CS209857B2 - Method of making the new derivatives of the aminoacids - 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

The invention relates to a process for the production of novel amino acid derivatives, some of which have valuable pharmacological properties, 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 represented by the general formula I,

R ^{1 -NH-CH-CO-1} _{(CH2) n}

CO-N (CH) _m - (CH2) _t ¹ -B

R 2 (I) wherein is

A ¹ hydroxy, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, C 7 -C 9 aralkoxy, phenoxy optionally substituted by nitro and / or halogen and / or C 5 -C 4 alkoxy on the phenyl core or a group of the general formula - (N-CH 2 -CO) _r -Y, where is

Y is hydroxy, (C 1 -C 4) alkoxy or (C 7 -C 9) aralkoxy and r is an integer of from 1 to 10,

B ^{1 is} halogen or a group of formula -SO 2 OH, -OSO 2 OH, -OPO (OH) 2 or -S-SR 3 wherein

R 3 represents a residue obtained by cleavage of group B ¹ from a compound of formula Ge ^; Г,

R is hydrogen or alkyl of ^: 1 to 4 carbon atoms,

R ¹ is hydrogen, alkoxycarbonyl, and 1-4 carbon atoms in the alkoxy part, aral ^L koxykarbonylovou group having 7-9 carbon atoms in the aralkyl oxyl part or Fe noxyk <arbonylowu group optionally substituted by halogen, C 1-4 ato * a carbon or nitro group on the phenyl core, furthermore an alkanoyl group having 1 to 4 carbon atoms or a benzoyl group ¹ ,

R2 is hydrogen, C1-C4alkyl, carboxyl, C1-C4alkoxycarbonyl209857 to the alkoxy moiety, phenoxycarbonyl or carboxamido, n number 1, 2, 3 or 4, m number 1, 2, or 3 at number 1, 2 or 3.

The invention also includes a process for the preparation of pharmaceutically acceptable salts or optically active antipodes of said compounds.

Among the compounds which can be prepared by the process according to the invention, owing to its biological effects, in particular χ-L-glutamyltaurine of the formula XXIV must be mentioned,

H2N — CH — COOH

CH2

CO-NH-CH2-CH2-SO2OH, [XXIV] which is characterized by a broad spectrum of therapeutical and preventive activity against pathological changes having a direct or indirect cause in the damage to the -aerobic spherical 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, skeletal muscle),

(c) authorities involved in the regulation of ion management (trans-transverse transport system: intestinal villi, renal ducts);

d) dentition needed for grinding food -and.the 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 process 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 skin and mucous membranes (formation of wet mucosal lysozyme, activation ciliated lining in the airways, etc.), increased protection against virus and fungal infections.

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

Said compounds act in part directly, in part by controlling the metabolism of vitamin A, by making the vitamin A metabolites more polar in nature. This effect is comparable to that of parathyroid hormone on the 25-hydroxycholecalciferol-1-α-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:

A. 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 increasingly introduced into. rat bone cartilage; 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 experimental rats and chickens induced by hypovitaminoses and hypervitaminoses, respectively; sedative effect on stress effects caused by rat ulcer; a beneficial effect on mast cell degranulation; lysozyme production-enhancing effect; treatment of trace element management (silicon, zinc, copper, manganese, fluorine); a beneficial effect on epithelial formation; escalating effect on alkaline phosphatase activity; acting on the formation of a granular vesicle induced by the local effect of vitamin A; very flat course of the dose / effect curve or 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; rhinoilaryngopharyngitis sicca; oziaena; chronic bronchitis; smobronchitis; 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 healing r ^: an skin and mucous membranes in operations; erosio colli; itch-induced decrease in olfactory and taste sense.

B. Effects Without Vitamin A Character

(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 experiments with a labyrinth of inactive animals; a dampening effect on experimentally induced fluorine and cadmium toxicosis; adenosine monophosphate-induced cyclic renal emptying effect; a mitigating effect on the symptoms of experimentally induced lathyrism; reduction of sensitivity to histamine; enhancing effect on liver enzyme tyrosine aminotransferase activity.

b) Therapeutic effects

Slight radiation damage; local lack of dye in the skin; muscular hypotonia; psychoonergetizing effect; a beneficial effect on involutionary and gerontological states as well as on mnestic functions; tendency to form scab fibromas; spondylosis ankylopoetics; musculoskeletal disorders - induced by wear; sclerotic fundus; aimyloidase; morphea; fibrocystic

When administering the compounds of the invention, the treatment time varies greatly. Many diseases (such as rhieolaryeg · opharyegitis sicca) do not show symptoms after two weeks of oral administration of 5 µg three times a day; for example, for spondylosis ankylpoetica), treatment must be for a quarter to a half year.

