Patent EA-000875-B1 (EA)
Title: Tetrahydroquinolines as nmda antagonists
Inventor: DI FABRIO ROMANO
IPC: C07D/
Filed: 1996-09-26
Abstract: 1. A compound of formula (I)   or a salt thereof or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO2R2 or COR2, wherein R2 represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; R1 represents hydrogen, alkyl, alkoxy, nitro, trifluoromethyl, halogen or (CH2)nR3 wherein R3 is hydroxy, COR4, NR5R6, NHCOR7, or NHCONR8R9 group; R4 represents an alkoxy, amino or hydroxyl group; R5 and R6 each independently represent hydrogen or alkyl group or R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5-7membed ring, optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen; R7 represents a hydrogen atom or optionally substituted alkyl, alkoxy, aryl or heterocyclic group; R8 represents hydrogen or alkyl group; R9 represents hydrogen, optionally substituted alkyl, aryl, heterocyclic or cycloalkyl group; n is zero or an integer from 1 to 4; wherein "alkyl" represents alkyl group with straight or branched chain having 1 to 4 carbon atoms, "optionally substituted alkyl" represents alkyl, substituted by one or more hydroxy, carboxy or amino group, "cycloalkyl" represents C3-C7 cycloalkyl group, which is optionally substituted by one or two C1-C4 alkyl groups, "aryl" represents optionally substituted phenyl or 5- or 6-membered heteroaryl, where 5-membered heteroaryl group contains 1 or 2 heteroatoms selected from oxygen, sulfur or nitrogen, and 6-membered heteroaryl group contains 1 or 2 nitrogen atoms, "optionally substituted phenyl" represents phenyl group substituted by maximum three substituents selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, amino, alkylamino, hydroxy, trifluoromethyl, carboxyl or metoxycarbonyl, "heterocyclic group" represents 5-7-membered saturated heterocyclic group containing one or two heteroatoms selected from oxygen, sulfur or nitrogen. 2. A compound as claimed in claim 1 wherein m is 1 or 2, and R is a halogen atom in the 5 and/or 7 position. 3. A compound as claimed in claim 1 or 2 wherein m is 2 and R is chlorine atom in the 5 and 7 position. 4. A compound as claimed in claims 1-3 wherein R1 is hydrogen, chlorine, (CH2)nCOR4 wherein R4 is hydroxyl or amino, (CH2)nNR5R6 wherein R5 and R6 are each hydrogen or NR5R6 represents a morpholino group, (CH2)nNHCOR7 wherein R7 is hydrogen or C1-C4 alkyl, (CH2)nNHCONH2 and n is zero, 1 or 2. 5. A compound as claimed in claim 4 wherein R1 represents hydrogen, chlorine, carboxymethyl, carbamoylmethyl, amino, morpholinomethyl, (CH2)nNHCOR7 (wherein n is zero, 1 or 2 and R7 is hydrogen, methylisopropyl or isobutyl) or CH2NHCONH2. 6. A compound as claimed in claim 1 wherein R1 represents hydrogen, alkyl, alkoxy, nitro, trifluoromethyl, halogen or (CH2)nR3, wherein R3 is hydroxy, COR4, NR5R6, NHCOR7, or NHCONR8R9 group; R4 represents an alkoxy or hydroxyl group; R5 and R6 each independently represent hydrogen or alkyl group or R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5-7membed ring, optionally containing an additional heteroatom selected from oxygen, sulfur or nitrogen; R7 represents optionally substituted alkyl, alkoxy, aryl or heterocyclic group; R8 represents hydrogen or alkyl group; R9 represents hydrogen, optionally substituted alkyl, aryl, heterocyclic group or cycloalkyl; n is zero or an integer from 1 to 4. 7. A compound as claimed in claim 6 wherein m is 2 and R is chlorine in the 5 and 7 position, and R1 represents hydrogen, (CH2)nCOR4, (CH2)nNR5R6, (CH2)nNHCOR7, or  (CH2)nNHCONH2, n is zero, 1 or 2, R4 is hydroxyl, R5and R6 each is  hydrogen or NR5R6 is morpholino, R7 is C1-C4 alkyl. 8. (+-) (E) 4-(4-acetylamino-phenylcarbamoylmethylene)-5,7-dichloro-1,2,3,4-tetrahydro quinoline-2-carboxylic acid or a physiologically acceptable salt thereof. 9. A compound selected from  (+-) (E) 5,7-Dichloro-4-phenylcarbamoylmethylene-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 7-Chloro-4-phenylcarbamoylmethylene-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 5,7-Dibromo-4-phenylcarbamoylmethylene-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 4-(4-Amino-phenylcarbamoylmethylene)-5,7-dichloro-1,2,3,4-tetrahydro-quino line-2-carboxylic acid, (+-) (E) 4-(3-Acetylamino-phenylcarbamoylmethylene)-5,7-dichloro-1,2,3,4-tetrahydro -quinoline-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-(4-isobutytrylamino-phenylcarbamoylmethylene)-1,2,3,4-tetra hydro-quinoline-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-[4-(3-methyl-butyrylamino)-phenylcarbamoylmethylene]-1,2,3, 4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-(3chloro-phenylcarbamoylmethylene)-1,2,3,4-tetrahydro-quino line-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-[4-(isobutyrylamino-methyl)-phenylcarbamoylmethylene]-1,2,3 ,4-tetrahydro-quinoline-2-carboxylic acid  (+-) (E) 5,7-Dichloro-4-[4-(ureidomethyl)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 4-[4-(Acetylamino-methyl)-phenylcarbamoylmethylene]-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-(4-formylaminomethyl-phenylcarbamoylmethylene)-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-(4-morpholin-4-ylmethyl-phenylcarbamoylmethylene)-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 4-[4-(2-Acetylamino-ethyl)-phenylcarbamoylmethylene]-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 5,7-Dichloro-4-[4-(2-isobutyrylamino-ethyl)-phenylcarbamoylmethylene]-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 4-(4-Carbamoylmethyl-phenylcarbamoylmethylene)-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, (+-) (E) 4-(4-Carboxymethyl-phenylcarbamoylmethylene)-5,7-dichloro-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid, and physiologically acceptable salts thereof. 10. A pharmaceutical composition comprising a compound as claimed in any claim 1 to 9 in admixture with one or more physiologically acceptable carriers or excipients. 11. Use a compound as claimed in any claim 1 to 9 in production of a medicament for antagonizing the effects of excitatory amino acids on the NMDA receptor complex. 12. Use a compound as claimed in any claim 1 to 9 as a therapeutic agent. 13. A method of treatment of a mammal including man, for a condition where antagonizing the effects of excitatory amino acids on the NMDA receptor complex is of therapeutic benefit comprising administration to a mammal in need thereof an effective amount of a compound as claimed in any claim 1 to 9.