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US 7,459,453 B2Granted
Pyridazin-3(2H)-one derivatives as PDE4 inhibitors
AssigneeLaboratorios Almirall, S.A.
InventorsVittorio Dal Piaz, Maria Paola Giovannoni, Claudia Vergelli, Nuria Aguilar Izquierdo
Life of this patent
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Abstract
New pyridazin-3(2H)-one derivatives having the chemical structure of general formula (I) are disclosed; as well as process for their preparation, pharmaceutical compositions comprising them and their use in therapy as inhibitors of phosphodiesterase 4.
Claims9
A compound chosen from:
- 5-Acetyl-4-[(3,5-difluorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3,5-dichlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(3-nitrophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(2-methoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-{[4-(methylthio)phenyl]amino}-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(4-acetylphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-{[4-(dimethylamino)phenyl]amino}-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-(2-naphthylamino)-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-phenyl-4-([3-(trifluoromethoxy)phenyl]amino)pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-phenyl-4-([2-(trifluoromethyl)phenyl]amino)pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(2,5-dimethoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(2-fluoro-3-methoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(2,3-dichlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(5-chloro-2-methoxyphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(5-fluoro-2-methoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- Methyl 4-({5-acetyl-2-ethyl-6-[4-(methylthio)phenyl]-3-oxo-2,3-dihydropyridazin-4-yl}amino)benzoate;
- 5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-[4-(methylthio)phenyl]pyridazin-3(2H)-one;
- 4-({5-Acetyl-2-ethyl-6-[4-(methylthio)phenyl]-3-oxo-2,3-dihydropyridazin-4-yl}amino)benzoic acid;
- 5-Acetyl-2-ethyl-6-[4-(methylthio)phenyl]-4-(1-naphthylamino)pyridazin-3(2H)-one;
- 5-Butyryl-2-ethyl-4-[(3-fluorophenyl)amino]-6-[4-(methylthio)phenyl]pyridazin-3(2H)-one;
- 2-Ethyl-5-(2-ethylbutanoyl)-4-[(3-fluorophenyl)amino]-6-[4-(methylthio)phenyl]pyridazin-3(2H)-one;
- 2-Ethyl-5-(2-ethylbutanoyl)-6-[4-(methylthio)phenyl]-4-(naphth-1-ylamino)pyridazin-3(2H)-one;
- Methyl 4-({5-acetyl-2-ethyl-6-[4-(methylsulphinyl)phenyl]-3-oxo-2,3-dihydropyridazin-4-yl}amino)benzoate;
- 5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-[4-(methylsulphinyl)phenyl]pyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-[4-(methylsulphinyl)phenyl]pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(2-methylphenyl)amino]-6-[4-(methylsulphinyl)phenyl]pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-[4-(methylsulphinyl)phenyl]-4-(1-naphthylamino)pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-[4-(methylsulphinyl)phenyl]-4-[(3-nitrophenyl)amino]pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-[4-(methylsulphinyl)phenyl]-4-[(2-methoxyphenyl)amino]pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-[4-(methylsulphinyl)phenyl]-4-[(3-methoxyphenyl)amino]pyridazin-3(2H)-one;
- 5-Acetyl-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one;
- 5-Acetyl-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-ethyl-4-(1-naphthylamino)pyridazin-3(2H)-one;
- 5-Acetyl-2-methyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3,5-difluorophenyl)amino]-2-methyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-methyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-benzyl-4-[(3,5-difluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-benzyl-4-[(3-fluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-benzyl-4-[(3-chlorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-(cyclopropylmethyl)-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-(cyclopropylmethyl)-4-[(3-fluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-(1-naphthylamino)-6-phenyl-2-pyridin-4-ylmethylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-fluorophenyl)amino]-6-phenyl-2-pyridin-4-ylmethylpyridazin-3(2H)-one;
- 4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acid;
- 2-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acid;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-bromophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H-one;
- 5-Acetyl-4-[(3,4-dimethoxyphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-{[4-(hydroxymethyl)phenyl]amino}-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-(1,1′-biphenyl-4-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-phenyl-4-(5,6,7,8-tetrahydronaphthalen-1-ylamino)pyridazin-3(2H)-one;
- 5-acetyl-4-{[3-(cyclopentyloxy)-4-methoxyphenyl]amino}-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-(1,3-benzodioxol-5-ylamino)-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(4-methoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(4-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(4-bromophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-6-phenyl-4-{[3-(trifluoromethyl)phenyl]amino}pyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chloro-4-methoxyphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(3-hydroxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 3-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acid;
