SE441356B - AMINO ACID DERIVATIVES, WHICH ARE INTERMEDIATES FOR THE PREPARATION OF CERTAIN COMPOUNDS, WHICH HAVE BIOLOGICAL AND PHARMACOLOGICAL VALUE PROPERTIES - 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 A1 stands for hydroxy, C 1-4 alkoxy, cycloalkoxy, aralkoxy, substituted aralkoxy, aryloxy, substituted aryloxy or a group of the general formulae: wherein R14 is hydrogen, C 1-4 alkyl or aralkyl, R6 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, B1 is a group of the formulae -SO 2 OH, -OSO 2 OH, -O-PO(OH) 2 or -S-S-R11, wherein R11 is C 1-4 alkyl, aralkyl or aryl or a residue obtained when removing group B1 from the general formula (I), R stands for hydrogen, C 1-4 alkyl or aralkyl, Rx stands for hydrogen or halogen, R1 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 R6 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), R2 stands for hydrogen, C 1-4 alkyl, or aralkyl or R2 and R2 may each stand for a -CO- group and form a ring through an o-phenylene, alkylene or -CH=CH- group, R3 stands for hydrogen, carboxy or carbalkoxy, R4 stands for hydrogen, halogen, C 1-4 alkyl or hydroxy, R5 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

Or a C 1 -C 4 alkyl group, Y is hydroxyl or a C 1-6 alkoxy group and r is an integer 1-10; R 1 = a hydrogen atom, a C 1 -C 4 alkoxycarbonyl group or one optionally with one or more substituents, namely halogen, alkoxy or nitro, substituted G 7 -G 9 aralkoxycarbonyl group; R = hydrogen or a C 1 -C 4 alkyl group; R5 = hydrogen or a carboxyl group; B1 = a group -SO OH, _- OPO (OH) 2 or -SSR11, where R61 is the B1-linked residue of the amino derivative of formula I; n = an integer 1 or 2; And Ü = an integer 1 or 2, where A1 does not represent hydroxyl, if R * represents hydrogen.

The object of the present invention are compounds of the general formula a R 1 HN-GH-co-A1 <<> H2> n co-N- on - (oH2) tB1 (I) R R5 All the compounds of the invention are novel and among these the following should be especially emphasized: (Këbenzyl) -glutamyl-α '] -taurine, tβ-carbobenzyloxy-N-benzyl) -aspartyl-α -taurine, G-benzyl) -aspartyl-α-homotaurine, [N-carbo-benzyloxy-GX- benzyl) -aspartyl-β -cholinamine phosphate, [N-carbo-benzyloxy-GC-benzyl) -glutamyl-ï-hilomotaurine, (N-carbobenzyloxy-G1-benzyl) -glutamyl-K-choline amine-phosphate, [N-carbobenzylamloxy] -C -E'cysteic acid, t fi-carbobenzyloxy-Qf-cysteamide) -glutamyl4 -glycine ethyl ester, N-carbobenzyloxy- (γ-ftaurine-glutamyldx -glycine-ethyl ester, N-carbobenzyloxy- (1, -taurine-glutamyl-4-glycine-γ-glycine taurine) -L- glutamyl-4 -glycine, EN-carbobenzyloxy-QX-benzyl) -L-glutamyl -X-taurine. The present invention also includes pharmacologically acceptable salts and optically active isomers of compounds I. - .. v ........, ...-....-. .. A common structural property for all the compounds is that they contain a dicarboxylic acid which is substituted in the substitution or also a derivative thereof which is also substituted in other positions and which, in the case of the sinibecarboxyl group, is attached with an acid. amide bond at a primary or secondary alkylamine, which dicarboxylic acid or derivative thereof in addition to various substituents on the alkyl side chain contains a group of strongly acidic character in the position.

The compounds of the invention are prepared by (a) for the preparation of compounds of general formula I containing a sulfonyl or phosphoryl oxy group oxidizing or hydrolysing, reacting with alkali metal or alkali metal hydrogen sulphite, with sulfuric acid or phosphoric acid or derivatives thereof, compounds of the general formula R1-HN-on-co-A1 (GH) ester 2 n 2 co-N-GH - (cH2) tB R R5 (V) where A1 and R1 have the meanings given above and B2 is 1SH, -SOOH -OH, p-toluenesulfonyloxy, halogen or -SOER O, where RO is a C1-C4 alkoxy or aralkoxy group, or (b) for the preparation of compounds of formula I, wherein B1 is on, with alkali metal salts of haloalkylsulphonic acid reacting compounds of the general formula 30 nl-HN-on-co-A1 << = H2> n co-N-Rlg B15 (vx) where R1 and A1 have the meanings given above and B12 is hydrogen or a C 1 -C 4 alkyl group and B 15 is alkali metal, or (c) for the preparation of compounds of formula I, wherein B 1 is -S 02-OH, oxidizes compounds of the general formula R7-nN = cH-co-A4 (CH2) n co-N- en ~ (cH2) ts- R R5 (VII) where A5 is hydroxyl, aralkozy, preferably benzyloxy, substituted aralkoxy, preferably p-methoxybenzyloxy or n-nitrobenzyloxy and R? is a C1-C4 alkoxycarbonyl group or one optionally with one or more substituents, namely halogen, alkoxy or nitro, substituted G7-G9 aralkoxycarbonyl group, or g (d) reactes compounds of the general formula R7 - N - a - coon O: "_ (cH2) n (XVI) with compounds of the formula N- a - (cH2) t-B1 R5 H2 or salts thereof, in which formulas the general symbols have the meanings given above, or (e ) for the preparation of compounds of general formula I, wherein B1 is -SSR11, where R11 has the meaning given above, react compounds of the general formula H7-HN-on-co-A4 <<> H2> n co-A7 (XVIII ) where A4 and R4 have the meanings given above and A7 is hydroxyl, p-nitrophenyloxy, pentachlorophenyloxy or C2-C4-alkoxycarbonyloxy, with compounds having the general formula 2) t'S 'NH-? H - (CH RS 2 (XIX) where R and R 5 have the meanings given above, or (f) react compounds of the above general formula XVIII with compounds of the general formula 1 HN-GH_ - (CH2) tB R R5 (xx) where R, H5 ooh B1 have the meanings given above, or (g) cleaves the protecting group on the OL-amino group from compounds of the general formula n7HN-ca-co-A4 (enar, co-N - GH - (cH2) t-B1 R R5 (xxx) where the general symbols have the meanings given above, or (h) removes the protecting group from the α (-carboxyl group from compounds of the above formula XII, or (i) for the preparation of compounds of the general formula RIHN-TH-oo-A8 (from co-N- on - (cH2) t-B1 R H5 (XXIII) 1 which A8 is - (NH-GHR6-co) rr and the other general symbols have as defined above, reactivated activated derivatives of K -aminocarboxylic acid-containing peptides react with compounds of the general formula HN- ca - (cH2) -B4 R115 (xxIv) where B4 is -SO 2 -OH, -O-PO (OH) 2 or -SH and the other general symbols have the meanings given above, and optionally oxidize the mercapto group, whereupon the compounds thus obtained are converted into salts thereof or liberated. The compounds are made from salts thereof and / or the compounds are prepared in the form of optically active isomers by using optically active reactants in an arbitrary reaction step or by subjecting the compounds to racemate separation.

