CH617183A5 - - Google Patents

Description

The present invention relates to the processes defined in claims 1, 9 and 18 for producing the new amino acid derivatives of the formulas (I), (V) and (X), in which the symbols have the meaning given.

Some of these compounds have valuable pharmacological properties. Still other of these compounds are intermediaries for the production of substances with valuable biological or pharmacological effects. All of these compounds are new.

Among the new compounds, especially the y-L-ghitamyl-taurine, which has the formula (XXIV)

H-H - CH - COOH *!

ce0 (: cxiv)

! *

CO - HH - CHg - CH2- S020E

corresponds to and has a broad therapeutic and preventive spectrum of effects for indirect or directly attributable to violations of the "AGAS" (aerobiospheric genetic adaptation system).

To explain the term “AGAS”, the most important tissues and organs that make up this system are listed below.

a) all biological interfaces that are in contact with the outside air as a biosphere (skin and skin structures, cornea and conjunctiva, oral and pharynx cavities, airways and lungs);

b) skeleton and limbs (long bones and spongy bones, ball joints, synovial membrane, skeletal muscles);

c) the organs participating in the regulation of the ion balance (transepithelic transport system: villi and kidney channels);

d) the theko-donte (fixed in the tooth socket by root) needed for the crushing of the food;

e) Hearing, smell and voice organs.

The new compounds therefore have a beneficial biological or therapeutic effect on the organs or tissues of the AGAS system listed here.

The new compounds also act on the following functions associated with the AGAS system: radiation protection, wound healing, mesenchyme generally activating, protection against the ever increasing risk of infection and pollution of the skin and mucous membranes (lysocyte production of the moist mucous membranes, Activation of the epithelium in the respiratory tract, etc.), increased protection against infections caused by viruses and fungi.

The compounds according to the invention are effective against the constantly and greatly increasing stress effects (e.g. meteorological influences, strong differences between day and night temperatures, increased risk of injury) of life on the mainland by stabilizing the adaptation syndrome and at the same time ward off the peripheral tissue damage of the glucochorticoids (e.g. damage to the connective tissue, injuries to the bone matrix population, etc.). Development of immune homeostasis (increased knowledge of the body which cells are in the body and which are not).

The compounds according to the invention exert their effect partly directly, partly via the control of the vitamin A metabolism, by producing vitamin A metabolites of a more polar character. This effect is comparable to that of the parathyroid hormone on the 25-hydroxy-cholecalciferol-l-a-hy-hydroxylase enzyme of the kidney channels. This explanation explains the broad pharmacological, biochemical and therapeutic effects of the compounds according to the invention. The directions of action of the connections are as follows:

A. Effects with vitamin A character a) Pharmacological and biochemical effects: Labeled sulfates are incorporated to an increased extent in the rat's sword cartilage or the eye lens, the liver and lung tissue of the chicken embryo; radioactively labeled phosphorus is incorporated into the rat's sword cartilage to an increased extent; the effect of increasing chondroitin sulfate synthesis; beneficial effect on wound healing or experimentally worsened wound healing in rats and dogs by administration of cortisone; the potentiating effect of vitamin A in hypo- or hypervitaminosis experimentally induced in rats and chickens; the effects moderating the ulcer-related stress effects in rats; degranulation. beneficial effect of mastocytes; increasing effect on the production of lysosym; Effects on the household of trace elements (silicon, zinc, copper, manganese, fluorine); promoting effect on epithelial formation; increasing effect on alkaline phosphatase activity; the effect exerted on the granuloma sack formation caused by local exposure to vitamin A; the very flat course of the dose-response curve or the change in the sign of the effect at large doses; activating effect on the Golgi apparatus; beneficial effect on the formation of calyx cells; increasing effect on the concentration of vitamin A.

b) Clinical-therapeutic effects: keratocunjunctivis sicca; Sjogren's syndrome; rhino-laryngo-pharyngitis sicca; Ozaena; Chronic bronchitis; Sinobronchitis; Cystic fibrosis; constitutional lung diseases in young children; Para-dentose; Tendency to infect the skin and mucous membranes for viruses and fungi; cortisone-antagonistic effect; beneficial effect on the healing process in surgical wounds and mucosal wounds; erosio colli; pruritus-like; Reduced sense of smell and taste.

B. Effects without vitamin A character a) Pharmacological and biochemical effects: effects on the blood sugar level in the sense of a temporary decrease; increasing effect on phosphaturia, lowering effect on phosphorus level in serum; radioprotective effect; in labyrinth experiments with inactive animals

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the time-reducing effect required to achieve the goal; reducing effect on experimentally induced fluorine and cadmium toxicosis; cyclic adenosine monophosphate emptying of the kidney; the symptoms of experimentally induced lathyrism moderate effect; Reduction in sensitivity to histamine; increasing effect on the activity of the liver enzyme Tyrosi naminotransferase.

b) Therapeutic effects: weak radiation damage; Vitiligo; Muscle hypotension; psychoenergetic effect; beneficial effect on involutional and gerontological conditions as well as on mnestic functions; cheloidal tendencies; Ankylopoetic spondylosis; wear and tear diseases of the locomotive organs; sclerotic fundus; Amyloidosis; Morphea; fibrocystic mastopathy.

When the new compounds are administered, the duration of the treatment is extremely different. Some diseases (e.g. rhino-laryngo-pharyngitis sicca) become symptom-free after just two weeks after oral administration of 3x5 micrograms daily; symptomatic improvement of other diseases (e.g. paradentosis, Sjögren's syndrome) takes one to two months , with other diseases (e.g. spondylosis ankylopoetica) a quarter to half a year has to be treated.

Any pharmaceutical, preventive, cosmetic or veterinary preparations can be produced in a simple manner from the new compounds. The preparations can contain a single active ingredient or a combination of active ingredients. The dose of pure active ingredient is 50-500 nanograms per day and kilo of body weight and is administered in three separate doses.

One tablet contains 2 to 20 micrograms, preferably 10 micrograms of active ingredient and also biologically inert carriers (eg milk sugar, starch) as well as the usual tabletting aids (granulating and lubricating agents such as polyvinylpyrrolidone, gelatin, talc, magnesium stearate) , Aerosil etc.).

