HU211274A9 - Novel compounds and pharmaceutical compositions containing them - Google Patents

Description

The present invention relates to a novel formula (I)

R is hydrogen, straight or branched C 1 -C 6 alkoxy,

R ¹ is hydrogen or C 1 -C 6 straight or branched alkyl,

R ² is hydrogen or C 1 -C 6 straight or branched alkyl,

R ³ is hydrogen, C 1 -C 6 alkyl optionally substituted by C 1 -C 6 straight or branched chain, optionally substituted by one or two hydroxy and / or one or two C 1 -C 4 straight or branched alkoxy groups, or

C4-C7 cycloalkyl,

R ⁴ is hydrogen. C 1 -C 6 alkyl, C 1-6 straight or branched, optionally substituted with one or two hydroxy and / or one or two C 1-4 straight or branched alkoxy groups. Or C4-C7 cycloalkyl;

a group of 4-8 members. optionally substituted with up to two C 1 -C 4 straight or branched alkoxy groups and / or up to two C 14 straight or branched alkyl groups, optionally substituted with one carbon atom selected from oxygen, sulfur and [j N-R ^5].

- where R ⁵ is hydrogen or C 1-6 straight or branched aliphatic alkyl - optionally the 4- to 8-membered ring may be fused to a benzene ring;

R ⁶ is hydrogen or C 1 -C 10 acyl - compounds and their salts, their preparation, pharmaceutical compositions containing them and their preparation.

R may mean, inter alia, the following alkoxy groups: Methoxy. ethoxy. propyloxy, isopropyloxy. butoxy, pentoxy. hexyloxy.

^R1 and ^R2 as methyl. ethyl. propyl, isopropyl. butyl. isobutyl. tert-butyl. Ed-butyl. pentyl, i-pentyl may be R ⁴ and R ⁴ and

R ¹ and R ² , and 2-hydroxyethyl, among others. cyclohexyl. piperidino. pipcrazinil-. 4-methyl-1-piperazinyl, morpholino. hexamethyleneimino or 1-pyrrolidino. R ⁶ is for example an acetyl or benzoyl group can.

The compounds of formula (I) were previously unknown in the literature and may be prepared by hydrolyzing a compound of formula (II) wherein R, R ¹ and R ² are as defined in claim 1, X is a halide ion, and the resulting compound of formula (III) wherein R, R 'and R ² are as defined in claim 1, Me is a metal atom compound a) a compound of formula (IV): wherein

Y is a halogen atom or an arylsulfonyl group, is reacted with a racemic or optically active amino alcohol derivative. obsession

(b) a compound of formula (V): wherein:

with the epoxypropylamine derivative according to claim ¹ , wherein R, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 1, R ⁶ is hydrogen. optionally acylating the active compounds to a compound of formula I where R ⁶ is as defined in claim 1 but different from hydrogen, or resolving the racemic compounds of formula I in either manner known per se or by racemic or optically active The salts of the compounds of the formula I are formed or liberated from the salts of the compounds of the formula I.

According to the process of the present invention, the hydrolysis of the compounds of formula (II) can be carried out in aqueous organic solvents, preferably aqueous aliphatic alcohols, by addition of bases, preferably alkali metal hydroxides. In a preferred embodiment, the reaction mixture is carried out at the boiling point of the solvent mixture by adding the alkali metal hydroxides or their aqueous solutions to the reaction mixture. However, the hydrolysis of the compounds of formula (Π) also occurs at lower temperatures, so that the hydrolysis can be carried out by stirring at room temperature.

Although the hydrolysis of the compounds of formula (II) begins already after the addition of one molar equivalent of alkali, the process is rather slow and it is advisable to use an excess of alkali. Ameny2

If the compounds of formula (111) are reacted with the compounds of formula (IV) or their salts or salts of compounds (V), the amount of alkali required to liberate the bases may be added to the reaction mixture by hydrolysis of the compounds of formula (II). When the thiols (III) are reacted with salts of the compounds (IV), the reaction is conveniently carried out in the presence of 2-6 mol of alkali. When the compounds of formula (IV) or (V) are added in the form of a base, the amount of alkali used is reduced proportionally.

The thiols of formula (III) which, after hydrolysis, are in solution in the form of their salts are conveniently reacted with the compounds of formula (IV) or (V) without isolation. The compounds of formula (IV) or (V) may be added to the reaction mixture in the form of their salts or in the solid state. salts of compounds of formula (IV) or (V) in water or water-miscible organic solvents. preferably dissolved in a mixture of alcohols and then added dropwise to the reaction mixture. The dropwise addition may be carried out at reflux temperature of the reaction mixture or may be carried out at lower temperatures. The compounds of formula (IV) or (V) may also be used in the form of the free base and may be added in the presence or absence of a solvent.

After the addition of the compounds of formula (IV) or (Vi), the reaction mixture is either refluxed or cooled at a lower temperature, if necessary with further cooling. The compounds of formula (I) formed during the reaction remain in solution as the free base. After completion of the reaction, the products of formula (I) are isolated by conventional processing methods, preferably the carbon solvent is distilled off in vacuo, and the products of formula (1) are separated from the remaining aqueous medium as an oily substance or crystalline. the base crystallizes, is isolated from the mother liquor by filtration, and the oily crude products are separated from the aqueous phase by extraction, using water-immiscible solvents commonly used for this purpose, such as ethers. e. g., hydrocarbons, halogenated hydrocarbons, etc. After extraction, the solutions are dried and the solvent evaporated in vacuo. The evaporation residue is an oily substance which crystallizes on standing or rubbing on several occasions. since crystalline and oil-like materials may be present among the bases of the compounds of formula (I).

The purification of the crude products of formula (I) may be carried out on the crude bases or may be carried out in the same manner. to form the crude bases into salts with mineral or organic acids and, if desired, further purifying the salts. Methods of purification, such as recrystallization, are commonly used in organic synthetic chemistry. chromatographic procedures, etc. used. Preferred and pharmaceutically acceptable salt-forming compounds are, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid or phosphoric acid, citric acid, acetic acid, formic acid, succinic acid, lactic acid, malonic acid, maleic acid, propionic acid, fumaric acid, organic acid.

