HRP920569A2 - Novel compounds, pharmaceutical compositions containing them and the process for preparing the same - Google Patents

Description

Field of invention

The invention is from the field of preparative organic and pharmaceutical chemistry.

Technical problem

This invention relates to new compounds of the general formula (I):

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where:

R denotes hydrogen or a C1-6 alkoxy group of a normal or branched chain,

R1 denotes hydrogen or a C1-6 alkyl group of a normal or branched chain,

R2 represents hydrogen or a C1-6 alkyl group of a normal or branched chain,

R3 denotes hydrogen, a C1-6alkyl group of a normal or branched chain optionally substituted with one or two hydroxyl groups and/or one or two C1-4alkyl groups of a normal or branched chain, or a C4-7cycloalkyl group,

R4 denotes hydrogen or a C1-6alkyl group of a normal or branched chain optionally substituted with one or two hydroxyl groups and/or with one or two C1-4alkyl groups of a normal or branched chain, or a C4-7cycloalkyl group or

R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 8-membered cyclic group of the formula

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optionally substituted with one or two C1-4 alkoxy groups of a normal or branched chain and/or with one or two C1-4 alkyl groups of a normal or branched chain, where optionally the oxygen and sulfur atoms or the N-R5 group can be substituted for the carbon atom of the ring , where R5 denotes hydrogen or a C1-6 aliphatic alkyl group of a normal or branched chain, a 4- to 8-membered ring optionally fused with a benzene ring,

R6 denotes hydrogen or a C1-10 acyl group,

and their salts as well as pharmaceutical preparations containing them.

The invention also relates to a process for obtaining the above new compounds and preparations.

State of the art

Compounds of general formula (I) are unknown in the literature to date.

Description of the solution to the technical problem with examples

R as alkoxy denotes a methoxy, ethoxy, propyloxy, isopropyloxy, butoxy, pentoxy or hexyloxy group.

R1 and R2 can denote, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, secondary butyl, pentyl or isopentyl group.

R3 and R4 can denote the groups defined for R1 or R2 as well as a 2-hydroxyethyl or cyclohexyl group.

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may denote a piperidinyl, piperazinyl, 4-methyl-1-piperazinyl, morpholinyl, hexamethyleneimino or 1-pyrrolidinyl group.

R6 can represent, for example, an acetyl or benzoyl group.

The frequency of allergic diseases, especially bronchial asthma, is continuously increasing. Socio-economic and environmental conditions, improvement of efficiency, diagnostics and lack of adequate, really reliable healing therapy are at the basis of this increase. Despite or even partly due to the increased consumption of the drug, the mortality rate also shows an increasing tendency.

Asthma is characterized by increased sensitivity of respiratory smooth muscles to most of the various stimuli leading to reversible narrowing or obstruction of the airways. Chronic asthma eventually leads to irreversible obstruction of the airway.

Here, the uncontrolled inflammatory process of the respiratory tract is the basis. The therapy, which is based only on bronchodilation without influencing or masking the above process, represents a mainly symptomatic treatment that is mostly harmful and often contributes to increased mortality.

In contrast, anti-inflammatory therapy suppresses inflammation and slows down the harmful basic process, as well as reducing the frequency of the need for bronchodilator treatment.

In cases where drugs are currently present, the problem arises that adverse effects greatly reduce their usefulness.

Thus, the most appropriate therapy can be provided using a drug that is effective against intermediate substances that cause spasm of respiratory smooth muscles and at the same time has an anti-inflammatory or anti-allergic effect without negative side effects.

Due to the pathological nature of bronchial asthma, the effects against the largest number of intermediate substances, which cause narrowing or are even inflammatory in nature, it is very important that the action of many types of endogenous substances be simultaneously expressed. It would be arbitrary to assume an extraordinary role of some component. Thus, the simultaneous presence of each of the effects defined above is significant for these drugs intended for the treatment of bronchial asthma.

Now, it was found during the pharmacological study of the compounds of the general formula (I) that these substances antagonize the effects of mediators of the constriction type (eg histamine, acetylcholine, serotonin), show antiallergic activity and have an antiinflammatory effect.

Thus, the compounds of the general formula (I) have a bronchodilator type effect (similar to beta2 antagonists or theophylline) as well as anti-allergic or anti-inflammatory action (similar to glucocricoides, cromoline or nedocromil).

Therefore, the compounds of general formula (I) broadly satisfy the therapeutic requirements discussed above as they combine bronchodilator, antiallergic and antiinflammatory activities with suitable toxicity without harmful side effects (no negative effects).

The invention also relates to a process for obtaining new compounds of the general formula (I), where

R denotes hydrogen or a C1-6 alkoxy group of a normal or branched chain,

R1 denotes hydrogen or a C1-6 alkyl group of a normal or branched chain,

R2 represents hydrogen or a C1-6 alkyl group of a normal or branched chain,

R3 denotes hydrogen, a C1-6alkyl group of a normal or branched chain optionally substituted with one or two hydroxyl groups and/or one or two C1-4alkyl groups of a normal or branched chain, or a C4-7cycloalkyl group,

R4 denotes hydrogen or a C1-6alkyl group of a normal or branched chain optionally substituted with one or two hydroxyl groups and/or one or two C1-4alkyl groups of a normal or branched chain, or a C4-7cycloalkyl group, or

R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 8-membered cyclic group of the formula

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optionally substituted with one or two C1-4 alkoxy groups of a normal or branched chain and/or one or two C1-4 alkyl groups of a normal or branched chain, where optionally an oxygen or sulfur atom can be substituted for a carbon atom of the ring, where R5 denotes hydrogen or a C1-6alkyl group, a 4- to 9-membered ring optionally fused with a benzene ring,

R6 denotes hydrogen or a C1-10 acyl group,

and their salts, which includes the hydrolysis of compounds of the general formula (II)

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where R, R1 and R2 are as defined above and X denotes a halide ion, then reacting the resulting derivative of the general formula (III)

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where R, R1 and R2 are as defined above and Me denotes a metal atom

a) with a racemic or optically active amino alcohol derivative of the general formula (IV),

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Y denotes a halogen or arylsulfonyl group, or

b) with an epoxypropylamine derivative of the general formula (V)

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[image] then, if it is desired to acylate the thus obtained active compounds of the general formula (I), where R, R1, R2, R3, R4 and R5 are as defined above and R6 denotes hydrogen using known procedures to obtain compounds of the general formula ( I), where R 6 is as defined above, except hydrogen; or decomposition of racemic compounds of general formula (I) by known procedures, or conversion of racemic or optically active compounds of general formula (I) into their salts; or release of free compounds of general formula (I) from their salts.

