DD268948A5 - PROCESS FOR THE PREPARATION OF TETRAHYDROBENZOTHIAZOLE CHINOLINES AND THEIR USE - Google Patents

Abstract

The invention relates to a process for the preparation of novel compounds of general formula I, wherein R1, R2 and R3 are defined in the description. These new compounds are useful as drugs for drugs. Formula I

Description

Characteristic of the known state of the art

Several structural analogues of apomorphine have been synthesized by Berney, D. and Schuh, K., of which the pyrrole compound

and the pyrazole compound

CH ₃

as more well-known compounds to have an apomorphine-like dopaminergic effect (Berney, D., Schuh, K., Helvetica Chimica Ada, 65, 1304-9, 1982).

However, the clinical use of apomorphine is only possible to a very limited extent because of the narrow therapeutic range.

The compound of the formula

(R ₁ - CH,)

is known (Berney, D., Schuh, K., supra.

About a possible dopaminergic effect of this compound but no statement is made. Aim of the invention

The aim of the invention is to propose new dopaminergic acting Vorbindungen that allow a targeted, as possible side effect-free therapeutic use.

Explanation of the essence of the invention The invention has for its object to produce new compounds of formula I. It has been found that compounds of the formula I and their acid addition salts are useful as medicaments when in the

general formula I for

Ri is a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an allyl or propargyl radical, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part,

R _{2 is} a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an allyl or propargyl radical, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part, where the phenyl ring is replaced by fluorine, chlorine, bromine or by a hydroxy, methoxy, Methyl, amino or monosubstituted by a trifluoromethyl or may be disubstituted by these radicals-also in various combinations-wherein the phenyl ring is substituted by one of said substituents preferably in the 4-position, an alkanoyl group having 1 to 3 carbon atoms, which also may be substituted by a mono- or disubstituted phenyl radical as indicated above,

R _{3 is} a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an allyl or propargyl radical

stands.

The definition of R ₂ as alkanoyl group, as optionally substituted phenylalkanoyl group and as optionally

substituted phenylalkyl group having 1 to 3 carbon atoms in the alkyl part is only valid if R _{3 is defined} as H or CH ₃ .

In addition, R, is not a methyl radical, when both radicals R ₂ and R _{3 are} hydrogen. Preferably, the radical R ₁

in addition to hydrogen methyl, ethyl, n-propyl, iso-propyl, butyl, pentyls and hexyls such as. As η-butyl, iso-butyl, tert-butyl, n-

Pentyl, iso-pentyl, n-hexyl, iso -hexyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3-methylpentyl, 4-methylpentyl; the benzyl, one Phenethyl or phenyf-propyl group.

while for the radicals R ₂ and R ₃

in addition to the above-mentioned residues the

4-chlorobenzyl, 4-fluorobenzyl, 4-bromobenzyl, 4-hydroxybenzyl, 4-methoxybenzyl, 4-aminobenzyl, 4-trifluoromethylbenzyl and the corresponding substituted phenylethyl and phenylpropyl groups, the 3,4-dichlorobenzyl, 3 , 4-Difluorobenzyl, 3,4-dibromobenzyl, 3,4-dihydrobenzyl, 3,4-dimethoxybenzyl, 3,4-dimethylbenzyl, 3,4-diaminobenzyl and the corresponding disubstituted phenylethyl and phenylpropyl groups and the corresponding mixed disubstituted benzyl, phenylethyl and phenylpropyl groups which include benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl, 4-aminobenzoyl, 4-trifluoromethylbenzoyl, 4-chlorophenylacetyl, 4-fluorophenylacetyl, 4-bromophenylacetyl, 4 Hydroxyphenylacetyl, 4-methoxyphenylacetyl, 4-

Methylphenylacetyl, 4-aminophenylacetyl, 3- (4-chlorophenyl) propanoyl, 3- (4-fluorophenyl) propanoyl, 3- (4-bromophenyl)

propanoyl, 3- (4-hydroxyphenyl) propanoyl, 3 (4-aminophenyl) propanoyl, 3- (4-methoxyphenyl) propanoyl, formyl, acetyl or propionyl group

be considered.

Particularly preferred compounds of the above general formula I are compounds in which

Ri is a hydrogen atom, an alkyl group having 1 to 4, especially 3 carbon atoms, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part,

R _{2 is} a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkanoyl group having 1 to 3 carbon atoms, which may be substituted by a phenyl radical or by chlorine, bromine, fluorine, a hydroxy, methoxy, methyl, amino or a trifluoromethyl group mono- or di-substituted phenyl radical,

R _{3 is} a hydrogen atom or an alkyl group having 1 to 3 carbon atoms

where Ri is not methyl when both R ₂ and R _{3 are} hydrogen.

The new compounds can be used as racemates or pure enantiomers, but also as mixtures of the enantiomers in any Conditions exist. Surprisingly, it has been found that the compounds of the formula I according to the invention have a strong, highly selective

develop presynaptic dopamine agonistic action and open up more targeted and effective therapeutic uses compared to the prior art.

