SK297A3 - Dihydrobenzofuranes, manufacturing process thereof, pharmaceutical composition containing same and their use - Google Patents

Abstract

The invention concerns compounds of formula (I). These compounds are effective PDE-inhibitors.

Description

Dihydrobenzofurans, process for their preparation, pharmaceutical composition containing them and their use

Technical field

The invention relates to novel substances which are used in the pharmaceutical industry for the manufacture of medicaments.

BACKGROUND OF THE INVENTION

International patent application WO92 / 12961 discloses benzamides having PDE-inhibitory properties. International Patent Application WO93 / 25517 discloses trisubstituted phenyl derivatives as selective PDE-IV inhibitors. International patent application WO94 / 02465 discloses c-AMP phosphodiesterase inhibitors and TNF inhibitors.

SUMMARY OF THE INVENTION

It has been found that the benzamides described in more detail below, which differ from the previously published compounds by a completely different substitution at positions 2 and 3 on benzamide, have surprising and particularly advantageous properties.

The invention therefore relates to compounds of formula I

in which

R 1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylme2 toxic, benzyloxy or wholly or partially fluorine substituted 1-4C-alkoxy,

R 2 is 1-4C-alkyl,

R 3 is hydrogen or 1-4C-alkyl, or

R2 and R3 together, including the two carbon atoms to which they are attached, are a 5-, 6-, or 7-membered hydrocarbon ring, interrupted by an oxygen atom as desired,

R4 is phenyl, pyridyl, R41-, R42- and R43-substituted phenyl or R44-, R45-, R45- or R47-substituted pyridyl, wherein

R 41 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 -4Calkylamino or 1-4C-alkylcarbonylamino,

R 42 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy,

R 43 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R 44 is hydroxyl, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino,

R 45 is hydrogen, halogen, amino, or 1-4C-alkyl, R 46 is hydrogen or halogen, and R 47 is hydrogen or halogen, salts thereof and N-oxides of pyridines and salts thereof.

1-6C-Alkoxy is a radical which, in addition to the oxygen atom, contains a linear or branched alkyl radical having 1 to 6 carbon atoms. Alkyl radicals having 1 to 6 carbon atoms which may be mentioned are, for example, hexyl, isohexyl, (2-methylpentyl), non-hexyl (2,2-dimethylbutyl), pentyl, isopentyl (3-methylbutyl), neopentyl (2 (2-dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

3-7C-cycloalkoxy is, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C-cycloalkylmethoxy is, for example, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.

Fully or partially fluorine substituted 1-4C-alkoxy radicals which may be mentioned are, for example, 1,2,2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, perfluoroethoxy and in particular 1,1,2,2-tetrafluoroethoxy trifluoromethoxy , 2,2,2-trifluoroethoxy and difluoromethoxy radical.

The 5-, 6- or 7-membered hydrocarbon rings, if desired interrupted by an oxygen atom which may be mentioned herein, are cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran and tetrahydropyran rings. When R2 and R3, taken together and including the two carbon atoms to which they are attached, form a 5-, 6- or 7-membered hydrocarbon ring, they form a spiro compound.

1-4C-alkyl is a straight or branched chain alkyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

Halogen is understood to mean bromine, chlorine or fluorine in the present invention.

1-4C-Alkoxy is a radical which, in addition to the oxygen atom, contains one of the abovementioned 1-4C-alkyl radicals. Examples which may be mentioned are the methoxy and ethoxy radicals.

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 (CH 2 O-CO-) and the ethoxycarbonyl (CH 3 CH 2 O-CO-) radical.

1-4C-alkylcarbonyl is a carbonyl group to which one of the abovementioned 1-4C-radicals is attached. An example that may be mentioned is the acetyl radical (CH 2 CO-).

1-4C-alkylcarbonyloxy is a radical which, in addition to the oxygen atom, contains one of the abovementioned

1-4C-alkylcarbonyl radicals. An example that may be mentioned is the acetoxyl radical (CH 2 CO-O-).

The mono- or di-C 1-4 -alkylamino group which may be mentioned is, for example, methylamino-, dimethylamino- and diethylamino.

The 1-4C-alkylcarbonylamino group which may be mentioned is, for example, the acetylamide radical (NHCOCH4).

Examples of R 41 -, R 42 - and R 43 -substituted phenyl radicals which may be mentioned are the 2-acetylphenyl radicals,

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 and 2,6-dichloro-4-ethoxycarbonylphenyl.

Examples of R44-, R45-, R46- and R47-substituted pyridyl radicals which may be mentioned 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-tetrachloropyrid-4-yl, 3,5-dichloro- 2,6-difluoropyrid-4-yl, 3,5-dibromopyridine

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.

Suitable salts of the compounds of formula I, depending on substitution, are any acid addition salts, but especially any salts with bases. Special mention may be made of pharmacologically tolerable inorganic and organic acids and bases commonly used in pharmacy. Pharmacologically intolerable salts, for example formed initially as process products during the preparation of the compounds of this invention on an industrial scale, are converted to pharmacologically tolerable salts by methods known to those skilled in the art. Those which are suitable are, on the one hand, water-soluble and water-insoluble acid addition salts with acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D- gluconic, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, sulfosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid , methanesulfonic acid or acid

3-hydroxy-2-naphthoic acid, whereby it is possible that the acids are used to prepare the salt - depending on whether it is mono) or polybasic acid and depending on what salt is required - in an equimolar quantitative ratio or in a ratio different from this ratio.

On the other hand, salts with bases are also particularly suitable. Examples of basic salts which may be mentioned are lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, N-methyl-D-glucamine or guanidine salts, and can also be used here in equimolar quantitative ratio during salt preparation. or in a ratio that is different from that.

Substances of formula I to be highlighted are those in which:

R 1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or fully or partially fluorine-substituted 1-4C-alkoxy,

R 2 is 1-4C-alkyl, and

R 3 is hydrogen or 1-4C-alkyl, or

R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

R4 is phenyl, pyridyl, R41-, R42- and R43-substituted phenyl or R44-, R45-, R46- or R47-substituted pyridyl, wherein

R42

R43

R44

R45

R46

R 47 is hydrogen or is hydrogen or

R 41 is halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl, is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, is hydrogen, halogen, 1- 4C-alkyl or 1-4C-alkoxy, is halogen or 1-4C-alkyl, is hydrogen or halogen, halogen, and halogen, salts thereof and N-oxides of pyridines and salts thereof.

Substances of formula I which should be particularly highlighted are those in which:

R 1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or fully or partially fluorine-substituted 1-4C-alkoxy,

R 2 is 1-4C-alkyl, and

R 3 is hydrogen or 1-4C-alkyl, or

R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

R 4 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-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-37-yl, 3,5-dibromopyrid-2-yl 3,5-dibromopyrid-4-yl, 2-chlorophenyl, 2,3,5,6-tetrachloropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid4 -yl or 2,6-dichloropyrid-3-yl, salts thereof and pyridine N-oxides and salts thereof.

Preferred compounds of formula I are those in which:

R 1 is methoxy, ethoxy, cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy,

R 2 is methyl or ethyl, and

R 3 is hydrogen or methyl, or

R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

R 4 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-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2-chlorophenyl, 2,3,5,6-tetrafluoropyrid-4-yl, 3-chloro-2,5,6-trifluoropyrid-4-yl, 3,5-dichloro-2,6-difluoropyrid4- yl or 2,6-dichloropyrid-3-yl, salts thereof and pyridine N-oxides and salts thereof.

Particularly preferred compounds of formula I are those in which:

R 1 is methoxy, ethoxy, cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy,

R 2 is methyl or ethyl, and

R 3 is hydrogen or methyl, or

R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring,

R 4 is 3,5-dichloropyrid-4-yl, 2,6-difluorophenyl or 2,6-dichlorophenyl, salts thereof, and pyridine N-oxides and salts thereof.