When the compounds of formula (I) are converted into salts with optically active acids, it is possible to separate the optically active antipodes by crystallization of the salts. The process may be carried out under conventional resolution conditions with optically active acids commonly used for this purpose, such as d-tartaric acid and its derivatives, d-camphorsulfonic acid, d-camphoric acid and the like. The salt formation may be carried out in organic solvents or mixtures thereof, and the crystallization salts may be purified by recrystallization from organic solvents, preferably alcohols (ethanol, isopropanol). After resolution, the addition of alkali gives the optically active bases. With mineral acids, the salts of antipodes with mineral acids can be obtained without the release of bases, which can be obtained from the optically active bases with mineral acids.

Compounds of formula I wherein R ⁶ is C 1 -C 10 acyl are prepared by acylation of compounds of formula I. wherein R ⁶ is hydrogen. The acylation can be carried out in a manner known per se with acid halides, acid anhydrides, preferably in the presence of organic or inorganic bases. The reaction may be carried out with or without a solvent, e.g. excess acylating agent (acetic anhydride). Suitable solvents are all solvents which do not react with the acylating agents (e.g. hydrocarbons, halogenated hydrocarbons, pyridine). The products were isolated by evaporation and crystallization according to conventional methods.

The starting compounds of formula (II) are known from U.S. Patent No. 2,426,267. From the German Patent Application. where their preparation is also described.

The compounds of formula (IV) are known and are prepared according to J. Org. Chem. 25, p 1424 (1960). The compounds of formula (V) are known and are prepared according to J. Am. Chem. Soc. 80 p 1257 (1958).

The incidence of bronchial asthma, especially allergic diseases, is increasing. The reason for this growth is socio-economic-environmental factors, increased diagnostic efficiency, and the lack of appropriate, truly curative therapy. In spite of the increasing use of medicines, the mortality rate is also increasing, partly as a result.

Asthma is characterized by an increased sensitivity of the airway smooth muscle to a variety of stimuli, which leads to reversible narrowing and obstruction of the airways. Chronic asthma sometimes results in irreversible airway obstruction.

This is due to the uncontrolled inflammation of the airways. Therapy based solely on bronchodilation, which does not interfere with, or even obscure, the above process, is merely symptomatic, essentially harmful and is likely to contribute to an increase in the death rate.

HU 211 274 A9

In contrast, anti-inflammatory therapy suppresses inflammation and at least slows down the deleterious background process and reduces the need for concurrent, separate bronchodilator therapy.

A further problem with currently available drugs is the existence of adverse side effects which greatly reduce their utility.

Based on the above, a drug would provide optimal therapy that is effective against mediators that cause respiratory smooth muscle spasms, but also has anti-inflammatory and anti-allergic effects and has no adverse side effects.

Due to the pathological nature of bronchial asthma, the existence of as many constrictors or even inflammatory mediators is important because a variety of endogenous substances act together. It is arbitrary to assume the prominent role of any component. Therefore, it is important to coexist with each of the above listed effects for the development of bronchial asthma for these drugs.

In pharmacological studies of compounds of formula I, they have been found to antagonize the action of constructor-type mediators (e.g., histamine, acetylcholine, serotonin), to exhibit antiallergic activity and to have anti-inflammatory activity. Based on the foregoing, it has a reservoir-inhibitory effect (similar to β-2 antagonists or theophylline). and anti-allergic. or antiinflammatory agents (like glucocorticoids, cromolvn or nedocromyl) have the compounds of formula ti).

Thus, the therapeutic needs outlined below will be largely met by the new compounds of formula (I) after administration by a reservoir. antiallergic and anti-inflammatory activity without adverse side effects and favorable toxicity.

The pharmacological effects described above were determined using the following methods.

/. SPASMOGENE AGAINST MEDIATORS

IMPACT ASSESSMENT [J. C. Castillo I /) modified method]

Isolated organ ι tests were performed as follows:

300-400 g guinea pigs of both sexes with OHF Lt / R9 strain were over-anesthetized with pentobarbital. Their trachea was removed and cut lengthwise into the opposite side of the smooth muscle. Subsequently, a strip-like preparation was obtained in the form of an article-shaped cut.

His organs were suspended in a 37 ° C organ bath bubbled with carbogen gas (95¾ O ₂ + 5% CO ₂ ) containing 35 ml of Krebs solution.

A resting load of 0.5 g was applied. During the half-hour incubation period, several washes were performed.

The change in airway muscle tension is isometric. It was followed by a Grass FT-03 type gauge sensor. Following a cumulative dose series of a given mediator (e.g., histamine), washing was applied. After the baseline was recovered, 15 minutes after the tax administration of the test inhibitor (anlastic agent), a further cumulative dose of the mediator was followed. In the case of inhibitory effect, the dose level of the second mediator dose was reduced compared to the first (control) magnitude.

To characterize the degree of competitive antagonist activity, pA ₂ was determined according to the Schield (2) method. A pd ' ₂ value was used to characterize the potency of the non-competitive antagonist (3). The higher the pA ₂ and pd ' ₂ values, the stronger the antagonistic effect.

Theophylline was used as reference material.

Against histamine, the pd ' ₂ value of theophylline = 5.80

Theophylline has a pd ' ₂ value of 6.43 versus acetylcholine

Against serotin, the pd ' ₂ of theophylline = 6.49 (1) JC Castillo et al; Exp. Ther. 90 p. 104 (1947) (2) Η. O. Schield; J. Pharmacol. 4 p.m. 277 (1949) (3) JM Van Rossum; Arch Int Pharmacodyn 143 p. 317-321 (1963)

The results of the above-described testing of the compounds of the formula I according to the invention are described in

Table 1 summarizes.

/. Spreadsheet

Example number illustrating the preparation of the compound of formula I tested Isolated guinea pig tracheal contraction effect on smooth muscle histamine: pd ' ₂ First 5.04 Second 4.91 Third 4.57 4th 4.30 5th 4.34 6 6.69 7th 4.76 8th 4.87 9th 4.38 10th 3.98 11th 4.45 12th 4.81 13th 4.90 14th 4.58 15th 4.46 16th 4.49 17th 5.74 18th 6.91 19th 4.01 20th 21st 5.54 22 5.14 23rd 4.76 24th 5.93 25th 6.38 26th 5.06 27th 6.27 28th 6.36 theophylline 5.80

HU 211 274 A9

11. ANT1ALLEROGICAL EFFECTS

1. The effect on active local anaphylactic reaction was measured according to M. Koltay's method (4).

Weighing 160-180 g, female. OFA rats were sensitized to 50 g of AL (OH) ₃ gel by absorbing bovine serum albumin (BSA) in parallel with Bordalella pertussis vaccine.

