JPS60120995A - Production of new amino acid derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention relates to a pharmaceutical composition and a method for producing the same.

The novel compound of the present invention corresponds to the following formula (1).

H2N-C)l-Coon (CH2)2) CO-NH-('CH2)2-So,H Salts and optically active isomers of the above compounds are also included within the scope of the present invention.

Some of the novel compounds of this invention have useful pharmaceutical properties, and others can be used as intermediates in the preparation of compounds with useful physiological or pharmaceutical properties.

With respect to biological activity, a particularly advantageous novel compound of the invention is gamma L-glutamyl taurine of the general formula:

1 (2N-CH-COOH!?0'〒H' CO2NH-CH, -CH2-8o, OH
ospherical-Genetical-Adap
tional-8 system) has a wide range of therapeutic and preventive effects on pathological changes directly or indirectly related to damage.

To explain the concept of AGAS, we will list the most important tissues and organs that make up this system.

(a) Biological interfaces forming the boundary between living organisms and the atmosphere as their habitat (skin and other skin-like structures, - cornea and conjunctiva, oral cavity and pharyngeal cavity, respiratory tract and lungs); (h) skeletal system; Limbs (tubular and cancellous bones, two-socket joints, synovium,
skeletal muscle tissue); (c) organs involved in the regulation of terrestrial ionic balance (trans-epithelial transport system, catgut and renal tubules); (d) row teeth (dental bases) necessary for the breakdown of solid food; m terrestrial auditory, olfactory and sound-forming organs;

The compound 18 produced according to the present invention exhibits favorable biological therapeutic effects on the organs of the above-mentioned systems as well as their tissues.

Moreover, with respect to the AGAS system, the compounds of the invention also exhibit the following effects: radioprotection, promotion of wound healing, systemic mensenchyma fti 1 effect, prevention of infections and contamination of the mucous membranes and skin. Protection against increasing risks (rhisomal production of moist mucous membranes, development of hairy epithelium of the respiratory tract, etc.), increased protection against viral and bacterial infections of the skin.

Significantly increased stress effects on terrestrial life (e.g.

This compound simultaneously prevents peripheral tissue damage (e.g., damage to connective tissue prematrix) induced by glycocorticosteroids (climatic and severe diurnal changes, increased risk of damage). tend to stabilize the adaptation syndrome.

Development of immune dynamic equilibrium (improved recognition of self and non-self cells).

The compounds of the invention exert their activity partly directly and partly through inhibition of vitamin A metabolism through the production of more polar vitamin metabolites. This activity is
25-hydroxycholecalciferol-1- in renal tubules
α-hydroxylase (25-hydroxy-chol)
ecalciferol-1-α-hyoroxyl
ase ) enzymes similar to those caused by parathyroid hormones. The above facts explain the wide and diverse biochemical, pharmacological and therapeutic activities of the 18 compounds of the present invention.

(A) Effects of human properties of vitamins (a) Pharmacological and biochemical effects Action to promote the incorporation of labeled sulfate into rat cartilage, and into the crystalline lens and liver and lung tissues of chicken embryos; rat cartilage Action to promote the incorporation of labeled phosphorus into the body; action to promote the synthesis of chondroitin sulfate; action to favor wound healing (also effective against the decline in wound healing induced by administering cortisone to rats and dogs). effective); fertilizer t4I
Effect of increasing the reduction of granules in I+ cells; Strong effect of vitamin A in cases of experimental vitamin deficiency or hyperemia in rats and chickens; Effect of reducing stress ulcers in rats, increasing lysozyme production; .

Actions that affect the alternation of copper, zinc, manganese, fluorine);
Action to promote epithelial formation; action to increase the activity of alkaline phosphate enzyme; action exerted on cyst formation induced by local action of vitamin A; very flat course of the dose-response curve and high dosage Changes in aura symptoms depending on the dose; action to activate the Golgi apparatus; action to promote the production of goblet cells; action to increase the concentration of serum vitamin A.

fb) Use in clinical treatment Keratoconjunctivitis sicca; Shogren's syndrome; Nasopharyngitis sicca; Odorosis: Chronic bronchitis:
pancreatic fibrosis; childhood pheumopa thy
) trends; periodontal disease; increased predisposition of the skin and mucous membranes to viral and bacterial infections; cortisone antagonism; surgical wounds and lesions of the mucous membranes; colonic erosions; pruritic complexes; taste and olfactory disorders.

(B) Effect of non-vitamin A properties (a) Pharmacological and biochemical effects Transient hypoglycemic effect; decreases phosphate urine.

