Phthalazine derivatives as phosphodiesterase 4 inhibitors

A compound of formula I

• wherein
• is a single bond;
• B is methylene;
• A is pyridine substituted by one or more substituents;
• R is optionally substituted aryl or heterocycle, (C1-8)-alkyl, optionally substituted by aryl or heterocycle, (C2-8)-alkenyl, optionally substituted by aryl or heterocycle, (C2-8)-alkynyl, optionally substituted by aryl or heterocycle, aryloxy, heterocyclyloxy, aryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy, amino substituted by one or two C1-4-alkyl, aryl-amino, heterocyclyl-amino, aryl-C1-4-alkyl-amino, or heterocyclyl-C1-4alkylamino;
• R1 is a C1-6-alkyl optionally containing an oxygen atom, or C4-7-cycloalkyl group optionally containing an oxygen atom;
• R2 is a C1-6-alkyl or polyfluoro C4-6-alkyl group;
• R3 is absent;
• the N→O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof;
• wherein heterocycle and heterocyclyl are independently selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole, isoxazole and thiophene.

A compound of formula I

• wherein
• is a single or double bond;
• B is methylene, or a C2-6 alkylene chain optionally branched and/or unsaturated and/or interrupted by a C5-7 cycloalkyl residue;
• A is a phenyl optionally substituted by one or more substituent(s), a heterocycle optionally substituted by one or more substituent(s), or a COR4 group wherein R4 is hydroxy, C1-4alkyl, amino optionally mono- or di-substituted by a C1-6-alkyl or optionally monohydroxy substituted;
• R represents two hydrogen atoms or a C═O group when is a single bond or, when is a double bond, optionally substituted aryl, optionally substituted heterocycle, (C1-8)-alkyl, optionally substituted by aryl or heterocycle, (C2-8)-alkenyl, optionally substituted by aryl or heterocycle, (C2-8)-alkynyl, optionally substituted by aryl or heterocycle, aryloxy, heterocyclyloxy, aryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy, aryl-amino, heterocyclyl-amino, aryl-C1-4-alkyl-amino, or heterocyclyl-C1-4-alkylamino;
• R1 is a C1-6-alkyl, optionally containing an oxygen atom, aryl, optionally containing an oxygen atom, aryl-C1-10-alkyl, optionally containing an oxygen atom, or C4-7-cycloalkyl, optionally containing an oxygen atom;
• R2 is a C1-6 alkyl or polyfluoro C1-6-alkyl group;
• R3 is absent when is a double bond, or, when is a single bond, is hydrogen, C1-6-alkyl, optionally substituted by aryl, C1-6-alkyl, optionally substituted by heterocycle, C1-6-alkyl, optionally substituted by a COR5 group wherein R5 is hydroxy, C1-4-alkoxy or hydroxyamino, —COR6 wherein R6 is hydrogen, aryl, aryl-C1-6-alkyl, amino optionally alkylated or monohydroxylated, hydroxy, C1-4-alkoxy, carboxy, C1-4-alkoxycarbonyl,
• alkyl optionally substituted by heterocycle, or C1-4-alkyl-sulfonyl;
• the N→O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof;
• provided that when is a double bond, A is phenyl or nitrogen heterocycle, optionally substituted, R1 is an aryl, aryl-C1-10-alkyl, C4-7-cycloalkyl optionally containing an oxygen atom;
• then R is not phenyl or (C1-4) alkyl optionally substituted by aryl,
• wherein heterocycle and heterocyclyl are independently selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole, isoxazole and thiophene.