In the process outlined above under (a), the compound V is suitably reacted with permyric acid or a mixture of glacial acetic acid and hydrogen peroxide or the compound is heated with an aqueous solution of an alkali metal sulphite.

In the process outlined in (b) above, compound VI is suitably reacted with alkali metal salts of bromomethanesulfonic acid or bromopropanesulfonic acid.

In the process outlined above under (c), compound VII is suitably reacted with a mixture of glacial acetic acid and 50% hydrogen peroxide.

In the process outlined above under (d), compound XVI, preferably pyroglutamic acid, is suitably reacted with taurine or homotaurine.

In the above-described preparation of salts of the compounds of general formula I, compounds of general formula I are suitably reacted with hydroxides or carbonates of alkali metals or alkaline earth metals or with organic bases. In the process outlined above under (e), compounds of general formula XVIII, preferably N-carbobenzyloxyaminodicarboxylic acid uL-benzyl-11-p-nitrophenyl ester are suitably reacted with a mixture of pyridine and water or N-carbobenzyloxyamino-dicarboxylic acid benzyl ester in the form of its mixed anhydride, with cystamine.

In the process outlined above under (f), compounds of general formula XVIII, preferably N-carbobenzyloxyaminocarboxylic acid-6% -p-nitrophenyl ester are suitably reacted in a mixture of pyridine and water with compounds of general formula XX, preferably with taurine, N-methyltaurine, homotaurine, cholamine phosphate or cystamic acid.

In the process outlined above under (g), the carbobenzyloxy group is preferably removed from the compound of general formula XXI, preferably the N-carbobenzyloxy-OC-benzyl ester derivative with hydrobromic acid in glacial acetic acid.

Finally, in the process outlined above under (h), the ether group is conveniently removed from compounds of the general formula XXI, preferably the N-carbobenzyloxy-β-benzyl ester derivative, by pre-administration.

The invention will be illustrated in more detail in the following examples, but it is of course not limited to the details given in the examples.

Example 1: (a) 40.85 3 (0.1 mol) of carbobenzyloxy-L-glutamic acid ck-benzyl ester (Liebigs Annalen 655, 200, 19% 2) were dissolved in 500 ml of acetonitrile. The solution was cooled to exclusion of humidity to -1500 and added dropwise with stirring first with 1.5.4 ml (0.1 mol) of triethylamine and then with 15.4 ml (0.1 mol) of chloroformic acid isobutyl esters. The reaction mixture was stirred at -15 ° C for 40 minutes and then added with 28 ml (0.2 mol) of triethylamine and subsequently with 11.26 g (0.05 mol) of cystamine hydrochloride and again subsequently with 250 ml of acetonitrile . The mixture was stirred at -15 ° C for an additional 2 hours and then at room temperature for 4 hours.

After completion of the reaction time, the mixture was evaporated at 5000 in vacuo. The residue was taken up with stirring and cooling in 200 ml of ice water and the mixture was evaporated again in vacuo, this time at 5500. The residue was poured together with 250 ml of water and 500 ml of ethyl acetate into a separatory funnel and the organic phase was separated. The organic phase was shaken first with 250 ml of water, then with a 5% sodium carbonate solution (2 times 250 ml) then with N-HO1 (2 gner 250 ml) and finally with P50 ml of water. From the aqueous phase obtained on precipitation with sodium carbonate solution, it was possible to recover by acidification with hydrochloric acid and shaking with ether about 5 g of unreacted carbobenzyloxy-L-glutamic acid-OC-benzyl- ester.) The ethyl acetate phase was dried over anhydrous sodium sulfate and then evaporated in vacuo at 5000 to dryness. In this way a thick, oily residue was obtained, which soon solidified to a crystalline mass. This was triturated with 250 ml of absolute ether, after which 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. There was thus obtained 29.5 g of N, N'-bis- [D-carbobenzyloxy-α- (α-benzyl) -L-glutamyl] -cystamine, m.p. 91-9200.

Elemental analysis for C 44 H 5 ON 4 O 10 OS 2 (M - 859.05) Calculated: c = s1.52%; H = 5.89%; N = 6.52%; s = 7.46% Found: C = 60.85%; H = 5.91%; N = 6.61%; S = 7.72% (b) Of the product thus obtained, 25.77 g (0.05 mol) were dissolved in 75 ml of glacial acetic acid. The ice-cooled solution was added dropwise over 15 minutes with a freshly prepared mixture of 75 ml of 50% hydrogen peroxide and 225 ml of glacial acetic acid. After the addition, the cooling was removed and the reaction mixture was stirred for 4 hours at room temperature. Subsequently, it was evaporated in vacuo at 5000. The oily product was dried in a desiccator first over phosphorus pentoxide and then over solid potassium hydroxide. There were thus obtained 28.5 g of carbobenzyloxy-β '(α-benzyl) -L-glutamyltaurine. The crude product can be used without purification to produce β'-L-glutamyltaurine. (c) 26.52 g (55 mmol) of this carbobenzyloxy-7f- (ge-benzyl) -L-glutamyltaurine were dissolved in 50 ml of glacial acetic acid. The solution was added with 4 moles of hydrogen bromide dissolved in 50 ml of glacial acetic acid. A lively carbon dioxide development was observed. The reaction mixture was allowed to stand at room temperature for 2 hours and then evaporated in vacuo at 50 ° C. The clear residue was dissolved in 170 ml of water and shaken with ether (5 times 70 ml). The aqueous phase was evaporated at 55 ° C in vacuo to give 20.42 g of 1 (- (o & -benzyl) -L-glutamyltaurine, which was recrystallized from 90% ethanol, m.p. 204 DEG-204 DEG.