Examples of substances according to the invention are given in the following tables:

Table 1

Substances of formula I (see appended Sheet of formulas I) with R4

3,5-dichloropyrid-4-yl and the following meanings of other substituents:

R1 R 2 R3 - OCH ₃ ch ₃ H oc ₂ h ₅ ^CH 3 H OCH ₂ C ₃ H ₅ ch ₃ H ocf ₂ h ^CH 3 H ocf ₃ ch ₃ H OCH ₂ CF ₃ ch ₃ H och ₃ C-H2 o CH. • ^OC 2 ^H 5 ^C 2 ^H 5 CH ₃ OCH ₂ C ₃ ^H 5 c ₂ h ₅ ch ₃ ocf ₂ h ^C 2 ^H 5 ch ₃ ocf ₃ ^C 2 ^H 5 ch ₃ OCH ₂ CF ₃ ^C 2 ^H 5 ^CH 3 och ₃ CH _? CH _? CH _? ^OC 2 ^H 5 ch ₂ ch ₂ ch ₂ OCH ₂ C ₃ H ₅ ch ₂ ch ₂ ch ₂ ocf ₂ h CH _? CH _? CH _? ocf ₃ CH _? CK _? CH _? ock ₂ CF ₃ CH _? CH _? CH _? ° ch ₃ CH _? CH _? CH _? CH _? 0C ₂ h- ch ₂ ch ₂ ch ₂ ch ₂ och ₂ c ₃ h ₅ ch ₂ ch ₂ ch ₂ ch ₂ ocf ₂ h CH _? CH _? CH _? CH _? ocf ₃ CH ₂ CH ₂ CH ₂ CH ₂ OCH ₂ CF ₃ CH ₂ CH ₂ CH ₂ CH ₂ och ₃ CH _? -O-CH _? ^OC 2 ^H 5 CH ₂ -O-CH ₂ • ^OCH 2 ^C 3 ^H 5 ch ₂ -o-ch ₂ ocf ₂ h ch ₂ -o-ch ₂

Table 1 - continued

R1 R 2 R3 OCF ₃ CH ₂ -O-CH ₂ och ₇ cf _? CH ₂ -O-CH ₂ och ₃ CH ₂ CH ₂ -O C ₂ ^H 5 CH ₂ CH ₂ -O OCH ₂ C ₃ H ₅ CH ₂ CH ₂ -O ocf ₂ h CH ₂ CH ₂ -0 ocf ₃ CH ₂ CH ₂ -O och _? cf ₇ CH ₂ CH ₂ -O och ₃ ch _? ch _? -o-ch ₂ ^OC 2 ^H 5 CH ₂ CH ₂ -O-CH ₂ OCH ₂ ^c 3 ^K 5 CH ₂ CH ₂ -O-CH ₂ ocf ₂ h ch ₇ ch ₂ -o-ch ₂ ocf ₃ ch ₇ ch _? -o-ch ₂ OCH ₂ CF ₃ CH ₂ CH ₂ -O-CH ₂

Table 2

Substances of formula I (see appended Sheet of formulas I) with R4

2,6-dichlorophenyl and with the following meanings of other substituents:

R1 R 2 R3 OCH ₃ CH ₃ H OC ₂ ^H 5 ch ₃ H ^OCH 2 ^C 3 ^H 5 ch ₃ H ocf ₂ h ^CH 3 H ocf ₃ ch ₃ H OCH _? CF _? ch ₃ H OCH ₃ ^C 2 ^H 5 ^CH 3 OC ₂ ^H 5 ^C 2 ^H 5 ch ₃ OCH ₂ ^C 3 ^H 5 ^C 2 ^H 5 ch ₃ ocf ₂ h c ₂ h ₅ ^CH 3 ocf ₃ ^C 2 ^H 5 ch ₃ OCH ₂ CF ₃ ^C 2 ^H 5 ch ₃

- io Table 2 - continued

R1 R2 R3 och ₃ CH ₂ CH ₂ CH ₂ ^OC 2 ^H 5 CH ₂ CH ₂ CH ₂ ^OCH 2 ^C 3 ^H 5 CH ₂ CH ₂ CH ₂ ocf ₂ h CH ₂ CH ₂ CH ₂ ° cf ₃ CH ₂ CH ₂ CH ₂ OCH ₂ CF ₃ Cli ₂ CII ₂ CII ₂ och ₃ CH ₂ CH ₂ CH ₂ CH ₂ ^OC 2 ^H 5 CH ₂ CH ₂ CH ₂ CH ₂ och ₂ c ₃ h ₅ CH CH ₂ CH ₂ CH ₂ ocf ₂ h ch _? ch ₇ ch ₇ ch _? ocf ₃ CH ₂ CH ₂ CH ₂ CH ₂ OCH ₂ CF ₃ CH ₂ CH ₂ CH ₂ CH ₂ och ₃ CH ₂ -O-CH ₂ ^OC 2 ^H 5 ch ₂ -o-ch ₂ och ₂ c ₃ h ₅ CH-O-CH 1; 2 ocf ₂ h CH ₂ -O-CH ₂ ^0CF 3 CH ₂ -O-CH ₂ och _? cf ₇ CH ₂ -O-CH ₂ och ₃ CH ₂ CH ₂ -O C ₂ ^C 5 CH ₂ CH ₂ -O OCH ₂ C ₃ H ₅ CH ₂ CH ₂ -O ocf ₂ h CH ₂ CH ₂ -O ° ^CF 3 CH ₂ CH ₂ -O och _? cf ₃ CH ₂ CH ₂ -O och ₃ CH ₂ CH ₂ -O-CH ₂ ^OC 2 ^H 5. CH ₂ CH ₂ -O-CH ₂ och ₂ c ₃ h ₅ CH ₂ CH ₂ -O-CH ₂ ocf ₂ h CH ₂ CH ₂ -O-CH ₂ ^0CF 3 CH ₂ CH ₂ -O-CH ₂ OCH-CF _o CH _n CH_-O-CH_

I

Table 3

Substances of formula I (see appended Sheet of formulas I) with R4

2,6-difluorophenyl and with the following meanings of other substituents:

R1 R 2 R3 och ₃ CH ₃ H 0C ₂ h ₅ ch ₃ H OCH ₀ CH _c Z o 0 ch ₃ H OCr'K ch ₃ H ocf ₃ ^CH 3 H och _? cf ₃ ^CH 3 H och ₃ ^C 2 ^H 5 CH ^0C 2 ^K N ^C 2 ^H 5 CH ^OCH 2 ^C 3 ^H 5 c ₂ n ₅ CH ocf ₂ h ^C 2 ^H 5 CH. ocf ₃ c ₂ h ₅ CH, och ₂ cf ₃ c ₂ H ₅ CH, och ₃ ch ₂ ch ₂ ch ₂ oc ₂ h. ch ₂ ch ₂ ch ₂ ^OCH 2 ^C 3 ^H 5 ch ₂ ch ₂ ch ₂ ocf ₂ h ch ₇ ch ₇ ch _? ocf ₃ ch _? ch _? ch ₇ och ₂ cf ₃ CH ₂ CH ₂ CH ₂ och ₃ CH ₂ CH ₂ CH ₂ CH ₂ ^OC 2 ^H 5 CH ₂ CH ₂ CH ₂ CH ₂ ^OCK 2 ^C 3 ^H 5 CH ₂ CH ₂ CH ₂ CH ₂ OCF. H CH _? CH _? CH _? CH _? ocf ₃ CH ₂ CH ₂ CH ₂ CH ₂ OCH ₂ CF ₃ CH ₂ CH ₂ CH ₂ CH ₂ och ₃ ch ₂ -o-ch ₂ ^OC 2 ^H 5 CH ₂ -O-CH ₂ och ₂ c ₃ h ₅ CH ₂ -O-CH ₂ ocf ₂ h ch _? -o-ch _? OCF CH _? -O-CH _? OCH ₂ CF ₃ CH ₂ -O-CH ₂

Table 3 - continued

R1 R2 R3

och ₃ CH ₂ CH ₂ -O OC ₂ ^H 5 CH ₂ CH ₂ -O OCH ₂ C ₃ H ₅ CH ₂ CH ₂ -O ocf ₂ h CH ₂ CH ₂ -O ocf ₃ CH ₂ CH ₂ -O OCH ₂ CF ₃ CH ₂ CH ₂ -O och ₃ CH ₂ CH ₂ -O-CH ₂ ^OC 2 ^H 5 CH ₂ CH ₂ -O-CH ₂ ^OCH 2 ^C 3 ^H 5 CH ₂ CH ₂ -O-CH ₂ ocf ₂ h ch ₂ ch ₂ -o-ch ₂ ocf ₃ CH ₂ CH ₂ -O-CH ₂ OCH ₂ CF ₃ CH ₂ CH ₂ -O-CH ₂

Table 4

Compounds of formula I (see appended List of formulas I) with R 4 2-chloropyrid-2-yl and the following meanings of other substituents:

