CS209856B2 - 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 preparation of novel amino acid derivatives, of which a part is characterized by 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 represented by the general formula I,

R ¹ -NH-CH-COA ¹

I (CH 2) n

CO-N (CH) _n - (CH 2) t B ¹

IIRR ² (I) where is

A ^one hydroxyl, alkoxy having 1-4 carbon atoms, cycloalkoxy having 3 to 6 carbon atoms, aralkoxy group having 7 to 9 carbon atoms, phenoxy optionally substituted by nitro and / or halogen and / or alkoxy having 1 to 4 carbon atoms) or a group of the formula - (NH-CH 2 -CO), -Y, where is

Y is hydroxy, C 1 -C 4 alkoxy or C 7 -C 9 aralkoxy, and an integer from 1 to 1θ

B ^{1 a} group of formula --SO 2 OH, - OSO 5 OH, 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, phenoxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or nitro, C 1 -C 4 alkanoyl or benzoyl ,

R @ ^{2 is} hydrogen, C1 -C4 alkyl or carboxyl, C1 -C4 alkoxy or C1 -C4 alkoxy or carboxamido, n number 1, 2, 3 or 4; number-1, 2 or .3 and 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 prepared by the process according to the invention, it is necessary to mention in particular γ-L-glutamyltaurine because of its biotogic209856. formula XXIV,

HzN — CH — COOH

CH2

CH2

CO — NH — CH2 — CH2 — SOZOH (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 aerobiospheric genetic adaptation system (AGAS).

To clarify the concept of AGAS, the most important tissues and organs constituting the following are listed below: system;

a) All biological boundaries - areas that are in contact with outside air as a 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) organs .. involved in the regulation of ionic economy (trans-epithelial transport system: intestinal villi, renal ducts), M

d) c ^{h RUP} potfebný for dimension therein ^el p otra- | H and you. fixed beds in dental roots, ™

(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 according to the invention acting further on the functions mentioned below. which - - are related to AGAS: protective effect against radiation, - healing effect - - wounds and generally activating mesenchym, protection against increasing danger - - infection and contamination of skin and mucous membranes - - (formation of lysozyme of wet mucous membranes, activation - - - - - ciliated 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 large extent with increasing stress effects (e.g. meteorological effects, considerable differences - between day and night temperature, increased risk of injury) on shore life by stabilizing adaptive -syndrome and damage to peripheral tissues by glucocorticoids (e.g. damage to connective tissues, damage to bone matrix, etc.). The emergence of immunohomoeostasis (escalated - the ability of knowing the body which cells - belong to the body and which do 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. 25-hydroxycholecalciferol-1-a-hydroxylase enzyme of kidney channels. Thus, the broad pharmacological, biochemical and therapeutic action of the compounds prepared by the process of the invention becomes understandable. The areas of action of these compounds are as follows:

Vitamin A effects

(a) Pharmacological and biochemical effects The radiolabelled sulphates are increasingly incorporated into the bone cartilage of the rat or eye lens, - liver and lung tissue of the chicken embryo; radiolabeled phosphorus - is increasingly incorporated into rat 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 experimentally induced hypovitaminoses or hypervitaminoses in rats and chickens; sedative effect on - stress effects caused by rat ulcer; beneficial effect on mast cell degranulation; lysozyme production-enhancing effect; effects on the management of trace elements (silicon, zinc, copper, manganese, fluorine); a beneficial effect on epithelial formation; escalating effect on alkaline phosphatase activity; action - formation of granuloma vesicle due to local action of vitamin A; very flat curve - dose / effect, eventual 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 sicca; ozaena; chronic bronchitis; sinobronchitis; mucoviscidosis; constitutional lung disease in young children; periodontitis; susceptibility of skin and mucous membranes 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. Vitamin A - free effects

(a) Pharmacological and biochemical effects

Effect on blood sugar in the sense 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;

adenosine monophosphate-induced cyclic renal emptying effect; a mitigating effect on the symptoms of experimentally induced lathyrism; decreasing the sensitivity to histamine; potentiating effect on the activity of the liver enzyme tyrosine aminotransferase.

b) Therapeutic effects

Slight radiation damage; local lack of dye in the skin; muscular hypotonia; psychoenergetic effect; a beneficial effect on involutional and gerontological conditions as well as on mnestic functions; tendency to scar fibroma formation; spondylosls-alkylopoetica; musculoskeletal disorders caused by wear; sclerotic fundus; amyloidosis; morphea; fibrocystic mastopathy.

