CZ196A3

CZ196A3 - Substituted benzamides, process of their preparation and pharmaceutical compositions containing thereof

Info

Publication number: CZ196A3
Application number: CZ961A
Authority: CZ
Inventors: Dieter Flockerzi; Beate Gutterer; Armin Hatzelmann; Christian Schudt; Rolf Beume; Ulrich Kilian; Horst P O Wolf
Original assignee: Byk Gulden Lomberg Chem Fab
Priority date: 1993-07-02
Filing date: 1994-07-02
Publication date: 1996-06-12
Also published as: JP3093271B2; JPH08512041A; RU2137754C1; CY2010015I1; PT706513E; FI956333A0; CN1046939C; CY2010015I2; CA2165192A1; WO1995001338A1; PL178314B1; HUT73232A; NO305598B1; PL311820A1; FR10C0052I2; DE59410119D1; NO2010018I1; NO2010018I2; SK161795A3; SK283263B6

Abstract

Compounds of formula (I), in which one of the substituents R1 or R2 stands for hydrogen, 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or totally or partially fluorine-substituted 1-4C-alkoxy, and the other stands for totally or partially fluorine-substituted 1-4C-alkoxy, and R3 stands for phenyl, pyridyl, R31, R32 and R33- substituted phenyl or R34, R35, R36 and R37- substituted pyridyl, in which R31 stands for hydroxy, 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; R32 stands for hydrogen, hydroxy, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy; R33 stands for hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy; R34 stands for hydroxy, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino; R35 stands for hydrogen, halogen, amino or 1-4C-alkyl; R36 stands for hydrogen or halogen; and R37 stands for hydrogen or halogen. These compounds constitute new effective bronchotherapeutic drugs.

Description

- 1 -

their production and pharmaceutical

Substituted benzamides, method of compositions containing them

Technical field

The present invention relates to substituted amides which are phosphodiesterase nucleotide inhibitors. The invention also relates to a process for the preparation of these substances and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION International patent application W92 / 12961 describes benzamides as phosphodiesterase PDE inhibitors. Further international patent application WO93 / 25517 is then described. trisubstituted phenyl derivatives as selective PDE-IV inhibitors. International patent application WO94 / 02465 discloses c-AMP phosphodiesterase and TNF inhibitors.

It has now been found that certain groups of benzamide derivatives, particularly those containing fluoroalkoxy groups as substituents at the 3-position or 4-position of the beozamide ring, have surprising and very advantageous properties.

SUMMARY OF THE INVENTION

The present invention provides substituted benzamides of formula I / 2

wherein one of R 12 and R 2 is hydrogen, alkoxy of 1 to 6 carbon atoms, cycloalkoxy of 3 to 7 carbon atoms, cycloalkyl alkylthio of 3 to 7 carbon atoms in the alkyl moiety, Penzyloxy or alkoxy of o C 1 -C 4, fully or partially substituted by fluorine and the other being C 1 -C 4 alkoxy; totally partially substituted by fluorine,

R 3 is fe.nyl and 31. R32 or a34. R 35, R 36 pyridyl, phenyl, 33 R or pyridyl 37 or R, wherein substituted with 31 R groups represents a hydroxy group, a halogen atom, a cyano group, a carboxyl group, a trifluoromethyl, an alkyl group, an alkoxy group, an alkoxycarbonyl group, an alkylcarbonyl group or an alkyl group. C 1 -C 4 -carbonyloxy, C 1 -C 4 alkyl, C 1 -C 4 alkyl or C 1 -C 4 alkylcarbonylamino, R 2 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, alkyl or alkoxy having from 1 to 4 carbon atoms; 33 R is hydrogen, halogen, alkyl or alkoxy of 1 to 4 carbon atoms, 34 R is hydroxy, halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl or amino group, R represents a hydrogen atom or a halogen atom, amine R is hydrogen or halogen; and 37 R is hydrogen or halogen; salts of these compounds; and N-oxides of pyridine derivatives and salts thereof.

According to Embodiment a), the invention relates to substituted benzamides of the formula I wherein one of R and R is hydrogen, alkoxy of 1-6 carbon atoms, cycloalkoxy or cycloalkylmethoxy each of 3 to 7 carbon atoms, oenzyloxy or alkoxy 1 to 4 carbon atoms, not completely! or partially substituted by fluorine and the other by C 1 -C 4 alkoxy, wholly or partially fluorine substituted, 3 R is phenyl, pyridyl, phenyl, substituted by 31 32 33 R, R or R or pyridyl substituted. . . "34" 35 "36" 37,, R, R, R, and R, where 31 R is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl or alkylcarbonyl-oxy each time by 1 C 4 to C 4, amino-4, mono- or dialkylamino or alkyl-carbonylamino having 1 to 4 carbon atoms in the alkyl moiety, 32 R represents a hydrogen atom, a hydroxy group, a halogen atom, an amino group, a trifluoromethyl group, an alkyl group or an alkoxy group; R 1 is hydrogen or halogen, alkyl or alkoxy each having 1 to 4 carbon atoms; R is hydrogen or halogen, cyano, carboxyl, alkyl, alkoxy, or alkoxycarbonyl each of 1 to 4 carbon atoms in the alkyl or alkoxy moiety or amino, R is hydrogen or halogen, amino (or alkyl of 1 to 4 carbon atoms) R 3 represents a hydrogen atom or a halogen atom, and 37 R represents a hydrogen atom or a halogen atom, a salt thereof, and an N-oxide of a pyridine derivative and its salts, with the exception of compounds wherein R 4 is an alkoxy group having 1 to 4 carbon atoms; wholly or partially fluorine-substituted R and R is cycloalkyl of 3 to 7 carbon atoms.

According to embodiment b), the invention relates to substituted benzamides of formula I wherein R 1 is C 1 -C 4 alkoxy, wholly or partially fluorine substituted and 2 R is methoxy or R 1 is hydrogen, alkoxy of 1 to 6 atoms 5 carbon, cycloalkoxy of 3-7 carbon atoms or cycloalkylmethoxy of 3-7 carbon atoms in the cycloalkyl, benzyloxy or alkoxy of 1 to 4 carbon atoms and R is methoxy, wholly or partially fluorine substituted; is cycloalkoxy of 3-7 carbon atoms, cycloalkylmethoxy of 3-7 carbon atoms in the cycloalkyl moiety or benzyloxy and R is alkoxy, wholly or partially fluorine-substituted, or R1 is C1-4alkoxy substituted in whole or in part fluorine and 2 R are cycloalkylmethoxy of 3 to 7 carbon atoms in the cycloalkyl moiety or ben zyloxy, 3 R represents phenyl, pyridyl, phenyl, substituted with 31 32 33 us R, R 'and R or pyridyl, substituted with R 1', R 4 ', R 4' and R 4 ', where 31 R represents hydroxy, halogen atom , cyano, carboxyl, trifluoromethyl, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl or alkylcarbonyloxy each having 1 to 4 carbon atoms in the alkyl, amino, mono- or dialkylamino group or alkylcarbonylamino having 1 to 4 carbon atoms in the alkyl R, is hydrogen, hydroxy, halo, amino, trifluoromethyl, alkyl or alkoxy each having 1 to 4 carbon atoms, 33 R is hydrogen or halogen, alkyl or alkoxy having from 1 to 4 carbon atoms, 6 or 4 carbon atoms, 6 or 4 carbon atoms. R 'is hydroxy, halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyloxy each having 1 to 4 carbon atoms in the alkyl or amino group, R is hydrogen or halogen, amino or al R 1 is hydrogen or halogen; and 37 R is hydrogen or halogen, salts thereof, and N-oxides of pyridine derivatives and salts thereof.

(C1 -C6) -alkoxy is a radical that contains, in addition to the oxygen atom, a straight or branched alkyl radical of 1 to δ carbon atoms. C1-6 alkyl radicals include 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 methyl.

C 3 -C 7 cycloalkoxy is, for example, cyclopropyloxy-, cyclobutyloxy-, cyclopentyloxy-, cyclo-, oxy- hexyloxy- and cycloheptyloxy, with preferred groups. are cyclopropyloxy, cyclobutyloxy and cyclopentyloxy.