The anaphylactic reaction was elicited on day 14 by injecting 100 µg BSA under the scalp of the right hind paw.

Measurements were made before and 30 minutes after the reaction was induced. The test compound was orally administered 1 hour prior to BSA administration. Results are expressed as percent inhibition relative to control group (% mean +/- SEM).

(4) M. Koltay. Arch. Allergy. App. Immun. 71 p. 181-187. (1983).

2. Acute antiinflammatory activity was measured using the rat carrageenan foot edema test (5).

Female CFY rats weighing 100-120 g were fasted for 24 hours.

Inflammation was induced by injecting 0.1 ml of 1% carrageenin subcutaneously in the right hind foot.

Inflammation was measured using a Ugo-Basilc plethysmomcter. Measurements were taken before, and after 1.5 to 3 and 4.5 hours after the onset of inflammation

The test compound was administered orally 1 hour before the injection of carragenin.

The effect was expressed as the percent inhibition relative to the control group.

(5) C. A. Winker. R. A. Ricle}. G-W. Nuss, Proc. Soc. Exp. Med. 544-547. (1962).

3. Rat Dextran Foot Edema Test.

Experiments were performed according to the method of S. Gourvaisier and R. Dúc (6)

The procedure of the experiment is as described for the Carragenin Edema Test. with the exception that measurements were taken between 30 60. 90. 120 and 180 minutes after the onset of inflammation.

(6) Arch. Int Pharmacodyn. Ther. 102 p. 33. (1955).

For use as a pharmaceutical, the compounds of the formula I and their salts, after the addition of additives, are in the form of tablets, dragees, suppositories according to the usual methods in the pharmaceutical industry. capsule, solution, powder mixture or in the form of an injection or inhalation formulation. The salts of the compounds of formula (I) are generally well soluble in aqueous media. therefore, they can be readily used to formulate solutions which can be used in medicine either by injection or by inhalation.

In the above studies, the following reference molecules have been used, the activity data of which are also given:

1. Inhibition of contraction of guinea pig isolated tracheal smooth muscle spasmogenic mediators

histamine serotonin acetylcholine Teoflllin / dp'2 5.80 6.16 6.43

2. Effect on active local anaphylactic reaction in rat

compound oral dose (mg / kg) percent protective effect at 30 minutes naproxen 30 2.2 BW 755C 50 52.9 dexamelhasone 0.5 45.5

3. Rat Carragenin Foot Edema Test:

compound oral dose * Mg / kg (h) percent protective effect 1.5 3 4.5 hours naproxen 20 33.2 44.3 40.4

4. Rat Dextran Foot Edema Test:

take a seat - oral dose (Mg / kg) percent protective effect 30 60 90 120 180 minute naproxen 20 16.9 20.1 18.9 23.3 21.6 BW-755C 50 15.4 12.3 17.2 7.9 11.3 dexamethasone Sone 0.5 42.7 36.8 51.1 52.1 45.5

Further details of the invention are illustrated by the following examples, without limiting our claims.

Example I

3.85 g of S- [α-Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene] methyl] -isothiouromium bromide (preparation described in our previous patent: 2,426). German Patent Application No. 267).

of ethanol and 20 ml of water while heating. To the solution was added 16.0 ml of 10% sodium hydroxide, the reaction mixture was refluxed for 1.5 hours and 1.7 g was added dropwise.

A solution of 3-diethylamino-1-chloropropanol-2 in 10 ml of methanol was prepared by reaction of diethylamine and epichlorohydrin in methanol according to a method known in the literature, J. Org. Chem. 25, 1424 (1960)]. The reaction mixture was refluxed for 6 hours and the organic solvent was evaporated in vacuo. To the residual water-to-oil mixture was added dropwise HCl to pH 5-6, the solution was decolorized with charcoal, filtered and the filtrate basified with 10% sodium hydroxide. A yellow oil separates which solidifies on scratching. Filter, dry and dissolve in 20 ml of isopropanol. The solution was dissolved in hydrochloric acid abs. acidify with alcohol5

HU 211 274 A9 after all. 1.8 g of 2- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-diethylamino-2-hydroxypropyl) mercaptoacetonitrile hydrochloride are obtained. M.p. 179 Analysis: C ₂₀ H ₃₀ ClN ₃ O ₃ S Molar weight: 427.99

Calculated Found

N, 9.82

Cl 8.28 8.40

S, 7.49 7.50%.

Example 2

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide are 3dimethylamino-1-chloropropanol-2-ve. By working in the same manner as in Example 1, 2.1 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-diethylamino-2-hydroxypropyl) -1-mercaptoacetonitrile hydrochloride are obtained. .: 149 '.

Analysis: C ₂₂ H ₃₄ ClN, O ₃ S. Molecular weight: 456.04

calculated Found N 9:22 9.08 cl 7.77 7.93 s 7:03 7:31%

Carregenin Rat Foot Edema Test

50 mg / kg 1.5 3 4.5 hours per os percent védőhalás -22.9. -20.6. -11.3

Inhibition of rat dextran scab

50 mg / kg 30 60 90 120 180 minutes per os percent inhibition -24 -21 -25 -23 -17

Example 3

3.85 g of S-o-cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isururonium bromide

Working with 3- (N-methyl-N-2-hydroxyethyl) amino-1-chloropropanol-2 in the same manner as in Example 1

2.6 g of 2- (6.7-dimethoxy-1.2.3.4-tetrahydro-1-isoquinolylidene-2 - [(3-N-methyl-N-2-hydroxyethylamino) -2-hydroxypropyl] -mercaptoacetonitrile hydrochloride are obtained. m.p .: 136 ¹ (abs. ethanol).

Analysis: C |. ₉ H ₂ S ClN, O ₄ S Molar weight: 429.96

calculated Found C 53.07 52.82 H 6:56 6.82 N 9.77 9:40 cl 8.25 8.13 s 7:46 7.50%

Example 4

3.85 g of S- [alpha] -Cyano-α- (6.7-dimethoxy-1.2.3.4-telrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

Working with 3- (N-bis-2-hydroxyethylamino) -1-chloropropan-2-ol in the same manner as in Example 1, 2.3 g.