R1 R2 R3

och ₃ ch ₃ H ^OC 2 ^H 5 ^CH 3 H och ₂ c ₃ h ₅ ch ₃ H ocf ₂ h ^CH 3 H ocf ₃ ch ₃ H och _? cf ₃ ch ₃ H och ₃ ^C 2 ^H 5 ch ₃ ^OC 2 ^H 5 ^C 2 ^H 5 ch ₃ och ₂ c ₃ h ₅ ^C 2 ^H 5 ch ₃ ocf ₂ h ^C 2 ^H 5 ch ₃ ocf ₃ ^C 2 ^H 5 ch ₃ och ₂ cf ₃ ^C 2 ^H 5 ch ₃

R1 Table 4 - continued R 2 R3 och ₃ CH ₂ CH ₂ CH ₂ ^C 2 ^C 5 CH ₂ CH ₂ CH ₂ och ₂ c ₃ h ₅ CH ₂ CH ₂ CH ₂ ocf ₂ h CH ₂ CH ₂ CH ₂ ocf ₃ CH ₂ CH ₂ CH ₂ och ₂ cf ₃ CH ₂ CH ₂ CH ₂ och ₃ CH ₂ CH ₂ CH ₂ CH ₂ ^OC 2 ^H 5 ch _? ch ₂ ch ₂ ch _? och ₂ c ₃ h ₅ ch ₂ ch ₂ ch ₂ ch _? OCF ₂ H ch _? ch _? ch _{2 ch?} ^0CF 3 CH ₂ CH ₂ CH ₂ CH ₂ och ₂ cf ₃ CH ₂ CH ₂ CH ₂ CH ₂ och ₃ ch ₂ -o-ch ₂ · ^C 2 ^H S CH ₂ -O-CH ₂ och ₂ c ₃ h ₅ ch ₂ -o-ch ₂ ocf ₂ h CH ₂ -O-CH ₂ ocf ₃ CH ₂ -O-CH ₂ och _? cf ₇ CH ₂ -O-CH ₂ och ₃ CH ₂ CK ₂ -O oc ₂ h ₅ CH ₂ CH ₂ -O and _from c ₃ h ₅ ch ₂ ch ₂ -o ocf ₂ h CH ₂ CH ₂ -O ocf ₃ CH ₂ CH ₂ -O OCK-CF, CH ₂ CH ₂ -O 0CH ₃ CH ₂ CH ₂ -O-CH ₂ oc ₂ H ₅ CH ₂ CH ₂ -O-CH ₂ OCH ₂ C ₃ H ₅ CH ₂ CH ₂ -O-CH ₂ ocf ₂ h CH ₂ CH ₂ -O-CH ₂ ocf ₃ CH ₂ CH ₂ -O-CH ₂ och ₂ cf ₃ CH ₂ CH ₂ -O-CH ₂

Table 5

Substances of formula I (see appended List of formulas I) with R 4 2-chloro-6-methylphenyl and with the following meanings of other substituents:

R1 R 2 R3 - ° ch ₃ CH ₃ H oc ₂ H ₅ ch ₃ H OCH ₂ C ₃ H ₅ ch ₃ H ocf ₂ h ch ₃ H ° cf ₃ ch ₃ H OCH ₂ CF ₃ ch ₃ H och ₃ ^C 2 ^H 5 ch ₃ ° 2 ^H 5 ^C 2 ^H 5 ch ₃ och ₂ c ₃ h ₅ ^C 2 ^H 5 ch ₃ ocf ₂ h ^C 2 ^H 5 ocf ₃ ^C 2 ^H 5 ch ₃ OCH ₂ CF ₃ ^C 2 ^H 5 ch ₃ och ₃ ck ₂ ch ₂ ch ₂ ^OC 2 ^H 5 CH ₂ CH ₂ CH ₂ och ₂ c ₃ h ₅ ^CH 2 ^CH 2 ^CH 2 ocf ₂ h ch _? ch _{2 ch?} ocf ₃ CH _? CH _? CH _? OCH ₂ CF ₃ CH ₂ CH ₂ CH ₂ och ₃ ch ₇ ch _? ch ₇ ch oc ₂ h ₅ CH ₂ CH ₂ CH ₂ CH, ^OCH 2 ^C 3 ^H 5 CH ₂ CH ₂ CH ₂ CH ocf ₂ h CH _? CH _? CH _? CH ocf ₃ CH _? CH _? CH _? CH OCH _? CF ^ CH _? CH _? CH _? CH OCH ₃ CH _? -O-CH _? oc ₂ h ₅ ch ₂ -o-ch ₂ och ₂ c ₃ h ₅ ch ₂ -o-ch ₂ ocf ₂ h CH _? -O-CH _? OCF _n CH _n -O-CH _o

- 15 Table 5 - continued

R1 R2 R3 and ₂ cf ₇

OCH * oc ₂ h ₅ and ₂ c ₃ h ₅ ocf ₂ h ocf ₃

OCH _? CF, ^OCH 3 ^OC 2 ^H 5

..CH ₂ C ₃ H ₅ ocf ₂ h ocf ₃ and ₂ cf ₃

CH ₂ -O-CH ₂

GH ₂ CH ₂ -O

CH ₂ CH ₂ -O

CH ₂ CH ₂ -O

CH ₂ CH ₂ -O ch ₂ ch ₂ -o

CH ₂ CH ₂ -O

CH ₂ CH ₂ -O-CH ₂

_{CH2 CH2 -O-CH2 CH2 CH2 -O-CH2}

CH ₂ CH ₂ -O-CH ₂

CH ₂ CH ₂ -O-CH ₂

CH ₂ CH ₂ -O-CH ₂

Table 6

Substances of formula I (see appended List of formulas I) with R 4 2-chloro-6-fluorophenyl and with the following meanings of other subsituitites:

R1 R2 R3

OCH ₃ ^CH 3 H ° C ₂ H ₅ ch ₃ H och ₂ c ₃ h ₅ ch ₃ H ocf ₂ h ch ₃ H ocf ₃ ch ₃ H OCH ₂ CF ₃ ch ₃ H och ₃ ^C 2 ^H 5 CH OC 'H _c C 'H _c CH

Table 6 - continued

rl R 2 R3 och ₂ c ₃ ^h 5 ^C 2 ^H 5 ch ₃ ocf ₂ h ^C 2 ^H 5 ^CH 3 ocf ₃ ^C 2 ^H 5 ch ₃ OCH ₂ CF ₃ c ₂ h. ^CH 3 och ₃ CH ₂ CH ₂ CH ₂ ° ú ^H ä CH ₂ CH ₂ CH ₂ och ₂ c ₃ h ₅ CH ₂ CH ₂ CH ₂ ocf ₂ h ch ₇ ch ₇ ch ₇ ocf ₃ CH _? CH _? CH _? OCH ₂ CF ₃ CH ₂ CH ₂ CH ₂ och ₃ CH ₂ CH ₂ CH ₂ CH ₂ OCjH ₅ CH ₂ CH ₂ CH ₂ CH ₂ ^OCH 2 ^C 3 ^H 5 CH ₂ CH ₂ CH ₂ CH ₂ ocf ₂ h CH _? CH _? CH _? CH _? ocf ₃ CH ₂ CH ₂ CH ₂ GH ₂ OCH ₂ CF ₃ CH ₂ CH ₂ CH ₂ CH ₂ och ₃ CH _? -O-CH ₇ ^OC 2 ^H 5 CH ₂ -O-CH ₂ ^OCH 2 ^C 3 ^H 5 CH ₂ -O-CH ₂ ' ocf ₂ h CH _? -O-CH ₇ ocf ₃ CH _? -O-CH _? OCH _? CF ^ CH _? -O-CH _? OCH ₃ CH _? CH _? -0 ^OC 2 ^H 5 CH ₂ CH ₂ -O OCH2C3H5 CH ₂ CH ₂ -O OCF ₂ H CH _? CH _? -0 ^0CF 3 CH _? CH _? -0 och ₂ cf ₃ CH _? CH _? -0 och ₃ ch ₇ ch ₇ -o-ch 0C ₂ h ₅ ch ₇ ch ₇ -o-ch och ₂ c ₃ h ₅ CH _? CH _? -O-CH ocf ₂ h ch ₇ ch _7- o-ch ocf ₃ ch ₇ ch ₇ -o-ch OCH ₂ CF ₃ CH _? CH _? -O-CH

