Pyridazin-3(2
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.
1. 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.
2. A compound according to claim 1 , chosen from:
5-Acetyl-2-ethyl-4-[(3-fluorophenyl)amino]-6-phenylpyridazin-3(2H)-one;
5-Acetyl-4-[(3,5-difluorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
5-Acetyl-2-ethyl-4-(1-naphthylamino)-6-phenylpyridazin-3(2H)-one;
5-Acetyl-4-[(2-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-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-4-[(2-methylphenyl)amino]-6-[4-(methylsulphinyl)phenyl]pyridazin-3(2H)-one;
5-Acetyl-6-[3-(cyclopentyloxy)-4-methoxyphenyl]-2-ethyl-4-[(3-fluorophenyl)amino]pyridazin-3(2H)-one;
5-Acetyl-4-[(3,5-difluorophenyl)amino]-2-methyl-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;
4-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzoic acids;
5-Acetyl-4-[(3-chlorophenyl)amino]-2-ethyl-6-phenylpyridazin-3(2H)-one;
3-[(5-Acetyl-2-ethyl-3-oxo-6-phenyl-2,3-dihydropyridazin-4-yl)amino]benzonitrile;
4-[5-Acetyl-6-(3-chlorophenyl)-2-ethyl-3-oxo-2,3-dihydropyridazin-4-ylamino]benzoic acid;
5-Acetyl-6-(3-chlorophenyl)-2-ethyl-4-[(3-fluorophenyl)amino]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-2-ethyl-4-(naphthalen-1-ylamino)-6-(3-nitrophenyl)pyridazin-3(2H)-one; and
5-Acetyl-2-(cyclopropylmethyl)-4-[(3,5-difluorophenyl)amino]-6-phenylpyridazin-3(2H)-one.
3. A process for preparing a compound of formula I
or a pharmaceutically acceptable salt thereof
wherein
R 1 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
—(CH 2 ) n —R 6
wherein n is an integer from 0 to 4 and wherein
R 6 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;
R 2 is H;
R 5 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;
R 3 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;
R 4 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
—(CH 2 ) n —R 6
with the proviso that when simultaneously R 2 is H, and R 3 and R 5 are unsubstituted phenyl, R 1 is not methyl;
comprising
reacting the corresponding 4-aminopyridazin-3(2H)-one derivative of formula (II)
with the corresponding boronic acid of formula (IIIa)
R 3 —B(OH)2 (IIIa);
and
optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.
4. A process for preparing a compound of formula I
or a pharmaceutically acceptable salt thereof
wherein
R 1 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
—(CH 2 ) n —R 6
wherein n is an integer from 0 to 4 and wherein
R 6 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;
R 2 is aryl or substituted aryl;
R 5 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;
R 3 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;
R 4 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
—(CH 2 ) n —R 6
with the proviso that when simultaneously R 2 is H, and R 3 and R 5 are unsubstituted phenyl, R 1 is not methyl;
comprising
reacting the corresponding 4-aminopyridazin-3(2H)-one derivative of formula (IV):
with the corresponding boronic acid of formula (IIIb)
R 2 —B(OH) 2 (IIIb)
and
optionally converting the compound of formula (I) into a pharmaceutically acceptable salt.
5. A process for preparing a compound of formula I
or a pharmaceutically acceptable salt thereof
wherein
R 1 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
—(CH 2 ) n —R 6
wherein n is an integer from 0 to 4 and wherein
R 6 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;
R 2 represents a substituent chosen from R 1 and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group;
R 5 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;
R 3 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;
R 4 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
—(CH 2 ) n —R 6
with the proviso that when simultaneously R 2 is H, and R 3 and R 5 are unsubstituted phenyl, R 1 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.
6. A pharmaceutical composition comprising a compound as claimed in claim 1 and at least one pharmaceutically acceptable carrier or diluent.
7. 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
R 1 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
—(CH 2 ) n —R 6
wherein n is an integer from 0 to 4 and wherein
R 6 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;
R 2 represents a substituent chosen from R 1 and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group;
R 5 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;
R 3 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;
R 4 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
—(CH 2 ) n —R 6
with the proviso that when simultaneously R 2 is H, and R 3 and R 5 are unsubstituted phenyl, R 1 is not methyl;
or a pharmaceutically acceptable salt of a compound of formula (I).
8. 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
R 1 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
—(CH 2 ) n —R 6
wherein n is an integer from 0 to 4 and wherein
R 6 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;
R 2 represents a substituent chosen from R 1 and an alkyl group, wherein the alkyl group is substituted by a hydroxycarbonyl or an alkoxycarbonyl group;
R 5 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;
R 3 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 p 2 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;
R 4 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
—(CH 2 ) n —R 6
with the proviso that when simultaneously R 2 is H, and R 3 and R 5 are unsubstituted phenyl, R 1 is not methyl:
or a pharmaceutically acceptable salt of a compound of formula (I).
9. A pharmaceutical composition comprising a compound as claimed in claim 2 and at least one pharmaceutically acceptable carrier or diluent.