Dihydrobenzofuranyl, the method of production thereof and pharmaceutical composition based on them

 

(57) Abstract:

Describes new dihydrobenzofuran General formula I, provided at the end of the description text, where R1- C1-C6-alkoxyl or completely or partly replaced by fluorine C1-C4-alkoxyl; R2- C1-C4-alkyl and R3is hydrogen or C1-C4-alkyl, or R2and R3together and including the two carbon atoms to which they are attached, form a 5-, 6 - or 7-membered carbon ring, optionally broken by oxygen atom; R4is phenyl, pyridyl, substituted radicals R41, R42and R43phenyl or substituted by the radicals R44, R45, R46and R47pyridyl, and R41- halogen or C1-C4-alkyl, R42is hydrogen, halogen or1-C4-alkyl, R43is hydrogen, halogen or1-C4-alkyl, R44- halogen or C1-C4-alkyl, R45is hydrogen or halogen, R46is hydrogen or halogen and R47is hydrogen or halogen, and salts of these compounds. They are novel effective inhibitors of phosphodiesterase (DE). Can be used for the treatment of diseases of the respiratory tract and skin. Describes how their floor new connections, used in pharmaceutical industry for the manufacture of medicines.

In the international application WO 92/12961 describes benzamide with any abscopal phosphodiesterase (PDE) properties. In the international application WO 93/25517 described tizanidine phenylpropane as a selective PDE-IV inhibitors. In the international application WO 94/02465 describes inhibitors of camp-phosphodiesterase (cycloaddition-phosphate phosphodiesterase) and TNF (tumor necrosis factor).

It was found that described in more detail below benzamide, which differs from the known prior publications compounds completely different substituents in positions 2 and 3 benzamide, have unexpected and valuable properties.

The subject of the invention is thus the compounds of formula I, provided at the end of the description text, where R1- C1-C6-alkoxy, C3-C7-cycloalkane, C3-C7-cycloalkylation, benzyloxy or completely or partly replaced by fluorine C1- C4-alkoxy, R2- C1-C4-alkyl and R3is hydrogen or C1-C4-alkyl, or R2and R3together and including the two carbon atoms to which they presidenl, pyridyl, substituted radicals R41, R42and R43phenyl or substituted by the radicals R44, R45, R46and R47pyridyl, and R41denotes hydroxy, halogen, cyano, carboxyl, trifluoromethyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxycarbonyl, C1-C4-alkylsulphonyl, C1-C4-alkylcarboxylic, amino, mono - or di-C1-C4-alkylamino or C1-C4-alkylcarboxylic, R42denotes hydrogen, hydroxy, halogen, amino, trifluoromethyl, C1-C4-alkyl or C1-C4-alkoxy, R43denotes hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy, R44hydroxy, halogen, cyano, carboxyl, C1-C4-alkyl, C1- C4-alkoxy, C1-C4-alkoxycarbonyl or amino, R45is hydrogen, halogen, amino or C1-C4-alkyl, R46is hydrogen or halogen and R47is hydrogen or halogen, and salts of these compounds and N-oxides of the pyridines and their salts.

C1-C4-alkoxy denotes a radical containing in addition an oxygen atom, a linear or branched alkyl radical with 1-6 carbon atoms. At the same time as alkyl rgtil), pencil, isopentyl (3-methylbutyl), neopentyl (2,2 - dimethylpropyl), butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

C3-C7-Cycloalkane means, for example, cyclopropane, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy or cycloheptanone, of which cyclopropylamine, cyclobutylamine, cyclopentyloxy preferred.

C3-C7-Cycloalkylation means, for example, cyclopropylmethoxy, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethoxy, cyclohexylmethoxy, of which cyclopropylmethoxy, cyclobutylmethyl, cyclopentylmethyl preferred.

As a fully or partially substituted by fluorine, C1-C4-alkoxy include, for example, 1,2,2-triptoreline, 2,2,3,3,3-pentafluoropropane, perforators and primarily 1,1,2,2 - tetrafluoroethoxy, triptoreline, 2,2,2-triptoreline, deformedarse.

As 5-, 6 - or 7-membered carbon-based ring, optionally broken by an oxygen atom should be called cyclopentane, cyclohexane, Cycloheptane, tertrahydrofuran ring and tetrahydropyrane ring. When R2and R3together, including both carbon atom to which they Ave the keel denotes a linear or branched alkyl radicals with 1-4 carbon atoms. As such radicals include, for example, butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl.

Halogen in the context of the present description denotes bromine, chlorine and fluorine.

C1-C4-alkoxy denotes a radical containing along with the oxygen atom of one of the above mentioned C1-C4-alkyl radicals. As such radicals include, for example, methoxy, ethoxy.

C1-C4-alkoxycarbonyl denotes a carbonyl group to which is attached one of the above C1-C4-CNS radicals. For example, this group can be called methoxycarbonyl (CH3O-CO-) and ethoxycarbonylphenyl (CH3CH2O-CO-) radicals.

C1-C4-Alkylsulphonyl denotes a carbonyl group to which is attached one of the above C1-C4-alkyl radicals. As such groups include, for example, acetyl radical (CH3CO-).

C1-C4-alkylcarboxylic contain along with the oxygen atom of one of the above C1-C4-alkylcarboxylic radicals. For example, you can call acetoxy (CH3CO-O-).

Kacha is ethylamino.

As C1-C4alquilervillapeniscola can be called, for example, acetylamino (-NH-CO-CH3).

As examples of substituted radicals R41, R42and R43the phenyl radicals can be called 2-acetylphenyl, 2-AMINOPHENYL, 2 - bromophenyl, 2-chlorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 4 - diethylamino-2-were, 4-bromo-2-triptoreline, 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-tryptophanyl, 2,6-dibromophenyl, 2-tianfeng, 4 - cyan-2-forfinal, 2-forfinal, 2,4-differenl, 2,6-differenl, 2-chloro-6-forfinal, 2-hydroxyphenyl, 2-hydroxy-4-methoxy-phenyl, 2,4-dihydroxyphenyl, 2-methoxyphenyl, 2,3-acid, 2,4 - acid, 2,6-acid, 2-dimethylaminophenyl, 2 - were, 2-chloro-6-were, 2,4-dimetilfenil, 2,6 - dimetilfenil, 2,3-dimetilfenil, 2-ethoxycarbonylphenyl, 2 - triptoreline, 2,6-dichloro-4-methoxyphenyl, 2,6-dichloro-4 - tianfeng, 2,6-dichloro-4-AMINOPHENYL, 2,6-dichloro-4 - ethoxycarbonylphenyl, 4-acetylamino-2,6-dichlorophenyl, 2,6 - dichloro-4-ethoxycarbonylphenyl.