When administering the compounds of the invention, the treatment time varies greatly. In many diseases (such as rhinoaryngopharyngitis -sicca), oral administration of 5 .mu.g three times a day does not show symptoms after only two weeks; symptomatic recovery of other diseases (e.g. periodontitis, Sjorgren's syndrome) requires one to two months; for example, in spondylosls ankylopoetica), 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 substance amounts to 50 to 500 _t ug per day, per 1 kg body weight, administered - are divided in three individual doses.

One tablet contains - 2 to 20 - g - preferably 10 - μξ of the active substance, and furthermore biologically inert carriers, for example milk sugar, starch, as well as conventional tabletting aids (granulating and glidants - substances for example polyvinylpyrrolidone, gelatin) , talc, magnesium stearate, aerosol, 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 small content of the active ingredient makes it possible to produce the active ingredient, even in the manufacture of many millions of tablets per year, only on a laboratory scale, at a price which is available to every patient. Since the active substances are stable, the tablets can be delivered to the market without an expiry date. The active substance content of the retarding tablets or of the spansular capsules may be in the range of 10 to 20 .mu.g. In the case of injectable preparations, the effective dose per vial is 5 to 10 [mu] g and, if desired, the preparation may be in the form of a powder vial in which the active ingredient is mixed with an inert water-soluble filler. Parenteral administration can be performed intramuscularly, subcutaneously or intravenously. At the concentration indicated, the active compounds do not have a detrimental effect on either. tissue - on the walls of blood vessels. The active ingredients may also be administered as an infusion. Suppositories contain 2 to 20, preferably about 10 µg of active ingredient and are made from cocoa butter or synthetic waxes or fats suitable for this purpose. The content of active substance in cosmetic ointments or ointments intended for skin healing is 0.1 to 1 μξ / g. The matrix composition may be hydrophilic or hydrophobic. and contains the usual ingredients, for example, cholesterol, paraffin, glycerin, lanolin, cocoa butter, linseed oil, etc. The active ingredients can also be formulated as aerosol formulations, wherein the active ingredient content is also in the range of 0.1 to 1 Atgfg - In the form of a perlingual tablet - the tablet contains 10 μξ of active substance, disintegration time is 0.5 - 1 hour. The sustained release polymers can be prepared, for example, as suspensions and contain from 1 to 5 μξ of active ingredient per 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 molar organic bases (e.g., histone, protamine), with 1 vial containing 10 to 20 µg of the active ingredient. Powders for cosmetic use or for use in the treatment of the skin are prepared with the usual carriers, for example with talc, and contain 0.1 to 1 pg of active ingredient per g of 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 in these preparations is 0.1 to 1 [mu] g / g. In children, the compounds of the invention should be administered 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 and foremost, those substances and the protection of their use.

Vitamins A, C, E and K, trace elements, cortisone and - its derivatives, progesterone, thyroid hormones, radiomimetic and immunosuppressive active substances, psychopharmaceuticals, especially · tranquilizers, timoleptics, organic silicon compounds, gerontolic preparations, substances cholesterol-lowering blood-oral, oral-antidiabetics, 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 to

28985 $ of nutritional or medicinal mixtures. They cause weight gain, reduce the need for vitamin A or improve its metabolism. Further, the compounds of the invention increase the absorption 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 is approximately 1 to 2% / kg or 1 to 2 mg / tonne, i.e., a concentration (D = 91 to 0.002 ppm), due to these very low concentrations. They are advantageously added to the vitamin premixes or used in the microcapsules containing the compounds according to the invention together with other necessary feed additives. use water in the Lord to feed cattle, in salt for licking or even in the form of a spray.

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

It is a common feature of the structure of all the compounds of formula (I) that they contain - .alpha.-taylic acid - substituted in the .beta.-position, or a derivative thereof - substituted in other positions, bound via its .alpha.-carboxyl group by a secondary alkylamine which, in addition to the various substituents on its alkyl side chain, contains in the ω-position a group strongly related to its nature.

