JPS58131961A - Manufacture of novel 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 novel amino acid derivative, a medical composition containing the same, and a method for producing the same.

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

R'-Nu-CD-CO-mu1 ! [During the ceremony.

A"H, hydroxy, 01-4 alkoxy, 03-6 cycloalkoxy, C)-9 aralkoxy, nitro,
C1-4 alkoxy may also be substituted with phenoxy, or -[< -(NH-OH-C
o), -Y (CC"t', R"・Bs is hydrogen, C1-S alkyl, aralkyl, hydroxy-substituted aralkyl or heteroaralkyl; Y is hydroxy, 01-4 alkoxy or C7-aralkoxy, r is an integer of 1 to 10); Milk is hydrogen or C□~4 alkyl; R1 is hydrogen, C1~4 alkoxycarbonyl, aralkoxycarbonyl, phenyl bond, halogen, alkoxy or phenoxycarbonyl which may have a nitro substituent.

C0-4 alkanoyl or benzoyl; B is hydrogen, C8-4 alkyl, carboxy.

01-4 alkoxycarbonyl, phenoxycarbonyl, or carboxamide, and 1, 2, 5. or 4: ■ is 1, 2. or 5; direct is 1, 2. or 5].

Salts and optically active isomers of the above compounds are also within the scope of the present invention @I#
c included.

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

9 Among the novel compounds of the present invention, outstandingly advantageous with regard to biological activity is gamma-L-glutamyltaurine of the general formula:

H,N-CH-Cool Strive CH.

CH.

Co-NH-CH, -OH, -80! OH This compound is one person GA8” (biosphere-development-adaptation strain Aerobi
ospbericml-Genetical-Ad
It has a wide range of therapeutic and preventive effects against pathological changes directly or indirectly related to damage to the application ml-87mtem).

To explain the concept of AGA8, we will list the most important tissues and organs that make up this system.

(a) Biological interfaces (skin and other skin-like structures) that form the boundary between living organisms and the atmosphere that serves as their habitat.

cornea and conjunctiva 2 oral and pharyngeal cavities, respiratory tract and lungs); (b
) Skeletal system and body limbs (1 bones and cancellous bones, 2 ball joints, synovium, skeletal muscle tissue); (c) Terrestrial (t@rrestriml) organs involved in the regulation of ionic balance (transport system through the epithelium, catgut); (a) Seed tooth (with tooth base and anchored by the tooth root) necessary for the breakdown of solid food; Art. Terrestrial auditory, olfactory and sound-forming chambers.

The compounds prepared according to the invention exert biologically favorable therapeutic effects on the organs of the above-mentioned systems as well as their tissues.

Moreover, the compounds of the invention also exhibit the following effects with respect to the muGA8 system: radioprotection, promotion of wound healing, systemic activation of men@encbymm, infection and contamination of mucous membranes and skin. protection against the increasing danger of
production of lysozyme in the mucous membranes, development of the hairy epithelium of the respiratory tract, etc.), and improved 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). tends to stabilize the adaptive climate.

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

The compounds of the present invention exert their activity partly directly and partly through inhibition of vitamin A metabolism through the production of more polar vitamin A metabolites. This activity is
25-hydroxycholecalciferol-1- in renal tubules
One-line hydroxylase (25-byroxy-cbol
scalc order aro1-1-a-hyoroxy1mm
@) Similar to what is caused by parathyroid hormones on enzymes. The above facts explain the wide and diverse biochemical, pharmacological and therapeutic activities of the compounds of the present invention.

(-Pharmacological and biochemical effects: Promote the incorporation of labeled sulfate into the cartilage of rats, as well as the lens, liver and lung tissues of the larvae; Promoting action; Promoting the synthesis of chondroitin sulfate: Promoting wound healing (also effective against decreased wound healing induced by administering cortisone to rats and dogs); Mast cell granules Effect of increasing the reduction; Vitamin-enhancing effect in cases of experimental vitamin deficiency or excess in rats and ducks:
Alleviating stress ulcers in rats, increasing lysozyme production; trace elements (silicon).

1111, ! Actions that affect the alternation of lead, manganese, fluorine): Actions that promote epithelial formation: Actions that increase the activity of alkaline phosphate enzymes; Actions exerted on cyst formation induced by the local action of vitamins; A very flat dose-response line and changes in precursor symptoms at high doses; Activates the Golgi apparatus; Promotes the production of goblet cells; Increases the concentration of self-extinguishing vitamins Action.

(b) Use in clinical treatment
pancreatic fibrosis: phsumopatby tendency in childhood: periodontal disease; increased predisposition of the skin and mucous membranes to viral and bacterial infections: surgical wounds and lesions of the cortisone antagonist mucosa; colonic erosions: Pruritus group; taste and smell disorders.

(-Pharmacological and biochemical effects Transient hypoglycemic effect: Reduces phosphate urine.