2- (6.7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2 - [(3-NN-bis-2-hydroxyethylamino-2-hydroxypropyl] mercaptoacetonitrile hydrochloride- Dihydrate, m.p. 135 '(from 96% elanol).

Analysis: C ₂₀ H ₃₄ ClN ₃ O ₇ S Molecular weight 496.02

calculated Found C 48.43 48.66 H 6.91 6.77 N 8.47 8.25 cl 7.15 7.45 s 6.46 6.31%.

Rat Carragenin Foot Edema Test:

mg / kg 1.5 3 Percentage Protective Effect 4.5 hours -25.0 -26.0-24.0

Example 5

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide 3 (N, N-bis-2) -hydroxyethylamino) -1-chloropropan-2-ol in the same manner as in Example 1, 3.1 g.

2- (6,7-diethoxy-1,2,3,4-tetrahydro-l-isoquinolinylidene) -2- [(3-N, N-bis-2-hydroxyethylamino) -2-hydroxypropyl] mercapto acetonitrile hydrochloride was obtained. M.p. 165 '(absolute ethanol).

Anal

calculated Found C 54.14 54.14 H 7.02 7.00 N 8.61 8.61 cl 7.27 7.31 s 6.57 6.30%

Rat Carragenin Foot Edema Test:

50 mg / kg 1.5 3 4.5 hours per os percent protective effect -21.0 -16,5-10, C

Example 6

3.85 g of S- [α-Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

By working with 3-isopropylamino-1-chloropropan-2-ol in the same manner as in Example 1, 2.6 g of 2- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- ( 3-Isopropylamino-2-hydroxypropyl) -mercaptoacetonitrile) -hydrochloride hemihydrate is obtained. 176 '(from isopropanol). Analysis: C ₁₉ H ₂₈ ClN ₃ O ₃ S.0.5H ₂ O Molar weight: 422.97

calculated Found C 53.95 53.60 H 6.91 6.69 N 9.94 10.24 cl 8.38 8.47 s 7.58 7.60%

Rat Carragenin Foot Edema Test:

50 mg / kg 1.5 3 4.5 hours per os percent protective effect 0 -17.0 0

Example 7

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide with 3-isopropylamino-1-chloropropan-2-ol in Example 1

Working in the same manner as described in A9, 2.8 g of 2- (6,7-diethoxy, 2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-isopropylamino-2-hydroxypropyl) mercapto acetonitrile hydrochloride was obtained. 185 ° (from isopropanol).

Analysis: C ₂₁ H ₃₂ ClN ₃ O ₃ S Molecular weight 442.01

calculated Found c 57.06 56.78 H 7:30 7.35 N 9.51 9.70 cl 8.02 8.31 s 7:25 7.05%:

Example 8

To 3.85 g of S- (a-Cyano-a- (6.7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide is added 80 ml of ethanol and 20 ml of water, and heat to dissolve the solid (1-2 minutes) Add 16.0 mL of 10% sodium hydroxide, reflux for 1.5 h, and add 2.02 g of 3-tert-butylamino-1 in portions. (Prepared by reaction of butylamine and epichlorohydrin in methanolic solution as described previously, followed by separation of the crude base from isopropanolic solution with hydrochloric alcohol. m.p. 160 DEG C.) The reaction mixture was refluxed for 5 hours. The crude base as a yellow oil crystallizes, m.p. 112 DEG, 3.6 g. 3,4-Tetrahydro-1-isoquin olidene) -2- (3-tert-butylamino-2-hydroxypropyl) mercaptoacetonitrile hydrochloride. Mp: 177 '.

Analysis: C ₂₀ H, CIN _; O ₃ S Molar weight: 427.99

Calculated Found C 56.12 56.40 H 7.07 6.87 N 9.82 9.82 cl 8:28 8:38 S 7:49 7.72%. Example 9 4.15 g of S- [α-Cyano-α- (6.7-diethoxy): 1,2,3,4-tetrahydroisoquinolyl

of ro-1-isoquinolylidene) methyl] isothiuronium bromide, treated with 3-t-butylamino-1-chloropropanol-2-hydrochloride in the same manner as in Example 8, 2.4 g of 2 (6,7-diethoxy-1.2.3, 4-Tetrahydro-1-isoquinolylidene) -2- (3-tert-butylamino-2-hydroxypropyl) -mercaptoacetonitrile hydrochloride hemihydrate is obtained. M.p. 160 '(from isopropanol).

Analysis: C ₂₂ H ₄ ClN ₃ O ₃ S.0.5H ₂ 0 Molar weight 465.05

Calculated Found C 56.82 56.70

H 7.59 7.76

N, 9.04 9.00

Cl 7.62 7.95

S 6.90 6.82%.

Example 10

3.85 c from S-la-Cyano-a-1,6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

2.7 g of 2- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) were treated with 3-cyclohexylamino-1-chloropropan-2-ol in the same manner as in Example 1. 2- (3-cyclohexylamino-2-hydroxypropyl) -mercaptoacetonitrile hydrochloride is obtained. M.p. 190 '(from isopropanol). Analysis: C ₂₂ H ₃₂ ClN ₃ O ₃ S Molecular weight 454.02

calculated Found C 58.20 58.00 H 7.10 7.40 N 9.26 9.02 cl 7.81 7.81 S 7.06 6.86%.

Rat Carragenin Foot Edema Test:

50 mg / kg 1.5 3 4.5 hours per os percent protective effect -14.8 -13.0 -7.2

Rat dextran soles:

mg / kg 30 60 90 120 180 min Percent inhibition -25 -24 -25 -27 -50 //. example

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide with 3-cyclohexylamino-1-chloropropan-2-ol In the same manner as in Example 1, 2.6 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-cyclohexylamino-2-hydroxypropyl) mercaptoacetonitrile hydrochloride. M.p. 182 '(from isopropanol).

Analysis: C ₂₄ H ₃₆ ClN ₃ O ₃ S Molar mass 482.08

calculated Found C 59.79 60.02 H 7.53 7.50 N 8.72 8.65 cl 7.36 7.16 s 6.65 6.45%.

Example 12

3.85 g of S- [α-Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

Working with 3- (1-pyrrolidino) -1-chloropropan-2-ol in the same manner as in Example 1, 2.1 g of 2- (6,7-dimethoxy-1,2,3,4-tetrahydro-1- isoquinolylidene) -2- [3- (1-pyrrolidino) -2-hydroxypropyl] -mercaptoacetonitrile hydrochloride hemihydrate is obtained. M.p. 194 ° (from ethanol).