Process according to the invention for production. compounds of the formula I, their salts and optical isomers, characterized in that in the compound of the formula II,

R1-NH-CH-COA1 (OH6) n

AND

CO — N— (CH) (CHpj: —-B ²

R-R 2 (Π) where

A1, ^-R! R 1, R ² , n, m and m are as defined above - t

B ² is halogen, hydroxy, -p-toluenesulfonyloxy or -SH, -SOOH, -SO ² R ⁴ -or -S-S-R ⁵ , where R is C 1 -C 4 -alkoxy, and R ^{5 is a} residue obtained by removing the group -B ² from a compound of formula II, the group B ² -converts -to a group B1 -t, optionally converting any of these compounds into their salt or liberating them from their salt and / or The above compound is prepared in optically active form using optically active reagents or by cleaving the obtained racemic product.

For the preparation of compounds of formula * IA,

R1-NH-CH-COA1 (CH2Jn);

AND

CO - N - (CH) _m - (CH 2) - SO 2 O.H

R R 2 (IA) where

A ¹ , R, R 1, -R 2, n, -m are as defined above, or a pharmaceutically acceptable salt thereof or an optically active portion thereof, oxidizes a compound of formula II A,

R1-NH-EH-C & A1

I (CHžjn

CO — N - (CH J - _m - (CH 2). - ® ³

R @ 2 --R @ 2 (HA), respectively

A 1, R ¹ , -R ¹ , R 2, n, mtt are as defined above and a

B ³ represents a group of the formula -SH, -SOOH or -S-S-iR ^e , where R ⁶ represents a residue obtained by -bonding the group B ³ -od of a compound of formula HIA .;

after the oxidation, any of the compounds thus obtained can be converted into their salt or liberated from their salt and / or prepared from the above-mentioned compounds in an optically - by using optically active starting materials or by resolving the racemic product obtained.

If he is to prepare a compound of the general formula -IB,

R 1 -NH-CH-COA 1 ('CH 2');

CO — N— (CH) ™ - (CH2J-B4 ⁾

R-R 2 (IS) where

A ¹ , -R, -R ¹ , -R 2, n, m and m are as defined above -a

B ^{4 -} represents a group of the formula —OSO2OH, —OP-O (OH) 2, the compound of the general formula is esterified

IIB, ’

R1-NH-CH-COA1

I.

(CH2) n

CO-N- (CH) _m - [CH ₂ H-OH

RR ² (IIB) where

A ¹ , R, R ¹ , R ² , n, m and m are as defined above, sulfuric acid or phosphoric acid or derivatives thereof, and optionally the compound thus obtained is partially hydrolyzed, or optionally any of the compounds thus obtained is converted into its salt or is liberated from its salt and / or any of the aforementioned compounds are prepared in optically active form using optically active starting materials or by cleavage of the obtained reaction product.

For the preparation of compounds of general formula

IC,

R1-NH-CH-COA ¹

I (CH2) n

CO - N - (CH) m - (CH 2) t - SO 2 OH

RR ² (IC) where

A1, R, R1, R2, n, m and t are as defined above, or a pharmaceutically acceptable salt thereof or an optically active isomer thereof with a compound of formula IIC,

R1-NH-CH-COA1

I (CH2) n

CO — N— (CH) _m - (CH2) - B ⁵

I I R R2 (IIC) where .....

A 1, R, R 1, R ² , n, and m are as defined above and

B ⁵ represents a halogen or p-toluenesulfonyloxy group, is reacted with sulfite or bisulfite of an alkali metal, optionally followed thus ^one obtained compound is converted in its salt or liberated from its salt and / / or any of the above uvedebých compounds are prepared in optically active form using optically active reactants or by resolving the racemic product obtained.

For the oxidation of compounds of formula HA to prepare compounds of formula IA, permenic acid or a mixture of glacial acetic acid and hydrogen peroxide is used.

The reaction of a compound of formula IIC with an alkali metal sulfite or bisulfite to give a compound of formula IC is carried out by heating the compound of formula IIC in the presence of an aqueous solution of an alkali metal sulfite.

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

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

Example 1

25.77 g (0.013 mol) of N, N'-bis [N-carbobenzyloxy-γ- (α-benzyl) -L-glutamyl] cystamine, obtained by the reaction of · a-benzyl carbobenzyloxy-L-glutamic acid ester, · triethylamine, isobutyl chloroformate and cystamine hydrochloride are dissolved in 75 ml of glacial acetic acid. A freshly prepared mixture of 75 ml of 30% hydrogen peroxide and 225 ml of glacial acetic acid was added dropwise over 15 minutes to the obtained ice-cooled solution. After. the addition was stopped cooling and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was then evaporated at 30 ° C under reduced pressure. The oily product is dried in a desiccator first with phosphorus pentoxide, then with solid potassium hydroxide. 28.5 g of carbobenzyloxy - [- (Q-benzyl) -L-glutamyltaurine are obtained, and the crude product can be used without purification for the preparation of γ-L-glutamyltaurine.

