Derivatives 2,8-disubstituted of hintlian or their salts, the pharmaceutical composition affecting the level cgmp and camp activity based on them

 

(57) Abstract:

Proposed new derivatives of 2,8-disubstituted of hintlian General formula (I), where a is oxiranyl, unsubstituted or substituted linear or branched alkyl with 1-8 carbon atoms, unsubstituted or substituted phenyl or a radical of the formula PA-PS, where R1is hydrogen or a linear or branched alkyl with 1-6 carbon atoms, R2- linear or branched alkyl with 1-8 carbon atoms, unsubstituted or substituted phenyl; R3- linear or branched alkyl with 1-5 carbon atoms or a group of the formula OR6where R6- linear or branched alkyl with 1-5 carbon atoms; R4- linear or branched alkyl with 2 to 10 carbon atoms, unsubstituted or substituted by phenyl, L is a radical of the formula-CO-, -CH(OH)-, -CH2-, -CH(N3or-CH(OSO2R7), where R7- linear or branched alkyl with 1-4 carbon atoms; R5- linear or branched alkyl with 3 to 8 carbon atoms, unsubstituted or substituted by phenyl, benzyl or 2-phenylethyl; D is hydrogen or a group of the formula - SO2-NR8R9, R8and R9together with the nitrogen atom form morpholino ring; F is linear or branched alkyl with 1-8 the position based on them, with the above mentioned activity. 2 S. and 2 C.p. f-crystals, 1 PL.

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The invention relates to new nitrogen-containing heterocyclic compounds with valuable pharmacological properties, in particular a derivative of 2,8-disubstituted of hintlian or their salts and pharmaceutical compositions affect the level cGMP and camp activity based on them.

From the application WO 93/12095 known derivatives of hintlian possessing biological activity, in particular affecting the level cGMP and camp activity.

Object of the invention is the expansion of the range of the derivative of hintlian possessing biological activity, in particular affecting the level cGMP and camp activity.

The problem is solved derived 2,8-disubstituted of hintlian General formula (I)

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where A is oxiranyl, unsubstituted or substituted linear or branched alkyl with 1-8 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

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where R1is hydrogen or a linear or branched alkyl with 1-6 carbon atoms,

R2- linear or branched alkyl with 1-8 carbon atoms, unsubstituted of July-OR6where R6means a linear or branched alkyl with 1-5 carbon atoms,

R4- linear or branched alkyl with 2 to 10 carbon atoms, unsubstituted or substituted phenyl,

L is a radical of the formula-CO-, -CH(OH), -CH2, -CH(N3or-CH(OSO2R7), where R7means a linear or branched alkyl with 1-4 carbon atoms,

R5- linear or branched alkyl with 3 to 8 carbon atoms, unsubstituted or substituted by phenyl, benzyl or 2-phenylethyl,

D is hydrogen or a group of the formula - SO2-NR8R9where R8and R9together with the nitrogen atom form morpholino ring,

E is a linear or branched alkyl with 1-8 carbon atoms, or their salts.

Preferred salts are physiologically tolerated salts with organic or inorganic acids. Preferably use salts with inorganic acids such as, for example, hydrochloric acid, Hydrobromic acid, phosphoric acid or sulfuric acid, or salts with inorganic carboxylic acids or sulphonic acids, such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, malotilate or naphthalenesulfonate.

Preferred are compounds of General formula (I), where

A - oxiranyl, unsubstituted or substituted linear or branched alkyl with 1 to 7 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

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where R1is hydrogen or a linear or branched alkyl with 1-5 carbon atoms,

R2- linear or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted phenyl,

R3- linear or branched alkyl with 1-4 carbon atoms or a group of the formula-OR6where R6means a linear or branched alkyl with 1-4 carbon atoms,

R4- linear or branched alkyl of 2-8 carbon atoms, unsubstituted or substituted phenyl,

L is a radical of the formula-CO-, -CH(OH), -CH2, -CH(N3or-CH(OSO2R7), where

R7means a linear or branched alkyl with 1-3 carbon atoms,

R5- linear or branched alkyl having 3-7 carbon atoms, unsubstituted or substituted by phenyl, or benzyl or 2 - phenylethyl,

D is hydrogen or a group of the formula-SO2-NR8R9where R8and R9together with the nitrogen atom signify morpholino ring,

E is a linear or branched ally (I), where

A - oxiranyl, unsubstituted or substituted linear or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

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where R1is hydrogen or an unbranched or branched alkyl with 1-3 carbon atoms,