According to the process of the invention, the compounds of the general formula (II) can be hydrolyzed in aqueous organic solvents, preferably in aqueous aliphatic alcohols by adding a base, preferably an alkali metal hydroxide. According to a preferred embodiment of this reaction, alkali metal hydroxide or its aqueous solution is added to the reaction mixture and the reaction is then carried out at the boiling point of the solvent mixture. However, the hydrolysis can also be carried out with stirring at room temperature since the compounds of the general formula (II) hydrolyze also at lower temperatures.

Although the hydrolysis of strains of the general formula (II) starts even after adding 1 molar equivalent of alkali, this process is very slow, so it is convenient to use excess alkali. When compounds of the general formula (III) react with compounds of the general formula (IV) or their salts or with salts of compounds of the general formula (V), the amount of alkali necessary to liberate the base from the last salts can already be added to the reaction mixture during the hydrolysis of the compounds of the general formula (II) ). When reacting thiols of general formula (III) with salts of compounds of general formula (IV), it is convenient to carry out the reaction in the presence of 2-6 moles of alkali. The amount of base used is proportionally lower when the compounds of general formulas (IV) and (V) are added in their base form to the reaction mixture.

It is suitable for thiols of general formula (III) present in a solution of their salts to react after hydrolysis without isolation with compounds of general formula (IV) or (V). Compounds of the general formula (IV) or (V) can be added as their solid salts to the reaction mixture, however alternatively, after dissolving the salts of the compounds of the general formula (IV) or (V) in water or in a mixture of water with an organic solvent mixed with water, preferably alcohol, their solutions can be added dropwise to the reaction mixture. The addition can be carried out while refluxing the reaction mixture, but lower temperatures can also be used. Substances of general formula (IV) or (V) can also be used in their free base form and the addition can be carried out with or without the use of a solvent.

After addition of compounds of general formula (IV) or (V), the reaction mixture is further heated under a reflux condenser or stirred at a lower temperature, if desired, even with cooling. Compounds of the general formula (I) awarded in the reaction remain in solution in the form of their free base. After completion of the reaction, the products of general formula (I) are isolated using generally known techniques. The organic solvent is preferably evaporated under reduced pressure, whereby the product of the general formula (I) is separated in the form of oil or in crystalline form from the remaining aqueous environment. The crystalline base of the general formula (I) is separated from the mother solution by filtration while the oily crude products are extracted from the aqueous base. The extraction can be carried out using solvents immiscible with water, eg ether, hydrocarbons, halogenated hydrocarbons and the like commonly used for this purpose. After extraction, the solutions are dried and the solvent is evaporated under reduced pressure. The residue of the evaporation is an oily product that becomes crystalline in many cases while standing or by rubbing, bases of the general formula (I) can appear as oily or crystalline substances.

The crude products of formula (I) can be purified as crude bases or, alternatively, the crude bases can be converted into salts with mineral or organic acids, and if desired, the resulting salts can be subjected to further purification. Procedures commonly used in synthetic organic chemistry such as recrystallization; chromatographic procedures and the like can be used for purification. Preferred pharmacologically acceptable salts can be prepared using, for example, HCl, HBr, HJ, H2SO4, HNO3 or H3PO4 as inorganic acids, or citric, acetic, formic, succinic, lactic, malonic, maleic, propionic, fumaric and absorbic acids as organic acids. Other organic or inorganic acids are also suitable.

The possibility of separating optically active antipodes includes building salts of compounds of the general formula (I) with optically active acids and then crystallization of the obtained salts. This process can be carried out under normal decomposition conditions using commonly used optically active acids such as d-tartaric acid and its derivatives, d-camphorsulfonic acid, d-camphoric acid and the like.

Salt formation can be carried out in organic solvents or their mixtures. Precipitated crystalline salts are purified by recrystallization from organic solvents, preferably from alcohol (eg ethanol, isopropanol). After decomposition, optically active bases are released by adding alkali. Salts of antipodes rewarded with mineral acids can be obtained by adding mineral acids without liberating bases, alternatively, these salts can be rewarded by reacting optically active bases with mineral acids.

Compounds of general formula (I) containing a C1-10 acyl group as R6 are obtained by acylation of compounds of general formula (I), where R6 is hydrogen. Acylation can be carried out using acyl halides or anhydrides, preferably in the presence of organic or inorganic bases in a known manner. This reaction can be carried out in a solvent or using an excess of acylating agent (eg, acetic anhydride) as a solvent. All solvents inert to acylating agents (eg hydrocarbons, halocarbons, pyridine) are applicable for this purpose. The products are isolated by usual procedures, eg evaporation or recrystallization.

The starting substances of the general formula (II) and the procedure for their preparation are known from the German patent specification no. 2 426 267.

Compounds of general formula (IV) are known and can be obtained according to J. Org. Chem. 25, 1424 (1960). Compounds of general formula (V) are also known and are prepared as described in J. Am. Chem. Soc. 80, 1257 (1958).

The pharmacological effects of the compounds according to the invention were investigated using the methods described below.

I. Study of effects against spasmogenic mediators

/Modified procedure of J. C. Castillo et. al: Exp. Ther. 90,104 (1974)/.

The test on isolated organs was performed as follows.

OHF Lt/R9 guinea pigs of both halves weighing 300-400 g were anesthetized using pentaharbital. Their tracheas are removed and dissected on the opposite side at the place of the smooth muscle longitudinally. Strip preparations are then obtained by special cutting.

The organ is suspended in an organic bath containing 35 ml of Krebs solution at 37ºC aerated with carbogen gas (containing 95% oxygen and 5% carbon dioxide).

A 0.5 g batch is used. During the incubation period of 30 minutes, several washes are performed.

Tracheal smooth muscle pressure change is monitored using an isometric Grass FT03 type sensor tensiometric device. Washout followed the cumulative dose series of the given mediator (eg, histamine). After reaching the base line, 15 minutes after the administration of the given concentration of the inhibitory (antiasthmatic) substance being tested, the following cumulative dose series of mediators are given. In the case of inhibitory action, the strength of the effect following the second dose series of the mediator is increased compared to that of the first control series.

To characterize the strength of the competitive antagonistic effect, the pA2 value was determined according to the Schield /Br method. J. Pharmacol. 4, 277 (1949)/. pd'2 value is calculated /J. M. Van Rossum: Arch. Int. Pharmacodyn 143,317 (1963)/ to characterize non-competitive antagonistic efficacy. Higher pA2 or pd'2 were respectively higher antagonistic effect.

Theophylline is used as a reference drug that has the following values:

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The results obtained in the above test using the compounds of general formula (I) of the invention are summarized in Table I.

Table I

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II Study of the antiallergic effect

1) The effect affecting the active local anaphylactic reaction was measured according to the method of M. Koltay / Arch. Allergy App. Immun. 71, 181 (1983)/.

Female OFA rats weighing 160-180 g each were sensitized using bovine serum albumin (BSA) adsorbed on 50 μg Al(OH)3 gel along with the simultaneous administration of Bordatella pertussis vaccine.

An anaphylactic reaction was induced by injecting 100 μg of BSA into the right hind paw on the 14th day.

Measurements were made before and 30 minutes after triggering the reaction. Animals were orally treated with the test compound 1 hour before BSA injection. Results are expressed as percent inhibition relative to the control group (mean %± S.E.M.).

2) Acute anti-inflammatory effect was determined using carrageenan-induced rat paw edema test /C.A. Winker et al.; Proc. Soc. Exp. Honey. 111,544 (1962)/.

Inflammation CFY rats weighing 100-120 g were used after being kept without food for 24 hours.

Inflammation was induced by injecting 0.1 ml of 1% carrageenan solution into the right hind paw.

The severity of the inflammation was determined using the Ugo-Basile type plethysmometer. The measurement was performed before and 1.5, 3 and 4.5 hours after inducing inflammation.

The animals were orally treated with the test substance 1 hour before carrageenan administration. The effect is expressed as a percentage of inhibition compared to the control group.

3) Dextran-induced rat paw edema test

The method of S. Gourvaisier and R. Ducrot /Arch was used. Int. Pharmacodyn. Ther. 102, 33 (1955)/.

The method for the carrageenan edema test was followed, except that the measurements were performed 30, 60, 90, 120 and 180 minutes after inducing inflammation.

For use as medicaments, the compounds of general formula (I) and their salts are formulated into pharmaceutical preparations such as tablets, dragees, suppositories, capsules, solutions, powder mixtures, preparations for injection or inhalation after the addition of various additives by methods commonly used in pharmaceutical industry. Since they are easily soluble in water, the salts of the compounds of the general formula (I) are suitable for use in obtaining solutions that can be used therapeutically in preparations for injections and inhalation.

The reference substances given below along with their pharmacological values were used in the tests discussed below.

1. Inhibition of mediator-induced spasmogenic contraction of isolated guinea pig tracheal smooth muscle

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2. Effect affecting active local anaphylactic reaction in rats

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3. Rat paw edema induced with carrageenan

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4. Rat paw edema induced with dextran

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The invention is further illustrated in detail by the following non-limiting examples.

Example 1

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-diethylamino-2-hydroxypropyl)

mercaptoacetonitrile hydrochloride

After dissolving 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-methyl/isothiuronium bromide (obtained as described in our earlier German Patent Specification No. 2 426 267) in a mixture of 80 ml of ethanol and 20 ml of water by heating, 16 ml of 10% sodium hydroxide solution is added and the reaction mixture is refluxed for 20 minutes, then 1.7 g of 1- chloro-3-diethyl-amino-2-propanol dissolved in 10 ml of methanol / obtained by reacting diethylamine with epichlorohydride in methanol according to J. Org. Chem. 25 1424 (1960)/. After refluxing the reaction mixture for 6 hours and evaporating the organic solvent under reduced pressure, concentrated HCl is added dropwise to the residual water-oil residue until a pH value of 5-6 is reached. The solution is clarified using activated carbon, filtered and the filtrate is made alkaline by adding 10% sodium hydroxide solution. A yellow oil is deposited, which hardens by rubbing. After filtering and drying, the product is dissolved in 20 ml of isopropanol and acidified by adding hydrogen chloride to the abs solution. of alcohol to obtain 1.8 g of the title compound, mp: 179ºC.

Analysis for C20H30ClN3O3S (molecular weight 427.99)

calculated: N 9.82 Cl 8.28 S 7.49%

found N 9.91 Cl 8.40 S 7.50%

Example 2

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-(3-diethylamino-2-hydroxy-propyl)-mercapto

-acetonitrile hydrochloride

The procedure described in Example 1 is followed, except that 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-methyl/ isothiuronium bromide and 1-chloro-3-diethylamino-2-propanol as reactants to obtain the title compound in a yield of 2.1 g mp: 149ºC.

Analysis for C22H34ClN3O3S (molecular weight 456.04)

calculated: N 9.22 Cl 7.77 S 7.03%

found N 9.08 Cl 7.93 S 7.31%

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

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Inhibition of rat paw edema development induced by dextran 50 mg/kg (p.o.)

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Example 3

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolidene)-2-/3-(N-methyl-N-2-hydroxyethylethyl)-amino-2

-hydroxypropyl)-mercapto-acetonitrile hydrochloride

Follow the procedure described in example 1 using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)methyl/-isothiuronium bromide and 1 -chloro-3-(N-methyl-N-2-hydroxyethyl)-amino-2-propanol as a starting substance to obtain the title compound in a yield of 2.6 mg, mp: 136ºC (from absolute ethanol)

Analysis for C19H28ClN3O4S (molecular weight 429.96)

C H N Cl S

calculated: 53.07 6.56 9.77 8.25 7.46%

found: 52.82 6.82 9.40 8.13 7.50%

Example 4

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-/3-(N,N-bis-2-hydroxyethyl)-amino-2

-hydroxypropyl)-mercapto-acetonitrile hydrochloride dihydrate

Follow the procedure described in example 1 using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linidene)methyl/-isothiuronium bromide and 1 -chloro-3-(N,N-bis-2-hydroxyethyl)-amino-2-propanol as a starting substance for obtaining the title compound in a yield of 2.3 g, mp: 135ºC (from 96% ethanol)

Analysis for C20H34ClN3O7S (molecular weight 496.02)

C H N Cl S

calculated: 48.43 6.91 8.47 7.15 6.46%

found: 48.66 6.77 8.25 7.45 6.31%

Results of rat edema test induced by carrageenan, 50 mg/kg (p.o.)

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Example 5

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-(2-hydroxy-3-isopropylaminopropyl)

-mercaptoacetonitrile hydrochloride hemihydrate

The procedure described in example 1 is followed, using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)methyl/isothiuronium bromide and 1 -chloro-3-isopropylamino-2-propanol as a starting substance to obtain the title compound in a yield of 2.6 g, mp: 176ºC (from isopropanol).

Analysis for C19H28ClN3O3S.0.5H2O (molecular weight 422.97)

C H N Cl S

calculated: 53.95 6.91 9.94 8.38 7.58%

found: 53.60 6.69 10.24 8.47 7.60%

Results of rat paw edema test induced by carrageenan, 50 mg/kg (p.o.)

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Example 7

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-(2-hydroxy-3-isopropylaminopropyl)

mercaptoacetonitrile hydrochloride

The procedure described in example 1 is followed, using 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro isoquinolidene)methyl/-isothiuronium bromide and 1-chloro- 3-isopropylamino-2-propanol as a starting substance to obtain the title compound in a yield of 2.8 g, mp: 185ºC (from isopropanol)

Analysis for C21H32ClN3O3S (molecular weight 442.01)

C H N Cl S

calculated: 57.06 7.30 9.51 8.02 7.25%

found: 56.78 7.35 9.70 8.31 7.05%

Example 8

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-(3-tert-butylamino-2-hydroxypropyl)

mercaptoacetonitrile hydrochloride

After adding 80 ml of ethanol and 20 ml of water to 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)methyl/isothiuronium bromide, the mixture is heated until the solid dissolves (1-2 minutes). After adding 16.0 ml of 10% sodium hydroxide solution, the mixture is refluxed for 90 minutes. Then 2.02 g of 3-tert-butylamino-1-chloro-2-propanol hydrochloride (obtained by reacting tert-butylamine with epichlorohydrin in methanol as described in the literature cited above, and precipitation of the salt from an isopropanol solution of the crude base) is then added in portions , by adding HCl solution, mp: hydrochloride 160ºC) to the reaction mixture, which is then refluxed for 5 hours, after which the ethanol is evaporated under reduced pressure. The residue is a yellow oily crude base, which becomes crystalline on standing, mp: 112ºC. The crude base is obtained in a yield of 3.6 g.

By adding an ethanolic solution of HCl to an isopropanol solution of the crude base, the title hydrochloride is obtained, mp: 177ºC.

Analysis for C20H30ClN3O3S (molecular weight 427.99)

C H N Cl S

calculated: 56.12 7.07 9.82 8.28 7.49%

found: 56.40 6.87 9.82 8.38 7.72%

Example 9

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinidene)-2-(3-tert-butylamino-2-hydroxypropyl)

mercaptoacetonitrile hydrochloride hemihydrate

Follow the procedure described in example 8 using 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)isothiuronium bromide and 3-tert- butylamino-1-chloro-2-propanol hydrochloride as a starting substance to obtain the title compound in a yield of 2.4 g, mp: 160ºC (from isopropanol)

Analysis for C22H34ClN3O3S.0.5H2O (molecular weight 465.05)

C H N Cl S

calculated: 56.82 7.59 9.04 7.62 6.90%

found: 56.70 7.76 9.00 7.95 6.82%

Example 10

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-cyclohexylamino-2-hydroxy-propyl)

mercaptoacetonitrile hydrochloride

The procedure described in Example 1 is followed, using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-methyl/isothiuronium bromide and 1-chloro-2-cyclohexylamino-2-propanol as a starting substance for obtaining the title product in a yield of 2.7 g, mp: 190ºC (from isopropanol)

Analysis for C22H32ClN3O3S (molecular weight 454.02)

C H N Cl S

calculated: 58.20 7.10 9.26 7.81 7.06%

found: 58.00 7.40 9.02 7.81 6.86%

Results of rat paw edema test induced with carrageenan 50 mg/kg (p.o.)

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Inhibition of rat paw edema development induced with dextran 50 mg/kg (p.o.)

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Example 11

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-cyclohexylamino-2-hydroxypropyl

mercaptoacetonitrile hydrochloride

The procedure described in Example 1 is followed using 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-methyl/isothiuronium bromide and 1 -chloro-3-cyclohexylamino-2-propanol as a starting substance to obtain the title compound in a yield of 2.6 g, mp: 182ºC (from isopropanol)

C H N Cl S

calculated: 59.79 7.53 8.72 7.36 6.65%

found: 60.02 7.50 8.65 7.16 6.45%

Example 12

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-pyrrolidinyl)propyl)

mercaptoacetonitrile hydrochloride hemihydrate

The procedure described in example 1 is followed using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-methyl/isothiuronium bromide and 1 -chloro-3-(1-pyrrolidinyl)-2-propanol as starting substance to obtain 2.1 g of the title compound, mp: 194ºC (from ethanol).

Analysis for C20H28ClN3O3S.0.5H2O (molecular weight 434.98)

C H N Cl S

calculated: 55.22 6.72 9.66 8.15 7.37%

found: 55.18 7.03 9.90 8.15 7.55%

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

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Inhibition of rat paw edema development induced by dextran 50 mg/kg (p.o.)

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Example 13

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-hydroxy-3-(1-pyrrolidinyl)propyl/

mercaptoacetonitrile hydrochloride

The procedure described in example 1 is followed using 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-methyl/isothiuronium bromide and 1 -chloro-3-(1-pyrrolidinyl)-2-propanol to obtain the title product in a yield of 2.6 g mp: 195ºC (from ethanol).

Analysis for C22H32ClN3O3S (molecular weight 454.02)

C H N Cl S

calculated: 58.20 7.10 9.26 7.81 7.06%

found: 57.92 7.30 9.20 7.48 6.82%

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

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Example 14

Preparation of 2-(1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-piperidinyl)propyl/ mercaptoacetonitrile

The procedure described in Example 8 was followed using 3.25 g of S-/alpha-cyano-alpha-(1,2,3,4-tetrahydro-1-isoquinolinylidene) methyl/isothiuronium bromide and 1-chloro-3-(1- piperidinyl)-2-propanol to obtain the title compound in a yield of 2.1 g, mp: 103ºC (from isopropanol).

Analysis for C19H25N3OS (molecular weight 343.48)

C H N S

calculated: 66.43 7.34 12.23 9.34%

found: 66.17 7.14 12.50 9.24%

The hydrochloride of the title product is obtained by adding HCl solution to abs. ethanol base dissolved in abs. ethanol, mp: 187ºC.

Inhibition of an active local anaphylactic reaction:

The percentage of inhibition achieved with an oral dose of 50 mg/kg of body weight is 44.1% 30 minutes after triggering the reaction.

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

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Example 15

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-(2-hydroxy-3-(1-piperidinyl)propyl)

mercaptoacetonitrile hydrochloride

After dissolving 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl/isothiuronium bromide in a mixture of 80 ml of ethanol with 20 ml of water with heating, 16 ml of 10% sodium hydroxide solution is added and the reaction mixture is refluxed for 2 hours, then it is cooled to room temperature and 2.2 g of 1-chloro-3-(1-piperidinyl)-2-propanol hydrochloride is added to the reaction mixture with mixing. The mixture is stirred at room temperature for 2 days and then processed as described in Example 1. In this way, 2.7 g of the title hydrochloride are obtained, mp: 210ºC (from ethanol).

Analysis for C21H30N3O3S (molecular weight 440.00)

C H N S

calculated: 57.32 6.87 9.55 7.29%

found: 56.99 7.01 9.32 7.43%

Example 16

Obtaining 2-(1,2,3,4-tetrahydro-1-isoquinolidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile

hydrochloride hemihydrate

The procedure described in Example 15 was followed using 3.25 g of S-/alpha-cyano-alpha-(1,2,3,4-tetrahydro-1-isoquinolinylidene) methyl/isothiuronium bromide and 1-chloro-3-(4- morpholinyl)-2-propanol hydrochloride as starting substances to obtain the title compound, mp: 195ºC (from ethanol).

Analysis for C18H24ClN3O2S.0.5H2O (molecular weight 390.93)

C H N S

calculated: 55.30 6.44 10.75 8.20%

found: 55.10 6.30 10.50 8.37%

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

[image]

Example 17

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl)

mercaptoacetonitrile hydrochloride

The procedure described in Example 15 was followed using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-methyl/isothiuronium bromide and 1 -chloro-3-(4-morpholinyl)-2-propanol as starting material to obtain the title compound in a yield of 3.3 g, mp: 210ºC (from ethanol).

Analysis for C20H28ClN3O4S (molecular weight 441.97)

C H N Cl S

calculated: 54.35 6.39 9.51 8.02 7.26%

found: 54.42 6.52 9.63 8.00 7.54%

Inhibition of active local anaphylactic reaction:

The percentage of inhibition achieved with an oral dose of 50 mg/kg is -53.4% 37 minutes after triggering the reaction.

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

[image]

Inhibition of rat paw edema development induced by dextran 50 mg/kg (p.o.)

[image]

Example 18

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-hydroxy-3-(4-morpholinyl)propyl/

of mercaptoacetonitrile

After adding 80 ml of ethanol and 20 ml of water to 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene) methyl/isothiuronium bromide, the reaction mixture is heated until complete dissolution (1-2 minutes). After adding 11.0 ml of 10% NaOH solution, the mixture is refluxed for 90 minutes. After adding 2.2 g of 1-chloro-3-(4-morpholinyl)-2-propanol hydrochloride, the reaction mixture was refluxed for 5 hours.

Then, the methanol is evaporated and the residue is cooled, thereby crystallizing the crude base to give the title product in 3.2 g yield, mp: 97ºC (from abs. ethanol).

Analysis for C22H31N3O4S (molecular weight 433.56)

C H N S

calculated: 60.94 7.21 9.69 7.40%

found: 60.72 7.40 9.51 7.17%

The hydrochloride of the above base is precipitated by adding an ethanolic solution of HCl to abs. ethanol base solvent, mp: 203ºC (from ethanol)

[image]

Inhibition of active topical anaphylactic reaction

The percentage of inhibition achieved with an oral dose of 50 mg/kg is -31% 30 minutes after eliciting the reaction.

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

[image]

Inhibition of rat paw edema development induced with dextran 50 mg/kg (p.o.)

[image]

Example 19

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-hexamethylanimino-2-hydroxypropyl)

of mercaptoacetonitrile

The procedure described in example 1 is followed using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)methyl/-isothiuronium bromide and 1 -chloro-3-hexamethyleneamino-2-propanol as starting material to obtain 1.7 g of the title base as a yellow oil.

The hydrochloride of the above base is precipitated from the ethanolic solution. The hydrochloride is crystallized with 1 mole of crystalline ethanol and half a mole of crystalline water, mp: 110-112ºC (from ethanol).

Analysis for C22H31N3O3S.HCl.C2H5OH.0.5H2O (molecular weight 509.10).

C H N Cl S

calculated: 56.42 7.72 8.25 6.96 6.30%

found: 56.66 8.05 8.20 6.70 6.65%

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

[image]

Inhibition of rat paw edema development induced with dextran 50 mg/kg (p.o.)

[image]

Example 20

2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propyl/

mercaptoacetonitrile hydrate

The procedure described in Example 15 was followed using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-methyl/isothiuronium bromide and 1- chloro-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)-2-propanol as starting material to obtain 3.1 g of the title product, mp: 140ºC (from ethanol).

Analysis for C22H30ClN3O3S.5H2O (molecular weight 506.05)

C H N Cl

calculated: 59.33 6.37 8.30 7.01%

found: 59.29 6.38 7.96 7.03%

Example 21

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-methyl-1-piperazinyl)propyl)

mercaptoacetonitrile hydrochloride

The procedure described in example 1 is followed using 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)methyl/isothiuronium bromide and 1- chloro-3-(4-methyl-1-piperazinyl)-2-propanol as starting material to obtain the title compound in a yield of 1.7 g, mp: 243ºC (from 90% ethanol).

Analysis for C21H32Cl2N4O3S (molecular weight 491.48)

C H N S

calculated: 51.32 6.56 11.40 6.52 %

found: 51.35 6.61 11.24 6.57%

Example 22

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-hydroxy-3-(4-methyl-piperazinyl)propyl/

mercaptoacetonitrile hydrochloride

The procedure described in Example 1 is followed using 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-methyl/isothiuronium bromide and 1 -chloro-3-(4-methyl-1-piperazinyl)-2-propanol as a starting substance to obtain 1.8 g of hydrochloride, which crystallizes with 2.5 moles of crystal water from 96% ethanol, mp: 220ºC.

Analysis for C23H36Cl2N4O3S.2.5H2O (molecular weight 564.57)

C H N S

calculated: 48.93 7.32 9.92 5.68%

found: 48.96 7.05 10.15 6.05%

Example 23

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-/2-acetoxy-3-(4-morpholinyl)propyl/

mercaptoacetonitrile hydrochloride

After adding 80 ml of benzene and 32 ml of acetic anhydride to 4.8 g of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)-2-(2-hydroxy-3- (4-morpholinyl)propyl/mercaptoacetonitrile, the reaction mixture was refluxed for 2 hours, then evaporated to dryness under reduced pressure. The residue is dissolved in isopropanol and acidified by adding abs. ethanolic HCl solution to obtain the title hydrochloride in a yield of 4.72 g, mp: 204ºC (from abs. ethanol).

Analysis for C22H30ClN3O5S (molecular weight 484.01)

C H N Cl S

calculated: 54.59 6.25 8.68 7.33 6.63%

found: 54.37 6.16 8.90 7.41 6.39%

Results of rat paw edema test induced with carrageenan 50 mg/kg (p.o.)

[image]

Example 24

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-/2-acetoxy-3-(4-morpholinyl)propyl/

of mercaptoacetonitrile

After adding 50 ml of benzene and 20 ml of acetic anhydride to 3.0 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-/2-hydroxy-3- (4-morpholinyl)propyl/mercaptoacetonitrile, the reaction mixture was refluxed for 1 hour, then evaporated to dryness under reduced pressure. After addition of ether, the residue is crystallized to give the title product in a yield of 2.47 g, mp: 133ºC (from isopropanol).

Analysis for C24H33N3O5 (molecular weight 475.59)

NS

calculated: 8.84 6.74%

found: 8.71 6.66%

inhibition of the constricting effect of acetylcholine pd'2: 5.02

inhibition of the narrowing action of serotonin pd'2: 5.05

Results of rat paw edema test induced with carrageenan 50 mg/kg (p.o.)

[image]

Example 25

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-benzoyloxy-3-(4-morpholinyl)propyl/

of mercaptoacetonitrile

After adding 40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chloride to 4.06 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-/ of 2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile, the reaction mixture was refluxed for 45 minutes, then cooled and filtered. After evaporation of the filtrate, the residue is crystallized by adding ethyl acetate to obtain the title product in a yield of 3.25 g, mp: 144ºC (from isopropanol).

Analysis for C27H31N3O5S (molecular weight 509.61)

C H N S

calculated: 63.63 6.13 8.25 6.29%

found: 64.03 6.37 8.58 6.37%

Inhibition of the constricting action of acetylcholine pd'2: 4.81

Results of rat paw edema test induced by carrageenan 50 mg/kg (p.o.)

[image]

Example 26

Obtaining 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-benzoyloxy-3-(4-morpholinyl)propyl/

mercaptoacetonitrile hydrochloride

40 ml of benzene, 1.0 g of triethylamine and 1.5 g of benzoyl chloride are added to 4.34 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-/ of 2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile and the reaction mixture was refluxed for 45 minutes, then cooled. After filtering and evaporating the solvent under reduced pressure, the residue is dissolved in isopropanol and acidified by adding abs. of ethanolic HCl solution. In this way, 3.77 g of the hydrochloride from the title crystallized, mp: 207ºC (from ethanol).

Analysis for C29H36ClN3O5S (molecular weight 574.13)

C H N Cl S

calculated: 60.66 6.32 7.32 6.18 5.59%

found: 60.80 6.37 7.22 6.24 5.88%

Inhibition of the constricting action of acetylcholine pd'2: 4.81

Example 27

Obtaining (-)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl)

mercaptoacetonitrile, d-camphorsulfonate

A mixture containing 8.0 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile and 3 .9 g of d-camphorsulfonic acid in 50 ml abs. of ethanol is heated until the solid material dissolves (several minutes). After cooling, the crystalline precipitate is filtered and recrystallized from 40 ml abs. of ethanol to obtain 5.0 g of the title salt, mp: 172ºC.

The base is released by adding NaOH to an aqueous solution of the camphorsulfonate salt.

The base melts at 97ºC, /α/=-11.3ºC (c=1, chloroform).

The product hydrochloride can be precipitated from anhydrous ethanolic solution by adding anhydrous ethanolic HCl solution.

Example 28

a) Preparation of (+)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)

propyl/mercaptoacetonitrile hydrochloride

The ethanol mother solution of the isolated salt described in example 1 is evaporated to dryness under reduced pressure and water is added to the residue. After alkalization of the obtained solution with 10% NaOH solvent, the separated oily yellow material is extracted in chloroform. After drying the chloroform solution over anhydrous sodium sulfate and evaporating the solvent under reduced pressure, the residue was dissolved in abs. ethanol and acidify by adding an ethanolic HCl solution. The title hydrochloride is obtained in a yield of 2.65 g, mp: 201ºC (from abs. ethanol). /α/=7.7º (c=1, water).

b) Obtaining (+)-2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)

propyl/mercaptoacetonitrile 1-camphorsulfonate

The procedure described in Example 27 was followed using 8.0 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl) propyl/mercaptoacetonitrile and 3.9 g of 1-camphorsulfonic acid as starting substances to obtain 5.2 g of the camphorsulfonate salt from the title, mp: 169-170ºC (from abs. ethanol)

Example 29

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl)

mercaptoacetonitrile hydrochloride

After adding 4 ml of 10% NaOH solution and 6 ml of ethanol, 0.48 g of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(/2-acetoxy-3-( 4-morpholinyl)propyl/mercaptoacetonitrile hydrochloride (product of Example 23), the reaction mixture is refluxed for 30 minutes, then the ethanol is evaporated under reduced pressure. The oily residue is crystallized, filtered, washed with water and dried. The obtained product is dissolved in 5 ml abs. of ethanol under heating and the solution is acidified using abs. ethanolic HCl solution to obtain 0.4 g of the title hydrochloride which is identical to the product of Example 17, mp: 210ºC.

Example 30

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-hydroxy-3-(4-morpholinyl)propyl/

mercaptoacetonitrile hydrochloride

After adding 4 ml of 10% NaOH solution and 6 ml of ethanol to 0.48 g of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-acetoxy-3- (4-morpholinyl)propyl/mercaptoacetonitrile (product of Example 24), the reaction mixture was refluxed for 30 minutes. After evaporation of the solvent, the residue is extracted with chloroform. The organic solution is dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue is dissolved in 5 ml of anhydrous ethanol with heating and acidified with abs. with ethanolic HCl solution to obtain 0.38 g of the title hydrochloride, which is identical to the product of Example 18, mp: 203ºC.

Example 31

Preparation of 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-piperidinyl)propyl)

mercaptoacetonitrile hydrochloride

After dissolving 3.85 g of S-/alpha-cyano-alpha-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)methyl/isothiuronium bromide in a mixture of 80 ml of methanol and 30 ml of water, 11.0 ml of 10% NaOH solution is added, the reaction mixture is refluxed for 2 hours and a solution containing 1.44 g of 1,2-epoxy-3-(1-piperidinyl)propane (obtained as described in J. Am. Chem. Soc. 80, 1257 (1958)) dissolved in 5 ml of methanol was added to the warm solution. The reaction mixture is refluxed for an additional 5 hours. After evaporation of the methanol under reduced pressure, the reaction mixture is worked up as described in Example 1 to obtain 2.3 g of the title hydrochloride which is identical to the product of Example 15, mp: 210ºC (from anhydrous ethanol).

Example 32

Preparation of 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-piperidinyl)propyl)

-mercaptoacetonitrile hydrochloride

The procedure described in Example 31 is followed, using 4.15 g of S-/alpha-cyano-alpha-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquino linylidene)methyl isothiuronium bromide and 1, 41 g of 1,2-epoxy-3-(1-piperidinyl)propane to obtain 2.6 g of the title hydrochloride, mp: 192ºC

Claims (7)