Any of the pharmaceutical, preventive, cosmetic or veterinary medicinal preparations 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 µg per day, based on 1 kg of body weight, and is administered in divided doses in three divided doses.

One tablet contains 2 to 30 µg, preferably -10 µg of the active ingredient and, in addition, biologically inert carriers such as milk sugar, starch, as well as conventional tableting aids (granulating and glidants such as 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. The small-active ingredient content -other- allows the active ingredient to be produced, even in the manufacture of many millions of tablets per year, only on a laboratory scale, at a price that is available to every patient. Since the active substances are stable, the tablets can be marketed without an expiry date. The active ingredient content of retarding tablets or capsule capsules may be in the range of 10 to 20 µg. For injectable preparations, the effective dose per vial is 5 to 10 µg, and the preparation may optionally be prepared in the form of a powder ampoule 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 not - active substance harmful effect neither on nor -tkáně -stěny ^{CE. UCI} nn y ^{E of a substance} can be administered as a museum. Alkyl, and ^P -obsaMp ² and ^Z 20, preferably about 10 pg of active ingredient and are produced from cocoa butter -se -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 pg / g. The basic material for the ointment may be hydrophilic or hydrophobic and -contains usual components, such as cholesterol, paraffin, glycerin, lanolin, cocoa máslo-, linseed oil, etc. ^{of the} active ^substance may also ^b ^ yl formulated like- aerosol preparations wherein the active substances it is also in the range of 0.1 to 1 µg. In the form of a perlingual tablet, the tablet contains 10 µg of active ingredient, the disintegration time being 0.5 to 1 hour. Polymers ^{for the} prolonged release of the active substance can be prepared e.g. I ^ k ^ o · suspension and contains 1 -to 5 pg of the active ingredient per 1 g of polymer. Delayed injectable preparations may be formulated using either high molecular weight polymers or salts of the compounds of the invention formed with high molecular weight organic excipients (e.g., h / ston, -protamine), with 1 vial containing 10 to 20 µg of active ingredient. Powders for cosmetic use or for use in the treatment of the skin are prepared with conventional carriers, for example talc, and contain from 0.1 to 1 pg of active ingredient per g of powder. For ophthalmology, the compounds of the invention are formulated as drops, or as ointments miscible, with tears or, if desired, immiscible with tears; The active ingredient content of these preparations is 0.1 to 1 µg. In children, the compounds of the invention should be administered at a dose of about - 0.2 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 enhanced and supplemented by numerous combinations. Suitable biologically active additives include, but are not limited to:

Vitamins A, C, E and K, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radiomimetically and immunosuppressive ^: active substances, psychoforms, · especially sedatives · timoleptics, organic compounds · silicon, gerontological preparations, blood cholesterol lowering agents, oral anti-inflammatory drugs, anti-inflammatory agents, antlbistamines, etc. The dosage of these active ingredients is generally the same as the usual therapeutic dose when the compounds are used alone.

The compounds produced by the process according to the invention can 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, and / or improve its metabolism. Further, the compounds of the invention increase the resorption of trace elements and their level in the blood. When the compounds according to the invention are used as feed additives, the oral dose is expediently 200 [mu] g / kg per day. When mixed with feed, this dose corresponds to approximately 1 to 2 µg or 1 to 2 mg / t of feed, i.e. a concentration of 0.001 to 0.002 ppm. Due to these very low concentrations, the use of the compounds according to 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 watering cattle, in salt for licking or, optionally, in the form of spray.

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

A common feature of the structure of all the compounds of formula I is 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 the acid amide bond to; a primary or secondary alkylamine which, in addition to the various substituents on its side alkyl chain, contains a strongly acidic group in the ω-position.

The process according to the invention for the preparation of the compounds of the formula I, their compounds and the optically active antipodes is carried out by:

R1-NH-CH-COA ¹

I (CHzjn

AND

CO-A (II) wherein

R1, A1 and n are as defined above and

A represents a hydroxyl group, a pmitrophenoxy group, a pentachlorophenoxy group or a (C 2 -C 4) alkoxycarbonyloxy group, and reacts with a compound of the general formula. III,

NH- (CH) _m - (CH 2) _t -B ²

RR ² (III) where

R ,. R ² · mat have the abovementioned meaning and

B2 represents a halogen or a group of the formula —SO2 OH, —OSO2OH, - OPO (OH) 2, or —S — S — R4, wherein R4 represents a residue obtained by cleaving the group B2 from the compound * of the general formula · III, and the compound thus obtained is optionally converted into its salt or released from: its salt and / or the compound is prepared in optically active form using optically active starting materials or the racemic product obtained is resolved in your folder.

