CS209858B2 - 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 also includes a process for the production of pharmaceutically acceptable salts or salts. optically active antipodes of said compounds.

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

HžN — CH — COOH

CH2

AND

CH2

CO-NH-CH2-CH2-SO2OH (XXIV) which is characterized by a broad spectrum of therapeutic and preventive efficacy against patho209858 lpg changes, directly or indirectly causing damage to the aerobiospheric genetic adaptation system (AGA'S).

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

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

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

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

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

(e) auditory, olfactory and vocal organs.

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

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

The compounds obtained by the process of the invention are effective against increasingly and increasingly with stress effects (e.g., meteorological effects, significant differences between day and night temperature, increased risk of injury) on shore life by stabilizing adaptation syndrome while averting damage to peripheral tissues of glucocorticoids (for example, damage to the underlying bone mass, etc.). Origin of immunohomoeostasis (increased ability to recognize 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 on the 25-hydroxycholecalciferol-1-α-hydroxylase enzyme of the renal tubules. The broad pharmacological, biochemical and therapeutic effect of the compounds prepared by the process of the invention becomes understandable by this explanation. The areas of action of these compounds are:

A. Vitamin A effects

(a) Pharmacological and biochemical effects

Sulfate-contaminated radioactive elements are increasingly introduced into the rat's cartilage, optionally into the lens, liver and lung tissue of the chicken embryo; radiolabeled phosphorus is increasingly incorporated into rat bone cartilage; chondroitin sulfate synthesis enhancing effect; a beneficial effect on wound healing, optionally on wound healing experimentally impaired by administration of cortisone in rats and dogs; Vitamin A potentiating effect on experimentally ^! rats and chickens induced by hypovitaminoses and, optionally, hyper vitaminoses; sedative effect on stress effects caused by rat ulcer; a beneficial effect on mast cell degranulation; lysosyme production-enhancing effect; action on the trace element farmer (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; Golgi activating effect / calyx cell-forming beneficial effect; Vitamin A concentration-increasing effect

b) Clinical therapeutic effects

Keratoconjunctivitis sicca; Sjorgren's syndrome; rhinolaryngopharyngitis sicca; ozaena; chronic bronchitis, sinobronchltis; 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; erocio colli; reduction of olfactory and taste sense caused by itching.

B. Vitamin A - free effects

(a) Pharmacological and biochemical effects

Effect on blood sugar in terms of transient reduction; escalating effect on phosphaturia; reducing the effect on serum phosphorus; a radio-protective effect, an effect reducing the time required to reach the target in experiments with a labyrinth of inactive animals; a dampening effect on experimentally induced fluorine and cadmium toxicosis; adenosine monophosphate-induced cyclic renal emptying effect; a mitigating effect on the symptoms of experimentally induced lathyrism; decreased sensitivity to histamine; enhancing effect on liver enzyme tyrosine aminotrainsferase 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. Many diseases (eg rhinolaryngopharyngitis sicca) do not show symptoms after two weeks with oral administration of 5 µg three times a day, symptomatic salvation of other diseases such as periodontitis, Sjorgren's syndrome requires one to two months, other diseases (eg spondylosis) ankylopoetica) treatment must take place for a quarter to half a year).

Of the compounds prepared by the process of the present invention, simple methods are possible. to produce any pharmaceutical preventive, cosmetic or veterinary therapeutic preparations. These preparations may contain a single active ingredient or. combination of active substances. The dose of pure active substance is 50 to 500 μξ per day, based on 1 kg of body weight, and is administered in three divided doses.

One tablet contains 2 to 20 µg, preferably 10 µg. active ingredients 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, magnesium stearate, aerated, etc.).

