Pyridazin-3(2H)-One Derivatives And Their Use As Pde4 Inhibitors
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Abstract
The invention relates to new therapeutically useful pyridazin-3(2H)-one derivatives, to processes for their preparation and to pharmaceutical compositions containing them. These compounds are potent and selective inhibitors of phosphodiesterase 4 (PDE4) and are thus useful in the treatment, prevention and suppression of related pathological conditions, diseases and disorders, in particular asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, topic dermatitis, psoriasis or irritable bowel disease.
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Citations
34 Claims
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1-18. -18. (canceled)
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19. A compound of formula (I)
- View Dependent Claims (20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)
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20. A compound according to claim 19 wherein R1 is a hydrogen atom or lower alkyl group, which is optionally substituted by one or more substituents selected from halogen atoms and hydroxy, alkoxy, alkylthio, hydroxycarbonyl and alkoxycarbonyl groups.
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21. A compound according to claim 19 wherein R2 is an heteroaryl group which is optionally substituted by one or more substituents selected from halogen atoms and hydroxy, lower alkyl, hydroxyalkyl, hydroxycarbonyl, alkoxy, alkylenedioxy, alkoxycarbonyl, aryloxy, acyl, acyloxy, alkylthio, arylthio, amino, nitro, cyano, mono-alkylamino, di-alkylamino, acylamino, carbamoyl, mono-alkylcarbamoyl, di-alkylcarbamoyl, difluoromethyl, trifluoromethyl, difluoromethoxy, and trifluoromethoxy groups.
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22. A compound according to claim 19 wherein R2 is a N-containing heteroaryl group.
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23. A compound according to claim 19 wherein R2 is optionally substituted by one or more substituents selected from halogen atoms and lower alkyl groups.
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24. A compound according to claim 19 wherein R3 represents a group of formula:
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G-L1-(CRR′
)n—wherein n is an integer from 0 to 3; R and R′
are independently selected from hydrogen atoms or lower alkyl groups;L1 is a linker selected from a direct bond or —
CO—
, —
O(CO)—
, —
O(CO)O—
or —
(CO)O—
groups; andG is selected from hydrogen atoms or alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups said groups being optionally substituted with one or more substituents selected from; halogen atoms; alkyl and alkenyl groups, which are optionally substituted by one or more substituents selected from halogen atoms; and hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, amino, mono-alkylamino, di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, ureido, N′
-alkylureido, N′
,N′
-dialkylureido, alkylsulfamido, aminosulfonyl, mono-alkylaminosulfonyl, di-alkylaminosulfonyl, cyano, difluoromethoxy, and trifluoromethoxy groups.
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25. A compound according to claim 24 wherein R3 represents a group of formula:
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G-L1-(CRR′
)n—wherein n is an integer from 0 to 3; R and R′
are independently selected from hydrogen atoms or methyl groups;L1 is a linker selected from a direct bond or —
CO—
, —
O(CO)—
, —
O(CO)O—
or —
(CO)O—
groups; andG is selected from alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups said groups being optionally substituted with one or more halogen atoms.
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26. A compound according to claim 25 wherein R3 represents a group of formula:
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G-L1-(CRR′
)n—wherein n is 0 or 1 R is a hydrogen atom R′
is a hydrogen atom or a methyl groupL1 is a linker selected from a direct bond —
O(CO)O—
or —
(CO)O—
; andG is selected from alkyl or cycloalkyl groups said groups being optionally substituted with one halogen atom.
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27. A compound according to claim 19 wherein R4 represents a phenyl, pyridyl, or thienyl group, which is optionally substituted by one or more substituents selected from:
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halogen atoms; alkyl groups, which are optionally substituted by one or more substituents selected from halogen atoms and hydroxy, hydroxyalkyl, alkoxy, alkylthio, mono-alkylamino, di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono-alkylcarbamoyl, and di-alkylcarbamoyl groups; and hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylsulfamoyl, amino, mono- or di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- or di-alkylcarbamoyl, ureido, N′
-alkylureido, N′
,N′
-dialkylureido, alkylsulfamido, aminosulfonyl, mono-alkylaminosulfonyl, di-alkylaminosulfonyl, cyano, difluoromethoxy, and trifluoromethoxy groups.
