CS209859B2 - Method of making the new derivatives of the amino acids - Google Patents

Description

The subject of the invention is a process for producing new ones. amino acid derivatives, some of which have valuable pharmacological properties, others are intermediates for the production of substances with valuable biological or pharmacological effects. All compounds obtained by the process of the invention are novel.

The compounds which can be prepared by the process according to the invention can be represented by the general formula I

R ¹ -NH-CH-COOH _{(CH2) n}

CO-NH- (CH) _m - ^(B-1 CHzJt

Ø ² (I) where is

B ^{1 is a} group of formula -SO 2 OH, -OSO 2 OH, or -OPO (OH) 2 or -S-S-R ³ , wherein R ³ is a residue obtained by cleavage of group B ¹ from a compound of formula I,

R ^{1 is} hydrogen, C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl, halogen-substituted phenoxycarbonyl, C 1 -C 4 alkoxy or nitro, C 1 -C 4 alkanoyl or benzoyl group

R ² is hydrogen, alkyl having 1 to 4 carbon atoms or a carboxyl group, an alkoxycarbonyl group having 1 to 4 carbon atoms in the alkoxy part or fenoxykarbortylovou or carboxamido, n is 1, 2, 3 or 4, m is 1, 2 net 3 at number 1, 2 or 3.

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

Among the compounds prepared by the process according to the invention, owing to its biology, in particular, χ-L-glucamyl taurine of the formula XXIV must be mentioned,

H2N — CH — COOH

CH2

CH2

CO-NH-CH2-CH2-SO2OH (XXIV) which is characterized by a broad spectrum of tera209859 ipeutic and preventive activity 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 forming 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, mouth 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) bodies involved in the regulation of ion management (trans-epithelial transport system: intestinal villi, renal ducts),

- dj teeth, 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 process of the invention furthermore have the following AGAS-related functions: radiation protection, wound healing effect and generally activating roesenchyma, protection against the ever increasing risk of infection and contamination of skin and mucous membranes (formation of wet mucosal lysozyme, activation cilia lining in the airways, etc.), increased protection against infectious diseases caused by viruses and fungi.

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. glucocorticoids (for example, damage to the connective tissues, damage to the underlying bone mass, etc.).

Said compounds act in part directly, in part by controlling the metabolism of vitamin A, by producing vitamin A metabolites of a more polar 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 as follows:

A. Vitamin A effects

(a) Pharmacological and biochemical effects

The radiolabeled sulphate is increasingly incorporated into the bone cartilage of the rat, optionally into the lens of the eye, liver and lung tissue of the chicken embryo; radiolabeled phosphorus is increasingly incorporated into rat bone cartilage; chondroitin sulfate synthesis enhancing effect; a beneficial effect on wound healing or wound healing, optionally exacerbated by administration of cortisone in rats and dogs; Vitamin A potentiating effect in 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

I s ·,

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 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; itching caused by a decrease in olfactory and taste sense.

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; 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; decreased sensitivity to histamine; enhancing effect on liver enzyme tyrosine aminotransferase activity.

bj Therapeutic effects

Slight radiation damage; local lack of dye in the skin; muscular hypotonia; a psychopathetic effect; beneficial effect on involution and gerontological conditions as well as on. mnesťcké funkce; tendency to scar fibroma formation; spondylosis ankylopoetica; musculoskeletal disorders caused by wear; sclerotic fundus; amyloldose; morphea; fibrocystic mastopathy.

When administering the compounds of the invention, the treatment time varies greatly. In many diseases (eg rhinolaryngopharyngitis siccaj, oral administration of 5 µg three times a day does not show symptoms after only two weeks, for symptomatic recovery of other diseases (eg periodontitis Sjorgren's syndrome) requires one to two months, in other diseases (eg spondylosis) ankylopoetica), treatment must be done 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 is 50 to 500 μξ per day, based on 1 kg of body weight, given in three divided doses.

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

Because of the extremely low dosage, 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 active substance content 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, so that the tablets can be supplied to the market without an expiry date. The content of the active substance in retarding tablets and in the case of spansular capsules can be in the range of 10 to 20 µg. For injectable preparations, the effective dose per ampoule is 5-10 g, 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 have no deleterious effect on either the tissue or the vessel walls. The active ingredients may also be administered as an infusion. Suppositories contain from 2 to 20, preferably about 10, g of active ingredient and are made from cocoa butter or synthetic waxes or fats suitable for this purpose. The active substance content of cosmetic ointments or ointments intended for skin healing is 0.1 to 1 pg / g. The ointment base may be hydrophilic or hydrophobic and contains conventional ingredients, for example, cholesterol, paraffin, glycerin, lanolin, cocoa meat, linseed oil, etc. The active ingredients may also be formulated as aerosol preparations, the active ingredient content being also in the range of 0, 1 to 1 μ ^^. In the form of a perlingual tablet the 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 compound per g of polymer. Delayed-release injectables 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), each ampoule containing 10-20 µg of active ingredient. Cosmetic or skin treatment powders are prepared with conventional carriers, for example talc, and contain from 0.1 to 1 µg of active ingredient per gram of powder. For ophthalmic medicine, 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 / g. Children should be. the compounds of the invention are 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 primarily the following substances and protect their use ^:!

