Novel process

A process for the preparation of a compound of formula (I)

• 14
• wherein
• X is NR2R3, SR1, S(═O)R1, S(═O)2R1 or OR1;
• R1 is hydrogen;
• C3-6-cycloalkyl or (C3-6-cycloalkyl)C1-6-alkyl, wherein the C3-6-cycloalkyl group is optionally mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy;
• a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms, optionally being mono- or polysubstituted with halogen, cyano, trifluoromethyl, C1-6-alkyl, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, aryl, arylalkyl, hydroxy, oxo, nitro, amino, C1-6-monoalkyl or dialkylamino;
• straight or branched C1-18-alkyl, C2-18-alkenyl or C2-18-alkynyl, wherein each of the groups is optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkyl, nitro, amino, C1-6-monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C1-6-alkoxycarbonyl, carbamoyl, formylamino, C1-6-alkylcarbonylamino, aryl, aryloxy, arylalkoxy;
• or bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, wherein each of the groups is optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkyl, C1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, C1-6-monoalkyl- or dialkylamino, cyano, oxo, acyl or C1-6-alkoxycarbonyl;
• R2 is hydrogen;
• hydroxy;
• C1-6-alkoxy;
• or C1-6-alkyl, C3-6-cycloalkyl, C2-6-alkenyl or C2-6-alkynyl optionally mono- or polysubstituted with halogen;
• R3 is hydrogen;
• C3-6-cycloalkyl or (C3-6-cycloalkyl)C1-6-alkyl, wherein the C3-6-cycloalkyl group is optionally mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy;
• a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms;
• or straight or branched C1-18-alkyl optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C1-6-monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C1-6-alkoxycarbonyl, or carbamoyl;
• or
• R3 is —OR4;
• —C(═Z)R4;
• —NR4R5;
• or bicycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl, optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkyl, C1-6-alkoxy, aryloxy, arylalkoxy, nitro, amino, C1-6-monoalkyl- or dialkylamino, cyano, oxo, acyl or C1-6-alkoxycarbonyl;
• R4 is hydrogen;
• C3-6-cycloalkyl or (C3-6-cycloalkyl)C1-6-alkyl, wherein the C3-6-cycloalkyl group is optionally mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy;
• a 3-6 membered saturated ring system comprising one or more nitrogen-, oxygen- or sulfur atoms;
• or straight or branched C1-18-alkyl optionally mono- or polysubstituted with halogen, hydroxy, C1-6-alkoxy, C1-6-alkylthio, C3-6-cycloalkyl, aryl, aryloxy, arylalkoxy, nitro, amino, C1-6-monoalkyl- or dialkylamino, cyano, oxo, formyl, acyl, carboxy, C1-6-alkoxycarbonyl, or carbamoyl;
• Z is O or S;
• R5 is hydrogen;
• C1-6-alkyl;
• C2-6-alkenyl;
• C3-6-cycloalkyl optionally mono- or polysubstituted with C1-6-alkyl, halogen, hydroxy or C1-6-alkoxy;
• or
• when R3 is —NR4R5, R4 and R5 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C1-6-alkyl, hydroxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, nitro, amino, cyano, trifluoromethyl, C1-6-monoalkyl- or dialkylamino, or oxo;
• or
• when X is —NR2R3, R2 and R3 together with the nitrogen atom form a 3-12 membered mono- or bicyclic system, in which one or more of the carbon atoms may be exchanged with nitrogen, oxygen or sulfur, each of these ring systems optionally being mono- or polysubstituted with halogen, C1-6-alkyl, hydroxy, C1-6-alkoxy, C1-6-alkoxy-C1-6-alkyl, nitro, amino, cyano, trifluoromethyl, C1-6-monoalkyl- or dialkylamino or oxo;
• A together with the carbon atoms forming bond e of formula I represents a 5 membered heterocyclic system comprising one or more nitrogen-, oxygen- or sulfur atoms, the heterocyclic system optionally being mono- or polysubstituted with halogen;
• C1-18-alkyl;
• C3-6-cycloalkyl;
• hydroxy;
• C1-6-alkoxy;
• C1-6-alkoxy-C1-6-alkyl;
• nitro;
• amino;
• cyano;
• cyanomethyl;
• perhalomethyl;
• C1-6-monoalkyl- or dialkylamino;
• sulfamoyl;
• C1-6-alkylthio;