- 5-Acetyl-2-ethyl-4-[(2-fluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 4-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydro-pyridazin-4-ylamino)-benzoic acid ethyl ester;
- 5-Acetyl-2-ethyl-4-[(4-fluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 2-[(5-acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]-4-fluorobenzoic acid;
- 3-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;
- 4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]-2-hydroxybenzoic acid;
- 5-Acetyl-2-ethyl-4-[(3-hydroxy-4-methoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzamide;
- 5-Acetyl-2-ethyl-4-{[3-(methylthio)phenyl]amino}-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(3-methoxyphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-acetylphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- {4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]phenyl}acetic acid;
- 5-Acetyl-4-[4-(tert-butylphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzenesulphonamide;
- 4-{4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]phenyl}-4-oxobutanoic acid;
- 3-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]-N-butylbenzenesulphonamide;
- 5-Acetyl-2-ethyl-4-[(1-oxo-2,3-dihydro-1H-inden-5-yl)amino]-6-phenylpyridazin-3(2H)-one;
- N-{4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]phenyl}acetamide;
- 4-[5-Acetyl-6-(3-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ylamino]benzoic acid;
- 5-Acetyl-6-(3-chlorophenyl)4-[(3-chlorophenyl)amino]-2-ethylpyridazin-3(2H)-one;
- 5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(4-fluorophenyl)pyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-bromophenyl)amino]-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-(3-fluorophenyl)pyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(3-fluorophenyl)pyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-(3-nitrophenyl)pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-(3-nitrophenyl)pyridazin-3(2H)-one;
- 4-{[5-Acetyl-2-ethyl-6-(3-nitrophenyl)-3-oxo-2,3-dihydropyridazin-4-yl]amino}benzoic acid;
- 5-Acetyl-4-[(3-bromophenyl)amino]-2-ethyl-6-(3-nitrophenyl)pyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-(naphthalen-1-ylamino)-6-(3-nitrophenyl)pyridazin-3(2H)-one;
- 5-Butyryl-4-[(3-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-6-phenyl-2-propylpyridazin-3(2H)-one;
- 5-Acetyl-2-butyl-4-[(3-chlorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-bromophenyl)amino]-2-butyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[N-(3,5-dichlorophenyl)-N-(3-fluorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[bis(3-fluorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[bis(3-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-ethyl-4-[bis(3-methylsulphanylphenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[bis(3-acetylphenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[bis-(3,5-dichlorophenyl)amino]-2-ethyl-6-phenyl-2H-pyridazin-3-one;
- methyl 4-{N-(5-acetyl-2-ethyl-6-(4-methylsulphinylphenyl)-3-oxo-2,3-dihydropyridazin-4-yl)-N-[4-(methoxycarbonyl)phenyl]amino}benzoate;
- 5-Acetyl-2-(cyclopropylmethyl)-4-[(3,5-difluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-fluorophenyl)amino]-2-methyl-6-phenylpyridazin-3(2H)-one;
- 4-[(5-Acetyl-2-methyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acids;
- 5-Acetyl-4-[(3,5-dichlorophenyl)amino]-2,6-diphenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-fluorophenyl)amino]-2,6-diphenylpyridazin-3(2H)-one;
- 5-Acetyl-4-(1-naphthylamino)-2,6-diphenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3,5-difluorophenyl)amino]-2,6-diphenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2,6-diphenylpyridazin-3(2H)-one;
- 5-Benzoyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-methylpyridazin-3(2H)-one;
- 5-[(3-Chlorophenyl)amino]-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carbaldehyde;
- Methyl 5-[(3-chlorophenyl)amino]-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylate;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-(2-hydroxyethyl)-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)amino]-2-[2-(dimethylamino)ethyl]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-2-cyclobutyl-4-[(3,5-dichlorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
- 5-Acetyl-4-[(3-chlorophenyl)(2-hydroxyethyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- N-(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)-N-(3-chlorophenyl)urea;
- 4-[(3-Chlorophenyl)amino]-5-[(dimethylamino)acetyl]-2-ethyl-6-phenylpyridazin-3(2H)-one;
- 4-{[2-Ethyl-5-(methoxyacetyl)-6-phenyl-3-oxo-2,3-dihydropyridazin-4-yl]amino}benzoic acid;
- 5-[(3-Cyanophenyl)amino]-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxamide;
- 5-[(3-Cyanophenyl)amino]-1-ethyl-6-oxo-3-phenyl-1,6-dihydropyridazine-4-carboxylic acid;
- 3-{4-Acetyl-5-[(3,5-difluorophenyl)amino]-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl}benzoic acid;
- 3-{4-Acetyl-5-[(3,5-difluorophenyl)amino]-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl}benzonitrile;
- N-(3-{4-Acetyl-5-[(3,5-difluorophenyl)amino]-1-ethyl-6-oxo-1,6-dihydropyridazin-3-yl}phenyl)urea;
- and
- 5-Acetyl-4-[(3-chlorophenyl)amino]-6-phenylpyridazin-3(2H)-one.
