Patent EA-001704-B1 (EA)
Title: Tetrahydroquinaline derivatives as eaa antagonists
Inventor: DI-FABIO ROMANO
IPC: C07D215/48
Filed: 1997-08-14
Abstract: 1. A compound of formula (I)   a physiologically acceptable salt, or a metabolically labile ester thereof wherein R represents a group selected from halogen, C1-4alkyl, C1-4alkoxy, amino, C1-4alkylamino, diC1-4alkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO2R2 or COR2 wherein R2 represents hydroxy, methoxy, amino, C1-4alkylamino or diC1-4alkylamino; m is zero or an integer 1 or 2; R1 represents a group (CH2)nCN, -CH=CHR3, (CH2)nNHCOCH2R4 or O(CH2)pNR5R6; R3 represents cyano or the group COR7; R4 represents C1-4alkoxy or a group NHCOR8; R5 and R6 each represent independently hydrogen or C1-4alkyl, or R5 and R6 together with the nitrogen atom to which they are attached represent a (5-7)-membered saturated heterocyclic group which contains one or two heteroatoms selected from oxygen, sulfur or nitrogen, or R5 is hydrogen and R6 is the group COR9; R7 represents an C1-4alkoxy, amino or hydroxyl group; R8 represents a hydrogen atom or C1-4alkyl or C1-4alkoxy group optionally substituted with one or more hydroxy-, carboxy or amino group, phenyl group optionally substituted with substituents up to three selected from halo, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkylamino group, hydroxy, trifluoromethyl, carboxyl, or methoxycarbonyl, 5-membered heteroaryl group comprising 1 or 2 heteroatoms, selected from oxygen, sulfur or nitrogen, 6-membered heteroaryl group comprising 1 or 2 nitrogen atoms, or (5-7)-membered saturated heterocyclic group which contains one or two heteroatoms selected from oxygen, sulfur or nitrogen, optionally N-substituted with C1-4 alkyl, acyl or C1-4 alkoxycarbonyl. R9 is the group R8 or the group NR10R11 wherein R10 represents hydrogen or C1-4 alkyl group; R11 represents C1-4 alkyl group, optionally substituted with one or more hydroxy-, carboxy or amino group, phenyl group optionally substituted with substituents up to three selected from halo, C1-4 alkyl, C1-4 alkoxy, amino, C1-4 alkylamino group, hydroxy, trifluoromethyl, carboxyl, or methoxycarbonyl, 5-membered heteroaryl group comprising 1 or 2 heteroatoms, selected from oxygen, sulfur or nitrogen, 6-membered heteroaryl group comprising 1 or 2 nitrogen atoms, (5-7)-membered saturated heterocyclic group which contains one or two heteroatoms selected from oxygen, sulfur or nitrogen, optionally N-substituted with C1-4 alkyl, acyl or C1-4 alkoxycarbonyl or C3-7 cycloalkyl group optionally substituted with 1 or 2 C1-4 alkyl groups. n is zero or an integer from 1 to 4; p is an integer from 2 to 4. 2. A compound of formula (I) as claimed in Claim 1, wherein m is 1 or 2, and R is halogen atom in the 5 and /or 7 position. 3. A compound of formula (I) as claimed in any of Claims 1-2 wherein m is 2 and R is chlorine in the 5 and 7 position. 4. A compound of formula (I) as claimed in any of Claims 1-3 wherein R1 is the group (CH2)nCN, -CH=CHR3, (wherein R3 is cyano or COR7, in which R7 is C1-4 alkoxy or amino), (CH2)nNHCOCH2R4 (wherein R4 is C1-4 alkoxy or NHCOR8 wherein R8 is hydrogen or C1-4alkyl), O(CH2)pNR5R6 (wherein R5 and R6 are hydrogen or NR5R6 represents morpholino or R5 represents hydrogen and R6 is COR9 wherein R9 is hydrogen or C1-4alkyl), n is zero, 1 or 2; p is 2, 3 or 4. 5. A compound of formula (I) as claimed in Claim 4 wherein R1 is the group: cyanomethyl, 2-isobutyrylamino-ethoxy, 2-methoxy-acetylamino, isobutyrylamino-methylcarbonylamino, 2-morpoholin-4-yl-ethoxy or CH=CHR3 wherein R3 is a tert-butoxycarbonyl, carbamoyl or cyano group. 6. A compound selected from (+-) (E) 5,7-dichloro-4-[4-(2-methoxy-acetylamino)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E) 5,7-dichloro-4-[4-(2-isobutyrylamino-methylcarbonylamino)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E) 5,7-dichloro-4-(4-cyanomethyl-phenylcarbamoylmethylene)-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E,E) 5,7-dichloro-4-[4-(2-cyano-vinyl)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E,E) 4-[4-(2-tert-butoxycarbonyl-vinyl)-phenylcarbamoylmethylene]-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E,E) 4-[4-(2-carbamoyl-vinyl)-phenylcarbamoylmethylene]-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E) 5,7-dichloro-4-[4-(2-isobutyrylamino-ethoxy)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; (+-) (E) 5,7-dichloro-4-[4-(2-morpholin-4-yl-ethoxy)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; and physiologically acceptable salts thereof, e.g. sodium salt, metabolically labile esters or enantiomers thereof. 7. 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 excipients. 8. The use of a compound as claimed in any of the Claims 1 to 6 in the manufacture of a medicament for antagonising the effects of excitatory amino acids upon the NMDA receptor complex. 9. Compounds as claimed in any of the Claims 1 to 6 for use in therapy. 10. A method of treatment of a mammal including man for conditions where suppression the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration of a compound as claimed in any of Claims 1 to 6.