R2is unbranched or branched alkyl with 1-6 carbon atoms, unsubstituted or substituted phenyl,

R3is unbranched or branched alkyl with 1-4 carbon atoms or a group of the formula-OR6where R6denotes unbranched or branched alkyl with 1-3 carbon atoms,

R4- linear or branched alkyl with 2-7 carbon atoms, unsubstituted or substituted phenyl,

L is a radical of the formula-CO-, -CH(OH), -CH2, -CH(N3or-CH(OSO2R7), where R7means a linear or branched alkyl with 1-3 carbon atoms,

R5- linear or branched alkyl of 3-6 carbon atoms, unsubstituted or substituted by phenyl, benzyl or 2 - phenylethyl,

D is hydrogen or a group of the formula-SO2-NR8R9where R8and R9together with the nitrogen atom signify morpholino ring,

E is a linear or branched alkyl with 1-4 carbon atoms, or their salts.


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where D has the above value,

T - alkyl with 1-4 carbon atoms,

R10is halogen, preferably bromine or iodine, is subjected to cyclization with formamide, the resulting compounds of General formula (III)

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where D, E, and R10have the above meanings, is subjected to the interaction with compounds of General formula (IV)

R1- CH = CH - R2,

where R1and R2have the above meanings, in an inert solvent in the presence of a base and three-on-tolylphosphino and palladium acetate II and the resulting compounds of General formula (Ia)

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where D, E, R1and R2have the above significance, is treated as follows: the double bond can be subjected to hydrogenation, if A denotes a substituted oxiranyl, the double bond is subjected to oxidation by treatment with an oxidising agent known techniques in the inert solvent and the obtained epoxy compound is transferred by breaking the ring into the corresponding hydroxyl compounds, which, if necessary after activation, is subjected to a nucleophilic substitution reaction or hydroxyl compounds are oxidized to exocoetidae.

The above Spa

The above method is suitable inert organic solvents which do not change under the reaction conditions. To them, preferably belong ethers, such as, for example, a simple diethyl ether, dioxane, tetrahydrofuran, simple picolino or glycolytically ether, halogenated hydrocarbons, such as, for example, di-, tri - or tetrachloride methane, dichloroethylene, trichloroethylene, complex ethyl ester acetic acid, acetonitrile, dimethylformamide, triamide hexamethylphosphoric acid and acetone. Needless to say that it is also possible to use mixtures of these solvents. Especially preferred are dichloromethane and dimethylformamide.

The reaction temperature may usually fluctuate within wide limits. Typically operate in the range from -20 to 200oC, preferably from 0 to 25oC.

The cyclization is usually carried out at temperatures from 50 to 200oC, preferably from 160 to 180oC.

Obtaining compounds of General formula (Ia) is usually carried out in the environment of one of the abovementioned solvents, preferably dimethylformamide, in the presence of a base.

As a basis you can use all REORGCHK, for example, sodium carbonate, potassium carbonate or cesium carbonate, an alkaline alcoholate or alkaline earth metal amides alkali or alkaline earth metals, such as, for example, sodium methylate or potassium, sodium ethylate or potassium tert.-butyl potassium or potassium amide, or organic amines (trialkylamine with 1 - carbon atoms in each alkyl group), such as, for example, triethylamine or tributylamine. Particularly preferably used tributylamine.

Usually the base is used in amounts of 0.05 mol to 10 mol, preferably 1 to 2 mol based on 1 mol of the compounds of formula (III).

The reaction is usually carried out at temperatures from 0oC to 180oC, preferably from 30 to 150oC.

All operations are usually carried out at atmospheric pressure. However, it is also possible to work at elevated or reduced pressure (e.g. from 0.5 to 5 bar).

Epoxidation is carried out in the environment of one of the abovementioned solvents, preferably dry trichloromethane, in the presence of an oxidant, such as, for example, m-chlormadinone acid or hydrogen peroxide. Preferably use m-chlormadinone acid.

Epoxidation but are usually in the environment of one of the above alcohols, preferably methanol.

As the catalyst is usually suitable palladium compounds. Preferably using palladium on coal.

The catalyst is used in an amount of 0.01 to 0.4 mol, preferably 0.05 to 0.2 mol, in terms of mol of the corresponding alcohol.

The hydrogenation is usually carried out at temperatures from -20 to +50oC, preferably from 0 to 30oC.

The hydrogenation is usually carried out at atmospheric pressure. However, you can also work at elevated or reduced pressure (for example, in the range from 0.5 to 5 bar).