Because of the extremely low dosage, it is expedient to add the active ingredient to the mass from which the tablets are then compressed before granulation, in the form of a solution. In this way, an even distribution of the active ingredient is achieved. Moreover, the small amount 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. The active substances are stable; therefore, the tablets can be supplied to the store without an expiry date. The active substance content of retarding tablets or spansular capsules may be in the range of 10 to 20 pg. . For injectable preparations, the effective dose per ampoule is 5 to 10 μξ, 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. The stated concentration of active substance · have a detrimental effect on either the tissue or the blood vessels ^hundred n ^{y. Of} active ^la t ^ky can be administered as an ⁱ n ^f millen. Suppositories containing ^{y s 2} and ^20, preferably about 10 μ% 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 μ 1 / g. The ointment base may be hydrophilic or hydrophobic and contains conventional ingredients such as cholesterol, paraffin, glycerin, lanolin, cocoa butter, linseed oil, etc. The active ingredients may also be formulated as aerosol formulations, the active ingredient content being range. 0.1 to 1 pg / g. In the form of a perlingual tablet, the tablet contains 10 .mu.g of active substance, the disintegration time being 0.5 to 1 hour. 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 action injectables may be formulated using either high molecular weight polymers or. salts of compounds of the invention formed with high molecular weight organic bases (e.g. histone, protamine), wherein 1 ampoule contains 10 to 20 µg. active substance. Powders for cosmetic or skin treatment are prepared with conventional carriers, for example talc, and contain 0.1 to 1 pg of active ingredient per g powder. For ophthalmology, the compounds of the invention are formulated as drops, optionally as tear-miscible or non-tear-miscible ointments; . the active ingredient content of these preparations is 0.1 to 1 µg. In children, the compounds of the invention should be administered at a dose of about 0.3 µg per kg body weight. weight.

Sterile preparations are conveniently produced by sterilization filtration. .

Desired preventive pharmacological or cosmetic effect. The above-described preparations can be increased and supplemented by numerous combinations, as the following biologically active ingredients are considered and the use of these substances can be mentioned first and foremost:

Viiamrny A, C, E and K, trace elements, cortisone and its. derivatives, progresterone, thyroid hormones, radical and immunosuppressive agents, psychopharmaceuticals, especially soothing agents, timoleptics, organic silicon compounds, gerontological agents, blood cholesterol lowering agents, oral antidiabetics, anti-inflammatory agents, antihistamines, etc. The ingredients are generally the same as the usual therapeutic dose using these. of the substances themselves.

The compounds produced by the process according to the invention can also be used as an additive in nutritional or medicinal mixtures. On the one hand, they trigger an increment to. weight, both reduce the need for vitamin A,. possibly 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 expediently 200 pg / kg per day. When admixed with feed · .odpovídá this dose concentration of approximately 1-2 pg / / k ^g POPR ^and fall ^of 1 to ² m ^g / ton ^{of feed,} i.e. ^{a concentration of} from 0.001 to 0.002 ppm. Due to these very low concentrations, their use as feed additives is extremely economical. Preferably, these compounds are added to the vitamin masterbatches or used in microcapsules containing the compounds of the invention together with other needed ones. - feed additives. The compounds according to the invention can also be used in drinking water for feeding cattle, in salt for licking and optionally in the form of a spray.

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

It is a common feature of the structure of all compounds of formula I that they contain a dicarboxylic acid substituted in the α-position, or a derivative thereof substituted in other positions, linked through its «-carboxyl group by bonding the acid amide to the primary or secondary - an alkylamine which, in addition to the various substituents on its alkyl ™ side chain, contains a strongly acidic group in the ω-position.

The process according to the invention for the preparation of the compounds of the formula I, their pharmaceutically acceptable salts and the optical isomers is carried out by acylating the? -Amino group of the compound of the formula II to introduce the radical R1;

HzN — CH — COOH

I (OH2) '

AND

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

R 2 (H) wherein

R, R 2, n, there are above- defined above and B2 represents a group of formula --SO2 OH, -OSO2OH, -OPO (OH) 2 or -S-S-R ⁴ wherein R ⁴ represents a residue obtained by removing the group B ² -OC the compound of formula (II) and any of the compounds thus obtained are optionally converted into their salt or released from their salt, and / or - any of the above compounds are prepared in an optically active form using optically active reactants or thereby The process according to claim 1, characterized in that the racemic product obtained is resolved.

In a preferred embodiment, the compound of formula II, preferably β-L-glutamyltaurine, is subjected to acetylation or benzoylation. In the preparation of salts of the compounds of formula (I), the compound of formula (I) is reacted with an alkali metal or alkaline earth metal hydroxide or carbonate or an organic base.