In order to prepare the salts of the compounds according to the invention, the compound of formula I is reacted with an alkali metal or alkaline earth metal hydroxide or carbonate or an organic base.

In a preferred embodiment of the process of the invention, the compound of formula (II), preferably the α-benzyl-.beta.-nitrophenyl ester of N-carbobenzyloxyaminodicarboxylic acid, is reacted with cystamines in the presence of aqueous solution. Pyridine, or · the compound of the general formula II, preferably the N-carbobenzylamino-dicarboxylic acid α-benzyl ester, is reacted in the form of its mixed anhydride with cystamine.

In another preferred embodiment of the process according to the invention, the compound of the general formula (I '), preferably the N-carbobenzyloxyamino-1-carboxylic acid, α-benzo-p-nitrophenyl ester, is reacted with a compound of the general formula (III), preferably with taurine; N-methyltaurine, homotaurine; cholamine phosphate or cysteic acid in the presence of aqueous pyridine.

In a further preferred embodiment of the process according to the invention, the compound of the formula II, preferably N-carbobenzyloxyaminodicarboxylic acid, α-benzyl ester, is reacted in the form of its mixed anhydride with hydrohalide and C1 -C3 haloalkyl amine.

According to the method of the invention, the compounds; of the general formula I are obtained by forming an acid amide bond. The .alpha.-aminodicarboxylic acid derivative, substituted on the amino group or on the amino and carboxyl group with a protective group, optionally with several protecting groups or with other groups, is coupled through its ω-carboxyl group, e.g. · Acid · 2209857

aminoethane sulfone, 3-aminopropanesulfone or 2-phosphonethanolamine. Various protecting groups may be used to form the acid amide bond. The most suitable coupling procedure is the active ester method (monograph to form and selectively remove protecting groups and coupling procedure: E. Schröder, K. Liibke: Peptides, Vol. 1: Methods of Peptide Synthesis, Academic Press, 1965),

Alternatively, cystamine or its substituted derivatives can be acylated at the amino group with α-aminodicarboxylic acid derivatives. The acylation of cystamine can be carried out by various processes, for example the active ester process or the mixed anhydride process.

The process according to the invention is illustrated by the following examples.

Example 1

40.85 g (0.11 mol) of carbobenzyloxy-L-glutamic acid α-benzyl ester (Liebigs Annalen 655, p. 200, 1962) is dissolved in 500 ml of acetonitrile. The solution was cooled to -15 ° C in the absence of atmospheric humidity. While stirring, 15.4 ml (0.1.1 mol) of triethylamine, then 15.4 ml (0.11 mol) of isobutyl chloroformate were added dropwise to the solution. The reaction mixture was stirred at -15 ° C for 40 minutes before adding 28 ml (0.2 mol) of triethylamine, then 11.26 (0.05 mol) of cystamine hydrochloride and finally 250 ml of acetonitrile. The mixture was stirred at -15 ° C for 2 hours, then at room temperature for a further 4 hours.

After completion of the reaction, the reaction mixture was evaporated at 30 ° C under reduced pressure. The residue was dissolved in 200 ml of ice water with stirring and cooling and the mixture was re-evaporated at 35 ° C under reduced pressure. The resulting residue, together with 250 ml of water and 500 ml of ethyl acetate, is added to a separatory funnel and the organic phase is separated. The organic phase is shaken successively with 250 ml of water, then twice with 250 ml of 5% sodium carbonate solution each, then twice with 250 ml of 1 N hydrochloric acid and finally with 250 ml of water (from the aqueous phase obtained by shaking with sodium carbonate solution). by acidifying with hydrochloric acid and shaking with ether to recover approximately 5 g of unreacted carbobenzyloxy-L-glutamic acid α-benzyl ester). The ethyl acetate phase is dried over anhydrous sodium sulphate and then evaporated to dryness at 30 ° C under reduced pressure. A thick oily residue is obtained which soon solidifies to a crystalline mass. This was triturated with 250 ml of anhydrous ether and the crystals were filtered off. The crude product (40-42 g) was recrystallized from a mixture of 100 ml of ethyl acetate and 170 ml of ether to give 29.3 g of N, N'-bis- [N-carbobenzyloxy-γ- [α-benzyl] -L-giu tamyl] cystamine having a melting point of 91-92 ° C.