C 3 -C 7 cycloalkylmethoxy is, for example, cyclopropylmethoxy-, cyclo-butylmethoxy-, cyclopentylmethoxy-, cyclohexylmethoxy- and cycloheptylmethoxy, with cyclopropylmethoxy-, cyclobutylmethoxy- and cyclopentylmethoxy- groups being preferred. 7

C 1 -C 4 -alkoxy, with or without fluorine, is, for example, 1,2,2-trifluoroethoxy-, 2,2,3,3,3-pentafluoropropoxy-, perfluoroethoxy- and especially 1,1,2,2- tetrafluoroethoxy-, trifluoromethoxy-, 2,2,2-trifluoroethoxy- and difluoromethoxy.

Halogen is understood to mean a bromine, chlorine or fluorine atom in the application.

(C 1 -C 4) alkyl means a straight or branched chain alkyl radical of 1 to 4 carbon atoms. Examples of such radicals include butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl, or methyl.

(C 1 -C 4) -alkoxy is a radical which, in addition to the oxygen atom, contains one of the abovementioned C 1 -C 4 alkyl radicals. By way of example, methoxy or ethoxy.

C 1 -C 4 alkoxycarbonyl is a carbonyl group to which one of the above 1 to 4 carbon atoms is bonded. Examples include methoxycarbonyl CH 2 O-CO- or ethoxycarbonyl CH 2 CH 2 O-CO-.

C 1 -C 4 alkylcarbonyl is a carbonyl group to which one of the above 1 to 4 carbon atoms is bonded.

An example is acetyl CH 2 CO-.

C 1 -C 4 alkylcarbonyloxy groups contain, in addition to the oxygen atom, one of the abovementioned C 1 -C 4 alkylcarbonyl radicals. By way of example, the acetoxy group is CH 2 CO-O-. Mono or dialkylamino groups having 1 to 4 carbon atoms in the alkyl moieties include methylamino, dimethylamino or diethylamino. C 1 -C 4 alkylcarbonylamino groups include, for example, acetylamido-group -NH-CO-CH 3 ·

Examples of phenyl radicals substituted with 31 32 33 by R, R and R pins include 2-acetylphenyl, 2-amino-phenyl, 2-bromophenyl, 2-chlorophenyl, 2, -dichlorophenyl, 2,4-di- chlorophenyl, 2-diethylamino-2-methylphenyl, 4-bromo-2-trifluoromethylphenyl, 2-carboxy-5-chlorophenyl, 3,5-dichloro-2-hydroxyphenyl, 2-chloro-4-carboxy-5 -hydroxyphenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,4, 5-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, 3-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-methoxycarbonyl-phenyl, 4-acetamino-2-dichloro phenyl and 2,6-dichloro-4-ethoxycarbonylphenyl.

As an example of pyridine residues, substituted by?

Λί Λ / · AW pins RJ, RJ, RJ and RJ include 3,5-dichloropyrid-1. 4-yl, 2,6-diaminopyrid-3-yl, 4-aminopyrid-3-yl, 3-methylpyridin-2-yl, 4-methylpyrid-2-yl, 5-hydroxypyrid-2-yl, 4-chloro-; pyrid-3-yl, 3-chloropyrid-2-yl, 3-chloropyrid-4-yl, 2-chloro-pyrid-3-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3,5- dichloro-2,6-difluoropyrid-4-yl, 3,5-dibromopyrid-2-yl, 3,5-dibromopyrid-4-yl, 3,5-dichloropyrid-4-yl, 2,6-dichloropyrid- 3-yl, 3,5-

19-dimethylpyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl and 2,3,5-trifluoropyrid-4-yl.

Depending on the type of substitution, the acid addition salts, and in particular all the base salts, may be chosen from the salts of the compounds of formula (I). Of particular importance are pharmacologically acceptable salts with inorganic or organic acids and bases. Pharmacologically unacceptable salts which are formed, for example, during the preparation of the compounds of the invention on an industrial scale, can be conveniently converted into pharmacologically acceptable salts. These salts include water-soluble and insoluble acid addition salts such as hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, acetic, citric, D-gluconic, benzoic, 2- (4-hydroxybenzoyl) benzoic acid; butyric, sulfo-salicylic, maleic, lauric, malic, fumaric, succinic, oxalic, tartaric, embonic, stearic, toluenesulfonic, methanesulfonic or 3-hydroxy-2-naphthoic, depending on whether it is a monobasic or a polyhydric acid and, depending on the salt desired, use an equimolar or different amount of the acid.

With regard to salts with bases which are also suitable, examples of such salts include lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium or meglumine or guanidinium salts, and in this case also in the manufacture of salts can be used in equimolar or different amounts of base. Significant compounds of formula I include those in which one of the substituents 12-R and R is alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 5 carbon atoms, cycloalkyloxy of 3 to 5 carbon atoms, cycloalkyl, benzyloxy or alkoxy having 1 to 4 carbon atoms, wholly or partially fluorine substituted and the other being 1 to 4 carbon alkoxy, fully or partially fluorine substituted and 3 R being phenyl, pyridyl, phenyl, substituted phenyl By R, R and R or pyridyl, substituted by. "34" 35 "36" 37,, pmami R, R, R and R, where 31 R represents a halogen atom, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl, R 32 represents an alkoxy atom each R 33 is an alkoxy atom R 34 is a carbon atom, R 35 is an R 35 atom is an R 37 atom is a hydrogen or halogen atom, an alkyl or C 1 -C 4 alkyl, hydrogen or halogen atom, an alkyl or C 1 -C 4 halogen or alkyl o 1 to 4 hydrogen or halogen atoms, hydrogen or halogen and hydrogen or halogen, salts thereof and N-oxides of pyridine derivatives and salts thereof. Significant compounds of formula (I) from embodiment (a) are those in which one of the symbols 1112, "----------- R and R" represents an alkoxy group of 1 to 4 carbon atoms, cycloalkoxy of 3 to 5 carbon atoms, cycloalkylmethoxy of 3 to 5 carbon atoms in the cycloalkyl moiety, benzyloxy or alkoxy of 1 to 4 carbon atoms, wholly or partially fluorine substituted and the other of which is 1 to 4 carbon alkoxy, in whole or in part fluorine substituted R, " is phenyl, pyridyl, phenyl, substituted with 31, 33, R, R and R or pyridyl, substituted with ac. _34 _35 _36 _37. pm, R, R, R and R, wherein 31 R is halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl moiety, R32 is hydrogen or halogen, alkyl or alkoxy each by 1 R 4 represents a hydrogen atom or a halogen atom, or an alkyl group having from 1 to 4 carbon atoms; R 34 represents a carbon atom, a halogen atom or an alkyl group having from 1 to 4 carbon atoms; hydrogen or halogen; and 37 R represents a hydrogen or halogen atom, salts of these compounds and the N-oxides of pyridine derivatives and salts thereof, with the exception of compounds wherein R 1 represents an alkoxy group of 1 to 4 carbon atoms, wholly or partially fluorinated and R is cycloalkoxy of 3 to 5 carbon atoms. Significant compounds of embodiment (b) are those compounds of formula (I) wherein R 1 is C 1 -C 4 alkoxy, wholly or partially fluorine substituted and R 2 is methoxy, R 1 is C 1 -C 4 alkoxy, (C 3 -C 5) cycloalkoxy, (C 3 -C 5) cycloalkyl-cycloalkyl, (C 1 -C 4) alkoxy, fluorine-substituted wholly or partially and R (2) is methoxy, in whole or in part fluorine substituted, or R ^ " is cycloalkoxy of 3 to 5 carbon atoms, cycloalkylmethoxy of 1 to 5 carbon atoms in the cycloalkyl or benzyloxy and R2 is an alkoxy of 1 to 4 carbon atoms, completely or partially fluorine substituted, or R5 is alkoxy of 1 to 1 4 carbon atoms, la or partially substituted by fluorine and 2 R is cycloalkylmethoxy of 3 to 5 carbon atoms in the cycloalkyl moiety, 3 - R denotes phenyl, pyridyl, phenyl, substituted by 31 32 33 by R, R and R or pyridyl; _34 "35" 36 "37,. R, R, R and R, where R 31 is halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl moiety, 13 R < 2 > is hydrogen or halogen, alkyl or alkoxy of 1 to 4 carbon atoms, 33 R is hydrogen or halogen, alkyl or alkoxy having 1 to 4 carbon atoms, 34 R is halogen or alkyl of 1 to 4 carbon atoms, R represents a hydrogen atom or a halogen atom; is hydrogen or halogen; and 37 R is hydrogen or halogen, as well as salts of these compounds, N-oxides of pyridine derivatives and salts thereof.

