DD293811A5 - PROCESS FOR PREPARING 3- (2-MERCAPTO-ETHYL) = CHINAZOLIN-2,4- (1H, 3H) -dione II - Google Patents

Abstract

The invention relates to a process for preparing immunomodulatory active * of the general formula I with R1H or a substituent such as methyl, methoxy, fluorine, chlorine, bromine or iodine in positions 6 or 8 and R2H or a C1-C3-alkyl, benzyl or phenyl radical. These compounds of the general formula I are prepared from * the general formula II by the action of nascent hydrogen. The compounds of the general formula II are prepared from the general formula IV and alkyl chloroformates. The compounds of the general formula IV are prepared from * the general formula VI and cystamine or cystaminium chloride / auxiliary base. In the case of the optionally substituted compounds of the general formula II, IV and VI, R 1 and R 2 have the meanings given for the compounds of the general formula I. The invention is of interest to the chemical and pharmaceutical industries. Formula I {potentially biologically active compounds; Starting products for active ingredients; Intermediates for the chemical and pharmaceutical industries; * Bis (quinazolinylethyl) disulfane; chloroformate; Cystaminiumchlorid}

Description

Field of application of the invention

The invention relates to a process for the preparation of 3- (2-mercapto-ethyl) quinazoline-2,4 (1 H, 3H) -diones of the general formula I.

Such compounds can gain importance as biologically active substances, in particular on the basis of their immunomodulatory properties, and find use for producing active substances. The invention is also of interest to the chemical industry.

Characteristic of the known state of the art

Compounds of general formula I are not yet described in the technical and patent literature.

Object of the invention

The aim of the invention is to present 3- (2-mercapto-ethyl) quinazoline-2,4 (1 H, 3H) -diones of the general formula I from readily available starting materials in high yields.

Explanation of the essence of the invention

The object of the invention is to find a technically applicable synthesis route for the preparation of 3- {2-mercapto-ethyl) quinazoline-2,4 (1 H, 3H) -diones of the general formula I.

According to the invention, this object is achieved in that 2H-3,1-benzoxazine-2,4 (1H) -diones of the general formula VI,

Vl

wherein R ^{1 is} a Η-atom or another substituent such as methyl, methoxy, fluorine, chlorine, bromine or iodine in the positions 6 or 8 and R ^{2 is} a Η-atom or an alkyl (C ₁ -C ₃ ), benzyl or represents a phenyl radical, with cystamine of the general formula V

(H ₂ NCH ₂ CH ₂ SJ ₂ V

or its salts, preferably its dihydrochloride, to the bis [2- (2-amino-benzoylamino) ethyl] disulphanes of general formula IV,

IV

where R 'in positions 5 or 3 and R ^{2 have} the meanings given above, are reacted. The optionally purified and dry compounds of general formula IV are then reacted with a alkyl chloroformate of general formula III,

CICOOR ³

III

wherein R ^{3 represents} an alkyl (C ₁ -Ca) residue, to the bis [2- (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfanes of the general Formula II,

implemented, wherein R ¹ in the positions 6 or 8 and R ^{2 have} the meanings given above.

The optionally purified and dry compounds of general formula II are thereafter by the action of

nascent hydrogen to the 3- (2-mercapto-ethyl) quinazoline-2,4 (1H, 3H) -diones of general formula I,

СН _г СН ₂ 5Н

implemented, wherein R ¹ in the positions 6 or 8 and R ^{2 have} the meanings given above.

embodiments

The invention will be explained in more detail below on 6 exemplary embodiments:

example 1

3- (2-mercapto-ethyl) quinazoline-2,4 (1H, 3H) -dionl; R '= R ² = H

6.5 g (40 mmol) of 2H-3,1-benzoxazine-2,4 (1H) -dione VI (R ¹ = R ² = H) are dissolved in 30 ml of DMF and mixed with 4.5 g (20 mmol) of cystaminium chloride ( Cystamine dihydrochloride), 20 ml of DMF and 6 g (60 mmol) of triethylamine prepared suspension. The batch is heated to 70 ^° C. in a water bath for 45 minutes. After cooling, the precipitate is separated and washed with 20 ml of DMF. The filtrate and washings are combined and poured into 150 ml H ₂ O. After several hours of storage in the refrigerator, the precipitate is filtered off with suction, washed with H ₂ O and dried. There are obtained 7.0 g (yield: 90%) of pure bis [2- (2-amino-benzoylamino) ethyl] disulfane IV (R ¹ = R ² = H), which are used without further purification for the subsequent reaction can. Mb: 129-131 ° C (EtOH / H ₂ O), 0.98g (2.5mmol) IV (R '= R ² = H) are dissolved in 10mL of pyridine. Under ice-cooling, 1 ml (10 mmol) of ethyl chloroformate III (R ³ = C ₂ H ₆ ) is added dropwise. The batch is refluxed for 1 h and, after cooling, added to the mixture prepared from 15 ml of HCl (1 mol / l) and 10 ml of ice water. After prolonged storage in the refrigerator, the precipitate is filtered off with suction, washed with H ₂ O and dried. The intermediate obtained is suspended in powdered form in the mixture of 8 ml NaOH (3 mol / l) and 1.6 mol EtOH, shaken in a sealed reaction vessel for 6 h and stored at room temperature for a further 24 h. 30 ml of warm H ₂ O are added and the batch is filtered. The filtrate is acidified with dil. HCl, the precipitate is filtered off with suction and dried. There are 0.85 g (yield: 77%) of pure bis [2- (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfane II (R ¹ = R ² = H), which can be used without further purification for the subsequent reaction. Schmb: 270-272X (propane-1-ol).

200 mg of Il (R ¹ = R ² = H), 200 mg of zinc dust and 12 ml of acetic acid are refluxed for 3 hours. The mixture is mixed with the mixture prepared from 16 ml HCl (1 mol / l) and 28 ml H ₂ O and brought to the boil again. Filter and store the filtrate in the refrigerator for 1-2 days in a closed container. The precipitate is filtered off with suction and dried. 150 mg (yield: 75%) of pure I (R ¹ = R ² = H) are obtained. Shear: 193-195 ° C.

Example 2

3- (2-Mercapto-ethyl) -1-methyl-quinazoline-2,4 (1H, 3H) -dione I; R ¹ = H, R ² = CH ₃ To 7.1 g (40 mmol) of 1-methyl-2H-3,1-benzoxazine-2,4 (1H) -dione VI (R ¹ = H, R ² = CH ₃ ) in 30 ml of DMF, the suspension prepared from 4.5 g (20 mmol) of cystaminium chloride, 20 ml of DMF and 4 g (40 mmol) of triethylamine is added. The batch is heated to 70 ^° C. in a water bath for 45 minutes. After cooling, the precipitate is separated and washed with 20 ml of DMF. The filtrate and washings are combined and poured into 150 ml H ₂ O. After several hours of storage in the refrigerator, the precipitate is filtered off with suction, washed with H ₂ O and dried. There are obtained 7.3 g (yield: 87%) of pure bis [2- (2-methylaminobenzoylamino) ethyl] disulfane IV (R ¹ = H, R ² = CH ₃ ), which is used without further purification for the subsequent reaction can be. Schmb .: 110 to 110.5 ⁰ C (EtOH).

1.05 g (2.5 mmol) of IV (R ¹ = H, R ² = CH ₃ ) are dissolved in 10 ml of pyridine. While cooling with ice, 1 ml (10 mmol) of ethyl chloroformate III (R ³ = C ₂ H ₅ ) is added dropwise. The batch is refluxed for 1 h. After cooling, it is filtered and the filtrate is added with cooling 50 ml HCl (0.3 mol / l). It is extracted by shaking twice with 8 ml CHCl ₃ each time and the organic extract is washed 4x with 15 ml HCl (1 mol / l) and twice with 15 ml H ₂ O each time. The organic phase is dried over Na ₂ SO ₄ . After separation of the drying agent, the solvent is i.Vak. distilled off and the residue with 8 ml of NaOH (3 mol / l) and 1.6ml EtOH added. The batch is shaken for 6 h and stored at room temperature for a further 24 h. The precipitate is filtered off, washed with H ₂ O and dried. There are 0.97 g (yield 82%) of pure bis [2- (1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfane II ( R ¹ = H, R ² = CH ₃ ), which can be used without further purification for the subsequent reaction

 Mb: 186-187 ° C (methyl glycol / propan-1-ol).