126 more elements
A process for preparing a compound of formula I
- or a pharmaceutically acceptable salt thereof
- wherein
- R1 represents:
- a hydrogen atom;
- a group chosen from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- wherein n is an integer from 0 to 4 and wherein
- R6 represents:
- a cycloalkyl group;
- an aryl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- and di-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy groups;
- or
- a 3- to 7-membered ring comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, wherein the 3- to 7-membered ring is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- and di-alkylamino, nitro, cyano and trifluoromethyl groups;
- R2 is H;
- R5 represents a monocyclic or bicyclic aryl group, wherein the monocyclic or bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R3 represents a monocyclic or bicyclic aryl group,
- wherein the monocyclic aryl group is substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- wherein the bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R4 represents:
- a hydrogen atom;
- a hydroxy, alkoxy, amino, mono- or di-alkylamino group;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;:
- or
- a group of formula
- —(CH2)n—R6
- with the proviso that when simultaneously R2 is H, and R3 and R5 are unsubstituted phenyl, R1 is not methyl;
- comprising
- reacting the corresponding 4-aminopyridazin-3(2H)-one derivative of formula (II)
- with the corresponding boronic acid of formula (IIIa)
- R3—B(OH)2 (IIIa);
- and
- optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.
46 more elements
A process for preparing a compound of formula I
- or a pharmaceutically acceptable salt thereof
- wherein
- R1 represents:
- a hydrogen atom;
- a group chosen from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- wherein n is an integer from 0 to 4 and wherein
- R6 represents:
- a cycloalkyl group;
- an aryl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- and di-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy groups;
- or
- a 3- to 7-membered ring comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, wherein the 3- to 7-membered ring is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- and di-alkylamino, nitro, cyano and trifluoromethyl groups;
- R2 is aryl or substituted aryl;
- R5 represents a monocyclic or bicyclic aryl group, wherein the monocyclic or bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkoxycarbonyl, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R3 represents a monocyclic or bicyclic awl group,
- wherein the monocyclic awl group is substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- wherein the bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R4 represents:
- a hydrogen atom;
- a hydroxy, alkoxy, amino, mono- or di-alkylamino group;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- with the proviso that when simultaneously R2 is H, and R3 and R5 are unsubstituted phenyl, R1 is not methyl;
- comprising
- reacting the corresponding 4-aminopyridazin-3(2H)-one derivative of formula (IV):
- with the corresponding boronic acid of formula (IIIb)
- R2—B(OH)2 (IIIb)
- and
- optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.
46 more elements
A process for preparing a compound of formula I
- or a pharmaceutically acceptable salt thereof
- wherein
- R1 represents:
- a hydrogen atom;
- a group chosen from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- wherein n is an integer from 0 to 4 and wherein
- R6 represents:
- a cycloalkyl group;
- an aryl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- and di-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy groups;
- or
- a 3- to 7-membered ring comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, wherein the 3- to 7-membered ring is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- and di-alkylamino, nitro, cyano and trifluoromethyl groups;
- R2 represents a substituent chosen from R1 and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group;
- R5 represents a monocyclic or bicyclic aryl group, wherein the monocyclic or bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R3 represents a monocyclic or bicyclic aryl group,
- wherein the monocyclic aryl group is substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- wherein the bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R4 represents:
- a hydrogen atom;
- a hydroxy, alkoxy, amino, mono- or di-alkylamino group;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- with the proviso that when simultaneously R2 is H, and R3 and R5 are unsubstituted phenyl, R1 is not methyl;
- comprising
- reacting the corresponding 4-nitropyridazin-3(2H)-one derivative of formula (V):
- with the corresponding amine of formula (VI)
- and
- optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.
