Derivatives of pyrimido[6,1-a]isoquinolin-4-one

A composition comprising a compound of general formula I:

• 29
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalklyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• and a veterinarily or pharmaceutically acceptable carrier or diluent.

A compound of general formula I

• 30
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-4 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-4 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• for use in medicine.

A compound of general formula I:

• 31
• wherein
• each of R1 and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl amino, C1-6 alkylamino, di(C1-6 alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• for use as an inhibitor of a phosphodiesterase isoenzyme.

A compound of general formula I:

• 32
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• for use in the prevention or treatment of a disease in which raising the intracellular concentration of cAMP is desirable.

A compound of general formula I:

• 33
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• for use in the prevention or treatment of asthma.

A compound of general formula I:

• 34
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-16 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• for use in the prevention or treatment of chronic obstructive pulmonary disease (COPD).

The use of a compound of general formula I:

• 35
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• in the manufacture of an inhibitor of a type III/IV phosphodiesterase isoenzyme.

The use of a compound of general formula I:

• 36
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-4 alkoxy or C1-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• in the manufacture of a bronchodilator.

The use of a compound of general formula I:

• 37
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1,6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• in the manufacture of an anti-asthmatic.

The use of a compound of general formula I:

• 38
• wherein
• each of R1and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2,7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof;
• in the manufacture of a medicament for the prevention or treatment of chronic obstructive pulmonary disease (COPD).

A method for the treatment or prevention of a disease in a mammal where a phosphodiesterase isoenzyme inhibitor and/or a bronchodilator would be expected to be of benefit, which method comprises administering to said mammal an effective, non-toxic amount of a compound of general formula I:

• 39
• wherein
• each of R1 and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1,6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof.

A method for the treatment or prevention of asthma in a mammal, which method comprises administering to said mammal an effective, non-toxic amount of a compound of general formula I:

• 40
• wherein
• each of R1 and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof.

A method for the treatment or prevention of chronic obstructive pulmonary disease (COPD) in a mammal, which method comprises administering to said mammal an effective, non-toxic amount of a compound of general formula I:

• 41
• wherein
• each of R1 and R2 independently represents a C1-6 alkyl or C2-7 acyl group;
• X represents OCH2 or a group CR3R4, wherein each of R3 and R4 independently represents a hydrogen atom or a C1-3 alkyl group;
• R5 represents a hydrogen atom or a C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl group;
• R6 represents a hydrogen atom or a C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, amino, C1-6 alkylamino, di(C1-6) alkylamino or C2-7 acylamino group;
• each of R7 and R8 independently represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• R9 represents a hydrogen or halogen atom or a hydroxy, trifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C2-7 acyl, C1-6 alkylthio, C1-6 alkoxy or C3-6 cycloalkyl group;
• or a salt thereof.