Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-12-07
2001-10-16
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C546S282100, C546S283100, C549S417000, C549S476000, C549S478000, C514S336000, C514S460000, C514S473000
Reexamination Certificate
active
06303789
ABSTRACT:
FIELD OF APPLICATION OF THE INVENTION
The invention relates to novel benzamides which are used in the pharmaceutical industry for the production of medicaments.
1. Known Technical Background
The international patent applications WO93/25517, WO95/01338 and WO96/03399 disclose trisubstituted phenyl derivatives as selective PDE4 inhibitors. The international patent applications WO94/02465 and WO95/20578 also describe 3- or polysubstituted phenyl derivatives as inhibitors of phosphodiesterase 4 and of TNF secretion.
2. Description of the Invention
It has now been found that the compounds described below in greater detail, which differ from the previously published compounds by a different type of substitution, have surprising and particularly advantageous properties.
The invention thus relates to compounds of the formula I,
in which
R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or 1-4C-alkoxy which is completely or predominantly substituted by fluorine,
R2 is hydrogen and
R3 is hydrogen
or
R2 and R3 are together a methylene group,
R4 is hydrogen, 1-8C-alkyl, 1-6C-alkoxy-1-4C-alkyl, 1-6C-alkylthio-1-4-alkyl, 1-6C-alkylsulfonyl-1-4C-alkyl, alkyl, 1-6C-alkylsulfonyl-1-4C-alkyl, 1-8C-alkylcarbonyl, 3-7C-cycloalkyl, 3-7C-cycloalkymethyl, phenyl-1-4C-alkyl or 1-4C-alkyl which is completely or predominantly substituted by fluorine,
R5 is phenyl, pyridyl, phenyl substituted by R51, R52 and R53 or pyridyl substituted by R54, R55, R56 and R57, where
R51 is hydroxyl, halogen, cyano, carboxyl, trifluoromethyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, amino, mono- or di-1-4C-alkylamino or 1-4C-alkylcarbonylamino,
R52 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy,
R53 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy,
R54 hydroxyl, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino,
R55 is hydrogen, halogen, amino or 1-4C-alkyl,
R56 is hydrogen or halogen and
R57 is hydrogen or halogen,
n is 1 or 2,
m is 1 or 2,
where the sum of m and n may only assume the values 2 or 3, the salts of these compounds and the N-oxides of the pyridines and their salts.
1-8C-Alkyl is straight-chain or branched alkyl radicals having 1 to 8 carbon atoms. Examples which may be mentioned are the octyl radical, isooctyl radical (6-methylheptyl radical), heptyl radical, isoheptyl radical (5-methylhexyl radical), hexyl radical, isohexyl radical (4-methylpentyl radical), neohexyl radical (3,3-dimethylbutyl radical), pentyl radical, isopentyl radical (3-methylbutyl radical), neopentyl radical (2,2-dimethylpropyl radical), butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and the methyl radical.
1-4C-Alkyl is straight-chain or branched alkyl radicals having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl radical, isobutyl radical, sec-butyl radical, tert-butyl radical, propyl radical, isopropyl radical, ethyl radical and methyl radical.
1-6C-Alkoxy is a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples of alkoxy radicals having 1 to 6 carbon atoms which may be mentioned are the hexyloxy radical, isohexyloxy radical (4-methylpentyloxy radical), neohexyloxy radical (3,3-dimethylbutoxy radical), pentyloxy radical, isopentyloxy radical (3-methylbutoxy radical), neopentyloxy radical (2,2-dimethylpropoxy radical), butoxy radical, isobutoxy radical, sec-butoxy radical, tert-butoxy radical, propoxy radical, isopropoxy radical, ethoxy radical and the methoxy radical.
3-7C-Cycloalkoxy is cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.
3-7C-Cycloalkylmethoxy is cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.
Examples of 1-4C-alkoxy which is completely or predominantly substituted by fluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropoxy radical, the perfluoroethoxy radical, the 1,2,2-trifluoroethoxy radical in particular the 1,1,2,2-tetrafluoroethoxy radical, the 2,2,2-trifluoroethoxy radical, the trifluoromethoxy radical and preferably the difluoromethoxy radical.
1-6C-Alkoxy-1-4C-alkyl is one of the above-defined 1-4C-alkyl radicals which is substituted by a 1-6C-alkoxy radical. Examples which may be mentioned are the methoxymethyl radical, t-butoxymethyl radical, 1-ethoxyethyl radical and the 1-methyl-1-methoxyethyl radical.
1-6C-Alkylthio-1-4C-alkyl is a 1-4C-alkyl radical which is substituted by a 1-6C-alkylthio radical. Examples which may be mentioned are the methylthiomethyl radical and the tert-butylthiomethyl radical.
1-6C-Alkylsulfinyl-1-4C-alkyl is a 1-4C-alkyl radical which is substituted by a 1-6C-alkylsulfinyl radical. An example which may be mentioned is the methylsulfinylmethyl radical.
1-6C-Alkylsulfonyl-1-4C-alkyl is a 1-4C-alkyl radical which is substituted by a 1-6C-alkylsulfonyl radical. An example which may be mentioned is the methylsulfonylmethyl radical
1-8C-Alkylcarbonyl is a radical which, in addition to the carbonyl group, contains one of the abovementioned 1-8C-alkyl radicals. An example which may be mentioned is the acetyl radical, propanoyl radical and the butanoyl radical.
3-7C-Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, of which 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. Preferably, the 3-5C-cycloalkylmethyl radicals cyclopropylmethyl, cyclobutylmethyl and cyclopentylmethyl may be mentioned.
Phenyl-1-4C-alkyl is one of the abovementioned 1-4C-alkyl radicals which is substituted by phenyl. Examples which may be mentioned are the phenethyl radical and the benzyl radical.
Examples of 1-4C-alkyl which is completely or predominantly substituted by fluorine which may be mentioned are the 2,2,3,3,3-pentafluoropropyl radical, the perfluoroethyl radical, the 1,2,2-trifluoroethyl radical, in particular the 1,1,2,2-tetrafluoroethyl radical, the 2,2,2-trifluoroethyl radical, the trifluoromethyl radical and preferably the difluoromethyl radical.
Halogen within the meaning of the invention is bromine, chlorine and fluorine.
1-4C-Alkoxycarbonyl is a carbonyl group to which one of the abovementioned 1-4C-alkoxy radicals is bonded. Examples which may be mentioned are the methoxycarbonyl radical (CH
3
O-C(O)—) and the ethoxycarbonyl radical (CH
3
CH
2
O-C(O)—).
1-4C-Alkylcarbonyloxy radicals, in addition to the oxygen atom, contain one of the abovementioned 1-4C-alkylcarbonyl radicals. An example which may be mentioned is the acetoxy radical (CH
3
C(O)O—).
Mono- or di-1-4C-alkylamino radicals, in addition to the nitrogen atom, contain one or two of the abovementioned 1-4C-alkyl radicals. An example which may be mentioned is the dimethylamino radical.
An example of a 1-4C-alkylcarbonylamino radical which may be mentioned is the propionylamino radical (C
3
H
7
C(O)NH—) and the acetylamino radical (CH
3
C(O)NH—).
Examples of phenyl radicals substituted by R51, R52 and R53 which may be mentioned 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-dimethyl
ByK Gulden Lomberg Chemische Fabrik GmbH
Jacobson & Holman PLLC
Trinh Ba K.
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