45 more elements
A method for treating asthma in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula (I):
- wherein
- R1 represents:
- a hydrogen atom;
- a group chosen from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl:
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- wherein n is an integer from 0 to 4 and wherein
- R6 represents:
- a cycloalkyl group;
- an aryl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- and di-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy groups;
- or
- a 3- to 7-membered ring comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, wherein the 3- to 7-membered ring is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- and di-alkylamino, nitro, cyano and trifluoromethyl groups;
- R2 represents a substituent chosen from R1 and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group;
- R5 represents a monocyclic or bicyclic aryl group, wherein the monocyclic or bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R3 represents a monocyclic or bicyclic aryl group,
- wherein the monocyclic aryl group is substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- wherein the bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′, N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R4 represents:
- a hydrogen atom;
- a hydroxy, alkoxy, amino, mono- or di-alkylamino group;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- with the proviso that when simultaneously R2 is H, and R3 and R5 are unsubstituted phenyl, R1 is not methyl;
- or a pharmaceutically acceptable salt of a compound of formula (I).
40 more elements
A method for treating atopic dermatitis in a subject in need thereof, comprising administering to said subject an effective amount of a compound of formula (I):
- wherein
- R1 represents:
- a hydrogen atom;
- a group chosen from acyl, alkoxycarbonyl, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- wherein n is an integer from 0 to 4 and wherein
- R6 represents:
- a cycloalkyl group;
- an aryl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, alkylthio, amino, mono- and di-alkylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, cyano, trifluoromethyl, difluoromethoxy and trifluoromethoxy groups;
- or
- a 3- to 7-membered ring comprising 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulphur, wherein the 3- to 7-membered ring is optionally substituted by one or more substituents chosen from halogen atoms, and alkyl, hydroxy, alkoxy, alkylenedioxy, amino, mono- and di-alkylamino, nitro, cyano and trifluoromethyl groups;
- R2 represents a substituent chosen from R1 and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group;
- R5 represents a monocyclic or bicyclic aryl group, wherein the monocyclic or bicyclic aryl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′, N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R3 represents a monocyclic or bicyclic aryl group,
- wherein the monocyclic awl group is substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and
- phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- wherein the bicyclic awl group is optionally substituted by one or more substituents chosen from:
- halogen atoms;
- alkyl and alkylene groups,
- wherein the alkyl and alkylene groups are, each independently, optionally substituted by one or more substituents chosen from halogen atoms, and phenyl, hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- and p2 phenyl, hydroxy, alkylenedioxy, alkoxy, cycloalkyloxy, alkylthio, alkylsulphinyl, amino, mono- and di-alkylamino, acylamino, nitro, acyl, hydroxycarbonyl, alkoxycarbonyl, carbamoyl, mono- and di-alkylcarbamoyl, ureido, N′-alkylureido, N′,N′-dialkylureido, alkylsulphamido, aminosuphonyl, mono- and di-alkylaminosulphonyl, cyano, difluoromethoxy and trifluoromethoxy groups;
- R4 represents:
- a hydrogen atom;
- a hydroxy, alkoxy, amino, mono- or di-alkylamino group;
- an alkyl group, which is optionally substituted by one or more substituents chosen from halogen atoms, and hydroxy, alkoxy, aryloxy, alkylthio, oxo, amino, mono- and di-alkylamino, acylamino, hydroxycarbonyl, alkoxycarbonyl, carbamoyl and mono- and di-alkylcarbamoyl groups;
- or
- a group of formula
- —(CH2)n—R6
- with the proviso that when simultaneously R2 is H, and R3 and R5 are unsubstituted phenyl, R1 is not methyl:
- or a pharmaceutically acceptable salt of a compound of formula (I).
39 more elements
Dependencies are inferred from the claim text.