The sought effect is found predominantly in one of two enantiomeric forms, generally in the (-) - Enantiomers. For the influence of the substituents on the effect qualities of the new compounds, certain trends can be observed. This is how chain extensions can have a positive effect. For example, it has been shown that - with unchanged meaning

of R ₂ and R ₃ (e.g., both hydrogen) and variation of R, - the chain extension of methyl via ethyl to propyl is one

Increasing the effect entails; this shows up u.a. in increased dopamine utilization (see below). For the preparation of the novel compounds of formula I are known per se methods:

1. A benzoquinoline compound of the formula is halogenated

(III)

wherein Ri has the above meaning, preferably with bromine, and then sets the resulting halogen derivative of the compound III with a «; m thiourea of the general formula

(IV),

with the radicals R ₂ and R ₃ as described above.

The halogenation can within a wide temperature range, advantageously at 0-100 ⁰ C, preferably at 15-35 ⁰ C and advantageously in a suitable solvent, such as. As glacial acetic acid, chlorinated hydrocarbons, lower aliphatic alcohols such as methanol or ethanol, take place.

The reaction of the Halogenderiyats the compound III with IV is carried out between 0 ⁰ C and 150 ⁰ C, preferably between 50 and 7O ⁰ C in the used in the halogenation or another suitable solvent, for example lower alcohols.

The starting materials of the formula III are known or can be obtained by conventional methods. The following synthetic scheme shows the preparation of the starting materials of formula III and the reaction pathway described:

NaOH

III

Pol yposphoric acid

11.BrCH ₂ -COOEt 12.NaBH ₄

EtOOC-H ₂ C

R '

NC-NH ₂

2. dealkylation of a compound of the formula

(0,

where R _{1 is} a group to be removed by known Entaikylierungsverfahren and replaced by hydrogen, preferably methyl or benzyl, and R ₂ and R _{3 have} the meaning described above. The Entmethyiierung can be useful, for example oxidatively with perbenzoic acid and iron (II) chloride, carry out the debenzylation most easily catalytically with hydrogen in the presence of palladium-carbon

 3. Amidation of a compound of the formula

(Π,

wherein R ₂ 'and R ₃ ' are hydrogen and R / has the meaning described for R ₁ in formula I, with eir em acid chloride of the formula

R - C - Cl

4 Il 0

wherein R _{4 may represent} one of the alkyl or phenyl groups described above in the acyl or phenylacyl radicals described for R ₂ .

The reaction takes place in a wide temperature range, preferably at 0-100 ⁰ C, in an inert solvent, such as Tetrahydrofu. on, dimethylformamide, ethanol, chlorinated hydrocarbons, in the presence of an acid-binding agent such as NaHCO ₃ , Na ₂ CO ₃ , K ₂ CO ₃ , CaO or triethylamine, ethyldicyclohexylamine, pyridine, at reflux temperature.

4. Reduction of a compound of the formula

(D,

wherein R ₁ "has the meaning described for R ₁ in formula I and R ₂ " acyl or phenylacyl radicals and R ₃ "are hydrogen, in a suitable solvent, such as ether, dioxane, preferably tetrahydrofuran, with a complex

Metal hydride, preferably lithium aluminum hydride, at temperatures between -10 and 15O ⁰ C, preferably at 0 to The following synthesis scheme shows the above-described reaction routes 2, 3, and 4 .:

Perbenzoesöure

FeCl

VII

U) tartaric acid (-) - tartaric acid

(-hEnantiomer (+) - enantiomer

LiAlH,

R ₂ -N- <'HS

R

VI

The resulting racemic compounds of general formula I can be prepared by conventional methods in their enantiomers

separated, for example by column chromatography on a chiral phase, or by separation of their diastereomers

Salts with optically active acids such as tartaric acid, 0,0-Dibenzoyl-wainsäurd, camphoric acid, camphorsulfonic or

a-methoxy-phenylacetic acid by means of fractional crystallization or by column chromatography of their conjugates.

The resulting compounds of formula I can be in their acid addition salts, in particular in their physiological

convert compatible acid addition salts with inorganic or organic acids. Examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid,

Succinic acid, maleic acid, fumaric acid or oxalic acid into consideration. As far as salts are initially obtained, these can

be transferred by conventional methods in the free bases.