• C1-6-alkylsulfonyl;
• C1-6-alkylsulfinyl;
• C1-6-alkylcarbonylamino;
• arylthio, arylsulfinyl, arylsulfonyl, aryl, arylalkyl, or aryloxy, wherein the aryl group is optionally mono- or polysubstituted with C1-6-alkyl, perhalomethyl, halogen, hydroxy or C1-6-alkoxy;
• C1-6-alkoxycarbonyl;
• C1-6-alkoxycarbonyl-C1-6-alkyl;
• carbamyl;
• carbamylmethyl;
• C1-6-monoalkyl- or dialkylaminocarbonyl;
• C1-6-monoalkyl- or dialkylaminothiocarbonyl;
• ureido;
• C1-6-monoalkyl- or dialkylaminocarbonylamino;
• thiocarbamyl;
• thioureido;
• C1-6-monoalkyl- or dialkylaminothiocarbonyl-amino;
• C1-6-monoalkyl- or dialkylaminosulfonyl;
• carboxy;
• carboxy-C1-6-alkyl;
• acyl;
• formyl;
• or a 5-6 membered nitrogen, oxygen or sulfur containing ring, optionally substituted with C1-6-alkyl or phenyl, wherein the phenyl group is optionally mono- or polysubstituted with C1-6-alkyl, perhalomethyl, halogen, hydroxy or C1-6-alkoxy;
• or
• a salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer thereof, or a tautomeric form thereof, or metabolites or prodrugs thereof, comprising one of the following methods:
• a) reacting a compound of formula (II)
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• wherein A is as defined above, L is a leaving group selected from alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, nitro or halogen and Q is halogen, with a compound of formula (III),
• 16
• wherein X is NR2R3, wherein R2 and R3 are defined above, or a suitable salt thereof, in the presence of a base in solvent 1, to form a compound of formula (IV)
• 17
• wherein A, L and X are as defined above, and cyclizing the compound of formula (IV) in solvent 2, optionally in the presence of a base, and optionally with a metal catalyst, to form a compound of formula (I), or
• b) reacting a compound of formula (II)
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• wherein A is as defined above, L is a leaving group selected from alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or halogen and Q is halogen, with a compound of formula (III)
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• wherein X is SR1, S(═O)R1 or S(═O)2R1, wherein R1 is defined above, or a suitable salt thereof, in the presence of a base in solvent 1, to form a compound of formula (IV)
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• wherein A, L and X are as defined above, and cyclizing the compound of formula (IV) in solvent 2, optionally in the presence of a base, and optionally with a metal catalyst, to form a compound of formula (I), or
• c) reacting a compound of formula (II)
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• wherein A is as defined above, L is a leaving group selected from alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl or halogen and Q is halogen, with a compound of formula (III),
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• wherein X is OR1, wherein R1 is defined above, or a suitable salt thereof, in the presence of a base in solvent 1, to form a compound of formula (IV)
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• wherein A, L and X are as defined above, and cyclizing the compound of formula (IV) in solvent 2, optionally in the presence of a base, and optionally with a metal catalyst, to form a compound of formula (I), or
• d) transforming a compound of formula (IV) to a compound of formula (IV′)
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• wherein A, L and X are as defined above, and X is transformed into X′, wherein X′ is selected from the groups defined for X, with the proviso that X′≠X, and cyclizing the compound of formula (IV′) in solvent 2, optionally in the presence of a base, and optionally with a metal catalyst, to form a compound of formula (I), or
• e) transforming a compound of formula (I), prepared as described above, by oxidation or substitution or both, to form another compound of formula (I).