Particularly important compounds of the formula I are those in which one of the substituents 12 "R and R" is alkoxy of 1 to 4 carbon atoms, cycloalkoxy of 3 to 5 carbon atoms, cycloalkylmethoxy of 3 to 5 carbon atoms in the cycloalkyl group the moiety, benzyloxy or alkoxy having 1 to 4 carbon atoms, wholly or partially fluorine substituted and the other being 1 to 4 carbon alkoxy, fully or partially fluorine substituted and 3 R is 2-bromophenyl, 2,6-dichloro-4 -ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2 , 6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,6 -tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-do-chloro, 2,5-difluoropyrid-4-yl or 2,6-dichloropyrid-- 3-yl, 14 salts of these compounds, as well as the N-oxides of the pyridine derivatives and its salts salts.

Particularly important compounds of formula I in embodiment a) are those in which one of R 12 and R 2 is C 1 -C 4 alkoxy, cycloalkoxy of 3 to 5 carbon atoms, cycloalkylmethoxy of 3 g to 5 atoms carbon in a cycloalkyl, benzyloxy or alkoxy group having from 1 to 4 carbon atoms, wholly or partially fluorine substituted and the other being C1-4 alkoxy, wholly or partially fluorine substituted, 3R 2-bromophenyl, 2, 6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,5-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6- difluorophenyl, 2,6-dichlorophenyl, 3,5-chloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5, -dibromopyrid-2-yl, 2,3,5 , 5-tetrahydropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloro-pyrid-3 -yl, salts of these compounds, N-oxides of pyridine derivatives and its salts thereof, with the exception of compounds in which R 1 is C 1 -C 4 alkoxy, wholly or partially fluorinated and R 3 is C 3 -C 5 cycloalkyl.

Particularly important compounds of formula (I) in embodiment (b) are those in which R5 is C1-4 alkoxy, wholly or partially fluorine substituted and R15 is methoxy or C1-4 alkoxy , cycloalkoxy of 3 to 5 carbon atoms, cycloalkyl-methoxy of 3 to 5 carbon atoms in the cycloalkyl, benzyloxy or alkoxy of 1 to 4 carbon atoms, in whole or in part by fluorine and 2 R is methoxy, in whole or in part the fluorine-substituted moiety, or R 5 'is cycloalkoxy of 3 to 5 carbon atoms, cycloalkylmethoxy of 3 to 5 carbon atoms in the cycloalkyl moiety, or benzyloxy, and R "is an alkoxy group having 1 to 4 carbon atoms, wholly or partially fluorine substituted, or R 1 is C 1 -C 4 alkoxy, wholly or partially fluorine-substituted and R 2 is cycloalkylmethoxy with 3 to 5 carbon atoms in the cycloalkyl or benzyloxy group, R 3 represents 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonyl-phenyl, 2,5-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl , 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro -pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,6-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3 , 5-dichloro-2,5-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl, salts of these compounds, M-oxides of pyridine derivatives and salts thereof. Preferred compounds of formula I are those wherein R 1 is difluoromethoxy, is methoxy, ethoxy, isopropoxy, isobutoxy, cyclopentyloxy, cyclopropylmethoxy, cyclobutylmethoxy, difluoromethoxy or 2,2,2-trifluoroethoxy; means 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6- dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5, β-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,5-difluoropyrid-4-yl; yl, or 2,6-dichloropyrid-3-yl, salts thereof, N-oxides of pyridine derivatives and salts thereof. Preferred compounds of formula (I) are also those wherein R 1 is methoxy, n-propoxy, η-butoxy, cyclopropylmethoxy or 2,2,2-trifluoromethoxy, p, R is difluoromethoxy and R is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-5-methylphenyl, 2,6-dimethylphenyl, 2,6 -difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5 , 6-tetrafluoro-17-pyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl, or 2,6- dichloropyrid-3-yl, salts thereof, and N-oxides of pyridine derivatives and salts thereof. Preferred compounds of formula (I) in embodiment (a) are those wherein R5 is difluoromethoxy, R2 is methoxy, ethoxy, isopropoxy, isobutoxy, cyclopropylmethoxy, cyclobutylmethoxy, difluoromethoxy or 2,2, 2-trifluoromethoxy and q R is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro- 5-methylphenyl, 2,6-dimethylphenyl, 2, β-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3 , 5-dibromopyrid-2-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyride -4-yl or 2,6-dichloro-pyrid-3-yl, salts of these compounds, as well as the N-oxides of pyridine derivatives and their salts. Also preferred compounds of formula (I) in embodiment (a) are those wherein R1 is methoxy, n-propoxy, η-butoxy, cyclopropyl methoxy, or 2,2,2-trifluoroethoxy, pR is difluoromethoxy, and 18 R R isamene 2-bromophanyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-isoxy-2-fluorophenyl, 2,4,6- trifluoromethyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophartyl, 2,5-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3,5-difluoropyrid-2-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyridine 4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloro-pyrid-3-yl, salts of these compounds as well as the N-oxides of pyridine derivatives and their salts. Preferred compounds of formula (I) in embodiment (b) are those wherein R 1 is difluoromethoxy 2 R is methoxy, cyclopropylmethoxy, cyclobutylmethoxy or difluoromethoxy and R 1 is 2-bromophenyl, 2,5-dichloro-4 -ethoxycarbonylphenyl, 2,5-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-dimethylphenyl, 2,6- difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5, 6-tert-fluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloro-pyrid-3-one; yl, salts of these compounds, as well as the N-oxides of pyridine derivatives and their salts. Preferred compounds of formula (I) in embodiment (b) are also those wherein R 1 is methoxy, n-propoxy, η-butoxy, cyclopropylmethoxy, or 2,2,2-trifluoroethoxy, 2 R is difluoromethoxy and 3 R is 2-fluorophenyl, 2,6-dichloro-4-ethoxycarbonylphenyl, 2, β-dimethoxyphenyl, α-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-5- methylphenyl, 2,6-dimethylphenyl, 2, β-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3 , 5-difluoropyrid-2-yl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,3,5-trifluoropyridine-4-yl, 3,5-dichloro-2,5 -fluoropyrid-4-yl or 2,6-dichloro-pyrid-3-yl, salts thereof, as well as the N-oxides of pyridine derivatives and their salts.

The invention also relates to a process for the preparation of compounds of the formula I and their salts and to the N-oxide of pyridine derivatives and their salts. This process involves reacting a compound of formula II

Wherein R < 2 > and R < 2 > are as defined above, and X is a suitable leaving group, with amines of formula R < 3 > wherein R is as defined above, and the resulting products of formula (I) are converted to salts and / or the pyridine derivatives obtained are converted to the N-oxides and then optionally to the salts, or the optionally obtained salts of the compounds of the formula I are converted into the free compounds.

A suitable X group is readily selected by one skilled in the art. For example, starting from an acid halide of formula II wherein X is chlorine or bromine. The reaction proceeds as described in the following examples or in a known manner, for example according to International Patent Application No. WO 92/12961. The N-oxidation can be carried out in a manner known per se, for example by treatment with m-chloroperoxybenzoic acid in dichloromethane at room temperature. Suitable reaction conditions for each reaction are readily determined by one skilled in the art.

The resulting products can be isolated and purified in a manner known per se, for example by distilling off the solvent in vacuo and recrystallizing the residue from a suitable solvent or purification by column chromatography on a suitable material. 21

The salts can be obtained by dissolving the free substance in a suitable solvent, for example a chlorinated hydrocarbon such as methylene chloride or chloroform or in a low molecular weight aliphatic alcohol, for example ethanol or isopropanol containing the desired acid or base, or add the desired acid or base additionally. The salts can be isolated by filtration, precipitated from a solvent in which the salt is insoluble or by evaporation of the solvent. The salts obtained can be converted into the free compounds by alkalization or acidification, and the resulting free materials can be converted into salts again. In this way, pharmacologically unacceptable salts can be used to prepare salts which are pharmacologically acceptable.

The compounds of formula (II) and the amines of formula (-NHg) are known or can be prepared by known methods.