Vitamins A, C, E and K, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radiomimetic and immunosuppressive agents, psychopharmaceuticals, especially soothing agents, timoleptics, organic silicon compounds, gerontological agents, lowering agents blood cholesterol, oral antidiabetics, prot ^; inflammatory substances, antihistamines, etc. The dosage of these active ingredients is generally the same as the usual therapeutic dose using the substances 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 po1

The use of the compounds of the invention as feed additives is expediently 200 µg / kg daily. When mixed with feed, this dose is approximately 1 to 2 µg / kg or 1 to 2 mg / t feed, i.e. a concentration of 0.001 to 0.00.2 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 used in microcapsules containing the compound of the invention together with other necessary feed additives. The compounds according to the invention can also be used in drinking water for cattle feeding, in licking salts or optionally in the form of a spray.

In veterinary medicine, the compounds of the invention have similar fields of application 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 at the position «or a derivative thereof substituted at other positions, linked via its ω-carboxyl group by bonding the acid amide to a primary or secondary alkylamine which The various substituents on its alkyl side chain contain 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 salts and their optical isomers is carried out by reacting a compound of the formula II,

R1-CH-COOH

O = C- (CH2n (Π) where

R ^{1 and} n have the above meanings, is reacted with a compound of formula III ·

H ₂ N- (CH) _m - (CH ₂ ) _t -B ² R ² (III) or a salt thereof, wherein

R ^2, there are as defined above and

B ² represents a group of the formula -SO 2 OH, -OSOaOH, -OPO (OH) 2 or -S-S-R ⁴ , where

R ⁴ represents a residue obtained by cleavage of a group

B ² from a compound of formula III, and any of the compounds thus obtained are optionally converted into or released from their salt and / or any of the compounds obtained is prepared in optically active form using optically active reagents or by resolution of the racemic product obtained.

The process according to the invention consists in reacting pyrrolidine-1-one-S-carboxylic acid ("pyroglutamic acid") or piperid-1-one-6-carboxylic acid with, for example, taurine, homotaurine, N-methyltaurine etc., or other amines containing a strong acidic functional group, or with its alkali salts or with salts formed with a tertiary base, in which the lactam ring opening reaction forms ω-amides.

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

The method according to the invention is illustrated in more detail by the following example:

4.43 g (10 mmol) of the dicyclohexylamine salt of carbobenzyloxy-L-pyroiglutainioic acid (Liebigs Annalen 840, 145, 1961), 1.25 g (10 mmol) of taurine and 0.84 g (10 mmol) of sodium bicarbonate are dissolved. in 50 ml of water. The resulting solution was heated for 4 hours (or allowed to stand at room temperature for 24 hours) and then evaporated under reduced pressure. The residue was dissolved in water and the solution was applied to an ion exchange column (Dowex 50), which was then eluted with water. The eluate obtained is evaporated. The remaining material is catalytically hydrogenated with shaking in the presence of 0.5 g of activated carbon containing 10% palladium catalyst. The catalyst is preferably added in 2 portions of 0.26 g. When hydrogen uptake ceases, the solution is filtered and then concentrated at 30 ° C under reduced pressure. The oily residue is dried in a desiccator with phosphorus pentoxide to give a product which is very soluble in water, insoluble in ethanol. By adding small amounts of water and ethanol in small portions, the product can be recrystallized. Recrystallization from ethanol-water gave 2.03 g of γ-L-glutamyltaurine. The crystalline crude product melts at 202-204 ° C.

Claims (2)

SUBJECT VYNALEZU 1. A process for the production of new amino- R1-N-CH-COOH acids of formula I, O = C- (CH 2) n R1-NH-CH-COOH (CH ₂ ) " CO-NH- (CH), _n- (CH 2) t -B ¹ R ² (I) wherein is R 1 is hydrogen, C 1 -C 4 alkoxycarbonyl, C 7 -C 9 aralkoxycarbonyl, phenyloxycarbonyl optionally substituted by halogen, C 1 -C 4 alkoxy or phenyl-substituted nitro, alkanoyl C 1 -C 4 or benzoyl, R ^{2 is} hydrogen, C 1 -C 4 alkyl, carboxy, C 1 -C 4 alkoxycarbonyl, phenoxycarbonyl or carboamido, B ^{1 is a} group of the formula -SO 2 OH, -OSO 2 OH, -O-OOH, or -S-S-R ³ , wherein: R ³ represents a residue obtained by cleavage of group B ¹ from a compound of formula I, n number 1, 2, 3 or 4, m number 1, 2 or 3, and at number 1, 2 or 3, or a pharmaceutically acceptable salt thereof active antipodes, characterized in that the compound of formula (II), (II) wherein R ^{1 and} n have the above meanings, is reacted with a compound of "formula IIII H 2 N - (CH) _m - (CH 2) _t —B ² R ² (ΠΙ) or a salt thereof, where R ^2, there are as defined above and B ² represents a group of the formula -SO 2 OH, -OSO 2 OH, -PO (OH) 2 or -S-S-R ⁴ , where R ⁴ represents a residue obtained by cleavage of group B ² from a compound of the formula ΠΙ, and any of the compounds thus obtained is optionally converted into or released from its salt and / or any of the compounds obtained is prepared in optically active form using optically active reaction components or by resolution of the racemic product obtained. 2. Method according to claim 1, characterized in that a compound of formula II wherein R ^{1 and} n are as defined in paragraph 1, preferably, pyroglutamic acid is reacted with taurine or homotaurínem.