As examples of substituted radicals R44, R45, R46and R47peredelnyh radicals can title the-mud, 4-chloropyrid-3-yl, 3 - chloropyrid-2-yl, 3-chloropyrid-4-yl, 2-chloropyrid-3-yl, 2,3,5,6 - tetraterpene-4-yl, 3,5-dichloro-2,6-diporphyrin-4-yl, 3,5 - dibromine-2-yl, 3,5-dibromine-4-yl, 3,5-dichlorine-4-yl, 2,6-dichlorine-3-yl, 3,5-dimethylpyridin - 4-yl, 3-chloro-2,5,6-triptorelin-4-yl and 2,3,5-triptorelin-4-yl.

As salts of the compounds of formula I - depending on the substitution can be considered all of the acid additive salt, but first of all salts with bases. Among these one should mention first of all pharmacologically acceptable salts of inorganic and organic acids and bases commonly used in Galenika. Pharmacologically unacceptable salts formed as the initial products in the process, for example when obtaining the compounds according to the invention on an industrial scale, using methods known to the person skilled in the art are translated into pharmacologically acceptable salts. As such, suitable, on the one hand, water-soluble and water-insoluble acid additive salts with such acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-Glukhova key is, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, albanova acid, stearic acid, toluensulfonate acid, methanesulfonate acid or 3-hydroxy-2-naphthoic acid, and upon receipt of salts, depending on use, whether one - or polybasic acid, and a salt is required to obtain the acid used in equimolar or in some other proportion.

On the other hand, are primarily considered salts with bases. As an example of such basic salts should be mentioned salts of lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidine, and in this case, when receiving the salt of the base used in equimolar or more different proportions.

Among the compounds of formula I it is necessary to select those in which R1- C1-C4-alkoxy, C3-C5-cycloalkane,3-C5-cycloalkylation or completely or partly replaced by fluorine C1-C4-alkoxy,

R2- C1-C4-alkyl and

R3is hydrogen or C1-C4
R4is phenyl, pyridyl, substituted radicals R41, R42and R43phenyl or substituted by the radicals R44, R45, R46and R47pyridyl, and R41- halogen, cyano, carboxyl, C1-C4-alkyl, C1-C4-alkoxy or C1-C4-alkoxycarbonyl,

R42is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy,

R43is hydrogen, halogen, C1-C4-alkyl or C1-C4-alkoxy,

R44- halogen or C1-C4-alkyl,

R45is hydrogen or halogen,

R46is hydrogen or halogen and

R47is hydrogen or halogen, and salts of these compounds and N-oxides of the pyridines and their salts.

Among the compounds of formula I may be highlighted such that

R1- C1-C4-alkoxy, C1-C4-cycloalkane, C3-C5-cycloalkylation or completely or partly replaced by fluorine C1-C4-alkoxy,

R2- C1-C4-alkyl and

R3is hydrogen or C1-C4-alkyl or

R2and R3together and including AoE or tetrahydropyrane ring,

R4- 2-bromophenyl, 2,6-dichloro-4 - ethoxycarbonylphenyl, 2,6-acid, 4-cyan-2-forfinal, 2,4,6-tryptophanyl, 2-chloro-6-were, 2,6-dimetilfenil, 2-chloro-6-forfinal, 2,6-differenl, 2,6-dichlorophenyl, 3,5-dichlorine-4 - yl, 3-methylpiperid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromine-2-yl, 3,5-diporphyrin-4-yl, 2-chlorophenyl, 2,3,5,6-tetraterpene-4-yl, 3-chloro-2,5,6 - triptorelin-4-yl, 3,5-dichloro-2,6-diporphyrin-4-yl or 2,6-dichlorine-3-yl, and the salts of these compounds and N-oxides of the pyridines and their salts.

Preferred compounds of formula I, in which

R1- methoxy, ethoxy, cyclopropylmethoxy, deformedarse, triptoreline or 2,2,2-triptoreline,

R2is methyl or ethyl and

R3denotes hydrogen or methyl, or

R2and R3together and including the two carbon atoms to which they are attached, form a cyclopentane, cyclohexane, tertrahydrofuran ring or tetrahydropyrane ring,

R4- bromophenyl, 2,6-dichloro-4 - ethoxycarbonylphenyl, 2,6-acid, 4-cyan-2-forfinal, 2,4,6-tryptophanyl, 2-chloro-6-were, 2,6-dimetilfenil, 2-chloro-6-forfinal, 2,6-differenl, 2,6-dichlorophenyl, 3,5-dichlorine-4-yl, 3-methylpiperid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromine-2-yl, 3,5-diporphyrin-4-yl, 2-chlorophenyl, 2,3,5,6 compounds, and N-oxides of the pyridines and their salts.

Particularly preferred compounds of formula I, in which

R1- methoxy, ethoxy, cyclopropylmethoxy, deformedarse, triptoreline or 2,2,2-triptoreline,

R2is methyl or ethyl and

R3is hydrogen or methyl, or

R2and R3together and including the two carbon atoms to which they are attached, form a cyclopentane, cyclohexane, tertrahydrofuran ring or tetrahydropyrane ring,

R4- 3, 5-dichlorine-4-yl, 2,6-dichlorophenyl or 2,6-differenl,

salts of these compounds and N-oxides of the pyridines and their salts.

Examples of compounds according to the invention are given in table. 1 - 8. These examples also include the salts listed in the table of connections.