Because of the extraordinarily small dose, it is advisable to add the active ingredient in the form of a solution to the tablet mass before granulation. In this way, the active ingredient is distributed evenly. Incidentally, the low active substance content enables the active substance to be produced even in the case of the manufacture of millions of tablets annually on the scale of a large laboratory, and at a price that is acceptable to every patient. The active ingredients are stable, so the tablets can be put on the market without specifying a time limit for consumption. The active substance content of delayed-acting tablets or capsules can be 10-20 micrograms. In the case of injectable preparations, the appropriate dose per ampoule is 5-10 micrograms, and the preparation can, if desired, be prepared as a powder ampoule in which the active ingredient is mixed with an indifferent, water-soluble excipient. Parenteral administration can be carried out intramuscularly, subcutaneously or intravenously. In the specified concentration, the active ingredients do not damage tissue or vessel walls. The active ingredients can also be administered as an infusion. Suppositories contain 2 to 20, preferably about 10 micrograms of active ingredient and are made from cocoa butter or from synthetic waxes or fats (eg Imhausen mass produced in the Federal Republic of Germany) suitable for this purpose. The active ingredient content of cosmetic ointments used to heal the skin is 0.1-1 micrograms / g. The ointment base can be hydrophilic or hydrophobic and contains the usual components: e.g. As cholesterol, paraffin, glycerol, lanolin, cocoa butter, linseed oil, etc. The active ingredients can also be formulated as aerosol preparations, the active ingredient content also

0.1-1 microgram / g. When formulated as a perlingual tablet, one tablet contains 10 micrograms of active ingredient; the tablet's disintegration time is half an hour to an hour. Polymers for the sustained release of the active ingredient can, for. B. be prepared as a suspension and contain 1-5 micrograms of active ingredient / g of polymer. Injection preparations with retarder effect can be formulated either using high molecular weight polymers or from the salts of the compounds according to the invention formed with high molecular weight organic bases (e.g. histone, protamine), one ampoule containing 10-20 micrograms of active ingredient. Powders for cosmetic or skin healing purposes are prepared with the usual carriers (e.g. talc) and contain 0.1-1 g active ingredient / g powder. For ophthalmology, the compounds are formulated as drops or as ointments that are miscible or immiscible with the tear fluid; the active substance content of these preparations is 0.1-1 microgram / g. Children should be given the compounds according to the invention in a dosage of about 0.3 micrograms per kilogram of body weight.

The sterile preparations are expediently produced by sterile filtration.

The desired preventive pharmacological or cosmetic effect of the preparations listed above can be increased and supplemented by numerous combinations. The following are explicitly mentioned as possible biologically active additives and their use is to be protected:

Vitamins A, C, E and K, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, ra-diomymetic and immunosuppressive substances, psy-chopharmaca, especially tranquilizers, timoleptics, organic silicon compounds, gerontological preparations, which lower the blood cholesterol level Substances, oral antidiabetics, anti-inflammatory substances, antihistamines, etc. The dosage of these active additives is generally the same as the usual therapeutic dose when the substances are used alone.

The new compounds can also be used as an additive to nutritional or pharmaceutical premixes. They partly cause weight gain, partly they reduce the need for vitamin A or improve its metabolism. Furthermore, the absorption of the trace elements is increased by the compounds, their level in the blood is raised. When the compounds are used as an additive to animal feed, the dosage orally is expediently 200 nanograms / kg and day. Mixed into the feed, this corresponds approximately to a concentration of 1-2 micrograms / kg or 1-2 mg / tonne of feed, i.e. H. a concentration of 0.001 to 0.002 ppm. In view of these very low concentrations, use as a feed additive is extremely economical. The compounds vitamin amine premixes are preferably admixed or used in microcapsules which contain the compounds according to the invention in addition to other necessary feed additives. The compounds can also be used when soaking with drinking water, in leaking salt or occasionally as a spray.

In veterinary medicine, the new compounds have similar fields of application as in human medicine, i.e. H. for example skin damage (peeling), wound healing, broken bones etc.

It is a common structural property of all compounds of the general formula (I) that they contain a dicarboxylic acid substituted in the a-position or its derivative which is also substituted in other places via its w -carboxyl group with an acid amide bond bonded to a primary or secondary alkylamine, which except various

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Substituents on its alkyl side chain in the w position contains a group of strongly acidic character.

The polymeric or oligomeric derivatives can also be formed from the compounds of the general formula (I). These compounds are obtained by reaction of a-poly-lyaminodicarboxylic acid a> active esters - e.g. B. a-Poly-L-glutaminic acid-y-p-nitrophenyl ester - obtained with taurine, homotaurine or cysteamine (in the case of cysteamine, oxidation is also required). If necessary, these polymers can be broken down into the monomeric compounds of the general formula (I). This can e.g. B. done by hydrolysis with carboxypeptidase or leucine aminopeptidase.

example 1

40.85 g (0.11 mol) of carbobenzyloxy-L-glutamic acid a-benzyl ester (Liebigs Annalen 655,200,1962) are dissolved in 500 ml of acetonitrile. The solution is cooled to —15 ° C. with the exclusion of air humidity. With stirring, first 15.4 ml (0.11 mol) of triethylamine, then 15.4 ml (0.11 mol) of isobutyl chloroformate are added dropwise. The reaction mixture is stirred at -15 ° C for 40 minutes and then 28 ml (0.2 mol) of triethylamine, then 11.26 g (0.05 mol) of cystamine hydrochloride and finally 250 ml of acetonitrile are added. The mixture is stirred at -15 ° C for a further two hours, then at room temperature for a further four hours.

After the reaction time has elapsed, the mixture is evaporated in vacuo at 30 ° C. The residue is taken up in 200 ml of ice water while stirring and cooling, and the mixture is again evaporated at 35 ° C. in vacuo. The residue is placed together with 250 ml of water and 500 ml of ethyl acetate in a separatory funnel and the organic phase is separated off. The organic phase is shaken out successively first with 250 ml of water, then twice with 250 ml of 5% sodium carbonate solution, then twice with 250 ml each in hydrochloric acid and finally with 250 ml of water. (From the aqueous phase obtained by shaking with sodium carbonate solution, about 5 g of unreacted carbobenzyloxy-L-glutamic acid a -benzyl ester can be recovered by acidification with hydrochloric acid and shaking with ether.) The ethyl acetate phase is dried over anhydrous sodium sulfate and then in vacuo evaporated to dryness at 30 ° C. A thick, oily residue is obtained which soon solidifies to a crystalline mass. This is triturated with 250 ml of absolute ether, the crystals are filtered off. The crude product (40-42 g) is recrystallized from a mixture of 100 ml of ethyl acetate and 170 ml of ether. 29.3 g of N, N'-bis- [N-carbobenzyloxy-y- (a-benzyl) -L-glutamyl-cystamine are obtained, which melts at 91-92 ° C.

