CS209855B2 - Method of making the new aminoacids derivatives - Google Patents

Abstract

1504541 Compositions containing amino acid derivatives CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT 28 April 1975 [29 April 1974 26 March 1975] 17608/75 Heading A5B [Also in Divisions C2 and C3] Cosmetic and pharmaceutical compositions contain (I) and/or salts thereof as active ingredient wherein A<SP>1</SP> stands for hydroxy, C 1-4 alkoxy, cycloalkoxy, aralkoxy, substituted aralkoxy, aryloxy, substituted aryloxy or a group of the general formulae: wherein R<SP>14</SP> is hydrogen, C 1-4 alkyl or aralkyl, R<SP>6</SP> is hydrogen, C 1-5 alkyl, aralkyl, hydroxysubstituted aralkyl, heteroaralkyl or a group of the general formula: Y is hydroxy, amino, alkylamino, dialkylamino, C 1-4 alkoxy or aralkoxy, and r is an integer of from 1 to 10 or an average polymerization grade of up to 2000, B<SP>1</SP> is a group of the formulae -SO 2 OH, -OSO 2 OH, -O-PO(OH) 2 or -S-S-R<SP>11</SP>, wherein R<SP>11</SP> is C 1-4 alkyl, aralkyl or aryl or a residue obtained when removing group B<SP>1</SP> from the general formula (I), R stands for hydrogen, C 1-4 alkyl or aralkyl, R<SP>x</SP> stands for hydrogen or halogen, R<SP>1</SP> stands for hydrogen, C 1-4 alkyl, aryl, aryl having a nitro or alkoxy substituent, aralkyl, substituted aralkyl, alkoxycarbonyl, cycloalkoxycarbonyl, aralkoxycarbonyl, substituted aralkoxycarbonyl having, e.g. a halogen, alkoxy, nitro, phenylazo or alkoxyphenylazo substituent, unsubstituted or substituted aryloxycarbonyl, acyl, arylsulfonyl or group (wherein R<SP>6</SP> has the same meanings as defined above and p is an integer of from 1 to 10 or an average polymerization degree of up to 2000), R<SP>2</SP> stands for hydrogen, C 1-4 alkyl, or aralkyl or R<SP>2</SP> and R<SP>2</SP> may each stand for a -CO- group and form a ring through an o-phenylene, alkylene or -CH=CH- group, R<SP>3</SP> stands for hydrogen, carboxy or carbalkoxy, R<SP>4</SP> stands for hydrogen, halogen, C 1-4 alkyl or hydroxy, R<SP>5</SP> stands for hydrogen, halogen, C 1-4 alkyl, carboxy, carboxamido, carbalkoxy or carboaralkoxy, m is 1, 2 or 3, n is 1, 2, 3 or 4, s is 0, 1, 2, 3 or 4, and t is 1, 2 or 3.

Description

(54) A method for producing novel amino acid derivatives

The present invention provides a process for the production of novel amino acid derivatives, some of which have valuable pharmacological properties, while others are intermediates for the production of substances with valuable biological or pharmacological effects. All compounds obtained by the process of the invention are novel.

The compounds which can be prepared by the process according to the invention can be illustrated in general. formula I,

^{R1-NH-CH-CO-1} (CH ₂₎ h

AND

CO - N - (CH) _m - (CH 2) _{t -} B1

RR ² (I) where is

A 1 is hydroxy, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, C 7 -C 9 aralkoxy, phenoxy optionally substituted on the nucleus with nitro, halogen, or - (NHCH 2 -CO) _r -Y wherein Y is hydroxyl, C 1 -C 4 alkoxy or C 7 -C 9 aralkoxy, and ar is an integer. from 1 to 10,

B1 a group of the formula —SO2 OH, —OSO2H, or —OOP (OH) 2,

R is hydrogen or (C1-C4) -alkyl,

R 1 is hydrogen, C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl or ferrocarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or nitro phenyl core, C1 -C4 alkanoyl or benzoyl;

R @ ^{2 is} hydrogen, C1 -C4 alkyl or carboxyl, C1 -C4 alkoxycarbonyl or phenoxycarbonyl or carboxamido, n number 1, 2, 3 or 4, m number 1, 2 or 3, t number 1, 2 or 3.

The invention also encompasses a process for preparing pharmaceutically acceptable salts or optically active antipodes of said compounds.

Among the compounds prepared by the process according to the invention, the γ-L-glutamyltaurine of the formula XXIV should be mentioned in particular because of its biological effects,

HaN — GH — COOH

GHa

AND

GHa

GO-NH-CH2-GH2-SO2OH, (XXIV) which is characterized by a broad spectrum of therapeutic and preventive efficacy against pathological changes having a direct or indirect cause in damage to the aeroblospheric genetic adaptation system (AGAS).

To clarify the concept of AGAS, the most important tissues and organs forming this system are listed below.

(a) All biological boundary surfaces in contact with the external air as the biosphere (skin and skin formations, cornea and conjunctiva, oral and esophagus, airways and lungs),

b) skeleton and limbs (hollow tubular bones and spongy bones, spherical joints, lining of the joint cavity, skeleton muscles),

c) bodies involved in the regulation of ion management (trans-epithelial transport system: intestinal villi and renal ducts),

d) dentition needed for grinding food and fixed roots in dental beds,

(e) auditory, olfactory and vocal organs.

The compounds prepared by the process according to the invention thus have a favorable biological or therapeutic effect on the above-mentioned organs or tissues of the AGAS system.

The compounds prepared by the method of the invention further act on the following AGAS-related functions: radiation protection, wound healing effect and generally activating mesenchym, protection against the ever increasing risk of infection and contamination of the skin and mucous membranes (formation of lysozyme of wet mucous membranes) , activation of cilia lining in the airways, etc.), increased · protection against infections caused by · viruses and fungi.

The compounds obtained by the process according to the invention are effective against constantly and to a high degree with increasing stress effects (for example meteorological effects, considerable differences between day and night temperature, increased risk of injury) onshore life by stabilizing adaptation syndrome while averting peripheral damage glucocorticoid tissue (e.g., damage to connective tissues, bone matrix damage, etc.). Origin of immunihomoeostasis (increased ability to recognize the body, which cells belong to the body and which do not).