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28. A compound according to claim 27 wherein R4 is optionally substituted by one or more substituents selected from halogen atoms and lower alkyl groups.
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29. A compound according to claim 28 wherein R4 is a phenyl group.
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30. A compound according to claim 19 which is one of:
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4-(methoxycarbonyl)benzyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-oxo-2-pyrrolidin-1-ylethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 3-amino-3-oxopropyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(dimethylamino)ethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 3-fluorobenzyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-oxo-2-pyridin-4-ylethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(dimethylamino)-2-oxoethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-aminoethyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (butyryloxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 3-oxo-1,3-dihydro-2-benzofuran-1-yl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (acetyloxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 1-(acetyloxy)ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(dimethylamino)-2-oxoethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 1-(acetyloxy)-1-methylethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-[(ethoxycarbonyl)oxy]ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-[(ethoxycarbonyl)oxy]ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-(acetyloxy)ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; ({[1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-4-yl]carbonyl}oxy)acetic acid; ethyl 1-ethyl-3-(3-methylphenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-3-(3-methylphenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-3-(3-fluorophenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (butyryloxy)methyl 1-ethyl-3-(3-fluorophenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-3-(4-fluorophenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (butyryloxy)methyl 1-ethyl-3-(4-fluorophenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 5-[(2-chloropyridin-3-yl)amino]-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; methyl 1-ethyl-6-oxo-3-phenyl-5-(quinolin-5-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-(4-methyloyridin-3-ylamino)-6-oxo-3-thien-2-yl-1,6-dihydropyridazin-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-fluorobenzyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-(methoxycarbonyl)benzyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-3-(4-methylphenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-3-(4-methylphenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-3-(4-methylphenyl)-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-3-(4-methylphenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-5-(isoquinolin-4-ylamino)-3-(4-methylphenyl)-6-oxo-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-3-(4-methylphenyl)-5-[(4-methylpyridin-3-yl)amino]-6-oxo-1,6-dihydropyridazine-4-carboxylate; 1-[(isopropoxycarbonyl)oxy]ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 1-[(isopropoxycarbonyl)oxy]ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-[(isopropoxycarbonyl)oxy]ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-6-oxo-3-phenyl-5-(thieno[2,3-c]pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-6-oxo-3-phenyl-5-(thieno[2,3-b]pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylpropanoyl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(thieno[2,3-b]pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 7-ethoxy-7-oxoheptyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 6-ethoxy-6-oxohexyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 3-amino-3-oxopropyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 1-{[(1-ethylpropoxy)carbonyl]oxy}ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 1-{[(1-ethylpropoxy)carbonyl]oxy}ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 1-{[(1-ethylpropoxy)carbonyl]oxy}ethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (butyryloxy)methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (acetyloxy)methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-(methoxycarbonyl)benzyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; (isobutyryloxy)methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (isobutyryloxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 4-fluorobenzyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-(methoxycarbonyl)benzyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(isopropoxycarbonyl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 7-ethoxy-7-oxoheptyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 6-ethoxy-6-oxohexyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-fluorobenzyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; chloromethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; [(2,2-dimethylbutanoyl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ({N-[(benzyloxy)carbonyl]-L-valyl}oxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; ethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(1-ethylpropoxy)carbonyl]oxy}methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (isobutyryloxy)methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 2-(acetyloxy)ethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-[(tert-butoxycarbonyl)amino]ethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(isopropoxycarbonyl)oxy]methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-ethoxy-2-oxoethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 2-(benzyloxy)-2-oxoethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(1-ethylpropoxy)carbonyl]oxy}methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(isopropoxycarbonyl)oxy]methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 6-ethoxy-6-oxohexyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; 7-ethoxy-7-oxoheptyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; ({[1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-4-yl]carbonyl}oxy)methyl N-(tert-butoxycarbonyl)-L-leucinate; 2-methoxy-2-oxoethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 4-fluorobenzyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-(methoxycarbonyl)benzyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; (butyryloxy)methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 