Rf (n-butanol / pyridine / glacial acetic acid / water 15: 10: 5: 12) 0.53 Rf (n-butanol / glacial acetic acid / water 4: 1: 1) = 0.59 (d) 20.42 g of this X- (β-benzyl) -L-glutamyltaurine was dissolved in 150 ml of N-KOH. The solution was allowed to stand for 4 hours at room temperature and then poured into an H + cycle existing with Dowex 10 15 20 25 50 55 40 7812884-0 9 50 x 2 (tangle, 0.75-0.150 mm) filled column 2 x 100 cm. The elution was performed with water. From the beginning of the washout, 500 ml of eluate were collected. This was evaporated in vacuo at 5500 and the oily residue thus obtained was crystallized by the addition of 8-10 ml of water and about 100 ml of ethanol. The crystals were filtered off, washed with alcohol and dried to give 15, 2 # L-glutamyltaurine. The crystalline product was recrystallized from 80% alcohol-water mixture. Mnn obtained on this sweet 0, 0 g pure product, which calculated on N, N'-bis- [ïN ~ carhobenzyloxy-QY- (gg-bennyl) ~ L ~ glutamyljioystamine corresponded to a yield of 70%.

Example 2: (a) 529 ml (1.1 mmol) of the carbobenzyloxy-1 '- (α-benzyl) -L-glutamyl-taurine prepared as in Example 1, step (b) was dissolved in 5 ml N-KOH and the solution was allowed to stand at room temperature for 4 hours. Then the solution was shaken with ether (5 times 5 ml). The aqueous phase was poured into a 1 x 20 cm column filled with Dowex 50 X 2 and eluted with water. 50 ml of solution were collected and evaporated in vacuo at 5500 to dryness. The correct carbobenzyloxy-1H-L-glytamyltaurine was obtained in this way, which was purified by paper electrophoresis performed at pH 6.5. The mobility in relation to cysteic acid amounted to 1.05. (h) The carbobenzyloxy X-L-glutamyltaurine thus prepared was dissolved in P ml of glacial acetic acid containing 4 moles of hydrogen bromide dissolved therein. The mixture was allowed to stand at room temperature for half an hour and then evaporated in vacuo at š5 ° C. The residue was grated several times with ether, after which the ether was decanted off.

The X-L-glutamyl taurine thus recovered was recrystallized as in Example 5.

Rf (n-butanol / pyridine / glacial acetic acid / water l5: 10: š: l2) = 0.5Ü.

Example Gel 2: 5.79 g (12.1 mmol) of the carbohensyloxy-β- (cs-benzyl) -L-glutamyltaurine prepared in the manner described in Example 1, step (b) was dissolved in a mixture of 100 ml of ethanol and 25 ml of water and hydrogenated with shaking in the presence of 0.5 3% palladium carbon as catalyst. The catalyst is suitably added in two portions of 0.25 g each. After no more hydrogen was consumed, the solution was filtered and then evaporated at 50 ° C in vacuo. The oily residue was dried in a desiccator over phosphorus pentoxide. There was thus obtained 5,1 3 10 15 20 25 50 55 40 781-2884-0 10 'I-L-glutamyltaurine, which is very readily soluble in water but insoluble in alcohol. By adding a small amount of water and alcohol in small portions, the product can be crystallized. The crystalline crude product had a melting point of 202-204 ° C.

The IR spectrum showed the following maxima for the characteristic groups: - I v rm; x os aeoo-auooyv NH (anna) 5515; v co (carboxyl) 1758; Q 00 (amide) 1666; O NH5 + 1576; Q S05 '1296, 1051 cm -1.

The crude product was recrystallized several times in 80% ethanol to give 2.02 g of pure final product, which was calculated on N, N1-bis- [ε-carbobenzyloxy-qf- (o <: -benzyl-D-L-glutamyl] -cystamine corresponding to a yield of 66% The pure product had a melting point of 219-220 ° C. [ɧ7šO = + lu ° (water, c = 1.02).

Mobility relative to cysteic acid was 0.75 in paper electrophoresis performed at pH 6.5 and 0.55 in paper electrophoresis performed at pH 1.8.

Rf (n-butanol / pyridine / glacial acetic acid / water 15: 10: 5: 12) = 0.19.

Analysis for C 11 H 14 N 2 O 6 S (M = 254.27) = Calculated: G 3543795 H 5.55% N 11.02; δ 573595 s 12.619á Found: C 55.15% H 5.76% N l0.94% 57.55% S 12, 17% Example 4: 5.42 g (11 mmol) of carbobenzyloxy-L-glutamic acid (0 ° -benzyl) 42'-p-nitrophenyl ester (Chem. Ber. 96, 204, 1955) dissolved in 50 ml of pyridine. The solution was cooled to 000 and added dropwise over half an hour and with vigorous stirring with a solution of 1.25 g (10 mmol) of taurine in 20 ml of water.

Then the mixture was added with 5.08 ml (22 mmol) of triethylamine and the cooling and stirring were stopped. The mixture was allowed to stand at room temperature for 72 hours and then evaporated in vacuo. The residue was dissolved in 50 ml of water and the yellow solution was added with N-HCl until it was removed. To remove p-nitrophenol, the solution was shaken with ether (10 times 50 ml).

The aqueous phase was evaporated in vacuo to give 5.9 g of carbobenzyloxy-Tf- (α-benzyl) -L-glutamyltaurine triethylammonium salt.

The substance was catalytically hydrogenated in the manner set forth in Example 5, step (a), and the solvent was removed by evaporation in vacuo. To remove the triethylamine, the substance was dissolved in a small amount of water and the solution was poured into a 2 x 40 cm column filled with Dowex 50 x 2. Elution was performed with water. Approximately 120 ml of eluate was collected and evaporated in vacuo at 5500. The product was crystallized and isolated as described in Example 5. 1.72 g of XL-glutamyl taurine was obtained, calculated on taarin corresponds to a yield of 68%.

The IR spectrum showed the following maxima for the characteristic groups: - 0 N55 * x on zeoo-auoo; 0 to (amide) 5315; O co (carboxyl) 1758; 9 co (amia) leee; 9 NH5 + 1576; Q snö '.29e, 1051 em'1.

