pyranyl. R2 represents hydrogen or methyl. R3 represents hydrogen. n is zero or an integer from 1 to 4 X= 0 or S. 2. A compound as claimed in Claim 1 wherein R1 and R2, each represent hydrogen. 3. A compound as claimed in Claim 1 or 2 wherein X represents oxygen. 4. A compound as claimed in any of Claims 1 to 3 wherein the substituent (CH2)nNR3CXNR1R2is at the 4 position on the phenyl ring. 5. A compound as claimed in any of Claims 1 to 4 wherein n is 1 or 2. 6. 4. 6-Dichloro-3-1(E)-2'-(4'-ureidomethyl phenylcarbamoyl) ethenyl] 3-1 H-indole 2-carboxylic acid and physiologically acceptable salts thereof. 7. A compound as claimed in any of Claims 1 to 6 for use in therapy. 8. The use of a compound as claimed in any of Claims 1 to 6 in the manufacture of a therapeutic agent for antagonising the effects of excitatory amino acids on the NMDA receptor complex. 9. A pharmaceutical composition comprising a compound as claimed in any of Claims 1 to 6 in admixture with one or more physiologically acceptable carriers or exdpients. 10. A method of treatment of a mammal including man for conditions where antagonising the effects of excitatory amino adds on the NMDA receptor complex is of therapeutic benefit comprising administration of an effective amount of a compound as claimed in any of Claims 1 to 6. 11. A process for preparing compounds as defined in Claim 1 which comprises: (a) A process for preparing compounds of formula (I) in which a compound of formula (II) in which A, R, R3, m and n have the meaning, defined in formula (I), R5 is carboxylic protecting group and R6 represents hydrogen or a nitrogen protecting group   with the compounds of formula (III) wherein X represents oxygen or sulphur and R1and.R2 have the meanings defined in formula (1) or is protected derivatives thereof, or the compounds (IV) wherein the R1 and R2 have the meaning defined in formula(l) or are protected derivatives thereof and R7 is optionally substituted phenoxyhalogen, or imidazole group; (b) A process for preparing compounds of formula (1) wherein A. R. m, R5 and R6 have the meanings defined above in which activated derivative of the carboxylic acid (V)   with the amine (VI)   wherein R1, R2.R3.n and X have the meanings defined in formula(l) or are protected derivative thereof; (c) A process for preparing compounds of formula (I) which comprises reacting a compound of formula (VII) in which R and m have the means given above, R5 is a carboxyl protecting group, R6 is hydrogen or a nitrogen protecting group and R8 is hydrogen atom   with an appropriate phosphorus reagent capable of converting the group CR8O into the group   wherein A, nX, R3, R2, R1 have meanings defined above for formula (I); and if necessary subjecting the resulting compound to one or more of the following operations: (i) removal of one or more protecting groups; (ii) isolation of the compound as a salt thereof; (iii) conversion of a compound of formula (I) into a physiologically acceptable salt thereof. 12. A compound of formula (II)   and salts thereof wherein A, R, R3 and m have the meanings defined in Claim, n is 1 to 4, R5 is hydrogen or a carboxyl protecting group and R6 is hydrogen or a nitrogen protecting group.