CH624098A5 - - Google Patents

Description

624 098

2nd

PATENT CLAIMS 1. Process for the preparation of new compounds of the general formula

R ^ KH-CH-CO-A1

(CHj

(I)

2'n

C0-N- (CH) - (CH -) .- SO-H II d x j

I I

MR*

bliss

A1 for hydroxyl, alkoxy or aralkoxy each having 1-4 carbon atoms in the alkyl part, aryloxy or for a group of the 15 general formula - (NH-CH-CO) r — Y,

R3

stands where

Y hydroxyl, Ca to C4 alkoxy or aralkoxy, 20

R3 denotes hydrogen, Q- to Cs-alkyl, aralkyl, aralkyl or heteroaralkyl substituted by hydroxyl groups, and r is an integer from 1 to 10,

R represents hydrogen or Ct to C4 alkyl, 25

R1 for alkoxycarbonyl, or aralkoxycarbonyl or acyl optionally substituted by halogen, alkoxy or nitro group (s),

R2 represents hydrogen or carboxyl,

n 1, 2 or 3 and 30

t is 1 or 2,

or their salts, characterized in that a compound of the general formula

R1-3SH-CH-C0-A1

The present invention relates to the process for the preparation of new amino acid derivatives of the formula I, in which the symbols have the meaning given there.

5 Some of these compounds have valuable pharmacological properties. Still other of these compounds are intermediaries for the production of substances with valuable biological or pharmacological effects. All compounds of the formula I are new.

Due to its biological effects, especially the y-L-glutamyl-taurine, which has the formula (XXIV)

(II)

wherein Rs is an alkali metal, with an alkali haloalkyl sulfonate of the formula

X - (CH) - (CH2) t -S03R5

wherein X represents halogen, and optionally releases the compound obtained from a salt or converted into a salt.

2. The method according to claim 1 for the preparation of a compound of the general formula (I), characterized in that a compound of the general formula (II) is reacted with an alkali salt of a bromoethanesulfonic acid or a bromopropane sulfonic acid.

3. The method according to claim 1, characterized in that a compound of the formula I obtained, in which A1 is an aryloxy or aralkoxy group, is converted into the free carboxylic acid by hydrolysis.

4. A process for the preparation of a compound of the formula I in which hydrogen is instead of R 1, characterized in that a compound of the formula I is prepared by the process of claim 1 and the group Ra is split off therefrom by hydrolysis.

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H2H

CH - COOH!

CH-! *

CH-!

CO - NH - CH- -

(XXIV)

CH2-SOgOH

35

corresponds to and has a broad therapeutic and preventive spectrum of effects for indirect or directly attributable to violations of the "AGAS" (aerobiospheric genetic adaptation system).

To explain the term “AGAS”, the most important tissues and organs that make up this system are listed below.

a) All biological interfaces that are in contact with the outside air as a biosphere (skin and skin structures, cornea and conjunctiva, oral and pharynx cavities, airways and lungs);

b) skeleton and limbs (long bones and spongy bones, ball joints, synovial membrane, skeletal muscles);

c) the organs participating in the regulation of the ion balance (transepithelic transport system: villi and kidney channels);

d) the theko-donte (fixed in the tooth socket by the root) teeth required for crushing the food;

e) Hearing, smell and voice organs.

The accessible compounds therefore exert a beneficial biological or therapeutic effect on the organs or tissues of the AGAS system listed here.

The accessible compounds also act on the following functions associated with the AGAS system: radiation protection, wound healing, mesenchyme generally activating, protection against the ever increasing risk of infection and contamination of the skin and mucous membranes (lysocyte production of the moist mucous membranes, Activation of ciliated epithelium in the respiratory tract, etc.), increased protection against infections caused by viruses and fungi.

The accessible connections are effective against the constantly and greatly increasing stress effects (e.g. meteorological influences, strong differences between day and night temperature, increased risk of injury) by stabilizing the adaptation syndrome and at the same time warding off the peripheral tissue damage of the glucochorticoids (see above) for example damage to the connective tissue, injuries to the bone matrix stock, etc.). Development of im-mun homoeostasis (increased knowledge of the body which cells are in the body and which are not).