Analysis: C ₂₀ H _{2 g} ClN ₃ O ₃ S.0.5 ₂ O Molar mass: 434.98

calculated Found C 55.22 55.18 H 6.72 7.03 N 9.66 9.90 cl 8.15 8.15 s 7.37 7.55%

Rat Carragenin Foot Edema Test:

50 mg / kg 1.5 3 4.5 hours per os percent protective effect -27.2 -18.9 -17.6

HU 211 274 A9

Rat dextran soles:

mg / kg 30 60 90 120 180 min Percent Inhibition -20.2 -15.6 -14.7 -14.6-12.6

Example 13

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

with (1-pyrrolidino) -1-chloropropan-2-ol as in Example 1. in example working in the same way as written 2.6 g 2- (6,7-diethoxy 1,2,3,4-tetrahydro-1 -isoquinol ylidene) -2- [3- (1 pyrrolidinyl) - 2-hydroxypropyl] -mercapto-acetonitrile hydrochloride we get. Op .: 195 ' (absolute ethanol). Analysis: C ₂₂ H ₅₂ ClN _? O, S Molecular Weight: 454.02 calculated Found C 58.20 57.92 H 7:10 7:30 N 9:26 9:20 cl 7.81 7:48 s 7:06 6.82%. Rat Carragenin Foot Edema Test: 50 mg / kg 1.5 3 4.5 hours per os percent protective effect -31.8-21.8 -9.05 Example 14 3.25 g S- | c /.- Cu inn-a-i 1.2.3.4-tetrahydro-1-isoquino- lilidene) methyl from l-isothiuronium bromide 3- | piperidino-1 - chloro-propan-2-ol in the same way as in Example 8 working on the don 2.1 t : 2-t 1.2.3.4-Telrahydro- 1-isoquinolyl den) -2- (3-pipendine) o-2-hydroxypropyl) -merkaplo-aceto- nitrile was obtained. op .: 103 '(from isopropanol) Analysis: C, H; N _: OS Molecular Weight: 343.48 calculating Found C 66.43 66.17 H 7:34 7:14 N 12:23 12:50 S 9:34 9:24%.

The hydrochloride salt of the product is abs. hydrochloric acid abs. ethanol. M.p .: 187.

Inhibition of active local anaphylactic reaction.

Effect of an oral dose of 30 mg / kg body weight within 30 minutes of reaction induction: - 44.1%.

Rat carragenin foot test:

mg / kg 1.5 3 4.5 hours oral percentage protective effect -20.9 -20.0 -20.0

Example 15

3.85 g of S-cis-cyano-α- <6.7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene i-methyl 1-isothiouronium bromide are dissolved in 80 ml of ethanol and 20 ml of water with heating, 16 ml of 10% sodium hydroxide solution are added to the solution. The reaction mixture was refluxed for two hours and then cooled to room temperature. While stirring, the reaction mixture was added

2.2 g of 3-piperidino-1-chloropropan-2-ol hydrochloride. The reaction mixture was stirred at room temperature for two days and worked up as described in Example 1. 2.7 g of 2- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-piperidino-2-hydroxypropyl) mercaptoacetonitrile hydrochloride are obtained. 210 ° (absolute ethanol).

Analysis: C ^ HH-toClNjOjS Molecular weight: 440.00

calculated Found C 57.32 56.99 H 6.87 7.01 N 9.55 9.32 S 7.29 7.43%

Example 16

3.25 g of S- [α-Cyano-α- (1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide with 3-morpholino-1-chloropropan-2-ol hydrochloride in Example 15 2.7 g of 2- (1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) -mercaptoacetonitrile hydrochloride hemihydrate were obtained in the same manner as described. 195 ° (from ethanol) Analysis: C ₎ 8H ₂₄ ClN, O ₂ S.0.5H ₂ O Molecular weight: 390.93

calculated Found C 55.30 55.10 H 6.44 6.30 N 10.75 10.50 S 8.20 8.37%

Rat Carragenin Foot Edema Test:

50 mg / kg 1.5 3 4.5 hours per os percent védőhalás -29.3 -22.2 -20.0

Example 17

3.85 g of S- [α-Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

Working with 3-morpholino-1-chloropropan-2-ol hydrochloride in the same manner as in Example 15, 3.3 g of 2- (6.7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino) -2-hydroxypropyl) mercaptoacetonitrile hydrochloride is obtained. 210 ° (from ethanol).

Analysis: C ₂₀ H ₂₈ ClN ₃ O ₄ S Molecular weight 441.97

calculated Found C 54.35 54.42 H 6.39 6.52 N 9.51 9.63 cl 8.02 8.00 s 7.26 7.54%.

Inhibition of active local anaphylactic reaction.

Effect of an oral dose of 30 mg / kg 30 minutes after the reaction was induced: -53.4%.

Rat Carragenin Foot Edema Test: 50 mg / kg 1.5 3 4.5 hours per os percent protective effect —4.2 0 0 Rat Dextran Foot Edema Test: 50 mg / kg '30 60 90 120 180 minutes per os percent inhibition 27.5 32.5 32.1 32.4 20.3

HU 211 274 A9

Example 18

To 4.15 g of S- [α-cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide is added 80 ml of methanol and 20 ml of water until the reaction mixture is dissolved ( 1-2 minutes). 11.0 ml of 10% sodium hydroxide solution 5 are added and the mixture is refluxed for 1.5 hours. To the reaction mixture was added 2.2 g of 3-morpholino-1-chloropropan-2-ol hydrochloride. reflux for five hours. The methanol was evaporated, the reaction mixture cooled, and the crude base 10 crystallized. 3.2 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercapioacetonitrile are obtained. M.p. 97 '(absolute ethanol).

Analysis: C ₂₂ H ₃ , N ₃ O ₄ S Molecular Weight: 433.56 Calculated Found 15 C 60.94 60.72 H 7:21 7:40 N 9.69 9.51 S 7:40 7:17%. 20

The hydrochloride salt of the product is abs. from an ethanolic solution by addition of hydrochloric ethanol. Mp: 203 '

nőiből). Analysis: C ₂₂ H _3n ClN, O ₃ SH ₂ O Molecular weight: 506.05 DL ₅ (, = 91.57 mg / kg arc. rat male calculated Found 152.98 mg / kg arc. rat female 25 C 59.33 59.29 165.76 mg / kg iv. mouse male H 6.37 6.38 150. (X) mg / kg iv. mouse female N 8.30 7.96 1204.59 mg / kg after. mouse male cl 7.01 7.03%

1034.65 mg / kg after. mouse female Inhibition of active local analgesic reaction.

mg / kg oral dose 30 min after reaction induction: -31 '<.