Said compounds act in part to mediate, in part, by controlling the metabolism of vitamin A, by producing vitamin A metabolites of a more polar nature. This effect is comparable to that of parathyroid hormone on the 25-hydroxycholecalciferol-1α-hydroxylase enzyme of the renal tubules. By this explanation the broad pharmacological, biochemical and therapeutic effect of the compounds prepared by the process according to the invention becomes understandable. The areas of action of these compounds are as follows:

Vitamin A effects

(a) Pharmacological and biochemical effects

The radiolabeled sulphate is increasingly incorporated into the bone cartilage of the rat, optionally into the lens of the eye, liver and lung tissue of the chicken embryo; radiolabeled phosphorus is injected to an increased extent into the bone cartilage of the rat; chondroitin sulfate synthesis enhancing effect; a beneficial effect on wound healing or wound healing, optionally exacerbated by administration of cortisone in rats and dogs; Vitamin A potentiating effect in experimentally induced hypovitaminoses or hypervitaminoses in rats and chickens; calming · action on · stress effects caused by ulcers in rats; a beneficial effect on mast cell degranulation; lysozyme production-enhancing effect; effects on the management of trace elements (silicon, zinc, copper, manganese, fluorine); beneficial effect on epital formation; escalating effect on alkaline phosphatase activity; action on granuloma vesicle formation induced by the local action of vitamin A; very flat dose-effect curve, eventually change of the effect sign at large doses; activating effect on Golgi; a favorable effect on the formation of calyx cells; Vitamin A concentration-increasing effect

b) Clinical therapeutic effects

Keratoconjunctivitis sicca; Sjorgren's syndrome; rhinolaryngopharyngitis siccca; ozaena; · Chronic bronchitis; sinobronchitis; mucoviscidosis; constitutional lung disease in young children; periodontitis; susceptibility of the skin and mucosa to infection by viruses and fungi; cortisone antagonist; beneficial effect on wound healing of skin and mucosa during surgery; erosio colli; itch-induced decrease in olfactory and taste sense.

B) Non-vitamin A effects a) Pharmacological and biochemical effects

Effect on blood sugar in terms of transient · reduction; escalating effect on phosphaturia; reducing the effect on serum phosphorus; radio-protective effect;

an effect reducing the time required to reach the target in labyrinth experiments of inactive animals; a dampening effect on experimentally induced fluorine and cadmium toxicosis; escalating effect on adenosine monophosphate-induced cyclic renal emptying; a mitigating effect on the symptoms of experimentally induced lathyrism; · Decreased sensitivity to histamine; enhancing effect on liver enzyme tyrosine aminotransferase activity.

b) Therapeutic effects Mild radiation damage; local lack of dye in the skin; muscular hypotonia; psychoenergetic effect; beneficial effect on involution and gerontdlogic states as well as on mnestic functions; tendency to form fibrosis; spondylosts ankylopoetica; musculoskeletal disorders caused by wear; sclerotic fundus; amyloidosis; morphea; fibrocystic mastopathy.

The duration of treatment varies greatly when administering the compounds of the invention. In many diseases (eg rhinolaryngopharyngitis siccaj) · when given orally three times a day · 5 µg · symptoms do not occur after two weeks, symptomatic recovery of other diseases (eg periodontitis, Sjorgren's syndrome) requires one to two months, in other diseases ( for example, in spondylosis ankylopoetica), treatment must be for a quarter to a half year.

Any pharmaceutical, preventive, cosmetic or veterinary medicinal product can be prepared in a simple manner from the compounds prepared by the process according to the invention. These preparations may contain a single active ingredient or a combination of active ingredients. The dose of pure active ingredient is 50 to 500 ng per day, based on 1 · kg of body weight, and is administered in three divided doses.

One tablet contains 2 to 20 µg, preferably 10 µg of active ingredient and, in addition, biologically inert carriers (e.g., milk sugar, starch) as well as conventional tabletting aids (granulating and glidants, e.g. polyvinylpyrrolidone, gelatin, talc) , magnesium stearate, aerosil, etc.].

Because of the extremely low dosages, it is expedient to add the active ingredient to the mass from which the tablets are then compressed, prior to granulation, in the form of a solution. In this way, an even distribution of the active ingredient is achieved. Moreover, the low content of active substance enables the active substance to be produced, even in the manufacture of many millions of tablets per year, only on a laboratory scale, and at a price that is available to every patient. Since the active substances are stable, tablets can be supplied to the market without an expiry date. The active substance content of retarding tablets or spansular capsules may be in the range of 10 to 20 pg. For injectable preparations, the effective dose per vial is 5 to 10 µg, and the preparation can optionally be prepared in the form of a powdered formulation in which the active ingredient is mixed with an inert water-soluble filler. Parenteral administration can be performed intramuscularly, subcutaneously or intravenously. At the indicated concentration, the active compounds do not have a deleterious effect on either the tissue or the vessel walls. · The active agents can be administered ^{also to} the I · n ^{i mergers} of. Suppositories containing ^{y s 2} and ^20, preferably about 10 ug of active substance and are made from cocoa butter or synthetic waxes or fats suitable for this · · purpose. The active ingredient content of the cosmetic ointment or skin healing ointment is 0.1 to 1 ₍ g / g. Ointment base may be hydrophilic or hydrophobic and contains conventional ingredients, for example, cholesterol, paraffin, glycerin, lanolin, cocoa. butter, linseed oil, etc. The active ingredients may also be formulated as aerosol formulations, the active ingredient content also being in the range of 0.1 to 1 µg / g. In the form of a perlingual tablet the tablet contains 10 µg of the active ingredient, tablet disintegration time. The sustained release polymers can be prepared, for example, as suspensions and contain 1 to 5 µg of active ingredient / g polymer. Delayed injection preparations can be formulated using either high molecular weight polymers. or salts of compounds of the invention formed with high molecular weight organic bases (e.g., histone, protamine), p wherein one ampoule contains 10 to 20 µg of active ingredient Powders for cosmetic or skin treatment are prepared with conventional carriers, for example talc, and contain 0.1 to 1 µg of active ingredient / g powder. For ophthalmology, the compounds of the invention are formulated as drops, optionally as tear-miscible or non-tear-miscible ointments; the active ingredient content of these preparations is 0.1 to 1 pg / g. Children should be administered the compounds of the invention at a dose of about 0.3 µg per kg body weight.

