Pyrazolone derivatives as PDE4 inhibitors
View Patent ↗The compounds of a certain formula 1, in which R1, R7, R8, R9 and n have the meanings as given in the description, are novel effective inhibitors of the type 4 phosphodiesterase.
1. A compound of formula 1
wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R5 is 1-2C-alkyl;
R6 is selected from the group consisting of hydrogen and 1-2C-alkyl;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is 1-3C-alkyl;
R8 is 1-3C-alkyl;
or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring;
R9 is —N(R11)R12,
wherein
R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3-dione-2-yl-, 2-oxo-2,3-dihydro-1H-indol-1-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and a thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and
n is 1 or 2;
or a stereoisomer thereof.
2. A compound of formula 1 according to claim 1 , wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R5 is 1-2C-alkyl;
R6 is selected from the group consisting of hydrogen and 1-2C-alkyl;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is 1-3C-alkyl;
R8 is 1-3C-alkyl;
or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring;
R9 is —N(R11)R12,
wherein
R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3-dione-2-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl, morpholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring, and
n is 1 or 2;
or a stereoisomer thereof.
3. A compound of formula 1 according to claim 1 , wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R5 is 1-2C-alkyl;
R6 is selected from the group consisting of hydrogen and 1-2C-alkyl;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is 1-3C-alkyl;
R8 is 1-3C-alkyl;
or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R9 is —N(R11)R12,
wherein
R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3-dione-2-yl-, 2-oxo-2,3-dihydro-1H-indol-1-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and
n is 1 or 2;
or a stereoisomer thereof.
4. A compound of formula 1 according to claim 1 , wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R5 is 1-2C-alkyl;
R6 is selected from the group consisting of hydrogen and 1-2C-alkyl;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is 1-3C-alkyl;
R8 is 1-3C-alkyl;
or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R9 is —N(R11)R12,
wherein
R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, isoindol-1,3-dione-2-yl-, pyrrolidin-2-one-1-yl-, piperidin-2,6-dione-1-yl, morpholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl-, thiomorpholine-1-oxide-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and
n is 1 or 2;
or a stereoisomer thereof.
5. A compound of formula 1 according to claim 1 , wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R3 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R5 is methyl;
R6 is hydrogen;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is 1-3C-alkyl;
R8 is 1-3C-alkyl;
R9 is —N(R11)R12,
wherein
R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, morpholin-3,5-dione-4-yl-, thiomorpholin-3,5-dione-4-yl- and thiomorpholine-1,1-dioxide-3,5-dione-4-yl-ring; and
n is 1 or 2;
or a stereoisomer thereof.
6. A compound of formula 1 according to claim 1 , wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is methoxy;
R3 is methoxy;
R4 is methoxy;
R5 is methyl;
R6 is hydrogen;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is methyl;
R8 is methyl;
R9 is —N(R11)R12,
wherein
R11 and R12 together and with inclusion of the nitrogen atom to which they are bonded, form a heterocyclic ring selected from the group consisting of a pyrrolidin-2,5-dione-1-yl-, morpholin-3,5-dione-4-yl- and a thiomorpholin-3,5-dione-4-yl-ring, and
n is 1.
7. A compound according to claim 1 selected from the group consisting of
4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)morpholine-3,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-diethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-[2-(4-{3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}piperidin-1-yl)-2-oxoethyl]pyrrolidine-2,5-dione;
1-[2-(4-{3-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}piperidin-1-yl)-2-oxoethyl]pyrrolidine-2,5-dione;
1-[2-(4-{3-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}piperidin-1-yl)-2-oxoethyl]pyrrolidine-2,5-dione;
1-(2-{4-[3-(3-ethoxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-diethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-methyl-5-oxo-4-propyl-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[4-(3,4-dimethoxyphenyl)-1-oxo-2,3-diazaspiro[4.4]non-3-en-2-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
2-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)-1H-isoindole-1,3(2H)-dione;
5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-{1-[(2-oxopyrrolidin-1-yl)acetyl]piperidin-4-yl}-2,4-dihydro-3H-pyrazol-3-one;
1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}-2-oxo-ethyl)-piperidine-2,6-dione;
4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)thiomorpholine-3,5-dione;
4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)thiomorpholine-3,5-dione 1,1-dioxide;
1-(3-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}-3-oxo-propyl)-pyrrolidine-2,5-dione;
and stereoisomers thereof.
