CS209860B2 - Method of making the new derivatives of the amino acids - Google Patents

Description

The invention relates to a process for the production of novel amino acid derivatives, some of which are derived from amino acids. characterized by valuable pharmacological properties, other? then they 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,

H 2 _N -CH-COGI 1 (CH 2) _n

CO - NH - (CH _{2 m} - (C 2 H 2 -, - S Cl)?

R ^{2 is} hydrogen, C 1 -C 4 alkyl, carboxyl, C 1 -C 4 alkoxycarbonyl or carboxamide, n number 1, 2, 3 or 4, m number 1, 2 meto 3 and n number 1, 2 or · 3,

The invention also encompasses a process for the production of pharmaceutically acceptable salts or a process for the preparation of a pharmaceutically acceptable salt. of optically active antipodes mentioned by means. Of the compounds prepared by the process of the invention,? in view of its therapeutic effects, it is particularly necessary to mention ydlrgltttsmyltararin of formula XXIV ,.

HžN — CH — CODH

CH ,:

Cl-b

CO — NH — CH2 — UJW-SWHF which is characterized by a wide spectrum of therapeutic and preventive efficacy against pathological changes having a direct or? indirect cause in the damage to the aerobiospheric genetic adaptation system (ACASj.

To clarify the term ACAS are? The most important tissues and organs making up this system are listed below:

aj All biological boundary surfaces that are in contact with the outside air as the biosphere (skin and skin formations, cornea and conjunctiva, oral and esophagus, airways and lungs j,

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 ion management (trans-epithelial transport system: intestinal villi, renal ducts), denture teeth, necessary for pulverizing food and fixed roots in dental beds;

(e) auditory, olfactory and vocal organs.

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

The compounds prepared by the process of the invention furthermore have the following AGAS-related functions: radiation protection, wound healing effect and generally activating mesenchyrin, protection against the ever-increasing risk of infection and contamination of skin and mucous membranes (formation of wet mucosal lysozyme, activation ciliary linings 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 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 the connective tissues, damage to the underlying bone mass, etc.). Emergence of immunohomoestasis (an 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 paratbormone on the 25-hydroxycholecalciferol-1-a-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

and). Pharmacological and biochemical effects

Sulfate-labeled radioactive elements are increasingly incorporated into rat bone cartilage or lens, liver and lung tissue of chicken embryo, respectively; radiolabeled phosphorus is increasingly incorporated into rat bone cartilage; chondroitin sulfate synthesis enhancing effect; a beneficial effect on wound healing or wound healing, optionally impaired by the 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; a beneficial effect on mast cell degranulation; lysosyme 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 on granuloma vesicle formation induced by the local action 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

bj Clinical therapeutic effects

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

B. Vitamin A-free effects as well as pharmacological and biochemical effects

Effect on blood sugar in the sense of a 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; 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; decreased sensitivity to histamine; enhancing effect on liver enzyme tyrosine transferase activity.

(b) therapeutic effects

Slight radiation damage; local lack of dye in the skin; muscular hypotonia; psychoenergetic effect; a beneficial effect on involutionary and gerontological states as well as on mnestic functions; tendency to scar fibroma formation; spondylosis ankylopoetica; 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

299860 (for example in rhinolaryngopharingitis sicca) there are no symptoms after two weeks of oral administration 5 times a day, symptomatic recovery of other diseases (eg periodontitis, Sjorgren's syndrome) takes one to two months, in other diseases (eg spondylosis ankylopoetica) treatment run 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 body weight, and is administered in three divided doses.

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

Because of the extremely low dosages, it is expedient to add the active ingredient to the mass from which the tablets are then compressed, prior to granulation, in the form of a solution. In this way, an even distribution of the active ingredient is achieved. Moreover, the low content of active substance makes it possible to produce the active substance - 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 supplied to the market without an expiry date. The active substance content of retarding tablets or spansular capsules may range from 10 to 20 μg.

For injectable preparations, the effective dose per ampoule 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, the active compounds do not have a deleterious effect on either the tissue or the vessel walls. The active ingredients may also be administered as an infusion. Suppositories contain from about 2 to about 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 the active substance in cosmetic ointments or in ointments intended for skin healing is 0,1 to 1 μg / g. The ointment base may be hydrophilic or bydrophobic and contains conventional ingredients, for example, cholesterol, paraffin, glycerin, lanolin, cocoa butter, linseed oil, etc. The active ingredients may also be formulated as aerosol formulations, the active ingredient content being also in the range of 0. 1 to 1 / zg / g. In the form of a perlingual tablet, 1 tablet contains 10 μg of active substance, the disintegration time is 0.5 to 1 hour. The sustained release polymers can be prepared, for example, as a suspension and contain 1 to 5 µg 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 molecular weight organic bases (e.g., histone, protamine), each ampoule containing 10 to 20 µg of the active ingredient. for the treatment of the skin, they are prepared with customary carriers, for example talc, and contain from 0.1 to 1 [mu] g of active ingredient in 1 g of powder For ophthalmology, the compounds of the invention are formulated as drops or tear-miscible ointments; The active substances in these preparations are 0.1 to 1 [mu] g, and the compounds of the invention are to be administered to children in a dosage of about 0.3 [mu] g / l kg of 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. Among the biologically active additives that may be considered are, in the first place, the following substances and their use:

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

The compounds produced by the process according to the invention can also be used as an additive in nutritional or medicinal mixtures. They cause weight gain, reduce the need for vitamin A or improve its metabolism. Further, the compounds of the invention increase the resorption of trace elements and their level in the blood. When the compounds of the invention are used as feed additives, the oral dose is conveniently 200 µg / kg daily. When mixed with the feed, this dose corresponds approximately to a concentration of 1 to 2 µg / kg 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 of the invention as feed additives is extremely economical. Preferably, these compounds are added to the vitamin premixes or are used in microcapsules containing the compounds of the invention together with other necessary feed additives. The compounds of the invention are also

2 »» S60 can be used in drinking water to feed cattle, licking salt or spray.