The compounds of formula I, as Deputy-R2and-CH2R3not identical, are chiral compounds. Therefore, the invention includes not only the pure enantiomers and their mixtures in any ratio, including the racemates.

Another object of the invention is a method of obtaining compounds of formula I and their salts and N-oxides of the pyridines and their salts. The method is characterized in that compounds of the formula II, listed at the end of the corresponding leaving group, subjected to interaction with amines R4-NH2and that if necessary, the obtained compound of formula I transferred into their salts and/or derived pyridine transferred to the N-oxides and then, if necessary, in salt, or if necessary, the salts of compounds of formula I transferred into the free compounds.

Specialist in the art based on his knowledge and experience to know what is acceptable leaving group X. for Example, originate from the corresponding halides of the acids of formula II (X is Cl or Br). Otherwise, the interaction takes place as described, for example, in the following examples or as is obvious to a person skilled (for example as described in international application WO 92/12961).

N-oxidation is also a way well known to a person skilled in the technical field, for example, using m-chloroperoxybenzoic acid in dichloromethane at room temperature. Specialist in this field technique based on his knowledge and experience to know what the reaction conditions necessary for carrying out the method.

Isolation and purification of the substances according to the invention carried out in a known manner, for example so that the solvent distillate is estce one of the usual methods, such as column chromatography on appropriate media.

Salt is obtained by dissolving the free compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methylene chloride or chloroform, or a low molecular weight aliphatic alcohol (ethanol, isopropanol) which contains the desired acid, respectively, or to which you then add the desired acid respectively base. Salt is obtained by filtering the resultant deposition rates, deposition nerastvorim salt accession, or by evaporation of the solvent. The salts can be converted by alkalization, respectively acidification in the available connections, which again can be translated in salt. Thus pharmacologically unacceptable salts can be converted into pharmacologically acceptable salts.

The compounds of formula II can be obtained according to the General reaction scheme for the attached sheet II with formulas. For example, obtaining compounds of formula II are described in the following examples in the section "Initial connection". Other compounds of formula II can be obtained in a similar way.

Amines R4-NH2known or can be is.

Reducing CT denotes room temperature.

Examples.

The final products.

1. N-3,5-Dichloro-4-pyridylamino 2,3-dihydro-2,2-dimethyl-7 - methoxybenzophenone-4-carboxylic acid.

0,22 g of sodium hydride (80% in paraffin) are suspended in 20 ml of anhydrous tetrahydrofuran (THF) and then with stirring, added dropwise a solution of 0.5 g of 4-amino-3,5-dichloropyridine in 5 ml of abs. THF. Stirring is continued for 30 minutes and then added dropwise a solution of acid chloride 2,3-dihydro-2,2-dimethyl-7 - methoxy-benzofuran-4-carboxylic acid (obtained from 0.8 g of 2,3 - dihydro-2,2-dimethyl-7-methoxybenzophenone-4-carboxylic acid see example A1) in 10 ml of abs. THF. After 10 minutes, poured into water, the pH adjusted to 4 with 2n. HCl, extracted 3 times with ethyl acetate, the combined extracts dried over sodium sulfate and filtered. Remaining after concentration in a rotary evaporator, the oily residue chromatographic on a column of silica gel in the solvent system dichloromethane/methanol (98: 2). Chromatographically pure fractions are combined concentrated and crystallized from diethyl ether. This way obtain 0.7 g specified in the connection header with tPL140-142oC.

Analogously to example 1 from 0.55 g of sodium hydride (80% in paraffin) in 50 ml of abs. THF, 1.5 g of 4-amino-3,5-dichloropyridine in 20 ml of abs. THF and 2.5 g of the acid chloride 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'- cyclopentane-4-carboxylic acid get 1.4 g specified in the connection header with tPL168-170oC (from diethyl ether).

3. N-3,5-Dichloro-4-pyridylamino 7 deformedarse-2,3-dihydro - benzofuran-2-Spiro-1'-cyclopentane-4-carboxylic acid.

Analogously to example 1 from 0.15 g of sodium hydride (80% in paraffin) in 20 ml of abs. THF, 0,41 g of 4-amino-3,5-dichloropyridine in 10 ml of abs. THF and a solution of the acid chloride 7 deformedarse-2,3 - dihydrobenzofuran-2-Spiro-1'-cyclopentane-4-carboxylic acid (obtained from 0.7 g of 7-deformedarse-2,3-dihydrobenzofuran-2 - Spiro-1'-cyclopentane-4-carboxylic acid see example B1) in 10 ml of abs. THF after chromatography (silica gel, solvent system: ethyl acetate/petroleum ether 4:6) to obtain 0.15 g specified in the connection header with tPL152-153oC (from diisopropyl ether).

4. N-3,5-Dichloro-4-pyridylamino 2,3-dihydro-7 - methoxybenzophenone-2-Spiro-1'-cyclohexane-4-carboxylic acid.

Analogously to example 1 from 0,46 g of sodium hydride (80% in paraffin) in 20 ml of abs. THF, 1.24 g of 4-amino-3,5-karbonovoi acid (obtained from 2 g of 2,3-dihydro-7-methoxybenzophenone - 2-Spiro-1'-cyclohexane-4-carboxylic acid, see example 1) in 20 ml of abs. THF obtain 2.9 g specified in the connection header with tPL169-170oC.

5. N-3,5-Dichloro-4-pyridylamino 2,3-dihydro-7 - methoxybenzophenone-2-Spiro-1'-(4'-oxocyclohexyl)-4-carboxylic acid.

Analogously to example 1 from 0,22 g of sodium hydride in 40 ml of abs. THF, and 0.62 g of 4-amino-3,5-dichloropyridine in 20 ml of abs. THF and a solution of the acid chloride 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'-(4'- oxocyclohexyl)-4-carboxylic acid (obtained from 1 g of 2,3 - dihydro-7-methoxybenzophenone-2-Spiro-1'-(4'-oxocyclohexyl)-4 - carboxylic acid, see example 1) in 10 ml of abs. THF obtain 0.3 g specified in the connection header with tPL208-210oC.