Action to increase serum phosphate level; radiation protection action; action to promote target reaching in maze tests in inert animals; action to reduce experimental fluorosis and cadmium poisoning;
Effect of alleviating experimental Egyptian bean toxicity; Effect of increasing renal cyclic adenosine-phosphate excretion; Effect of increasing enzyme activity of hepatic tyrosine aminotransferase.

(b) Use in clinical treatment Less severe irradiation injury; vitiligo: myasthenia; mental uplifting effect; effect to improve degenerative aging condition and memory function; keloid predisposition; Disease; sclerotic basis (sclerolic fnndaa)
: Starchoid disease; patchy scleroderma; fibrous mammopathy.

The duration of treatment with the compounds of the invention varies within wide limits. When given an oral dose of 5 sl of chemically pure active substance 5 times a day, 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)
However, in the case of other diseases, a treatment period of 5 to 6 months is required (Example 9: Ankylosis formation and spondylosis).

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

The compositions may contain only the compounds of the invention as active ingredients or may also contain other biologically active substances. The active agent of the present invention has a body weight of 1
Preferably, the dosage is 50 to 500 nanograms per 11 ip per 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, gelatin, talc, magnesium stearate, ultrafine silica, etc.) ) of the active ingredient of the present invention in admixture with 2 to 20A? , preferably about 10μ
! contains.

Considering this very low dosage, in order to uniformly disperse the active substance in one tablet, the active ingredient in solution form is mixed with the tablet mass before granulation, and a homogeneous mixture is created using a mixer. Preferably, it is prepared. Because the required effective dosage is so low, even when producing trillions of tablets, the active ingredients of the present invention can be produced satisfactorily and cost-effectively in large laboratory-scale equipment. The active ingredient is stable so the 9 tablets can be stored for a long time. The active ingredient content in depot tablets or spmnsuled capsules is 10 to 50 sl.

Injectable preparations containing the active ingredient of the invention in powder ampoules, optionally mixed with a biologically inert water-soluble diluent, contain from 5 to 10 sl of active ingredient per ampoule. It is preferable to be there. Parenteral application is preferably by intramuscular, subcutaneous or intravenous injection. Since the active ingredient of the present invention at a predetermined St does not irritate tissues or vessel walls, it can also be applied in the form of 9 drops.

Herbal medicines can be used for this purpose, such as cacao pata or synthetic pilgrim waxes (e.g. imhausen mass).

2 to 20 m1 using GF a). Preferably, it can be prepared with an active ingredient content of about 10 sl.

Dermatological or cosmetic ointments prepared with conventional hydrophilic or hydrophobic ointment bases (e.g., cholesterol, paraffin, glycerin, lanolin, hempseed oil, etc.) have active ingredient contents ranging from α1 to 1. osp7p is sufficient.

Aerosol formulations contain the active ingredient in cLl to 1.0μl/
It is better to contain 18f. The active ingredient content of sublingual tablets is approximately 10 tsl per tablet, and the decomposition time is (15 to 1
It's time.

Polymers of high molecular weight with a sustained effect can also be prepared, for example in the form of a suspension with an active ingredient content of 1 to 5 st7p. Similarly, a salt of this polymer or a compound of the invention and a high molecular weight organic base (e.g., protane,
Injectable preparations with a sustained effect can be prepared from mixtures with histones (histones).

The composition contains active ingredient in an amount of 1 to 20 sl per ampoule.

Powders for skin diseases and cosmetics have an active ingredient content of Q, 1
to 1jII/l of a common carrier (e.g.

Contains talc).

Eye drops and ointments miscible or immiscible with tears for ophthalmological applications have an active ingredient content of α1 to 1. Osl
/l.

What is the most preferred dosage for pediatric use?

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

All germicidal compositions are conveniently prepared by sterile filtration.

The use of the above-mentioned vehicles in combination with the compounds of the present invention increases the intended prophylactic, therapeutic or cosmetic effects.

to strengthen or improve; The following combination supplementary ingredients will mainly be used: vitamin C, vitamin C.

Vitamin E, vitamins, trace elements, cortisone and its derivatives, progesterone, thyroid hormones, radium mimics and products of immunosuppressive action, psychotropic drugs (qi!, tranquilizers and 1,000 Molebitis).

tbymolepNcs) e Bridged silicon compound, gerontological preparation, oral antidiabetic agent, anti-inflammatory agent, pile hista 2
agents, etc. The appropriate amount of each component in the combination formulation is generally about the same as the usual therapeutic amount when used alone.

The compounds of the invention can also be used as additives in therapeutic and nutritional premixes. When used in such compositions, the compounds increase weight gain and also reduce vitamin A demand and/or improve vitamin A absorption and metabolism.

This compound improves the absorption of trace elements and also increases their blood levels. When used as a feed additive, it can be administered to animals in daily oral doses of 100 to 500 nanograms per body weight, preferably about 200 nanograms per body weight. this is.