The Ve. Bindur.gen the general F τηβΙ I are the known from the prior art compounds in their

clearly superior to pharmacological properties. Particularly valuable are the (-) - enantiomers, preferably with Ri as

Ethyl or propyl group. The novel compounds and their physiologically compatible acid addition salts are suitable

due to its / surprising and valuable pharmacological property especially for a therapeutic

Application: Bntralnervösen, neuropsychi & tric diseases, especially schizophrenia, Parkinson's Disease and prolactin overproduction. Compared to the known racemic compound 6-methyl-9-amino-5,6,6a, 7-tetrahydro-4H-benzo [de] thiazolo [4,5-g]

quinoline

For example, the compounds ((-! - enantiomers)

a = 9-amino-5,6,6a, 7-tetrahydro-4K-benzo [de] thiazolo [4,5-g] quinoline

b = 6-ethyl-9-amino-5,6,6 aJ-t, -hydroxyH-benzo [de] thiazolo [4,5-g] quinoline.

c = 6-Propyl-9-amino-5,6,6a, 'cetrahydro-4H-benzo [de] thiazolo [4,5-g] quinoline - 6-methyl-9-benzylamino-5,6,6a, 7 Tetrahydro-4 H-benzo [de] thiazolo (4,5-g] quinoline = 6-ethyl-9-methylamino-5,6,6a, 7-tetrahydro-4H-benzo [de] thiazolo (4,5-) g] quinoline = 6-ethyl-9-dimethylamino-5,6,6a, 7-tetrahydro-4H-benzo [de] thiazolo [4,5-g] quinoline.

with respect to their influence on presynaptic dopamine receptors, first testing the effect on the exploratory activity of mice and then influencing the dopamine utilization and the

Dopamine synthesis in rats were determined as follows:

1. Inhibition of exploratory activity

The activity was measured in observation cages equipped with an infrared light barrier. The frequency of interruption of the light beam by a group of 5 mice is measured within 5 minutes. Groups of 5 animals each receive the substance to be tested at a dose of 10 mg / kg injected subcutaneously. 1 hour later, the animals are placed in the observation cages, where the measurement of expiratory activity is started immediately for 5 minutes. In parallel or alternating with groups which have been treated with test substance, saline-treated control groups (0.9%, 0.1 ml / 10 g body weight subcutaneously) are examined.

All those substances were included in the further series of experiments, which had as a precondition an inhibition of the exploratory activity compared to the controls of> 50%, as was demonstrated, for example, for the above-described compounds a, b, c, d, e and f.

2. Determination of dopamine utilization

Dopamine utilization was measured in rats. In animals treated with α-methylparatyrosine (AMPT) (250 mg / kg intraperitoneally)

treated, the dopamine concentration in the whole brain decreases with the duration of the experiment. Substances which act on autoreceptors may reduce dopamine waste (compared to control animals treated with saline solution -i).

The test substances are prepared at time 0 and 2 hours of the experiment unless otherwise stated

a dose-response curve with 0.01 to 10 mg / kg s.c. applied. At the time of 4 hours of the experiment, the animals are killed and the brains of dopamine determination by high pressure liquid chromatography with electrochemical

Detection supplied. The percentage increase in dopamine utilization caused by the test substance is determined AMPT treatment. For example, the following results were obtained: Percentage increase

the dopamine utilization 34 64

112

Side effects did not appear in the dosages used so far.

Furthermore, the compounds prepared according to the invention are largely non-toxic. Thus, in the study of the substances in rats with doses between 100 and 200mg / kg s.c. no deaths are detected. Because of their pharmacological properties, the compounds of general formula I and their physiologically acceptable acid addition salts according to the invention in the treatment of central nervous, neuropsychiatric disorders, in particular schizophrenia, in the treatment of Parkinson's disease and in a prolactin overproduction.

For therapeutic use, the novel compounds and their physiologically acceptable acid addition salts, optionally in combination with other active ingredients, can be incorporated into the usual pharmaceutical application forms such as dragees, tablets, powders, suppositories, suspensions, drops or ampoules. The single dose is 1 to 4 times daily 0.01-5 mg / kg body weight, but preferably 0.1-3 mg / kg body weight.

substance Dose (mg / kg) s.c. comparison 10 b 10 C 10

Examples of pharmaceutical preparations are: Example I: Dragoes

5.0 parts of active ingredient according to the invention

33.5 parts milk sugar

10, OTeNe cornstarch

1.0 part gelatin

0.5 part of magnesium stearate

The powdered ingredients, lactose and corn starch are granulated with aqueous gelatin solution and dried. The granules are mixed with the magnesium stearate and pressed into dragee seeds of SO mg weight and coated by known methods.

Example II: suppositories

10 parts of active ingredient according to the invention

1690 parts suppository mass (eg WitepsolW45)

The finely powdered substance is uniformly dispersed by a homogenizer in the molten abgokühlten to 4O ⁰ C suppository mass. From the mixture are suppositories weighing., 7g formed.

Example III: Drops

0.035 parts of methyl p-hydroxybenzoate

0.015 parts of n-propyl p-hydroxybenzoate

0.05 part anisole

0.06 part of menthol 10.0 parts of pure ethanol

0.5 parts of active substance according to the invention

0.7 part of citric acid

0.3 part sodium phosphate sec. H 2H ₂ O

1.0 part sodium cyclamate

15.0 parts glycerin

ad 100.0 ml of dist. water

The p-hydroxybenzoic acid, anisole and menthol are dissolved in ethanol (solution I).