Example 5: (a) 0.48 g (1 mmol) of carbobenzyloxy-o <-L-glutamyl- (Z'-p-nitrophenyl ester) -glycine ethyl ester (Acta Cbim. Head. Soi. Hunq. 65, 375, 1970) was dissolved in 6 ml of ethyl acetate. The solution was cooled with ice water. At 0 ° C, 0.08 g (1 mmol) of cysteamine in 1 ml of dimethylformamide was first added and then 0.14 ml (1 mmol) of triethylamine was added dropwise. A precipitate slowly began to form and the reaction mixture was allowed to stand for another time in ice water and then for a full day at room temperature. Finally, it was diluted with a mixture of ether and ethyl acetate (Izl). The precipitate was centrifuged off and washed first with a mixture of ether and ethyl acetate (üzl) and then with ether several times. After the precipitate was allowed to dry over sulfuric acid, it was washed three times with N-H01, twice with water, twice with a saturated solution of sodium hydrogencarbonate, and finally twice with water. It was then allowed to dry in vacuo over sulfuric acid. 0.55 g of carbobenzyloxy-at-L-glutamyl- (ff-cysteamine) glycine ethyl ester were thus obtained in a yield of 85%.

Analysis for C 18 H 25 O 6 N 5 S (M = 41, 4): Calculated: C 52.5% H 6.1% S 7.8% runner = c 55.4% H e, 5% s 7.7% IR spectrum showed for the characteristic groups the following maxima: NH 5310 cm -1, c = o (Goose) 1748 cm -1, ceo z) 1e9ocm „1, c = ø (amia) 1655 cm -1 1. 100 g carbobenzyloxy-α-L-glutamyl (2f-cysteamine) -glycine ethyl ester was dissolved in 2 ml of glacial acetic acid and the solution was added with 0.5 ml of 30% hydrogen peroxide, the reaction mixture was allowed to stand for 4 hours under ice-cooling, the progress of the reaction was monitored by paper electrophoresis. The reaction mixture was obtained and the final product was obtained in the form of a foam, 0.1 g of carbobenzyloxy-α-L-glutamyl- (b'-taurine) -glycine ethyl ester (95%) was obtained, BO 55 duo 7812884-0 12 (b 100 mg of this carbobenzyloxy-of-L-glutamyl- (aftaurine) glycine ethyl ester was dissolved in a mixture of 1 ml of trifluoroacetic acid and 1 ml of concentrated hydrochloric acid, the solution was allowed to stand for 3 hours at 55 ° C in a closed bomb tube. evaporated solution one in vacuo, the residue was digested with ether and n-hexane several times and then evaporated again. A white, amorphous substance was obtained, which on electrophoretic examination proved to be uniform and which gave a positive ninhydrin stain.

The product was n: -L-glutamyl- ('U -taurirÛ-glycine.

Yield 0.06 g (88%.

Analysis for C 9 H 17 N 5 O 7 S (M = E 11, δ): Calculated: S 10.5% Eunnet: S 10.0% IR spectrum showed for the characteristic groups the following maximaz-NH; 5100 cm -1 (width fi); on (coon) 5200 em'1 (brevt); C = O (COOH) 1750 cm -1; C = O (amide-I) 1680 cm -1; C = O (amide-II) 1560; s = o (sozo fi) 1220 cm “1 (intense); s = o - (so, o ') 1045 cm -1 (intensive). H Hydrolysis' 20 mg of the substance was kept in 1 ml of 6 N-H01 in a molten glass tube for 24 hours at 105 ° C. After cooling, it was subjected to a sample of the solution electrophoresed at pH 1.8 The solution contained glutamic acid, glycine and taurine 100 mg of the thus-prepared 06-L-glutamyl - (? '- taurine) glycine was dissolved in 25 ml of a 0.2 -molar ammonium bicarbonate buffer pH 8.5 The solution was added with 1 mg carboxypeptidase A (manufactured by Serva, Heidelberg) dissolved in 0.5 ml water.

The mixture was kept in a thermostat at a temperature of š? ° C for 24 hours and then lyophilized. The dried lyophilizate detected U-lglutamyl taurine and glycine. The pure ¶'-L-glutamyl taurine can be recovered by electrophoresis or chromatography on a column of Dowex 50.

Example 6: (a) 0.4? g (1 mmol) of carbobenzyloxy-α-L-glutamyl- (β-nitrophenyl ester) -glycine methyl ester were dissolved in 6 ml of pyridine.

Under ice-cooling, first 0.125 g (1 mmol) of taurine in 2 ml of water and then 0.28 ml (2 mmol) of triethylamine were added in such small portions that the solution remained clear. The reaction mixture was then allowed to stand at room temperature for 5 days and then evaporated in vacuo. An oil was obtained which, after thorough digestion in ether and then in petroleum ether, was dried in vacuo over sulfuric acid. Carbobenzyloxy-Oc-L-glutamyl- (β'-taurine) -glyein methyl ester is obtained. (b) 100 mg of the so-prepared carbobenzyloxy- ° <-L- glutamyl ~ (1§-taurine) -glycine methyl ester was added at room temperature with 4 ml of a 2-normal ïBr solution in acetic acid, until the whole amount substance dissolved (about 30 minutes). The clear solution thus obtained was poured into 30 ml of ether and the whole was allowed to stand for a whole day? in a cold place. The precipitate formed was centrifuged off, washed several times with ether and then dried in vacuo over potassium hydroxide, sulfuric acid and phosphorus pentoxide. there was thus obtained the hydrobromide of the mfL-clutamyl- (B-taurine) -glycine methyl ester in practically pure form, which was determined by electrophoretic examination. (c) The salt thus prepared was reacted under ice-cooling for 5 hours with 2 ml of N-NaOH. The progress of the hydrolysis was monitored by electrophoresis. The reaction mixture was subjected to ion exchange with 10 ml of Dowex 50 in the H + form and then lyophilized. Since the electrophoresis showed that there were still impurities in the product, it was recrystallized in aqueous ethanol several times, until the required purity was achieved. There was thus obtained # 0 mg (59%) of α-L-glutamyl- (15-taurine) -glycine.