Elemental analysis for C44HsoN4010S2 (M = 859.05):

Calc .: C 61.52 H 5.89 N 6.52 S 7.46%

Found: C 60.85 H 5.91 N 6.61 S 7.72%

Example 2

25.77 g (0.03 mol) of the N, N'-bis- [N-carbobenzyloxy-y- (a-benzyl) -L-glutamyl] -cystamine obtained in Example 1 are dissolved in 75 ml of glacial acetic acid. A freshly prepared mixture of 75 ml of 30% hydrogen peroxide and 225 ml of glacial acetic acid is added dropwise to the solution, which is cooled in ice, within 15 minutes. After the addition, the cooling is removed and the reaction mixture is stirred at room temperature for 4 hours. It is then evaporated in vacuo at 30 ° C. The oily product is dried in the desiccator first over phosphorus pentoxide, then over solid potassium hydroxide. 28.5 g of carbonbenzyloxy-y- (a-ben-cyl) -L-glutamyl taurine are obtained. The crude product can be used to prepare the y-L-glutamyl taurine without purification.

Example 3

26.32 g (55 mmol) of the carbobenzyloxy-y- (a-benzyl) -L-glutamyl taurine prepared according to Example 2 are dissolved in 50 ml of glacial acetic acid. 4 moles of bromine water, dissolved in 50 ml of glacial acetic acid, are added to the solution. A lively development of carbon dioxide can be observed. The reaction mixture is left to stand at room temperature for 2 hours and then evaporated in vacuo at 30 ° C. The oily residue is dissolved in 170 ml of water and extracted five times with 70 ml of ether each time. The aqueous phase is evaporated in vacuo at 35 ° C. This gives 20.42 g of y- (a-benzyl) -L-glutamyl taurine, which is recrystallized from 90% ethanol.

Rf (n-B ut anol-pyridine-glacial acetic acid-water 15 15: 10: 3: 12) = 0.53

Rf (n-butanol glacial water 4: 1: 1) = 0.39.

Example 4

529 mg (1.1 mmol) of the 20 carbobenzyloxy-y- (a-benzyl) -L-glutamyl taurine produced according to Example 2 are dissolved in 5 ml in potassium hydroxide solution and left to stand at room temperature for 4 hours. Then the solution is extracted three times with 3 ml ether. The aqueous phase is applied to a column of 1 × 20 cm 25 filled with Dowex 50 × 2 and eluted with water. 50 ml of solution are collected and evaporated to dryness in vacuo at 35 ° C. Crude carbobenzyloxy-y-L-glutamyl taurine is obtained, which is purified by paper electrophoresis carried out at pH 6.5. The relative mobility related to cysteic acid is 1.05.

R {(n-butanol-pyridine-glacial acetic acid-water 15:10: 3:12) = 0.57.

Example 5

35 5.79 g (12.1 mmol) of the carbobenzyloxy-y - (a -benzyl) -L-glutamyltaurine prepared according to Example 2 are dissolved in a mixture of 100 ml of ethanol and 25 ml of water and with shaking in the presence of 0 , 5 g of 10% palladium-carbon hydrogenated as a catalyst. The catalyst is expediently added in two portions of 0.25 g each. After no more hydrogen is consumed, the solution is filtered and then evaporated in vacuo at 30 ° C. The oily residue is dried in a desiccator over phosphorus pentoxide. 3.1 g of y-L-glutamyl taurine are obtained, which is very good in water and insoluble in alcohol. The product can be crystallized by adding little water and alcohol in small portions. The crystalline crude product melts at 202-204 ° C.

The crude product is recrystallized several times from 80% ethanol. 2.02 g of pure end product are obtained, which - based on N, N '-bis- [N-carbobenzyloxy-y- (a -benzyl) -L-glutamyl] -cystamine - corresponds to a yield of 66%. The pure product melts at 219-220 ° C. [a] D2U = + 14 ° C (water, c = 1.02). The relative mobility related to cysteic acid was 0.73 for paper electrophoresis at pH 6.5 and 0.53 for pH 1.8.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.19.

Analysis for (^ H ^ OeS (M = 254.27):

60 reports: C 33.07 H 5.55 N 11.02 O 37.75 S 12.61%

Found: C 33.15 H 5.76 N 10.94 O 37.53 S 12.17%

Example 6

The y- (a-benzyl) -L-glutamyl-65 taurine (20.42 g) obtained according to Example 3 is dissolved in 150 ml in potassium hydroxide solution. The solution is allowed to stand at room temperature for 4 hours and then on a column of Dowex 50 x 2 (Fluka, 100-200 mesh) which is in the H + cycle

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Dimensions 2 x 100 cm applied. It is eluted with water. From the start of washing out, 300 ml of eluate are collected. This is evaporated in vacuo at 35 ° C. The oily residue is crystallized by adding 8-10 ml of water and about 100 ml of ethanol. After filtering, washing with alcohol and drying, 13.7 g of y-L-glutamyl taurine are obtained. The crystalline product is recrystallized from 80% aqueous alcohol. 9.79 g of pure product are obtained, which corresponds to a yield of 70% based on N, N'-bis- [N-carbobenzyloxy-y- (a-benzyl) -L-glutamyl] -cystamine.

Example 7

5.42 g (11 mmol) of carbobenzyloxy-L-glutamic acid (p.-benzyl) -y-p-nitrophenyl ester (Chem. Ber. 96, 204, 1963) are dissolved in 50 ml of pyridine. The solution is cooled to 0 ° C. and a solution of 1.25 g (10 mmol) of taurine in 20 ml of water is added dropwise over the course of half an hour with vigorous stirring. Then the mixture is mixed with 3.08 ml (22 mmol) of triethylamine, cooling and stirring are switched off. The mixture is left at room temperature for 72 hours and then evaporated in vacuo. The residue is dissolved in 50 ml of water and added to the yellow solution in hydrochloric acid until it decolorises. In order to remove the p-nitrophenol, the solution is shaken out ten times with 50 ml ether. The aqueous phase is evaporated in vacuo. 6.9 g of carbobenzyloxy-y- (a-benzyl) -L-glutamyltaurine triethylammonium salt are obtained.

The substance is catalytically hydrogenated in the manner described in Example 5 and the solvent is removed by evaporation in vacuo. To remove the tri-ethylamine, the substance is dissolved in a little water and applied to a Dowex 50 x 2 column of 2 × 40 cm. It is eluted with water. About 120 ml of eluate is collected and this is then evaporated in vacuo at 35 ° C. The product is crystallized and isolated in the manner described in Example 5. 1.72 g of y-L-glutamyl taurine are obtained, which corresponds to a yield of 68% based on taurine.