Example 2

Dissolve 100 mg of carbobenzyloxy-α-L-glutamyl [γ-cystamine) glycine ethyl ester in 2 ml of glacial acetic acid and add 0.5 ml of 30% hydrogen peroxide to the solution. The reaction mixture was allowed to stand for 4 hours while cooling with ice water. The course of the reaction is monitored by paper electrophoresis. After dilution with water, the reaction mixture is lyophilized. The resulting product is obtained in the form of a foam. 0.11 g of carbobenzyloxy-α-L-glutamyl (γ-taurine) glycine ethyl ester is obtained. Yield: 95%.

Example 1 a d 3

4.68 ml (5 mmol) of phosphorus oxychloride is added dropwise to the solution while cooling and stirring

1.8 ml of water (Biochem. Preparations * 6, p. 76, 1958). 1.9 g (10 mmol) of γ-L-glutamylcholamine, made from carhobenzyloxy-γ-ph-benzyl-β-glutamylcholamine, was added in small portions. The mixture was stirred at 60 ° C for 2 hours, after cooling, 0.72 ml of water was added with stirring, and then left to stand at room temperature for 2 hours. 10 ml of 96% ethanol and then 10 ml of ether are added dropwise with stirring. The reaction mixture was allowed to stand overnight at 4 ° C and then 5 ml of 96% ethanol was added. The precipitate was filtered off, washed first with ethanol, then with ether and finally recrystallized from ethanol / water. 1.75 g of χ-L-glutamylcholaminophosphate are obtained.

sodium sulfite heptahydrate. The solution was stirred at 40 ° C for 24 hours and then evaporated under reduced pressure. The residue was dissolved in a small amount of water, and the solution was applied to a column of tonic exchanger, from which it was eluted with water. The eluate was evaporated under reduced pressure and the residue was dried with potassium hydroxide. Recrystallization from 80% -ethanol gave 1.6 g of γ-L-glutamyltaurine.

Example 5

He attaches

4.14 g (10 mmol) of carbobenzyloxy-γ- (α-β-benzyl) -L-glutamylcholamine are dissolved in 40 ml of pyridine and cooled to -10 ° C. In small doses, 2.1 g (11 mmol) of p-toluenesulfonyl chloride were added thereto with vigorous stirring. The reaction mixture is stirred for 3 hours at -0 DEG C. and then poured onto 40 g of melting ice. The precipitate formed is filtered off, washed with water and then recrystallized from a mixture of ethanol and petroleum ether. The product is subjected to catalytic hydrogenation. The material obtained by hydrogenation is dissolved in 30 ml after drying. water and to the solution - add 10.1 g (40-mmol)

To 4.14 g (10 mmol) of carbobenzyloxy-γ- (α-benzyl) -L-glutamylcholic acid was added 15 ml of thionyibromide and the mixture was stirred for 3 hours. Then - ether, precipitated 1. . .

And the precipitate was filtered and recrystallized from ¹ mixture of acetone ^and petroteiberu. ^From Iskan ^- Шka was dissolved in a mixture of dimethylformamide and water, and • the solution with stirring -Add 10.1 g (40 mmol) of cerium sulfite Kindred. The mixture was stirred at room temperature for 24 hours, then at 50 ° C for a further 8 hours, then filtered. The clear solution was evaporated under reduced pressure to give carbobenzyloxy-χ- (α-benzyl) -L-glutamylcholamine sulfate.