200 mg of Il (R ¹ = H, R ² = CH ₃ ), 200 mg of zinc dust and 12 ml of acetic acid are refluxed. The mixture is added to the mixture prepared from 16 ml HCl (1 mol / l) and 32 ml H ₂ O and boiled again. Filter and store the filtrate in the refrigerator for 1-2 days in a closed container. The precipitate is filtered off with suction and dried. 165 mg (yield: 82%) of pure I (R ¹ = H, R ^! = CH ₃ ) are obtained. Shear: 128-129X.

Example 3

1-Benzyl-3- (2-mercapto-ethyl) quinazoline-2,4 (1H, 3H) -dione I; R ¹ = H, R ² = CH ₂ C ₆ H ₆ 2.5 g (10 mmol) of 1-benzyl-2H-3,1-benzoxazine-2,4 (1 hbdion VI (R ¹ = H, R ² = CH ₂ C ₆ H ₆₎ are suspended in 12.5 ml H ₂ O and treated with (1.1 g of 5 mmol) Cystaminiumchlorid, 2.5 ml H ₂ O and 1 g (10 mmol) of triethylamine prepared solution. the mixture

is heated for 45 minutes on the boiling water bath, kept in the refrigerator and the precipitate is sucked off. After recrystallization from EtOH, 1.7 g (yield: 60%) of pure bis [2- (2-benzylaminobenzoylamino) ethyl] disulphane IV (R ¹ = H, R ² = CH ₂ C ₆ H ₅ ), which can be used without further purification for the subsequent reaction. Mp: 126-127 ° C (EtOH).

1.43 g (2.5 mmol) of IV (R ¹ = H, R ² = CH ₂ C ₆ H ₆ ) and 14 ml of ethyl chloroformate III (R ³ = C ₂ H ₅ ) are refluxed for ₂ h. The solvent is i. Vak. distilled off and the residue after cooling with 8ml NaOH (3mol / l) and 1.6ml EtOH added. The batch is shaken for 6 h and stored at room temperature for a further 24 h. The precipitate is filtered off, washed with H ₂ O and recrystallized from propan-1-ol. There are 1.26 g (yield: 81%) of pure bis [2- (1-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfane II ( R ¹ = H, R ² = CH ₂ C ₆ H ₅ ), which can be used without further purification for the subsequent reaction. Schmb .: 174-176 ⁰ C (propane-1-ol).

200 mg of Il (R ¹ = H, R ² = CH ₂ C ₆ H ₆ ), 200 mg of zinc dust and 12 ml of acetic acid are refluxed for 3 h. The mixture is mixed with the mixture prepared from 16 ml of HCl (1 mol / l) and 4 ml of H ₂ O and brought to the boil again. Filter and store the filtrate in the refrigerator for 1-2 days in a closed container. The precipitate is sucked out and dried aD. There are obtained 155 mg (yield: 77%) of pure I (R ¹ = H, R ² = CH ₂ C ₆ H ₅ ). Shear: 143-145 ° C.

Example 4

3- (2-mercapto-ethyl) -1-phenyl-quinazoline-2,4 (1H, 3H) -dione I; R ¹ = H, R ² = C ₆ H ₅ 9.6 g (40 mmol) of 1-phenyl-2 H-3,1-benzoxazine-2,4 (1 H) -dione V ¹ (R ¹ = H, R ² = C ₆ H ₅₎ are suspended in 50 ml H ₂ O and H ₂ O are added and 4 g (40 mmol) of triethylamine prepared solution with (from 4.5 g 20 mmol) Cystaminiumchlorid, 10ml. The mixture is heated for 45 minutes on the boiling water bath and kept in the refrigerator. The precipitate is separated, dried and recrystallized from EtOH. The product obtained is mixed with a little diethyl ether and filtered with suction. There are 5,4g (Ex .:

50%) of pure bis [2- (2-phenylamino-benzoylamino) ethyl] disulphane IV (R ¹ = H, R ² = C ₆ H ₆ ), which can be used without further purification for the subsequent reaction. Schmb .: 130-131 ⁰ C (EtOH).

