CS209863B2 - Method of making the new derivatives of the amino acids - Google Patents

Description

It is an object of the present invention to provide novel amino acid derivatives, some of which possess valuable pharmacological properties, while others are intermediates for the production of substances having advantageous biological or pharmacological effects. All compounds prepared 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-CO-A ¹ (CH 2) _n

CO - N - (CH 2) _{m -} (CH 2) _{t -} SC 2 H

R (I), where is

A ^one hydroxyl, alkoxy having 1 to 4 carbon atoms or aralkoxy of 7 to 9 carbon atoms, optionally substituted with at least one nitroskuplnou and / or halogen and / or alkoxy having 1 to 4 carbon atoms,

R is hydrogen or (C1-C4) -alkyl,

R ^{1 is} hydrogen, C 1 -C 4 alkoxycarbonyl, phenyloxycarbonyl or C 7 -C 9 aralkoxycarbonyl optionally substituted by at least one C 1 -C 4 alkoxy and / or nitro and / or halogen , n is 1, 2, 3 or 4, m is 1, 2 or 3 t is 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 which can be prepared by the process according to the invention, owing to its biological effects, it is necessary to mention in particular χ-L-glutamyltaurine of the formula XXIV,

H2N — CH — COOH

CH2

CH2

CO — NH — CH2 — CH2 — SO2 OH (XXIV) which is characterized by a broad spectrum of therapeutic 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:

(a) All biological boundary surfaces in contact with the external air as the 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) bodies involved in the regulation of ion management (trans-epithelial transport system: intestinal villi, 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 bioogical or therapeutic effect on the above-mentioned organs or tissues of the AGAS system.

The compounds produced by the process 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 skin and mucous membranes (formation of wet mucosal lysozyme, activation rasp linings in the respiratory tract, etc.), increased protection against infections caused by beliefs 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 by stabilizing adaptation syndrome while averting damage to peripheral tissues by glucocorticoids such as damage to the connective tissues, damage to the underlying bone, 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 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. 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:

Vitamin A effects

(a) Pharmacological and biochemical effects

The sulphates labeled with the radioactive element are increasingly incorporated into the bone cartilage of the rat, optionally into the lens of the 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; 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 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 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 hunts; cortisone antagonist; beneficial effect on wound healing of skin and mucosa during surgery; erosio colli; a reduction in the olfactory and taste sense caused by itching.

B) Effects without Vitamin A

(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; escalating effect on adenosine monophosphate-induced cyclic renal emptying; a mitigating effect on the symptoms of experimentally induced lathyrism; reducing sensitivity to histamine; enhancing effect on liver enzyme tyrosine aminotransferase 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; phyrocystic 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 when given orally at 5 µg three times a day, symptomatic recovery of other diseases (eg periodontitis, Sjorgren's syndrome) takes one to two months, other diseases (eg spondylosis) ankylopetica must be treated 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 ng per day, based on 1 kg of body weight, and is administered in three divided doses.

One tablet contains 2 to 20 μξ, preferably 10 μξ of active ingredient, and in addition biological inert carriers such as milk sugar, starch as well as conventional tabletting aids (granulating and glidants such as polyvinylpyrrolidone, gelatin, talc, magnesium stearate) , 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. The low active substance content makes it possible to produce the active substance - even when producing many millions of tablets a year - only on a laboratory scale, at a price that is available to every patient. Since the active substances are stable, the tablets can be marketed 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 vial is 5 to 10 μg and, where appropriate, the preparation may 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 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 active ingredient content of the cosmetic ointment or skin healing ointment is 0.1 to 1 µg / g. The ointment matrix may be hydrophilic or hydrophobic and contains conventional ingredients, for example, cholesterol, paraffin, glycerin, lanolin, cocoa butter, 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 µg / g. 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 1-5 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 10-20 µg of the active ingredient. Powders for cosmetic or skin treatment are prepared with the usual carriers, for example talc, and contain 0.1 to 1 μ% of active ingredient per gram of powder. For ophthalmology, the compounds of the invention are formulated as drops, optionally as ointments miscible or immiscible with tears; the active ingredient content of these preparations is 0.1 to 1 µg / 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, in the first place, the following substances and protect their use:

Vitamins A, C, E and K, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radiomimetics and immunosuppressive agents, psychopharmaceuticals, especially soothing agents, timoleptics, organic silicon compounds, gerontological preparations, cholesterol lowering agents in the blood, oral antidiabetics, anti-inflammatory agents, antihistamines, etc. The dosage of these active ingredients is generally the same as the usual therapeutic dose when using the agents 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 using the compounds of the invention as feed additives, the oral dose is conveniently 200 ng / kg daily. When mixed with feed, this dose is approximately 1 to 2 µg / kg or 1 to 2 mg / t of feed, i.e. 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 used in microcapsules containing the compounds of the invention together with other feed additives needed. The compounds according to the invention can furthermore be used in drinking water for cattle feeding, in licking salts, 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 the compounds of formula I that they contain a dicarboxylic acid substituted at even other positions, linked via its ω-carboxyl group by bonding the acid amide to a primary or secondary alkylamine containing, in addition to various substituents on its side alkyl chain, ω-position group of strongly acidic character.

The inventive method for the manufacture of compounds of formula I and their pharmaceutically acceptable salts and their optical antipodes is carried out by reacting a compound of formula II R5- ^NH-CH-CO-1 (CH) n

R ³ z

CO — N \

R ⁴ (Π) where

A ¹ and n are as defined in formula I,

R ³ represents hydrogen or alkyl with 1 to 4 carbon atoms,

R ⁴ represents an alkali metal and

R ⁵ has the same meaning as R ¹ except hydrogen, is reacted for alkylation with C 2 -C 6 alkanesulfonic acid or C 2 -C 6 alkali metal haloalkyl sulfonate and optionally from the compound of formula I thus formed the protecting group R ⁵ is cleaved and / or the compound thus obtained is converted into or released from the salt and / or is prepared in optically active form using optically active reactants or by resolution of the racemic product obtained.

For the preparation of salts, a compound of formula (I) wherein A ¹ , R, R ¹ , n, and m are as defined above is reacted with an alkali or alkaline earth metal hydroxide or carbonate or an organic base.

In a preferred embodiment, the compound of formula II is reacted with an alkali metal salt of bromoethanesulfonic acid or bromopropanesulfonic acid. It is also possible to start with glutamine or asparagine or substituted derivatives thereof (with the exception of acid amides). In this case, one of the hydrogen atoms of the acid amide having an acidic character is substituted, for example, with sodium metal, and the compound thus obtained is converted to a compound of formula I by reaction with 2-bromoethanesulfonic acid or its salts or alkanesulfonic acid. α-aminodicarboxylic acid amides, for example ω-vinylamide or ω-amide, in which the amine component is a three-membered cyclic compound containing a nitrogen atom (aziridine). Both types of compounds may be treated with an alkali metal sulfite or bisulfite to form compounds of Formula I.

To prepare salts of the compounds of the invention, the compound of formula (I) is reacted with an alkali metal 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:

3.02 g (10 mmol) of sodium carbobenzyloxy-L-glutamine (Liebigs Annalen 640, 145, 1961) are dissolved in 50 ml of dimethylformamide, and an oil suspension containing 12 mmol of sodium hydride is added thereto, and the mixture is then heated. A solution of 2.11 g (10 mmol) of sodium bromoethanesulfonic acid in 50 ml of dimethylformamide is added dropwise to the solution, and the mixture is heated for a further 2 hours. The dry substance was dissolved in water, the solution was applied to an ion exchange column (Dowex 50), which was then eluted with water, the eluate was evaporated under reduced pressure, and the residue was dried with potassium hydroxide. it is catalytically hydrogenated in the presence of 0.5 g of activated carbon containing 10% palladium as catalyst. 25 g. After hydrogen congestion 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 γ-L-glutamyltaurine which is very soluble in water but insoluble in alcohol. By adding small amounts of water and alcohol in small proportions, the product can be recrystallized. After recrystallization from ethanol and water to give 1.5 g of L-χ glutamyltaurinu melting point ranging from 219-220 ° C, [a] _D ²⁰ = '- | -14 ° (water, c = 1.02 ).

An analogous procedure yields:

χ-L-glutamyl-N-methyltaurine

In paper electrophoresis, the resulting product travels both at pH 6.5 and at pH 1.8 in the anode direction. The relative mobility relative to cysteine acid is at pH 6.5, 0.68, at pH 1.8 0.49.