Sterile preparations are conveniently produced by sterilization filtration.

The desired preventive pharmacological or cosmetic effect of the above-described preparations can be increased and supplemented by numerous combinations. Biologically active additives which may be considered are, first of all, the following substances which are explicitly mentioned and protected for their use:

vitamins A, C, E and K, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radiomimetic and immunosuppressive active substances, psychopharmaceuticals, · especially calming agents, timoleptics, organic silicon compounds, · gerontologic preparations, substances reducing blood cholesterol levels, oral anti-diabetic drugs, anti-inflammatory agents, antihistamines, etc. The dosage of these active ingredients is generally the same as the usual therapeutic dose when used alone.

The compounds produced by the process according to the invention can also be used as an additive in nutritional or medicinal mixtures. On the one hand, they cause weight gain, on the other hand they reduce the need for vitamin A or improve its metabolism. Further, the compounds of the invention increase the resorption of trace elements and their level in the blood. When using the compounds of the invention as feed additives, the oral dose is expediently 200 µg / kg daily. When mixed with feed, this corresponds to approximately a concentration of 1-2 g / kg or 1-2 mg / t of feed, i.e. a concentration of 0.091 to 0.002 ppm. Due to these very low concentrations, the use of the compounds of the invention as feed additives is extremely economical. Preferably, these compounds are added to the vitamin premixes or used in microcapsules containing the compounds of the invention together with other necessary feed additives. The compounds according to the invention can furthermore be used in drinking water for feeding cattle, in salt for licking or optionally in the form of a spray.

In veterinary medicine, the compounds of the invention have similar fields of application as in human medicine, e.g., in skin diseases, wound healing, bone fractures, etc.

It is a common feature of the structure of all compounds of formula I that they contain a dicarboxylic acid substituted at the α-position, or a derivative thereof substituted at other positions, linked via its ω-carboxyl group by linking the acid amide to the primary or secondary alkylamine. it contains a strongly acidic group in its ω-position on its alkyl side chain.

The process according to the invention for the preparation of the compounds of the formula I, their salts and optical isomers is carried out by reacting from the compound of the formula II:

R ³ -NH-CH-CO-A ²

I (CH ₂ ) _n

AND

CO-N (CH) _m - ^(B-1 CHžJt

RR ² (П) where is

A ^two hydroxyl, alkoxy having 1 to 4 carbon atoms, cycloalkoxy. C 3 -C 6 aralkyl, C 7 -C 9 aralkoxy, phenoxy. optionally substituted nitro, (C 1 -C 4) alkoxy or halogen on the phenyl ring, or - (NH-CH 2 -CO) _r -Y, wherein

Y represents a hydroxyl group, a C 1 -C 4 alkoxy group or a C 7 -C 9 aralkoxy group and an integer ranging from 1 to 10,

R ^{3 is} hydrogen, C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl or phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or nitro on the phenyl core a (1-4C) alkanoyl group or a benzoyl group, wherein when R ³ is hydrogen, A ² is other than a hydroxyl group, and

R ¹ , R, R ² , n, m and m are as defined above, cleave the protecting group (s) attached to the α-amino and / or ο-carboxyl group of the compound of formula (I), optionally in a compound of formula (I) A ¹ is a hydroxyl group and R, R ¹ , R ² , B ¹ , n, m and m are as defined above, esterify the β-carboxyl group and optionally convert any of the compounds thus obtained into their pharmaceutically acceptable salts or prepare into an optically active form using optically active starting materials or by resolution of the racemic product obtained.

For the preparation of compounds of formula IA containing a free carboxyl group,

H-N-CH-COOH

I (СНэ) _п

CO — N— (CH) _m - (GHz) t — в ¹

RR ² (IA) where

R 1, R ² , B ¹ , n, are as defined above, from a compound of formula 1IA,

R @ 1 --NH - CH - COOH

I (HzHzh

CO-N (CH u- (CH2} _t ¹ -B

RR ² (HA) where

R ⁴ represents an alkoxycarbonyl group having 1 to 4 carbon atoms, an aralkoxycarbonyl group having 7 to 9 carbon atoms, an aralkoxy group, a phenoxycarbonyl group, optionally substituted by halogen, a (C 1 -C 4) alkoxy group, or a nitro group on the phenyl core, alkanoyl C 1 -C 4 or benzoyl; and

R, R ^2, B ^1, n, there are as defined above, by acidolysis, hydrogenolysis, treatment with dilute sodium or ammonium hydroxide deprotection of R ^4th

Compounds of formula IA are also obtained when: - a compound of formula IIB,

H 2 N - CH - COA ³ (CH 2 _{n -}

CO-N - (CH) _m - ^(B-1 CHžjt

I I

R. R2 (IIB) wherein

A ³ is C 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, C 7 -C 9 aralkoxy, phenoxy optionally substituted by nitro, C 1 -C 4 alkoxy or halogen on the phenyl core, or a group of the formula - (NH-CH 2 -CO) _r -Y, wherein

Y is C 1 -C 4 alkoxy or C 7 -C 9 aralkyloxy and r is an integer from 1 to 10; and

R, R ² , B ¹ , m, and n are as defined above, saponification, acidolysis, hydrogenolysis or enzymatic hydrogenolysis for cleavage of the α-carboxyl-linked protecting group.

Compounds of formula (e-IA) containing a free primary amino group and a free carboxyl group can also be prepared by starting from a compound of formula (I). vzoir.ce IIC,

R 4 -NH-CH-CO-A3

I (CHžjn

I. - CO — N— (CH) _m - (CH2jt — B *)

RR ² (IIC) wherein R 1, R ² , R 4, A ³ , B1, n, have the same meaning as described above, simultaneously cleave the α-amino and α-carboxy-protected protecting groups, acidolysis, alkaline hydrolysis, hydrogenolysis or sodium treatment.

In all of these variations, the compounds obtained can be converted into their salts or released from their salts and / or any of the above compounds can be prepared in optically active form using optically active starting materials or by resolution of the racemic product obtained.