The invention will now be illustrated by the following non-limiting examples. Other compounds of the invention and starting materials can be obtained in an analogous manner to the examples. EXAMPLES 1. N- (3,5-dichloropyrid-4-yl) -4-difluoromethoxy-3-methoxybenzamide 6.0 g of 4-difluoromethoxy-3-methoxybenzoic acid was boiled in 40 ml of toluene together with 19 6 g of thionyl chloride until gas evolution ceases under reflux. 22

The solution is evaporated to dryness in vacuo and the residue is dissolved in about 60 ml of anhydrous tetrahydrofuran. The solution is added dropwise to a suspension of 4.9 g of 4-amino-3,5-dichloropyridine and 2.0 g of sodium hydride as a 30% slurry in mineral oil under stirring and cooling at 15 to 20 ° C. 60 ml of anhydrous tetrahydrofuran. After stirring for 1 hour, the mixture was acidified to pH 2 by addition of 1N hydrochloric acid, the toluene and tetrahydrofuran phases were separated and the aqueous phase was extracted twice more with ethyl acetate. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulfate and evaporated in vacuo. The residue is recrystallized from isopropanol. Yield: 5.8 g (58.6% of theory); Starting from the starting materials described below, the method of Example 1 may be followed by reacting the corresponding benzoic acids with 4-amino-3,5-dichloropyridine, 4-amino-3,5-dichloro-2, β-difluoropyridine, 2 , 6-dichloroaniline, 2,6-dimethylaniline, 3-amino-2-chloropyridine, 2-amino-; -3,5-dibromopyridine, 4-amino-2,3,5,6-tetrafluoropyridine, 2,4,6-trifluoraniline, 2,6-dichloro-4-ethoxycarbonylaniline, 2,6-difluoraniline, 2-bromoaniline, 2-chloro-6 -methylaniline, 2-methylaniline, 4-amino-3-chloro-2,5,6-trifluoropyridine and 2-amino-3-methylpyridine to obtain the following products. N - (3,5-dichloropyrid-4-yl) -3,4-bis-difluoromethoxybenzamide, (melting point: 134 ° C). 3. N- (3,5-dichloropyrid-4-yl) -3-cyclobutylmethoxy-4-difluoromethoxy-benzamide (m.p. 155 DEG C.). 23 4. N- (3,5-dichloropyrid-4-yl) -3-cyclopentyloxy-4-difluoromethoxybenzamide (mp 128.5-129 ° C). 5. N- (3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (m.p. 158 DEG C.). 6. N- (3,5-dichloro-2,6-difluoropyrid-4-yl) -3-difluoromethoxy-4-methoxybenzamide (m.p. 218 DEG C.). 7. N- (2,6-dichlorophenyl) -3-difluoromethoxy-4-methoxybenzamide (m.p. 164 DEG C.). 8. N- (2,6-dimethylphenyl) -3-difluoromethoxy-4-methoxybenzamide (m.p. 164 DEG C.). 9. N- (2-chloropyrid-3-yl) -3-difluoromethoxy-4-methoxybenzamide (m.p. 165 DEG C.). 10. N- (3,5-dibromopyrid-2-yl) -3-difluoromethoxy-4-methoxybenzamide (m.p. 143 DEG C.). 11. N- (3,5-dichloropyrid-4-yl) -3-difluoromethoxy-4-methoxybenzamide, (m.p. 178 DEG C.). 12. N- (3,5-dichloropyrid-4-yl) -3-difluoromethoxy-4-propoxybenzamide (m.p. 159 ° C). N- (3,5-dichloropyrid-4-yl) -3-ethoxy-4-difluoromethoxybenzamide (m.p. 134 ° C). N- (3,5-dichloropyrid-4-yl) -4-benzyloxy-3-difluoromethoxybenzamide (m.p. 152 ° C). 15. N- (3,5-dichloropyrid-4-yl) -4-butoxy-3-difluoromethoxybenzamide (m.p. 146 DEG C.). 24 16. N- (3,5-dichloropyrid-4-yl) -4-cyclopropylmethoxy-3-difluoromethoxybenzamide (m.p. 159 ° C). N- (3,5-dichloropyrid-4-yl) -4-difluoromethoxy-3- (1-methylethoxy) benzamide (m.p. 99.5 UC). N- (3,5-dichloropyrid-4-yl) -4-difluoromethoxy-3- (2,2,2-trifluoroethoxy) benzamide (m.p. 147 ° C). N- (3,5-dichloropyrid-4-yl) -4-difluoromethoxy-3- (2-methylpropoxy) benzamide (m.p. 153 ° C). 20. N- (2,3,5,6-tetrafluoropyrid-4-yl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 146 DEG C.). 21. N- (2,4,6-trifluorophenyl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 145 ° C). N- (2,6-dichloro-4-ethoxycarbonylphenyl) -4-difluoromethoxy-3-methoxyberisamide (m.p. 176 ° C). 23. N- (2,6-dichlorophenyl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 186 ° C). N- (2,6-difluorophenyl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 139 ° C). 25. N- (2,6-dimethylphenyl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 143 DEG C.). 26. N- (2-Bromophenyl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 121 DEG C.). 27. N- (2-chloro-6-methylphenyl) -4-difluoromethoxy-3-methoxybenzamide (melting point: 144 DEG C.). 25. 28. N- (2-chloropyrid-3-yl) -4-difluoromethoxy-3-methoxy-2-enoramide (m.p. 137.5 ° C). 29. N- (2-methylphenyl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 125 DEG C.). 30. N- (3,5-difluoropyrid-2-yl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 141 ° C). 31. N- (3,5-dichloro-2,6-difluoropyrid-4-yl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 174 ° C). 32. N- (3-chloro-2,5,6-trifluoropyrid-4-yl) -4-difluoromethoxy-3-methoxybenzamide (m.p. 141 DEG C.). 33. N- (3-methylpyrid-2-yl) -4-difluoromethoxy-3-methoxybenzamide (melting point: 96 DEG C.). Starting materials A. 4-Difluoromethoxy-3-methoxybenzoic acid

To a mixture of 10.0 g of 4-difluoromethoxy-3-methoxybenzaldehyde, 6.5 g of amidosulphuric acid and 50 ml of glacial acetic acid, a solution of 7.3 g of 80% sodium chloride in 15 ml of water is added dropwise with stirring. The internal temperature of the mixture is thereby maintained by cooling the water / ice mixture in the range of 30 to 35 ° C. After the addition was complete, the mixture was stirred for 1 hour and then diluted with water. The precipitated 4-difluoromethoxy-3-methoxybenzoic acid is filtered off with suction, washed with water, dried under vacuum and recrystallized from a mixture of acetonitrile and petroleum ether with a boiling point of 40 ° C in a ratio of 2: 3. 7.1 g of product with a melting point of 170 ° C.

The following benzoic acid derivatives can also be prepared analogously: 3,4-bis-difluoromethoxybenzoic acid (melting point 104.5 ° C), 3-cyclobutylmethoxy-4-difluoromethoxybenzoic acid (melting point: 132 ° C), 3- cyclopentyloxy-4-difluoromethoxybenzoic acid (melting point: 125.5 ° C), 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (m.p. 118-118.5 ° C), 3-ethoxy-4-difluoromethoxybenzoic acid (m.p. 157 ° C) C), 4-difluoromethoxy-3- (1-methyl) ethoxybenzoic acid (m.p. 93 ° C), 4-difluoromethoxy-3- (2,2,2-trifluoroethoxy) benzoic acid (mp: 109 ° C) 3-difluoromethoxy-4-methoxybenzoic acid (melting point: 178 ° C), 3-difluoromethoxy-4-propoxybenzoic acid (m.p. 148 ° C), 4-benzyloxy-3-difluoromethoxybenzoic acid (melting point: 169 ° C) , 4-butoxy-3-difluoromethoxybenzoic acid (melting point 136 ° C), 4-cyclopropylmethoxy-3-difluoromethoxybenzoic acid (melting point: 150 ° C)

B. 4-Difluoromethoxy-3-methoxybenzaldehyde

Chlorodifluoromethane gas is introduced into the mixture of 20C of vanillin, 6.7 g of benzyltrimethylammonium chloride, 314 g of 50% sodium hydroxide and 2 liters of dioxane with vigorous stirring, then the mixture is partitioned between ethyl acetate and water with ice, the organic phase The aqueous phase is extracted twice more with ethyl acetate, the organic phases are combined, dried over magnesium sulphate and evaporated in vacuo. To remove unreacted vanillin, the oil obtained is chromatographed on neutral silica gel using toluene. After evaporation of the eluate, 249 g of 4-difluoromethoxy-3-methoxybenzaldehyde are obtained in the form of an oil.