Although compounds of formula II containing a free amino group and a free N-carboxyl group are used as starting compounds, partially substituted derivatives are obtained. Acyl derivatives, for example acetyl, benzoyl or p-toluyl derivatives, can thus be obtained by known methods.

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

Example 1

Dissolve 25.4 mg (0.1 mmol) of χ-L-glutarnyltaurine in 100 μΐ of 2 N sodium hydroxide solution. The solution is cooled to 0 ° C and then a total of 36 μΐ of acetic anhydride and 180 ° -μΐ of 4N sodium hydroxide solution are added in three portions every 5 minutes with vigorous stirring. The alkaline solution was diluted to 2 ml with water and then allowed to stand for 12 hours at room temperature. To remove sodium ion, the solution is applied to an ion exchange column (1 cm, 10 cm Dowex 50) and eluted with water. The 50-ml eluate was collected and evaporated under reduced pressure at 35 ° C. The product obtained is N-acetyl-γ-L-glutamyltaurine. This product is dissolved in water and purified by paper electrophoresis at pH 6.5. The relative mobility relative to cysteic acid is 1.22.

Rf (mixture of n-butanol, pyridine, glacial acetic acid and water 15: 10: 3: 12) = 0.25.

Example 2

25.4 mg (0.1 mmol) of χ-L-glutamyllaurine is benzylated using 13 µl of benzoyl chloride following the procedure of Example 1 for acetylation. Removal of the sodium ions on the Dowex ion exchange column and evaporation of the eluate gave N-benzoyl-γ-L-glutamyltaurine, which was purified by paper electrophoresis at pH 6.5. The relative mobility relative to cysteic acid is 1.06.

Rf (mixture of n-butanol, pyridine, glacial acetic acid and water 15: 10: 3: 12) = 0.47.

Claims (3)

OBJECT OF THE INVENTION 1. A process for the preparation of novel amino acid derivatives of formula I, R1-NH-CH-COOH [CH2] n CO - N - (CH) m - (CH 2) _{t -} B1 R 1 R 2 (I) wherein is Bi group of formula —SO2OH, —OSO2OH, —PO (0H) 2, or —S — S — R3, wherein R ³ represents a residue obtained by removing the group B of the compound of formula I R is hydrogen or (C1-C4) -alkyl, R 1 is C 1 -C 4 alkanoyl or benzoyl, R ^{2 is} hydrogen, C 1 -C 4 alkyl, carboxyl, C 1 -C 4 alkoxycarbonyl, phenoxycarbonyl or carboxamide, n number '1, 2, 3 or' 4, m number '1 , 2 or 3 at 1, 2 or 3. or a pharmaceutically acceptable salt thereof or an optically active antipode thereof, characterized in that the .alpha.-amino group of the compound of formula II is acylated to introduce a radical R @ 1; HzN — CH — COOH 1 (CH2) n CO - N - (CH) m - (CH 2) t - B2 R 2 (Π) where R, R ² , n, 'and m' are as defined above and B2 represents a group of the formula —SO2OH, —OOO2OH, —OPO (OH) 2, or —S — S — R4, wherein R4 represents a radical obtained by cleavage of Formula II and any of the compounds thus obtained are optionally converted into or released from their salt, and / or any of the compounds thus obtained are prepared in optically active form using optically active reagents or by resolution of the racemic product obtained. 2. A method according 'to claim 1, wherein the' compound of the formula · 'II wherein R, R ^2, n, m, B2 are those defined in paragraph 1, preferably χ L-glutamyltaurin, acetylated or benzoylizes, 3. The process of item 1 for producing compounds of formula I wherein B1, R, R1 are as defined in item 1 and R2 is hydrogen, carboxyl, C1 -C4 alkoxycarbonyl or carboxamido, n is 1, or 2 and. (m + ie is 2 or 3, or pharmaceutically acceptable salts or optically active antipodes, characterized in that to introduce the radical, R1 is acylated .alpha.-amino this compound • the general formula II where R, ^R2 n, m, t and B ² are as defined above.