The IR spectrum for the characteristic groups showed the following maximaz- NH 5510 cm -1; NH; 3100 cm -1 (broad), e = o (coon) 1750 cm -1; 0 = 0 (amide I) 1650 cm -1; C = O (amide II) 1570 om'l; S = 0 1220 (intensive, 1045 cm -1 (intensive). (D) 100 mg of the thus prepared o <~ -L-ç; l11 +; am3.f1- (K-taurinyl) glycine was dissolved in 25 ml of a 0, 2 molar ammonium bicarbonate buffer pH 8.5 The solution was added with 1 mg carboxipeptidae A (prepared by Serva, Heidelberg) dissolved in 0.5 ml water, kept in a thermostat with a temperature of ÉÜOC for 24 hours and then lyophilized, The dried lyophilisate detected KL-glutamyltaurine and glvein The pure 1 -L-glutamyltaurine can be recovered by electrophoresis or chromatography on a column of Dowex 50.

Example Z: (a) 1.082 ((2.2 mmol) of carbobenzyloxy-L-glutamic acid - α, β-benzyl) -Xp-nitrophenyl ester was dissolved in 6 ml of a mixture of pyridine and water (2: 1). The solution was first added with 278 mg (2 mmol) of homotaurine and then with 0.59 ml (4.2 mmol) of triethylamine. The yellow solution was allowed to stand at room temperature for 72 hours, after which it was evaporated in vacuo. The oily residue was dissolved in water, the solution was neutralized with hydrochloric acid and then subjected to continuous extraction with ether for 8 hours to remove the p-nitrophenol. The aqueous phase was evaporated in vacuo. There was thus obtained 1.68 g of carbobenzyloxy-3-G-benzyl) -L-glutamyl homo-aHrin- (b) The whole amount of this substance was dissolved in 10 ml of a 50% aqueous ethanol, then the solution was added with 0, 5 g of 10% palladium activated carbon, after which hydrogen was passed through the suspension for 4 hours. Then the solution was filtered and evaporated in vacuo. The residue was dissolved in 1-2 ml of water and, to remove the triethylamine, the whole was poured into a 1x35 cm column containing Dowex 50 x 2 in the H + form. The elution was carried out with water and 50 ml of eluate were collected and evaporated in vacuo. The remaining 440 ml of X-L-glutamylhomotaurine were obtained, corresponding to a yield of 82%. The electrophoresis carried out at pH 6.5 showed that the product contained a small amount of contaminants of both neutral and acidic substances (homotaurine and glutamic acid, respectively). The product can be purified, for example by preparative electrophoresis.

Both at the pH 6.5 and at the electrophoresis performed at pH 1.8, the substance migrated towards the cathode. Its mobility relative to cysteic acid was 0.68 at pH 6.5 and 0.50 at pH 1.8.

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

The IR spectrum for the characteristic groups has the following maximaz-0 -NH = 5545; 0 111152 0H = 5200-2200; ~ J co = 1740; 9 00-1111 .- 16/45; x) SO 5 '= 1240, 1190, 1150, 1058, 5 -NH = 1570, 1555; 6 'so; = 590 cnfl Example 8: (a) 1.083 g (2.2 mmol) of carbobenzyloxy-L-glutamic acid-Q% -benzyl) -Xp-nitrophenyl ester were reacted in the manner set forth in Example 7a with 278 mg (2 mmol) of N -methyltaurine. 1.59 g of carbobenzyloxy (X-GN-benzyl) -L-glutamyl-N-methyl-taurine were obtained. (15) The entire amount of this product was subjected to catalytic hydrogenation in the manner set forth in Example Tb. 423 mg of Å1L-glutamyl-N-methyltaurine were obtained in a yield of 79 %.

During paper electrophoresis, the substance migrated towards the anode both at pH 5.5 and at pH 1.8. The mobility in relation to cysteic acid was 0.68 at pH 6.5 and 0.49 at pH 1.8.

Rf (n-butanol / pyridine / glacial acetic acid / water 15: 10: E: 12) = 0.15.

Example 9: (a) 2.87 g (6.6 mmol) of carbobenzyloxy-L-glutamic acid (C-benzyl) -Xp-nitrophenyl ester were dissolved in 20 ml of pyridine and the solution was added with a solution of 1.25 g (5 mmol) L-cysteic acid monohydrate in a mixture of 17 ml of water and 1? ml pyridine. After adding 2.6 ml (18, G mmol) of triethylamine, the reaction mixture was allowed to stand for 72 hours at room temperature, then it was evaporated in vacuo at 3000. The residue was dissolved in 20 ml of water and the aqueous solution was acidified with concentrated hydrochloric acid. whereupon it was shaken with ether (15 times 10 ml). The aqueous phase was evaporated in vacuo at 5500 to give carbobenzyloxy-X (GX-benzyl) -L-glutamyl-L-cysteic acid. (b) This product was dissolved in 20 ml of water, the solution was charged with 0.6 g of 10% palladium activated carbon and hydrogen was passed through the suspension for 5 hours. The reaction mixture was worked up as described in Example 7b to give XL-glutamyl-L-cysteic acid, m.p. 18700. The mobility relative to cysteic acid on paper chromatography was pH 6.5 to 1.21 and at 1.8 to 0.54. * R spectrum shows for the characteristic groups the following maxima: ~ ~> spirits) 51125; and May, 011 3500-2200 Ü CO (carboxyl) 1748, 1712; Ü GO (amid) 1627; wlmxamia) 1527- i s z '1221, 1109, 10115; Isos 525 cm -1 Analysis 0% H% N% 5% calculated for C 8 H 14 N 2 O 8 S (M = 298.28) 52.86 H,? 5 9.59 10,? S 55.05 5.28 9.05 11, Found 10 Example 10: (a) 1.085 g (2.2 mmol) of carbobenzyloxy (L-glutamic acid-QX-benzyl) -Xp-nitrophenyl ester was dissolved in G ml of a mixture of pyridine and water (2: 1) . The solution was first added with 282 mg (2 mmol) of cholamine phosphate (U.S. Pat. No. 2,750.5M2) and then with 0.87 ml (0.2 mmol) of free ethylamine. The reaction mixture was then allowed to stand at room temperature for 72 hours, after which it was evaporated in vacuo. The further work-up was carried out in the manner described in Example 7a in connection with carbobenzyloxy (XLQX-benzyl) -L-glutamylhomotaurine. 1.25 g of carbobenzyloxy- ((-GK-benzyl) -L-glutamyl-cholamine phosphate were obtained. (b) The entire amount of this product is subjected to catalytic hydrogenation in order to remove the protecting groups. The hydrogen exchange and purification by ion exchange was carried out in the manner set forth in Example 7b to prepare XÄL-glutamyl homotaurine. 470 mg of XLL-glutamylcholamine phosphate were obtained, corresponding to a yield of Ülß. The product, however, contained about 1% -: GO chain »mine phosphate as an impurity, as evidenced by paper electrophoresis. As a purification procedure, e.g. electrophoresis come into play.