Claims (10)

object of the invention Process for the preparation of novel amino acid derivatives of the general formula I, R ¹ -ΝΉ-CH-COA ¹ · I (CH2) n CO-N (CH) _m - (CH2) _t ¹ -B R 2 (I) where R is - A ¹ hydroxy, C 1 -C 4 alkoxy, C 3 -C 6 cycloalkoxy, C 7 -C 9 aralkoxy, carbon, phenoxy, optionally substituted with nitro and / or halo, and / or (C 1 -C 4) alkoxy, or - (NH-CH 2 -CO) _r -Y, where: Y is hydroxy, alkoxy having 1-4 carbon ¹ - -or atoms, aralkoxy group having 7 9 carbon atoms -to a- r an integer of -from 1 to 10, | B ¹ is -SO 2 OH, -OSO 2 OH I or -OPO (OH) 2, I R @ 1 is hydrogen or C1 -C4 alkyl; R @ ^{1 is} hydrogen, alkoxycarbonyl, p C 1 -C 4, C 7 -C 9 aralkoxycarbonyl, phenoxycarbonyl optionally substituted by halogen, and / or C 1 -C 4 alkoxy and / or nitro, further C 1 -C 4 alkanoyl carbon atoms or benzoyl group, R 2 is hydrogen, C 1 -C 4 alkyl or carboxyl, C 1 -C 4 alkoxycarbonyl in the alkoxy portion of the phenoxycarbonyl group, or carboxanf. that number, n number 1, 2, - 3 or 4, m number 1, 2 or 3 and t number 1, 2 or 3. and pharmaceutically acceptable salts or optically active isomers thereof, characterized in that in the compound of formula (II): R ¹ -NH-CH-COA ¹ (CH 2) n CO - N - (CH) _m - (CH 2) _{t -} B ² RR ² (II) where A ¹ , R, R 1, R 2, n, m -at are as defined above I B2 is halogen, hydroxy, pI toluunsutf'onyloxy6.kupmu or a group of the formula -SH -SOOH or -SO2R4, or -S-S-R 5 wherein R ⁴ represents C 1 -to 4 carbon atoms and R5 - rest -Obtained removal of the group B2 of compound of formula II, the group B ² is converted into a group B ¹ and optionally either converting the resulting compound in its salt or liberated from its salt and / or any of the above compounds are prepared in optically active form by using optically active starting materials or by resolution of the racemic product obtained. 2. The process of item 1 for producing compounds of formula IA: R1-NH-CH-COA1 I (CH 2) n ', CO - N - (CH) - _> - (CH 2 t - SO 2 OH) I I R 2 (IA) wherein A ¹ , R, R 1, R 2, n, m and m are as defined above, or a pharmaceutically acceptable salt thereof or an optically active isomer thereof, characterized in that a compound of formula (IIA) is oxidized, R1-NH-CH-COA1 (CH2) n CO - N - (CH) m - (CH 3) -B ⁵ I I R 2 (IIA) wherein A 1, R, R 1, R 2, n, m and t are as defined above and a B ³ is a group of the formula -SH, -SOOH or -S-S-R ⁶ , wherein R ⁶ is a group obtained by cleaving the group B ³ from a compound of formula IIA; and any of the compounds thus obtained is optionally converted into its salt or released from its salt and / or any of the above compounds are prepared in optically active form using optically active starting materials or by resolution of the racemic product obtained. 3. The process of item 1 for producing compounds of formula IB, R1-NH-CH-COA1 I (CH 2) n AND CO - N - (CH) m - (CH 2) _{t -} B 4 I I R 2 (IB) wherein A1, R, R1, R2, n, Mat maj ^{ye e} defined above, and B ⁴ denotes ^the case ^{of the} formula - OSO 2 OH or -OPO (OH) 2. or a pharmaceutically acceptable salt thereof or an optically active isomer thereof, characterized in that the compound of formula (IIB), R 1 -NH-CH-COA1 (CH 2) n CO-N- (CH), m- (CH 2) t -OH RR ² (IIB) where A 1, R, R 1, R ² , n, m and m are as defined above, esterified with sulfuric acid or phosphoric acid or derivatives thereof, and optionally the compound thus obtained is partially hydrolysed, and optionally any compound thus obtained is converted into its salt or released salts thereof and / or any of the above compounds are prepared in optically active form using optically active starting materials or by resolution of the racemic product obtained. 4. The process of item 1 for preparing compounds of formula (IC): R1-NH-CH-COA1 (CH2) n AND! CO — N- (CH) _m - (CH2h-SOaOH) R 2 (IC) wherein A1, R, R1, ^R2, n have are as defined above, or its pharmaceutically acceptable salts or optically active isomers, characterized in that a compound of the formula IIC R 1 -NH-CH-COA ¹ (CH 2) n CO - N - [CH) _m - (CH 2) t - B ⁵ R 1 R 2 (HC) wherein A ¹ R ^{1, R 2, n and n} are as defined above and B ⁵ represents a halogen or p-toluenesulfonyloxy group, is reacted with sulfite or bisulfite of an alkali · metal, and optionally either converting the resulting compound in its salt or liberated from its salt and / or any of the above compounds are prepared in optically active form using. of optically active reactants or by resolution of the racemic product obtained. 