1.36 g (2.5 mmol) of IV (R '= H, R ² = C ₆ H ₅ ) and 14 ml of ethyl chloroformate III (R ³ = C ₂ H ₅ ) are refluxed for ₂ h.

The solvent is i.Vak. distilled off, the residue triturated with a little diethyl ester and filtered off with suction the following day.

The resulting intermediate is suspended in powdered form in the mixture of 8 mL NaOH (3 mol / L) and 1.6 mL EtOH, shaken for 6 h and stored at room temperature for a further 24 h. The precipitate is filtered off, washed with H ₂ O, dried and boiled with methyl glycol. There are 1.1 g (yield: 74%) of pure bis [2- (1-phenyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfane II (R ¹ = H, R ² = C ₆ H ₅ ), which can be used without further purification for the subsequent reaction. Schmb .: 277-280 ⁰ C (methyl glycol).

400 mg of Il (R ¹ = H, R ² = C ₆ H ₅ ), 400 mg of zinc dust and 24 ml of acetic acid are refluxed for 3 hours. The mixture is added to the mixture prepared from 32 ml HCl (1 mol / l) and 8 ml H ₂ O and boiled again. Filter and store the filtrate in the refrigerator for 1-2 days in a closed container. The precipitate is filtered off with suction and dried. 260 mg (yield: 65%) of pure I (R ¹ = H, R ² = C ₆ H ₆ ) are obtained. Melting point: 208-210 ° C.

Example 5

3- (2-mercapto-ethyl) -8-methyl-quinazoline-2,4 (1H, 3H) -dionl; R ¹ = 8-CH ₃ , R ² = H 1.8 g (10 mmol) 8-methyl- ² H -3,1-benzoxazine-2,4 ( ¹ H) -dione V ¹ (R ¹ = 8-CH ₃ , R ² = H) are dissolved in 7.5 ml of DMF and admixed with the suspension prepared from 1.1 g (5 mmol) of cystaminium chloride, 5 ml of DMF and 1.5 g (15 mmol) of triethylamine. The mixture is heated to 70 ^° C. in a water bath for 45 minutes. After cooling, the precipitate is separated and washed with 5 ml of DMF. The filtrate and washings are combined and poured into 40 ml H ₂ O. After prolonged storage in the refrigerator, the precipitate is filtered off with suction, washed with H ₂ O and dried. There are obtained 1.5 g (yield: 72%) of bis [2- (2-amino-3-methylbenzoylamino) ethyl] disulphane IV (R ¹ = 3-CH ₃ , R ² = H), which without further purification for the subsequent reaction can be used. M.p .: 152-154 ° C (ethyl acetate / cyclohexane [1: 1]).

1.05 g (2.5 mmol) of IV (R ¹ = 3-CH ₃ , R ² = H) are dissolved in 10 ml of pyridine. Under ice-cooling, 1 ml (10 mmol) of ethyl chloroformate III (R ³ = C ₂ H ₅ ) is added dropwise. The mixture is refluxed for 1 h and, after cooling, added to the mixture prepared from 15 ml HCl (1 mol / l) and 10 ml ice water. After storage in the refrigerator, the precipitate is filtered off with suction, washed with H ₂ O and dried. The resulting intermediate is suspended in powdered form in the mixture of 8 ml NaOH (3 mol / l) and 1.6 ml EtOH, shaken for 6 h and stored at room temperature for a further 24 h. Add 50 ml of warm 50% EtOH and filter. The filtrate is acidified with dil. HCl, the precipitate is filtered off with suction and dried. There are 0.8 g (yield: 68%) of pure bis [2- (8-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfane II ( R ¹ = 8-CH ₃ , R ² = H), which can be used without further purification for the subsequent reaction. M.p .: 280-282 ° C (methyl glycol / propan-1-ol [1: 1]).

400 mg of Il (R ¹ = 8-CH ₃ , R ² = H), 400 mg of zinc dust and 24 ml of acetic acid are refluxed for 3 hours. The mixture is treated with the mixture prepared from 32 ml of HCl (1 mol / l and 8 ml of H ₂ O) and boiled again, filtered and the filtrate is kept in a closed container in the refrigerator for 1-2 days and 295 mg (yield: 73%) of pure I (R ¹ = 8-CH ₃ , R ² = H) are obtained, mp: 234-235 ° C.

Example 6

6-bromo-3- (2-mercapto-ethyl) quinazoline-2,4 (1H, 3H) -dione I; R ¹ = 6-Br, R ² = H 2.4g (10mmol) 6-bromo-2H-3,1-benzoxazine-2,4 (1H) -dione VI (R ¹ = 6-Br, R ² = H) are suspended in 12.5 ml H ₂ O and treated with the solution prepared from 1.1 g (5 mmol) cystaminium chloride, 2.5 ml H ₂ O and 1 g (10 mmol) triethylamine. The mixture is heated for 45 minutes on the boiling water bath, kept in the refrigerator and the precipitate is sucked off. After recrystallization from EtOH, 1.3 g (yield: 47%) of bis [2- (2-amino-5-bromo-benzoylamino) ethyl] disulphane IV (R ¹ = 5-Br, R ² = H) are obtained can be used without further purification for the subsequent reaction. Schmb .: 190-195 ⁰ C (CHCl ₃ / n-hexane {[1: 1]).

1.1 g (2 mmol) of IV (R ¹ = 5-Br, R ² = H) are dissolved in 10 ml of pyridine. Under ice-cooling, 1 ml (10 mmol) of ethyl chloroformate III (R ³ = C ₂ H ₅ ) is added dropwise. The batch is refluxed for 1 h. After cooling, it is filtered and the filtrate is added with cooling with 50 ml of HCl (0.3 mol / l). It is shaken 4x with 10 ml of CHCl ₃ and the organic

Extract 4x with 20 ml HCI (1 mol / l) and 2x with 20 ml H ₂ O each. The organic phase is dried over Na ₂ SO ₄ . After separation of the drying agent, the solvent i. Vak. distilled off and the residue with 8 ml NaOH (3mol / l) and 1.6 ml of EtOH. The batch is shaken for 6 h and stored at room temperature for a further 24 h. Add 80 ml of warm 50% EtOH and filter. The filtrate is acidified with dil. HCl, the precipitate is filtered off with suction and dried. After recrystallization from DMF, 0.72 g (yield: 60%) of pure bis [2- (6-bromo-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-3-yl) ethyl] disulfane II (R ¹ = 6-Br, R ² = H), which can be used without further purification for the subsequent reaction. Schmb: 334-336X (DMF).

400 mg of H (R ¹ = 6-Br, R ² = H), 400 mg of zinc dust and 38 ml of acetic acid are refluxed for 3 hours. The mixture is mixed with 32 ml of HCl (1 mol / l) and brought to boiling again. Filter and store the filtrate in the refrigerator for 1-2 days in a closed container. The precipitate is filtered off with suction and dried. There are obtained 210 mg (yield: 52%) of pure I (R ¹ = 6-Br, R ² = H). Schmb.: 298-300 ⁰ C.

Studies on immunoregulatory effects of 3- (2-mercapto-ethyl) quinazoline-2,4 (1 H, 3H) -diones of general formula I.

Some of the compounds of general formula I were tested for immunoregulatory activity.

Evidence of immunoregulatory efficacy has been obtained in guinea pigs (albino colony breeding) and by the following techniques:

Percutaneous test for the detection of delayed-type contact hypersensitivity (effector T-lymphocyte activity)

- Taktsy test for detection of DNP-specific serum antibodies (humoral immune response)

The detection of immunostimulatory effects was further performed on the mouse (inbred strain CBA) using the following detection method:

- Plaque assay for detection of SE-specific IgM and IgG-PBZ

1. Percutaneous test for detecting a contact hypersensitivity

The epicutaneous application of DNFB leads to the development of delayed hypersensitivity in the guinea pig and the mouse, an immune status that is linked to the clonal multiplication of TNP-specific T lymphocytes (Тотн-Ly). Renewed application of DNFB after a latency period of at least 5 days results in a reaction with the Tdth-L-У of this skin area, a release of lymphokines and thus a localized inflammatory reaction.