Rat carragenin scab test:

mg / kg 1.5 3 4.5 hours oral protective effect -35. 8 -29.5-28.4

Rat dextran foot edema test 30 60 mg / kg oral inhibition 29.8 38.7

120 180 minutes

30.4 26.3 28.4

Example 19

3.85 g of S- [alpha] -Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

Working with 3-hexamethylenimino-1-chloropropan-2-ol in the same manner as in Example 1, 1.7 g of 2- (6,7-dimethoxy-1.2.3.4-tetrahydro-1-isoquinolylidene) -2- (3-hexamethyleneimino- 2-Hydroxy-propyl (mercapto-acetonitrile) was obtained as a yellow oil.

The hydrochloride salt of the product is separated from a solution of ethanol which crystallizes with one mole of crystal alcohol and half a mole of crystalline water. 110-112 (from ethanol). Analysis: C ₂₂ H ₂₂ N 3, G _; S.HC1.C ₂ H <OH. (). 5H ₂ O

Molar weight: 509.10 Calculated Found C date, 48.93 Found 48.96 C 56.62 56.66 H 7.32 7.05 H 7.72 8:05 N 9.92 10.15 N 8:25 8:20 60 S 5.68 6.05%

cl 6.96 6.70 s 6.30 6.65% Rat Carragenin Foot Edema Test: 50 mg / kg 1.5 3 4.5 hours per os percent protective effect -29.0 -24.2 -19.5

Rat dextran soles test:

50 mg / kg per os 30 60 90 120 180 minutes percent inhibition -28.2 -26.6 -27.3 -27.8 -22.8

Example 20

3.85 g of S- [α-Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

Working with 3- (1,2,3,4-tetrahydro-2-isoquinolyl) -1-chloropropan-2-ol in the same manner as in Example 15, 3.1 g.

2- (6.7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2-hydroxypropyl] mercaptoacetonitrile hydrochloride hydrate is obtained. . M.p. 140 '(from ethanol).

Example 21

3.85 g of S- [alpha] -Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide 3- (4-methyl-1-piperazinyl) -1-chloropropan-2-ol] Working in the same manner as in Example 1, 1.7 g of 235 (6.7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2,3- (4-methyl-1 piperazinyl) -2-hydroxypropyl] mercaptoacetonitrile hydrochloride is obtained. Mp: 243 (90% ethanol).

Analysis: C ₂ , H, ₂ Cl ₂ N ₄ O ₃ S, M: 491.48

Calculated, Found C 51.32 51.35 H 6:56 6.61 N 11.40 11.24 S 6.52 6.57%

Example 22

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide 3- (4-methyl-1-piperazinyl) ) Working with 1-chloropropan-2-ol in the same manner as in Example 1, 1.8 g of 2- (6,7-dieloxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (4-Methyl-1-piperazinyl) -2-hydroxypropyl] -mercaptoacetonitrile hydrochloride was obtained from 96% ethanol.

It precipitates out with 2.5 moles of crystalline water. Mp .: 220

Analysis: C ₂₃ H ₃₆ Cl _; N ₄ O ₃ S.2.5H ₂ O Molecular Weight: 564.57

HU 211 274 A9

Example 23

To 4.8 g of 2- (6.7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morolino-2-hydroxypropyl) -mercaptoacetonylryl are added 80 ml of benzene and 32 ml of acetic anhydride, the reaction mixture was refluxed for two hours. After evaporation to dryness in vacuo, the residue is dissolved in isopropanol and the solution is taken up in hydrochloric acid. acidified with ethanol. 4.72 g of 2- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-acetoxypropyl) -mercapioethanonitrile hydrochloride are obtained. M.p. 204 '(abs. Ethanol abs.

Analysis: CsiHroClNrO5S Molecular Weight 484.01

calculated Found c 54.59 54.37 H 6:25 6:16 N 8.68 8.90 cl 7:33 7.41 S 6.63 6:39% Rat earragenin foot edema test: 50 mg / kg 1.5 3 4.5 hours per os percent protective effect -33.8 -30.9 -29.5

Example 24

3.0 g of 2-i6.7-Diethoxy-1.2.3.4-telrahydro-1-isoquinolylidene) -2- (3-mortololio-2-hydroxypropyl) -mercaptoacetone / 50 ml of benzene and 20 ml of acetic anhydride are added. reflux for one hour. Evaporate to dryness in vacuo and crystallize out from the addition of the remaining ether. 2.47 g of 2 (6.7-diethyl-1,2,3,4-teiralidro-1-isoquinolylidene) -2- (3-morpholino-2-acetyl-propyl) -mercapioethanol are obtained. M.p. 135% in isopropanol).

Analysis: C _: 4H; 475.59

Calculated Found

N, 8.84 8.71

S 6.74 6.66%.

Inhibition of the contractile action of acetylcholine: pd - - 5.02

Inhibition of serotonin contractile activity: pd '_; = 5.05

Rat Earragenin Foot Edema Test:

50 mg / kg 1.5 3 4.5 hours per os percent protective effect -25.8 -20.3 -20.0

Example 25

To 4.06 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morolinol-2-hydroxypropyl) -mercaptoacetonitrile is added 40 ml of benzene. Triethylamine (1.0 g) and benzoyl chloride (1.5 g) were added and the reaction mixture was refluxed for three-quarters of an hour. After cooling, the solution is filtered and the filtrate is concentrated in vacuo. The residue crystallized upon addition of ethyl acetate. 3.25 g of 2- (6,7-dimethyl-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morloxy-2-benzoyloxypropyl) mercaptoacetonitrile are obtained in a melting point of 144 ml of isopropanol). Analysis: C, _H;) N .O .Mólsúly ₅ S: 509.61

calculated Found C 63.63 64.03 H 6.13 6.37 N 8.25 8.58 S 6.29 6.37%

Inhibition of the astringent effect of acetylcholine: pd ' ₂ = 4.81

Rat Earragenin Foot Edema Test:

mg / kg 1.5 3 4.5% oral protective effect -26.6 -17.7 -16.0

Example 26

To 4.34 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2 - (- 3-morpholino-2-hydroxypropyl) -mercaptoacetonitrile, 40 ml of benzene, 1.0 g triethylamine and 1.5 g of benzoyl chloride were added and the reaction mixture was refluxed for three-quarters of an hour. After cooling, the solution was filtered and the solvent evaporated in vacuo. The residue was dissolved in isopropanol and the solution was dissolved in hydrochloric acid. acidified with ethanol. 3.77 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-benzoyloxypropyl) mercaptoacetonitrile hydrochloride are crystallized, m.p. ).