5. Method according to claim 2, characterized in that a compound of formula IIA, wherein the symbols A ^1, R, R ^1, R ^2, n, m, that B ³ have the meanings indicated in point 2, is reacted with performic acid or with a mixture of glacial acetic acid and hydrogen peroxide. 6. The process of item 1 for producing a compound of formula I, wherein it is A ^one hydroxyl, alkoxy having 1-4 carbon atoms, aralkoxy group having 7 to 9 carbon atoms or • a group of formula - (NH - CH2 --CO) _r -Y, wherein Y is hydroxy, (C1-C4) alkoxy, or (C1-C4) aralkoxy, and r is an integer from 1 to 10, B ¹ - SO 2 OH, -OSO 2 OH, or - OPO (OH) 2, R is hydrogen or (C1-C4) -alkyl, R @ ^{1 is} hydrogen, benzyloxycarbonyl, C1 -C4 alkanoyl or benzoyl, R ^{2 is} hydrogen, carboxyl, C 1 -C 4 alkoxycarbonyl or carboxamido, n number 1 or 2, (mt) number 2 or 3, and pharmaceutically acceptable salts or optically active isomers thereof, characterized in that: A compound of formula II wherein A ¹ , R, R ¹ , R ² , n, m and m are as defined above and B ² is a halogen hydroxy group, a group of the formula —SH or —S — S — R ⁵ , wherein R is ⁵ represents a residue obtained by cleavage of group B ² from a compound of formula II, transforms group B ² into group V ^1, and optionally converting any compound thus obtained into its salt or released from its salt and / or preparing any of the above compounds optically active form using optically active starting materials or by resolution of the racemic product obtained. 7. A process according to items 1 and 6 for the preparation of compounds of the general formula IA, wherein A ¹ , R, R ¹ , R ² , n, m and m are as defined in point 6, or their pharmaceutically acceptable salts or their optically active isomers. by oxidizing a compound of formula (IIA) wherein A ¹ , R, R ¹ , R ² , n, m and m are as defined in 6 and B ³ is a group of the formula —SH or —S — S — R ⁶ , wherein R ⁶ represents a group obtained by cleavage of group B ³ from a compound of formula IIA, and any of the compounds thus obtained is optionally converted into or released from their salt and / or any of the above compounds is prepared in optically active form using optically active starting materials or by resolution of the racemic product obtained. 8. A process according to items 1 and 3 for the preparation of compounds of formula IB, wherein A ¹ , R, R ¹ , R ² , n, and m are as defined in 6 and B ⁴ is a group of formula -OSO 2 OH or -OOP (OH) 2, or a pharmaceutically acceptable salt thereof, or an optically active isomer thereof, characterized in that the compound of formula (IIB) wherein A ¹ , R, R ¹ , R ^2, n are as defined above is esterified with sulfuric acid or phosphoric acid. or derivatives thereof, and optionally the compound thus obtained is partially hydrolyzed and optionally any of the compounds so obtained is converted into or released from its salt and / or any of the above compounds are prepared in optically active form using optically active starting materials or by resolution. of the racemic product obtained. 9. A process according to items 1 and 4 for the preparation of compounds of the general formula IC, wherein A ¹ , R, R ¹ , R ² n, m and m are as defined in point 6, or their pharmaceutically acceptable salts or their optically active isomers. A compound of formula IIC wherein A ¹ , R, R ¹ , R ² , n, m and m is as defined above and B ⁵ is halogen is reacted with an alkali metal sulfite or bisulfite and optionally any of the compounds thus obtained converted into its salt or released from its salt and / or any of the above compounds are prepared in optically active form using optically active reactants or by resolution of the racemic product obtained. 10. A method according to claims 2 and 5, characterized in that a compound of formula IIA, wherein A ^1, R, R ^1, R ^2, n have are as defined in paragraph 6, and B ³ has the meaning given in paragraph 7 , is reacted with a formic acid or a mixture of glacial acetic acid and hydrogen peroxide.