During the paper electrophoresis, the substance migrated in the direction of the anode both at pH 6.5 and at pH 1.8. The mobility in relation to cysteic acid was at pH fi.5 to 0.75 and at pH 1.8 to 0.56.

Rf (n-butanol / pyridine / glacial acetic acid / water 15: 10: 5: 12) = 0.1.

Example 11: (a) 526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid (GX-benzyl) β-nitrophenyl ester (Chem. Ber. 97, 1789, 1964) were dissolved in 5 ml of pyridine. The solution was cooled to 0 ° C and added in small portions with a solution of 125 mg (1 mmol) of taurine in 2 ml of water and then with 0.28 ml (2 mmol) of triethylamine. The reaction mixture was allowed to stand for 48 hours at room temperature and then evaporated in vacuo. the residue was dissolved in 5 ml of water and the yellow solution was initially added with N-H01 until it was decolorized. To remove the p-nitroenol, the solution was shaken with ether (10 times 5 ml). The aqueous phase was evaporated in vacuo to give 478 g of carbobenzyloxy (Q (QX-benzyl) -L-aspartyltaurine. (b) The entire amount of this product was dissolved in 6 ml of a 50% aqueous ethanol. The solution was charged with 100 mg of 10% palladium activated carbon and then hydrogenated for 4 hours by initiating hydrogen. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The triethylamine was removed from the product in the manner set forth in Example 7b in connection with the preparation of X-L-glutamyl homotaurine. 172 mg / 5-L-aspartyltaurine was obtained, which corresponds to a yield of 71%. The product is slightly contaminated with taurine, which can be removed by electrophoresis.

During the paper electrophoresis, the substance migrated both at pd 10 15 20 25 EO 55 40 1? 7812884-0 G, 5 as at pH 1.8 against the anode. The ratio of .5 to 0.58 for cysteic acid was 0.77 at pH 1.8.

RF (n-butanol / pyridine / glacial acetic acid / water l5: 10:?: L2) = 0.1G.

Example 12: (a) 526 mg (1.1 mmol) of carbobenzyloxy-L-aspartic acid-GX-benzyl) -β-nitrophenyl ester and 139 g (1 mmol) of homotaurine were reacted as in Example 11. Carbobenzyloxy- (β-GX-benzyl) -L-aspartyl homotaurine was obtained. (b) The product thus obtained was subjected to catalytic hydration at night as uu fl ívuü ï ~ x ~ mpnl 7b_ She nrh fi ll Üñï mg (84%), 6-L-aspartyl homotaurine.

During the paper electrophoresis, the substance migrated in the direction of the anode both at pH 6.5 and at pH 1.8. The mobility in relation to cysteic acid amounted to 0.2% at pH 6.5 and to Opsš Vid. pH 1.8.

Rf (n-butanol / pgridine / glacial acetic acid / water 15:10: Z: 12) = 0.17.

Example Gel 13: (a) Carbobenzyloxy-L-aspartic acid (M-benzyl) 7β-p-nitrophenyl ester and cholamine phosphate were reacted with each other as in Example 10. Carbobenzyloxy- (K-benzyl) -L- aspartylcholamine phosphate. (b) The product thus obtained undergoes catalytic hydrogenation in the manner set forth in Example 7b. One obtained 1, ß-L-asperty1 ~ cholamine phosphate.

During the paper electrophoresis, the substance migrated towards the anode both at pH 6.5 and at pH 1.8. The mobility in relation to cysteic acid amounted to 0.1% at pH 4, S and to 0.40 at pH 1.8.

Rf (n-bintanol / pyridine / glacial acetic acid / water Ig: 10:?: 12) = 0.14.

Example Gel 14:25, # mg (0.1 mmol) X-L-glutamyltaurine was dissolved in 2 ml of water and the solution was added with 10 ml of 0.01 N-NaO 2. The mixture was evaporated in vacuo at 80 ° C and the white crystalline residue thus obtained was dried in a desiccator over phosphorus pentoxide. There was thus obtained the monosodium salt of XZL-glutamyl-taurine. The product had no sharp melting point but began to shrink at 20,000. The color became darker and the product charred at about 25,000. The product is as sparingly soluble in methanol as in ethanol.

Example 15: To 7.5 mg (šO, pmol) of X-L-glutamyltaurine was added 10 ml of absolute methanol, which contained 0.5 HO1 per liter. Suspension- 10 15 20 à; The ice was stirred at room temperature for 24 hours. The pure product was isolated by descending paper chromatography using either of the following two solvents: Rf (n-butanol / pyridine / glacial acetic acid / water 15: 10: 5: 12) = 0.27 Rf (n-butanol / glacial acetic acid / water 4: 1: 1) = 0.14. g X-O 2 -methyl) -L-glutamyltaurine was obtained.

Example 16: The esterification was carried out as indicated in Example 15 but using ethanol containing H01. He obtained Xlu-ethyl) -L-glutamyltaurine. RT (n-butanol / pyridine / glacial acetic acid / water l5: 10: Z: 1?) = 0.25 Rf (n-butanol / glacial acetic acid / water 4: J: 1) g Example 17: XLL-glutamine taurine (prepared on The procedure set forth in one of Examples 1 to 4 and 14) was purified by recrystallization as follows: 500 mg of crude substance was dissolved at room temperature with stirring in 5 ml of anhydrous dimethyl sulfoxide. The opalescent solution was filtered and the filter was washed with 0.5 ml of dimethyl sulfoxide. The filtrate and washings were combined and added with 55 ml of absolute ethanol. The mixture was then allowed to stand at room temperature for 12 hours, after which the substance was filtered off, washed with 2.5 ml of absolute ethanol and dried in a vacuum desiccator over phosphorus pentoxide to a weight constant. He obtained 240 mg of crystalline X-L-glutamyltaurine (80% recrystallization yield). * Instead of ethanol, the same amount of dioxane, ether or acetone can be used for the recrystallization. The quality of the crystalline product is the same in all cases. Melting point (according to Boetius): 2l8e2l9 ° G. The product is thin layer chromatographically uniform.