Seven days after immunization with 1% DNFB, the flanks of the experimental animals were depilated and, by applying one drop each, 0.5%, 0.1%, 0.05%, 0.025% and 0.01% DNFB Solution tested. The still positive concentration is inversely proportional to the degree of sensitization. The test results are based on the strength and number of positive skin reactions, the stimulation index (SI) from the comparison of the test and control animals. The substance treatment took place orally. A gavage was given a daily dose of 2 mg / kg of body mass as a suspension in water. Treatment duration: Day +1 (one day after immunization) to +6. The control animals received only the lactose used as propellant.

2. Takatsy test

After immunization with dinitrofluorobenzene, guinea pigs also produce DNP-specific humoral antibodies, which preferably belong to the IgG _r subclass.

14 days after primary epicutaneous administration of DNFB, blood was taken from the experimental animals by candle aspiration. The determination of the antibody concentration was carried out according to a method described by Takatsy (Takatsy, G .: A new method for the preparation of serial dilutions in a quick and accurate way Kiserletes Orvostudomany 2 [1950] 263-396). TNP-loaded sheep erythrocytes were used as indicator cells (coupling according to Rittenberg and Pratt, Rittenberg, MB and Pratt, KL: antitrinitrophenyl (TNP) plaque assay, Primary response of BALB / c mice to soluble and particulate immunogen., Proc. Soc. Exp Med. 132 [1969] 575-579).

3. Results

Sensitization degree (%) and serum antibody concentration (AK titer difference) compared to the respective control group

3- (2-mercapto-ethyl) - Kontaktdermatidis 48 hr reaction DNP quinazoline-2,4 (1H, 3H) -dione (Control: 100) 130 spec. the general 24 hr reaction 150 antibody formula 1 150 150 +2.4 R ¹ = R ² = H 150 100 + 1.4 R ¹ = H, R ² = CH ₃ 160 100 + 1,9 R == H, R - CH 2 C 5 H 5 120 120 +1.0 R '= H, R ² = C ₆ H ₅ 120 +0.3 R ¹ = 8-CH ₃ , R ² = H 150 -0.6 R ¹ = 6-Br, R ² = H

From the data it is clear that compounds of general formula I (R ¹ = R ² = H; R ¹ - = H, R ² = CH ₃ ; R ¹ = H, R ² = CH ₂ C ₆ H ₅ ) have a good have detectable stimulating effect on the effector T-lymphocyte-dependent delayed hypersensitivity and on the humoral immune response.

4. Plaque assay for detection of SE-specific IgM and IgG PBZ

For testing immunostimulating effects, i.a. also investigated the influence of some compounds of general formula 1 on the humoral immune response to mice of the inbred strain CBA and by means of hemolysis plaque test (HPT). This technique allows the quantitative and separate detection of IgM and IgG antibody producing cells (= plaque forming

cells; PBZ). Immunization with sheep erythrocytes (SE) was performed on day 0, substance administration (daily dose 1-10 ⁶ mol / kg body mass, peroral) on days -1 to +3 (for detection of IgM-PBZ) or on days +1 to +5 (for detection of IgG-PBZ).

5. Results

Number of IgM or IgG-PBZ / 1 · 10 ⁶ nucleated cells (KHZ) compared to the control group

3- (2-Mercapto-ethyl) -quinazoline-2,4 (1H, 3H) -dione of general formula I.

number

IgM-PBZ / 1 -10 ⁶ KHZ

(Day +4)

number

lgG-PBZ / 1 -10 ⁶ KHZ (day +6)

R ¹ = H, R ² = CH ₃ 1050 ± 344 » 7 098 ± 1346 * R ¹ = H, R ² = CH ₂ C ₆ H ₆ 1228 + 490 » 4792 ± 1444 · * control 650 ± 274 3040 ± 1320

Probability of error for differences to the respective control group: · P <0.1%; ** P <1%.