Example 8

The carbobenzyloxy-y-L-glu-tamyl taurine obtained in Example 4 is dissolved in 2 ml of glacial acetic acid containing 4 mol of hydrogen bromide. The mixture is left to stand at room temperature for half an hour and then evaporated at 35 ° C. in vacuo. The residue is triturated several times with ether and then separated from the ether by decanting. The y-L-glutamyl taurine obtained is recrystallized in the manner described in Example 5.

Example 9

25.4 mg (0.1 mmol) of y-L-glutamyl taurine are dissolved in 2 ml of water and 10 ml of 0.01N sodium hydroxide solution are added to the solution. The mixture is evaporated in vacuo at 30 ° C. The white crystalline residue is dried in a desiccator over phosphorus pentoxide. The mono-sodium salt of y-L-glutamyl taurine is obtained. The product has no sharp melting point, begins to shrink at 200 ° C, its color progressively darkens, and chars at around 250 ° C çs. The product is equally poorly soluble in methanol and ethanol.

Example 10

10 ml of absolute methanol, which contains 0.5 mol of hydrogen chloride per liter, are added to 7.5 mg (30 / <mol) of y-L-glutamyl taurine. The suspension is stirred at room temperature for 24 hours. The pure product is isolated by descending paper chromatography, using one of the following two flow agents:

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.27

Rf (n-butanol glacial water 4: 1: 1) = 0.14.

Y- (a-methyl) -L-glutamyl taurine is obtained.

Example 11

The esterification is carried out in the manner described in Example 10, but ethanol containing hydrogen chloride is used. Y- (a-ethyl) -L-glutamyl-taurine is obtained.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.37

Rf (n-butanol glacial water 4: 1: 1) = 0.22.

Example 12

25.4 mg (0.1 mmol) of y-L-glutamyl taurine are dissolved in 100 wl of 2N sodium hydroxide solution. The solution is cooled to 0 ° C and then three portions of a total of 36 ul of acetic anhydride and 180 for 4N sodium hydroxide solution are added every 5 minutes, with vigorous stirring. The alkaline solution is diluted to 2 ml with water and then left to stand at room temperature for 12 hours. In order to remove the sodium ions, the solution is applied to a Dowex 50 x 2 column of 1 x 10 cm and eluted with water. 50 ml of eluate are collected and evaporated in vacuo at 35 ° C. The product obtained is N-acetyl-y-L-glutamyl taurine. It is dissolved in water and purified by paper electrophoresis carried out at pH 6.5. The relative mobility related to cysteic acid is 1.22.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.25.

Example 13

25.4 mg (0.1 mmol) of y-L-glutamyl taurine are benzylated with 13 fA benzoyl chloride, following the procedure given in Example 12 for acetylation. After removing the sodium ions on the Dowex column and evaporating the eluate, N-benzoyl-y-L-glutamyl-taurine is obtained, which is purified by means of paper electrophoresis carried out at pH 6.5. The relative mobility related to cysteic acid is 1.06.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.47.

Example 14

0.48 g (1 mmol) of carbobenzyloxy-a-L-glutamyl (y-p-nitro-phenyl ester) glycine ethyl ester (Acta Chim. Acad. Sci. Hung. 65, 375, 1970) are dissolved in 6 ml of ethyl acetate. The solution is cooled with ice water. At 0 ° C., 0.08 g (1 mmol) of cysteamine in 1 ml of dimethylformamide are first added to the solution, then 0.14 ml (1 mmol) of triethylamine are added dropwise. Precipitation slowly begins to fail. The reaction mixture is left in ice water for some time, then left to stand at room temperature for 1 day and finally diluted with a 1: 1 mixture of ether and ethyl acetate. The precipitate is centrifuged off and washed first with a 4: 1 mixture of ether and ethyl acetate, then several times with ether. After drying over sulfuric acid, the precipitate is washed three times with in hydrochloric acid, twice with water, twice with saturated sodium bicarbonate solution and finally twice more with water and then dried in vacuo over sulfuric acid. 0.35 g of carbobenzyloxy-a-L-glutamyl- (y-cysteamine) glycine ethyl ester is obtained, which corresponds to a yield of 85%.

Analysis for Ca8H2S06N3S (M = 411.4):

Calc .: C 52.6 H 6.1 S 7.8%

Found: C 53.4 H 6.5 S 7.7%

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The infrared spectrum has the following maxima for the characteristic groups: NH 3310 cm-1, C = 0 (COOEt) 1748 cm "1, C = 0 (Z) 1690 cm" 1, C = 0 (amide) 1655 cm- 1.

100 mg of carbobenzyloxy-a-L-glutamyl (y-cysteamine) glycine ethyl ester are dissolved in 2 ml of glacial acetic acid and 0.5 ml of 30% hydrogen peroxide are added to the solution. The reaction mixture is left under ice-water cooling for 4 hours. The progress of the reaction is monitored by paper electrophoresis. After dilution with water, the reaction mixture is lyophilized. The end product is obtained in the form of a foam. 0.11 g of carbobenzyloxy-a -L-glutamyl- (y-tau-rin) -glycine ethyl ester (95%) are obtained.

Example 15

0.47 g (1 mmol) of carbobenzyloxy-a-L-glutamyl- (y-p-nitro-phenyl ester) -glycine methyl ester are dissolved in 6 ml of pyridine. While cooling with ice, 0.125 g (1 mmol) of taurine in 2 ml of water are added to the solution, then 0.28 ml (2 mmol) of triethylamine in small portions so that the solution always remains clear. The reaction mixture is left to stand at room temperature for three days. After evaporation in vacuo, an oil is obtained which, after thorough digestion in ether, then in petroleum ether, is dried in vacuo over sulfuric acid. Carbobenzyloxy-a-L-glutamyl- (y-taurine) -glycine methyl ester is obtained.

Example 16

100 mg of the carbobenzyl-oxy-a-L-glutamyl (y-taurine) glycine ethyl ester prepared according to Example 14 are concentrated in a mixture of 1 ml of trifluoroacetic acid and 1 ml. Hydrochloric acid dissolved. The solution is kept in a sealed bomb tube at 35 ° C for 3 hours. The solution is then evaporated in vacuo, the residue is digested several times with ether and n-hexane and then evaporated again. A white amorphous substance is obtained which turns out to be uniform in electrophoretic examination and gives a positive ninhydrin stain. The product is a-L-glut-amyl- (y-taurine) -glycine. Yield: 0.06 g (88%).