The following benzaldehyde derivatives can also be prepared analogously: 3-cyclobutylmethoxy-4-difluoromethoxybenzaldehyde (melting point: 0.1-cyclopropylmethoxy-4-difluoromethoxybenzaldehyde (oil), 4-difluoromethoxy-3- (1-methyl) ethoxybenzaldehyde (oil)) , 4-difluoromethoxy-3- (2,2,2-trifluoromethoxy) benzaldehyde (oil), 2,4-bis-difluoromethoxybenzaldehyde (oil), 3-cyclopentyloxy-4-difluoromethoxybenzaldehyde (oil), 3-ethoxy-4-difluoromethoxybenzaldehyde (oil), 4-difluoromethoxy-3- (2-methylpropoxy) benzaldehyde (oil), 3-difluoromethoxy-4-methoxybenzaldehyde (m.p. 41 ° C), 3-Difluoromethoxy-4-propoxybenzaldehyde (oil), 4-benzyloxy- 3-difluoromethoxybenzaldehyde (m.p. 52-52.5 ° C, 28 4-butoxy-3-difluoromethoxyberaldehyde (oil), 4-cyclopropylmethoxy-3-difluoromethoxybenzaldehyde (oil)).

Industrial usability

The derivatives of the invention have valuable pharmacological properties. These are cyclic nucleotide phosphodiesterase (PDE) inhibitors, i.e. Type IV, which are useful for therapeutic purposes, for example, to treat airway obstruction due to its bronchial dilatation effect and its beneficial effect on breath depth. In particular, they are suitable for the treatment of diseases of an inflammatory nature, for example respiratory diseases such as asthma, bowel diseases, ocular diseases and joint disorders caused by various mediators such as histamine, platelet activating factor (PAF), derivatives arachidonic acids such as leucotrienes and prostaglandins, cytokine, interleukins IL-1 to IL-12, interferon alpha, beta and gamma, tumor necrosis factor (INF) or oxygenated radicals and proteases. Furthermore, the derivatives according to the invention have low toxicity, are well absorbed by oral administration, therefore have a high bioavailability, moreover, they have a great therapeutic width and, at the same time, there are no more serious side effects;

Due to its PDE inhibitory activity, the compounds of the invention can be used in human and veterinary medicine, for example for the treatment and prophylaxis of the following diseases: acute and chronic, especially inflammatory and allergic diseases of the respiratory tract, such as bronchitis, allergic bronchitis and bronchial asthma, various dermatoses, in particular proliferative, inflammatory and allergic, such as psoriasis, toxic and allergic contact eczema, atopic eczema, ebeborrhoic eczema, lichen simplex sunburn, pruritus in genital and anal areas, alopecia 29 area, hypertrophic scars, discoid lupus erythematosus, follicular and suppurative skin inflammation, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin diseases caused by increased release of TNF and leukotrienes, such as joint inflammation, for example rheumatoid arthritis yew, rheumatold spondylitis, osteoarthritis and other joint diseases, can also be diseases of the immune system, such as AIDS, shock symptoms such as septic shock, endotoxin shock, shock by infection with gram-negative microorganisms, toxic shock syndrome and ARDS (adult airway deficiency) as well as inflammatory conditions in the digestive system such as Crohn's disease and ulcerative colitis, as well as other allergic diseases and / or chronically absent immune responses, particularly in the airways and adjacent areas, for example, eyes, may be allergic rhinitis, sinusitis, allergic conjunctivitis, nasal polyps, but may also be heart disease, such as cardiac insufficiency or other diseases that may be beneficial to PDE inhibitors such as kidney colic or ureteric colic associated with with the formation of urinary stones.

The derivatives according to the invention can then be used in the form of pharmaceutical compositions for the treatment of mammals suffering from the aforementioned diseases, including humans. An effective dose of one or more derivatives of the invention is administered.

The invention also relates to the use of the compounds according to the invention for the preparation of pharmaceutical compositions for the treatment and / or prophylaxis of any of the above-mentioned diseases.

The invention also provides pharmaceutical compositions for the treatment and / or prophylaxis of said diseases comprising at least one derivative of the invention. 30 30

The pharmaceutical compositions of the invention are prepared in a manner known per se. These compositions contain the active ingredients of the invention as such or preferably in combination with suitable pharmaceutical excipients. For example, the compositions may take the form of tablets, dragees, capsules, suppositories, patches, emulsions, suspensions, gels, or solutions, wherein the active ingredient content of these compositions is preferably from about 0.1% to about 95%.

Suitable excipients for the desired dosage form are readily determined by one skilled in the art. These may be solvents, gel forming agents, ointment bases and other carriers, but also antioxidants, dispersants, emulsifiers, preservatives, co-solvents or absorption aids may also be used. In the case of the treatment of respiratory diseases, the derivatives according to the invention can also be preferably administered by inhalation. For this purpose, said derivatives may be administered directly in the form of a powder, preferably in micronized form, or by spraying a solution or suspension containing the active ingredients. Reference is made to European Patent Specification No. 163,965 for this purpose. In the treatment of dermatoses, the derivatives of the present invention are used in particular in a form suitable for topical administration. In the preparation of such dosage forms, the active ingredient is preferably mixed with suitable excipients and formulated into the desired dosage form. For example, a suitable dosage form is a powder, emulsion, suspension, oil, ointment, fat ointment, cream, paste, gel or solution. The dosage forms of the invention are prepared by known procedures. The dosage of active ingredient corresponds to the usual dosage for PDE inhibitors. This means that the dosage forms for the topical administration, for example dermatosis ointments, contain the active ingredient, for example, in a concentration of 0.1 to 99%. The dose for administration by inhalation is normally 0.01 to 0.5 mg / kg. The usual dose for systemic administration is 0.05 to 2 mg per day.

Biological Experiments Activation of inflammatory cells is of great importance in monitoring PDE IV inhibition at the cellular level. For example, N-formylmethionylleucylphenylalanine-induced neutrophil granulocyte production, FMLP, which can be measured by luminal enhanced chemoluminescence according to Mc Phail LC, Scrum SL, Leine PA, and Sozzani S., The neutrophil respiratory burst mechanism, " Immunology Series " 57, 47-76, 1992, ed. Coffey RG, Marcel Decker, Inc., New York-3asel-Hong Kong. Agents that inhibit chemoluminescence, cytokine secretion and inflammatory cell mediating secretion of mediators, particularly neutrophilic and eosinophilic granulocytes, are agents that cause PDE IV inhibition.

This phosphodiesterase isoenzyme is mainly found in granulocytes. Its inhibition leads to an increase in the concentration of cyclic AMP in these cells, thereby inhibiting cell activation. Thus, PDE IV inhibition by the compounds of the invention is an essential indicator of suppression of inflammatory processes, as described in Giembycz MA, Could Esensyme - selective phosphodiesterase inhibitors render bronchodilator therapy redundant in the treatment of bronchial asthma? Biochem Pharmacol 43: 2041-2051, 1992, Torphy TJ et al., Phosphodiesterase Inhibitor: new opportunities for treatment of asthma, Thorax 46: 512-523, 1991, Schudt C. et al., Zardaverina, and cyclic AMP PDE Ιΐΐ / χν inhibitor , 32 " New Drugs for Asthma Therapy ", 379-402, Birkhauser Verleg Basel 1991, Schudt C. et al., Influence of selective. phosphodiesterase inhibitors on hurricane neutrophils and levels of cAMP and Ca., Naunyn-Schmiedeberg Arch Pharmacol 334: 682-690, 1991, Nielson CP et al., Effects of selective phosphodiesterase inhibitors in polymorphonuclear leukocytes respirators burst, J. Allergy Clin Immunol, 86, 801-808, 1990, Scgade et al., The Specific Type III and IV phosphodiesterase · inhibitor of the suppressin suppress formulation of tumor necrosis factor by macrophages, European Jour nalof Pharmacology 230, 9-14, 1993.