By cleavage of the protecting group attached to the α-amino group of the compound of the formula

IIC, se. to obtain a compound of formula IB,

H2N — CH — COA3

I ...

(CH2) n:

CO - N - (CH) m - (CH 2) t - B1

R R2

(Ib) wherein R, R 2, A ³ , Β ¹ , n and t are as defined above, and. by cleavage of the protecting group bound to the. - the carboxyl group of the compound of formula IIC to give a compound of formula IC,

R ⁴ -NH-CH-COOH.

(CH2) ’n

CO-N (CH) _m - (CH2) t-B1

R 1 - R 2 (IC) wherein R, R 2, R 4, B 1, n, m - and t are as defined above.

In the preparation of a compound of formula IA containing a free primary amino group, the deprotection of the nitrogen-bonded protecting group of the compound of formula IIA is achieved by treatment with anhydrous hydrogen halide, preferably hydrogen bromide, by trifluoroacetic acid or catalytic hydrogenation.

In the preparation of a compound of formula IA containing a free carboxyl group, the saponification of the compound of formula IIB is carried out with an alkali metal hydroxide, preferably in the presence of water, alcohol and / or acetone, or the compound of general formula IIB reacted with anhydrous hydrogen halide, preferably hydrogen bromide, or - with trifluoroacetic acid, or - is subjected to catalytic hydrogenation or enzymatic hydrolysis using a leucine aminopeptidase.

During preparations ' . compounds of formula IA containing a free primary amino group and a free carboxyl group -protective groups, cleaves from -compounds of formula IIC by treatment with hydrogen bromide in glacial acetic acid or by treatment with an alcoholic solution of gaseous hydrogen chloride - or by treatment with - trifluoroacetic acid - or - catalytic hydrogenation.

In the preparation of the compound of formula (IB), the carbobenzyloxy group of the compound of formula (IIC), preferably the N-carbobenzyloxy-α-benzyl ester derivative, is cleaved by treatment with hydrogen bromide in glacial acetic acid.

In the preparation of a compound of general formula

IC is ester group of compound 209855

12, it is cleaved by saponification of the compound PС, preferably the N-carbobenzyloxy-ar-benzyl ester derivative.

In the preparation of γ-glutamyltaurine, either N-carbobenzyloxy-γ- (n-benzyl) L-glutamyltaurine is subjected to catalytic hydrogenation, preferably in the presence of palladium on activated carbon as catalyst, or γ- (α-benzyl) L-glutamyltaurine is saponified in aqueous potassium hydroxide solution.

In the preparation of salts, the compound of formula (I) is reacted with an alkali or alkaline earth metal hydroxide or carbonate or an organic base.

The esterification of the α-carboxyl group in the compound corresponding preferably to γ-L-glutamyltaurine is carried out with an alkanol, preferably methanol or ethanol, in the presence of anhydrous hydrochloric acid.

In the preparation of a pharmaceutical composition comprising as active ingredient a compound of formula I or a salt thereof, or an optically active isomer thereof, the active ingredient is converted into a pharmaceutically acceptable form for oral, sublingual, parenteral, rectal or external application by mixing with a suitable pharmaceutical carrier, diluent and / or excipients.

The invention is illustrated by the following examples.

Example 1

26.32 g (55 mmol) of carbobenzyloxy-γ- (α-benzyl) L-glutamyltaurine, prepared from N, N -bis- [N-carbobenzyloxy-γ- (α-benzyl) -L; glutamyl] cystamine by treatment with hydrogen peroxide and glacial acetic acid are dissolved in 50 ml of glacial acetic acid. 4 moles of hydrogen bromide dissolved in 50 ml of glacial acetic acid are added to the obtained solution. After this solution was added, carbon dioxide began to evolve. The reaction mixture is allowed to stand after. 2 hours at room temperature, then evaporated under reduced pressure at 30 ° C. The oily residue is dissolved in 170 ml of water and shaken 5 times with 70 ml of ether each time. The aqueous phase is evaporated at 35 ° C. under reduced pressure. 20.42 g of γ- (α; -benzyl) -L-glutamyltaurine is obtained, which is recrystallized from 90% ethanol.

Rf (mixture of n-butanol, pyridine, glacial acetic acid and water 15: 10: 3: 12) = 0.53,

R _f (mixture of butanol, glacial acetic acid: water 4: 1: 1) = 0.39.

EXAMPLE 2 529 mg (1.1 mol) of carbobenzyloxy-γ- (α-benzyl) -L-glutamyltaurine are dissolved in ml of 1 N potassium hydroxide solution and the solution is allowed to stand at room temperature for 4 hours. Shake 3 times with 3 ml of ether each time. The aqueous phase was passed through a 1 X 20 cm ion exchanger column (Dowex 50 X 2), which was then eluted with water. 50 ml of the solution are collected and evaporated to dryness at 35 ° C under reduced pressure. Crude carbobenzyloxy-γ-L-glutamyltaurine is obtained and purified by paper electrophoresis at pH 6.5. The relative mobility relative to cysteic acid is 1.05,

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

Example 3 5.79 g (12.1 mol) of carbobenzyloxy-γ - (n-benzyl) -L-glutamyltaurine are dissolved in a mixture of 100 ml of ethanol and 25 ml of water and shaken in the presence of 0.5 g. activated carbon containing 10% palladium catalyst is hydrogenated. The catalyst is preferably added in two portions of 0.23 g. When hydrogen uptake ceases, the solution is filtered and then concentrated under reduced pressure at 310 ° C. The oily residue is dried in a desiccator with phosphorus pentoxide to give 3.1 g of γ-L-glutamyltaurine, which is very soluble in water but insoluble in alcohol. By adding small amounts of water and alcohol in small proportions, the product can be recrystallized. The crystalline crude product melts at 202-204 ^° C.

The crude product is recrystallized several times from 80% ethanol. 2.02 g of pure product are obtained, corresponding to a yield of 66% based on N, N'-bis- (N-carbobenzyloxy-γ- (α-benzyl) -L-glutamyl) cystamine. to 220 ° C.

[α] _D 20 = 14 ° (water, c = 1.02).