Table 7

Compounds of formula I (see appended List of formulas I) with R4 3,5-difluoropyrid-4-yl and the following meanings of other substituents:

R1 R 2 R3 OCH ₃ CH ₃ H ^OC 2 ^H 5 ch ₃ H och ₂ c ₃ h ₅ ch ₃ H ocf ₂ h ^CH 3 H ocf ₃ ch ₃ H OCH _? CF _? ^CH 3 H och ₃ ^C 2 ^H 5 ch ₃ oc ₂ h ₅ ^C 2 ^H 5 ch ₃ OCH ₂ C ₃ H ₅ ^C 2 ^H 5 ^CH 3 ocf ₂ h ^C 2 ^H 5 ch ₃ ocf ₃ ^C 2 ^H 5 ch ₃ och ₂ cf ₃ ^C 2 ^H 5 ch ₃ och ₃ ch ₇ ch ₇ ch ₇ ^OC 2 ^H 5 CH ₂ CH ₂ CH ₂ OCH ₂ C ₃ ^H 5 CH ₂ CH ₂ CH ₂ OCF ₂ H CH _? CH _? CH _? ocf ₃ CH _? CH _? CH _? OCH ₂ CF ₃ ch ₂ ch ₂ ch ₂ OCH ₃ ch ₂ ch ₂ ch ₂ ch ₂ ^OC 2 ^H 5 CH ₂ CH ₂ CH ₂ CH ₂ OC ^h 2C ₃ ^H 5 CH ₂ CH ₂ CH ₂ CH ₂ ocf ₂ h ch ₇ ch ₇ ch _? ch _? ocf ₃ CH ₂ CH ₂ CH ₂ CH ₂ OCH ₂ CF ₃ ch ₂ ch ₂ ch ₂ ch ₂ och ₃ CH _? -O-CH _? OC ₂ ^H 5 CH ₂ -O-CH ₂ OCH ₂ ^C 3 ^H p ch ₂ -o-ch ₂ OCF ₂ H ch ₇ -o-ch _? ocf ₃ CH ₂ -O-CH ₂

Table 7 - continued

R1 R2 R3

OCH ₂ CF ₃ CH ₂ -O-CH ₂ ^0CH 3 CH ₂ CH ₂ -O ^OC 2 ^H 5 CH ₂ CH ₂ -O OCH ₂ C ₃ ^H 5 CH ₂ CH ₂ -O ocf ₂ h CH ₂ CH ₂ -O ocf ₃ CH ₂ CH ₂ -O och _? cf ₃ CH ₂ CH ₂ -O OCH * CH ₂ CH ₂ -O-CH ₂ ^OC 2 ^H 5 CH ₂ CH ₂ -O-CH ₂ och ₂ c ₃ to ₅ CH ₂ CH ₂ -O-CH ₂ ocf ₂ h CH _? CH _? -O-CH _? ocf ₃ CH _? CH _? -O-CH _? OCH ₂ CF ₃ CH ₂ CH ₂ -O-CH ₂

Table 8

Substances of formula I (see appended List of formulas I) with R 4 2-chlorophenyl and with the following meanings of other substituents:

R1 R 2 R3 OCH ₃ CH ₃ H ° C ₂ ^H 5 ch ₃ H OCH ₂ ^C 3 ^H 5 ch ₃ H ocf ₂ h ch ₃ H ocf ₃ ch ₃ H and ₇ cf ₇ ch ₃ H och ₃ C ₂ ^H 5 ch ₃ ^OC 2 ^H 5 ^C 2 ^H 5 ch ₃ OCH ₂ C ₃ H ₅ ^C 2 ^H 5 ch ₃ ocf ₂ h c ₂ h. ch ₃ ocf ₃ ^C 2 ^K 5 ch ₃ och ₂ cf ₃ ^C 2 ^H 5 ch ₃

Table 8 - continued R1 R2 R3 OCH. OCF. Ú OCH.CF. ^0CH 3 OC ₂ ^H 5 and ₂ c ₃ h ₅ ocf ₂ h oc ₂ h ₅ and ₂ c ₃ h ₅ ocf ₂ h ocf ₃ OCH.CF. ^0CH 3 _{OC2 H5, OCH2} C ₃ H ₅ OCF ₂ H 3 ^0CF OCH.CF- ° ^CH3 _{OC2 H5 OCH2} C ₃ H ₅ OCF ₂ OCF ₃ hours OCH.CF., ^0CH 3 OC _{2 H5,} OCH ₂ C ₃ H ₅ ocf ₂ h ocf ₃ and ₂ cf ₃ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH _{2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 -O-CH2 CH2 -O-CH2 CH2} -o-ch ₂ CH ₂ -O-CH ₂ CH ₂ -O-CH ₂ ch ₂ -o-ch ₂ CH ₂ CH ₂ -O CH ₂ CH ₂ -O CH ₂ CH ₂ -O CH ₂ CH ₂ -O CH ₂ CH ₂ -O CH ₂ CH ₂ -O ch ₂ ch ₂ -o-ch ₂ CH ₂ CH ₂ -O-CH ₂ CH ₂ CH ₂ -O-CH ₂ CH ₂ CH ₂ -O-CH ₂ CH _{2 CH2 -O-CH2 CH2 CH2 -O-CH2}

and salts of the substances listed in the tables.

Compounds of formula I are chiral when the substituents -R 2 and -CH 2 R 3 are not identical. The invention therefore includes both pure enantiomers and mixtures thereof in any mixing ratio, including racemates.

The invention further relates to a process for the preparation of the compounds of the formula I and their salts and also to the N-oxides of pyridines and their salts. The method comprises reacting the compounds of formula II

wherein R 1, R 2 and R 3 have the meanings indicated above and X is a suitable leaving group, with amines R 4 -NH 2 and, if desired, converting the obtained compound of formula I into its salts and / or converting the obtained pyridines to N-oxides and, if desired, to salts or, if desired, converting the obtained salts of the compounds of formula I into free compounds.

Suitable leaving groups X are known to those skilled in the art on the basis of their expert knowledge. Starting materials are, for example, suitable acid halides of formula II (X = C1 or Br). Otherwise, the reaction is carried out, for example, as described in the following examples, or in a manner known per se to those skilled in the art (for example, as described in International Patent Application WO 92/12961).

The N-oxidation is carried out in a manner also known to those skilled in the art, for example with the aid of m-chloroperoxybenzoic acid in dichloromethane at room temperature. Those skilled in the art will, on the basis of their expert knowledge, know the reaction conditions that are particularly necessary for carrying out this process.

The isolation and purification of the compounds of the invention is carried out in a manner known per se, for example by distilling off the solvent under vacuum and recrystallizing the residue obtained from a suitable solvent, or subjecting it to one of the usual purification methods, such as column chromatography on a suitable support.

The salts are obtained by dissolving the free material in a suitable solvent, for example a chlorinated hydrocarbon such as dichloromethane or chloroform, or in a low molecular weight aliphatic alcohol (ethanol, isopropanol) containing the desired acid or base, or into which the desired acid or the principle then adds. The salts are obtained by filtering, reprecipitating, precipitating in a non-solvent addition medium or by evaporating the solvent. The salts obtained can be converted by alkalization or acidification to the free substances, which in turn can be converted to salts. In this way, pharmacologically intolerable salts can be converted into pharmacologically tolerable salts.

Compounds of formula II may be prepared according to the general reaction scheme. By way of example, the preparation of the compounds of formula II is described in the following examples under the designation of the starting material. The preparation of other compounds of formula II can be carried out in an analogous manner.

The amines R 4 -NH 2 are known or can be prepared in a known manner.

Reaction scheme of co ₂ ch ₃ co ₂ ch ₃

OH

R1

R 2

R3 k ₂ co ₃

DMR

R1

^ R3

R 2: H ₂ = PPh ₃

R 2

R3

1, NaOH

2. SOC1.

R3

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention in greater detail without limiting it.

LT stands for room temperature, h stands for hour (s), min. indicates minute (s) and m.p. indicates the melting point.