6-ethoxy-6-oxohexyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(1-ethylpropoxy)carbonyl]oxy}methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; 7-ethoxy-7-oxoheptyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; ({[1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-4-yl]carbonyl}oxy)methyl L-leucinate; benzyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 3-amino-3-oxopropyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-fluorobenzyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-(methoxycarbonyl)benzyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(2-methylbutanoyl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 4-(methoxycarbonyl)benzyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 7-ethoxy-7-oxoheptyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 7-ethoxy-7-oxoheptyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 4-fluorobenzyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 6-ethoxy-6-oxohexyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 6-ethoxy-6-oxohexyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-5-(1,7-naphthyridin-5-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; benzyl 1-ethyl-6-oxo-3-pyridin-4-yl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; ({[1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazin-4-yl]carbonyl}oxy)methyl morpholine-4-carboxylate; {[(methylamino)carbonyl]oxy}methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; {[(dimethylamino)carbonyl]oxy}methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (acetyloxy)methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; [(dibutoxyphosphoryl)oxy]methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (acetyloxy)methyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(isopropoxycarbonyl)oxy]methyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; (acetyloxy)methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(isopropoxycarbonyl)oxy]methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; (acetyloxy)methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; [(isopropoxycarbonyl)oxy]methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-(2-thienyl)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-6-oxo-5-(pyridin-3-ylamino)-3-(3-thienyl)-1,6-dihydropyridazine-4-carboxylate; 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate—
Enantiomer 1;1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate—
Enantiomer 2;chloromethyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (propionyloxy)methyl 1-ethyl-5-[(4-methylpyridin-3-yl)amino]-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; {[(1-ethylpropoxy)carbonyl]oxy}methyl 1-ethyl-3-(4-fluorophenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; {[(cyclohexyloxy)carbonyl]oxy}methyl 1-ethyl-3-(4-fluorophenyl)-6-oxo-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; chloromethyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (propionyloxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; (propionyloxy)methyl 1-ethyl-5-(isoquinolin-4-ylamino)-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate; (pentanoyloxy)methyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 2-oxo-1,3-dioxolan-4-yl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; fluoromethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate; 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate—
Enantiomer 1;
or1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-ethyl-6-oxo-3-phenyl-5-(pyridin-3-ylamino)-1,6-dihydropyridazine-4-carboxylate—
Enantiomer 2;or a pharmaceutically acceptable salt thereof.
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31. A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by inhibition of phosphodiesterase 4, which method comprises administering to said subject an effective amount of a compound according to claim 19.
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32. A method according to claim 31, wherein the pathological condition or disease is asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, atopic dermatitis, psoriasis or irritable bowel disease.
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33. A combination product comprising:
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(i) a compound according to claim 19; and (ii) another compound selected from (a) steroids, (b) immunosuppressive agents, (c) T-cell receptor blockers, (d) antiinflammatory drugs, (e) β
2-adrenergic agonists and (f) antagonists of M3 muscarinic receptorsfor simultaneous, separate or sequential administration to a human or animal.
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34. A method for treating a subject afflicted with a pathological condition or disease susceptible to amelioration by inhibition of phosphodiesterase 4, which method comprises administering to said subject an effective amount of a combination product according to claim 33.
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20. A compound according to claim 19 wherein R1 is a hydrogen atom or lower alkyl group, which is optionally substituted by one or more substituents selected from halogen atoms and hydroxy, alkoxy, alkylthio, hydroxycarbonyl and alkoxycarbonyl groups.
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30-1. A pharmaceutical composition comprising a compound according to claim 19 in admixture with a pharmaceutically acceptable diluent or carrier.
Specification
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Current AssigneeLaboratories Almirall SA (Grupo Corporativo Landon SL)
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Original AssigneeLaboratories Almirall SA (Grupo Corporativo Landon SL)
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InventorsWarrellow, Graham, Masdeu Margalef, Maria Del Carmen, Aguilar Izquierdo, Nuria, Lumeras Amador, Wenceslao, Gracia Ferrer, Jordi, Carrascal Riera, Marta, Dal Piaz, Vittorio
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Application NumberUS11/629,527Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/236.500CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 19/00 Drugs for skeletal disordersA61P 19/02 for joint disorders, e.g. a...A61P 29/00 Non-central analgesic, anti...A61P 43/00 Drugs for specific purposes...C07D 237/24 Carbon atoms having three b...C07D 401/12 linked by a chain containin...C07D 401/14 containing three or more he...C07D 405/14 containing three or more he...C07D 409/14 containing three or more he...C07D 471/04 Ortho-condensed systemsC07D 495/04 Ortho-condensed systems