Action to increase serum phosphate levels; radioprotective action; action to promote target reaching in maze tests in inactive animals; action to reduce experimental fluorosis and cadmium poisoning;
Effect of alleviating experimental Egyptian bean bulkiness; Effect of increasing renal cyclic adenosine-phosphate excretion; Effect of increasing enzyme activity of hepatic tyrosine amine transferase.

fb) Use in clinical treatment Less severe irradiation injury; vitiligo; myasthenia; mental uplifting effect; effect of improving degenerative aging condition and memory function: keloid predisposition; disease of locomotor organs originating from the impairment of tonic formation ; sclerotic fundus (5clerotic fundus);
Starchosis; patchy scleroderma; fibrocystic mastopathy.

The duration of treatment with the compounds of the invention varies within wide limits. After 6 oral doses of 5 μm of chemically pure active substance per patient, some patients no longer had symptoms after 2 weeks (eg.

Dry nasal laryngopharyngitis), treatment of certain other diseases may require 1 to 2 months (e.g., periodontal disease, Shogren's syndrome)
In addition, in the case of other diseases, a treatment period of 6 months is required (Example 1: Stressing rigidity formation).

The compounds of the invention can be converted into cosmetic or pharmaceutical compositions for use in human and veterinary treatment.

The composition may contain only the compound of the present invention as an active ingredient, or may contain other biologically active substances together. Preferably, the active agent of the invention is administered at a dosage of 50 to 500 nanograms per ton of body weight six times a day.

One tablet consists of a biologically inert carrier (e.g. lactose, starch) and the usual auxiliary substances (e.g. granulating agents and lubricants such as polyvinylpyrrolidone, ceratin, Merck, magnesium stearate, ultrafine silica, etc.) from 2 to 20μ, preferably about 10μ, of the active ingredient of the present invention in admixture with
Contains.

Considering this very low dosage, it is even possible to manufacture 10ml of liquid active ingredient by mixing it with the tablet mass before granulation and using a mixing machine in order to uniformly disperse this active substance in the tablet. of the active ingredient can be produced at a satisfactory cost in large laboratory-scale equipment. This active ingredient is stable.

-Tablets can be stored for a long time. The active ingredient content in depot tablets or 5 pansulated capsules is between 10 and 30 microns! It is.

Injectable preparations containing the active ingredient of the invention in powder ampoules, optionally mixed with a biologically inert aqueous diluent, contain from 5 to 10 microns of active ingredient per ampoule. It is preferable to have one. Parenteral application is preferably by intramuscular, subcutaneous or intravenous injection. The active ingredient of the invention at a given concentration does not irritate tissues or vessel walls and can also be applied in the form of two drops.

Herbal medicines can be used for this purpose, such as cocoa butter or synthetic waxes (eg Imhausen mass).

GFR) using 2 to 20μ! , preferably about 1
It can be prepared with an active ingredient content of 0 μi.

Common hydrophilic or hydrophobic ointment bases (e.g., cholesterol, paraffin, glycerin, lanolin, instant linseed oil)
The dermatological or cosmetic ointment prepared in I'
i! I component content is 0.1 to 1.0μp/t
That's fine.

Aerosol formulations contain 0.1 to 1.0μ of active ingredients! /
It is preferable that it is contained at a P concentration. The active ingredient content of sublingual tablets is approximately 10μ per tablet! The decomposition time is 0.5 to 1 hour.

Polymers of high molecular weight with a sustained effect can also be prepared, for example with an active ingredient content of 1 to 5 μ! // can be made into a suspension form. Similarly, salts of this polymer or a compound of the invention and a high molecular weight organic base (e.g., protamine,
Injectable preparations with a sustained effect can be prepared from mixtures with histones (histones).

The composition contains 10 to 20 microns of active ingredient per ampoule.

Powders for skin diseases and cosmetics contain active ingredients.
or 1 by 7p and 2 common carriers (eg.

Contains talc).

Eye drops applied for ophthalmology and ointments miscible or immiscible with tears have an active ingredient content of 0.01 to 1.0 μp.
// is.

What is the most preferred dosage for pediatric use?

The ratio is 0.5 microns of active ingredient per 1 body weight.

Preferably, all sterile compositions are prepared by sterile filtration.

Combinations of the above formulations containing the compounds of the present invention enhance the intended prophylactic, therapeutic or cosmetic effect.

Improve or improve. Primarily, the following co-supplemental ingredients will be used: Vitamin A, vitamin C.