End products

1. 2,3-Dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylic acid N-3,5-dichloro-4-pyridylamide

0.22 g of sodium hydride (80% w / w in paraffin) was suspended in 20 ml of anhydrous THF and a solution of 0.5 g of 4-amino-3,5-dichloropyridine in 5 ml of absolute THF was added dropwise with stirring. The mixture was stirred for 30 min. and a solution of 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl chloride (prepared from 0.8 g of 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylic acid) , see Example A1) in 10 mL of absolute THF. After 10 min. The reaction mixture was poured onto water, the pH was adjusted to 4 with 2M HCl, extracted 3 times with ethyl acetate, and the combined extracts were dried over sodium sulfate and filtered. The oily residue remaining after concentration in a rotary evaporator was chromatographed on a silica gel column using dichloromethane / methanol (98: 2). Chromatographically pure fractions were combined, concentrated and crystallized using diethyl ether. 0.7 g of the title compound of m.p. 140 to 142 “C.

2. 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid N-3,5-dichloro-4-pyridylamide

Analogous to Example 1, 0.55 g sodium hydride (80% w / w in paraffin) was suspended in 50 ml absolute THF, 1.5 g 4-amino-3,5-dichloropyridine in 20 ml absolute

THF and 2.5 g of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carbonyl chloride gave 1.4 g of the title compound of m.p. 168 DEG-170 DEG C. (from diethyl ether).

3. 7-Difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid N-3,5-dichloro-4-pyridylamide

Analogous to Example 1, 0.15 g of sodium hydride (80% w / w in paraffin) was suspended in 20 ml of absolute THF, 0.41 g of 4-amino-3,5-dichloropyridine in 10 ml of absolute THF and a solution of 7-difluoromethoxy- 2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carbonyl chloride (prepared from 0.7 g of 7-difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid, see Example Cl) in 10 mL of absolute THF after chromatography (silica gel, eluent: ethyl acetate / petroleum ether 4: 6) gave 0.15 g of the title compound with mp. 152-153 ° C (from diisopropyl ether).

4. 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclohexane-4-carboxylic acid N-3,5-dichloro-4-pyridylamide

Analogous to Example 1, 0.46 g of sodium hydride (80% w / w in paraffin) was suspended in 20 ml of absolute THF, 1.24 g of 4-amino-3,5-dichloropyridine in 20 ml of absolute THF and a solution of 2,3- dihydro-7-methoxybenzofuran-2-spiro-1'-cyclohexane-4-carbonyl chloride (prepared from 2 g of acid)

2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclohexane-4-carboxylic acid, see Example D1) in 20 mL of absolute THF gave 2.9 g of the title compound of m.p. Mp 169-170 ° C.

5. 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1 '- (4'-oxycyclohexane) -4-carboxylic acid N-3,5-dichloro-4-pyridylamide

Analogous to Example 1, 0.22 g of sodium hydride (80% w / w in paraffin) was suspended in 40 ml of absolute THF, 0.62 g of 4-amino-3,5-dichloropyridine in 20 ml of absolute

- 25 THF and a solution of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '- (4' oxycyclohexane) -4-carbonyl chloride (prepared from 1 g of 2,3-dihydro-7-methoxybenzofuran-2-spiro acid) 1 '- (4'-oxycyclohexane) -4-carboxylic acid, see Example E1) in 10 mL of absolute THF gave 0.3 g of the title compound of m.p. 208-210 ’C.

6. 2,2-Diethyl-7-methoxybenzofuran-4-carboxylic acid N-3,5-dichloro-4-pyridylamide

Analogous to Example 1, 0.3 g of sodium hydride (80% w / w in paraffin) was suspended in 20 ml of absolute THF, 0.8 g of 4-amino-3,5-dichloropyridine in 10 ml of absolute THF and a solution of 2,2- diethyl-2,3-dihydro-7-methoxybenzofuran-carbonyl chloride (prepared from 1.2 g of 2,2-diethyl-2,3-dihydro-7-methoxybenzofuran-4-carboxylic acid, see Example F1) in 20 ml of absolute THF gave after chromatography ( silica gel, eluent: dichloromethane / methanol 98: 2), 0.9 g of the title compound of m.p. 171 to 172 ’C.

7. 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid 2,6-dichloroanilide

A solution of 0.65 g of 2,6-dichloroaniline and 0.7 ml of triethylamine in 20 ml of dioxane was heated to 40-50 ° C, and then a solution of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 'was added dropwise. cyclopentane-4-carbonyl chloride (prepared from 1 g of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid, see Example A1) in 10 ml of dioxane. The mixture was stirred for 1 h at 50 ° C, then poured onto water and extracted with ethyl acetate. The organic extract was dried over sodium sulfate and concentrated, and the residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether 4: 6. Chromatographically pure fractions were combined, concentrated, and crystallized using diisopropyl ether. 0.2 g of the title compound of m.p. M.p. 172-174 ° C.

8. 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid 2,6-difluoroanilide

Analogous to Example 7, 0.65 g of 2,6-difluoroaniline,

0.9 ml triethylamine and 2,3-dihydro-7-methoxybenzofuran-2spiro-1'-cyclopentane-4-carbonyl chloride (prepared from 1.5 g 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 ') -cyclopentane-4-carboxylic acid, see Example A1) gave 1.2 g of the title compound of m.p. 142-145 ° C (from diisopropyl ether).

Starting materials

Al: 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carbonyl chloride

0.8 g of 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylic acid was heated under reflux for 1 hour in a mixture of 50 ml of absolute toluene and 3 ml of thionyl chloride. The solvent was distilled off in a rotary evaporator and then toluene (about 30 ml) was added two more times and the mixture was concentrated again. The residue was dried under high vacuum and used in Example 1 without further purification.

A2: 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylic acid

5.5 g of methyl 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylate were stirred at 60 ° C for 2 h in a mixture of 150 ml of ethanol and 50 ml of 2M NaOH. Ethanol was distilled off, the residue was taken up with water and the solution was adjusted to pH 4 with 2 mol / L HCl. The product thus precipitated was filtered off with suction, washed with water and dried. 4.7 g of the title compound of m.p. Mp 147-149 ° C.

A3: Methyl 2,3-dihydro-2,2-dimethyl-7-methoxybenzofuran-4-carboxylate

15.6 g of methyl 3-hydroxy-4-methoxy-2- (2-methyl-2-propenyl) benzoate was dissolved in 250 ml of absolute dichloromethane and treated with 3 ml of concentrated sulfuric acid. The mixture was stirred at RT for 12 h, then treated with water and the pH of the aqueous phase was adjusted by the addition of 2 M NaOH. After separation of the organic phase, the aqueous phase was extracted a further 2 times with ethyl acetate. The combined organic phases were concentrated and the oily residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure product fractions s = 0.6 were combined and concentrated. 6.6 g of the title compound of m.p. 65 to 67 C.

A4: methyl 3-hydroxy-4-methoxy-2- (2-methyl-2-propenyl) benzoate methyl 4-methoxy-3- (2-methyl-2-propenyloxy) benzoate was dissolved in 60 ml quinoline and the mixture was heated at 180-190 ° C for 2 h. After cooling, it was treated with ethyl acetate and the quinoline was extracted with 2 M HCl. The organic phase was washed a further 2 times with water and concentrated. The oily residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined, concentrated and dried under high vacuum. 15.6 g of the title compound was obtained as a pale yellow oil.

A5: methyl 4-methoxy-3- (2-methyl-2-propenyloxy) benzoate g of methyl 3-hydroxy-4-methoxybenzoate was dissolved in 200 ml of anhydrous DMF and then 41 g of ground potassium carbonate and 14.7 g were added. ml of 3-chloro-2-methyl-propene. The mixture was stirred at 60 ° C for 5 h. After cooling, the precipitate was filtered off with suction, water was added to the filtrate and then extracted 3 times with ethyl acetate. The residue remaining after concentration of the extracts was crystallized using petroleum ether. 21 g of the title compound of m.p. Mp 62-63 ° C.

BI: 2,3-dihydro-7-methoxybenzofuran-2-spiro-1´-cyclopentane-4-carbonyl chloride

The title compound was prepared in analogy to the starting material A1 from 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid in 50 ml absolute toluene and 3 ml thionyl chloride and reacted further without further purification .

B2: 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid

2.6 g of methyl 2,3-dihydro-7-methoxybenzofuran-2-spiro-1-cyclopentane-4-carboxylate were hydrolyzed analogously to Example A2 in 50 ml of ethanol and 10 ml of 2M NaOH. 2.3 g of the title compound of m.p. Mp 166-168 ° C.