Example 18: Carbobenzyloxy-X-GM-benzyl) -L-glutamyloholamine was prepared in a manner suitable for the preparation of glutamic acid X-amides (Acta Chim.Acad.Sci.Hung. 64, 285, 1970). 4.14 g of this product (10 mmol) were dissolved in 50 ml of absolute pyridine and the solution was added with 9 g (55 mmol) of diphenylphosphoric acid chloride. The reaction mixture was kept at 000 for 12 hours and then diluted with 80 ml of chloroform. The precipitated product was filtered off, washed with dilute hydrochloric acid and then with water and finally dried in a desiccator over potassium hydroxide. The dry substance was dissolved in 15 ml of glacial acetic acid containing 5.5 mol / l HBr. The solution was allowed to stand for 15 minutes and then evaporated at 55 ° C in vacuo. The residue was dissolved in 50 ml of N-NaOH and the solution was allowed to stand for one hour at room temperature. Then the pH of the solution was adjusted to acetic acid with 4 and extraction was performed with ether (three times 30 ml) to remove the phenol and the benzyl alcohol. . The aqueous phase was poured into a column filled with Dowex 50 in the H + form and elution was performed with water. The element was evaporated in vacuo and the residue was recrystallized from a mixture of acetone and water (2: 1). 0.8 g of X-L-glutamylcholamine phosphate was obtained.

Example 19: 4.68 ml (5 mmol) of phosphorus oxychloride were added dropwise with cooling and stirring in 1.8 ml of water (Biochem. Preparations 6, 76, 1958). The solution was added with 1.9 g (10 mmol) of Y-L-glutamylcholamine (prepared from carbcbenzyloxy-X-GK-benzyl) -L-glutamylcholamine according to Example 18) in small portions. The mixture was stirred at 6000 for 2 hours, added after cooling with stirring with 0.72 ml of water and then allowed to stand at room temperature for 2 hours. In connection with this, 10 ml of 96% ethyl alcohol and then 10 ml of ether were added dropwise and with stirring. The reaction mixture was then allowed to stand at 400 overnight, then added with 5 ml of 96% ethanol. The precipitated product was filtered off, washed first with ethanol and then with ether and subsequently recrystallized from a mixture of ethanol and water. 1.75 g of ¥ -L-glutamylcholinamine phosphate were obtained.

Example 20: 4.1 g (10 mmol) of carbobenzyloxy (X-QX-benzyl) -L-glutamylcholamine were dissolved in 40 ml of pyridine and the solution was cooled to -1000. 2.1 g (11 mmol) of p-toluenesulfonyl chloride were added in small portions and with vigorous stirring. The reaction mixture was then stirred at 0 ° C for 5 hours, then poured onto 40 g of melting ice. The precipitate formed was filtered off, washed with water and finally recrystallized from a mixture of ethanol and petroleum ether. The product was subjected to catalytic hydrogenation as given in Example 3. The product obtained by the hydrogenation and dried was dissolved in 30 ml of water, the solution was added with 10.1 g (40 mmol) of sodium sulfite heptahydrate and stirred at 40 ° C for 24 hours, after which it was evaporated in vacuo. The residue was dissolved in a small amount of water and poured into a column filled with Dowex 50. Elution was performed with water and the eluate was evaporated in vacuo. The residue was dried over potassium hydroxide and recrystallized from 80% ethanol. 1.6 g of X-L-glutamyltaurine were thus obtained.

Example 21: To 4.1 g (10 mmol) of carbobenzyloxy-K- (M-benzyl) -L-glutamylcholamine was added 15 ml of thionyl bromide and the mixture was stirred for 5 hours. Then ether was added, the formed precipitate was filtered off and recrystallized from a mixture of acetone and petroleum ether. The resulting substance was dissolved in a mixture of dimethylformamide and water, and the solution was added with stirring with 10.1 g (WO mmol) of sodium sulfite heptahydrate. The mixture was then stirred for 24 hours at room temperature and further for G hours at 50 ° C, after which it was filtered. The clear solution was evaporated in vacuo and the residue was subjected to catalytic hydrogenation in the manner set forth in Example 5. The substance obtained by the hydrogenation and dried was dissolved in a small amount of water (1,511 .mu.l) in the present liquid. I Ilse-LI Hoz-w "WW. I-Zluf-z-ïixrj --_« - n_ was carried out with water and the eluate was evaporated in vacuo. The residue was recrystallized from 80% ethanol to give 1,2 3 XL-glutamyltaurine.

Example 22: 3.71 g (10 mmol) of carbobenzyloxy-L-glutamic acid d-benzyl ester were dissolved in 60 ml of acetonitrile. The solution was cooled to -1500 and added with stirring first with 1.4 ml (10 mmol) of chloroformic acid isobutyl ester and then with 1.1 ml (10 mmol) of triethylamine. The reaction mixture was stirred for 30 minutes at -1500 and then added with 2.05 (10 mmol) of bromomethylamine hydrobromia, 1.4 ml (10 mmol) of triethylamine and no m1 to -15 ° C cooling acetonitrile. The mixture was stirred at -1500 for 2 hours and then at room temperature for a further 4 hours, after which it was filtered. The filtrate was evaporated in vacuo at 55 ° C and the residue was dissolved in a mixture of dimethylformamide and water. The solution was added with 10.1 g of sodium sulfite heptahydrate. The mixture was worked up as described in Example 21 to give 1.45 g of X-L-glutamyltaurine. In Example 25: 5.02 g (10 mmol) of carbobenzyloxy-L-glutamine sodium salt (Liebigs Annalen 640, 145, 1961) were dissolved in 50 ml of dimethylformamide. The solution was added with a 12 mmol sodium hydride containing oily suspension and then heated for 2 hours to exclude the humidity. In addition, 2.11 g (10 mmol) of bromethanesulfonic acid sodium salt in 50 ml of dimethylformamide were added dropwise and the mixture was heated for a further 2 hours and then evaporated in vacuo. The residue was extracted with ether and the extract was dried.

The dry substance was dissolved in water and the solution was poured into a column filled with Dowex 50. Elution was carried out with water and the eluate was evaporated in vacuo. The residue was dried over potassium hydroxide and the dried substance was subjected to catalytic hydrogenation in the manner set forth in Example 2. Recrystallization from ethanol / water gave 1.55 g of X-L-wlutamyltaurine.