6. N-3,5-Dichloro-4-pyridylamino 2,2-diethyl-2,3-dihydro-7 - methoxybenzophenone-4-carboxylic acid.

Analogously to example 1 from 0.3 g of sodium hydride (80% in paraffin) in 20 ml of abs. THF, 0.8 g of 4-amino-3,5-dichloropyridine in 10 ml of abs. THF and a solution of acid chloride of 2,2-diethyl - 2,3-dihydro - 7-methoxybenzophenone-4 - carboxylic acid (obtained from 1.2 g of 2,2-diethyl-2,3-dihydro-7 - methoxybenzophenone-4-carboxylic acid see example E1) in 20 ml of THF after chromatography (silica gel, dichloromethane/methanol 98:2) to obtain 0.9 g specified in the connection header with tPL171-172oC.

8. 2,6-Difterence 2,3-dihydro-7 - methoxybenzophenone-2-Spiro-1'-cyclopentane-4-carboxylic acid.

Analogously to example 7 from 0,65 ml of 2,6-diferencia, 0.9 ml of triethylamine and the acid chloride 2,3-dihydro - 7-methoxybenzophenone - 2 - Spiro-1' - cyclopentane-4-carboxylic acid (obtained from 1.5 g of carboxylic acid, see example A1) receive 1.2 g specified in the connection header with tPL142-145oC (from diisopropyl ether).

The original connection.

A1. Loranger benzofuran-4-carboxylic acid is boiled in a mixture of 50 ml of abs. toluene and 3 ml of thionyl chloride for 1 h under reflux. The solvent is distilled off on a rotary evaporator and then add another two portions of toluene (30 ml) and again concentrated. The residue is dried in high vacuum and used without further purification in example 1.

A2. 2,3-Dihydro-2,2-dimethyl-7-methoxybenzophenone-4-carboxylic acid.

5.5 g of methyl ester of 2,3-dihydro-2,2-dimethyl-7-methoxybenzophenone-4 - carboxylic acid is stirred in a mixture of 150 ml of ethanol and 50 ml of 2n. NaOH for 2 h at 60oC. the Ethanol is distilled off, the residue is dissolved in water and the pH adjusted to 4 with 2n. HCl. Drop down in the precipitated product is filtered under vacuum, washed with water and dried. In this way receive 4.7g specified in the connection header with tPL147-149oC.

A3. Methyl ester of 2,3 - dihydro-2,2-dimethyl-7-methoxybenzophenone-4-carboxylic acid.

15.6 g of methyl ester of 3-hydroxy-4-methoxy-2-(2-methyl-2 - propenyl)benzoic acid are dissolved in 250 ml of abs. dichloromethane and the solution is mixed with 3 ml of concentrated sulfuric acid. The mixture is stirred for 12 h at RT, then mixed with water and the addition of 2n. NaOH pH value was adjusted in the aqueous phase to 5. After separation organically balance chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether (4:6). Chromatographically pure fractions of product with Rf~ 0,6 unite and concentrate. This way obtain 6.6 g specified in the connection header with tPL65-67oC.

A4. Methyl ester of 3-hydroxy-4-methoxy-2-(2-methyl-2-propenyl)benzoic acid.

20 g of methyl ester 4-methoxy-3-(2-methyl-2 - propenyloxy)benzoic acid are dissolved in 60 ml of quinoline, and the mixture is heated for 2 h to 180-190oC. After cooling, mixed with ethyl acetate and extracted with quinoline 2n. the hydrochloric acid. The organic phase is twice washed with water and concentrated. The oily residue chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether (4:6). Chromatographically pure fractions are combined concentrated and dried in high vacuum. This way obtain 15.6 g specified in the connection header in the form of light yellow oil.

A5. Methyl ester of 4-methoxy-3-(2-methyl-2 - propenyloxy)benzoic acid.

22 g of methyl ester of 3-hydroxy-4-methoxybenzoic acid are dissolved in 200 ml of anhydrous dimethylformamide (DMF) and then to the solution was added 41 g of crushed potassium carbonate and 14.7 ml of 3 - chloro-2-methylpropene. The mixture is stirred for 5 h at 60oohms. Formed after concentration of the extracts, the residue is crystallized from petroleum ether. So by getting 21 grams specified in the connection header with tPL62-63oC.

B1. The acid chloride 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'- cyclopentane-4-carboxylic acid.

Specified in the header connection receive similar way to the original connection A1 of 2,3-dihydro-7-methoxybenzophenone-2 - Spiro-1'-cyclopentane-4-carboxylic acid in 50 ml of abs. toluene and 3 ml of thionyl chloride and used without additional purification in subsequent reactions.

B2. 2,3-Dihydro-7-methoxybenzophenone-2-Spiro-1'-cyclopentane-4 - carboxylic acid.

2.6 g of methyl ester of 2,3-dihydro-7-methoxybenzophenone-2 - Spiro-1'-cyclopentane-4-carboxylic acid omelet analogously to example A2 in 50 ml of ethanol and 10 ml of 2n. NaOH. This way obtain 2.3 g specified in the connection header with tPL166-168oC.

B3. Methyl ester of 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'- picopeta-4-carboxylic acid.

10.2 g of methyl ester of 2-cyclopenten-1-ylmethyl-3-hydroxy-4 - methoxybenzoic acid are dissolved in 500 ml of anhydrous n-hexane and mixed with approximately 5 g of amberlyst 15. The mixture is stirred for 3 Stela ethyl acetate/petroleum ether (4:6), chromatographically pure fractions are combined concentrated and dried in high vacuum. This way obtain 7.2 g specified in the title compound as a yellow oil.

B4. Methyl ester 2-cyclopenten-1-ylmethyl-3-hydroxy-4 - methoxybenzoic acid.

12.7 g of methyl ester of 3-(2-methylenecyclopropane)-4 - methoxybenzoic acid mixed with 50 ml of quinoline, and the mixture is stirred for 1 h at 190oC. After cooling, mixed with water, the pH using a 2H. HCl set to 3 and extracted with ethyl acetate. Formed after concentration of the solvent the residue chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether (4:6). Khromatograficheskii pure fractions are concentrated and dried in high vacuum. This way obtain 10.2 g specified in the title compound as a yellow oil.