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

A common feature of the structure of all compounds of formula (I) is that they contain a .alpha.-carboxylate substituted by a .alpha.-carboxylate group by bonding the acid amide to a primary or secondary alkyianadine which is substituted at the .alpha. besides various substituents on its side alkyl chain, it contains a strongly acidic group in the ω-position.

The method · of the invention for production of new amino acid derivatives of formula I wherein R ^2, n, m · T have the abovementioned meaning, or for the manufacture of pharmaceutically acceptable salts or optically active antipodes is carried out by reacting a compound of formula II

WHAT. _t rcr> ^{! 1 CU} RCM _4> = ^n-C ° (II) wherein n is as defined above and Me is sodium or potassium ·, · allowed to react with a compound; of formula (III), hal - (CH) _m - (CH 2) - SO 2 OH

R ² (• III) wherein m, t and R ² have the above meanings and Hal is halogen · since with the reindeer, and the resulting compound of »vzorce- IV

lf

(CM ^ _:

R ² · (IV) where ·

R ^2, n have are as defined above, and partially bydrolyzuje The resulting compound of formula V

where

R ^2, m, mat are as defined above, is treated with hydrazine. and the resulting compound of formula I wherein R ^2, n "mat are as defined above ,, is optionally converted in its salt or liberated from its salt and / or; any of the above compounds are prepared in optically active form using optically active reagents or by resolution of the racemic product,

To prepare a salt of the compounds of the invention, the compound of formula (I) is reacted with hydroxide or carbonate. alkali metal or alkaline earth metal or organic base.

The process according to the invention is illustrated in more detail by the following example;

0.48. g clay mmol] carbobenzylbxy-.alpha.] -L-glucamyl-.beta. Acad. Sci. Hung. 65 p. 375 · ,. 1970) was dissolved in ethyl acetate. The resulting solution was cooled with ice-cold. At 0 [deg.] C., the solution is firstly treated with 0 [mu] g of mmol of eystamine in 1 ml of dimethylformamide, then 0.14 ml of mmol is added dropwise: turtethylamiir. the precipitate begins to precipitate. Reaction mixture; The mixture is allowed to stand in ice water for one day, then at room temperature for one day, and finally diluted with a 1: 1 mixture of ether and ethyl acetate. The precipitate is centrifuged several times. Wash first with a 4: 1 mixture of ether and ethyl acetate, then ether. After drying with sulfuric acid, the precipitate is washed three times with 1 ¹ N hydrochloric acid, twice with water, twice with saturated sodium bicarbonate and finally kydrogenubličitamci twice with water, dried with sulfuric acid under reduced pressure. 0.35 g. Of carbobenzyloxy-cr-1209860 is obtained

-glutamyl-cysteine-glycine ethyl ester, corresponding to a yield of 85%.

Analysis for C 18 H 25 O 5 N 3 S (M = 411.4): calculated:

5 (2.6% C, 6.1% H, 7.8% w / w S;

found:

C 53.4%, H 6.5%, S 7.7%

The infrared spectrum shows the following maxima for the characteristic groups:

NH 3310 cm ^-1 ,

C = O (COOCH 2 H 5) 1748 cm ^-1 ,

C = O (Z) 1690 cm ^-1

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

100 mg of carbobenzyloxy-.alpha.-glutamyl (γ-cystamine glycine ethyl ester) was dissolved in 2 ml of glacial acetic acid and 0.5 ml of 30% hydrogen peroxide was added and the reaction mixture was allowed to stand for 4 hours while cooling with ice water. After dilution with water, the reaction mixture is lyophilized to give the title product as a foam, 0.11 g of carbobenzyloxy-α-L-glutamyl (χ-taurine) glycine ethyl ester.

Yield: 95%.

Claims (1)

Subject A process for the preparation of novel amino acid derivatives of the formula I, II 2 N —CH-COOH 11 CO — NH- (CH) _m - (CH2- _t -SO2OH) R ² ω where it means R ^{2 is} hydrogen, C 1 -C 4 alkyl, carboxyl, C 1 -C 4 alkoxycarbonyl or carboxamide, n number 1, 2, 3 or 4, m number 1, 2 or 3 and t number 1, 2 or 3, or a pharmaceutically acceptable salt thereof, or an optically active antipode thereof, wherein the compound of formula (II): OF THE INVENTION O 11 C (CH 2 -C 2 O); wherein n is as defined above and Me is sodium or potassium, reacts with a compound of formula III, hal- (CH) _m - (CH2) _t -SO2OH R2 (III) wherein R Mata ² have the abovementioned meaning and Hal represents halogen, or a salt thereof and the resulting compound of the general pattern IV O li '- ...... C0 _x ^ CH U ~~ (CH) ú (CHJrSO.OH co I 1 1 ₉ ¹ * CzO R ^{from L} (IV) where R ^2, n have are as defined above, are partially hydrolysed and the resulting compound of formula V, CO _X N-CH-COOH ^C0 (CH3 n CO-NH-iCH 2 CH 2 SO 4 OH ^R (V) where R ² , n, m and m are as defined above, are treated with hydrazine and the compound of formula I thus formed, wherein R ² , n, m and m is as defined above, 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 reagents or resolution of the racemic product.