The buffer substances, the active substance and sodium cyclamate are dissolved in dest. Dissolved water and glycerol added (solution II). Solution I is stirred into solution II and the mixture is washed with dist. Water is filled to the given volume. The finished dropping solution is filtered through a suitable filter. The production and bottling of the dripping solution must be carried out under light protection and under protective gassing

 The following examples are intended to illustrate the preparation of known intermediate or starting compounds in more detail.

Example A

1-Methyl-2-ethyl-dihydroisoquinolinium bromide (Formula 2 with Ri - C ₂ H ₆ ).

0.1 mol of the isoquinolinyl compound (1) as a known starting material is alkylated at room temperature with ethyl bromide (0.1 molar acetonitrile (150 ml).) After concentration, the solid residue is recrystallized from alcohol.

Yield: 15.5 g (61% of theory); M.p. 118-121 ⁰ C.

In an analogous manner to Example A were

1-methyl-2-propyl-dihydroisoquinolinium bromide (formula 2 where R) = C ₃ H ₇ ),

Yield: 90% of theory; M.p. 144-146 ⁰ C

and 1,2-dimethyl-dihydro-isoquinolinium iodide (Formula 2 where R ₁ = CH ₃ ),

Yield: 63% of theory; M. 193-194 ⁰ C produced.

Example B

Ethyl 2-ethyltetrahydro-i-isoquinolinium propionate (Formula 4, Ri = C ₂ H ₆ ) To the compound of Formula 2 (R ₁ - C ₂ H ₆ ) (31 g, 0.12 mol) dissolved in 30 ml of water , 60ml NaOH (2N) are added and stirred at room temperature for 1 h. The reaction mixture is extracted with ether, the ether extracts are concentrated. The residue is dissolved in 303 ml of toluene, treated with bromoacetate (0.12 mol) and 8h. heated to boiling at reflux.

It is then diluted with 100 ml of CH ₃ OH. NaBH ₄ (5.7 g) is dissolved in 50 ml NaOH (1 N) and added dropwise at 10 ° C. The reaction mixture is stirred for 2 hours at room temperature, poured onto water and extracted with ethyl acetate. The organic phase is concentrated, the residue is purified on silica gel with cyclohexane / ethyl acetate (3: 1).

Yield: 26.4 g (84% of theory)

Analogous to Example B were

Ethyl 2-propyl-tetrahydro-1-isoquinolinyl-propionate (formula 4, R ₁ = C ₃ H ₇ ) Yield: 68% of theory

and 2-methyl-tetrahydro-1-isoquinolinyl-propionsäureethyleoter (Formula 4, R _t = CH ₃₎ Yield: 66% of theory were prepared.

Example C

1-ethyl-hexahydro-1H-benzo [de] -quinolin-7-one (formula III, R ₁ = C ₂ H ₆ ).

Product (4) with R, = C ₂ H ₆ (0.1 mol) is heated in 300 g of polyphosphoric acid for 15 min at 140 ° C, cooled to room temperature and treated with ice. The acidic solution is made alkaline with ammonia and extracted with ethyl acetate. After., Concentration of the solvent, the residue is purified over silica gel with methylene chloride / ethyl acetate / methanol (70:20:10).

Yield: 15.4 g (75% of theory);

Analogous to Example C were

1-Propyl-hexahydro-1H-benzo [de] quinolin-7-one (formula III, Ri = C ₂ H ₇ )

Yield: 82% of theory

and 1-methyl-hexahydro-1H-benzo [de] quinolin-7-one (formula III, R ₁ = CH ₃ ),

Yield: 82% of theory, prepared. The following examples are intended to explain in more detail the preparation of the compounds according to the invention: example 1

6-ethyl-9-amino-5,6,6a, 7-tetrahydro-4H-benzenoid] thiazolo [4,5-g] quinoline

0.02 mol of compound III with R ₁ as C ₂ H ₆ are dissolved in glacial acetic acid and brominated at room temperature with 3.2 g of bromine. After this

Concentration of the residue is dissolved in 50 ml of glacial acetic acid and with 1.5 g of thiourea of the general formula IV with R ₂ and R ₃ = H

Heated under reflux for 1 hr. It is then poured onto ice water, made alkaline with ammonia and extracted with ethyl acetate. After concentration, the residue is purified on silica gel with methylene chloride / ethyl acetate / methanol (70:20:10) and recrystallized from ethyl acetate.

Yield: 1.6 g (30% of theory); M.p. 158-160 ⁰ C Example 2

6-propyl-9-amino-5,6,6a, 7-tetrahydro-4H-benzo [de] thiazolo [4,5-g] quinoline

In analogy to Example 1, this compound was prepared with a yield of 21% of theory, m.p. 184-188 ⁰ C. Example 3

6-ethyl-9-methylamino-5,6,6a, 7-tetrahydro-4H-benzo [de] thiazolo [4,5-g) quinoline

In analogy to Example 1, this compound was prepared as dihydrochloride hemihydrate (from monomethylthiourea) with a Yield of 36% of theory, mp. 255-257 ° C, prepared. Example 4

In analogy to Example 1, this compound was prepared as dihydrochloride (from dimethylthiourea) in a yield of 44% of theory, mp> 260 ° C.