The relative mobility relative to cysteine acid in paper electrophoresis performed at pH 6.5 is 0.73, at pH 1.8 it is 0.53.

_Rf (n-butanol, pyridine, glacial acetic acid and water, 15: 10: 3: 12) - 9.19.

Analysis for C 7 H 14 N 2 O 6 S (M = 254.27):

Calculated:

C 33.07% H 5.55% N 11.02% 0 37.75% S 12.61%.

Found:

C 33.15% H 5.76% N 10.94%

O 37.53% S 12.17%.

Example 1 a d 4

20.42 g of γ- (α-benzyl) -L-glutamyltaurine obtained according to Example 1 are dissolved in

150 ml of 1 N potassium hydroxide solution.

The resulting solution was allowed to stand for 4 hours at room temperature and then loaded onto a 2 X 100 cm ion exchanger column (Dowex 50 X 2) in an H + cycle of 100 to 20 mesh. The column was then eluted with water. Collect 300 ml of eluate, counted from the beginning of the wash. The eluate was evaporated at 35 ° C under reduced pressure. The oily residue is crystallized by the addition of 8-10 ml of water and about 100 ml of ethanol. After filtration, washing with alcohol and drying, 13.7 g of γ-L-grutamyltaurine is obtained. The crystalline product is recrystallized from 80% aqueous alcohol. 9.79 g of pure product is obtained, corresponding to a yield of 70% based on N, N‘-bis- [N-carbobenyyloxy-γ (α-benzyl) -L-glutamyl] cystamine.

Example 5

5.42 g (11 mmol of carbobenzyloxy-L-glutamic acid α-benzyl-β-nitrophenyl ester (Chem. Ber. 96, 204, 1963)) are dissolved in 50 ml of pyridine, cooled to 0 ° C and a solution of 1.25 g (10 mmol) of taurine in 20 ml of water is added dropwise with vigorous stirring over a period of 3 hours, then 3.08 ml (22 mmol) of triethylamine are added to the mixture and the cooling and stirring is discontinued. The residue is dissolved in 50 ml of water and 1N hydrochloric acid is added to the yellow solution until the solution is decolorized, and the solution is shaken 10 times to remove p-nitrophenol. ml of ether, and the aqueous phase was evaporated under reduced pressure to give 6.9 g of triethylammonium salt of carbobenzyloxy-γ- (α-benzyl) -L-glutamyltaurine.

This material was catalytically hydrogenated as described in Example 3 and the solvent was removed by evaporation under reduced pressure. To remove triethylamine, dissolve the substance in a small amount of water and apply the solution to a 2 X 40 cm ion exchange column (Doweo 50 X 2). Elution is carried out with water. About 120 ml of eluate are collected, which is then evaporated at 35 ° C under reduced pressure. Crystallization and isolation of the product was carried out according to Example 3. This gave 1.72 g of γ-glutamyltaurine with a melting point of 219-220 ° C, corresponding to a yield of 68% based on taurine, [α] _D 20 = + 14 ° ( c = 1, water).

Analogously to the procedure described above, γ-D-glutamyltaurine is prepared by catalytic hydrogenation of carbobenzoyl-γ- (α-benzyl) -D- (α-benzyl) -D-11-aurine, methyl aurine, prepared according to the procedure of Example 5. The obtained γ- _D -glutamyltaurine melts at 219 DEG-220 DEG C., [ _{.alpha.] D} @ 20 = -13.9 DEG (c = 1, water).

Example 6

The carbobenzylooy-γ-L-ylutamyllaginine obtained according to Example 2 is dissolved in 2 ml of glacial acetic acid containing 4 moles of hydrogen bromide. The mixture was allowed to stand for half an hour at room temperature and then evaporated at 35 ° C under reduced pressure. The residue is triturated several times with ether, which is then separated by decantation. The resulting γ-γ-γ-ethynyltaurine is recrystallized as described in Example 3.

Example 7

25.4 mg (0.1 mmol) of γ-L-glutamyltaurine are dissolved in 2 ml of water and 10 ml of 0.01 N sodium hydroxide solution are added. The mixture is concentrated to dryness at 30 ° C under reduced pressure. The white crystalline residue is dried in the eosicator with phosphorus pentoxide. Y-L-glutamyltaurine mononatrium salt is obtained. This product is not characterized by a sharp melting point, it begins to shrink at 200 ° C, its color becomes darker and charcoal at approximately 250 ° C. The product is as poorly soluble in methanol as in ethanol.

Example

To 7.5 mg (30 μΐηοΐύ) of γ-L-glutamyltaurines, add 10 · ml of anhydrous methanol containing 1 · 1 liter of hydrogen chloride. The suspension was stirred at room temperature for 24 hours. The pure product is isolated by descending paper chromatography using one of the following solvent systems:

_Rf (n-butanol, pyridine, glacial acetic acid: water 15: 10 * 3: 12) = 0.27;

Rf (n-butanol / glacial acetic acid / water 4: 1: 1) = 0.14, ...........

Γ- (α-methyl) -L-glutamyltaurine is obtained.

Example 1 and d 9

The esterification was carried out as described in Example 8, but using ethanol containing hydrogen chloride. Γ - (N-ethyl) -L-glutams Itaurine is obtained.

Rf (mixture of n-butanol, pyridine, glacial acetic acid and water 15: 10 · 3: 12) = 0.37,

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

Example 10

Dissolve 100 mg of carbobenzoyl-α-L-glutamyl (γ-taurine-ethynyl ethyl esters) with 1 ml of trifluoroacetic acid and 1 ml of concentrated hydrochloric acid and leave the solution in a sealed tube for 3 hours at 35 ° C. the solution is evaporated under reduced pressure, the residue is triturated several times, with ether and n-hexane, and then evaporated again to give a white amorphous substance, uniform in electrophoresis, which shows a positive reaction in the ninhydrin test. taurine) glycine.

Yield: 0.06 g [88%).

Analysis for C9H17N3O7S (M = 311.3):

Calculated: S 10.3%;

Found: 10.3%.