3rd

624 098

The accessible compounds exert their effects partly directly, partly via the control of the vitamin A metabolism, by the production of vitamin A metabolites of a more polar character. This effect is comparable to that of the parathyroid hormone on the 25-hydroxy-cholecalciferol-la-hydro-xylase enzyme of the kidney channels. This explanation explains the broad pharmacological, biochemical and therapeutic effects of the available compounds. The directions of action of the connections are as follows:

A. Effects with a vitamin A character:

a) Pharmacological and biochemical effects: Labeled sulfates are incorporated to an increased extent in the rat's sword cartilage or the eyeline, the liver and lung tissue of the chicken embryo; radioactively labeled phosphorus is incorporated into the rat's sword cartilage to an increased extent; the chondroitin sulfate synthesis enhancing effect; beneficial effect on wound healing or experimentally worsened wound healing in rats and dogs by administration of chortisone; the potentiating effect of vitamin A in hypo- or hypervitaminosis experimentally induced in rats and chickens; the effects moderating the ulcer-related stress effects in rats; beneficial effect on degranulation of mastocytes; increasing effect on the production of lysosym; Effect on the household of trace elements (silicon,

Zinc, copper, manganese, fluorine); promoting effect on epithelial formation; increasing effect on alkaline phosphatase activity; the effect exerted on the granuloma sack formation caused by local exposure to vitamin A; the very flat course of the dose-response curve or the change in the sign of the effect at large doses; activating effect on the Golgi-Ap-parat; beneficial effect on the formation of calyx cells; increasing effect on the concentration of vitamin A.

b) clinical-therapeutic effects: keratocunjunctivis sicca; Sjogren's syndrome; rhino-laryngo-pharyngitis sicca; Ozaena; Chronic bronchitis; Sinobronchitis; Cystic fibrosis; constitutional lung diseases in young children; Parades tose; Tendency to infect the skin and mucous membranes for viruses and fungi; chortisone antagonistic effect; beneficial effect on the healing process in surgical wounds and mucosal wounds; erosio colli; pruritus-like; Reduced sense of smell and taste.

B. Effects without vitamin A character a) Pharmacological and biochemical effects: effects on the blood sugar level in the sense of a temporary decrease; increasing effect on phosphaturia, lowering effect on phosphorus level in serum; radioprotective effect; in the case of labyrinth experiments with inactive animals, the time-reducing effect required to achieve the goal; reducing effect on experimentally induced fluorine and cadmium toxicosis; cyclic adenosine monophosphate emptying of the kidney; the symptoms of experimentally induced lathyrism moderate effect; Reduction in sensitivity to histamine; increasing effect on the activity of the liver enzyme Tyrosi naminotransferase.

b) Therapeutic effects: weak radiation damage; Vitiligo; Muscle hypotension; psychoenergetic effect; beneficial effect on involutional and gerontological conditions as well as on mnestic functions; cheloidal tendencies; Ankylopoetic spondylosis; wear and tear diseases of the locomotive organs; sclerotic fundus; Amyloidosis; Morphea; fibrocystic mastopathy.

When administering the accessible compounds, the duration of the treatment is extremely different. Some diseases (e.g. Rhino-laryngo-pha-ryngitis sicca) become symptom-free after just two weeks after oral administration of 3x5 micrograms daily; symptomatic improvement of other diseases (e.g. paradentosis, Sjögren's syndrome) takes one to two months other diseases (e.g. spondylosis ankylopoetica) have to be treated for a quarter to half a year.

Any pharmaceutical, preventive, cosmetic or veterinary preparation can be produced in a simple manner from the accessible compounds. The preparations can contain a single active ingredient or a combination of active ingredients. The dose of pure active ingredient is 50-500 nanograms per day and kilo of body weight and is administered in three individual doses.

One tablet contains 2 - 20 micrograms, preferably 10 micrograms of active substance and also biologically inert carriers (e.g. milk sugar, starch) as well as the usual tableting aids (granulating and lubricating agents such as polyvinylpyrrolidone, gelatin, talc, magnesium stearate, Aerosil etc.) ).