Analysis: C10 H13 ClN3 O3 S Molecular weight: 574.13

calculated Found C 60.66 60.80 H 6.32 6.37 N 7.32 7.22 cl 6:18 6.24 s 5:59 5.88%

Inhibition of the astringent effect of acetylcholine: pd = 4.81

Example 27

8.0 g of 2- (6.7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene-2- (3-morpholino-2-hydroxypropyl) -mercaptoacac etonitrile 3.9 g of d-camphorsulfonic acid and 50 ml of anhydrous Ethanol was added and the reaction mixture was heated to dissolve the solid (several minutes) After cooling, the precipitated crystalline material was filtered off and recrystallized from 40 mL of hot absolute ethanol to give 5.0 g of (-) - 2- (6,7-diethoxy-1,2.3-4). (tetrahydroisoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile d-camphorsulfonate, m.p.

The base is separated from the camphorsulfonic acid salt by the addition of sodium hydroxide in aqueous solution.

M.p. 97 °. [a] = -11.3 (measured in 1% chloroform solution)

The hydrochloric acid salt of the product can be isolated from anhydrous ethanolic solution by addition of hydrochloric anhydrous ethanol.

Example 28

the)

The alcoholic mother liquor of Example 27 was evaporated to dryness in vacuo, water was added to the residue, and the solution was made basic with 10% sodium hydroxide. The separated yellow oily material was extracted with chloroform. the chloroform solution is sodium10

After drying over A9 sulfate, the solvent was evaporated in vacuo. The remaining abs. dissolved in ethanol. The solution was acidified with ethanolic hydrochloric acid. 2.65 g of (+) - 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolinidene) -2- (3-morpholino-2-hydroxypropib-mercaptoacetonitrile hydrochloride, m.p. 201 (absolute ethanol).

([a] = 7.7 "(measured in 1% aqueous solution),

b)

From 8.0 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) -mercaptoacetonitrile, 3.9 g of 1-camphorsulfonic acid was prepared in a similar manner to 5.2 g. (+) - 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile-1-camphorsulfonate is obtained. M.p. 169-170 ° (absolute ethanol).

Example 29

0.48 g of 2- (6.7-Dimethoxy-1.2.3.4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-acetoxypropyl) mercaptoacetonitrile hydrochloride (product of Example 23) in 4 ml of 10% sodium hydroxide (6 ml) and ethanol (6 ml) were added and the reaction mixture was refluxed for half an hour. The ethanol was evaporated in vacuo. the oily residue which crystallizes out. Filter, wash with water and dry. 5 ml abs /. dissolved in ethanol with heating, and the solution was dissolved in abs. acidified with ethanol. 0.4 g of 2- (6.7-Dimethoxy-1.2.3.4-tetrahydro-1-isoquinolylidene) -2- (3-inorolino-2-hydroxypropyl) -mercaptoacetonitrile hydrochloride is obtained, which is identical to the product of Example 17. Mp: 210.

Example 30

0.48 g of 2- (6.7-diethoxy-1.2.3.4-tetrahydro-1-isoquinolylidene) -2- (3-morloxy-2-acetoxypropyl) -neraptoacetonitrile (product of Example 24) 4 ml of 10% sodium hydroxide and ethanol (6 ml) were added and the reaction mixture was refluxed for half an hour. The solvent was evaporated. the residue was extracted with chloroform. The chloroform solution was dried over sodium sulfate and the solvent was evaporated. The residue was dissolved in 5 ml of anhydrous ethanol with heating, and the solution was acidified with absolute hydrochloric acid ethanol. 0.38 g of 2- (6,7-diethyl-1,2,3-4-tetrahydro-1-isoquinolylidene) -2- (3-morolinol-2-hydroxypropyl) -mercaptoacetonitrile hydrochloride is obtained. The same as the product of example. M.p .: 203 '.

Example 31

3.85 g of S 1 -Cyano-α- (6,7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline-1-yl) methyl] -1-thiuronium bromide are dissolved in 80 ml of methanol and 20 ml of water under heating. To the solution was added 11.0 mL of 10% sodium hydroxide. The reaction mixture was refluxed for two hours, added dropwise to the warm solution.

1.41 g of a solution of 3-piperidno-1,2-c-propoxypropane (known in the literature: 1. Am. Chem. Soc. 80, 1257 (1958)) in 5 ml of methanol were added and the reaction mixture was refluxed for 5 hours. The methanol was evaporated in vacuo. The reaction mixture was worked up as described in Example 1 (2.3 g of 2-t6.7-dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene ι-2-t-3-piperidino-2-hydroxypropyl). mercaptoacetonitrile hydrides] was obtained which was identical to the product of Example 15. 210 ° (from anhydrous ethanol).

Example 32

4.15 g of S- [α-Cyano-α- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) methyl] isothiuronium bromide

Working with 1.41 g of 3-piperidino-1,2-epoxypropane as in Example 31, 2.6 g of 2- (6,7-diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-piperidino-2-hydroxypropyl) -mercaptoacetonitrile hydrochloride

Claims (38)

