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,

• 8
• 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, COR8, 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 C1-6-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;
• 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 the formula II:
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• wherein R1 to R3 have the meaning 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 the general formula III:
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• wherein R1 to R3 have the meaning according to the general 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
• 11
• wherein R1 to R4 have the meaning according to the general formula I and R5 and R6 together denote the group ═O.

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

• 12
• 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 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 C1-6-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;
• 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 reacting a compound of formula IV,
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• wherein R1 to R4 have the meaning according to formula I and R5 and R6 together deonote the group ═O, with a nucleophile in a polar solvent.

A method for the preparation of substituted 1,5-dihydropyrrol-2-one compounds of the general formula I,

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• 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 and R6 each denotes H;
• 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 C1-6-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;
• 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 reducing a compound of the formula I wherein R5 and R6 together denote ═O.

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

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• 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, 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, COR8, 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 C1-6-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.