From the data it is clear that compounds of general formula I (R ¹ = H, R ² = CH ₃ ; R ¹ = H, R ² cause significant increase in the number of IgM or IgG PBZ.

CH ₂ C ₈ H ₆ ) one

Claims (12)

claims: 1. A process for the preparation of 3- (2-mercaptoethyl) quinazoline-2,4 (1H, 3H) -diones of general formula I, \ CH, CH, SH characterized in that 2H-3,1-benzoxazine-2,4 (1H) -diones of general formula VI, R ¹ : 0 Vl wherein R ^{1 is} a Η-atom or another substituent such as methyl, methoxy, fluorine, chlorine, bromine or iodine in the positions 6 or 8 and R ^{2 is} a Η-atom or an alkyl (C ₁ -C ₃ ), benzyl or a phenyl radical, with cystamine or cystaminium chloride to the bis [2- (2-aminobenzoylamino) ethyl] disulphanes of the general formula IV, _г СН _г 5 ~ IV where R ¹ in the positions 5 or 3 and R ^{2 have} the meanings given above, are reacted in a solvent and these optionally purified and dry compounds with alkyl chloroformates of the general formula III, CICOOR ³ III wherein R ^{3 represents} an alkyl radical (Ci-C ₃ ), to the bis- [2- (2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-3-yl) ethyl] disulfanes of the general Formula Il СН _г СН _г 5- in a solvent or mixture, where R ¹ in positions 6 or 8 and R ^{2 have} the meanings given above, and these optionally purified and dry compounds by the action of nascent hydrogen in a solvent or mixture to the 3- (2-mercapto-ethyl) -quinazoline-2,4 (1 H, 3H) -diones of general formula I are reacted where R ¹ in positions 6 or 8 and R ^{2 have} the meanings given above. 2. The method according to claim 1, characterized in that the preparation of the compounds of general formula IV with heating, if necessary. Up to the boiling point of the reaction mixture is carried out. 3. The method according to claim 1 and 2, characterized in that an aqueous or aqueous-dipolar aprotic or dipolar aprotic solvent is used for the preparation of the compounds of general formula IV. 4. The method according to claim 1,2 and 3, characterized in that is preferably used as the dipolar aprotic solvent dimethylformamide. 5. The method according to claim 1,2,3 and 4, characterized in that the reaction of the compounds of general formula VI with cystaminium chloride in the presence of an auxiliary base, preferably triethylamine, in the moral ratio of 1: 0.5-0.65: 1 -2 takes place. 6. The method according to claim 1, characterized in that the compounds of the general formula IV are first reacted with alkyl chloroformates of the general formula III and that the resulting, non-purified intermediates subsequently by the action of aqueous or aqueous-alkanolic or alkanolic Alkali lye to the compounds of general formula II are implemented. 7. The method according to claim 1 and 6, characterized in that the reaction of the compounds of general formula IV with alkyl chloroformates of the general formula III is preferably carried out with heating to the boiling point of the reaction mixture. 8. The method of claim 1,6 and 7, characterized in that in the reaction of the compounds of general formula IV with chloroformates of general formula III, if appropriate, dipolar aprotic solvents, preferably pyridine, are used. 9. The method of claim 1, 6,7 and 8, characterized in that the resulting from the reactions of the compounds of general formula IV with alkyl chloroformates of the general formula IiI, non-purified intermediates below preferably at room temperature and with shaking or stirring the reaction mixture to the compounds of general formula II are implemented. 10. The method according to claim 1, characterized in that the preparation of the compounds of general formula I by reacting the compounds of general formula II with zinc and, if appropriate, a dilute carboxylic acid or a dilute aqueous or aqueous-alkanolic or alkanolic mineral acid. 11. The method according to claim 1 and 10, characterized in that the preparation of the compounds of general formula I with heating, if appropriate. Up to the boiling point of the reaction mixture. 12. The method according to claim 1, 10 and 11, characterized in that the compounds of general formula I are prepared by heating the compounds of general formula II and zinc dust in acetic acid.