B3: methyl 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylate

10.2 g of methyl 2-cyclopenten-1-ylmethyl-3-hydroxy-4-methoxybenzoate was dissolved in 500 ml of anhydrous n-hexane and treated with about 5 g of Amberlyst 15. The mixture was stirred at RT for 3 days, filtered and concentrated. The residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6), the chromatographically pure fractions were combined and concentrated, and the residue was dried under high vacuum. 7.2 g of the title compound were obtained as a yellow oil.

B4: methyl 2-cyclopenten-1-ylmethyl 3-hydroxy-4-methoxybenzoate

12.7 g of methyl 3- (2-methylenecyclopentyloxy) -4-methoxybenzoate was treated with 50 ml of quinoline and the mixture was stirred at 190 ° C for 1 h. After cooling, it was treated with water, adjusted to pH 3 using 2M HCl and extracted with ethyl acetate. The residue remaining after concentration of the solvent was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined and concentrated and dried under high vacuum. 10.2 g of the title compound were obtained as a yellow oil.

B5: methyl 3- (2-methylenecyclopentyloxy) -4-methoxybenzoate

28.5 g of methyltriphenylphosphonium bromide was suspended under nitrogen in 300 ml of anhydrous THF and cooled to -40 ° C. 50 ml of n-butyllithium (1.6 mol / l) in hexane was then added dropwise with stirring. After stirring at -20 ° C to -10 ° C for 30 min. a solution of 20 g of methyl 4-methoxy-3- (2-oxocyclopentyloxy) benzoate in 100 ml of absolute THF was added dropwise. The mixture was allowed to warm to LT and stirred for an additional 1h. Poured onto water and extracted with ethyl acetate. The oil remaining by concentration of the organic phase was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined, concentrated and dried under high vacuum. 12.7 g of the title compound were obtained as a colorless oil.

B6: methyl 4-methoxy-3- (2-oxocyclopentyloxy) benzoate

23.8 g of methyl 3-hydroxy-4-methoxybenzoate was dissolved in 200 ml of anhydrous DMF and treated with 35 g of potassium carbonate (ground) and 13 ml of 2-chlorocyclopentanone. The mixture was stirred at 60 ° C for 3 hours, then the solid was filtered off with suction and the filtrate was concentrated in vacuo. The residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined, concentrated, and dried under high vacuum. 24.3 g of the title compound was obtained as a pale yellow oil.

C1: 7-Difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carbonyl chloride

Analogous to Example A1, 0.7 g of 7-difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carboxylic acid was reacted in a mixture of 20 ml of absolute toluene and 2 ml of thionyl chloride and reacted without further purification.

C2: 7-Difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-cyclopentane-4-carboxylic acid

Analogous to Example A2, 2.4 g of ethyl 7-difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carboxylate gave 2 g of the title compound of m.p. 143 to 145 C.

C3: Ethyl 7-difluoromethoxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carboxylate

2.7 g of ethyl 2,3-dihydro-7-hydroxybenzofuran-2-spiro-1-cyclopentane-4-carboxylate were dissolved in 70 ml of dioxane, 3 ml of 50% NaOH solution and 0.1 g of benzyltrimethylammonium chloride were added, and then it was passed into the difluorochloromethane mixture under stirring at 70-75 ° C until the reaction was complete (about 1h). After cooling, the mixture was poured onto water and extracted 3 times with 100 ml of ethyl acetate. After drying over sodium sulfate, the organic phase was concentrated and the residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined, concentrated and dried under high vacuum. 2.4 g of the title compound were obtained as a pale yellow oil.

C4: ethyl-2,3-dihydro-7-hydroxybenzofuran-2-spiro-1'-cyclopentane-4-carboxet

4.1 g of ethyl 7-benzyloxy-2,3-dihydrobenzofuran-2-spiro-3'-cyclopentane-4-carboxylate, 0.5 g of Pd / C (10% by weight) and 20 ml of cyclohexane were heated under reflux for 4 h. 100 ml toluene. After cooling, the mixture was filtered and the filtrate was concentrated to dryness. 2.7 g of the title compound were obtained as a pale brown oil.

C5: ethyl 7-benzyloxy-2,3-dihydrobenzofuran-2-spiro-1'-cyclopentane-4-carboxylate g of a mixture of sodium methyltriphenylphosphonium bromide amide (FLUKA 69500) was suspended in 100 ml of absolute THF under N 2 atmosphere and stirred at LT for 0.5 h. A solution of 7 g of 4-benzyloxy-3- (2-oxocyclopentyloxy) benzoate in 20 mL of absolute THF was then added dropwise over 30 minutes. The mixture was stirred at RT for 2 h, then poured onto water and extracted 3 times with 100 mL of ethyl acetate. After drying over sodium sulfate, the organic phase was concentrated to dryness. The oily residue was stirred at 190 ° C for 1.5 h to slide. After cooling, 100 ml of toluene were added, 10 g of Amberlyst 15 (anhydrous) was added, and the mixture was stirred at 80 ° C for 3 h. It was then filtered and washed with methanol, and the filtrate was concentrated to dryness. The residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Fractions containing the main product (Rf = 0.8) were combined, concentrated, and dried under high vacuum. 4.1 g of the title compound were obtained as a pale yellow oil.

C6: ethyl 4-benzyloxy-3- (2-oxocyclopentyloxy) benzoate

Analogous to Example B6, 34 g of ethyl 4-benzyloxy-3-hydroxybenzoate, 35 g of potassium carbonate and 15 ml of 2-chlorocyclopentanone gave 36 g of the title compound as a colorless oil.

D1: 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclohexane-4-carbonyl chloride

Analogous to Example A1, 2 g of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclohexane-4-carboxylic acid were treated with 5 ml of thionyl chloride in 50 ml of toluene.

D2: 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1'-cyclohexane-4-carboxylic acid

Analogous to Example A2, 10.3 g of methyl 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylate afforded 9 g of the title compound of m.p. Mp 171-173 ° C.

D3: methyl 2,3-dihydro-7-methoxybenzofuran-2-spiro-1'-cyclopentane-4-carboxylate

Analogous to Example B3, 17 g of methyl 2-cyclohexen-1-ylmethyl-3-hydroxy-4-methoxybenzoate in 500 ml of n-hexane and 15 g of Amberlyst 15 (4 h at 60 ° C) gave 10.3 g of the title compound. the title of this paragraph as yellow oil,

D4: Methyl 2-cyclohexen-1-ylmethyl-3-hydroxy-4-methoxybenzoate

Analogous to Example B4, 21 g of methyl 3- (2-methylenecyclohexyloxy) -4-methoxybenzoate (reaction 2h at 190 ° C) gave 17 g of the title compound as a yellow oil.

D5: methyl 3- (2-methylenecyclohexyloxy) -4-methoxybenzoate

43.8 g of methyltriphenylphosphonium bromide in 300 ml of absolute dimethoxyethane were treated portionwise under nitrogen with 3.6 g of sodium hydride (80% w / w in paraffin). The mixture was stirred at RT for 1 h and then a solution of 30 g of methyl 4-methoxy-3- (2-oxocyclohexyloxy) benzoate was slowly added dropwise. The mixture was stirred at RT overnight and then worked up in analogy to Example B5. 21 g of the title compound were obtained as a colorless oil.

D6: methyl 4-methoxy-3- (2-oxocyclohexyloxy) benzoate

Analogous to Example B6, 25 g of methyl 3-hydroxy-4-methoxybenzoate, 41 g of potassium carbonate and 17.5 ml of 2-chlorocyclohexanone in 200 ml of DMF gave 32.9 g of the title compound as a pale yellow oil.

E1: 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '- (4'-oxycyclohexane) -4-carbonyl chloride

Analogous to Example A1, 1 g of 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '- (4'-oxycyclohexane) -4-carboxylic acid was reacted in a mixture of 50 ml of toluene and 5 ml of thionyl chloride and further processed without further purification .

E2: 2,3-Dihydro-7-methoxybenzofuran-2-spiro-1 '- (4' oxycyclohexane) -4-carboxylic acid

Analogous to Example A2, 1.3 g of methyl 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '- (4'-oxycyclohexane) -4-carboxylate were hydrolyzed in a mixture of 50 ml of methanol and 10 ml of 1 mol / L. sodium hydroxide. 1 g of the title compound of m.p. Mp 194-196 ° C.