When mixed with animal feed, it generally contains 1 to 241*V (i.e. 1 to 2 cape/ton or α
001 to α002 ppm). required l
[In view of the very low It can also be administered. The compounds of the invention can also be used in veterinary medicine in a form similar to that used in human treatment (epithelialization).

wound healing, fractures, etc.).

A common structural feature of the compounds of general formula (1) is that they contain an α-substituted dicarboxylic acid moiety, in which the -monocarboxyl group, 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 +11 or its salt or optically active isomer can be produced according to the present invention by the following method.

General formula (11% formula% [In the formula, M', II'' and n each have the same meanings as above, and V is hydrogen or C0-4 alkyl.

am is an alkali metal or a vinyl group].

Alkylated with alkanesulfonic acids or alkali metal haloalkylsulfonates, or reacted with sodium sulfite or sodium bisulfite.

If necessary, the compound thus obtained is converted into or liberated from its salt, and/or said compound is converted into an optically active form by the use of an optically active reagent or by optical resolution of the racemic product obtained. Manufacture.

It is also possible to use glutamine, asparagine or substituted derivatives thereof as starting materials.

However, the substituent is bonded to a position other than the acid amide site. In this case9, according to the method of the present invention, one of the acidic hydrogen atoms of the acid amide group is replaced with, for example, metallic sodium,
The obtained compound is reacted with 2-bromoethanesulfonic acid or its salt or alkanesulfonic acid to form the general formula (
The compound of 1) is produced. Starting materials include .-vinyl amide or of the appropriate a-aminodicarboxylic acid.
Aziridine derivatives can be used as well. When both are reacted with alkali sulfite or alkali bisulfite, the desired product of general formula (1) is produced.

Example 3.027 (10 mmol) of carbobenzyloxy-
L-Glutamine Sodium Salt (Liebig”KameAn)
n, 640, 145/1961) in 50-dimethylformamide, 12 mmol of sodium hydride are added in the form of an oily dispersion, and the mixture is heated for 2 hours with exclusion of air moisture. Then 2.11#
A solution of (10 mmol) sodium bromoethanesulfonate in 50 d of dimethylformamide is added dropwise and the mixture is heated for a further 2 hours. The mixture is evaporated in vacuo, the residue is extracted with ether, the residue is then dissolved in water, the solution is passed through a column packed with Dowex 50 ion exchanger, the column is eluted with water, and the The liquid is evaporated in vacuo and the residue is dried over solid potassium hydroxide. The material obtained is carbobenzyloxy-rL-glutamyl-taurine. Relative mobility (relati)
ve motility) (with respect to cysteine oxidation) 1.05° Rf = [L57 (in o-butanol, pyridine, glacial acetic acid and water = 15:10:5:12 mixture)
.

Finally, we will touch on preferred embodiments of the method of the present invention.

16 A method of reacting a compound of formula (-) with bromoethanesulfonic acid or bromopropanesulfonic acid.

2. A method in which the compound of formula (1) is reacted with an alkali metal or alkaline earth metal hydroxide or salt salt, or with a specific base.

Continuation of page 1 Priority claim March 26, 1975 ■ Hungary (H
U)■CI-1558 @l! Intermediate Jöran Herchel Hungarian State 1094 Budapest Marton Utsza 35/A @ Inventor Eržěbet Pendeifi Hungarian State 1122 Budapest Székács Utsza 17

Claims (1)

[Claims] 1. General formula (1) [In the formula. 51 is hydroxy, C0-4 alkoxy, C8-6 cycloalkoxy, C7-9 aralkoxy, phenoxy which Ii may be substituted with nitro, C1-4 alkoxy or )10, or Roxy-substituted aralkyl or heteroaralkyl ; Y is hydroxy, 08~
4 alkoxy or C, ~ 9 aralkoxy; rha1
-10 integer); R is hydrogen or C1-4 alkyl;
Hydrogen e C1-4 alkoxycarbonyl, aralkoxycarbonyl, phenoxycarbonyl which may have a halogen, alkoxy or nitro substituent on the phenyl ring. C1-4 alkanoyl or benzoyl; R2 is hydrogen, C□-4 alkyl, carboxy. C1-4 alkoxycarbonyl, phenoxycarbonyl, or carboxamide; n is 1.2.5. or 4; m is 1, 2 . or 5; t is 1, 2, . or 3] or a salt thereof, or an optically active isomer thereof. General formula (1) %Formula % [In the formula, I, Bl and oc each have the same meanings as above, and V is hydrogen or 08-4 alkyl. B1 is an alkali metal or a vinyl group]. Alkylated with alkanesulfonic acids or alkali metal 10-alkylsulfonates, or reacted with sodium sulfite or sodium bisulfite. If necessary, the compound thus obtained is converted into or liberated from its salt, and/or said compound is converted into an optically active form by the use of an optically active reagent or by optical resolution of the racemic product obtained. Manufacture. A method consisting of things.