Analysis for C9H17N307S (M = 311.3):

Calc .: S 10.3%

Found: S 10.0%

The infrared spectrum has the following maxima for the characterizing groups: NH3 + 3100 cm-1 (broad); OH (COOH) 3200 cm "1 (broad); C = 0 (COOH) 1730 cnT1; C = 0 (amide-I) 1680 cm" 1; C = 0 (Amide II) 1560; S = 0 (S020H) 1220 cm-1 (intense); S = 0 (S020 ~) 1045 cm-1 (intense).

Hydrolysis: 20 mg of the substance are held in 1 ml of 6N hydrochloric acid in a sealed glass tube for 24 hours at 105 ° C. After cooling, a sample of the solution is subjected to electrophoresis at pH 1.8. The solution contains glutamic acid, glycine and taurine.

Example 17

100 mg of the carbobenzyl-oxy-a-L-glutamyl- (y-taurine) glycine methyl ester prepared according to Example 15 are reacted with 4 ml of 2N glacial hydrogen bromide at room temperature until the entire substance has dissolved (approximately 30 minutes). The clear solution obtained is poured into 30 ml of ether and left in a cool place for 1 day. The resulting precipitate is centrifuged off, washed several times with ether and then dried in vacuo over potassium hydroxide, sulfuric acid and phosphorus pentoxide. As the electrophoretic investigation shows, the hydrogen bromide of the a-L-glutamyl- (y-tau-rin) -glycine methyl ester is obtained in practically pure form.

Example 18

The salt obtained according to Example 17 is reacted with 2 ml of sodium hydroxide solution for 3 hours while cooling with ice water. The progress of the hydrolysis is monitored electrophoresis. The reaction mixture is subjected to ion exchange with 10 ml of Dowex 50 in H + form and then lyophilized. Since the electrophoresis still shows impurities, the product is recrystallized several times from aqueous ethanol until the corresponding purity is reached. 40 mg (59%) of a-L-glutamyl- (y-taurine) -glycine are obtained.

For the characteristic groups, the infrared spectrum has the following maxima: NH 3310 cm-1; NH3 + 3100 cm'1 (wide); C = 0 (COOH) 1730 cnT1; C = 0 (amide-I) 1650 cm'1; C = 0 (Amide II) 1570 cnT1; S = 0 1220 (intensive), 1045 cm-1 (intensive).

Example 19

100 mg of the a-L-glutamyl- (y-taurine) glycine prepared according to Example 16 or 18 are dissolved in 25 ml of a 2m ammonium bicarbonate buffer with a pH of 8.5. 1 mg of carboxypeptidase A, dissolved in 0.5 ml of water, is added to the solution (manufacturer of the enzyme: Serva, Heidelberg). The mixture is kept at 37 ° C in the thermostat for 24 hours and then lyophilized. Y-L-glutamyl taurine and glycine can be detected in the dry lyophilisate. The pure y-L-glutamyl taurine can be obtained by electrophoresis or chromatography on a Dowex 50 column.

Example 20

1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -y-p-nitrophenyl ester are dissolved in 6 ml of a 2: 1 mixture of pyridine and water. First 278 mg (2 mmol) of homotaurine, then 0.59 ml (4.2 mmol) of triethylamine are added to the solution. The yellow solution is left at room temperature for 72 hours and then evaporated in vacuo. The oily residue is dissolved in water, neutralized with hydrochloric acid and then extracted with ether for 8 hours to remove the p-nitrophenol in a continuous extractor. The aqueous phase is evaporated in vacuo. 1.68 g of carbobenzyloxy-y- (a-benzyl) -L-glutamylhomotaurin are obtained.

Example 21

The entire amount of the substance prepared according to Example 20 (1.68 g) is dissolved in 10 ml of 50% aqueous ethanol, then 0.3 g of 10% palladium activated carbon is added and hydrogen is passed through the suspension for 4 hours. The solution is then filtered and evaporated in vacuo. The residue is dissolved in 1-2 ml of water and applied to remove the triethylamine on a H + form Dowex 50x2 column of 1 x 35 cm. It is eluted with water. 50 ml of eluate are collected and then evaporated in vacuo. The residue obtained is 440 ml of y-L-glutamyl homotaurine, which corresponds to a yield of 82%. The electrophoresis carried out at pH 6.5 shows a low level of contamination by partly neutral, partly acidic substances (homotaurin or glutamic acid). The product can e.g. B. cleaned by preparative electrophoresis.

In both the pH 6.5 and the pH 1.8 electrophoresis, the substance migrates in the direction of the cathode. Their relative mobility based on cysteic acid is 0.68 at pH 6.5 and 0.50 at pH 1.8.

R {(n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.19.

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Example 22

1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -y-p-nitrophenyl ester are reacted in the manner described in Example 20 with 278 mg (2 mmol) of N-methyl taurine. 1.59 g of carbobenzyloxy-y - (“- benzyl) -L-glut-amyl-N-methyltaurine are obtained.

Example 23

The entire amount of the substance prepared according to Example 20 (1.59 g) is catalytically hydrogenated in the manner described in Example 21. 423 mg of y-L-glutamyl-N-methyltaurine are obtained, which corresponds to a yield of 79%.

The substance migrates towards the cathode both at pH 6.5 and at pH 1.8 in paper electrophoresis. Relative mobility related to cysteic acid: pH 6.5: 0.68; pH 1.8: 0.49.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.16.

Example 24

2.87 g (6.6 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -type-nitrophenyl ester are dissolved in 20 ml of pyridine and mixed with a solution of 1.25 g (6 mmol) of L-cysteic acid monohydrate a mixture of 17 ml of water and 17 ml of pyridine. After adding 2.6 ml (18.6 mmol) of triethylamine, the reaction mixture is left to stand at room temperature for 72 hours. The solution is then evaporated in vacuo at 30 ° C. The residue is dissolved in 20 ml of water, with conc. Acidified hydrochloric acid and then shaken 15 times with 10 ml ether. The aqueous phase is evaporated in vacuo at 35 ° C. Carbobenzyloxy-y- (a-benzyl) -L-glutamyl-L-cysteic acid is obtained.

Example 25

The product prepared according to Example 24 is dissolved in 20 ml of water, 0.3 g of 10% palladium activated carbon is added and hydrogen is passed through the suspension for 3 hours. The reaction mixture is worked up in the manner described in Example 21. Y-L-glutamyl-L-cysteic acid is obtained, which melts at 187 ° C. Relative mobility in paper chromatography related to cysteic acid: at pH 6.5: 1.21; at pH 1.8: 0.54.