The infrared spectrum is characterized by the following maxima for the characteristic groups:

N ‰ ⁺ 3100 · cm -1 (wide); OH (COOH) 3200 cm -1 (wide); C = O (COOH) 1730 cm @ -1;

C = O (amide I), 1680 cm ^"4;

C = O (amid-II) 1560 cm ⁴ ;

S = O (SO 2 OH) 1220 cm -1 (intense);

- O (SO2O ") 1045 cm ^_1 (intense).

Hydrolysis: 20 mg of substance is left in 1 ml

Hydrochloric acid in a sealed glass tube for 24 h at 105 C. After cooling, ^q the sample solution is subjected to electrophoresis at pH 1.8. The solution contains glutamic acid, glycine and taurine.

Example 11

100 mg of carbobenzyloxy-.alpha.-glutamyl- (γ-taurine glycine methyl ester) was reacted at room temperature with 4 ml of a 2 N solution of hydrogen bromide in glacial acetic acid until all of the material had dissolved, which took approximately 30 minutes. 30 ml of ether and left to stand in a cool place for 1 day The precipitate formed is centrifuged, washed several times with ether, and then dried under potassium pressure, sulfuric acid and phosphorus pentoxide under electrophoresis. the taurine) glycine methyl ester is obtained in practically pure form.

Example 12

The salt obtained in Example 11 was treated with 2 ml of a 1 N sodium hydroxide solution under cooling with ice water for 3 hours. The course of hydrolysis is monitored by electrophoresis. The reaction mixture is subjected to ion exchange using an ion exchanger (10 ml of Dowex 50 in an H + -cycle) and lyophilized. Since impurities are still present according to the electrophoresis result, the product is recrystallized several times from aqueous ethanol until it reaches the appropriate purity. 40 mg (59%) of α-L-glutamyl-γ-taurine) glycine are obtained.

The infrared spectrum is characterized by the following maxima for the characteristic groups:

NH 3310 cm -1; NH 3 ⁺ 3100;

cm -1 (broad);

C = O (COOH) 1730, cm -1; C = O (amide-I) 1650 cm -1; C = O (amide-II) 1570 cm -1;

S = 0 1220 · cm -1 (intense), 1045 cm -1 (intense).

Example 13

100 mg of α-L-glutamyl- (γ-taurine) glycine prepared according to Example 10 or 12 are dissolved in 25 ml of a 0.2 M ammonium bicarbonate solution at pH 8.5. To the solution was added 1 mg of carboxypeptidase A dissolved in 0.5 mL of water. The mixture was kept in a thermostat at 37 ° C for 24 hours and lyophilized. Γ-L-glutamyltaurine and glycine can be detected in the dry lyophilisate. Pure γ-L-glutamyllaurine can be obtained by electrophoresis or column chromatography (Dowex 50).

Example 14

1.68 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamylhomotaurin was dissolved in 10 ml of 50% aqueous ethanol. 0.3 g of activated charcoal containing 10% palladium was added to the obtained solution, and the resulting suspension was stirred for 2 hours. Allow hydrogen to pass through for 4 hours. The solution was filtered and evaporated under reduced pressure.

The residue was dissolved in 1-2 ml of water and loaded onto a 1 X 35 cm ion exchange column (Dowex 50 X 2) in an H + -cycle to remove triethylamine. Elution is carried out with water. 50 ml of eluate are collected and evaporated under reduced pressure. 440 ml of γ-E-glutamylhomotaurin is obtained as a residue, corresponding to a yield of 82%. PH electrophoresis

6.5, slight contamination by both neutral and acidic substances (homotaurine or glutamic acid) is found. The product obtained can be purified, for example by preparative electrophoresis.

In electrophoresis carried out at pH 6.5 and at pH 1.8, the substance proceeds towards the cathode. Its relative mobility, based on cysteine acid, is at pH 6.5 0.68, at pH 1.8 0.50.

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

Example 1 a d 15

1.59 g of carbobenzyloxytyl (.alpha.-benzyl) -L-glutamyl-N-methyltaurme was catalytically hydrogenated as described in the taurine example, corresponding to a yield of 79%.

The product obtained travels at both pH 6.5 and pH 1.8 in paper electrophoresis. cathode. The relative mobility relative to cysteine acid is at pH 0.68, at pH 1.8 0.49.

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

Example 16

Dissolve carbobenzyloxy-γ- (α-benzyl) -L-glutamyl-L-cystelic acid in 20 mL of water, add 0.3 g of activated charcoal containing 10% palladium to the solution, and pass the resulting suspension for 3 hours with hydrogen. The reaction mixture was worked up as in Example 14. The obtained acid-yl-glutamyl-L-cysteine _e acid, which melts at 187 ° C. Reactive mobility in paper. chromatography, based on cysteine acid, at pH 6.5, 1.21, at pH 1.8, 0.54.

Example '17

1.25 g of carbobenzyloxy-γ- (α-benzyl) -L-glutamylcholaminophosphate was catalytically hydrogenated to remove the protecting groups. Hydrogenation as well as ion exchange purification is carried out as described in Chapter 14. 423 mg of γ-L-glutamyl-N-methylthi was obtained with the preparation of γ-L-glutamylhomotaurin (Example 14). 470 mg of γ-L-glutamylcholaminophosphate is obtained, corresponding to a yield of 91%. However, as shown by paper electrophoresis, the product contains about 15-20% cholamine phosphate as an impurity. For cleaning comes into consideration between. others · electrophoresis.

The product travels to the cathode both at pH 6.5 and at pH 1.8 in paper electrophoresis. The relative mobility relative to cysteic acid is at pH 6.5 0.75, at pH 1.8 0.36.

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

Example 18

478 mg of carbobenzyloxy- (S- (α-benzyl) -L-aspartyltaurine) was dissolved in 6 ml of 50% aqueous ethanol, 100 mg of activated carbon containing 10% palladium were added thereto, and the solution was then hydrogenated for 4 hours by feeding After filtration and evaporation under reduced pressure, triethylamine is removed from the product by ion exchange, as described in connection with the preparation of (-31-31-31-31-) - - - - - - - in Example 14. It is obtained. 172 mg of β-L-aspartyltaurine, which corresponds to a yield of 71% The product is contaminated with a small amount of taurine which can be removed, inter alia, by electrophoresis.