Analysis for C 44 H 50 N 4 O 10 S 2 (M = 859.05): calculated:

C 61.52 ° / o H 5.89% N 6.52% S 7.4.6 θ / ο,

О Я] О * 7 ΤΊ ·

С 60.85 θ / ο ,9 5.91% Ν 6.61% S 7.72 θ / ο.

К к 1 and d 2

5.42 g (11 mmol) of carbobenzyloxy-L-glutamic acid α-benzylY-p-nitrophenyl ester (Chem. Ber. 96, p. 204, 1963) are dissolved in 50 ml of pyridine. The solution was cooled to 0 ° C and a solution of 1.25 g (10 mmol) of taurine in 20 mL of water was added dropwise with vigorous stirring over half an hour. Then, 3.08 ml (22 mmol) of triethylamine was added to the mixture, and cooling and stirring were discontinued. The reaction mixture was allowed to stand for 72 hours at room temperature and then evaporated under reduced pressure. The residue was dissolved in 50 ml of water and 1N hydrochloric acid was added to the yellow solution until the solution was decolorized. To remove the p-nitrophone, the solution was shaken 10 times with 50 ml of ether each time. The aqueous phase was evaporated under reduced pressure to give 6.9 g of the triethylammonium salt of carbobenzyloxy-χ- (α-benzyl) -L-glutamyltaurine.

Example 3

0.47 g (1 mmol) of carbobenzyloxy-β-L-glutamyl (χ-p-nitrophenyl ester) glycine methyl ester is dissolved in 6 ml of pyridine. Under ice-cooling, to the solution is first added 0.125 g (1 mmol) of taurine in 2 ml of water, then 0.28 ml (2 mmol) of triethylamine in such small portions that the solution remains clear. The reaction mixture was then allowed to stand at room temperature for three days. Evaporation under reduced pressure yields an oil which, after thorough digestion with ether, is then dried with sulfuric acid under reduced pressure. Carbenzyloxy-α-L-glutamyl (χ-taurine) -glycine methyl ester is obtained.

Example 1 a d 4

1.083 g (2.2 mol) of carbobenzyloxy-L-glutamic acid α-benzyl-γ-p-nitrophenyl ester were dissolved in 6 ml of a 2: 1 mixture of pyridine and water. To the solution obtained, 278 mg (2 mmol) of homotaurine was first added, followed by 0.59 ml (4.2 mmol) of triethylamine. The resulting yellow solution was allowed to stand for 72 hours at room temperature, then evaporated under reduced pressure. The oily residue was dissolved in water, neutralized with hydrochloric acid and then extracted with ether in a continuous ex209857 traction apparatus to remove p-nitrophenol for 8 hours. The aqueous phase was evaporated under reduced pressure to yield

1.68 g of carbobenzyloxy-γ- (α-benzyl) -L-glucamylhomotaurine.

Example 5

1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid (N -benzyl) -p-nitrophenyl ester was treated with 278 mg (2 mmol) of N-methyltaurine as described in Example 4. 1.59 g of carbobenzyloxy- γ-ph-benzyl) -L-glutams of 1-N-methyltaurine.

Example Q

2.87 g (6.6 mmol) of carbobenzyloxy-L-glutamic acid (N-benzyl) -p-nitrophenyl ester are dissolved in 20 ml of pyridine and a solution of 1.25 g (6 mmol) of cysteine monohydrate in a mixture is added. 17 ml water and 17 ml pyridine. After addition of 2.6 ml (18.6 mmol) of triethylamine, the reaction mixture is allowed to stand for 72 hours at room temperature. The solution was then evaporated under reduced pressure at 30 ° C. The residue is dissolved in 20 ml of water, acidified with concentrated hydrochloric acid and then shaken 10 times with 10 ml of ether each time. The aqueous phase is evaporated under reduced pressure at 35 ° C. Carbobenzyloxy-γ- (N-benzyl) -L-glutamyl-L-cysteic acid is obtained.

Example 1 a d 7

1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid N -benzyl-4-nitrophenyl ester was dissolved in 6 ml of a 2: 1 mixture of pyridine and water. mmoles) of cholamine phosphate (see U.S. Patent No. 2,730,542) and then 0.87 ml (6.2 mmol) of triethylamine, and the reaction mixture is allowed to stand at room temperature for 72 hours, then evaporated under reduced pressure. work-up was carried out as described for carbobenzyloxy-γ- (--^ππ Ι) -L-glutamylhomotaurin (Example 4) to give 1.25 g of carbobenzyloxy-γ- (N-benzyl) -L-glutamylcholaminophosphate.

Example 8

52.6 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid N -benzyl-n-p-nitrophenyl ester (Chem. Ber. 97, p. 1789, 1964) are dissolved in 5 ml of pyridine. A solution of 125 mg (1 mmol) of taurine in 2 ml of water, followed by 0.28 ml (2 mmol) of triethylamine was added in small portions, and the reaction mixture was allowed to stand at room temperature for 48 hours. The residue is dissolved in 5 ml of water and 1N hydrochloric acid is added until the solution is initially yellow until the solution is decolorized, and the solution is shaken 10 times with 5 ml of ether 10 times to remove p-nitrophenol. There was obtained 478 mg of carbobenzyloxy-β- (n-methyl-l- aspartyltaurine).

Example 9

526 mg (1.1 m-mol) of carbobenzyloxy-L-aspartic acid (. Alpha.-benzyl) -. Beta.-nitrophenyl ester and 139 mg (1 mmol) of homotaurine were reacted as described in Example 8. The carbobenzyloxy- / M 'was obtained. N -benzyl-L-aspartylhomotaurin.

Example 10 Carbobenzyloxy-L-aspartic acid (N-benzyl) - N - (-) - N -butylphenyl ester and cholamphosphate were reacted together as described in Example 7. Carbobenzyloxy-β- (α-benzyl) was obtained. -L-aspartylcholamin phosphate.

Example 11

3.71 g (10 mmol) of carbobenzyloxy-L-glutamic acid N -benzyl ester are dissolved in 60 ml of acetorniril. The solution was cooled to -15 ° C and 1.4 ml (10 mmol) of isobutyl chloroformate were added thereto with stirring, followed by 1.4 ml (10 mmoles) of triethylamine. The reaction mixture was stirred at -15 ° C for 30 minutes, then 2.05 g (10 mmoles) of bromoethylamine hydrobromide, 1.4 mL (10 mmol) of triethylamine and 40 mL of acetonitrile cooled to -15 ° were added. C. The reaction mixture was stirred at -15 ° C for 2 hours, then at room temperature for a further 4 hours. The reaction mixture was filtered and the filtrate was evaporated at 35 ° C under reduced pressure.

The compounds obtained as the final product in the individual embodiments can be characterized by relative mobility values relative to cysteine acid, in paper electrophoresis:

example no. compound mobility at pH 6.5 2,0 2 carbohenzyloxy-γ- (α-benzyl) -L-gluta- Myltaurine (triethylammonium salt) 0.5 3 carbo-benzylo-xy-γ-methyl ester (L-gluta- myltauringlycine 0.51 4 carbobenzyloxy-γ- (n -benzyl) -L-gluta- mylhomotaurin 0.49 5 carbo-benzyloxy-γ-C-α-benzyl) -L-gluta- methyl-N-methyltaurine 0.49 7 carbobenzyloxy-γ- (n -benzyl) -L-gluta- my 1 c holamin phosphate 0.9 8 carbobenzyloxy-β- (α-benzyl) -L-aspar- tyltaurin 0.51 9 carbobenzyloxy-3- (α-benzyl) -L-as par- tylhomoraurin 0.50 10 carbobenzyloxy-β- (α-benzyl) -L-aspartylcholamine phosphate carbohtnzzloxy-α-L · glutamyl- (γ-cyste- 0.9 amdl) -glycinethyltsttr

The IC spectrum shows the following maxima for the characteristic group:

NH 3310 cm -1;

C = O (COOC 2 H 5) 1748 cm -1;

CO = (amide) 1960 cm ^-1 C = O (amide) 1655 om ^-1 .