B5. Methyl ester 3-(2-methylenecyclopropane)-4 - methoxybenzoic acid.

28.5 g of methyltriphenylphosphonium suspended in 300 ml of anhydrous THF under nitrogen atmosphere and the mixture cooled to -40oC. Then, with stirring, added dropwise 50 ml of n-utility (1.6 M in n-hexane. After stirring for 30 min at temperatures of the Oh of the acid in 100 ml of abs. THF. The mixture is allowed to warm to CT and stirred for 1 h was Poured onto water and extracted with ethyl acetate. Remaining after concentration of the organic phase oil chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether (4:6). Chromatographically pure fractions are combined concentrated and dried in high vacuum. This way obtain 12.7 g specified in the title compounds as colorless oils.

B6. Methyl ester of 4-methoxy-3-(2-oxocyclopent)benzoic acid.

of 23.8 g of methyl ester of 3-hydroxy-4-methoxybenzoic acid are dissolved in 200 ml of anhydrous DMF and the solution is mixed with 35 g (crushed) of potassium carbonate and 13 ml of 2-chlorocyclopentane. The mixture is stirred for 3 h at 60oC, then filtered off under vacuum from the solids and the filtrate concentrated in vacuo. The remainder chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether (4:6). Chromatographically pure fractions are combined concentrated and dried in high vacuum. In this way receive 24,3 g specified in the title compound as a pale yellow oil.

B1. The acid chloride 7 deformedarse-2,3 - dihydro-dihydrobenzofuran - 2-Spiro-1'-cyclopentane-4-carboxylic acid is subjected to interaction in a mixture of 20 ml of abs. toluene and 2 ml of thionyl chloride and without additional purification is subjected to further processing.

B2. 7 deformedarse-2,3 - dihydrobenzofuran-2-Spiro-1'-cyclopentane - 4-carboxylic acid.

Analogously to example A2 of 2.4 g of ethyl ester of 7-deformedarse-2,3 - dihydrobenzofuran-2-Spiro-1'- cyclopentane-4-carboxylic acid get 2 g specified in the connection header with tPL143-145oC.

B3. Ethyl ester of 7 - deformedarse-2,3-dihydrobenzofuran-2-Spiro-1'-cyclopentane-4 - carboxylic acid.

2.7 g of ethyl ester of 2,3-dihydro-7 - hydroxybenzophenone-2-Spiro-1'-cyclopentane-4-carboxylic acid are dissolved in 70 ml of dioxane, add 3 ml of 50% NaOH solution and 0.1 g of benzyltrimethylammonium and then into the mixture with stirring and at a temperature of 70-75oC enter diperchlorate until the end of the reaction (about 1 hour). After cooling, is poured on water and extracted 3 times with portions of ethyl acetate, 100 ml After drying over sodium sulfate concentrated and the residue chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether (4:6). Chromatographically pure fractions are combined concentrated and dried in high vacuum. This way obtain 2.4 g of ukazannogo-2-Spiro - 1'-cyclopentane-4-carboxylic acid.

4.1 g of ethyl ester of 7-benzyloxy-2,3-dihydrobenzofuran-2 - Spiro-1'-cyclopentane-4-carboxylic acid, 0.5 g of Pd/C (10%) and 20 ml of cyclohexane for 4 h refluxed in 100 ml of toluene. After cooling, filtered and the filtrate concentrated to dryness. This way obtain 2.7 g specified in the title compound as light brown oil.

B5. Ethyl ester of 7-benzyloxy-2,3 - dihydrobenzofuran-2 - Spiro-1'-cyclopentane - 4-carboxylic acid.

10 g of a mixture of methyltriphenylphosphonium and sodium amide (FLUKA 69500) are suspended in 100 ml of abs. THF under nitrogen atmosphere and stirred for 0.5 h at RT. Then within 30 minutes added dropwise a solution of 7 g of ethyl ester of 4-benzyloxy-3-(2 - oxacyclopentane)benzoic acid in 20 ml of abs. THF. Stirred for 2 h at RT, then poured on water and extracted 3 times with portions of etelaat 100 ml After drying over sodium sulfate concentrated to dryness. To rearrange the oil balance for 1.5 h and stirred at 190oC. After cooling, mixed with 100 ml of toluene, add 10 g of amberlist 15 (anhydrous) and the mixture for 3 h and stirred at 80oC. then filtered, optionally washed with methanol and the filtrate con is Romany ether 4:6. Fractions with the main product (Rf= ~0,8) are combined, concentrated and dried in high vacuum. This way obtain 4.1 g specified in the title compound as a pale yellow oil.

B6. Ethyl ester of 4-benzyloxy-3-(2 - oxacyclopentane)benzoic acid.

Analogously to example B6 34 g of ethyl ester of 4-benzyloxy-3 - hydroxybenzoic acid, 35 g of potassium carbonate and 15 ml of 2 - chlorocyclopentane receive 36 g specified in the title compounds as colorless oils.

G1. The acid chloride 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'- cyclohexane-4-carboxylic acid.

Analogously to example A1 2 g of 2,3-dihydro-7-methoxybenzophenone-2 - Spiro-1'-cyclohexane-4-carboxylic acid in 50 ml of toluene are subjected to interaction with 5 ml of thionyl chloride.

G2. 2,3-Dihydro-7-methoxybenzophenone-2-Spiro-1'-cyclohexane - 4-carboxylic acid.

Analogously to example A1 of 10.3 g of methyl ester of 2,3-dihydro - 7-methoxybenzophenone - 2-Spiro-1'-cyclohexane - 4-carboxylic acid get 9 g specified in the connection header with tPL171-173oC.

G3. Methyl ester of 2,3-dihydro-7-methoxybenzophenone-2-Spiro - 1'-cyclohexane-4-carboxylic acid.

Analogously to example B3 of 17 g m is 15 (4 h at 60oC) obtain 10.3 g specified in the title compound as a yellow oil.

G4. Methyl ester 2-cyclohexen-1-ylmethyl-3-hydroxy-4 - methoxybenzoic acid.

Analogously to example B4 of 21 g of methyl ester of 3-(2 - methyltrichlorosilane)- 4-methoxybenzoic acid (reaction for 2 h at 190oC) obtain 17 g specified in the title compound as a yellow oil.

G5. Methyl ester 3-(2-methyltrichlorosilane)-4 - methoxybenzoic acid.

43,8 g methyltriphenylphosphonium in 300 ml of abs. dimethoxyethane mixed portions in a nitrogen atmosphere with 3.6 g of sodium hydride (80% in paraffin). The mixture is stirred for 1 h at RT and then slowly added dropwise thereto a solution of 30 g of methyl ester 4-methoxy-3-(2-oxocyclohexyl)benzoic acid. The mixture is left overnight stirring at RT, after which it is treated analogously to example B5. So by getting 21 grams specified in the title compounds as colorless oils.

G6. Methyl ester of 4-methoxy-3-(2 - oxocyclohexyl)benzoic acid.

Analogously to example B6 of 25 g of methyl ester of 3-hydroxy-4 - methoxybenzoic acid, 41 g of potassium carbonate and 17.5 ml of 2 - chlorocyclohexanone in grid 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'- (4'-oxocyclohexyl)-4-carboxylic acid.

Analogously to example A1, 1 g of 2,3-dihydro-7-methoxybenzophenone-2 - Spiro-1'-(4'-oxocyclohexyl)-4-carboxylic acid is subjected to interaction in a mixture of 50 ml toluene and 5 ml of thionyl chloride and then processed without further purification.

2. 2,3-Dihydro-7-methoxybenzophenone-2-Spiro-1'-(4'- oxocyclohexyl)-4-carboxylic acid.

Analogously to example A2 1.3 g of methyl ester of 2,3-dihydro-7 - methoxybenzophenone-2-Spiro-1'-(4'-oxocyclohexyl)-4-carboxylic acid omelet in a mixture of 50 ml of methanol and 10 ml of 1N. caustic soda. In this way receive 1 g specified in the connection header with tPL194-196oC.

D3. Methyl ester of 2,3-dihydro-7-methoxybenzophenone-2-Spiro-1'- (4'-oxocyclohexyl)-4-carboxylic acid.

3.6 g of methyl ester of 4-methoxy-3-(4-methylentetrahydrofolate - 3-yloxy)benzoic acid are dissolved in 50 ml of quinoline and stirred for 1 h at 190-200oC. After cooling, poured into water, the pH value is set using a 2H. hydrochloric acid for 3 and extracted three times with ethyl acetate. After drying over sodium sulfate concentrated in vacuo to dryness and the residue (2.9 g) was dissolved in 150 ml of n-hexane. The solution is mixed with 2.9 g of amberlyst 15 and intensively stirred for 4 h at 60o

D4. Methyl ester of 4-methoxy-3-(4-methylentetrahydrofolate-3 - yloxy)benzoic acid.

18,2 g methyltriphenylphosphonium suspended in 200 ml of dimethoxyethane in nitrogen atmosphere and then portions add 1.5 g of sodium hydride (80% in paraffin). The mixture is stirred for 3 h at RT and then added dropwise within 30 minutes, add a solution of 13 g of methyl ester 4-methoxy-3-(4-oxitetraciclina-3 - yloxy)benzoic acid. This mixture is stirred overnight, then poured onto water and extracted three times with ethyl acetate. After drying over sodium sulfate concentrated in vacuo and the residue chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether 4:6. Chromatographically pure fractions are combined concentrated and dried in high vacuum. This way obtain 3.6 g specified in the title compound as a pale yellow oil.

D5. Methyl ester of 4-methoxy-3-(4-oxitetraciclina-3 - yloxy)benzoic acid.

Analogously to example B6 out of 36.4 g of methyl ether is 11.5g specified in the title compound as a pale yellow oil.

E1. The acid chloride of 2,2-diethyl-2,3-dihydro-7-methoxybenzophenone-4 - carboxylic acid.

Analogously to example A1 1.2 g of 2,2-diethyl-2,3-dihydro-7-methoxybenzophenone-4 - carboxylic acid is subjected to interaction in a mixture of 10 ml of toluene and 2 ml of thionyl chloride.

E2. 2,2-Diethyl-2,3-dihydro-7 - methoxybenzophenone-4-carboxylic acid.

1.5 g of methyl ester of 2,2-diethyl-2,3-dihydro-7 - methoxybenzophenone-4-carboxylic acid omelet analogously to example A2 in a mixture of 20 ml ethanol and 5 ml of 2n. sodium hydroxide and subjected to further processing. In this way receive 1.2 g specified in the connection header with tPL152-154oC.

E3. Methyl ether of 2,2-diethyl-2,3-dihydro-7 - methoxybenzophenone-4-carboxylic acid.

10 g of a mixture of methyltriphenylphosphonium with Amida sodium (FLUKA 69500) is injected at a temperature of about 10oC in an atmosphere of protective gas (nitrogen) in 100 ml of abs. THF, heated to CT and stirred for about 30 minutes Then added dropwise a solution of 5.3 g of methyl ester 4-methoxy-3-(1-methyl-2-oxobutanoic)benzoic acid. Stirred for 1 h at RT, then poured into water and extracted three times with portions of ethyl acetate approximately 50 ml combined extracts dried over sodium sulfate, 190-200oC, cooled and dissolved in 100 ml of toluene. The solution is mixed with 5 g of amberlyst 15 and intensively stirred over night at 80oC. Then filtered, concentrated and the residue chromatographic on a column of silica gel in the solvent system ethyl acetate/petroleum ether 4:6. Chromatographically pure fractions are combined concentrated and the residue is dried in high vacuum. In this way receive 1.5 g specified in the title compound as a pale yellow oil.

E4. Methyl ester of 4-methoxy-3-(1-methyl-2 - oxobutanoic)benzoic acid.

Analogously to example B6 out of 48.5 g of methyl ester of 3-hydroxy - 4-methoxybenzoic acid, 83 g of potassium carbonate and 43.9 g of 2 - bromantan-3-one in 200 ml of DMF obtain 68 g specified in the connection header with tPL63-65oC (thorough stirring with petroleum ether).

Industrial applicability.

Compounds according to the invention have valuable pharmacological properties, thanks to which they can find industrial application. As inhibitors of cyclic nucleotide phosphodiesterase (namely, type IV) they, on the one hand, suitable as bronchial therapeutics (for the treatment of obstruction is responsible in stimulating the breathing action), on the other hand, are primarily for the treatment of diseases, in particular inflammatory nature, e.g. of the Airways (prevention of asthma), skin, intestines, eyes and joints, mediated by mediators such as histamine, TAF (thrombocytapheresis factor), derivatives of arachidonic acid, such as leukotrienes and prostaglandins, cytokines, interleukins from IL-1 to IL-12, alpha-, beta - and gamma-interferon, tumor necrosis factor (TNF) or oxygen radicals and proteases. In this connection according to the invention differ little toxicity, good enteral resorption (high bioavailability), a wide range of therapeutic action and the absence of significant side effects.

Due to their PDE-inhibiting properties, the compounds according to the invention can be used in medicine and veterinary medicine as therapeutic agents, for example for the treatment and prevention of the following diseases: acute and chronic (in particular inflammatory and caused by allergen) diseases of the respiratory tract of various origins (bronchitis, allergic bronchitis, bronchial asthma); dermatoses (especially of proliferative, inflammatory and allergies the Skye eczema, seborrheic eczema, simple chronic shingles, sunburn, skin itch in genitoanal region, krugovidnoe baldness, hypertrophic scars, discoid lupus erythematosus, follicular and superficial pyoderma, endogenous and exogenous acne, acne rosacea and other proliferative, inflammatory and allergic skin disorders; disorders associated with excessive secretion of TNF (tumor necrosis factor) and leukotrienes, such as a disease with manifestations of arthritis (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions), disorders of the immune system (AIDS), forms of shock (septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, and respiratory distress syndrome in adults (rdsw)), and also generalized inflammations in the gastrointestinal region (Crohn's disease and ulcerative colitis); disorders associated with allergic and/or chronic, immunological abnormal responses in the upper respiratory tract (nasopharynx) and the adjacent regions (paranasal cavities of the nose, eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic, conjuncti the Naya failure; or diseases that can be treated through tenerissimo the action of the PDE inhibitors, such as renal colic and colic in the ureters in connection with kidney stones; or diseases of the Central nervous system such as depression or arteriosclerotic dementia.

Another object of the invention is a method of treating mammals, including humans, suffering from one of these diseases. The method differs in that the patient is administered to a mammal a therapeutically effective and pharmacologically acceptable amount of one or more compounds according to the invention.

Another subject of the invention are compounds according to the invention, intended for use in the treatment and/or prevention of the mentioned diseases.

The invention also relates to the use of compounds according to the invention for the manufacture of drugs used in the treatment and/or prevention of the mentioned diseases.

Further subject of the invention is a medicinal product for the treatment and/or prevention of the mentioned diseases, containing one or more compounds according to the invention.

Medicines projectors, the TV connection izobreteniya (= active substance) used either individually or preferably in combination with suitable for this purpose pharmaceutical auxiliary substances, for example in the form of tablets, pills, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, and content of active substance is preferably from 0.1 to 95%.

Specialist in the art based on his knowledge and experience is well known, any excipients suitable for the required formulations of medicines. Along with solvents, geleobrazovanie, the basics of ointments and other media of the active substance can be applied, for example, antioxidants, dispersants, emulsifiers, preservatives, agents, solubility or activators of penetration.

For the treatment of diseases of the respiratory tract, the compounds according to the invention is preferably used as the method of inhalation. To this end they are administered either directly in the form of a powder (preferably in micronized form), or by aerosol spray containing solutions or suspensions. More preparation and dosage forms described in European application 163965.

For the treatment of dermatoses compounds according to the invention are used in h is arctonyx means of connection according to the invention (= active substance) is preferably mixed with appropriate pharmaceutical excipients and processed in the appropriate dosage forms. As a suitable dosage forms include, for example, powders, emulsions, suspensions, aerosols, oils, ointments, fatty ointments, creams, pastes, gels or solutions.

Medicinal product according to the invention are produced by known methods. The dosage of active substances is of the order quantities, the usual PDE-inhibitors. Thus, dosage forms for topical use (for example, ointment) for the treatment of dermatoses contain active substances, for example, in a concentration of from 0.1 to 99%. Dose for inhalation use typically contains from 0.01 to 0.5 mg/kg the Usual dose for systemic therapy ranges from 0.05 to 2 mg/kg / day.

Biological studies.

When studying the inhibition of phosphodiesterase type IV (PDE IV) at the cellular level is of particular importance activation of inflammatory cells. As an example, should be called induced by N-formyl-methionyl-leucyl-phenylalanine (FMLP) production of peroxide neutrophilic granulocytes, which can be measured as reinforced lyuminola chemiluminescence method (McPhail L. C. , Strum S. L., Leone, P. A. and S. Sozzani, The neutrophil respiratory burst mechanism in Immunology Series 57: 47-76, 1992; edited by Coffey R. G. (Marcel Decker, Inc., New York-Basel-Hong Kong)).

Substances that suppress hemoglobine the particular neutrophilic and eosinophilic granulocytes, are substances that inhibit PDE IV. This enzyme family of phosphodiesterase is presented primarily in granulocytes. Its inhibition leads to increased intracellular concentrations of cyclic AMP and thus to the suppression of cell activation. Thus, inhibition of PDE IV substances according to the invention is the main indicator of the suppression of inflammatory processes (Giembycz, M. A. , Could isoenzyme-selective phosphodiesterase inhibitors render bronchodilatory therapy redundant in the treatment of bronchial asthma? in Biochem Pharmacol 43: 2041-2051, 1992; T. J. Torphy et al., Phosphodiesterase inhibitors: new opportunities for treatment of asthma. Thorax 46: 512-523, 1991; Schudt C. et al., Zardaverme: a cyclic AMP PDE III/IV inhibitor in "New Drugs for Asthma Therapy", 379-402, Birkhaeuser Verlag Basel 1991; Schudt C. et al., Influence of selective phosphodiesterase inhibitors on human neutrophil functions and levels of cAMP and Cai, Naunyn - Schmiedebergs Arch Pharmacol 344: 682-690, 1991; Nielson C. P. 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 suppresses formation of tumor necrosis factor by macrophages, European Journal of Pharmacology 230: 9-14, 1993).

Inhibition of the activity of PDE IV.

Method.

The test activity was carried out according to the method of Bauer and Schwab, modified for titration microplate (Naunyn-Schmie - deberg''s Arch. Pharmacol. 311, 193-198, 1980). At first stao the venom of Ophiophagus hannah (king Cobra) to uncharged nucleoside. In the third stage, the nucleoside is separated on ion-exchange columns from residual charged substrate. Column elute two ml of 30 mm ammonium formate (pH 6,0) directly in minneapoli, add 2 ml of scintillation fluid for counting of radioactivity.

The numerical values of inhibition, defined for compounds according to the invention (the numbers of the compounds correspond to the numbers of examples).

Inhibition of the activity of PDE IV.

Connection-log IC50< / BR>
1 - of 8.47

2 - 9,42

3 - 9,87

4 is a 9.09

5 - 8,57

6 - 8,63

7 - 8,57

8 - 8,42 e

1. Dihydrobenzofuran General formula I

< / BR>
where R1- C1-C6-alkoxyl or completely or partly replaced by fluorine1-C4-alkoxyl;

R2- C1-C4-alkyl;

R3is hydrogen or C1-C4-alkyl, or R2and R3together and including the two carbon atoms to which they are attached, form a 5-, 6 - or 7-membered hydrocarbon ring, optionally broken by oxygen atom;

R4is phenyl, pyridyl, substituted radicals R41, R42and R43phenyl or substituted by the radicals R44, R45, R461-C4-alkyl, R43is hydrogen, halogen or1-C4-alkyl, R44- halogen or C1-C4-alkyl, R45is hydrogen or halogen, R46is hydrogen or halogen and R47is hydrogen or halogen,

as well as salts of these compounds.

2. The compounds of formula I on p. 1, where R1- C1-C4-alkoxyl or completely or partly replaced by fluorine1-C4-alkoxyl, R2- C1-C4-alkyl and R3is hydrogen or C1-C4-alkyl, or R2and R3together and including the two carbon atoms to which they are attached, form a cyclopentane, cyclohexane, tertrahydrofuran ring or tetrahydropyrane ring, R4is phenyl, pyridyl, substituted radicals R41, R42and R43phenyl or substituted by the radicals R44, R45, R46and R47pyridyl, and R41- halogen or C1-C4-alkyl, R42is hydrogen, halogen or1-C4-alkyl, R43is hydrogen, halogen or1-C4-alkyl, R44- halogen or C1-C4-alkyl, R45is hydrogen or halogen, R46is hydrogen or halogen and R47is hydrogen or halogen, and salts of these compounds.

3. Link>
-C4-alkoxyl, R2- C1-C4-alkyl and R3is hydrogen or C1-C4-alkyl, or R2and R3together and including the two carbon atoms to which they are attached, form a cyclopentane, cyclohexane, tertrahydrofuran ring or tetrahydropyrane ring, R4- 2-bromophenyl, 2,4,6-tryptophanyl, 2-chloro-6-were, 2,6-dimetilfenil, 2-chloro-6-forfinal, 2,6-differenl, 2,6-dichlorophenyl, 3,5-dichlorine-4-yl, 3-methylpiperid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromine-2-yl, 3,5-diporphyrin-4-yl, 2-chlorophenyl, 2,3,5,6-tetraterpene-4-yl, 3-chloro-2,5,6-triptorelin-4-yl, 3,5-dichloro-2,6-diporphyrin-4-yl or 2,6-dichlorine-3-yl, and the salts of these compounds.

4. The compounds of formula I on p. 1, where R1- methoxy, ethoxy, deformedarse, triptoreline or 2,2,2-triptoreline, R2is methyl or ethyl and R3is hydrogen or methyl, or R2and R3together and including the two carbon atoms to which they are attached, form a cyclopentane, cyclohexane, tertrahydrofuran ring or tetrahydropyrane ring, R4- 2-bromophenyl, 2,4,6-tryptophanyl, 2-chloro-6-were, 2,6-dimetilfenil, 2-chloro-6-forfinal, 2,6-differenl, 2,6-dichlorophenyl, 3,5-dichlorine-4-yl, 3-methylpiperid-2-yl, 2-chloropyrid-3-yl, 3,5-dibromopyridin-4-yl or 2,6-dichlorine-3-yl, as well as salts of these compounds.

5. The compounds of formula I on p. 1, where R1- methoxy, ethoxy, cyclopropylmethoxy, deformedarse, triptoreline or 2,2,2-triptoreline, R2is methyl or ethyl and R3is hydrogen or methyl, or R2and R3together and including the two carbon atoms to which they are attached, form a cyclopentane, cyclohexane, tertrahydrofuran ring or tetrahydropyrane ring, R4- 3,5-dichlorine-4-yl, 2,6-dichlorophenyl or 2,6-differenl, as well as salts of these compounds.

6. The method of obtaining compounds of formula I on p. 1 or their salts, characterized in that compounds of the formula II

< / BR>
where R1-R3are specified in paragraph 1 values;

X is an appropriate leaving group,

subjected to interaction with the amine of formula III

R4-NH2,

where R4matter specified in paragraph 1,

and, if necessary, the obtained compound of formula I transferred into their salts, or, if necessary, the salts of compounds of formula I transferred into the free compounds.

7. Drugs having inhibitory action against cyclooctatetraenes type IV containing one Ilmi.

8. Connection on p. 1 having inhibitory action against cyclooctatetraenes type IV.

9. Connection on p. 1 having inhibitory action against cyclooctatetraenes type IV for the treatment of respiratory diseases.

10. Connection on p. 1 having inhibitory action against cyclooctatetraenes type IV for the treatment of dermatoses.

 

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