E3: methyl 2,3-dihydro-7-methoxybenzofuran-2-spiro-1 '- (4'-oxycyclohexane) -4-carboxylate

3.6 g of methyl 4-methoxy-3- (4-methylenetetrahydropyran-3-yloxy) benzoate was dissolved in 50 ml of quinoline and the solution was stirred at 190-200 ° C for 1 h. After cooling, it was poured into water and the pH of the mixture was adjusted to 3 using 2M HCl and extracted 3 times with ethyl acetate, after drying over sodium sulfate, the organic phase was concentrated in vacuo and the residue (2.9 g) was dissolved in 150 g. ml of n-hexane. The solution was treated with 2.9 g of Amberlyst 15 and vigorously stirred at 60 ° C for 4 h. It was then filtered, the filtrate was concentrated in vacuo and the oily residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined, concentrated and dried under high vacuum. 1.3 g of the title compound was obtained as a pale yellow oil.

E4: Methyl 4-methoxy-3- (4-methylenetetrahydropyran-3-yloxy) benzoate

18.2 g of methyltriphenylphosphonium bromide was suspended in 200 ml of dimethoxyethane under a nitrogen atmosphere and then 1.5 g of sodium hydride (80% w / w in paraffin) was added portionwise. The mixture was stirred at RT for 3 h and then stirred for 30 min. a solution of 13 g of methyl 4-methoxy-3- (4-oxotetrahydropyran-3-yloxybenzoate) was added dropwise, the mixture was stirred overnight and then poured onto water and extracted 3 times with ethyl acetate.After drying over sodium sulfate, the organic phase was concentrated under vacuum and the residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6) The chromatographically pure fractions were combined, concentrated and dried under high vacuum to give 3.6 g of the title compound as a pale yellow oil.

E5: Methyl 4-methoxy-3- (4-oxotetrahydropyran-3-yloxybenzoate)

Analogous to Example B6, 36.4 g of methyl 3-hydroxy-4-methoxybenzoate, 50 g of potassium carbonate and 27 ml of 3-chlorotetrahydropyran-4-one in 200 ml of DMF gave 11.5 g of the title compound as a pale yellow oil. .

F1: 2,2-diethyl-2,3-dihydro-7-methoxybenzofuran-carbonyl chloride

Analogous to Example A1, 1.2 g of 2,2-diethyl-2,3-dihydro-7-methoxybenzofuran-4-carboxylic acid was reacted in a mixture of 10 ml of toluene and 2 ml of thionyl chloride.

F2: 2,2-Diethyl-2,3-dihydro-7-methoxybenzofuran-4-carboxylic acid

1.5 g of methyl 2,2-diethyl-2,3-dihydro-7-methoxybenzofuran-4-carboxylate were hydrolyzed in a mixture of 20 ml of methanol and 5 ml of 2M sodium hydroxide analogously to Example A2 and worked up. 1.2 g of the title compound of m.p. Mp 152-154 ° C.

F3: Methyl 2,2-diethyl-2,3-dihydro-7-methoxybenzofuran-4-carboxylate Sodium methyl triphenylphosphonium bromide amide (FLUKA 69500) g was added to 100 mL of absolute THF at about 10 ° C under a protective atmosphere (nitrogen) ) and the mixture was warmed to RT and stirred for about 30 min. A solution of 5.3 g of methyl 4-methoxy-3- (1-methyl-2-oxobutoxy) benzoate was then added dropwise. The mixture was stirred at RT for 1 h, then poured onto water and extracted 3 times with about 50 mL of ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated, and the oily residue was dried under high vacuum. The oil obtained (3.8 g) was stirred at 190-200 ° C for 1 h, cooled and dissolved in 100 ml of toluene. The solution was treated with 5 g of Amberlyst 15 and vigorously stirred at 80 ° C overnight. Then, Amberlyst was filtered off, the solution was concentrated, and the residue was chromatographed on a silica gel column using ethyl acetate / petroleum ether (4: 6). Chromatographically pure fractions were combined and concentrated and the residue was dried under high vacuum. 1.5 g of the title compound was obtained as a pale yellow oil.

F4: methyl 4-methoxy-3- (1-methyl-2-oxobutoxy) benzoate

Analogous to Example B6, 48.5 g of methyl 3-hydroxy-4-methoxybenzoate, 83 g of potassium carbonate and 43.9 g of 2-bromopentan-3-one in 200 ml of DMF gave 68 g of the title compound of m.p. 63-65 ° C (stirring with petroleum ether).

Commercial use

The compounds of the invention have useful pharmacological properties which make them commercially useful. As inhibitors of cyclic nucleotide phosphodiesterase (PDE) (exactly type IV), they are suitable as bronchial therapeutics on the one hand (for the treatment of airway obstruction due to dilation, but also due to their respiratory frequency and respiratory boost), but on the other particularly for the treatment of disorders, particularly of the inflammatory nature, for example of the respiratory tract (asthma prophylaxis) of the skin, intestines, eyes and conjunctivae mediated by mediators such as histamine, PAF (platelet activating factor), arachic acid derivatives such as leukotrienes and prostaglandins, cytokines interleukins IL-1 to IL-12, alpha-, beta- and gamma-interferons, tumor necrosis factor (TNF), or oxygen-free radicals and proteases. The compounds of the invention are characterized by low toxicity, good enteral absorption (high bioavailability), a wide therapeutic range and the absence of significant side effects.

Due to their PDE-inhibitory properties, the compounds of the invention can be used in human and veterinary medicine as therapeutics, for example, for the treatment and prophylaxis of the following diseases: acute and chronic (particularly inflammatory and allergen-induced) respiratory disorders of various origins ( bronchitis, allergic bronchitis, bronchial asthma); dermatoses (particularly proliferative, inflammatory and allergic), such as psoriasis (vulgaris), toxic and allergic contact eczema, atopic eczema, seborrheic eczema, lichen simplex (lichen), sunstroke, anogenital itching, focal alopecia, hypertrophic scars, disc-like lupus erythematosus, follicular and widespread pyoderma, endogenous and exogenous acne, rosacea acne and other proliferative, inflammatory and allergic skin disorders; disorders based on excessive release of TNF and leukotrienes, for example, arthritic-type disorders (rheumatoid arthritis, rheumatoid spondylitis, oseoarthritis and other arthritic conditions), immune system disorders (AIDS), types of shock (septic shock, endotoxic shock, Gram-negative sepsis) shock and ARDS (adult respiratory distress syndrome), as well as generalized inflammation in the gastrointestinal region (Crohn's disease and ulcerative colitis; disorders based on allergic and / or chronic immunological reactions in the upper respiratory tract (pharynx, nose) and associated areas (sinus, eyes), such as allergic rhinitis, chronic sinusitis, allergic conjunctivitis, as well as nasal polyps, but also cardiac disorders that can be treated with PDE inhibitors such as cardiac insufficiency, or a disorder that may the treated on account of the tissue-relaxing action of the PDE inhibitors, such as the pins of kidney and ureter in connection with kidney stones; or alternatively CNS disorders such as depression or arteriosclerotic dementia.

The invention further relates to a method of treating a mammal, including a human, suffering from one of the aforementioned diseases. The method of treatment comprises administering to a diseased mammal a therapeutically active and pharmacologically tolerable amount of one or more compounds of the invention.

The invention further relates to the compounds according to the invention for the treatment and / or prophylaxis of said diseases.

The invention further relates to the use of the compounds according to the invention for the manufacture of medicaments which are used for the treatment and / or prophylaxis of said diseases.

The invention further relates to medicaments for the treatment and / or prophylaxis of said diseases comprising one or more substances according to the invention.

The drugs are prepared by methods known per se and well known to those skilled in the art. As medicaments, the substances according to the invention (= active substances) are used either alone or preferably in combination with suitable pharmaceutical auxiliaries, for example in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions. The active ingredient is preferably between 0.1 and 95% by weight.

It is known to those skilled in the art which excipients are suitable for the desired pharmaceutical preparations. In addition to solvents, gelling agents, ointment bases and other active agent vehicles, for example, antioxidants, dispersants, emulsifying agents, preservatives, solubilizers or permeation activators may be used.

For the treatment of respiratory-tract disorders, the compounds of the invention are preferably also administered by inhalation. For this purpose, they are administered either directly as powders (preferably in micronized form) or by atomizing solutions or suspensions containing them. For formulations and forms of administration, reference is made, for example, to European Patent 163,965.

