Benzofuran-4-carboxamides

Details Benzofuran-4-carboxamides Benzofuran-4-carboxamides

1999-02-05

2001-04-03

Rotman, Alan L. (Department: 1612)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S469000, C514S449000, C514S183000, C546S284100, C546S283400, C546S281700, C549S429000, C549S468000, C549S467000

Reexamination Certificate

active

06211203

ABSTRACT:

FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel benzofuran-4-carboxamides which are used in the pharmaceutical industry for the production of medicaments.
1. Known Technical Background
International Patent Application WO92/12961 describes benzamides having PDE-inhibiting properties.—International Patent Application WO93125517 discloses trisubstituted phenyl derivatives as selective PDE IV inhibitors.—International Patent Application WO94/02465 describes inhibitors of c-AMP phosphodiesterase and of TNF.—International Patent Application WO95/01338 describes fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors.—International Patent Application WO97/20833 discloses benzofuran carboxamides and sulphonamides as inhibitors of phosphodiesterase IV.
2. Description of the Invention
It has now been found that the novel benzofuran-4-carboxamides described in greater detail below have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I
in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or mainly substituted by fluorine,
R2 is 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
Ar is phenyl, pyridyl, phenyl which is substituted by R3, R4 and R5 or pyridyl which is substituted by R6, R7, R8 and R9, where
R3 is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-atkylcarbonyloxy, amino, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonylamino,
R4 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy,
R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is hydroxyl, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino,
R7 is hydrogen, halogen, amino or 1-4C-alkyl,
R8 is hydrogen or halogen and
R9 is hydrogen or halogen,
the salts of these compounds, and the N-oxides of the pyridines and their salts.
In particular the invention relates to compounds of the formula I, in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or mainly substituted by fluorine,
R2 is 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
Ar is phenyl, pyridyl, phenyl which is substituted by R3, R4 and R5 or pyridyl which is substituted by R6, R7, R8 and R9, where
R3 is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 14C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, amino, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonylamino,
R4 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy,
R5 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
R6 is hydroxyl, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino,
R7 is hydrogen, halogen, amino or 1-4C-alkyl,
R8 is hydrogen or halogen and
R9 is hydrogen or halogen,
and where R2 is not ethyl or 2,2-dimethylpropyl when R1 is methoxy,
the salts of these compounds, and the N-oxides of the pyridines and their salts.
1-2C-Alkoxy is a radical which, beside the oxygen atom, contains an ethyl radical or preferably a methyl radical.
1-2C-Alkoxy which is completely or mainly substituted by fluorine is, for example, the 1,2,2-trifluoroethoxy, the perfluoroethoxy and in particular the 1,1,2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and preferably the difluoromethoxy radical.
1-7C-Alkyl is straight-chain or branched alkyl radicals having 1 to 7 carbon atoms. Examples are the heptyl, isoheptyl (2-methylhexyl), hexyl, isohexyl (2-methylpentyl), neohexyl (2,2-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
3-7C-Cycloalkyl is the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl radical. The 3-5C-cycloalkyl radicals cyclopropyl, cyclobutyl and cyclopentyl are preferred.
3-7C-Cycloalkylmethyl is a methyl radical which is substituted by one of the abovementioned 3-7C-cycloalkyl radicals. The 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl are preferred.
Halogen within the meaning of the present invention is bromine, chlorine and fluorine.
1-4C-Alkyl is straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and the methyl radical.
1-4C-Alkoxy is a radical which, beside the oxygen atom, contains one of the abovementioned 14C-alkyl radicals. Examples are the methoxy and the ethoxy radicals.
1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples are the methoxycarbonyl (CH
3
O—CO—) and the ethoxycarbonyl radical (CH
3
CH
2
O—CO—).
1-4C-Alkylcarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkyl radicals is bonded. An example is the acetyl radical (CH
3
CO—).
1-4C-Alkylcarbonyloxy radicals, beside the oxygen atom, contain one of the abovementioned 1-4C-alkylcarbonyl radicals. An example is the acetoxy radical (CH
3
CO—O—).
Examples of mono- or di-1-4C-alkylamino radicals are the methylamino, the dimethylamino and the diethylamino radical.
An example of a 1-4C-alkylcarbonylamino radical is the acetylamido radical (—NH—CO—CH
3
).
The substituents R3, R4 and R5 can be linked to the phenyl radical in any desired position and combination. Exemplary phenyl radicals substituted by R3, R4 and R5 are the radicals 2-acetylphenyl, 2-aminophenyl, 2-bromophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4-diethylamino-2-methylphenyl, 4-bromo-2-trifluoromethylphenyl, 2-carboxy-5-chlorophenyl, 3,5-dichloro-2-hydroxyphenyl, 2-bromo-4-carboxy-5-hydroxyphenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4,6-trifluorophenyl, 2,6-dibromophenyl, 2-cyanophenyl, 4-cyano-2-fluorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2-hydroxyphenyl, 2-hydroxy-4-methoxyphenyl, 2,4-dihydroxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,6-dimethoxyphenyl, 2-dimethylaminophenyl, 2-methylphenyl, 2-chloro-6-methylphenyl, 2,4-dimethylphenyl, 2,6-dimethylphenyl, 2,3-dimethylphenyl, 2-methoxycarbonylphenyl, 2-trifluoromethylphenyl, 2,6-dichloro-4-methoxyphenyl, 2,6-dichloro-4-cyanophenyl, 2,6-dichloro-4-aminophenyl, 2,6-dichloro-4-methoxycarbonylphenyl, 4-acetylamino-2,6-dichlorophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 4-carboxyphenyl and 4-carboxy-2,6-dichlorophenyl.
The substituents R6, R7, R8 and R9 can be linked to the pyridyl ring in any desired position and combination. Exemplary pyridyl radicals substituted by R6, R7, R8 and R9 are the radicals 3,5-dichloropyrid-4-yl, 2,6-diaminopyrid-3-yl, 4-aminopyrid-3-yl, 3-methylpyrid-2-yl, 4-methylpyrid-2-yl, 5-hydroxypyrid-2-yl, 4-chloropyrid-3-yl, 3-chloropyrid-2-yl, 3-chloropyrid-4-yl, 2-chloropyrid-3-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl, 3,5-dibromo-pyrid-2-yl, 3,5-dibromopyrid-4-yl, 3,5-dichloropyrid-4-yl, 2,6-dichloropyrid-3-yl, 3,5-dimethylpyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl and 2,3,5-trifluoropyrid-4-yl.
Compounds of the formula I to be emphasized are those in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or mainly substituted by fluorine,
R2 is 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
Ar is phenyl, pyridyl, phenyl substituted by R3, R4 and R5 or pyridyl substituted by R6, R7, R8 and R9, where
R3 Is halogen, carboxyl or 1-4C-alkoxycarbonyl,
R4 is hydrogen or halogen,
R5 is hydrogen or halogen,
R6 is halogen,
R7 is hydrogen or halogen, and
R8 and R9 are hydrogen,
the salts of these compounds, and the N-oxides of the pyridines and their salts.
Preferred compounds of the formula I to be emphasized are those in which
R1 is 1-2C-alkoxy or 1-2C-alkoxy which is completely or mainly substituted by fluorine,
R2 is 1-7C-alkyl, 3-7C-cycloalkyl or 3-7C-cycloalkylmethyl,
Ar is phenyl, pyridyl, phenyl substituted by R3, R4 and R5 or pyridyl substituted by R6, R7, R8 and R9, where
R3 is hal

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