Because of the extraordinarily small dose, it is advisable to add the active ingredient in the form of a solution to the tablet mass before granulation. In this way, the active ingredient is distributed evenly. Incidentally, the low active substance content enables the active substance to be produced even in the case of the production of many millions of tablets on a large laboratory scale, and at a price that is acceptable to every patient. The active ingredients are stable, so the tablets can be put on the market without specifying a time limit for consumption. The active substance content of delayed acting tablets or capsular capsules can be 10-20 micrograms. In the case of injectable preparations, the appropriate dose per ampoule is 5-10 micrograms, and, if desired, the preparation can be prepared as a powder ampoule in which the active ingredient is mixed with an indifferent, water-soluble excipient. Parenteral administration can be carried out intramuscularly, subcutaneously or intravenously. In the specified concentration, the active ingredients do not damage tissue or vessel walls. The active ingredients can also be administered as an infusion. Suppositories contain 2-20, preferably about 10 micrograms of active ingredient and are made from cocoa butter or from synthetic waxes or fats suitable for this purpose (for example the Imhausen mass produced in the Federal Republic of Germany). The active substance content of cosmetic ointments used to heal the skin is 0.1-1 microgram / g. The ointment base can be hydrophilic or hydrophobic and contains the usual components: for example cholesterol, paraffin, glycerin, lanolin, cocoa butter, linseed oil etc. The active ingredients can also be formulated as aerosol preparations, the substance content also being 0.1-1 micrograms / g . When formulated as a perlingual tablet, one tablet contains 10 micrograms of active ingredient, the disintegration time of the tablet is V2 hour, polymers for the sustained release of the active ingredient can be prepared, for example, as a suspension and contain 1-5 micrograms of active ingredient / g polymer. Injection preparations with retarder effect can be formulated either using high molecular weight polymers or from the salts of the compounds according to the invention formed with high molecular weight organic bases (for example histone, protamine), one ampoule containing 10-20 micrograms of active ingredient. Powders for cosmetic or skin healing purposes are prepared with the usual carriers (for example talc)

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624 098

4th

and contain 0.1-1 g active ingredient / g powder. For ophthalmology, the compounds are formulated as drops or as ointments that are miscible or immiscible with the tear fluid; the active substance content of these preparations is 0.1-1 microgram / g. Children should be administered the compounds according to the invention in a dosage of about 0.3 micrograms per kilogram of body weight.

The sterile preparations are expediently produced by sterile filtration.

The desired preventive pharmacological or cosmetic effect of the preparations listed above can be increased and supplemented by numerous combinations. The following are explicitly mentioned as possible biologically active additives and their use is to be protected:

Vitamins A, C, E and K, trace elements, chortisone and its derivatives, progesterone, thyroid hormones, ra-diomymetic and immunosuppressive substances, psy-chopharmaca, especially tranquillizers, timoleptics, organic silicon compounds, gerontological preparations, lowering the blood cholesterol level Substances, oral antidiabetics, anti-inflammatory substances, antihistamines, etc. The dosage of these active additives is generally the same as the usual therapeutic dose when the substances are used alone.

The accessible compounds can also be used as an additive to nutritional or pharmaceutical premixes. They partly cause weight gain, partly they reduce the need for vitamin A or improve its metabolism. Furthermore, the absorption of the trace elements is increased by the compounds, their level in the blood is raised. When the compounds are used as an additive to animal feed, the dosage orally is expediently 200 nanograms / kg and day. When mixed into the feed, this corresponds approximately to a concentration of 1-2 micrograms / kg or 1-2 mg / ton feed, i.e. a concentration of 0.001-0.002 ppm. In view of these very low concentrations, use as a feed additive is extremely economical. The compounds are preferably admixed with vitamin premixes or used in microcapsules which contain the compound 5 according to the invention in addition to other necessary feed additives. The compounds can also be used when soaking with drinking water, in leaking salt or occasionally as a spray.

In veterinary medicine, the accessible connective fertilizers have similar fields of application as in human medicine, i.e. for example skin damage (peeling), wound healing, broken bones etc.

It is a common structural property of all compounds of the general formula (I) that they contain a dicarboxylic acid which is substituted in the a-position 15 or its derivative which is also substituted in other places via its m -carboxyl group with an acid amide bond bonded to a primary or secondary alkylamine, which contains a group of 20 strongly acidic characters in addition to various substituents on its alkyl side chain in the w position.

example

3.02 g (10 mmol) of carbobenzyloxy-L-glutamine sodium salt (Liebigs Annalen 640, 145, 1961) are dissolved in 50 ml of dimethyl-25 formamide. An oily suspension containing 12 mmol of sodium hydride is added to the solution, then the mixture is heated for 2 hours with the exclusion of atmospheric humidity, then the solution of 2.11 g (10 mmol) of bromomethane-sulfonic acid sodium in 50 ml of dimethylformamide is added dropwise 30 and the mixture is added Warmed for 2 hours. It is then evaporated in vacuo, the residue extracted with ether and then dried. The dry substance is dissolved in water, applied to a Dowex 50 column and eluted with water. The eluate is evaporated in vacuo and the residue is dried over potassium hydroxide. The dried substance is catalytically hydrogenated. After recrystallization from ethanol / water, 1.55 g of y-L-glutamyl taurine are obtained.

s