1. Inhibition of ODE IV activity

Methodology _

The efficacy assays were carried out by the method of Bauer and Schwabe after adaptation to microtiter plates according to Naunyn-Schmiedeberg with Arch. Pharmacol., 311, 193-1988, 1980. In the second step, the resulting 5'-nucleotide is cleaved with 5-nucleotidase from cobra venom to a nucleoside without charge. In the third step, the nucleoside is separated on the ion exchange column from the remaining charge-containing substrate. Columns are eluted with 2 ml of 30 mM ammonium formate pH 6.0 directly into mini-flasks, to which are then added 2 ml of scintillation fluid suitable for the computer used.

The values obtained for the compounds of the invention are summarized in Table 1 below, the compound number being the Example number. 33

Table 1 Inhibition of PDE IV compound -log activity icr_ 1 8.6 ^ 2 8.42 3 8.74 5 9.18 2. Influence of dyspnoea and migration of proinflammatory (immunocompetent) cells from blood vessels to the airways in an allergic reaction in awake guinea pigs

Under the influence of an allergic inflammatory reaction, immunocompetent blood cells, leukocytes, enter the airways. This pathological migration can in itself continue to self-sustain, leading to chronic changes and consequently to chronic airway obstruction in asthma, but also allergic rhinitis and / or allergic conjunctivitis. Thus, inhibition of this migration by pharmacological agents is an important principle of treatment and is a measure of anti-allergic or anti-inflammatory effect. Animal experimental methodology has been used for this purpose, in particular the acute effect of allergic respiratory reaction and cell migration, essentially as described by PA Hutson et al., Am. Roar. Respir. Dis., 137, 543, 1988 and JP Tarayre et al., J. Pharmacol. Meth., 23, 13, 1990 and also R. Beume et al., Atemw. Lungenkrkh., 11, 324, 1985. 34

The guinea pig group was sensitized intraperitoneally against egg albumin (20 micrograms + 20 mg A1 (OH) 2). After 14 days the following experiment was performed: -1 h 0 h +1 h + 24 h oral administration, provocation allergic reaction, thoracographic measuring latency time to onset of dyspnoea, absence of dyspnoea means protective effect, oral administration, narcosis with elimination of bronchial and alveoli, determination of total cell number and differential blood cell count in washout, determination of protein content in cell free supernatant.

Controls for placebo were included as controls for each test, followed by apparent provocation and placebo-controlled control and then provocation was initiated.

For the compound of Example 1, the following effects, shown in Table 2, could be demonstrated at an oral dose of 30 micromol / kg in this trial setup. It is clear from the table that no animal responded to apparent provocation and no dyspnoea occurred in two animals during actual provocation. these animals were spontaneously resistant, 8 animals were protected after administration of the active substance.

Provocation caused increased cell and protein penetration at high scattering. Example 1 adjusts these values to baseline (placebo + apparent provocation). 35

Table 2 placebo + apparent provocation placebo + provocation compound 1 + provocation number of animals 15 13 14 protected 15 2 8 g total leukocyte count x 10/10 ml diameter 2.2 (1) 9.8 (4.5) 2 5 (1.1) min-tnax 1.1-3.8 1.0-21.4 1.5-4.2 /? Neutrophil leukocytes x 10/10 ml diameter 0.04 (1) 0.44 (11) 0.0 (0) min.-max 0.01-0.1 0.01-1.1 0.0-0, 08 g Eosinophilic granulocytes x 10/10 ml r r r 0,8 (1) 5,8 (7,3) 1,2 (1,5) min-max 0,4-1,8 0,3-14, 5 0,6-2,5 c. Macrophages x 10/10 ml diameter 1,5 (1) 3,2 (2,1) 1,2 (0,8) min-max 0,3-2,3 0 , 7-6,2 0,9-2,3 Protein content mg / 10 ml min r 3,7 (1) 8,8 (2,4) 4,1 (1,1) min-max 2,3 -4.9 3.4-22.0 2.6-11.0

Represents:

Claims

PATENTS

o o c / * P ·· o rc

rt < ! AND

Substituted benzamides of the formula I

wherein the carbon atom is 7 carbon atoms, the alcohol in the alkyl moiety is 1 to 4 atomic carbon atoms. from the substitution of cyclo-R "means a hydrogen atom, aikoxyskup! carbonyl, cycloalkoxy of 3 to 7 carbon atoms having 3 to 7 carbon atoms, benzyloxy or alkoxy, carbon, fully or partially subst and the other being an alkoxy group having from 1 to 4 carbon atoms, wholly or partially substituted by fluorine, R is phenyl, phenyl, phenyl substituted with '1 32 π R, R or R- " or pyridyl, substituted with R 3, R 35, R 36 or R 37, wherein R 1 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, alkyl, alkoxy, alkoxycarbonyl, alkoxycarbonyl, or alkoxycarbonyl each with 1 to 6 carbon atoms, and C in C 1-4 alkyl, amino, mono- or di-alkylamino, C 4 -C 4 alkyl, or C 1-4 alkylcarbonylamino, -37-32-32 is hydrogen, hydroxy, halogen, amino. each of 1 to 4 carbon atoms, 3 is a hydrogen atom, a halogen atom, an alkyl or alkoxy group having 1 to 4 carbon atoms, R34 is a hydroxy group, a halogen atom, a cyano group, a carboxyl group, alkyl, alkoxy or or alkoxycarbonyl each of 1 to 4 carbon atoms in the alkyl or amino group, of 3, awm of hydrogen or alkyl of 1 to 4 R35 is a water atom R37 represents a hydrogen or halogen atom, an amino group of a carbon atom, or a halogen atom, or a halogen, a salt thereof and an N-oxide of a pyridine derivative and a salt thereof.

Substituted benzamides of the formula I according to claim 1, wherein R 6 represents a hydrogen atom, a C 1 -C 6 alkoxy group, a C 3 -C 7 cycloalkoxy group, a C 3 -C 7 cycloalkyl group, a benzyloxy group or an alkoxy group C1 to 4 carbon atoms, wholly or partially fluorine substituted, 2 R is alkoxy of 1 to 4 carbon atoms, fully or partially fluorine substituted, 39

Substituted benzamides of the formula I according to claim 1, wherein R 1 'represents a hydrogen atom, an alkoxy group having 1 to 6 carbon atoms, a cycloalkoxy group having 3 to 7 carbon atoms, a cycloalkylmethoxy group having 3 to 7 carbon atoms in a cycloalkyl group, a benzyloxy group or an alkoxy group C 1 -C 4, wholly or partially substituted by fluorine, 2 R; is methoxy, wholly or partially fluorine-substituted, R- is feryl, pyridyl, phenyl, substituted with 31 ^ 2 ^ 3, with R, R- and R- or pyridyl substituted with ET, R, R 10 and 5 T, wherein R 31 is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl or alkylcarbonyloxy each of 1 to 4 carbon atoms in the alkyl, amino, mono- or di- R is hydrogen, hydroxysuccin, halogen, amino, trifluoromethyl, alkyl or alkoxy having 1 to 4 carbon atoms; R is hydrogen or halogen; alkyl or alkoxy having from 1 to 4 carbon atoms, Rw is hydroxy, halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl or amino group; 40 of the salt and its 35 R is hydrogen or alkyl of 1 to 4 represents a hydrogen atom of 17 R " is a hydrogen atom of these compounds as well as salts thereof. or halogen, an amino group of carbon, or halogen and or halogen, N-oxides of pyridine derivatives

Substituted benzamides of the formula I according to claim 1, wherein R 1 represents a C 3 -C 7 cycloalkoxy group, a C 3 -C 7 cycloalkylmethoxy group or a benzyloxy group, 2 R represents a C 1-4 alkoxy group, wholly or completely fluorine-substituted, phenyl, pyridyl, phenyl substituted with R 31, R 32 and R 33 or pyridyl substituted with fluoro; "34 _35 -.36 -.37,. m, R, R, R and n, wherein RJ is a hydrexyl, naphtho, cyanosxupine, carboxyl, trifluoromethyl, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl or alkylcarbonyloxy group having from 1 to 4 carbon atoms in the alkyl, amino, mono- or dialkyl-amino or alkylcarbonylamino of 1-4 carbon atoms in the alkyl, 32 R is hydrogen, hydroxy, halogen, amino, trifluoromethyl, alkyl or alkoxy of 1-4 carbon atoms, 33 R is hydrogen or halogen , alkyl or alkoxy having 1 to 4 carbon atoms, 41 34 R represents hydroxy, halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl or amino group, R35 represents a hydrogen or halogen atom, amino or alkyl of 1 to 4 carbon atoms, 36a represents a hydrogen or halogen atom and 37 represents a hydrogen or halogen atom. salts of these compounds, as well as the N-oxides of pyridine derivatives and their salts.