In paper electrophoresis, the compound travels to the cathode at both pH 6.5 and pH 1.8. The relative mobility at pH 6.5 is 0.77, at pH 1.8 0.58 based on cysteine acid.

Rf (mixture of N-butanol, pyridine, glacial acetic acid and water 15: 10: 3: 12) = 0.16.

Example 19

Carbobenzyloxy-S- (α-benzyl) -L-aspartylhomotaurin was catalytically hydrogenated according to the procedure described in Example 14. 203 mg of β-L-aspartylhomocurur, corresponding to a yield of 84%, was obtained.

In paper electrophoresis, the prepared compound travels to the cathode at both pH 6.5 and pH 1.8. The relative mobility relative to cysteic acid is at pH

6.5-0.72, at pH 1.8 0.53.

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

Example 20

The procedure described in Example 14 was catalytic. hydrogenates carbobenzyloxy-4H-benzyl] -L-aspartylcholamine phosphate. Β-L-aspartylcholamine phosphate is obtained, which during paper electrophoresis travels to the cathode both at pH 6.5 and at pH 1.8. The relative mobility relative to cysteine acid is 0.81 at pH 6.5 and 0.40. at pH 1.8.

Rf (mixture of n-butanol, pyridine, glacial acetic acid and water 15: 10: 3: 12) = 0.14.

Example 21; © * © ..........

In a suitable manner. for the production of glutamic acid? -amides (Acta Chim. Akad. Sci. Hung. 64, 285, 1971), carbobenzoxy-χ- (α-benzyl) -L-glutamylcholamine is produced,

Dissolve 4.14 g (10 mmol) of the substance in 50 ml. of anhydrous pyridine and 9 g (33 mmol) of diphenylphosphoric acid chloride are added to the solution. The reaction mixture is left for 12 hours at room temperature. The mixture is diluted with 80 ml of chloroform. The precipitated product is filtered off, washed first with dilute hydrochloric acid and then with water. and then dried in a desiccator with potassium hydroxide. The obtained carbobenzyloxy - [- (. Alpha.-benzyl) -L-glutamylcholaminophosphate] was dissolved in 15 ml of glacial acetic acid containing 3.3 mol / L hydrogen bromide; the solution was allowed to stand for 15 minutes and then evaporated at 35 ° C. at a reduced rate. pressure. The residue was dissolved in 30 ml of 1 N sodium hydroxide solution and the solution was allowed to stand at room temperature for 1 hour. The pH of the solution was adjusted to 4 with acetic acid and the solution was removed to remove phenol and benzyl alcohol. extract three times with 30 ml each. of ether. The aqueous phase is applied to an ion exchange column

flats (Dowex 50] in H ⁺ form, which is then eluted with water, the eluate is evaporated under reduced pressure and the residue was recrystallized from water and acetone and the 2: 1. 0.8 g of the χ-L-glutamylcholaminfosfátu.

Claims (13)