Example S

e-Methyl-S-benzoylamino-S, e-.alpha.-tetrahydro-1-H-benzo-idylthiazoloKS-glinoline 0.01 mol of compound II is dissolved in 100 mL of tetrahydrofuran and treated with 1.5 g of triethylamine and 1.5 g of benzoyl chloride for 3h. under

Reflux heated. It is then poured into water and extracted with Methylenchloriri. Crystallized after concentration

the residue in ether.

Yield: 3g (83% of theory); M.p. 237-240 ⁰ C

Example β

e-methyl-9-benzylamino-5, e, 6a, 7-tetrahydro-4H-benzo [de] thiazolo [4,5-Glchinolin0,005MoI of the compound II is added in 50 ml of tetrahydrofuran with 0.5 g of lithium aluminum hydride and 7 hr. at the reflux. After cooling, 20 ml of a saturated diammonium tartrate solution is added. The residue is over

Silica gel with methylene chloride / ethyl acetate / methanol (70:20:10). The product crystallizes in ether. Yield: 1.2 g (63% of theory), mp. 85-96 ° C. Example 7

This compound is obtained as dihydrochloride by demethylation of the compound II (Rt = CH ₃ ) with perbenzoic acid and ferrous chloride. The procedure is carried out according to the method of Monkovic (Monkovic, I., et al., Synthesis, 770, 1985). Yield: 18% of theory, mp> 260 ° C

Example 8

The compound according to the invention which is mentioned in Example 7 can also be prepared by demethylating compound II by dissolving 2.6 g (0.01 mol) of compound II, 2 g (0.01 mol) of m-chloroperbenzoic acid, 150 ml of methylene chloride, 0.7 ml of water and FeCl ₂ are reacted as follows: Compound II is, dissolved in methylene chloride, submitted. Chloroperbenzoic acid is added in portions at -15 to -10 ⁰ C. The complete reaction takes place within 10 min, which is detectable by thin-layer chromatography {TLC) (methylene chloride, ethyl acetate, methanol, 70:20:10, methylene chloride / methanol, 80:20). The FeCl ₂ solution (50 mg in 0.7 ml of H ₂ O) and, after half an hour, about 50 mg of solid FeCl ₂ are added. The initial white crystals of the final N-oxide dye slowly turn green (14h RT). TLC 50% conversion takes place, TTWA 30ml 2N NaOH ι nd 50ml CH ₂ Cl ₂ are added, suction filtered through kieselguhr, thoroughly shaken with CH ₂ Cl _2, dried, concentrated and chromatographed übe- kieselguhr. Yield: about 150 mg, mp> 260 ° C

Example 9 The compound mentioned under Example 7 and their enantiomers can also be obtained according to the following reaction scheme

become:

acetic anhydride

CH ₂ -CH ₂ -NH ₂

O PPA'-CH ₂ -CH ₂ -NH-C-CH ₃ - * "

FROM CH ₃

benzyl bromide

EtOOC

N-CH.

1. Br-CH ₂ -COOEt

2. NaBH ₄

N-CH ₂ -

PPA

-CH-

CH ₂ -OH CH ₂ -OH

.N-CH ₂ -

, 2.Acetanhydride

H ₂ N- /

1.Br ₂ 2.H ₂ NC-NH ₂

/ HCl / glacial acetic acid

L U) tartaric acid / \ D (-) tartaric acid

C-)

C +)

PPA = polyphosphoric acid

The compounds A bi3 K designated in this Reaction Scheme are prepared as follows:

Connection A

242g Phenethylamln (2 mol) were initially charged in tetrahydrofuran, 204 g of acetic anhydride added dropwise at 15-2O ⁰ C and after ¹ Ah at

Room temperature (RT) concentrated. The residue was dissolved in ethyl acetate, once with ammonia, once with 2 N HCl and once with Washed water. The organic phase was dried and concentrated. Yield: 312g (95.7% of theory) Compound B

312g of compound A (1.91 mol) and 1 kg of polyphosphoric acid (PPA) were stirred at 20O-220 ° C for 2 h, allowed to cool to 100 ⁰ C, treated with ice, neutralized with ammonia and extracted with Essigester '/. The organic phase was dried, concentrated and distilled under high vacuum.

Yield: 166g (60% of theory), b.p. _{0 mm.} 60-62 ⁰ C Compound C

166 g of compound B (1.14 mol) were refluxed with 390 g of benzylbromide (2.28 mol) and 1.71 nitromethane for 2 hours, and the residue was filtered off with suction in acetone.

Yield: 254g (70% of theory), mp 203-205X Connection D

254 g of Compound C (0.8 mol) were dissolved in 420 ml of water and 420 ml of 2 N NaOH added. It was extracted by shaking with ether, the ether phase was dried and concentrated. The residue was dissolved in 800 ml of dimethylformamide (DMF), 134 g of bromoacetic acid ester (0.8 mol) were added, stirred for β hours at RT and diluted with 500 ml of methanol. 30 g of NaBH ₄ (0.8 mol) was added portionwise, stirred at RT for 1 hour, poured onto ice-water and shaken out with ethyl acetate. The organic phase was dried, concentrated and chromatographed over about 2 kg of silica gel (ethyl acetate / cyclohexane, 1: 3). Yield: 231 g (89% of theory).