8. A compound according to claim 1 selected from the group consisting of
4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)morpholine-3,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-diethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-[2-(4-{3-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}piperidin-1-yl)-2-oxoethyl]pyrrolidine-2,5-dione;
1-[2-(4-{3-[3-(cyclopropylmethoxy)-4-methoxyphenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}piperidin-1-yl)-2-oxoethyl]pyrrolidine-2,5-dione;
1-[2-(4-{3-[4-methoxy-3-(2,2,2-trifluoroethoxy)phenyl]-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl}piperidin-1-yl)-2-oxoethyl]pyrrolidine-2,5-dione;
1-(2-{4-[3-(3-ethoxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione,
1-(2-{4-[3-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{-4-[3-(7-methoxy-3H-spiro[1-benzofuran-2,1′-cyclopentan]-4-yl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-diethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-methyl-5-oxo-4-propyl-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione,
1-(2-{4-[3-(3,4-dimethoxyphenyl)-4-ethyl-4-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
1-(2-{4-[4-(3,4-dimethoxyphenyl)-1-oxo-2,3-diazaspiro[4.4]non-3-en-2-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione;
2-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)-1H-isoindole-1,3(2H)-dione;
5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-{1-[(2-oxopyrrolidin-1-yl)acetyl]piperidin-4-yl}-2,4-dihydro-3H-pyrazol-3-one;
1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}-2-oxo-ethyl)-piperidine-2,6-dione;
4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)thiomorpholine-3,5-dione;
4-(2-{4-[3-(3,4-dimethoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)thiomorpholine-3,5-dione 1,1-dioxide;
1-(3-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}-3-oxo-propyl)-pyrrolidine-2,5-dione;
1-(2-{4-[3-(3,4-Dimethoxy-phenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-pyrazol-1-yl]-piperidin-1-yl}-2-oxo-ethyl)-1,3-dihydro-2H-indol-2-one;
and stereoisomers thereof.
9. A pharmaceutical composition comprising at least one of the compounds or stereoisomers of the compounds according to claim 1 together with at least one pharmaceutically acceptable auxiliary.
10. A compound of formula 4,
wherein
R1 represents a phenyl derivative of formulae (a) or (b)
wherein
R2 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R3 is selected from the group consisting of 1-2C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R4 is selected from the group consisting of 1-2C-alkoxy and 1-2C-alkoxy which is completely or predominantly substituted by fluorine;
R5 is 1-2C-alkyl;
R6 is selected from the group consisting of hydrogen and 1-2C-alkyl;
or R5 and R6 together and with inclusion of the two carbon atoms, to which they are bonded, form a spiro-linked 5- or 6-membered hydrocarbon ring;
R7 is 1-3C-alkyl;
R8 is 1-3C-alkyl;
or R7 and R8 together with the carbon atom, to which they are bonded, form a spiro-linked 3-, 4-, 5- or 6-membered hydrocarbon ring;
a salt thereof, a stereoisomer thereof or a salt of the stereoisomer thereof.
11. A fixed combination comprising at least one of the compounds or stereoisomers of the compounds according to claim 1 , at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, β 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants and antibiotics, and at least one pharmaceutically acceptable auxiliary.
12. A fixed combination, non-fixed combination or kit of parts comprising at least one of the compounds or stereoisomers of the compounds according to claim 1 , at least one therapeutic agent selected from the group consisting of corticosteroids, anticholinergics, β 2 -adrenoceptor agonists, H1 receptor antagonists, leukotriene receptor antagonists, type 5 phosphodiesterase inhibitors, HMG-CoA reductase inhibitors, lung surfactants, antibiotics and anti-diabetic agents, and at least one pharmaceutically acceptable auxiliary.
13. A method for inhibiting type 4 phosphodiesterase in a patient comprising administering to a patient in need thereof a compound according to claim 1 or a stereoisomer thereof.