Example 26

1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (a-benzyl) -y-p-nitrophenyl ester are dissolved in 6 ml of a 2: 1 mixture of pyridine and water. First 282 mg (2 mmol) of cholamine phosphate (US Pat. No. 2,730,542) and then 0.87 ml (6.2 mmol) of triethylamine are added to the solution. The reaction mixture is left at room temperature for 72 hours and then evaporated in vacuo. Further workup is carried out in the manner described in connection with carbobenzyloxy-y- (a-benzyl) -L-glutamylhomotaurin (Example 20). 1.25 g of carbonbenzyloxy-y- (a-benzyl) -L-glutamylcholamine phosphate are obtained.

Example 27

The entire amount of the product obtained according to Example 26 (1.25 g) is catalytically hydrogenated to remove the protective groups. The hydrogenation and the purification by ion exchange are carried out in the manner described in connection with the preparation of the y-L-glutamyl homotaurin (Example 21). 470 mg of y-L-glutamylcholamine phosphate are obtained, which corresponds to a yield of 91%. However, as shown by paper electrophoresis, the product contains approximately 15 to 20% chol as an impurity.

amine phosphate. Electrophoresis is one of the possible cleaning processes.

In paper electrophoresis, the substance migrates towards the cathode both at pH 6.5 and at pH 1.8. Relative mobility related to cysteic acid: pH 6.5: 0.75; pH 1.8: 0.36.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.18.

Example 28

526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (a-benzyl) /? - p-nitrophenyl ester (Chem. Ber. 97, 1789, 1964) are dissolved in 5 ml of pyridine. The solution is cooled to 0 ° C. and then a solution of 125 mg (1 mmol) of taurine in 2 ml of water and then 0.28 ml (2 mmol) of triethylamine are added in small portions. The reaction mixture is left at room temperature for 48 hours and then evaporated in vacuo. The residue is dissolved in 5 ml of water and the solution, which is yellow at the beginning, is mixed with In hydrochloric acid until it decolorises. To remove the p-nitrophenol, the solution is shaken out ten times with 5 ml ether. The aqueous phase is evaporated in vacuo. 478 g of carbobenzyloxy- / 3- (a-benzyl) -L - aspartyl taurine are obtained.

Example 29

The total amount of the product obtained according to Example 28 is 50% in 6 ml. aqueous ethanol dissolved. The solution is mixed with 100 mg of 10% palladium activated carbon and then hydrogenated by bubbling in hydrogen gas for 4 hours. After filtering and evaporating in vacuo, the triethylamine is removed from the product by ion exchange in the manner already described in connection with the preparation of y-L-glutamyl homotaurine (Example 21). 172 mg / 3-L-aspartyl taurine are obtained, which corresponds to a yield of 71%. The product is contaminated with little taurine, which can be removed by electrophoresis, among other things.

In paper electrophoresis, the substance migrates to the cathode both at pH 6.5 and at pH 1.8. Relative mobility related to cysteic acid: pH 6.5: 0.77; pH 1.8: 0.58.

R {(n-butanol-pyridine-glacial acetic acid water 15: 10: 3: 12) = 0.16.

Example 30

526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (a-benzyl) - / 3-p-nitrophenyl ester and 139 g (1 mmol) of homotaurine are reacted in the manner described in Example 28. Carbobenzyloxy- / 3- (a-benzyl) -L-aspartylhomotaurin is obtained.

Example 31

The product obtained according to Example 30 is catalytically hydrogenated in the manner described in Example 21. 203 mg (84%) of β-L-aspartyl homotaurin are obtained.

In paper electrophoresis, the substance migrates towards the cathode both at pH 6.5 and at pH 1.8. Relative mobility related to cysteic acid: pH 6.5: 0.72; pH 1.8: 0.53.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 0.17.

Example 32

Carbobenzyloxy-L-aspartic acid (a-benzyl) - /? - p-nitro-phenyl ester and cholamine phosphate are reacted with one another in the manner described in Example 26. Carbobenzyloxy- / i- (ö-benzyl) -L-aspartylcholamine phosphate is obtained.

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Example 33

The substance obtained according to Example 32 is catalytically hydrogenated in the manner described in Example 21. Β-L-Aspartylcholamine phosphate is obtained.

In paper electrophoresis, the substance migrates towards the cathode both at pH 6.5 and at pH 1.8. Relative mobility related to cysteic acid: pH 6.5: 0.81; pH 1.8: 0.40.

Rf (n-butanol-pyridine-glacial acetic acid-water 15: 10: 3: 12) = 10.14.

Example 34

y-L-glutamine taurine (prepared according to Example 5, 6, 7, 8 or 19) is purified by recrystallization in the following manner: 300 mg of crude substance are dissolved in 5 ml of anhydrous dimethyl sulfoxide at room temperature with stirring. The opalescent solution is filtered and the filter washed out with 0.5 ml of dimethyl sulfoxide. The filtrate is combined with the washing liquid and 55 ml of absolute ethanol are added. The mixture is left to stand at room temperature for 12 hours, then the substance is filtered off, washed with 2.5 ml of absolute ethanol and dried in a vacuum desiccator over phosphorus pentoxide to constant weight. 240 mg of crystalline y-L-glutamyl taurine are obtained (yield of recrystallization: 80%).

Instead of ethanol, the same amount of dioxane, ether or acetone can also be used for recrystallization. The quality of the crystalline product is the same in all cases. Melting point (according to Boetius): 218-219 ° C. The product is uniform by layer chromatography.

Example 35

Carbobenzyloxy-y- (cc-benzyl) -L-glutamylcholamine is produced in a manner suitable for the preparation of glutamic acid-y-amides (Acta Chim. Acad. Sei. Hung. 64, 285, 1970). 4.14 g of this product (10 mmol) are dissolved in 50 ml of absolute pyridine and 9 g (33 mmol) of diphenylphosphoric chloride are added. The reaction mixture is kept at 0 ° C for 12 hours and then diluted with 80 ml of chloroform. The product which has separated out is filtered off, washed with dilute hydrochloric acid and then with water and finally dried in a desiccator over potassium hydroxide. The dry substance is dissolved in 15 ml of glacial acetic acid containing 3.3 mol / 1 hydrogen bromide, the solution is left to stand for 15 minutes and then evaporated at 35 ° C. in vacuo. The residue is dissolved in 30 ml in sodium hydroxide solution and the solution is left to stand at room temperature for 1 hour. Then its pH is adjusted to 4 with acetic acid and the solution is extracted three times with 30 ml ether to remove the phenol and the benzyl alcohol. The aqueous phase is applied to a H + form Dowex 50 column and eluted with water. The eluate is evaporated in vacuo and the residue is recrystallized from a 2: 1 mixture of acetone and water. 0.8 g of y-L-glutamylcholamine phosphate are obtained.