Example Gel 24: 2.58 g (10 mmol) of L-N- (E, G-dioxo-5-piperidyl) -phthalimide (J. Pharm.Sci. 57, 757, 1968) was dissolved in a sodium ethate solution prepared with absolute ethanol. The solution was evaporated in vacuo and the residue was dissolved in 50 ml of methylformamide. While stirring, the solution was added with 2.25 g (11 mmol) of bromomethanesulfonic acid sodium salt. The mixture was heated for “hours and then evaporated” in vacuo. The residue was dissolved in water and the solution was poured into a column filled with Dowex 50. The eluent was carried out with water and the eluate was evaporated in vacuo. The residue thus obtained was boiled in 100 ml of 0.5 N-H01 for 5 hours. After the solution was evaporated, 50 ml of ethanol and 0.7 ml of 72% hydrazine hydrate were added to the substance, after which the mixture was boiled for one hour and evaporated in vacuo. The residue was taken up in 25 ml of 2 N-H01 and the mixture was kept for 10 minutes at 5000 and then allowed to stand at room temperature for 50 minutes. The precipitated solid was filtered off, the filtrate was evaporated in vacuo and the residue was dried in a desiccator over potassium hydroxide. The dry substance was dissolved in a mixture of water, acetic acid and formic acid in a volume ratio of 90: 8: 2 and the solution was poured into a column 2 x 100 cm filled with Dowex 1. Equilibrium had previously been set in the column with said solvent mixture. First, elution was performed with said solvent mixture and 400 ml of eluate were collected. This fraction contained X-L-glutamyltaurine. It was then eluted with 0.5 N-FO and 400 ml of eluate were also collected. This fraction was evaporated to dryness in vacuo at 5500. The residue was dried in a desincator over solid potassium hydroxide and recrystallized from 80% ethanol. 1.0 was obtained in this way? g X-L-glutamyltaurine.

Example gel 25: 4.45 g (10 mmol) of carbobenzyloxy-L-pyroglutamic acid dicyclohexylamine salt (Liebigs Annalen 640, 145, 1961), 1.25 g (10 mmol) of taurine and 0.84 g (10 mmol) sodium bicarbonate was dissolved in 50 ml of water. The solution was heated for 4 hours (or allowed to stand at room temperature for 24 hours) and then evaporated in vacuo. The residue was dissolved in water, the solution was poured into a column containing Dowex 50, then eluting with water.

The eluate was evaporated and the substance thus obtained was subjected to catalytic hydrogenation in the manner set forth in Example 3. Recrystallization from a mixture of ethanol and water gave 2.05 g of X-L-glutamyltaurine.

Claims (13)

10 15 20 25 30 35 Patent claim 7812884-0 Amino acid derivatives, characterized in that they have the general formula R1HN-en-co-A1 (CH2) n I CO-N-CH- (CH2) tB1 R R5 pharmacologically acceptable salts and optically active isomers thereof, in which formula A1 a hydroxyl group, a C1-CA alkoxy- or an optionally in the p-position with alkoxy- or nitro-substituted C -C -aralkoxy group or the group - (NH-CHR6-CO) rY-, where R hydrogen or a C 1 -C 8 alkyl group, Y is hydroxyl or a C 1 -C 4 alkoxy group and r is an integer 1-10; a hydrogen atom, a C 1 -C 8 alkoxycarbonyl group or one optionally having one or more substituents, namely halogen, alkoxy or nitro, substituted C 7 -C 9 aralkoxycarbonyl group; hydrogen or a C 1 -C 6 alkyl group; hydrogen or a carboxyl group; 11, wherein R 11 is a group -SO 2 OH, -OPO (OH) 2 or -SSR the residue attached to B by the amino derivative of formula I; an integer 1 or 2 and an integer 1 or 2, wherein A1 does not represent hydroxyl, if R1 represents hydrogen, which compounds are useful as intermediates for the preparation of compounds which have biologically and pharmacologically valuable properties and which fall within the above indicated formula I, where all the general symbols have the meanings given above except that R1 represents only hydrogen A1 represents only hydroxyl and B1 represents only ~ SO2OH or ~ OPO (OH ) 2. Amino acid derivatives according to claim 1, n i m l i g e n [ïßerbenzyl) -glutamyl-27-taurine and pharmaceutically acceptable salts and optically active isomers thereof. Amino acid derivatives according to Claim 1, namely [N-carbobenzyloxy- (β-benzyl) -aspartyl-α-taurine and phenom $ D1ogigg¿ acceptable salts and optically active isomers thereof. Amino acid derivatives according to Claim 1, n i m l i g e n [T ° <~ benzyl) -aspartyl- $ _ / - homotaurine and pharmaceutically acceptable salts and optically active isomers thereof. An amino acid derivative according to claim 1, wherein 1β-carbobenzyloxy- (G <: benzyl) -aspartyl-β-cholamine phosphate and pharmacologically acceptable salts and optically active isomers thereof. An amino acid derivative according to claim 1, wherein [N-carbobenzyloxy- (wi-benzyl) -glutamyl-ÉL7 homotaurine and pharmacologically acceptable salts and optically active isomers thereof. An amino acid derivative according to claim 1, namely [N-carbobenzyloxy- (mL-benzyl) -glutamyl-K] cholamine phosphate and pharmacologically acceptable salts and optically active isomers thereof. An amino acid derivative according to claim 1, namely a β-carbobenzyloxy- (β-L-benzyl) -glutamyl-α-cysteic acid and pharmacologically acceptable salts and optically active isomers thereof. 10 l5 20 25 7812884-o 24 An amino acid derivative according to claim 1, wherein [N-carbobenzyloxy- (β-cysteamide) -glutamyl-0g7-glycine-ethyl ester. An amino acid derivative according to claim 1, wherein [N-carbobenzyloxy- (X'-taurine-glutamyl) -glycine ethyl ester. 11. ll. An amino acid derivative according to claim 1, namely an NN-carbobenzyloxy- (Zf-taurine-glutamyl-1-glycine methyl ester). The amino acid derivative of claim 1, wherein [KK-taurine] -L-glutamyl-N27-glycine and pharmacologically acceptable salts thereof. The amino acid derivative according to claim 1, namely [Û-carbobenzyloxy- (Q: -benzyl) -L-glutamyl] taurine and pharmacologically acceptable salts and optically active isomers thereof.