Claims (5)

1. A process for the preparation of novel amino acid derivatives of the general formula I: R1-NH-CH-CO-A1 '(CH2) n CO - N - (CH) m - (CH 2) t - B1 I I R 2 (I) wherein is A1 hydroxy, C1-C4 alkoxy, C3-C6 cycloalkoxy, 7 to 9 carbon aralkoxy, phenoxy optionally substituted by nitro and / or halogen and / or C1-C4 alkoxy or a group of the general formula - (N-CH 2 -CO) -Y, where is Y is hydroxy, (C 1 -C 4) alkoxy or (C 7 -C 9) aralkoxy -a r an integer from 1 to 10, B1 halogen or a group of formula -SO ₂ OH, -OSO2OH or -OPO (OH) 2 or -S-SR3 wherein R3 is a residue obtained by cleavage of group B1 from a compound of formula (I), R is hydrogen or (C1-C4) -alkyl, R 1 is hydrogen, C 1 -C 4 alkoxycarbonyl or C 7 -C 9 aralkoxycarbonyl or phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or nitro on the phenyl nucleus, furthermore an alkanoyl 1-4 carbon atoms or benzoyl, R 2 is hydrogen, C 1 -C 4 alkyl, carboxyl, C 1 -C 4 alkoxycarbonyl, phenoxycarbonyl or carboxamido, n number 1, 2, 3 or 4, m · number 1, 2, or 3 at number 1, 2 -or 3. or a pharmaceutically acceptable salt thereof, or an optically active antipode thereof, wherein the compound of formula (II): R1-NH-CH-COA1 I (CH 2) _n CO-A (Π) wherein ^{R 1,} A ¹ and ^- n are as Uve ^d Eny meaning and A is hydroxy, p-nitrophenoxy, pentachlorophenoxy or (C 2 -C 4) alkoxycarbonyloxy, reacted with a compound of formula III, NH- (CH) m- (CH 2) _t ² -B RR ² (III) where R, R ² , m and m are as defined above and B2 represents a halogen or a group of formula -SOaOH, -OSOžOH, -OPO- (OH) 2 or -S-S-R ⁴ wherein R 4 represents a residue obtained by removing the group B2 of compound of formula III, ··, and optionally the obtained takto- the compound is converted into its salt or released from its salt and / or the compound is prepared in optically active form using optically active starting materials, or the racemic product obtained is resolved into its components. 2. A process according to claim 1, wherein the compound of formula (II) wherein R1, A, A1 and n are as defined in claim 1, preferably N-carbobenzyloxyaminodicarboxylic acid [alpha] -benzyl-.beta.-nitrophenyl ester, reacted with cystamine in the presence of aqueous pyridine, optionally reacting the compound of formula II, preferably N-carbobenzyloxyaminodicarboxylic acid α-benzyl ester, as its mixed anhydride with cystamine. 3. A process according to claim 1, wherein the compound of formula II, wherein R1, A, A1 and n are as defined in item 1, preferably N-carbobenzyloxyaminodicarboxylic acid [alpha] -benzyl-n-nitrophenyl ester, is reacted with the compound. of formula III, wherein R, R ² , m, t and B 2 are as defined in item 1, preferably with taurineim, N-methyltaurine, homotaurin, choline, chlorine, phosphate or acid. cysteine in the presence of aqueous pyridine. 4. A process according to claim 1, wherein the compound of formula II, wherein R1, A, A1 and n are as defined in item 1, preferably the N-carbobenzyloxyaminodicarboxylic acid α-benzyl ester, is reacted in the form of its mixed anhydride with haloalkylamine haloalkylamine having 1 to 3 carbon atoms. 5. A process according to item 1 for the preparation of compounds of the general formula I, wherein it is A1 is hydroxy, (C1-C4) alkoxy, (C1-C4) aralkoxy, or - (NH-CH2-CO) r-Y, wherein Y is hydroxy, (C1-C4) alkoxy, or aralkoxy 7 to 9 carbon atoms and an integer from 1 to 10, B1 · halogen or a group of formula --SO2 OH, -OSO2OH, -OPO (OH) 2 or - S-R3, wherein R3 represents a residue obtained by removing the group B · ¹ from the compound of formula I, R is hydrogen or (C1-C4) -alkyl, R 4 is hydrogen, carbobenzyloxy, C 1 -C 4 alkanoyl or benzoyl, R2 is hydrogen, kaгboxytovou, alkoxycarbonyl having 1 to 4 carbon atoms or carboxamido, n is 1 or 2 and (m + t), the number 2 or 3, characterized in that a compound of formula II wherein R 1, A ^{1 and} n have above. and A is p-nitrophenoxy, pentachlorophenoxy or (C 2 -C 4) alkoxycarbonyloxy, reacted with a compound of formula III wherein R, R ² and (m-j) are as defined above, and B ² represents a halogen or a group of the formula -SOaOH, -OSO 2 OH, -OOPO (OH) 2 or -S-S-R ⁴ , where R ⁴ represents a residue obtained by cleavage of the group B2 from the compound of formula III.