Example 36

4.68 ml (5 mmol) of phosphorus oxychloride are added dropwise to 1.8 ml of water with cooling and stirring (Biochem. Preparation 6, 76, 1958). 1.9 g (10 mmol) of y-L-glutamylcholamine (made from carbobenzyloxy-y- (a-benzyl) -L-glutamylcholamine according to Example 35) are added to the solution in small portions. The mixture is stirred at 60 ° C for 2 hours, after cooling with stirring, 0.72 ml of water is added and then left to stand at room temperature for 2 hours. Then 10 ml of 96% ethyl alcohol and then 10 ml of ether are added dropwise with stirring. The reaction mixture is left to stand at 4 ° C. for one night and then 5 ml of 96% ethanol are added. The precipitated substance is filtered off, washed first with ethanol, then with ether and finally recrystallized from a mixture of ethanol and water. 1.75 gy-L-glutamylcholamine phosphate is obtained.

Example 37

4.14 g (10 mmol) of carbobenzyloxy-y- (a-benzyl) -L-glutamylcholamine are dissolved in 40 ml of pyridine and the solution is cooled to -10 ° C. 2.1 g (11 mmol) of p-toluenesulfonyl chloride are added in small portions with vigorous stirring. The reaction mixture is stirred at 0 ° C for 3 hours and then poured onto 40 g of melting ice. The precipitate which has separated out is filtered off, washed with water and finally recrystallized from a mixture of ethanol and petroleum ether. The product is subjected to a catalytic hydrogenation in the manner described in Example 5. The substance obtained after the hydrogenation and dried is dissolved in 30 ml of water and 10.1 g (40 mmol) of sodium sulfite heptahydrate are added to the solution. The solution is stirred at 40 ° C for 24 hours and then evaporated in vacuo. The residue is dissolved in a little water and applied to a Dowex 50 column, from which it is eluted with water. The eluate is evaporated in vacuo and the residue is dried over potassium hydroxide. After recrystallization from 80% ethanol, 1.6 g of y-L-glutamyl taurine are obtained.

Example 38

To 4.14 g (10 mmol) of carbobenzyloxy-y- (a-benzyl) -L-glutamylcholamine are added 15 ml of thionyl bromide and the mixture is stirred for 3 hours. Then ether is added, the precipitate which separates is filtered off and recrystallized from a mixture of acetone and petroleum ether.

The substance obtained is dissolved in a mixture of dimethylformamide and water, and 10.1 g (40 mmol) of sodium sulfite heptahydrate are added to the solution with stirring. The mixture is stirred for 24 hours at room temperature, then for a further 6 hours at 50 ° C and finally filtered. The clear solution is evaporated in vacuo, the residue is catalytically hydrogenated in the manner described in Example 5. The substance obtained after the hydrogenation and dried is dissolved in a little water, applied to a Do-wex 50 column and eluted with water. The eluate is evaporated in vacuo and the residue is recrystallized from 80% ethanol. 1.2 gy-L-glutamyltaurine is obtained.

Example 39

3.71 g (10 mmol) of carbobenzyloxy-L-glutamic acid a-benzyl ester are dissolved in 60 ml of acetonitrile. The solution is cooled to -15 ° C. and 1.4 ml (10 mmol) of isobutyl chloroformate are added, with stirring, then 1.4 ml (10 mmol) of triethylamine are added. The reaction mixture is stirred at -15 ° C for 30 minutes, then 2.05 g (10 mmol) of bromoethylamine hydrobromide, 1.4 ml (10 mmol) of triethylamine and 40 ml of acetonitrile cooled to -15 ° C are added. The mixture is stirred at -15 ° C for 2 hours, then at room temperature for an additional 4 hours. The mixture is then filtered and the filtrate is evaporated in vacuo at 35 ° C. The residue is dissolved in a mixture of dimethylformamide and water and 10.1 g of sodium sulfite heptahydrate are added to the solution. After working up the mixture in the manner described in Example 38, 1.45 g of y-L-glutamyl taurine are obtained.

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Example 40

4.43 g (10 mmoles) of carbobenzyloxy-L-pyroglutamic acid dicyclohexylamine salt (Liebigs Annalen 640, 145, 1961), 1.25 g (10 mmoles) of taurine and 0.84 g (10 mmoles) of sodium hydrogen carbonate are added 50 ml of water dissolved. The solution is warmed for 4 hours (or left at room temperature for 24 hours) and then evaporated in vacuo. The residue is dissolved in water, applied to a Do-wex 50 column and eluted with water. The eluate is evaporated. The substance obtained is catalytically hydrogenated in the manner described in Example 5. After Umkri-5 stallieren from an ethanol-water mixture, 2.03 g of y-L-glutamyl taurine.

s

Claims (22)