Substituted benzamides of the formula I according to claim 1, wherein a 1 represents a C 1 -C 4 alkoxy group, in whole or in part substituted by fluorine, 2 a represents a hydrogen atom, a C 1 -C 5 alkoxy group, a C 3-7 cycloalkoxy group carbon, cycloalkylmethoxy group having from 3 to 7 carbon atoms in the cycloalkyl moiety, benzyloxy group or alkoxy group having from 1 to 4 carbon atoms, wholly or partially fluorine substituted, 3 and phenyl, pyridyl, phenyl, substituted by a group of 31 32 33 us a, aaa or pyridyl substituted with a34, a35, a36 and a37, wherein 31 represents a hydroxyl group of a halogen atom, a cyano group, a carboxyl group, a trifluoromethyl, an alkyl, an alkoxy group, an alkoxy group having from 1 to 4 carbon atoms each a moiety, an amino group, a mono- or dialkylamino group or an alkylcarbonylamino group each having 1 to 4 carbon atoms in the alkyl moiety; hydrogen, hydroxy, halogen, amino, trifluoromethyl, alkyl or alkoxy of 1-4 carbon atoms, 33 R is hydrogen or halogen, alkyl or alkoxy having 1 to 4 carbon atoms, is hydroxy, halogen, cyano , carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl or amino group, i5 represents a hydrogen or halogen atom, an amino group or an alkyl group having 1 to 4 carbon atoms, Tg R " is hydrogen or halogen and .37. means an atom of a nonionic, salt and its compounds, as well as an N-oxide of a pyridine derivative of the salt.

Substituted oenzamides of the formula I according to claim 1, wherein R 1 represents a C 1 -C 4 alkoxy group, in whole or in part with fluorine, 2 R represents a C 3-7 cycloalkylmethoxy group in the cycloalkyl group, or R 3 is phenyl, pyridyl, phenyl substituted with R 31, R 32 and R 33 or pyridyl substituted with R 24, R 25, R 2, and R 27 wherein - 43 - η] R is hydroxy, halogen, cyano, carboxyl, trifluoromethyl, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl or alkylcarbonyloxy each having 1 to 4 carbon atoms in the alkyl moiety, amino, moiety- or dialkylamino or alkylcarbonylamino each having from 4 to 4 carbon atoms; R is hydrogen, hydroxy, halo, amino, trifluoromethyl, alkyl or alkoxy having 1 to 4 carbon atoms; R 1 is hydrogen or halo, alkyl or alkoxy; dy of l to 4 carbon atoms, "34th R is n-hydroxy, halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each of 1 to 4 carbon atoms in the alkyl or amino group, 35 R - is hydrogen or halogen, amino or alkyl of 1 to 4 carbon atoms, 3 δ R represents a hydrogen atom or a halogen atom and | R is hydrogen or halogen, salts thereof, and N-oxides of pyridine derivatives and salts thereof.

Substituted benzamides of the general formula I according to claim 1, wherein R 6 represents a C 1 -C 4 alkoxy group, a C 3 -C 5 cycloalkoxy group, a C 3 -C 5 cycloalkylmethoxy group, 44 - benzyloxy or alkoxy having 1 to 4 carbon atoms, in whole or in part substituted with fluorine, - p is R is alkoxy having 1 to 4 carbon atoms, wholly or partially fluorine substituted, R 3 is phenyl, pyr is -52 n is R , R w and R dyl, phenyl, substituted- or pyridyl-substituted phenyl; "34" 35 "35" 37,. R, R, R and R, in each case R, are halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each of 1 to 4 carbon atoms in the alkyl moiety, R is hydrogen or halogen, alkyl or alkoxy each of 1 to 4 carbon atoms; 4 carbon atoms, is hydrogen or halogen, alkyl or alkoxy of 1-4 carbon atoms, is halogen or alkyl of 1 to 4 carbon atoms, a-3 is hydrogen or halogen and a36 is hydrogen or halogen and 37 is R 1 is hydrogen or halogen, salts thereof, and N-oxides of pyridine derivatives and salts thereof. Substituted benzamides of the formula I according to claim 1, in which the alkoxy group has from 1 to 4 carbon atoms, a cycloalkoxy group having from 3 to 5 carbon atoms, a cycloalkyl methoxy group having from 3 to 5 carbon atoms in the cycloalkyl group, a benzyloxy group or C 1 -C 4 alkoxy, in whole or in part fluorine substituted, 2 R 2 is methoxy, wholly or partially fluorine substituted, 3 R is phenyl, pyridyl, phenyl substituted by 31 33 R, R w. and R or pyridinyl, substituted with • R 35, R 36, R 36, 37, R, R, R and R, wherein 31 - R represents a halogen atom, a cyano group, a carboxyl group, an alkyl group, an alkoxyl group or an alkoxycarbonyl group. carbon atoms in the alkyl, hydrogen or halogen, alkyl of 1 to 4 carbon atoms, hydrogen or halogen, alkyl or 1 to 4 carbon atoms, halogen or alkyl of 1 to 4 hydrogen or halogen, hydrogen or halogen and hydrogen or halogen , The N-oxides of the pyridine derivatives and R2R means the aoxoxyl atom always R '" means an aoxoxyl atom each of " 34 " denotes a carbon atom; 35 R denotes an atom of " 36 R denotes an R < 7 >atom;

Substituted benzamides of the formula I according to claim 1, wherein R 1 represents a C 3 -C 5 cycloalkoxy group, a C 3 -C 5 cycloalkylmethoxy group or a benzyloxy group, 46 p "R" means an alkoxy group of 1 to 4 carbon atoms, wholly or in part fluorine substituted, 3R denotes phenyl, pyridyl, phenyl, substituted with 31 32 33 by R, R and R or pyridyl, substituted by " 6 " R 10 and R 11, where R 11 is halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each of 1 to 4 carbon atoms in the alkyl, R 1 is hydrogen or halogen, alkyl or alkoxy is 1 to 1 4 carbon atoms, *; is a hydrogen or halogen atom, alkyl or alkoxy of 1 to 4 carbon atoms each, R34 is a halogen atom or an alkyl of 1 to 4 carbon atoms, oc; is hydrogen or halogen, and A36 is hydrogen or halogen and R37 is hydrogen or halogen, salts thereof and N-oxides of pyridine derivatives and salts thereof.

Substituted benzamides of the general formula I according to claim 1, wherein R 1 represents an alkoxy group having 1 to 4 carbon atoms, wholly or partially substituted with fluorine, p 1 represents an alkoxy group having 1 to 4 carbon atoms, a cycloalkoxy group having 3 to 5 atoms carbon, C 3 -C 5 cycloalkyl-methoxy in cycloalkyl 47 Part, benzyloxy or C 1 -C 4 -alkoxy substituted with fluorine, 3 R is phenyl, pyridyl, phenyl substituted by RJ, R 1e and RJ, or pyridyl, substituted with 14-315-7 37 with R-, Rw, R10 and R, wherein R31 is halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl each having 1 to 4 carbon atoms in the alkyl moiety; is alkoxyl in each case TT is W is a carbon atom, 35 is 36 is 37 is an atom of a salt of these compounds and a salt thereof. hydrogen or halogen, alkyl or C1-C4, hydrogen or halogen, alkyl or C1-C4, halo or alkyl of 1 to 4 hydrogen or halogen, hydrogen or halogen and hydrogen or halogen, N-oxides of pyridine Derivatives a

Substituted benzamides of the formula I according to claim 1, wherein R 6 represents a C 1 -C 4 alkoxy group, in whole or in part with fluorine, 2 R represents a cycloalkylmethoxy group of 3 to 5 carbon atoms in the cycloalkyl or benzyloxy group, 48 3 R represents phenyl, pyridyl, faryl substituted with 31 32 O by R, R and R, and pyridyl substituted by R, R, R and R, and R and R are halogen, cyano, carboxyl, alkyl, alkoxy or alkoxycarbonyl having 1 to 4 carbon atoms in the alkyl moiety, R, is hydrogen or halogen, alkyl or alkoxy having 1 to 4 carbon atoms, R33 is hydrogen or halogen, alkyl or alkoxy having 1 to 4 carbon atoms R 34 is a halogen atom or an alkyl group having from 1 to 4 carbon atoms, 35 R is a hydrogen atom or a halogen atom, R 35 is a hydrogen atom or a halogen atom, and R 37 is an acom of hydrogen or halogen; the N-oxides of the pyridine derivatives and their salts.