PATENT CLAIMS Claims 1. A racemic or optically active isoquinoline derivative of formula (I) - where R is hydrogen, straight or branched C 1 -C 6 alkoxy; R ¹ is hydrogen or C 1 -C 6 straight or branched alkyl; R ¹ is hydrogen or C 1 -C 6 straight or branched alkyl; R 'is hydrogen, C 1-6 alkyl, C 1-6 straight or branched, optionally substituted with one or two hydroxy and / or one or two C 1-4 straight or branched alkoxy, or C 4-7 cycloalkyl -group; R ⁴ is hydrogen, C 1 -C 6 alkyl, C 1-6 straight or branched, optionally substituted with one or two hydroxy and / or one or two C 1-4 straight or branched alkoxy groups, C 4-7 cycloalkyl-; or a group which may be taken together to form a 4- to 8-membered ring optionally substituted with up to two straight or branched alkoxy groups containing from 1 to 4 carbon atoms and / or up to two linear or branched alkyl groups containing from 1 to 4 carbon atoms; oxygen, sulfur ^vagyjíN-R5 group to which R ⁵ is hydrogen, or C 1-6 straight or branched aliphatic alkyl - and optionally the 4-8 membered ring may be fused to a benzene ring; R ⁶ is hydrogen or C 1 -C 10 acyl - and salts of compounds of formula I and hydrates of salts or free compounds. 2. The racemic or optically active compounds of claim 1. wherein R is methoxy or ethoxyII A9 R ¹ and R ² are hydrogen, R ³ is isopropyl, R ⁴ is hydrogen or the group is morpholino, R ⁶ is hydrogen, or benzoyl. The racemic or optically active compounds of claim 1 wherein R, R ¹ , R ² and R ⁶ are as defined in claim 1. is pyrrolidinyl, piperidino. morpholino or hexamethyleneimino. 4- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinol 1-idene) -2- (3-diethylamino-2-hydroxypropyl) -mercaptoacetonitrile or its hydrochloride. 5. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-diethylamino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 6. 2- (6.7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (N-methyl-N-2-hydroxyallylamino) -2-hydroxypropyl] - mercaptoacetonitrile or its hydrochloride. 7. 2- (6.7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinoline 1 idene) -2- (3- NN-bis-2-hydroxyethylamino) -2-hydroxypropyl] mercapto acetonitrile or its hydrochloride or dihydrate of the hydrochloride. 8. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinol) idene) -2- [3- (N, N-bis-2-hydroxyethylamino) -2-hydroxypropyl] - mercaptoacetonitrile or its hydrochloride. 9. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-isopropylamino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride or hemihydrate of the hydrochloride. 10. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-isopropylamino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 11.2- (6.7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-tert-butylamino-2-hydroxypropyl) -mercaptoacetonitrile or its hydrochloride. 12. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-tert-butylamino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride or hemihydrate of its hydrochloride. 13. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolidene) -2- (3-cyclohexylamino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 14. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-cyclohexylamino-2-hydroxypropyl) -mercaptoacetonitrile or its hydrochloride. 15. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (1-pyrrolidino) -2-hydroxypropyl] mercaptoacetonitrile or its hydrochloride or hemihydrate of its hydrochloride . 16. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (1-pyrrolidino) -2-hydroxypropyl] mercaptoacetonitrile or its hydrochloride. 17.2- (1,2,3,4-Tetrahydro-1-isoquinolylidene) -2- (3-piperidino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 18. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-piperidino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 19.2- (1,2,3,4-Tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride or hemihydrate of the hydrochloride. 20. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 21.2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. 22. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-hexamethylenimino-2-hydroxypropyl) -mercaptoacetonitrile or its hydrochloride or hemihydrate of its hydrochloride. 23. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolyl) -2- [3- (1,2,3,4-tetrahydro-2-isoquinolyl) -2 -hydroxypropyl] mercaptoacetonitrile or its hydrochloride or its hydrochloride monohydrate. 24. 2- (6,7-Dimethoxy-1; 2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (4-methyl-1-piperazinyl) -2-hydroxypropyl] mercaptoacetonitrile or its hydrochloride. 25. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- [3- (4-methyl-1-piperazinyl) -2-hydroxypropyl] mercaptoacetonitrile or the hydrochloride or hydrates of its hydrochloride. 26. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-acetoxypropyl) mercaptoacetonitrile or its hydrochloride. 27. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-acetoxypropyl) mercaptoacetonitrile. 28. 2- (6,7-Dimethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-benzoyloxypropyl) mercaptoacetonitrile. 29. 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-benzoyloxypropyl) mercaptoacetonitrile or its hydrochloride. 30. (-) - 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile (+) - camphorsulfonate. 31. (+) - 2- (6,7-Diethoxy-1,2,3,4-tetrahydro-1-isoquinolylidene) -2- (3-morpholino-2-hydroxypropyl) mercaptoacetonitrile or its hydrochloride. HU 211 274 A9 32. The process of the formula I is racemic or optically active -where R ¹ , R ² , R ³ , R ⁴ R ⁵ and R ⁶ are for the preparation of the compounds according to claim 1, characterized in that a compound of the formula II, wherein R ¹ , R ¹ and R ² are as defined in claim 1, X is a halide ion, is hydrolyzed and a) wherein R, R ¹ and R ² are as defined in claim 1 and Me is a metal atom a) a compound of formula IV wherein R is as defined in claim 1. Y is halogen or arylsulfonyl, reacted with a racemic or optically active amino alcohol derivative. obsession b) an epoxy of the formula V in which the group is as defined in claim 1 reacting with a propylamine derivative, the resulting active compounds of formula (I) wherein R, R ¹ , R ² , R ³ , R ⁴ are racemic or optically defined in claim 1, R ⁶ is hydrogen, are optionally known per se. by acylation of the compounds of the formula I, wherein R ⁶ is as defined in claim 1 but not hydrogen, or the racemic compounds of formula I are resolved by methods known per se, or the salts of the racemic or optically active compounds of formula I are formed or releasing optically active compounds of formula I. 33. The process of claim 32, wherein the compounds of Formula III are reacted with the compounds of Formula IV or V without isolation. 34. A pharmaceutical composition comprising one or more compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in Claim 1 and one or more pharmaceutically acceptable compounds thereof. containing a carrier or excipient. A process for the preparation of a pharmaceutical composition comprising one or more racemic or optically active compounds of formula I wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are as defined in claim 1. and converting the compound in association with one or more pharmaceutically acceptable carriers or excipients to form a pharmaceutical composition. 36. A process for preparing the racemic or optically active isoquinoline derivatives of the formula (I) as essentially described and disclosed herein. 37. The novel pharmaceutical composition essentially described and presented herein. 38. The process essentially described and illustrated herein is a compound of formula (I) wherein R, R ', R ² , R ³ , R ⁴ , R ⁵ and R ^{6 are as} defined in claim 34, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. a free compound for the preparation of a pharmaceutical composition comprising a pharmaceutically acceptable hydrate or salt thereof.