Gap epoxide carried out by known methods (see Takano and other Heterocycles 29 (1989), page 249), and in the environment of one of the abovementioned alcohols, preferably methanol, in the presence of iterate of nortryptaline.

The free hydroxyl compound is subjected to interaction with anhydrides of alkylsulfonate in the environment of one of the above solvents in the presence of one base, preferably above dichloromethane and triethylamine, at temperatures from -20 to +20oC, preferably 0oC and atmospheric pressure.

The introduction of azide carried out typically by reacting the s solvents, preferably dimethylformamide, at temperatures from 50 to 120oC, preferably 100oC and atmospheric pressure.

Ketones are obtained from the corresponding hydroxy compounds by known methods (for example, oxidation will Roll).

Pure enantiomeric compounds get known methods, for example by chromatography of racemic compounds of General formula (I) on chiral phases.

Compounds of General formula (II) partially known. You can get them due to the fact that compounds of General formula (V)

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where R10and T have the above meanings, is subjected to the interaction with the acid chloride of 2-n-alkyloxybenzoic acid of formula (VI)

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where D and E have the above meanings, in an inert solvent in the presence of a base.

As a suitable solvent of the above solvents, preferably using dichloromethane.

As suitable bases all cyclic amines, such as, for example, piperidine, pyridine, pyrimidine, dimethylaminopyridine or alkylamines followed with 1 to 4 carbon atoms, such as, for example, triethylamine. Preferably use triethylamine and pyridine.

The base is usually A formula (V).

The reaction temperature may vary within wide limits. Typically operate at temperatures from -20 to +200oC, preferably from 0 to 25oC.

Compounds of General formula (V) are known (see, for example, J. Heterocyclic. Chem. , 26 (5), 1989, pp. 1405 - 1413), and compounds of General formula (VI) are known, for example, from N application EP 0526004 Al.

Compounds of General formula (III) are new and can be obtained as described above.

Compounds of General formula (IV) is known.

Compounds of General formula (Ia) are novel and can be obtained in the manner described above.

The proposed compounds of General formula (I) and (Ia) are unexpected, valuable pharmacological action spectrum.

They inhibit one or more metabolizing cGMP phosphodiesterase. This leads to various higher level cGMP. Increased levels cGMP can lead to antithrombotic, dilates blood vessels, anti-arrhythmic and/or anti-inflammatory action. Selectivity is also determined by the content of isoenzymes in tissues.

In addition, the proposed connections enhance the action of substances, such as, for example, selected from the endothelium relaxation factor and atrial natriuretic for the treatment of inflammatory diseases, such as, for example, asthma, inflammatory dermatoses, high blood pressure, stable and unstable angina, diseases of the peripheral and cardiac vascular, cardiac arrhythmias, thromboembolic disease and ischemia, such as, for example, myocardial infarction, stroke, transistor and ischemic attacks, angina pectoris, peripheral circulatory disorders, prevention of restenosis, for example, after thrombolysis percutaneous transluminal angioplasty and bypass surgery, percutaneous transluminal angioplasty of coronary vessels, as well as septic shock and diseases of the urogenital system such as, for example, prostatic hypertrophy, impotence and incontinence.

Activity phosphodiesterase

Stimulated cGMP phosphodiesterase II ("PDE II"), inhibiting cGMP phosphorus disasters III ("PDE III") and specific regarding camp phosphodiesterase ("PDE-IV) was isolated from the myocardium of pigs or cattle. Stimulated calcium salt calmodulin fosfodiesterazu I ("PDE I) is separated from the aorta or brain of a pig. Specific relatively cGMP phosphodiesterase V ("PDE V) is obtained from the small intestine or the aorta of a pig and/or risovanny trademark of the Swedish company Pharmada) generally according to the method of M. Hoy, Mills D. of Housley, Biochemical Pharmacology, volume 40, pages 193 - 202 (1990).

The determination of the activity of the enzyme is carried out using a mixture of 100 μl of the tested compound in 20 mmol buffer Tris/HCl (pH of 7.5) containing 5 mmol of magnesium chloride, 0.1 mg/ml albumin bovine serum and3Ncamp radioactivity 800 BC or3Ncgmp radioactivity 800 BC. The final concentration of the respective nucleotides is 10-6mol/l Reaction start by adding the enzyme, the amount of which is chosen so that during the 30-minute incubation will react about 50% of the substrate. For research-driven cGMP PDE II is used as a substrate3Ncamp and to the original mixture is added 10-6mol/l unlabeled cGMP. For research-dependent calcium salt calmodulin PDE I to the reaction mixture was added 1 mmol of calcium chloride and 0.1 µmol calmodulin. The reaction is stopped by adding 100 μl of acetonitrile containing 1 mmol camp and 1 mmol AMP. 100 μl of the reaction mixture is shared by high-performance liquid chromatography and the resulting cleavage products quantitatively determined using scintillation flow meter. Measure the table (see at the end of the description.

Substances applicable in doses of 0.1 - 10 mg/kg or directly in the cavernous body, or intraduodenal, rectal, oral, transdermal, or intravenous.

The proposed pharmaceutical composition may be any standard product, such as, for example, tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions, solutions, which are prepared using inert non-toxic pharmaceutically suitable carriers or solvents. Thus therapeutically active compound should be contained in the preparations in effective amount, typically at a concentration of about 0.5 to 90% by weight of the whole mixture, i.e. in amounts which are sufficient to ensure the following dosages.

Drugs can do, for example, by mixing the active substances with solvents and/or carriers, if appropriate using emulsifiers and/or dispersing agents, whereby, for example, in the case of the use of water as a diluent it is possible to use organic solvents as auxiliary solvents.

The application of the preparations carried out by known techniques, preferably orally is the ATA for internal applications usually turned out to be a suitable application of the proposed active substance in an amount of about 0.001 to 10 mg/kg, preferably 0.01 to 10 mg/kg of body weight.

However, if necessary it may be appropriate deviation from the specified amount, namely depending on the type and weight of the subject to treatment of a patient, the method of villas, from individual behaviour to the patient regarding medications, the type and degree of the disease, type of drug and villas and torque or gaps villas funds. In some cases, the cottage in the number, the smaller the specified minimum number, may be sufficient, while in other cases the most specified maximum number of dose. In the case of villas of large quantities may be appropriate distribution of the total number of several individual doses per day.

The following examples illustrate the obtaining of the parent compounds.

Example I

Methyl ester 2-(2-n-propoxybenzene)-3-iodine-benzoic acid

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27.9 g (0.1 mol) of a compound methyl ester 2-amino-3-iodine-benzoic acid and 15.4 ml (0.11 mol) of triethylamine are dissolved in 170 ml of absolute methylene chloride. At a temperature of 0oC pin a solution of 20 g (0.1 mol) of acid chloride of 1-n-propoxybenzene acid in 80 ml of absolute chlorine is entrusted extracted with 100 ml of 1 N. hydrochloric acid, 100 ml of 1 N. sodium hydroxide and 100 ml of saturated solution of sodium chloride. The organic phase is dried over sodium sulfate, evaporated in vacuo and the residue purified by chromatography on silica gel (elution solvent a mixture of toluene and complex ethyl ester in the ratio 95:5).

Yield: 36 g (81,4 % of theory).

The value of Rf: 0,25 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 10:1).

Example II

Methyl ester 2-(2-n-propoxybenzene)-3-bromo - benzoic acid

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Analogously to example I get the above connection based on complex methyl ester 2-amino-3-bromo-benzoic acid.

Output: 60,4%.

The value of Rf: 0,19 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example III

2-(2-n-propoxyphenyl)-8-iodine-hinzelin-4-(3H)-he

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of 19.4 g (44,17 mmol) of the compound of example I in 216 ml of formamide is stirred at a temperature of 180oC for 10 hours. After cooling, add 500 ml of water and extracted 4 times, each time with 300 ml of methylene chloride. The combined organic phases are dried over magnesium sulfate, the solvent was evaporated in vacuum and ostellatovia of 250 ml of absolute ethanol.

Output: 14,56 g (81.2 % of theory).

Melting point: 174oC.

Example IV

2-(2-n-propoxyphenyl)-8-bromo-hinzelin-4-(3H)-he

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Analogously to example III receive the above compound from the compound of example II.

Yield: 60%.

The value of Rf: 0,7 (a mixture of toluene and complex methyl ester of acetic acid in the ratio 10:1).

The following examples illustrate obtain the desired products of formula (I).

Example 1

2-(2-n-propoxyphenyl)-8-(1-hepten-1-yl)-giansily-4(3H)-he

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5 g (12,31 mmol) of the compound of example III, and 3.7 ml (to 15.4 mmol) tributylamine, and 6.6 ml (46.2 mmol) of 1-Heptene, 375 mg (1,23 mmol) tri-o-tolylphosphino and 138 mg (0.6 mmol) of palladium acetate-II is stirred in 50 ml of dry dimethylformamide at a temperature of 100oC for 2.5 hours. Cooled to room temperature and after adding 50 ml complex ethyl ester acetic acid, washed three times, each time with 50 ml water. After drying over magnesium sulfate the organic phase is evaporated in vacuum and the residue chromatographic on silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in the ratio 95:5. Containing the product fractions erase together with 35 ml of petroleum ether.

Yield: 2.2 g (47.5 per cent).

Melting point: 94oC.

Example 2

2-(2-n-propoxyphenyl)-8-(3-phenyl-1-propen-1-yl)-hinzelin - 4(3H)-he

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Analogously to example 1 to obtain the above compound from the compound of example III and 3-phenyl-1-propene.

Output: 63,9%.

Melting point: 123 - 126oC (from diethyl ether).

Example 3

2-(2-n-propoxyphenyl)-8-(4-phenyl-1-butene - 1-yl)- hinzelin-4(3H)-he

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Analogously to example 2 obtain the above compound from the compound of example III and 4-phenyl-1-butene.

Output: to 49.9%.

The value of Rf: 0,27 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 10:1).

Examples 4 and 5

2-(2-n-propoxyphenyl)-8-(5-phenyl-2-penten-2-yl)-hinzelin - 4(3H)-he

2-(2-n-propoxyphenyl)-8-(5-phenyl-3-penten-3-yl)-hinzelin - 4(3H)-he

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Analogously to example 1 to obtain the above compound from the compound of example III and 5-phenyl-pentane-2.

Output: 64,6 %.

The mixture of both isomers, which hydronaut without separation (see example 8).

Example 6

2-(2-n-propoxyphenyl)-8-(1-heptyl)-hinzelin-4(3H)-he,

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20 mg of 10% palladium on coal pre hiderou the si 2 ml of absolute methanol and 0.8 ml of complex ethyl ester of acetic acid and hydronaut at a temperature of 20oC for 1 hour. The catalyst is filtered off and the solvent is removed in vacuum. The remainder analsouth thin-layer chromatography and crystallized under high vacuum. Yield: 180 mg (89.6% of theory). Melting point: 73oC.

Example 7

2-(2-n-propoxyphenyl)-8-(3-phenyl-1-propyl)-hinzelin-4(3H)-he

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Analogously to example 6 to obtain the above compound from the compound of example 2.

Yield: 79.7 per cent.

Melting point: 89oC.

Example 8

2-(2-n-propoxyphenyl)-8-(4-phenyl-1-butyl)-hinzelin-4(3H)-he

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Analogously to example 6 to obtain the above compound from the compound of example 3.

Yield: 86.2 per cent.

Melting point: 82oC.

Examples 9 and 10

2-(2-n-propoxyphenyl)-8-(5-phenyl-2-pentyl)-hinzelin-4(3H)-2-(2-propoxyphenyl)-8-(5-phenyl-3-pentyl)-hinzelin-4(3H)-he

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Analogously to example 6 receive the above compounds on the basis of a mixture of isomers of example 4. The separation is carried out by the working medium pressure chromatography on silica gel using as eluent a mixture of methylene chloride and complex ethyl ester of acetic acid in a ratio of 20:5.

Output connections the use of the methylene chloride and complex ethyl ester of acetic acid in the ratio 10 : 1).

The value of Rfconnection example 10: 0,51 (a mixture of methylene chloride and complex ethyl ester of acetic acid in the ratio 10 : 1).

Example 11

2-(2-n-propoxyphenyl)-8-{1,2-epoxy-1-heptyl)-hinzelin-4(3H)-he

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1.5 g (3,98 mmol) of the compound of example 1 is dissolved at a temperature of 0oC in 40 ml of dry chloroform. Then add 0,98 g (3,98 mmol) of 70% m-chloroperbenzoic acid. The reaction mixture is allowed to warm to room temperature, then stirred for another 3 hours. Washed three times, each time with 30 ml of a 10% aqueous solution of sodium bisulfite and then two more times, each time with 30 ml of 1 n sodium hydroxide solution, dried over magnesium sulfate and evaporated in vacuum. The residue (1.6 g) chromatographic on silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in the ratio 95:5.

Yield: 1.06 g (67,8%).

Melting point: 78oC.

Example 12

2-(2-n-propoxyphenyl)-8-(Z-phenyl-1,2-epoxy-1-propyl)- hinzelin-4(3H)-he

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Analogously to example 11 receives the above compound from the compound of example 2.

Yield: 47%.

The value of Rf: 0,27 (a mixture of toluene and complex ethyl ester in azolin-4(3H)-he

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Analogously to example 11 receives the above compound from the compound of example 3.

Output: 61,4%.

The value of Rf: 0,29 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 1:1).

Example 14

2-(2-n-propoxyphenyl)-8-(1-methoxy-2-hydroxy-1-heptyl)-hinzelin-4(3H)-he

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To a solution of 0.2 g (0.51 mmol) of the compound of example 11 in 6 ml of methanol was added dropwise at a temperature of 0oC 0.1 ml (from 0.76 mmol) of iterate of nortryptaline. After 20 minutes add at a temperature of 0oC 75 ml complex ethyl ester of acetic acid and the reaction mixture is extracted three times, each time with 50 ml water. The organic phase chromatographic on silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in the ratio of 5:1.

Yield: 160 mg (73,9% of theory).

The value of Rf: 0,19 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example 15

2-(2-n-propoxyphenyl)-8-(3-phenyl-1-methoxy-2-hydroxy-1-propyl)- hinzelin-4(3H)-he

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Analogously to example 14 to obtain the above compound from the compound of example 12.

Output: 32,5%.

The value of Rf: 0,20 (mixture tolyl)-8-(4-phenyl-1-methoxy-2-hydroxy-1-butyl)- hinzelin-4(3H)-he

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Analogously to example 14 to obtain the above compound from the compound of example 10.

Output: 74,4%.

The value of Rf: 0,17 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example 17

2-(2-n-propoxyphenyl)-8-(3-hydroxy-2-octyl)-hinzelin-4(3H)-he

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To a suspension of 0.14 g (1.53 mmol) of copper cyanide-I in 3 ml of absolute diethyl ether was added dropwise at a temperature of -78oC 1.9 ml (a 3.06 mmol) of a 1.6 molar solution metallice in diethyl ether. After one hour at a temperature of -78oC is heated to a temperature of -45oC and added dropwise to 200 mg (0.51 mmol) of the compound of example 11 in 2 ml of absolute diethyl ether. Stirred for 1 hour at a temperature of 0oC and then at a temperature of 20oC to the end of the reaction (monitoring by thin-layer chromatography after about an hour). After adding 50 ml complex ethyl ester acetic acid, washed three times, each time with 30 ml water. The organic phase is dried over sodium sulfate and evaporated in vacuum on a rotary evaporator. The remainder chromatographic on silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in the ratio of 7:1.

in the ratio 5:1).

Example 18

2-(2-n-propoxyphenyl)-8-(4-phenyl-3-hydroxy-2-butyl)-hinzelin - 4(3H)-he

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Analogously to example 14 to obtain the above compound from the compound of example 9.

Output: 38,5%.

The value of Rf: 0,21 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example 19

2-(2-n-propoxyphenyl)-8-(5-phenyl-3-hydroxy-2-pentyl)-hinzelin - 4(3H)-he

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Analogously to example 17 receive the above connection example on the basis of the compounds of example 13.

Output: 51,4%.

The mixture of diastereomers with values of Rf: of 0.18 and 0.24 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example 20

2-(2-n-propoxyphenyl)-8-(4-hydroxy-3-nonyl)-hinzelin-4(3H)-he

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of 1.02 ml of 3 M solution (3,05 mmol) of bromide of etermine in diethyl ether was added dropwise at -20oC to a solution of 240 mg (0.61 mmol) of the compound of example 11 and stirred at -20oC for 45 minutes and then at room temperature for 20 minutes. By adding 4 ml of absolute tetrahydrofuran is dissolved oily residue and again type of 1.02 ml of 3 M solution of bromide of ateline to complete the reaction. After 15 minutes is jdy times 50 ml of water. After drying the organic phase over sodium sulfate the solvent is evaporated in vacuo on a rotary evaporator and the residue chromatographic on silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in the ratio 10:1.

Yield: 40 mg (15.5 per cent).

The value of Rf: 0,24 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5 : 1).

Example 21

2-(2-n-propoxyphenyl)-8-(3-methanesulfonate-2-octyl)hinzelin-4(3H)-he

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740 mg (1,81 mmol) of the compound of example 17 and 0.3 ml (2,17 mmol) of triethylamine in 18 ml of absolute methylene chloride are mixed at a temperature of 0oC with 0.17 ml (2,17 mmol) of acid chloride of methansulfonate. The reaction mixture is allowed to warm to room temperature and additionally stirred for 30 minutes. Then shaken twice, each time 1 N. sodium hydroxide, and then two more times, each time with 30 ml of 1 N. hydrochloric acid, the organic phase is dried over magnesium sulfate and the solvent is distilled off in vacuum by evaporation on a rotary evaporator. The solid residue pereshivayut with a mixture of 30 ml of diethyl ether complex of acetic acid and 30 ml of petroleum ether and filtered product is n-propoxyphenyl)-8-(3-azido-2-octyl)-hinzelin-4(3H)-he

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50 mg (0,103 mmol) of the compound of example 18 and 13.4 ml (0,206 mmol) of sodium azide are stirred in 2 ml of absolute dimethylformamide at a temperature of 40oC during the night. Then add 5 ml of complex ethyl ester of acetic acid and shaken out three times, each time with 50 ml water. After drying the organic phase over sodium sulfate the solvent is removed in vacuum by evaporation on a rotary evaporator and the residue purified by flash chromatography on silica gel (elution solvent a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Yield: 31 mg (67% of theory).

The value of Rf: 0,59 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example 23

2-(2-n-propoxyphenyl)-8-(1-methoxy-2-oxo-1-heptyl)-hinzelin-4(3H)-he

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To of 0.21 ml (2,46 mmol) oxalicacid in 13 ml of absolute methylene chloride was added dropwise at -70oC of 0.38 ml (5.41 mmol) of absolute dimethyl sulfoxide in 4 ml of absolute methylene chloride. After 30 minutes, was added dropwise 870 mg (2.05 mol) of the compound of example 14 in 6 ml of absolute methylene chloride, and after a further 30 minutes was added dropwise to 1.42 ml (10,24 mmol) of triethylamine. Then reextract three times, each time 50 ml of methylene chloride, the combined phase methylene chloride is dried over magnesium sulfate and evaporated on a rotary evaporator. The residue is dissolved in 10 ml of ethanol and after addition of 3 ml of 1 N. hydrochloric acid is stirred at room temperature for 3 hours. The ethanol is evaporated in vacuo, the residue is mixed with 30 ml of complex ethyl ester of acetic acid and washed twice with water. After drying over magnesium sulfate evaporated in vacuum on a rotary evaporator and the residue is purified by chromatography on silica gel using as eluent a mixture of toluene and complex ethyl ester of acetic acid in the ratio of 98:2.

Yield: 510 mg (58.9% of theory).

The value of Rf: 0,26 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 5:1).

Example 24

2-(2-n-propoxy-5-morpholinosydnonimine)-8-(1-hepten-1-yl)- hinzelin-4(3H)-he

< / BR>
Analogously to example 1 are as above connection based on 2-(2-n-propoxy-5-morpholinylmethyl)-8-bromo - hinzelin-4(3H)-it and 1-Heptene.

Output: 53.2 per cent.

Melting point: 112oC (from diethyl ether).

Example 25

2-(2-n-propoxy-5-morpholinosydnonimine)-8-(1,2-the C connection example 24.

Yield: 90.7 percent.

Melting point: 96oC.

Example 26

2-(2-n-propoxy-5-morpholinosydnonimine)-8-(1-methoxy-2 - hydroxy - 1-heptyl)- hinzelin-4(3H)-he

< / BR>
Analogously to example 14 to obtain the above compound from the compound of example 25.

Output: 20,3%.

The value of Rf: 0,42 (a mixture of toluene and complex ethyl ester of acetic acid in the ratio 2:1).

Examples 27 and 28

2-(2-n-propoxy-5-morpholinosydnonimine)-8-(5-phenyl-2 - penten-2-yl)- hinzelin-4(3H)-2-(2-n-propoxy-5-morpholinosydnonimine)-8-(5-phenyl-3-penten-3-yl)- hinzelin-4(3H)-he

< / BR>
< / BR>
Analogously to example 1 are as above compounds based on 2-(2-n-propoxy-5-morpholinosydnonimine)-8-bromo - hinzelin-4(3H)-it 5-phenyl-2-pentene.

Yield: 39%.

The mixture of both isomers, which hydronaut without separation.

Examples 29 and 30

2-(2-n-propoxy-5-morpholinosydnonimine)-8-(5-phenyl-1 - pentyl)-hinzelin-4(3H)-2-(2-n-propoxy - 5-morpholinosydnonimine)-8-(5-phenyl-3-pentyl)-hinzelin-4(3H)-he

< / BR>
< / BR>
Analogously to example 6 receive the above compounds on the basis of a mixture of isomers of example 27. The separation is carried out by operating under an average pressure of the ester of acetic acid in the ratio 2 : 1. Output connection example 29: 36.3 per cent. The value of Rf: 0,44 (a mixture of methylene chloride and complex ethyl ester of acetic acid in the ratio 4 : 1). Output connection example 30: 18,4%. The value of Rf: 0,49 (a mixture of methylene chloride and complex ethyl ester of acetic acid in the ratio 4 : 1).

1. Derivatives 2,8-disubstituted of hintlian General formula I

< / BR>
where a is oxiranyl, unsubstituted or substituted linear or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

< / BR>
< / BR>
where R1is hydrogen or a linear or branched alkyl with 1 to 6 carbon atoms;

R2- linear or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted phenyl;

R3- linear or branched alkyl with 1 to 5 carbon atoms or a group of the formula-OR6where R6means a linear or branched alkyl with 1 to 5 carbon atoms;

R4- linear or branched alkyl with 2 to 10 carbon atoms, unsubstituted or substituted phenyl;

L is a radical of the formula-CO-, -CH(OH), -CH2, -CH(N3or-CH(OSO2R7), where R7means a linear or branched alkyl with 1 to 4 carbon atoms;
D is hydrogen or a group of the formula-SO2-NR8R9where R8and R9together with the nitrogen atom form morpholino ring;

E is a linear or branched alkyl with 1 to 8 carbon atoms, or their salts.

2. Derivatives 2,8-disubstituted of hintlian General formula I on p. 1, where a is oxiranyl, unsubstituted or substituted linear or branched alkyl with 1 to 7 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

< / BR>
< / BR>
where R1is hydrogen or a linear or branched alkyl with 1 to 5 carbon atoms;

R2- linear or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted phenyl;

R3- linear or branched alkyl with 1 to 4 carbon atoms or a group of the formula-OR6where R6means a linear or branched alkyl with 1 to 4 carbon atoms;

R4- linear or branched alkyl with 2 to 8 carbon atoms, unsubstituted or substituted phenyl;

L is a radical of the formula-CO-, -CH(OH), -CH2, -CH(N3or-CH(OSO2R7), where R7means a linear or branched alkyl with 1 to 3 carbon atoms;

R5- linear or branched alkyl with 3 to 7 carbon atoms, Nezami is UP>R9where R8and R9together with the nitrogen atom signify morpholino ring;

E is a linear or branched alkyl with 1 to 6 carbon atoms, or their salts.

3. Derivatives 2,8-disubstituted of hintlian General formula I on p. 1, where a is oxiranyl, unsubstituted or substituted linear or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

< / BR>
< / BR>
where R1is hydrogen or an unbranched or branched alkyl with 1 to 3 carbon atoms,

R2is unbranched or branched alkyl with 1 to 6 carbon atoms, unsubstituted or substituted phenyl;

R3is unbranched or branched alkyl with 1 to 4 carbon atoms or a group of the formula-OR6where R6denotes unbranched or branched alkyl with 1 to 3 carbon atoms;

R4- linear or branched alkyl with 2 to 7 carbon atoms, unsubstituted or substituted phenyl;

L is a radical of the formula-CO-, -CH(OH), -CH2, -CH(N3or-CH(OSO2R7), where R7means a linear or branched alkyl with 1 to 3 carbon atoms;

R5- linear or branched alkyl with 3 to 6 carbon atoms, unsubstituted or substituted R9together with the nitrogen atom signify morpholino ring;

E is a linear or branched alkyl with 1 to 4 carbon atoms or their salts.

4. The pharmaceutical composition affecting the level cGMP and camp activity containing the active substance based on the derivatives of hintlian and at least one inert non-toxic pharmaceutically suitable carrier, characterized in that it as a derivative of hintlian contains a compound of General formula I

< / BR>
where a is oxiranyl, unsubstituted or substituted linear or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted phenyl, or a radical of the formula

< / BR>
< / BR>
where R1is hydrogen or a linear or branched alkyl with 1 to 6 carbon atoms;

R2- linear or branched alkyl with 1 to 8 carbon atoms, unsubstituted or substituted phenyl;

R3- linear or branched alkyl with 1 to 5 carbon atoms or a group of the formula-OR6where R6means a linear or branched alkyl with 1 to 5 carbon atoms;

R4- linear or branched alkyl with 2 to 10 carbon atoms, unsubstituted or substituted phenyl;

L is a radical of the formula-CO - CH(OH), -CH2-Lerida;

R5- linear or branched alkyl with 3 to 8 carbon atoms, unsubstituted or substituted by phenyl, benzyl or 2-phenylethyl;

D is hydrogen or a group of the formula-SO2-NR8R9where R8and R9together with the nitrogen atom form morpholino ring;

E is a linear or branched alkyl with 1 to 8 carbon atoms, or its salt in an effective amount.

 

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