Connection E

231 g of compound D (0.71 mol) were stirred with 2.3 kg of PPA '/ 2 hour at 140-150 ° C, treated with ice, made alkaline with NH ₄ OH and shaken out with ethyl acetate. The organic phase was dried, concentrated and chromatographed in cyclohexane / ethyl acetate (3: 1).

Yield: 118.5 g (60% of theory) Connection F

118.5 g of compound E (0.43 mol), 89.8 g of p-toluenesulfonic acid (0.47 mol), 29.6 g of ethylene glycol (0.47 mol) and 3 L of toluene were cutted on a water separator for 24 h, poured into ice-water, and made alkaline with ammonia set and shaken out with ethyl acetate. The organic phase was dried and concentrated.

Yield: 96.5 g (70% of theory). Compound G

96.5 g of compound F (0.3 mol) were hydrogenated with 4.5 g Pd / C (10%), 96SmI tetrahydrofuran and 65 g acetic anhydride for 3 hours at 60-7O ⁰ C and 5 bar. The catalyst was filtered off with suction, the solution was concentrated and the residue was dissolved in glacial acetic acid / 2 N HCl (1.8 liters each). At RT was stirred for 2 hours, poured onto ice, made alkaline with ammonia and extracted with ethyl acetate. The organic phase was dried, concentrated and the residue was filtered off with suction in ether.

Yield: 55g (80% of theory) Connection H

55 g of compound G (0.24 mol), 550 ml of glacial acetic acid and 550 ml of concentrated HCl were refluxed for 24 hours (about 10ΟΌ, poured onto ice, basified with ammonia and extracted by shaking with ethyl acetate) The organic phase was dried, concentrated, the residue dissolved in acetone, ethereal HCl was added and the hydrochloric acid) was filtered off with suction.

Yield: 32.3 g (60% of theory), Compound I

32.3 g of compound H (0.14 mol) was placed in 1.61 glacial acetic acid and 23 g of bromine (0.14 mol) was added dropwise. It was applied to heated 3O ⁰ C, 10 min at 3O ⁰ C and stirred 44g thiourea (0,58MoI) was added thereto. Thereafter, 1 hour was submerged

Refluxed, poured on ice, made alkaline with concentrated ammonium hydroxide (NH ₄ OH) and with ethyl acetate

shaken. The organic phase was dried, concentrated and the residue was filtered off with suction in methanol.

Yield: 12.5 g (35.7% of theory) Mp: 159 ^° C. (decomposition) Compounds K (Enantiomers of Compound I)

a) (-) enantiomer

12.5 g of the compound I (0.051 mol), 7.7 g (.) Of tartaric acid (0.051 mol) were dissolved in 2 liters of hot water, treated with activated carbon and filtered with suction through diatomaceous earth and washed with water to give 10.3 g of the tartrate formed, which was recrystallized 4x from water to give 2.5 g of the pure tartrate The base, dissolved in water, made alkaline with ammonia and shaken out with ethyl acetate, became released and formed in ethanol the corresponding hydrochloride

 Yield: 1.3 g

Ia] g ⁶ = (-) 110, c = 0.1, water

(let ⁶ = (-) 90-, c = 0.1, acetone)

Base mp: 330 ° C (decomposition)

b) (+) enantiomer

From the aqueous mother liquors (all), the bases were released analogously, to give 8.7 g. These 8.7 g (0.036 mol) were dissolved with 5.4 g of D (-! Tartaric acid (0.036 mol) in 1 liter of hot water, treated with charcoal, filtered with suction through kieselguhr and left to crystallize overnight and recrystallized once from water to give 3.3 g of the tartrate formed.

The base was released therefrom as described above and the corresponding hydrochloride was formed in ethanol. Yield: 1.9g

Ia) J ⁶ = (+1110 ", C = 0.1, water

(MS * = (+) 91 °, c = 0.1, acetone)

Base mp: 33O ⁰ C (decomposition)

As further erfflndungsgemäBe connections can be prepared for example:

Ex. R

Salzform.Schmp. ⁰ C

10 H- C _£ H CO- o 5 11 C ₂ H ₅ - H- 12 CH ₃ - H- 13 OCH ₃ - H- 14 U) CH ₃ - H- 15 CH ₃ - C ₆ H ₅ CH ₂ - 16 C ₂ H ₅ - CH ₃ - 17 C ₂ H ₅ - CH ₃ - 18 CH ₃ - C ₆ H ₅ CO- 19 HC ₃ H ₇ - H ₃ C ^ __ 20 H- H- 21 (+) H- H-