Substituted benzamides of the general formula I according to claim 1, wherein R 1 represents a C 1 -C 4 alkoxy group, a C 3 -C 5 cycloalkoxy group, a C 3 -C 5 cycloalkylmethoxy group, a benzyloxy group or an alkoxy group o C1 to 4 carbon atoms, wholly or entirely of fluorine, 2 R is C1 -C4 alkoxy, wholly or entirely of fluorine, d6 R1 is 2-bromophenyl, 2,5-dichloro-1-ethoxycarbonyl phenyl, 2,5-dimethoxyphenyl, α-tert-cyan-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-6-methylphenyl, 2,6-α-methylphenyl, 2,6-difluorophenyl, 2,5-dichlorophenyl , 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,6-tetrahydro-pyrid-4 -yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,3-dichloro-2,3-difluoropyrid-4-yl or 2,5-dichloropyrid-3-yl; the compounds, the N-oxides of the pyridine derivatives and their salts.

Substituted benzamides of the formula I according to claim 1, wherein R 1 represents a C 1 -C 4 alkoxy group, a C 3 -C 5 cycloalkoxy group, a C 3 -C 5 cycloalkyl cycloalkyl group. part, benzyloxy or alkoxy having 1 to 4 carbon atoms, completely or partially fluorine substituted, 2. ". . R is methoxy, in whole or in part fluorine substituted, R 3 is 2-bromophenyl, 2,5-dichloro-4-ethoxycarbonylphenyl, 2,5-dimethoxyphenyl, 1,4-ylamino-2-fluorophenyl , 2,4,6-trifluorophenyl, 2-chloro-S-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl , 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,5-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyridine-4 -yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl, salts of these compounds, the N-oxides of the pyridine derivatives and their salts. 50

Substituted benzamides of the formula I according to claim 1, wherein R 1 represents a C 3 -C 5 cycloalkoxy group, a C 3 -C 5 cycloalkylmethoxy group, or a benzyloxy group, 2 R represents an alkoxy group of 1 to 4 carbon atoms, in whole or in part the fluorine-substituted moiety, 3R is 2-fluorophenyl, 2,5-dichloro-4-ethoxycarbonylphenyl, 2,5-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,5-trifluorophenyl, 2-chloro-3- methylphenyl, 2,5-dimethylphenyl, 2,2'-difluorophenyl, 2,5-dichlorophenyl, 3,5-dichloropyrid-4-yl, 2-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3, 5-dibromopyrid-2-yl, 2,3,5, δ-tetrafluoro-pyrid-4-yl, 3-chloro-2,5, δ-trifluoropyrid-4-yl, 3,5-di-chloro-2, 6-difluoropyrid-4-yl or 2, 5-dichloropyrid-3-yl, din derivatives and salts thereof, N-oxides of their salts.

Substituted benzamides of the formula I according to claim 1, wherein R 1 represents a C 1 -C 4 alkoxy group, in whole or in part with fluorine, 2 R represents a cycloalkoxy group of 3 to 5 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, cycloalkylmethoxy of 3 to 5 carbon atoms in the cycloalkyl, benzyloxy or alkoxy of 1 to 4 carbon atoms, in whole or in part substituted by fluorine, 51 R3 is 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonyl - phenynyl 2, 6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,5-trifluorophenyl, 2-chloro-5-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6 -dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,5-tetrafluoropyridine -4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,3-di-chloro-2,6-difluoropyrid-4-yl or 2,2-dichloropyrid-3-yl , sdli of these compounds, N-axides of pyridine derivatives and their salts.

Substituted benzamides of the general formula I according to claim 1, wherein R 6 represents a C 1 -C 4 alkoxy group, wholly or in part with fluorine-substituted moieties, 2 R represents a C 5 -C 5 cycloalkylmethoxy group in the cycloalkyl moiety, or benzyloxy, R means 2-bromophenyl, 2,5-dichloro-4-ethoxycarbonylphenyl, 2,3-dimethoxyphenyl, 4-cyano-2-fluoroethyl, 2,4,6-trifluorophenyl, 2-chloro-6-methyl : Enyi, 2,5-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl; 3,5-dibromopyrid-2-yl, 2,3,5,5-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-di-chloro- 2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl, salts of these compounds, N-oxides of pyridine derivatives and salts thereof.

Substituted benzamides of the formula I as claimed in claim 1, wherein R 5 is difluoromethoxy, 2 R is methoxy, ethoxy, isopropoxy, isooutoxy, cyclopentyloxy, cyclopropylbutoxy, cyclobutylmethoxy, difluoromethoxy or 2 2,2-trifluoroethoxy-3R is 2-bromophenyl, 2,5-dichloro-4-ethoxycarbonylphenyl, 2,5-dimethoxyphenyl, 4-ylamino-2-fluorophenyl, 2,4 , 6-trifluorophenyl, 2-chloro-5-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl , 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,5-tetrafluoropyridin-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl; yl, 3,3-dichloro-2,5-difluoropyrid-4-yl or 2, c-dichloropyrid-3-yl, salts of these compounds, M-oxides of pyridine derivatives and salts thereof. Substituted benzamides of the general formula I according to claim 1, wherein R 6 represents difluoromethoxy, 2 R represents methoxy, cyclopropylmethoxy, cyclobutylmethoxy or difluoromethoxy, R represents 2-bromophenyl, 2,6-dichloro-4-ethoxycarbonate oonylphenyl, 2,5-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-5-methylphenyl, 2,6-dimethylphenyl, 2,6- difluorophenyl, 2,5-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3, 5, 5-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-chloro-2,5-difluoropyrid-4-yl or 2,6-dichloropyridone -3-yl, salts of these compounds, N-oxides of pyridine derivatives and salts thereof. Substituted benzamides of the general formula I according to claim 1, wherein R * is methoxy, n-propoxy, η-butoxy, cyclopropylmethoxy or 2,2,2-trifluoroethoxy, pR 'is difluoromethoxy, R 3 is 2-bromophenyl, 2,6-dichloro-4-echoxycarbonylphenyl, 2,6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-5-methylphenyl2, 6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloro-pyrid-3-yl, 3,5- dibromopyrid-2-yl-2,3,5, 5-tetrafluoro-pyrid-4-yl, 3-chloro-2,3,5-difluoropyrid-4-yl, 3,5-di-chloro-2,5-difluoropyride -4-yl or 2,2-dichloropyrid-3-yl, salts of these compounds, N-oxides of pyridine derivatives and their salts. 2C. Substituted benzamides of formula I according to claim 1, wherein R 1 'is difluoromethoxy, 2 R is cyclopropylmethoxy, 2 R is 2-bromophenyl, 2, 5-dichloro-4-ethoxycarbonyl-2-yl, 2,6 - dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2,4,6-trifluorophenyl, 2-chloro-5-methylphenyl, 2,6-dimethylphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5 -dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 2,3,5,6-tetrafluoro-pyrid-4-yl , 3-chloro-2,5, S-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid-4-yl or 2,6-dichloropyrid-3-yl, salts thereof, N-oxides of pyridine derivatives and their salts. 54

A process for the preparation of substituted benzamides of the formula I according to claim 1, salts of these compounds, N-oxides of pyridine derivatives and their salts, by reacting a compound of the formula II and 1

(rr)

and wherein R 1 and R 2 are as defined above, and X is a suitable leaving group, with amines of the formula

Wherein R 3 is as defined above, whereupon the products of formula (I) optionally formed are converted to salts and / or the pyridine derivatives obtained are converted to N-oxides and optionally to salts, or the optionally obtained salts of compounds of formula (I) are converted into the free compounds .

Pharmaceutical composition for the treatment of respiratory diseases, various dermatoses and inflammatory diseases, characterized in that it contains as its active ingredient substituted benzamides of the formula I according to claim 1.

Substituted benzamides of the general formula I according to claim 1 for use in medical purposes.

Use of the substituted benzamides of the formula I according to claim 1 for the manufacture of pharmaceutical compositions for the treatment of respiratory diseases.

Use of the substituted benzamides of the formula I according to claim 1 for the manufacture of pharmaceutical compositions for the treatment of dermatoses. Represents: