WO1998008844A1

WO1998008844A1 - Thiazole derivatives useful as selective inhibitors of pde-iv

Info

Publication number: WO1998008844A1
Application number: PCT/EP1997/004397
Authority: WO
Inventors: Thomas Bär; Wolf-Rüdiger Ulrich; Hermann Amschler; Thomas Martin; Dieter Flockerzi; Beate Gutterer; Ulrich Thibaut; Armin Hatzelmann; Hildegard Boss; Dietrich Häfner; Hans-Peter Kley; Rolf Beume
Original assignee: Byk Gulden Lomberg Chemische Fabrik Gmbh
Priority date: 1996-08-26
Filing date: 1997-08-13
Publication date: 1998-03-05
Also published as: AU4298997A

Abstract

Compounds having the formula (I), in which R1, R2, R3, R4 and n have the meanings given in the description, are new effective bronchotherapeutic agents.

Description

THIAZOLE DERIVATIVES AS SELECTIVE INHIBITORS OF PDE-IV

Field of application of the invention

The invention relates to new thiazole derivatives which are used in the pharmaceutical industry for the manufacture of medicaments.

Known technical background

Japanese patent JP 46-15935 describes substituted 4- (carboxyphenyl) thiazoles and their use for the treatment of thrombosis, arteriosclerosis, gastric ulcers and hypersecretion. European patent applications EP 0 513 387 and EP 0 600 092 describe, inter alia, 4- (substituted phenyl) thiazole derivatives and their use as inhibitors of oxygen radical release by neutrophils. The compounds are therefore described as being suitable for the treatment of acute inflammatory processes such as ischemia and reperfusion damage.

International patent application WO94 / 12461 describes 4-substituted catechol diethers which are substituted in the 4-position with, inter alia, thiazole derivatives and their use as inhibitors of phosphodiesterase IV.

Description of the invention

It has now surprisingly been found that the new thiazole derivatives described in more detail below, which differ from the previously published thiazoles in particular by the substituents on the 4-phenyl ring and by the substituents in the 2-position of the thiazole ring, are selective inhibitors of phosphodiesterase IV.

The invention thus relates to compounds of the formula I (see attached formula sheet), in which

R1 is hydroxy, 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy, R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, phenyl-1-4C-alkoxy, 2-indanyloxy, 2-tetrahydronaphthalinyloxy or 2-norbornanyloxy,

R3 represents hydrogen or halogen,

R4 represents a phenyl or naphthyl ring substituted by R41, R42 and R43, represents a mono- or bicyclic heterocycle substituted by R44, R45 and R46, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, Pyrimidine, pyrazine, pyridazine, quinoxaline, quinazoline, cinnoline, benzimidazole, thiophene and furan or a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyrazole, imidazole, purine, oxazole, isoxazole, thiazole and isothiazole, where

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,

R42 is hydrogen, wholly or predominantly fluorine-substituted 1-4C-alkoxy, hydroxy, amino, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl, 1-4C-alkyl or 1 -4C-alkoxy,

R43 is hydrogen, 1-4C-alkoxy, halogen or hydroxy,

R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkoxy and

R46 is hydrogen, halogen, 1-4C-alkoxy or 1-4C-alkyl, n is 0, 1 or 2, where n is not 1 or 2, if R4 is phenyl, the salts of these compounds and the N-oxides of pyridines , Quinolines, isoquinolines, pyrimidines,

Pyrazines, imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.

1-4C-alkoxy represents a radical which, in addition to the oxygen atom, contains a straight-chain or branched alkyl radical having 1 to 4 carbon atoms. Examples of alkyl radicals having 1 to 4 carbon atoms are the butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

3-5C-Cycloalkoxy stands for example for cyclopropyloxy, cyclobutyloxy and cyclopentyloxy. 1, 2,2-tri-fluoroethoxy-, 2,2,3,3,3-pentafluoropropoxy-, perfluoroethoxy- and in particular 1, 1, 2,2-tetrafluoroethoxy, the trifluoromethoxy, the 2,2,2-trifluoroethoxy and the di-fluoromethoxy radical.

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

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

Phenyl-1-4C-alkoxy stands for one of the above-mentioned 1-4C-alkoxy radicals which is substituted by the phenyl radical. The benzyloxy and phenethoxy radicals may be mentioned as examples.

Halogen in the sense of the invention is fluorine, chlorine, bromine and iodine.

1-4C-Alkyl stands for straight-chain or branched alkyl radicals with 1 to 4 carbon atoms. Examples include the butyl, iso-butyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

Examples of mono- or di-1-4C-alkylamino radicals are the methylamino, the dimethylamino, the ethylamino, the diethylamino, the propylamino and the isopropylamino radical.

Mono- or di-1-4C-alkylaminocarbonyl stands for a carbonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino radicals is attached. The methylaminocarbonyl, the dimethylaminocarbonyl and the ethylaminocarbonyl radical may be mentioned as examples.

Mono- or di-1-4C-alkylaminosulfonyl stands for a sulfonyl group to which one of the abovementioned mono- or di-1-4C-alkylamino residues is bonded. Examples include the methylaminosulfonyl, dimethylaminosulfonyl and ethylaminosulfonyl radicals.

The 1-4C-alkylcarbonylamino radical may be mentioned, for example, the acetylamino radical (-NH-CO-CH ₃ ).

1-4C-alkoxycarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. Examples include the methoxycarbonyl (CH ₃ O-CO-) and ethoxycarbonyl (CH ₃ CH ₂ 0-CO-) radicals. 1-4C-alkylcarbonyl stands for a carbonyl group to which one of the above-mentioned 1-4C-alkyl radicals is attached. For example, the acetyl radical (CH ₃ CO-) may be mentioned.

In addition to the oxygen atom, 1-4C-alkylcarbonyloxy radicals contain a 1-4C-alkylcarbonyl radical. For example, the acetoxy residue (CH ₃ CO-O-) may be mentioned.

Hydroxy-1-4C-alkyl stands for the aforementioned 1-4C-alkyl radicals which are substituted by a hydroxyl group. For example, the hydroxyethyl and hydroxymethyl radicals may be mentioned.

1-4C-Alkylsulfonyl stands for a sulfonyl group to which one of the above-mentioned 1-4C-alkyl radicals is attached. For example, the methylsulfonyl radical (CH ₃ S0 ₂ -) may be mentioned.

1-4C-alkoxysulfonyl stands for a sulfonyl group to which one of the above-mentioned 1-4C-alkoxy radicals is attached. Examples include the methoxysulfonyl (CH ₃ 0-S0 ₂ -) and ethoxysulfonyl (CH ₃ CH ₂ 0-S0 ₂ -) groups.

The substituent R4 can be attached to the rest of the compounds of the formula I via any suitable ring position of the phenyl or naphthyl ring or of the heterocycle, the attachment of the heterocycles not taking place via a ring heteroatom.

Examples of R4 are phenyl, 3,4-dihydroxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3,5-dimethoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 3- Methoxy-4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-methoxyphenyl, 4-chlorophenyl, 4-ethoxycarbonylphenyl, 3,4-diethoxyphenyl, 3,4-dimethylphenyl, 4-fluorophenyl, 3-chloro-4- methylphenyl, 3-nitrophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 3,4-dibutoxyphenyl, 3,4-dipropoxyphenyl, 3-ethoxy-4-methoxyphenyl, 3-bromo-4,5-dimethoxyphenyl, 3, 4-diacetoxyphenyl, 4-dimethylaminophenyl, 3-methoxy-4-methylsulfonylphenyl, 3-methoxycarbonyl-4-hydroxyphenyl, 4-acetamido-3-fluorophenyl, 4-acetamidophenyl, 4-acetamidonaphthyl, 4-acetamido-3-trifluoromethoxyphenyl, 3-acetylphenyl, 4-acetylphenyl, 2-carbamoylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl, 2-carboxy-4-methoxyphenyl, 3-carboxyphenyl, 4-carboxyphenyl, 3-methoxycarbonytphenyl, 5-indolyl, 4-nitrophenyl, 4-sulfonamidophenyl, 4-sulfophenyl, pyrimidin-2-yl, thiophene-3- yl, thiophene-2-yl, pyrrol-2-yl, 2-hydroxypyridin-3-yl, (pyridine-N-oxide) -3-yl, 5-acetyl-2-hydroxy-6-methylpyrid-3-yl, 5-acetyl-2,4-dimethylpyrid-3-yl, 2-chloropyrid-3-yl, 2-chloropyrid-4-yl, 2-chloropyrazin-3-yl, quinolin-3-yl, 2,6-dihydroxy- 4-methylpyrid-3-yl, 4-nitropyrid-2-yl, purin-6-yl, 2-carboxypyrid-4-yl, 2-ethoxycarbonylpyrid-4-yl, 6-methylpyrid-2-yl, pyrazine-2- yl, 2-pyridyl, 3-pyridyl and 4-pyridyl.

Suitable salts for compounds of the formula I - depending on the substitution - are all acid addition salts or all salts with bases. Particularly noteworthy are the pharmacologically acceptable ones Salts of the inorganic and organic acids and bases commonly used in galenics. Suitable as such 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 acid, 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 3-hydroxy-2-naphthoic acid, the acids in the salt production - depending on whether it is a mono- or poly-based acid and, depending on which salt is desired, be used in an equimolar or a different quantity ratio.

On the other hand, salts with bases can also be used. Examples of salts with bases which may be mentioned are alkali (lithium, sodium, potassium) or calcium, aluminum, magnesium, titanium, ammonium, meluminum or guanidinium salts, the salt production also being used here Bases are used in the equimolar or a different ratio.

Pharmacologically incompatible salts, which may initially be obtained as process products in the preparation of the compounds according to the invention on an industrial scale, are converted into pharmacologically acceptable salts by processes known to the person skilled in the art.

Compounds of formula I to be emphasized are those in which

R1 is hydroxy, 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, phenyl-1-4C-alkoxy or 2-indanyloxy,

R3 represents hydrogen or halogen,

R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, pyrimidine, pyrazine, pyridazine, py - razole, imidazole, quinoxaiine, quinazoline, cinnoline, benzimidazole, oxazole, isoxazole, thiazole and isothiazole, where

R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy,

R44 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or Di-1-4C-alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy,

1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and R45 are hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 means when R4 is phenyl, the salts of these compounds and the N-oxides of pyridines, quinolines, isoquinolines, pyrimidines, imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.

Particularly noteworthy compounds of formula I are those in which

R1 is 1-4C-alkoxy, 3-5C-cycloalkoxy or completely or predominantly fluorine-substituted 1-4C-alkoxy,

R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 2-indanyloxy,

R3 means hydrogen,

R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine and pyrazine, where

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamiπo, 1-4C-alkylcarbonylamino, 1-4C-alkylsulfonyl, 1-4C-alkoxysulfonyl, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro,

R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 if R4 is phenyl, the salts of these compounds and the N-oxides of pyridines, quinolines and isoquinolines and their

Salts.

Preferred compounds of formula I are those in which

R1 is 1-4C-alkoxy or completely or predominantly substituted by fluorine-1-4C-alkoxy,

R2 is 3-5C-cycloalkoxy or 2-indanyloxy,

R3 means hydrogen, R4 represents a phenyl ring substituted by R41 and R42 or represents pyridine or pyrazine substituted by R44 and R45, where

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 if R4 is phenyl, the salts of these compounds and the N-oxides of pyridines and their salts.

Particularly preferred compounds of the formula I are those in which

R1 is 1-4C-alkoxy,

R2 means cyclopentyloxy or 2-indanyloxy,

R3 means hydrogen,

R4 represents a phenyl ring substituted by R41 or represents pyridine or pyrazine substituted by R44, where

R41 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl or hydroxy and

R44 is hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl or hydroxy, n is 0 or 1, where n is not 1 if R4 is phenyl, and the salts of these compounds.

Particularly preferred compounds of formula I to be emphasized are those in which

R1 means methoxy

R2 means cyclopentyloxy or 2-indanyloxy,

R3 means hydrogen,

R4 represents pyridine or pyrazine substituted by R44, where

R44 denotes hydrogen or 1-4C-alkoxycarbonyl, n denotes 0 or 1, and the salts of these compounds.

The invention further relates to a process for the preparation of the compounds of the formula I and their salts. The process is characterized in that compounds of the formula II (see attached formula sheet) in which R1, R2 and R3 have the meanings indicated above and Y represents a suitable leaving group with compounds of the formula III (see attached formula sheet) in which R4 and n has the meanings given above and Z represents the group -C (S) -NH ₂ , and that, if desired, subsequently obtained compounds of the formula I in their salts or, if desired, subsequently obtained salts of the compounds of the formula I in the transferred free connections.

The person skilled in the art is familiar with which leaving groups Y are suitable on the basis of his specialist knowledge. For example, suitable compounds of the formula II are assumed in which Y is halogen, in particular bromine or chlorine. Otherwise, the reaction is carried out in a manner familiar to the person skilled in the art (for example as described in EP 0 513 387 or EP 0 600 092) in a suitable solvent and in the presence or absence of a base, preferably at reaction temperatures between room temperature and the boiling point of the used solvent and with reaction times between one hour and two days. Suitable solvents are, for example, alcohols such as methanol, ethanol or propanol, cyclic hydrocarbons such as toluene or xylene, ethers such as diethyl ether, tetrahydrofuran or dioxane, halogenated hydrocarbons such as dichloromethane or chloroform, polar solvents such as dimethylformamide, acetonitrile or dimethyl sulfoxide or, if desired, mixtures of the solvents mentioned. Preferred bases that are used are nitrogen bases such as triethylamine, ethyldiisopropylamine, N-methylmorpholine or pyridine. The bases can be added in an equimolar ratio (based on compounds of the formula II) or preferably in excess.

If desired, compounds of the formula I obtained can also be converted into other compounds of the formula I by using methods known to those skilled in the art. The preparation of carboxamides of the formula I from the corresponding carboxylic acids of the formula I may be mentioned as an example. For this purpose, the carboxylic acids of the formula I can be reacted with suitable amines in a manner known to those skilled in the art for the synthesis of carboxamides. If desired, the carboxylic acid of the formula I is converted into a suitably activated derivative, for example a corresponding acid halide, before the aminolysis. Examples of suitable amines which can be used are ammonia, methylamine or ethylamine. The preparation of carboxylic acids of the formula I from corresponding esters of the formula I may also be mentioned, for example by saponification in a manner known to the person skilled in the art. If desired, quinolines, isoquinolines, pyrimidines, pyrazines, imidazoles, quinoxalines, quinazolines, benzimidazoles and in particular pyridines of the formula I obtained can also be converted into the corresponding N-oxides or their salts.

The N-oxidation takes place in a manner also familiar to the person skilled in the art, e.g. with the help of m-chloroperoxibenzoic acid in dichloromethane at room temperature. The person skilled in the art is familiar with the reaction conditions which are required for carrying out the process in detail on the basis of his specialist knowledge.

The substances according to the invention are isolated and purified in a manner known per se, e.g. such that the solvent is distilled off in vacuo and the residue obtained is recrystallized from a suitable solvent or subjected to one of the customary purification methods, such as, for example, column chromatography on a suitable carrier material.

Salts are obtained by dissolving the free compound in a suitable solvent, e.g. in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid or base, or to which the desired acid or base is subsequently added. The salts are obtained by filtration, reprecipitation, precipitation with a non-solvent for the addition salt or by evaporation of the solvent. Salts obtained can be converted into the free compounds by alkalization or acidification, which in turn can be converted into salts. In this way, pharmacologically incompatible salts can be converted into pharmacologically acceptable salts.

The compounds of the formula II in which R1, R2 and R3 have the meanings given above and Y is in particular chlorine or bromine are either known or can be obtained in a known manner, for example by chlorination or bromination of corresponding compounds of the formula II, in which Y is hydrogen. Alternatively, compounds of the formula II in which R1 and R2 have the meanings given above, R3 is hydrogen and Y is in particular chlorine or bromine, also by reacting compounds of the formula Ha (see attached formula sheet) in which R1 and R2 have the abovementioned Have meanings and A is a suitable leaving group, in particular chlorine or bromine, can be obtained with diazomethane and subsequent treatment with HCl or HBr. The reactions are otherwise carried out, for example, as described in the examples below, or in a manner familiar to the person skilled in the art.

Compounds of the formula IIa and compounds of the formula II in which R1, R2 and R3 have the meanings given above and Y is hydrogen are either known or can be based on known way. For example, the compounds of the formula II in which R1, R2 and R3 have the meanings indicated above and Y is hydrogen, by reacting the compounds of the formula IV (see attached formula sheet) in which R3 has the meaning indicated above, Y is hydrogen and X represents a suitable leaving group (for example chlorine, bromine or 1-4C-alkoxy), with compounds of the formula V (see attached formula sheet) in which R1 and R2 have the meanings given above. The reaction is otherwise carried out by methods known to the person skilled in the art from the specialist literature, for example by Friedel-Crafts acylation.

If the radicals R1 and / or R2 in compounds of the formula V are not stable under the acylation conditions, compounds of the formula V in which R1 and / or R2 represents a base-unprotected hydroxyl group can, if desired, be used as starting products. After acylation with compounds of the formula IV, the protective groups are removed and, if desired, from the compounds of the formula II, in which R1 and / or R2 is hydroxy, in a manner known to the person skilled in the art, the desired compounds in the formula II, in which R1 and R2 are the abovementioned Have meanings. This takes place in a manner known to the person skilled in the art for the synthesis of ethers, for example by alkylation with appropriate alkylating agents (for example 1-4C-alkyl halides etc.) or by reaction with corresponding compounds of the formula R1-H and / or R2-H (where R1 and R2 have the meanings mentioned above and where R1 and R2 does not have the meaning hydroxy) in the presence of triphenylphosphine and diethyl azodicarboxylate or diisopropyl azodicarboxylate, for example as described in the examples.

The person skilled in the art knows which protective groups are suitable. The chloroacetyl protective group may be mentioned, for example, as a suitable base-labile hydroxy protective group. The protective groups are attached or removed according to suitable, known standard methods (for example as described by T.W. Green in "Protective Groups in Organic Synthesis", John Wiley and Sons, 1981).

Compounds of the formula V in which R1 has the meaning indicated above and R2 represents a base-unprotected hydroxy group, for example chloroacetyloxy, Compounds of the formula V in which R2 has the meaning given above and R1 represents a base-unstable protected hydroxy group, for example chloroacetyloxy, or compounds of the formula V in which R1 and R2 represent a hydroxyl group which is protected in a base-labile manner are obtained in a known manner from pyrocatechol.

The compounds of formula V in which R1 and R2 have the meanings given above can also be obtained in a known manner from pyrocatechol. The compounds of the formula III, in which R4 and n have the meanings given above and Z represents the group —C (S) —NH ₂ , are either known (for example from EP 0 513 387 or EP 0 600 092) or can be analogous or other ways known to the person skilled in the art, for example by adding hydrogen sulfide to corresponding compounds of the formula III in which Z is cyano (-CN) [W. Christ, D. Rakow, S. Strauss, J. Heterocycl. Chem. 11, 397 (1974)].

The compounds of the formula IM, in which Z denotes cyano, can be described as described in the literature [for example analogously to T. Savaie, T. Ishiguro, K. Kawashima, K. Morita; Tetrahedron Lett. 1973, 2121-2124] from the corresponding compounds of formula III, in which Z is carbamoyl [-C (0) -NH ₂ ].

The following examples illustrate the invention without restricting it. The compounds according to the invention and the starting compounds can be prepared in a manner analogous to that described in the examples.

In the examples, mp stands for melting point, h for hour (s), RT for room temperature, min for minute (s), Toi. for toluene, EA for ethyl acetate, PE for petroleum ether, DMF for dimethylformamide, CCI ₄ for carbon tetrachloride and THF for tetrahydrofuran. The compounds mentioned in the examples and their salts are a preferred subject of the invention.

Examples

End products

1. 3-r4- (3-Cvclopentyloxy- methoxy-phenyl) -thiazot-2-vn-pyridine hydrochloride

315 mg (1.0 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 138 mg (1.0 mmol) of thionicotinamide are heated under reflux in 10 ml of ethanol for 2 hours. The mixture is concentrated, taken up in ethyl acetate and washed with dilute NaOH. The organic phase is concentrated and taken up in 10 ml of ethanol. By adding 10 drops of conc. HCI gives 181 mg (46%) of the title compound. 194 ^β C.

2. 4-f4- (3-Cvclopentyloxy-4-methoxyphenyl) thiazol-2-vn-pyridine hydrochloride

630 mg (2.0 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 280 mg (2.0 mmol) of isothionicotinamide are heated under reflux in 20 ml of ethanol for 2.5 h. The solvent is distilled off, 20 ml of 1N NaOH are added to the residue and the solution is extracted with 3 times 20 ml of ethyl acetate. The organic phase is dried over MgS0 ₄ , concentrated and the residue taken up in 10 ml of ethanol. The addition of 10 drops of concentrated hydrochloric acid gives 225 mg (29%) of the title compound. M.p. 218 ^β C (dec.).

3. 2-r4- (3-Cvclopentyloxy-4-methoxyphenyl) thiazol-2-vn-pyrazine hydrochloride

1.0 g (3.2 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 446 mg (3.2 mmol) of pyrazine-2-thiocarboxamide are mixed in 20 ml of ethanol at 60 for 2.5 h ° C stirred. The precipitated product is dried and 690 mg (61%) of the title compound of mp 129-131 ^β C. are obtained.

4. 2-r4-f3-Cvclopentyloxy-4-methoxy-phenvπ-thiazol-2-yl-methvn-pyridine dihydrochloride

800 mg (2.55 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 390 mg (2.55 mmol) of 2-pyridine thioacetic acid amide are refluxed in 15 ml of ethanol for 3 hours. The solvent is distilled off, 20 ml of water are added to the residue and the solution is extracted with 3 × 20 ml of ethyl acetate. The organic phase is dried over MgSO 4, concentrated and chromatographed on a silica column (Tol./EA = 4: 6). The residue is taken up in 10 ml of diethyl ether and mixed with ethereal HCl. This gives 790 mg (72%) of the title compound of mp. 182 C. ^β 5. 3-r4- (3-Cvclopentyloxy-4-methoxyphenyl) thiazol-2-yl-methvn-pyridine dihydrochloride

1.0 g (3.2 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 485 mg (3.2 mmol) of 3-pyridine-thioacetic acid amide are reacted analogously to Example 4 in 20 ml of ethanol. 570 mg (41%) of the title compound of mp 178-181 are obtained.

6. 4-r4-f3-Cvclopentyloxy-4-methoxy-phenylMhiazol-2-yl-methvπ-pyridine dihydrochloride

800 mg (2.55 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 390 mg (2.55 mmol) of 4-pyridine thioacetic acid amide are reacted analogously to Example 4 in 15 ml of ethanol. 540 mg (48%) of the title compound of melting point 190-194 ° C. are obtained.

7. 3- 4-r3- (2-indanyloxy) -4-methoxyphenvnthiazol-2-yl pyridine

500 mg (1.38 mmol) of α-bromo-3- (2-indanyloxy) -4-methoxy-acetophenone and 190 mg (1.38 mmol) of thionicotinamide are refluxed in 20 ml of ethanol for 1.5 hours. After the reaction solution has cooled, the precipitate is filtered off with suction and chromatographed on silica gel (tol: acetone = 9: 1). 227 mg (41%) of the title compound of mp 117-123 ^β C. are obtained.

8. Ethyl 4-r4-f3-Cvclopentyloxy-4-methoxyphenvπ-thiazole-2-vn-pyridine-2-carbonate

313 mg (1 mmol) of α-bromo-3-cyclopentyloxy-4-methoxy-acetophenone and 210 mg (1 mmol) of 2-ethoxycarbonyl-4-pyridinthiocarboxamide are dissolved in 10 ml of ethanol and mixed with 0.5 ml of triethylamine. The mixture is stirred at δO-C for 3 h. The solvent is removed in vacuo and the residue is partitioned between water and ethyl acetate. It is dried over MgS0 ₄ , concentrated and the resinous residue is crystallized from 3 ml of ethanol. There are 139 mg (31%) of the title compound of mp. 84-88 ^β C.

Starting products

A. α-Bromo-3-cvclopentyloxy-4-methoxy-acetophenone

11 g (50.0 mmol) of 3-cyclopentyloxy-4-methoxy-acetophenone and 8.4 g (100.0 mmol) of NaHC0 ₃ are placed in 100 ml of CCl ₄ and at the boiling point with 3.1 ml (60.0 mmol) of bromine in 15 ml of CCI ₄ was added dropwise with exposure. The mixture is then heated under reflux for 1 h. H ₂ 0 is added the organic phase and dries over MgS0 ₄ . After crystallization from cyclohexane, 7.3 g (47%) of the title compound of mp 60-63'C are obtained.

B. α, -Brom-3- (2-indanyloxy) -4-methoxy-acetophenone

To a mixture of 7.16 g (25.4 mmol) of 3- (2-indanyloxy) -4-methoxy-acetophenone and 4.3 g (50.7 mmol) of sodium hydrogen carbonate in 70 ml of CCI ₄ are at the boiling point and under Exposure 1.5 ml (30 mmol) of bromine was dropped in 4.5 ml of CCI ₄ . After refluxing for 30 minutes, the mixture is washed with water, dried over magnesium sulfate and concentrated. After chromatographic purification on silica gel (Toi.), 2.66 g (29%) of the title compound of mp 114 ° C. are obtained.

C. 3-Cvclopentyloxy-4-methoxy-acetophenone

157 g (0.94 mol) of 3-hydroxy-4-methoxyacetophenone, 205 ml (1.89 mol) of cyclopentyl bromide and 261 g (1.89 mol) of K ₂ CO ₃ are added in 500 ml of DMF for 1.5 hours 80 ° C stirred. Then the K ₂ C0 _{3 is} filtered off, the filtrate is evaporated down sharply and the residue is taken up in 1.0 l of diethyl ether. It is washed with 100 ml of water and 100 ml of semi-conc. HCI and neutralized the organic phase with saturated NaH-C0 ₃ solution. It is dried over MgS0 ₄ and concentrated. The cleaning is carried out by boiling the residue in 2.0 l of petroleum ether with the addition of 20 g of Tonsil (Südchemie AG Munich). After filtration, 199 g (85%) of the title compound, mp. 59-60 ° C., crystallize.

D. 3- (2-Indanyloxy) -4-methoxy-acetophenone

A solution of 10.0 g (60 mmol) of 3-hydroxy-4-methoxy-acetophenone, 10.6 g (78 mmol) of 2-indanol, 20.3 g (78 mmol) of triphenylphosphine and 11 ml (78 mmol) of diethyl azodicarboxylic acid are stirred in 900 ml of THF at RT for 1 h. After the reaction solution has been concentrated, the precipitated triphenylphosphine oxide and hydrazine-N, N'-dicarboxylic acid diethyl ester are filtered off and the mother liquor is chromatographed on silica gel (PE: EA = 8: 2). 8.88 g (52%) of the title compound of mp 120-122 ^o C. are obtained.

E. 3-Hydroxy-4-methoxy-acetophenone

1360 g (5.6 mol) of 3-chloroacetoxy-4-methoxy-acetophenone are mixed in a mixture of 3.4 I (19.2 mol) of 10% aq. NH ₃ , 1, 5 I methanol and 1, 5 I water suspended. After 2 h with 1050 ml of conc. HCl acidified, 1.0 I ethyl acetate added and stirred for 10 min. The organic phase is separated off and the aqueous phase is extracted 10 times with 500 ml of ethyl acetate each time. The combined organic phases are concentrated and the residue is suspended in 2.0 l of warm water (65 ° C.). When stirring cold in an ice bath, 157 g (93%) of the title compound, melting at 90 ° C., crystallize. F. 3-chloroacetoxy-4-methoxy-acetophenone

The synthesis of the title compound is known from the literature. Lit .: Tung et. al .; Yaoxue Xuebao 6 (1958) 164, 166; CA 1959, 14039.

G. 1-chloroacetoxy-2-methoxybenzene

The synthesis of the title compound is known from the literature. Lit .: Mannich, Drauzburg; Arch. Pharm. 250 (1912), 536.

H. Pyrazine-2-thiocarboxamide

The synthesis of the title compound is known from the literature. Lit .: Kushner et. al .; J. Amer. Chem. Soc. 74 (1952) 3617-3620.

I. 2-Pyridinthioessiqsäureamid

The synthesis of the title compound is known from the literature. Lit .: Gardner et. al .; J. Org. Chem. 19 (1954) 753.

J. 3-pyridine thioacetic acid amide

The synthesis of the title compound is known from the literature. Lit .: Gardner et. al .; J. Org. Chem. 19 (1954) 753, 755.

K. 4-Pyridinessiqsäurethioamid

L. 2-ethoxycarbonyl-4-pyridine thiocarboxamide

1.88 g (10.6 mmol) of the compound 2-ethoxycarbonyl-4-pyridinecarbonitrile are dissolved in 10 ml of pyridine and 2 ml of triethylamine. Hydrogen sulfide is passed in for 15 minutes and the mixture is left to stand at RT for 16 hours. The solvent is then removed and the residue between ethyl acetate and a sat. NaHC0 ₃ solution distributed. The separated aqueous phase is exhaustively extracted with ethyl acetate, the combined organic phases are dried over MgSO 4 and freed from the solvent. The amorphous residue is recrystallized from 20 ml of ethanol and 1.92 g (86%) of the title compound of melting point 170-172 ° C. is obtained.

M. 2-ethoxycarbonyl-4-pyridinecarbonitrile

The synthesis of the title compound is known from the literature. Lit .: G. Heinisch, G. Lötsch, Angew. Chem. 97 (1985) 694.

Industrial applicability

The compounds according to the invention have valuable pharmacological properties which make them commercially usable. As selective cyclic nucleotide phosphodiesterase (PDE) inhibitors (of type IV), they are suitable on the one hand as bronchial therapeutics (for the treatment of airway obstructions due to their dilating but also due to their respiratory rate or respiratory drive increasing effect) and for the eradication of erectile dysfunction due to the vasodilating effect, on the other hand, however, primarily for the treatment of diseases, in particular inflammatory in nature, for example the respiratory tract (asthma prophylaxis), the skin, the intestine, the eyes and the joints, which are mediated by mediators such as histamine, PAF (platelet activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines , alpha, beta and gamma interferon, tumor necrosis factor (TNF) or oxygen radicals and proteases. The compounds according to the invention are notable for low toxicity, good enteral absorption (high bioavailability), a wide therapeutic range and the absence of significant side effects.

On account of their PDE-inhibiting properties, the compounds according to the invention can be used as therapeutic agents in human and veterinary medicine, for example they can be used for the treatment and prophylaxis of the following diseases: Acute and chronic (in particular inflammatory and allergen-induced) respiratory diseases of various origins (bronchitis, allergic Bronchitis, bronchial asthma); Dermatoses (especially proliferative, inflammatory and allergic) such as psoriasis (vulgaris), toxic and allergic contact dermatitis, atopic eczema, seborrheic eczema, lying simplex, sunburn, pruritus in the genital area, alopecia areata, hypertrophic scars, discoid lupus follicular and extensive pyoderma, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin diseases; Diseases that are based on an excessive release of TNF and leukotrienes, such as diseases from the type of arthritis (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions), diseases of the immune system (AIDS, multiple sclerosis), manifestations of shock [septic Shock, endotoxin shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome)] as well as generalized inflammation in the gastrointestinal area (Crohn's disease and ulcerative colitis); Diseases based on allergic and / or chronic, immunological incorrect reactions in the area of the upper respiratory tract (throat, nose) and the adjacent regions (paranasal sinuses, eyes), such as allergic rhinitis / sinusitis, chronic rhinitis / sinusitis, allergic conjunctivitis and Nasal polyps; but also diseases of the heart that can be treated by PDE inhibitors, such as heart failure, or diseases that can be treated due to the tissue-relaxing effect of the PDE inhibitors, such as erectile dysfunction or colic Kidneys and the ureter related to kidney stones; or also diseases of the CNS, such as depression or arteriosclerotic dementia.

Another object of the invention is a method for the treatment of mammals, including humans, who are suffering from one of the abovementioned diseases. The method is characterized in that the sick mammal is administered a therapeutically effective and pharmacologically acceptable amount of one or more of the compounds according to the invention.

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

The invention also relates to the use of the compounds according to the invention for the production of medicaments which are used for the treatment and / or prophylaxis of the diseases mentioned.

The invention furthermore relates to medicaments for the treatment and / or prophylaxis of the diseases mentioned, which contain one or more of the compounds according to the invention.

The pharmaceuticals are produced by methods known per se and familiar to the person skilled in the art. The compounds according to the invention (= active ingredients) are used as pharmaceuticals either as such or preferably in combination with suitable pharmaceutical auxiliaries, e.g. in the form of tablets, dragees, capsules, suppositories, plasters, emulsions, suspensions, gels or solutions, the active ingredient content advantageously being between 0.1 and 95%.

The person skilled in the art is familiar with the auxiliaries which are suitable for the desired pharmaceutical formulations on the basis of his specialist knowledge. In addition to solvents, gel formers, ointment bases and other active substance carriers, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or permeation promoters can be used.

For the treatment of diseases of the respiratory tract, the compounds according to the invention are preferably also administered by inhalation. For this purpose, these are administered either directly as a powder (preferably in micronized form) or by atomizing solutions or suspensions containing them. With regard to the preparations and dosage forms, reference is made, for example, to the explanations in European patent 163 965.

For the treatment of dermatoses, the compounds according to the invention are used in particular in the form of those medicaments which are suitable for topical application. The compounds according to the invention (= active substances) are preferred wisely mixed with suitable pharmaceutical excipients and processed into suitable pharmaceutical formulations. Suitable pharmaceutical formulations include, for example, powders, emulsions, suspensions, sprays, oils, ointments, fatty ointments, creams, pastes, gels or solutions.

The pharmaceuticals according to the invention are produced by methods known per se. The active ingredients are dosed in the order of magnitude customary for PDE inhibitors. For example, topical forms of application (such as ointments) for the treatment of dermatoses contain the active ingredients in a concentration of, for example, 0.1-99%. The dose for inhalation is usually between 0.01 and 1 mg per spray. The usual dose for systemic therapy po or iv is between 0.1 and 200 mg per application.

Biological studies

Activation of inflammatory cells is of particular importance when studying PDE IV inhibition at the cellular level. An example is the FMLP (N-formyl-methionyl-leucyl-phenylalanine) -induced superoxide production of neutrophil granulocytes, which can be measured as luminol-enhanced chemiluminescence. (Mc Phail LC, Strum SL, Leone PA and Sozzani S, The neutrophil respiratory burst mechanism. In "Immunology Series" 57: 47-76, 1992; ed. Coffey RG (Marcel Decker, Inc., New York-Basel-Hong Kong)).

Substances which inhibit chemiluminescence and the cytokine secretion and the secretion of inflammation-increasing mediators on inflammatory cells, in particular neutrophilic and eosinophilic granulocytes, are those which inhibit PDE IV. This isoenzyme of the phosphodiesterase families is particularly represented in granulocytes. Its inhibition leads to an increase in the intracellular cyclic AMP concentration and thus to the inhibition of cellular activation. The PDE IV inhibition by the substances according to the invention is thus a central indicator for the suppression of inflammatory processes. (Giembycz MA, Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilatory therapy redundant in the treatment of bronchial asthma?. Biochem Pharmacol 43: 2041-2051, 1992; Torphy TJ et al., Phosphodiesterase inhibitors: new oppor- tunities for treatment of asthma. Thorax 46: 512-523, 1991; Schudt C et al., Zardavenne: a cyclic AMP PDE III / IV inhibitor. In "New Drugs for Asthma Therapy", 379-402, Birkhauser Verlag Basel 1991; Schudt C et al., Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Ca; Naunyn-Schmiedebergs Arch Pharmacol 344: 682-690, 1991; Nielsen CP et al., Effects of selective phosphodiesterase inhibitors on polymorphonuclear leukocyte respiratory burst. J Allergy Clin Immunol 86: 801-808, 1990; Schade et al., The specific type III and IV phosphodiesterase inhibitor zardaverine suppress formation of tumor necrosis factor by macrophages. European Journal of Pharmacology 230: 9-14, 1993).

1. Inhibition of PDE IV activity

methodology

The activity test was carried out according to the Bauer and Schwabe method, which was adapted to microtiter plates (Naunyn-Schmiedeberg's Arch. Pharmacol. 311, 193-198, 1980). The PDE reaction takes place in the first step. In a second step, the resulting 5'-nucleotide is cleaved by a 5'-nucleotidase of the snake venom from ophiophagus hannah (King Cobra) to the uncharged nucleoside. In the third step, the nucleoside is separated from the remaining charged substrate on ion exchange columns. The columns are eluted with 2 ml of 30 mM ammonium formate (pH 6.0) directly in minivials, into which 2 ml of scintillator liquid is added for counting.

The inhibition values determined for the compounds according to the invention are shown in Table 1 below, in which the numbers of the compounds correspond to the numbers of the examples.

Table 1

Inhibition of PDE IV activity

Connection -log IC ₅₀

1 7.91

2 8.06

7 7.95

FORMULA SHEET

(I)

(II)

o Y

(V)

Claims

claims

1. Compounds of the formula I

wherein

R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy, phenyl-1-4C-alkoxy, 2-indanyloxy, 2-tetrahydronaphthalinytoxy or 2-norbornanyloxy,

R3 represents hydrogen or halogen,

R43 is hydrogen, 1-4C-alkoxy, halogen or hydroxy,

R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkylcarbonyloxy, halogen, cyano or nitro, R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl, 1-4C-alkylcarbonyl, 1-4C-alkoxycarbonyl or 1-4C-alkoxy and R46 is hydrogen, halogen, 1-4C-alkoxy or 1- 4C-alkyl, n is 0, 1 or 2, where n is not 1 or 2, when R4 is phenyl, the salts of these compounds and the N-oxides of pyridines, quinolines, isoquinolines, pyrimidines, imidazoles, quinoxalines, quinazolines and Benzimidazoles and their salts.

2. Compounds of formula I according to claim 1, in which

R3 represents hydrogen or halogen,

R4 represents a phenyl ring substituted by R41 and R42 or represents a mono- or bicyclic heterocycle substituted by R44 and R45, which is selected from the group pyridine, pyrrole, quinoline, isoquinoline, indole, isoindole, indolizine, pyrimidine, pyrazine, pyridazine, py - razole, imidazole, quinoxaline, quinazoline, cinnoline, benzimidazole, oxazole, isoxazole, thiazole and isothiazole, where

R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyioxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy,

R45 is hydrogen, hydroxy, halogen, carboxyl, amino, 1-4C-alkyl or 1-4C-alkoxy, n is 0 or 1, where n is not 1 if R4 is phenyl, the salts of these compounds and the N-oxides the pyridines, quinolines, isoquinolines, pyrimidines,

Imidazoles, quinoxalines, quinazolines and benzimidazoles and their salts.

3. Compounds of formula I according to claim 1, in which

R2 is 3-7C-cycloalkoxy, 3-7C-cycloalkylmethoxy or 2-indanyloxy,

R3 means hydrogen,

R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alky! Aminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1- 4C-alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and

Salts.

4. Compounds of formula I according to claim 1, in which

R2 is 3-5C-cycloalkoxy or 2-indanyloxy,

R3 means hydrogen,

R4 represents a phenyl ring substituted by R41 and R42 or represents pyridine or pyrazine substituted by R44 and R45, where

R42 is hydrogen, hydroxy, nitro, halogen, 1-4C-alkoxycarbonyl, 1-4C-alkylcarbonyloxy, 1-4C-alkylcarbonyl, carboxyl or 1-4C-alkoxy, R44 hydrogen, carboxyl, 1-4C-alkoxycarbonyl, carbamoyl, hydroxysulfonyl, sulfamoyl, mono- or di-1-4C-alkylaminocarbonyl, mono- or di-1-4C-alkylaminosulfonyl, amino, mono- or di-1-4C- alkylamino, 1-4C-alkylcarbonylamino, hydroxy-1-4C-alkyl, hydroxy, 1-4C-alkoxy, 1-4C-alkyl, 1-4C-alkylcarbonyl, halogen or cyano and

5. Compounds of formula I according to claim 1, in which R1 is 1-4C-alkoxy,

R2 means cyclopentyloxy or 2-indanyloxy,

R3 means hydrogen,

6. Compounds of formula I according to claim 1, in which R1 is methoxy,

R2 means cyclopentyloxy or 2-indanyloxy,

R3 means hydrogen,

R4 represents pyridine or pyrazine substituted by R44, where

R44 is hydrogen or 1-4C-alkoxycarbonyl, n is 0 or 1, and the salts of these compounds.

7. Medicament containing one or more compounds according to claim 1, together with conventional pharmaceutical auxiliaries and / or carriers.

8. Compounds according to claim 1 for use in the treatment of diseases.

9. Use of compounds according to claim 1 for the manufacture of medicaments for the treatment of respiratory diseases.