22 (-) H-

H-

H- base > 260 H- base 158-160 ⁰ C H- 2 HCl > 260 ⁰ C (Base: 201-203 ⁰ C) H- 2 HCl 274-276 ⁰ C H- 2 HCl 276-277 ° C H- base 95-96 ⁰ C H- 2 HCl 255-257 ⁰ C

CH 2 HCl> 26O ⁰ C

23 (+) n-C H - H-

H-

Base 237-240 ⁰ C

2 HCl 256-258 ° C

2 HCl> 260 ° C

2 HCl 330 ° C (decomposition)

(Base: 223-225 ° C) 2 HCl 330 ° C (decomposition)

(Base: 223-225 ° C) 2 HCl 274-275 ⁰ C 2 HCL 273-275 ° C

Ex. H ₁

Salzform.Schrap. ⁰ C

25 C ₂ H ₅ - ClC H CO- 6 4 J ₂ CO- H- base 207-210 26 C ₂ H ₅ - ClC ₆ H ₄ CH ₂ - H- 2 HCl 190-192 27 C ₂ H ₅ - C ₆ H ₅ CO- H- base 222-224 28 C ₂ H ₅ - CH ₃ OC ₆ H ₄ (CH ₂ H- 2 HCl 198-200. 29 C ₂ H ₅ - C ₆ H ₅ CH ₂ - H- 2 HCl 220-222 30 C ₂ H ₅ - CH ₃ CO- H- base > 260 ° C 31 HC ₃ H ₇ - H- H- 2 HCl 264-266 32 HC ₃ H ₇ - C1C, H _A CO- 4 J ₂ CO- H- base 192-196 33 HC ₃ H ₇ - ClC ₆ H ₄ CH ₂ - H- HCl 194-197 34 HC ₃ H ₇ - CH ₃ CO- H- 2 HCl 258-260 35 HC ₃ H ₇ - CH ₃ OC ₆ H ₄ (CH ₂ H- 2 HCl 211-213 36 HC ₃ H ₇ - C, H _c C0-5 5 H- oxalate 258-259 37 HC ₃ H ₇ - C ₆ H ₅ CH ₂ - - (CH 2 CO 2 2 H- 2 HCl 240-242 38 HC ₃ H ₇ - C ₂ H ₅ - H- 2 HCl 254-255 39 HC ₃ H ₇ - c! ör ^CH H- 40 HC ₃ H ₇ ^H 3 ^C ° Y ^ r H- H ₃ Co - \ y 41 1-C ₃ H ₇ - H- H- 42 "-C ₄ H ₉ - H- CO H- 43 CH ₂ = CH-CH ₂ - C ₂ H ₅ - C ₂ H ₅ - 44 CH = C-CH ₂ - H- H- 45 C ₂ H ₅ - HOC ₆ H ₄ (CH ₂ J ₂ H- 46 HC ₆ H ₁₃ - H- H-

Ex. R

R salt form mp. ⁰ C

47 ! -C ₃ H ₇ - CHO 48 C ₂ H ₅ CH ₃ 49 C ₂ H ₅ CH ₃ - 50 W ^CH 2V 51 H- HC ₆ H ₁₃ - 52 C ₂ H ₅ - CH ₂ = CH-CH ₂ 53 H- CH = C-CH - 54 CH ₃ C ₆ H ₅ (CH ₂ J ₃ 55 C ₂ H ₅ H- 56 C ₂ H ₅ ⁿ " ^C 4 ^H 9

CH ₂ = CH-CH ₂ -

CH = C-CH ₂ -

C ₂ H ₅ -

ⁿ " ^C 6 ^H 13 H-

Claims (9)

