Substituted 1,5-dihydropyrrol-2-one derivatives active as NMDA receptor antagonists for treatment of states of pain

A method for the preparation of a substituted 1,5-dihydropyrrol-2-one compound of formula I:

• wherein
• X represents O or NR7;
• R1 represents H, OR11, SR11, COR8, CSR8, NR9R10, COOR8, CONR9R10, CSNR9R10, COCOR8, a C1-10-alkyl an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R2, R3, which are identical or different, represent H, F, Cl, Br, CF3, OR11, SR11, NR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represent an aryl group bonded via a C1-6-alkylene group;
• R4 represents H, OH, OR11, SR11, COR8, COOR8, COCOR8, CONR9R10, CSNR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R5, R6, which are identical or different, represent H, O, OH, OR11, SR11, CSR8, COOR8, COCOR8, CONR9R10, CSNR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represent an aryl group bonded via a C1-6-alkylene group or R5 and R6 together denote the group ═O;
• R7 represents H, OR11, SR11, COR8, COOR8, COCOR8, CONR9R10, CSNR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R8 represents H, OR11, SR11, NR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-10-alkylene group;
• R9 represents a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• represents a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• and
• R11 represents a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group,
• the method comprising
• A. reacting a tetram acid of formula II:
• wherein R1 to R8 have the meanings according to formula I, with an aqueous solution of an alkali metal nitrite at a low temperature in solution, to give rise to a compound of formula III:
• wherein R1 to R2 have the meanings according to formula I;
• B. converting a compound of formula III by alkylation with an alkylating agent or by reaction with an acid chloride, acid bromide, chlorocarbonic acid ester, fluorocarbonic acid ester, isocyanate or isothiocyanate in a non-polar solvent or a polar, aprotic solvent, or a polar, protic solvent into a compound of formula IV:
• wherein R1 to R4 have the meanings according to formula I, and R5 and R6 together denote the group ═O;
• C. optionally derivatizing a compound of formula IV, wherein R1 to R4 have the meanings according to formula II, and R5 and R8 together denote the group ═O, by reaction with a nucleophilte in a polar solvent to give a compound of formula V:
• wherein R1 to R4 and X have the meanings according to formula I, and R5 and R6 together denote the group ═O;
• D. optionally reducing a compound of formula V, wherein R1 to R4 and X have the meanings according to formula I, and R5 and R6 together denote the group ═O, to a compound of formula I, wherein R1 to R4 and X have the meanings according to formula I, and R5 and R6 each denote H by reaction with a reducing agent;
• and
• E. optionally further derivatizing a compound of formula V, wherein wherein R1 to R4 and X have the meanings according to formula I, and R5 and R6 each denote H, to give a compound of formula I, wherein R1 to R4 and X have the meanings according to formula I, and R6 and R8 are identical or different and each represent O, OH, OR11, SR11, CSR9, COOR8, COCOR8, CONR9R10, CSNR9R10, a C1-10-alkyl group, an aryl group or a heteroaryl group, or represent an aryl group bonded via a C1-6-alkylene group.

A pharmaceutical composition comprising a substituted 1,5-dihydropyrrol-2-one compound of formula Ia:

• wherein
• X represents O, S or NR7;
• R1 represents H, OR11, SR11, COR8, CSR8, NR9R10, COOR8, CONR9R10, CSNR9R10, COCOR8, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R2, R8, which are identical or different, represent H, F, Cl, Br, CF3, OR11, SR11, NR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represent an aryl group bonded via a C1-6-alkylene group;
• R4 represents H, OH, OR11, SR11, CORE, COOR8, COCOR8, CONR9R10, CSNR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R5, R6, which are identical or different, represent H, O, OH, OR11, SR11, CSR8, COOR8, COCOR8, CONR9R10, CSNR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represent an aryl group bonded via a C1-6-alkylene group or R5 and R6 together denote the group ═O;
• R7 represents H, OR11, SR11, COR8, COOR8, COOR8, CONR9R10, CSNR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R8 represents H, OR11, SR11, NR9R10, a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R9 represents a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R10 represents a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• R11 represents a C1-10-alkyl, an aryl or a heteroaryl group, or represents an aryl group bonded via a C1-6-alkylene group;
• in the form of its racemate, its enantiomers, its diastereomers or a corresponding physiologically tolerated salt, and a pharmaceutically acceptable excipient.