Vitamin E, vitamins, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radium-like and immunosuppressive products, psychotropic drugs (especially tranquilizers and thymolebotics).

thymo'l eptics) F organic silicon compounds, gerontological preparations, oral antidiabetic agents, anti-inflammatory agents, antihistamines, etc. The dosage of each component in the combination formulation is generally about the same as the usual therapeutic dosage when used alone.

The compounds of the invention can also be used as additives in therapeutic and nutritional premixes. When used in such compositions, this compound increases weight gain and also claims ■
η and/or enhance vitamin A absorption and metabolism.

This compound improves the absorption of trace elements and also increases their blood levels. If used as a feed additive, will this be 1 weight? A daily oral dose of 100 to 300 nanograms per day, preferably about 200 nanograms, can be administered to the animal. this is.

When mixed with animal feed, this generally corresponds to a concentration of 1 to 2 μP per feed IK (ie 1 to 2 μP/ton or 0001 to 0.002 ppm). Considering that the required concentration is very low.

The compounds of the invention can also be incorporated into microcapsules containing vitamin premixes or other useful feed additives, and can also be administered as an additive to drinking water or licking salts. The compound 18 of the present invention can also be used for veterinary medicine in the same form as it is applied for human treatment (epithelialization, wound healing, bone fractures, etc.).

A common structural feature of the compounds of general formula (1) is that they contain an α-substituted dicarboxylic acid moiety, the ω-carboxyl group of which is a strong acid at the ω position in addition to other substituents in the alkyl side chain. It is bonded to a primary or secondary amino group containing a functional group via an amide bond.

The compound of general formula (1) or its salt or optically active isomer can be produced according to the present invention by the following method.

That is, r-L-glutamyl-oligopeptide.

This method is characterized by reacting with taurine in the presence of γ-glutamyl transpeptidase.

The invention will be explained in more detail by the following examples.

However, the present invention is not limited to this.

Example 6, 051 (50 mmol) of 2-amino-2-(hydroxymethyl)-propane-1,s-diol (TRI
s), 4.58 l (75 mmol) of sodium chloride,
2.5 CM' (21:l mmol) of taurine and 6.
14 P (20 mmol) of kick-starting glutathione is 9
Dissolved in DD ml of water. 8 of the bath solution with concentrated hydrochloric acid
After setting it to 0, add water to make the volume of the solution 1! And so. 10
Oq r-glutamyl-transpeptidase enzyme (from pig kidney, M. Orlowski).

A, Meister, J, Biol, Chem.
240. 558 (1955)) was added to the solution.

After this solution was left at 57° C. for 1 hour, 100 d of 50% trichloroacetic acid solution was added. After removing the precipitate that appeared by centrifugation, trichloroacetic acid solution was extracted using a continuous extractor for 8 hours. The solution was then evaporated under vacuum at 50”°C to approximately 100 m/s and transferred to an ion exchange column packed with Dowex 1 (
2,2-50CIn). Substance adsorbed on column 7i-I NJ! m1li1 with if acid. After the appearance of the salt Gon, a bath solution of 50+x/ was received. This solution was first evaporated at 50°C/15mmH, then at room temperature 10.1
It was dried at mmH. The residue was recrystallized from 80% ethanol. γ-L-glutamyl-taurine of 250 to 500 μm was obtained.

Continuation of page 1 Priority claim [Phase] 197 Cape March 26 0 Hungary (
HU) 0 Inventor: Aalvard Furry Hungary 3 @ Inventor: Huerenc Sievesi Hajigaliyuteien 72 @ Inventor: Göran Herchel Banka IJ -/A @ Inventor: Erzibet Ben Hungary 17 ■Cl-1558 Country , 1074 Budapest, State of Cienzieri Ucza, 1103 Budapest, State of Gyergely Ucza,
1094 Budapest, Marlton 977735 Country,
1122 Budapest, Sekács-Ucza Procedural Amendr August 2, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1 Out of town indication 1982 Patent Application No. 215674 2 Title of the invention Process for producing new amino acid derivatives 3 Person making the amendment 41 related patent applicants fI: Hungary, Nidavest 4. Mr. Tou Utsa 1-5 Name: Kinoin Gogeorgsel Nis Gweziesetei Termekek Jarrah Erci 4, Agent

Claims (1)

[Scope of Claims] A method for producing γ-L-glutamyl-taurine of formula 1 (%). A method characterized in that r-L-glutamyl-oligopeptide is reacted with taurine in the presence of r-glutamyl transpeptidase.