Patent EA-003276-B1 (EA)
Title: Tetrahydroquinoline derivatives as glycine antagonists
Inventor: DI FABIO ROMANO
IPC: C07D401/04
Filed: 1999-06-08
Abstract: 1. A compound of formula (I) or a salt or a non toxic metabolically labile esters thereof, wherein Y represents a carbon atom; Z is the group CH which is linked to the group Y via a double bond and X is CH or Z is methylene or NR11 and X is a carbon atom linked to the group Y via a double bond; A represents a C1-2 alkylene chain and which chain may be substituted by one or two groups selected from C1-6 alkyl optionally substituted by hydroxy, amino, C1-4 alkyl amino or C1-4 dialkyl amino or which chain may be substituted by the group =O; R represents a halogen atom or C1-4 alkyl group; R1 represents a hydrogen, a halogen atom or C1-4 alkyl group; R2 represents phenyl which may be substituted with up to 3 groups selected from halogen, hydrogen, or (CH2)nR3 wherein R3 is COR4, NR6R5, NHCOR7, NHCONR9R8 or NHSO2R10 group or R2 is a 5 membered heteroaryl group containing 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogen atoms, R4 represents an amino, a hydroxyl or C1-4 alkoxy group; R5 and R6 each independently represents hydrogen or C1-4 alkyl group or R5 and R6 together with the nitrogen atom to which they are attached represent a saturated 5-7 membered heterocyclic group optionally containing an additional heteroatom selected from oxygen, sulphur or nitrogen; R7 represents a hydrogen atom or C1-4 alkyl, C1-4 alkoxy, or phenyl; R8 represents hydrogen or C1-4 alkyl group; R9 represents hydrogen, optionally substituted C1-4 alkyl (optionally substituted by one or more hydroxy carboxyl and amino group), phenyl; R11 represents hydrogen or C1-4 alkyl group; R10 represents hydrogen, C1-4 alkyl or a nitrogen protecting group; n is zero or an integer from 1 to 2. 2. A compound as claimed in claim 1 wherein R is chlorine and R1 is hydrogen or a chlorine atom. 3. A compound as claimed in Claims 1 or 2 wherein A is a chain selected from -CH2-, -(CH2)2- or C=O. 4. A compound as claimed in any of the claims 1-3 wherein Z is CH which is linked to the group Y via a double bond a methylene or a NH group. 5. A compound as claimed in any of the claims 1-4 wherein R2 is a group selected from phenyl (optionally substituted by acetylamino, methanesulphonylamino) or 3-pyridyl. 6. A compound as claimed in any of the claims 1-5 wherein R2 represents phenyl. 7. A compound as claimed in any of the claims 1-6 wherein A is a chain selected from -CH2-, -(CH2)2, and Z is the group CH which is linked to the group Y via a double bond, or a methylene group, or A is C=O and Z is a NH group, R is chlorine, R1 is chlorine or hydrogen and R2 is phenyl (optionally substituted by acetylamino or methanesulphonylamino) or 3 -pyridyl. 8. A compound as claimed in claim 1 which is (+-)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid, physiologically acceptable salts or non toxic metabolically labile esters thereof. 9. A compound as claimed in claim 1 which is sodium (+-) 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) 1,2,3,4-tetrahydro-2-quinolinecarboxylate. 10. A compound as claimed in claim 1 which is (-) sodium 7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene) 1,2,3,4-tetrahydro-2-quinolinecarboxylate. 11. A compound as claimed in claim 1 which is (+-)7-chloro-4-(1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid, physiologically acceptable salts or non toxic metabolically labile esters thereof. 12. A compound as claimed in claim 1 which is sodium (+-)7-chloro-4-(1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4 tetrahydro-2-quinolinecarboxylate. 13. A compound as claimed in claim 1 which is (-)-sodium 7-chloro-4-(1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4 tetrahydro-2-quinolinecarboxylate. 14. A compound as claimed in claim 1 which is (+-) Sodium 7-chloro-4-(1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate. 15. A compound selected from: (+-)-7-chloro-4-(1-(3-pyridin)-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (+-)-7-chloro-4-(1-phenyl-Delta<3>-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxlic acid, (+-)-5,7-dichloro-4-(1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (+/-)-7-chloro-4-(1-(4-acetylamino)-1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (+/-)7-chloro-4-(1-(4-methanesulfonylamino)-1-phenyl-Delta<3>-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid, (+-)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, (+-)-7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, (+-)-7-chloro-4-(2-oxo-1-(pyridin-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate, (+-)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, (+-)7-chloro-4-(2-oxo-1-((4-methanesulfonyl amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, 5,7-dichloro-4-(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinoline carboxylic acid, 5,7-dichloro-4-(2-oxo-1-phenyl-Delta<3>-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylic acid; and physiologically acceptable salts (e.g. sodium salts), non-toxic metabolically labile esters or enantiomers thereof. 16. A pharmaceutical composition comprising a compound as claimed in any of claims 1-15 in admixture with one or more physiologically acceptable carriers or excipients. 17. A process for the preparation of compounds as claimed in any of the claims 1-15 which comprises cyclization a compound of formula (II) in which R, R1, R2, A, X, Y, Z have the meanings defined in claim 1 and R12 is a carboxylic protecting group, R13 represents a bromine or iodine atom, R14 represents hydrogen or a nitrogen protecting group, followed where necessary or desired by one or more of the following steps: (I) removal of a protecting group; (ii) isolation of the compound as a salt thereof; (iii) conversion of a compound of formula (I) or a salt thereof into a metabolically labile ester thereof; (iv) separation of a compound of formula (I) or a derivative thereof into the enantiomers thereof.