Object of the invention A process for the preparation of novel amino acid derivatives of the general formula I, R ^{1 -NH-CH-CO-1} _(CH2) n CO-N (CH) _m - [B ¹ CHžjt- RR ² (I) where is A ^one hydroxyl, alkoxy having 1 to 4 carbon atoms, cycloalkoxy having 3 to 6 carbon atoms, aralkoxy group having 7 to 9 carbon atoms, phenoxy optionally substituted on the nucleus by nitro, halogen or a group of formula - (NH-CH2-CO ), .— Y, where Y represents a hydroxyl group, a C 1 -C 4 alkoxy group or a C 7 -C 9 aralkoxy group and an integer ranging from 1 to 10, B ^{1 a} group of the formula —SO2OH, —OSO2H, or —OPO (OH) 2, R is hydrogen or (C1-C4) -alkyl, R ^{1 is} hydrogen, C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl, or phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy, or nitro on the phenyl ring, alkanoyl C1-C4 or benzoyl, R 2 is hydrogen, C 1 -C 4 alkyl or carboxyl, C 1 -C 4 alkoxycarbonyl in the alkoxy moiety or phenoxycarbonyl or carboxamido group, n number 1, 2, 3 or 4, m number 1, 2 or 3, t number 1, 2 or 3. and pharmaceutically acceptable salts or optically active antipodes thereof, characterized in that the compound of formula (II) is: R ³ -NH-CH-CO-A ² I (CH 2) _n AND CO — N— (CH) _m - (CH2) t-B1 RR ² (П) where A ² is hydroxyl, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, C 7 -C 9 aralkoxy, phenoxy optionally substituted by nitro, C 1 -C 4 alkoxy or halogen on the phenyl core, or a group of the formula - (NH-CH2-CO) _r- Y, wherein Y represents a hydroxyl group, an alkoxy group having 1 to 4 carbon atoms or an aralkoxy group having 7 to 9 carbon atoms and r is an integer from 1 to 10, R ³ is hydrogen, C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl or phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or nitro on the phenyl core, (C 1 -C 4) alkanyl or benzoyl, wherein when R ³ is hydrogen, A ² is other than hydroxyl; and B ¹ , R, R ² , n, as defined above, cleave the protecting group or protecting groups attached to the α-amino group and / or to the α-carboxyl group of the compound of the formula II, optionally in the compound of the formula I, wherein A ¹ is a hydroxyl group and R, R ¹ , R ² , B ¹ , n, m and m are as defined above, esterify the α-carboxyl group and optionally convert any of the compounds thus obtained into their pharmaceutically acceptable salts or prepare optically active form using optically active starting materials or resolution of the racemic product obtained. 2. The process of item 1 for preparing compounds of formula IA: H ₂ N - CH - COOH (CH ₂ ) n CO-N (CH) _m - (CH2) ¹ -B RR ² (IA) where R, R ² , B ¹ , n, m and m are as defined in item 1, characterized in that: R ⁴ -NH-CH-COOH _{(CH2) n} AND CO — N— (CH) _in - (CH3Jt-B1 ⁾ RR ² (HA) where R ⁴ is C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl, phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or phenyl-substituted nitro, alkonoyl C 1 -C 4 or benzoyl; and R, R ² , B ¹ , n, m and m are as defined in 1, acidolysis, hydrogenolysis, sodium or ammonium hydroxide cleaves the protecting group R ⁴ , and optionally any of the compounds thus obtained is converted into a pharmaceutically acceptable salt thereof, or is liberated from its salt and / or any of the compounds thus prepared are prepared in optically active form using optically active reagents or by resolution of the racemic product obtained. 3. The process of item 1 for preparing compounds of formula IA, wherein R, R ² , B ¹ , n, and m are as defined in item 1, characterized in that the compound of formula IIB, H2N — CH — COA ³ (CH2) _n CO-N (CH) _nl - (CH 2) _t ¹ -B RR ² (IIB) where A ³ is C 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, C 7 -C 9 aralkoxy optionally substituted by nitro, C 1 -C 6 alkoxy Or a group of the formula - (NH-CH ² -CO) _r -Y, wherein Y is C 1 -C 4 alkoxy or C 7 -C 9 aralkoxy and ar is an integer from 1 to · 10 a R, R ² , B ¹ , m, nat as defined in point 1, undergo saponification, acidolysis, hydrogenolysis or enzymatic hydrogenolysis for cleavage of the α-carboxyl-linked protecting group, and optionally convert any of the compounds thus prepared into their pharmaceutically safe salt or liberated from its salt and / or any of the compounds thus prepared is prepared in optically active form using optically active reagents or by resolution of the racemic product obtained. 4. A process according to claim 1 for the preparation of compounds of formula (IA), characterized in that the protective groups are attached to the .alpha.-amino group and to the .alpha.-carboxyl group of the compound of formula (IIC); R ⁴ -NH-CH-CO-A ³ (CH ₂ ) _n AND CO-N (CH) _in - (CH) - B ¹ I I RR ² (IIC) where R, R ² , R ⁴ , A ³ B ¹ , n, as defined above, are simultaneously cleaved by acidolysis, alkaline hydrolysis, hydrogenolysis or sodium treatment, and optionally any of the compounds thus prepared is converted into its, salt or released from its salts and / or any of the above compounds are prepared in optically active form using optically active reagents or by resolution of the racemic product obtained. 5. The process of item 1 for preparing compounds of formula IB, H2N — CH — COA ³ I (CH 2) _n AND CO-N-CH 2 -fCH 2 -B ¹ I I RR ² (IB) where R, R ² , A ³ , B ¹ , n, as defined above, characterized in that the protecting group attached to the α-amino group of the compound of formula (IIC) is cleaved, and optionally any of the compounds thus obtained is converted into its or released from its salt and / or any of the compounds thus obtained is converted into an optically active form using optically active reactants or by resolution of the racemic product obtained. 6. The process of item 1 for preparing compounds of formula IC, R ⁴ - NH-CH-COOH _{(CH2) n} CO-N (CH) _m - (CH 2) t B ¹ RR ² (IC) where R, R ² , R ⁴ , B ¹ , n, as defined above, characterized in that the protecting group attached to the α-carboxyl group of the compound of the formula (PС) is cleaved and optionally any of the compounds thus obtained is converted into its salt or released from its salt and / or any of the above-obtained compounds are prepared in optically active form using optically active reagents or by resolution of the racemic product obtained. 7. A method according to claim 2 к · preparation of compounds of formula IA wherein R, R ^2, B ^1, n have are as defined in 1, containing free primary amino group, wherein the protecting group is attached to a carbon nitrogen of a compound of formula (IIA) wherein R ⁴ is C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl, phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy, or a nitro group on the phenyl core, a C 1 -C 4 alkanoyl group or a benzoyl group, and R, R ² , B ¹ , n, and m are as defined in point 1, removed by treatment with anhydrous hydrogen halide, preferably hydrogen bromide, trifluoroacetic acid or catalytic hydrogenation. 8. The method according to item 3 к preparation of compounds of formula IA wherein R, R ^2, B ^1, n have are as defined in Item 1 which contain a free carboxylic group, wherein the compound of formula IIB wherein A ³ is as defined in point 3 and R, R ² , B ¹ , m, n and n are as defined in point 1, saponified with an alkali metal hydroxide, preferably in the presence of water, alcohol and / or acetone, or reacted with anhydrous hydrogen halide, preferably hydrogen bromide or trifluoroacetic acid, or subjected to catalytic hydrogenation or enzymatic hydrolysis using a leucine aminopeptidase. 9. The method according to claim 4 к preparation of compounds of formula IA wherein R, R ^2, B ^1, n mat are defined as in point 1, which contain a free primary amino group and a free carboxyl group, characterized in that the protective groups the compounds of formula (IIC) wherein R, R ² , B ¹ , m, nat are as defined in point 1, R ⁴ is as defined in point 2 and A ³ is as defined in point 3, cleaved by treatment with hydrogen bromide in glacial acetic acid, by treatment with an alcohol containing dissolved anhydrous hydrogen chloride, by treatment with trifluoroacetic acid or by catalytic hydrogenation. 10. The method according to claim 5, characterized in that the xyskupina carbobenzyloxy compound of formula IIC wherein R, R ^2, B ^1, m, NAT are as defined in paragraph 1, R ⁴ has the meaning given under point 2, and ³ is as defined in point 3, preferably the N-carbobenzyloxy-α-benzyl ester derivative, cleaved by treatment with hydrogen bromide in glacial acetic acid. 11. The method of claim 6 к prepare compounds of formula IC, wherein R, R ^2, B ^1, III, NAT are as defined in paragraph 1 and R ⁴ has the meaning given under point 2, characterized in that the ester group of compound of formula (IIC) wherein R, R ² , B ¹ , n, and m are as defined above, R ⁴ is as defined in 2 and A ³ is as defined in item 3, preferably the N-carbobenzyloxy-α- derivative. benzyl ester, cleaved by saponification. 12. The process of claim 9 for the preparation of [beta] -L-glutamyltaurine, characterized in that N-carbobenzyloxy-γ- [α-benzyl] -L-glutamyltaurine is subjected to catalytic hydrogenation, preferably in the presence of palladium on activated carbon as a catalyst. 13. The process of claim 8 for preparing χ-L-glutamyltaurine, characterized in that the N- (α-benzyl) -L-glutamyltaurine is saponified in an aqueous potassium hydroxide solution.