R _{1 is} a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an allyl or propargyl radical, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part. R _{2 is} a hydrogen atom, a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, an allyl or propargyl radical, a phenylalkyl group having 1 to 3 carbon atoms in the alkyl part, the phenyl ring being replaced by fluorine, chlorine, bromine, hydroxyl, methoxy, methyl , Mono- or trifluoromethyl radicals monosubstituted or may be disubstituted by said radicals also in various combinations with each other, an alkanoyl group having 1 to 3 carbon atoms, which may be substituted by a mono- or disubstituted phenyl radical as indicated above. R _{3 can be} a hydrogen atom, a straight-chain or unbranched-chain alkyl group having 1 to 6 carbon atoms, an allyl or propargyl radical in which R _{1 is} then not the methyl group, if R ₂ and R _{3 are} simultaneously hydrogen, in the form of the racemates, the enantiomers and the respective acid addition salts, thereby in that a. a ketone of the general formula (IH), in which R _{1 has} the meaning of claims 1 to 4, is brominated and then with a thiourea of the formula N - C - NH ₉ (IV), in the R ₂ and R ₃ have the abovementioned meaning, is reacted, or that one b. a compound of the formula in which R has the abovementioned meaning and R ₂ 'and R ₃ ' are hydrogen, with an acid chloride of the formula R. - C - Cl 4., wherein R _{4 is} an alkyl or Phenyigruppe the above for R ₂ acyl or Phenylacylreste means, implements or that one c. a compound of the formula ^R 2 wherein R ₁ "is as defined above, R ₂ " is the acyl or phenylacyl groups and R ₃ "is hydrogen, with a metal hydride to a corresponding N-alkylamino compound reduced or that one d. a compound of the formula wherein R ₁ '"is a methyl or benzyl radical and R ₂ '" and R ₃ "'have the abovementioned meaning, demethylated or debenzylated and that, if desired, thus obtained racemic compounds are separated into their enantiomers by methods known per se and / or initially obtained salts are converted into free bases, initially obtained bases are converted into acid addition salts. 2. The method according to claim 1, characterized in that one produces compounds of the general formula JI I, wherein Ri is a hydrogen atom, a straight-chain or odd-chain alkyl group having 1 to 4 carbon atoms, benzyl or phenylethyl group R 2 is a hydrogen atom, a straight-chain or odd-chain alkyl group having 1 to 3 carbon atoms, benzyl, 4-chlorobenzyl, 3,4-dichlorobenzyl, phenylethyl, - an alkonyl group having 1 to 3 carbon atoms - which is replaced by a phenyl- or a phenyl radical substituted by F'oror, chlorine, bromine, hydroxy, methoxy or trifluoromethyl may be substituted, wherein R ₂ is alkanoyl or substituted phenylalkanoyl or phenyl-alkyl or substituted phenylalkyl group only when R _{3 is} a hydrogen atom or is a methyl group. R3 represents a hydrogen atom, a methyl, ethyl, n-propyl or i-propyl group and their enantiomers and the respective acid addition salts. 3. The method according to claim 1 and 2, characterized in that one produces compounds of general formula I / wherein R _{1 is} a hydrogen atom, a methyl, ethyl, n-propyl, i-propyl, butyl, benzyl or Phenyl-ethyl group,
R _{2 is} a hydrogen atom, a methyl, ethyl, an alknoyl group having 1 to 3 carbon atoms, which by a phenyl radical or one with fluorine, chlorine, bromine, hydroxyl, methoxy or Substituted trifluoromethyl substituted phenyl, R _{3 is} a hydrogen, a methyl or ethyl group and their enantiomers and the respective acid addition salts. 4. The method according to claim 1 to 3, characterized in that one produces compounds of general formula I, wherein R _{1 is} a hydrogen atom, an ethyl, n-propyl or i-propyl group, R _{2 is} a hydrogen atom, a methyl, ethyl, formyl, acetyl, propionyl, benzoyl, benzoylacetyl, 4-chlorobenzoyl, 4- Chlorophenylacetal or 3- (4-methoxyphenyl) propanoyl
R _{3 represents} a hydrogen atom, a methyl or ethyl group and their enantiomers and the respective acid addition salts. 5. The method according to claim 1 to 4, characterized in that one produces compounds of general formula I, wherein the phenyl ring of the phenylalkyl or the phenylalkanoyl group of R ₂ with fluorine, bromine, hydroxyl, methoxy, methyl or a trifluoromethyl radical in 4 Position is substituted. 6. The method according to claim ¹ to 5, characterized in that one produces one of the compounds mentioned below: S-amino-B.e.BaJ-tetrahydro ^ H-benzo / de / thiazoloM.B-g / quinoline, its enantiomers and the acid addition salts, 6-ethyl-9-amino-5,6,6a-7-tetrahydro-4H-benzo / de / thiazolo / 4,5- / quinoline, its enantiomers and the acid addition salts, e-propyl-S-amino-BAα-tetrahydro-1H-benzo / de / thiazoloM.B-g / quinoline, its enantiomers and the acid addition salts, e-methyl-S-benzylamino-SAe1-tetrahydro-VWH-benzo / de / thiazoloM.B-g / quinoline, its enantiomers and the acid addition salts, e-methyl-S-benzoyl-amino-B.e.eaJ-tetrahydro ^ H-benzo / de / thiazoloM.B-g / quinoline, its enantiomers and the acid addition salts, e-ethyl-S-methyl-amino-B ^ .BaJ-tetrahydro ^ H-benzo / de / thiazoloM.B-g / quinoline, its enantiomers and the acid addition salts, Enantiomers and the acid addition salts. 7. Use of a compound according to claims 1 to 6 or a physiologically acceptable acid addition salt, characterized in that it is used for the preparation of medicaments in the treatment of diseases that respond to presynaptic dopamine agonists. 8. Use of a compound or a physiologically acceptable acid addition salt according to claim 7, characterized in that it is used for the preparation of medicaments in the treatment of schizophrenia. 9. Use of a compound or a physiologically acceptable acid addition salt according to claim 7, characterized in that it is used for the preparation of medicaments in the treatment of Parkonson's disease and against prolactin overproduction. Field of application of the invention The invention relates to a process for preparing novel Tetrahydrobenzothiazolo-quinolines of the general formula and their enantiomers, in the form of their salts with an inorganic or organic acid or as bases, which can be used as medicaments in customary preparations.