_Rf (n-butanol: pyridine: glacial acetic acid: water 15: 10: 3: 12) = 0.16. β-L-aspartyltaurine

In paper electrophoresis, the resulting product travels at both pH 6.5 and pH 1.8 to the anode. The relative mobility relative to cysteine acid is at pH 6.5, 0.77, at pH 1.8 0.58.

_Rf (n-butanol: pyridine: glacial acetic acid: water 15: 10: 3: 12) = 0.16. Β-L-aspartylhomotaurin

In paper electrophoresis, the resulting product travels both at pH 6.5 and at pH 1.8 in the anode direction. The relative mobility relative to cysteine acid is at pH 6.5, 0.72, at pH 1.8 0.53.

γ- (α-methyl) -L-glutamyltaurine

Melting point: 187-189 ° C. Celsius,

_Rf (n-butanol: pyridine: glacial acetic acid: water 15: 10: 3: 12) = '0.37.

_Rf (n-butanol: glacial acetic acid: water 4: 1: 1) - 0.22.

χ-L-glutamylhomotaurin

Melting point: 207-209 ° C. [.Alpha.] _D @ ²⁰ = -19.5 DEG (water, c = 1).

The infrared spectrum (KBr) shows the following maxima for the characteristic groups:

v-NH- 3345, in NH ₃ + in OH 3200—2200, in CO 740, in CO — NH 1645, in SO ₃ - 1240, 1190, 1150, 1038, and — NH— 1570, 1535, $ SO3 ^- 590 cm ^-1 .

Analysis for C 6 H 16 N 2 O 6 S (molecular mass 268.3): calculated:

C 35.81, H 6.01, N 10.44, S 11.92% found:

C 35.35, H 6.17, N 10.26, S 11.62%

R _f (a mixture of phenol, water and concentrated ammonium hydroxide 120: 30: 1) = 0.31.

N-tert-butyloxycarbonyl-l-glutamyltaurine

Melting point 196 ° C (decomposition at 158 ° C), Rf (mixture of n-butanol, pyridine, glacial acetic acid and water 15: 10: 3: 12) = 0.36 and 0.54.

ω-aminoadipyltaurine

Melting point: 222-224 ° C. Celsius) alpha] D ^{24 '5} - 11.3 ° (water, c = 5).

Analysis for C ₈ H ₁₆ N ₂ O ₆ S (molecular weight 268.29): calculated:

C 35.82, H 6.01, N 10.44, S 11.95% found:

C 35.34, H 6.43, N 10.65, S 12.05%

Claims (2)

SUBJECT A process for the preparation of novel amino acid derivatives of the general formula I, ^R-NH-CH-CO-1 _(CH2) " CO - N - (CH ₂ ) _n - (CH ₂ ) _{t -} SO 3 H R Where I mean A ¹ · hydroxyl, C 1 -C 4 alkoxy or C 7 -C 9 aralkoxy optionally substituted with at least one nitro group and / or halogen and / or C 1 -C 4 alkoxy group, R is hydrogen or (C1-C4) -alkyl, R ^{1 is} hydrogen, C 1 -C 4 alkoxycarbonyl, phenyloxycarbonyl or C 7 -C 9 aralkoxycarbonyl, optionally substituted with at least one C 1 -C 4 alkoxy and / or nitro and / or halogen , n number 1, 2, 3 or 4, m number 1, 2 or 3 and t number 1, 2 or 3, as well as their pharmaceutically acceptable salts or their optically active antipodes, characterized in that the compound of formula II , R ^{5 -} NH - CH - CO - A ¹ (CH 2) n R ³ / CO — N \ R ⁴ (II) wherein A ¹ and n are as defined above, R ³ represents hydrogen or alkyl with 1 to 4 carbon atoms, R ⁴ represents an alkali metal and R ⁵ has the same meaning as R ¹ except hydrogen, is reacted for alkylation with C 2 -C 6 alkanesulfonic acid or C 2 -C 6 alkali metal halogenoalkyl sulfonate, and optionally from the compound of formula I thus formed the R ⁵ protecting group is cleaved and / or the resulting compound is converted into or released from the salt and / or prepared in optically active form using optically active reactants or by resolution of the racemic product obtained. 2. Method according to claim 1, characterized in that a compound of formula II wherein A ^1, R ^3, R ^4, R ⁵ and n are defined as in point 1, is reacted with the acid salt bromethansulfonové brompropansulfonové or an alkali metal.