A compound of formula I

• wherein
• is a single or double bond;
• B is NH, or a C2-6 alkylene chain optionally branched and/or unsaturated and/or interrupted by a C5-7 cycloalkyl residue;
• A is a phenyl optionally substituted by one or more substituent(s), a heterocycle optionally substituted by one or more substituent(s), or a COR4 group wherein R4 is hydroxy, C1-4alkyl, amino optionally mono- or di-substituted by a C1-6-alkyl or optionally monohydroxy substituted;
• R represents two hydrogen atoms or a C═O group when is a single bond or, when is a double bond, a hydrogen, optionally substituted heterocycle, (C1-8)-alkyl, optionally substituted by aryl or heterocycle, (C2-8)-alkenyl, optionally substituted by aryl or heterocycle, (C2-8)-alkynyl, optionally substituted by aryl or heterocycle, aryloxy, heterocyclyloxy, aryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy, amino substituted by one or two C1-4-alkyl group(s), aryl-amino, heterocyclyl-amino, aryl-C1-4-alkyl-amino, or heterocyclyl-C1-4-alkylamino;
• R1 is a C1-6-alkyl, optionally containing an oxygen atom, aryl, optionally containing an oxygen atom, aryl-C1-10-alkyl, optionally containing an oxygen atom, or C4-7-cycloalkyl, optionally containing an oxygen atom;
• R2 is a C1-6 alkyl or polyfluoro C1-6-alkyl group;
• R3 is absent when is a double bond, or, when is a single bond, is hydrogen, C1-6-alkyl, optionally substituted by aryl, C1-6-alkyl, optionally substituted by heterocycle, C1-6-alkyl, optionally substituted by a COR5 group wherein R5 is hydroxy, C1-4-alkoxy or hydroxyamino, —COR6 wherein R6 is hydrogen, aryl, aryl-C1-6-alkyl, amino optionally alkylated or monohydroxylated, hydroxy, C1-4-alkoxy, carboxy, C1-4-alkoxycarbonyl,
• or C1-4-alkyl optionally substituted by heterocycle, or C1-4-alkyl-sulfonyl;
• the N→O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof;
• provided that when is a double bond, A is phenyl or nitrogen heterocycle, optionally substituted, R1 is an aryl, aryl-C1-10-alkyl, C4-7-cycloalkyl optionally containing an oxygen atom;
• then R is not hydrogen, or (C1-4) alkyl optionally substituted by aryl,
• wherein heterocycle and heterocyclyl are independently selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole, isoxazole and thiophene.

A compound of formula I

• wherein
• is a double bond;
• B is methylene;
• A is a heterocycle optionally substituted by one or more substituent(s);
• R represents hydrogen, optionally substituted aryl, optionally substituted heterocycle, (C1-8)-alkyl, optionally substituted by aryl or heterocycle, (C2-8)-alkenyl, optionally substituted by aryl or heterocycle, (C2-8)-alkynyl, optionally substituted by aryl or heterocycle, aryloxy, heterocyclyloxy, aryl-C1-4-alkoxy, heterocyclyl-C1-4-alkoxy, amino substituted by one or two C1-4-alkyl group(s), aryl-amino, heterocyclyl-amino, aryl-C1-4-alkyl-amino, or heterocyclyl-C1-4-alkylamino;
• R1 is a C1-6-alkyl, optionally containing an oxygen atom, aryl, optionally containing an oxygen atom, aryl-C1-10-alkyl, optionally containing an oxygen atom, or C4-7-cycloalkyl, optionally containing an oxygen atom;
• R2 is a C1-6 alkyl or polyfluoro C1-6-alkyl group;
• R3 is absent;
• the N→O derivatives of the compounds of formula I and the pharmaceutically acceptable salts thereof;
• provided that when A is nitrogen heterocycle, optionally substituted, R1 is an aryl, aryl-C1-10-alkyl, C4-7-cycloalkyl optionally containing an oxygen atom;
• then R is not phenyl or (C1-4) alkyl optionally substituted by aryl,
• wherein heterocycle and heterocyclyl are independently selected from the group consisting of pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, piperazine, triazine, morpholine, pyrrolidine, pyrroline, imidazoline, pyrazoline, pyrazolidine, imidazolidine, piperidine, furan, pyran, isothiazole, isoxazole and thiophene.