1. Racemic or optically active isoquinoline derivatives of general formula (I) [image] where: R denotes hydrogen or a C1-6 alkoxy group of a normal or branched chain; R 1 denotes hydrogen or a C 1-6 alkyl group of a normal or branched chain; R 2 represents hydrogen or a C 1-6 alkyl group of a normal or branched chain; R 3 denotes hydrogen, a C 1-6 alkyl group of a normal or branched chain optionally substituted with 1 or 2 hydroxyl groups and/or 1 or 2 C 1-4 alkoxy groups of a normal or branched chain, or a C 4-7 cycloalkyl group; R 4 denotes hydrogen or a C 1-6 alkyl group of a normal or branched chain optionally substituted with 1 or 2 hydroxyl and/or with 1 or 2 C 1-4 alkoxy groups of a normal or branched chain; or a C4-7cycloalkyl group or R3 and R4 together with the nitrogen atom to which they are attached form a 4-8 membered cyclic group of the formula [image] optionally substituted with 1 or 2 C1-4 alkoxy groups of a normal or branched chain and/or 1 or 2 C1-4 alkyl groups of a normal or branched chain, where optionally an oxygen or sulfur atom or an N-R5 group can be substituted for a ring carbon atom, where R5 is hydrogen or a C1-6 aliphatic alkyl group of a normal or branched chain, 4-8 membered ring optionally fused with a benzene ring; R6 denotes hydrogen or a C1-10 acyl group, and their salts as well as hydrates of free compounds of the general formula (I) and their salts. 2. Racemic or optically active compounds according to claim 1, where R denotes a methoxy or ethoxy group, R1 and R2 are hydrogen, R3 denotes an isopropyl group and R4 denotes hydrogen: [image] R6 is hydrogen or a benzoyl group. 3. Racemic or optically active compounds according to claim 1, where R, R1, R2 and R6 are as defined in claim 1 and [image] hexamethyleneamino group. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-diethylamino-2-hydroxy-propyl)-mercaptoacetonitrile and its hydrochloride. 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-diethylamino-2-hydroxypropyl)-mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/3-(N-methyl-N-2-hydroxyethyl)amino-2-hydroxypropyl/mercaptoacetonitrile and its hydrochloride . 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/3-(N,N-bis-2-hydroxyethyl)amino-2-hydroxypropyl/ mercaptoacetonitrile and its hydrochloride as well as hydrochloride dihydrate. 2-(6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/3-(N,N-bis-2-hydroxyethyl)amino-2-hydroxypropyl/mercaptoacetonitrile and its hydrochloride . 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-hydroxy-3-(isopropylaminopropyl) mercaptoacetonitrile or its hydrochloride as well as hydrochloride hydrate. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-isopropylaminopropyl) mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-tert-butylamino-2-hydroxypropyl)mercaptoacetonitrile or its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-tert-butylamino-2-hydroxypropyl) mercaptoacetonitrile as well as the hydrochloride hemihydrate. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-cyclohexylamino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-cyclohexylamino-2-hydroxypropyl) mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-pyrrolidinyl)propyl/ mercaptoacetonitrile and its hydrochloride as well as the hydrochloride hemihydrate. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-pyrrolidinyl)propyl/mercaptoacetonitrile and its hydrochloride). 2-(1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-piperidinyl)propyl/mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(1-piperidinyl)propyl/mercaptoacetonitrile and its hydrochloride. 2-(1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile and its hydrochloride as well as the hydrochloride hemihydrate. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(3-hexamethyleneimino-2-hydroxypropyl)mercaptoacetonitrile and its hydrochloride as well as the hydrochloride hemihydrate. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-/2-hydroxy-3-(1,2,3,4-tetrahydro-2-isoquinolinyl)propyl/ mercaptoacetonitrile and its hydrochloride as well as hydrochloride monohydrate. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-methyl-1-piperazinyl)propyl/mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-methyl-1-piperazinyl)propyl/mercaptoacetonitrile and its hydrochloride as well as hydrochloride hydrates. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-acetoxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile and its hydrochloride. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-acetoxy-3-(4-morpholinyl)propyl/ mercaptoacetonitrile. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-benzoyloxy-2-(4-morpholinyl)propyl/ mercaptoacetonitrile. 2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-benzoyloxy-3-(4-morpholinyl)propyl/ mercaptoacetonitrile and its hydrochloride. (-)-2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/mercaptoacetonitrile (+)-camphorsulfonate . (+)-2-(6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolinylidene)-2-(2-hydroxy-3-(4-morpholinyl)propyl/ mercaptoacetonitrile and its hydrochloride. 4. Process for obtaining racemic or optically active isoquinoline derivatives of the general formula (I) [image] where: R denotes hydrogen or a C1-6 alkoxy group of a normal or branched chain; R 1 denotes hydrogen or a C 1-6 alkyl group of a normal or branched chain; R 2 represents hydrogen or a C 1-6 alkyl group of a normal or branched chain; R 3 denotes hydrogen, a C 1-6 alkyl group of a normal or branched chain optionally substituted with 1 or 2 hydroxyl and/or 1 or 2 C 1-4 alkoxy groups, or a C 4-7 cycloalkyl group; R 4 denotes hydrogen or a C 1-6 alkyl group of a normal or branched chain optionally substituted with 1 or 2 hydroxyl and/or 1 or 2 C 1-4 alkoxy groups of a normal or branched chain or a C 4-7 cycloalkyl group; or R3 and R4 together with the nitrogen atom to which they are attached form a 4-8 membered cyclic group of the formula [image] optionally substituted with 1 or 2 C1-4 alkoxy groups of a normal or branched chain and/or 1 or 2 C1-4 alkyl groups of a normal or branched chain, where optionally an oxygen or sulfur atom or an N-R5 group can be substituted for the carbon atom of the ring, where R5 is hydrogen or a C1-6 aliphatic alkyl group, the 4- to 8-membered ring is optionally fused to a benzene ring; R6 denotes hydrogen or a C1-10 acyl group, and their salts as well as hydrates of free compounds of the formula (I) and their salts, indicated by the fact that it includes the hydrolysis of the compound of the general formula (II), [image] where R, R1 and R2 are as defined above and X denotes a halide ion, then reacting the resulting derivative of the general formula (III) [image] where R, R1 and R2 are as defined above and Me denotes a metal atom. a) with a racemic or optically active amino alcohol, a derivative of the general formula (IV) [image] [image] Y denotes a halogen or arylsulfonyl group, or b) with an epoxypropylamine derivative of the general formula (V) [image] [image] then, if desired, acylation of the thus obtained compounds of the general formula (I), where R, R1, R2, R3, R4 and R5 are as defined above and R6 denotes hydrogen, by known procedures to obtain compounds of the general formula (I), where R 6 is as defined above, except hydrogen; or decomposition of racemic compounds of the general formula (I) by known procedures; or converting racemic or optically active compounds of the general formula (I) into their salts; or release of free compounds of the general formula (I) from their salts; or release of free racemic or optically active compounds of general formula (I) from their salts. 5. The method according to claim 32, characterized in that it comprises reacting the compounds of the general formula (III) without isolation with the compounds of the general formula (IV) or (V), respectively. 6. Pharmaceutical preparation, indicated by the fact that it comprises as an active ingredient a racemic or optically active isoquinoline derivative of the general formula (I) [image] where: R denotes hydrogen or a C1-6 alkoxy group of a normal or branched chain; R 1 denotes hydrogen or a C 1-6 alkyl group of a normal or branched chain; R 2 represents hydrogen or a C 1-6 alkyl group of a normal or branched chain; R 3 denotes hydrogen, a C 1-6 alkyl group of a normal or branched chain optionally substituted with 1 or 2 hydroxy and/or 1 or 2 C 1-4 alkoxy groups of a normal or branched chain; or a C4-7 cycloalkyl group; R 4 denotes hydrogen or a C 1-6 alkyl group of a normal or branched chain optionally substituted with 1 or 2 hydroxy groups and/or 1 or 2 C 1-4 alkoxy groups of a normal or branched chain; or a C4-7cycloalkyl group or R3 and R4 together with the nitrogen atom to which they are attached form a 4-8-membered cyclic group of the formula [image] optionally substituted with 1 or 2 C1-4 alkoxy of a normal or branched chain and/or 1 or 2 C1-4 alkyl groups of a normal or branched chain, where optionally an oxygen or sulfur atom or an N-R5 group can be substituted for a carbon atom of the ring, where R5 denotes hydrogen or a C1-6 aliphatic alkyl group of normal or branched chain, the 4-8 membered ring is optionally condensed with a benzene ring; R6 denotes hydrogen or a C1-10 acyl group, or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable hydrate of the free compound of the general formula (I) or its salt in admixture with carriers and/or additives commonly used in the pharmaceutical industry. 7. A process for obtaining a pharmaceutical preparation, indicated by the fact that it comprises mixing the active composition, racemic or optically active isoquinoline derivatives of the general formula (I), where R, R1, R2, R3, R4, R5 and R6 are as defined in the claim 34 or its pharmaceutically acceptable salts or hydrates of the free compound of the general formula (I) or its salt, obtained according to the process of claim 32, with carriers and/or additives usually used in the pharmaceutical industry and transforming it into a pharmaceutical preparation.