617 183 / <1 W - CH - CÛ - A (CH,) 1 - CII - CO ^ (L0), I? cckaJ - A-t (u) 2'n CO - N - (CHz) m - S R oxidized and the protective groups present in the compounds obtained, and the compounds of the formula (V) thus obtained converted into their salts or released from their salts. 2'n 2. The method according to claim 1, characterized in that compounds of the general formula (II), preferably N-carbobenzyloxyaminocarboxylic acid a-benzyl-co-p-nitrophenyl ester in a mixture of pyridine and water with compounds of the general formula (III), preferably with taurine, N-methyl taurine, homotaurine, cholamine phosphate or systemic acid. (2) is implemented and the protective groups present in the compounds obtained are removed, and, if appropriate, the compounds of the formula (I) thus obtained are converted into their salts or released from their salts. 2nd PATENT CLAIMS 1. Process for the preparation of compounds of general formula (I) R - HH - CH - COA (f2> D CO - ÏJ - (CH) I lo R (CH2) t - BJ (i) R bliss R1 for a hydrogen atom, an alkoxycarbonyl, cyclo-alkoxycarbonyl, aralkoxycarbonyl group, aralkoxycarbonyl group substituted by halogen, alkoxy or nitro, aryloxycarbonyl group or acyl group substituted by alkyl, A1 for a hydroxyl group or an alkoxy, cycloalkoxy, optionally substituted aralkoxy group with 1-4 carbon atoms in the alkyl part, R represents a hydrogen atom or an alkyl group with 1-4 carbon atoms, R2 represents a hydrogen atom or a carboxyl group and B1 represents -S020H, -0S020H or -OPO (OH) 2, n represents an integer between 1 and 3 and t represents 1 or 2, and of salts of these compounds, characterized in that compounds of the general formula (II) H \ / H ■ OH - CO CO » * 3rd 617 183 in which an existing a-amino group and / or a-carboxyl group is protected and A7 denotes a hydroxyl, azide, suc-cinimidoxy, p-nitrophenyloxy, pentachlorophenyloxy group or alkoxycarbonyl group with 2-4 carbon atoms, with compounds of the general formula (VII) in the i E (\ an converts the compounds of general formula (VIII) obtained H \ 3. The method according to claim 1, characterized in that the protective groups are removed with glacial hydrogen bromide, with dry hydrochloric acid gas dissolved in alcohol or with trifluoroacetic acid. 45 50 55 M - GH - COA CO - N - (CH2) m-S020H R bliss R1 for a hydrogen atom, an alkoxycarbonyl, cyclo-alkoxycarbonyl, aralkoxycarbonyl group, aralkoxycarbonyl group substituted by halogen, alkoxy or nitro, aryloxycarbonyl group or acyl group substituted by alkyl, A1 for a hydroxyl group, an alkoxy, cycloalkoxy or optionally substituted aralkoxy group each having 1-4 carbon atoms in the alkyl part, R represents a hydrogen atom or an alkyl group with 1-4 carbon atoms, n stands for an integer between 1 and 3 and m stands for 2 or 3, and of salts of these compounds, characterized in that compounds of the general formula (II) 60 R 4th 4. The method according to claim 1, characterized in that the protective groups by catalytic hydrogenation 5. The method according to claim 1, characterized in that in N-carbobenzyloxy-a-benzyl ester derivatives, the carbobenzyloxy protective group is removed by saponification, for example with acetic acid bromide. 6. The method according to claim 1 for the preparation of a salt, characterized in that a compound of the general formula (I) obtained is reacted with an alkali metal or alkaline earth metal hydroxide or carbonate or with an organic base. 7. The method according to claim 1, characterized in that acylated in a compound of formula (I) obtained, the free a-amino group corresponding to R1. 7 in which an existing a-amino group and / or a-carboxyl group is protected and A7 denotes a hydroxyl, azide, suc-cinimidoxy, p-nitrophenyloxy, pentachlorophenyloxy group or alkoxycarbonyloxy group with 2-4 carbon atoms, with compounds of the general formula ( III) HET! R (OH) - (CH2) t - B1 I O R ' (m) 8. The method according to claim 1, characterized in that in a compound of formula (I) obtained 30 a-carboxyl group esterified according to A1. 9. Process for the preparation of compounds of the general formula (V) 10. The method according to claim 9, characterized in that compounds of the general formula (II), s preferably N-carbobenzyloxyaminodicarboxylic acid a-benzyl-w-p-nitrophenyl ester, in a mixture of pyridine and water or N-carbobenzyloxyaminodicarboxylic acid a-benzyl ester in the form of its mixed anhydride with cystamine. 11. The method according to claim 10, characterized in io that the compounds of general formula (VIII) are reacted with a mixture of glacial acetic acid and 30% hydrogen peroxide. 12. The method according to claim 9, characterized in that the protective groups with glacial acetic acid bromine is removed with dry hydrochloric acid gas dissolved in alcohol or with trifluoroacetic acid. 13. The method according to claim 9, characterized in that compounds of the general formula (IX), preferably of N-carbobenzyloxy-a-benzyl ester derivatives, 14. The method according to claim 9, characterized in that compounds of the general formula (IX), preferably N-carbobenzyloxy-a-benzyl ester derivatives, 25 the protective group is removed by saponification. 15. The method according to claim 9 for the preparation of a salt, characterized in that a compound of the general formula (V) obtained with an alkali or alkaline earth metal hydroxide or carbonate or with an organic base. 30 is set. 15 removed. 16. The method according to claim 9, characterized in that in a compound of the formula (V) obtained the a-amino group corresponding to R1. 17. The method according to claim 9, characterized in 35 that the a-carboxyl group corresponding to A1 is esterified in a compound of formula (V) obtained. 18. Process for the preparation of new compounds of the general formula (X) R1 - IM - OH - CüA1 CO - im - (oh) - (CH2) t - B1 (X) bliss R1 for a hydrogen atom, alkoxycarbonyl, cycloalkoxycarbonyl, aralkoxycarbonyl group, aralkoxycarbonyl group substituted by halogen, alkoxy or nitro, aryloxycarbonyl group substituted by alkyl or acyl group, A1 for a hydroxyl group, alkoxy, cycloalkoxy, optionally substituted aralkoxy group each having 1-4 carbon atoms in the alkyl part, R2 represents a hydrogen atom or a carboxyl group, B1 represents -S020H, -OSOzOH, OPO (OH) 2, n is an integer between 1 and 3, t means 1 or 2, and of salts of these compounds, characterized in that a compound of the general formula (XI) ii3 - N - OH - CÜ0H I I 0 = C - (CH2) n (XJJ R £ ^ wherein R3 is a group of the formula R15-0-C- O in which R15 stands for alkyl group with 1-4 carbon atoms, cycloalkyl group, optionally substituted aralkyl or optionally substituted aryl group, 55 and n has the meaning given above, or their salt with a compound of the general formula (XII) 60 H2N-CH- (CH2) t-B1 R2 (XII) or their salt, in which R2, B1 and t are as defined above, and the protective group R3 is split off and that, if appropriate, a compound of the formula (X) is converted into a salt 65 or released from a salt. 19. The method according to claim 18, characterized in that reacting a compound of formula (XI), preferably pyroglutamic acid, with taurine or homotaurine. 617183 20. The method according to claim 18 or 19 for the preparation of a salt, characterized in that a compound of the general formula (X) obtained is reacted with an alkali or alkaline earth metal hydroxide or carbonate or with an organic base. 20 removed the carbobenzyloxy protecting group with glacial hydrogen bromide. 20th 25th (il) K " 21. The method according to claim 18, characterized in that in a compound of formula (X) obtained the a-amino group corresponding to R1. 22. The method according to claim 18, characterized in that the α-carboxyl group corresponding to A1 is esterified in a compound of the formula (X) obtained.