For the treatment of dermatoses, the compounds of the invention are administered in particular in the form of those drugs which are suitable for topical application. For the manufacture of medicaments, the compounds of the present invention (= active ingredients) are mixed with suitable pharmaceutical excipients and further processed to provide suitable pharmaceutical preparations. Suitable pharmaceutical preparations which may be mentioned are, for example, powders, emulsions, suspensions, sprays, oils, ointments, fat ointments, creams, pastes, gels or solutions.

The medicaments according to the invention are prepared by methods known per se. The dosage of the active substances is carried out within the range of values usual for PDE inhibitors. Thus, for topical dosage forms (such as ointment) for the treatment of dermatoses, the active ingredients contain, for example, 0.1 to 99% by weight. The dose for administration by inhalation is usually between 0.01 and 0.5 mg / kg. The usual dose for systemic therapy is between 0.05 and 2 mg / kg per day.

Biological researches

In the investigation of PDE IV inhibition at the cellular level, the activation of inflammatory cells is of particular importance. An example that may be mentioned is FMLP (N-formyl-methionyl-leucylphenylalanine) -induced neutrophil granulocyte superoxide formation, which can be measured as luminol-enhanced chemiluminescence. (McPhail LC, Strum SL, Leone PA and Sozzani S., The neutrophil respirators of burst raechanism. In Immunology Serie 57, 47-76, 1992; ed. Coffey RG (Marcel Decker, Inc., New York-Basle-Hong Kong) )).

Agents that inhibit chemiluminescence and cytokine secretion and secretion of pro-inflammatory mediators of inflammatory cells, particularly neutrophil and eosinophilic granulocytes are those that inhibit PDE IV. This phosphodiesterase family isoenzyme is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular concentration of cyclic AMP and thus to inhibition of cellular activation. Thus, PDE IV inhibition by the compounds of the invention is a central indicator of suppression of inflammatory processes (Giembycz MA, Could isoenzyme-selective phosphodiesterase inhibitors provide bronchodilatory therapy redundant in the treatment of bronchial asthma? Biochem. Pharmacol. 43, 2041-2051 (1992); Torphy. Thorax 46, 512-523 (1991); Schudt C. et al., Zardaverine: Cyclic AMP PDE II / IV Inhibitor In New Drugs for Asthma Therapy, 379-48, et al., Phosphodiesterase Inhibitors; 402, Birkhäuser Verlag Basel 1991; Schudt C. et al., Effect of Selective Phosphodiesterase Inhibitors on Human Neutrophil Functions and Levels of c-AMP and Ca.Naunyn-SchmiedebergsArch.Pharmacol. et al., Effects of Selective Phosphodiesterase Inhibitors on Polymorphonuclear Leukocyte Respiratory Attack, J. Allergy Clin Immunol., 86: 801-808 (1990); A specific type II and IV phosphodiesterase inhibitor zardaverine that suppresses the formation of tumor necrosis factor by macrophages. European Journal of Pharmacology 230, 9-14 (1993)).

1. Inhibition of PDE IV activity

methodics

The activity assay was performed according to the method described by Bauer and Schwabe, which was adapted for microtiter plates (Naunyn-Schmiedebergs Arch. Pharmacol. 311. 193-198, (1980)). In the first step, the PDE reaction takes place. In a second step, the generated 5 ' -nucleotide is cleaved to an uncharged nucleoside by 5 ' -nucleotidase from the snake venom Ophiophagus hannah (royal cobra). In a third step, the nucleoside is separated from the remaining charged substrate on an ion exchange column. The column is eluted with 2 ml of 30 mmol / l ammonium formate (pH 6.0) directly into the minivioles to which additionally 2 ml of liquid scintillator is added to measure the radioactivity.

The inhibitory values determined for the compounds of the invention can be seen in the following Table A, in which the substance numbers correspond to those of the Examples.

Table A

Inhibition of PDE IV activity by substance

-log IC _5Q

8.47

9.42 9.87 9.09 8.57 8.63 8.57

8:42

Claims (10)

A compound of formula I wherein R1 is 1-6C-alkoxy, 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, benzyloxy or fully or partially fluorine-substituted 1-4C-alkoxy, R 2 is 1-4C-alkyl, R 3 is hydrogen or 1-4C-alkyl, or R2 and R3 together, including the two carbon atoms to which they are attached, are a 5-, 6- or 7-membered hydrocarbon ring, optionally interrupted by an oxygen atom, R4 is phenyl, pyridyl, R41-, R42- and R43-substituted phenyl or R44-, R45-, R46- or R47-substituted pyridyl, wherein R 41 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 -4Calkylamino or 1-4C-alkylcarbonylamino, R 42 is hydrogen, hydroxyl, halogen, amino, trifluoromethyl, 1-4C-alkyl or 1-4C-alkoxy, R 43 is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, R 44 is hydroxyl, halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy, 1-4C-alkoxycarbonyl or amino, R 45 is hydrogen, halogen, amino, or 1-4C-alkyl, R 46 is hydrogen or halogen, and R 47 is hydrogen or halogen, salts thereof and N-oxides of pyridines and salts thereof. A compound of formula I according to claim 1, wherein R 1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or wholly or partially fluorine-substituted 1-4C-alkoxy, R 2 is 1-4C-alkyl, and R 3 is hydrogen or 1-4C-alkyl, or R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring, R4 is phenyl, pyridyl, R41-, R42- and R43- substituted phenyl or R44-, R45-, R46- or R47-substituted pyridyl, wherein R41 R42 R43 R44 R45 R46 R 47 is halogen, cyano, carboxyl, 1-4C-alkyl, 1-4C-alkoxy or 1-4C-alkoxycarbonyl, is hydrogen, halogen, 1-4C-alkyl or 1-4C-alkoxy, is hydrogen, halogen, 1- 4C-alkyl or 1-4C-alkoxy, is halogen or 1-4C-alkyl, is hydrogen or halogen, halogen, and halogen, is hydrogen or is hydrogen or salts thereof and N-oxides of pyridines and salts thereof. A compound of formula I according to claim 1, wherein R 1 is 1-4C-alkoxy, 3-5C-cycloalkoxy, 3-5C-cycloalkylmethoxy, or wholly or partially fluorine-substituted 1-4C-alkoxy, R 2 is 1-4C-alkyl, and R 3 is hydrogen or 1-4C-alkyl, or R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring, R4 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-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 3,5-dibromopyrid-4-yl, 2-chlorophenyl, 2,3,5,6-tetrachloropyrid-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 pyridine N-oxides and salts thereof. A compound of formula I according to claim 1, wherein R 1 is methoxy, ethoxy, cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy, R 2 is methyl or ethyl, and R 3 is hydrogen or methyl, or R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring, R 4 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-chloro-6-fluorophenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 3,5-dichloropyrid-4-yl, 3-methylpyrid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromopyrid-2-yl, 3,5-difluoropyrid-4-yl, 2-chlorophenyl, 2,3, 5,6-tetrafluoropyrid-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 of this pyridine N-oxides and their salts. A compound of formula I according to claim 1, wherein R 1 is methoxy, ethoxy, cyclopropylmethoxy, difluoromethoxy, trifluoromethoxy or 2,2,2-trifluoroethoxy, R 2 is methyl or ethyl, and R 3 is hydrogen or methyl, or R2 and R3 together, including the two carbon atoms to which they are attached, are a cyclopentane, cyclohexane, tetrahydrofuran or tetrahydropyran ring, R4 is 3,5-dichloropyrid-4-yl, 2, 6-difluorophenyl or 2,6-dichlorophenyl, salts thereof and pyridine N-oxides and salts thereof. A process for the preparation of the compounds of formula I according to claim 1 and their salts as well as the N-oxides of pyridines and their salts, characterized in that it comprises reacting the compounds of formula II in which R 1, R 2 and R 3 have the meanings indicated above; X is a suitable leaving group, with amines R 4 -NH 2 and, if desired, converting the obtained compound of formula I into its salts and / or converting the obtained pyridines into N-oxides and, if desired, into salts, or if desired, converting the obtained salts of the compounds of formula I into free compounds. A pharmaceutical composition comprising one or more substances according to claim 1 together with the usual pharmaceutical excipients and / or vehicles. 8th 9th treatment 10. treatment Compounds according to claim 1 for use in the treatment of diseases. Use of the substances according to claim 1 for the manufacture of medicaments for respiratory disorders. Use of the substances according to claim 1 for the manufacture of medicaments for dermatoses.