DK155672B - METHOD OF ANALOGUE FOR THE PREPARATION OF AMINO ACID DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE SALTS OR OPTICALLY ACTIVE ISOMER THEREOF - Google Patents

Description

DK 155672 B

The present invention relates to an analogous process for the preparation of novel amino acid derivatives of the general formula 5 R 1 -NH-CH-COA 1 (CHO)

CO-N- (CH2) -0P0 (OH) 2 R

1 1 10 wherein A, R, R, n and t have the meanings specified in the preamble of the claim, or physiologically acceptable salts thereof or optically active isomers thereof.

These compounds have valuable biological and pharmacological effects. All of the inventories of the invention are novel.

The compounds of the present invention have a broad therapeutic and preventive spectrum of action against morbid changes that can be traced back to damage by "AGAS" (the aerobiospheric genetic adaptation system).

20 In order to elucidate the term "AGAS", the following are the main tissues and organs that form this system.

(a) all biological interfaces in contact with the external air such as the biosphere (skin and skin formation, eye cornea and conjunctiva, oral and pharyngeal cavities, respiratory tract and lung); B) skeleton and joints (tubular and spongy bones, joints, synovial membranes, skeletal muscle); (c) the organs involved in the regulation of the ion household (transepithelial transport system: intestinal tract and renal duct); (D) the teodets necessary for the comminution of the nourishment (rooted in the tooth anaolobes); (e) hearing, smell and voice organs.

Thus, the compounds of this invention exert a favorable biological or therapeutic effect on the organs or tissues of the AGAS system herein.

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DK 155672 B

In addition, the compounds of the present invention act upon the following functions associated with the AGAS system: radiation protection, favor of wound healing, common activating effect on mesenchymal, protection against the ever-increasing infection and contamination hazards of skin and mucous membranes ( the lysozyme production of the moist mucosa, activation of the gut epithelium in the respiratory tract, etc.), increased protection against the infections caused by viruses and fungi.

The 10 compounds made by the process of the invention are effective against the ever-increasing stress effects associated with mainland life (e.g., meteorological influence, large differences between day and night temperature, increased risk of injury) as they stabilize. adaptation syndrome and at the same time mitigates the peripheral tissue damage of the glucocorticoids (such as damage to the connective tissue, injuries to bone matrix components, etc.). Development of immune homeostasis (increasing body recognition of which cells are suitable and which are not).

The binding compounds produced by the process according to the invention exert their effect, both directly and partly through the regulation of vitamin A metabolism, in the production of vitamin A metabolites of a stronger polar nature. This effect is comparable to the effect of the parathormone on the 25-hydroxycholecalciferol-Ια-hydroxylase enzyme in the renal tract. The directions of action of the precursors are as follows: A) Vitamin A character effects: a) Pharmacological and biochemical effects: increasing effect on chondroitin sulfate synthesis; beneficial effect on the wound healing or on the experimentally reduced wound healing in cortisone in rats and dogs; potentiating effect on vitamin A's effect in rats and chickens in experimentally induced hypo- or hypervitaminoses; attenuating effect on the ulceration-related stress effects in rats; beneficial effect on the degranulation of mastocytes; increasing effect on the production of lysozyme; effect on household traceability (silicon, zinc, copper, manganese, fluorine); promoting effect on epithelial formation; promoting effect on the alkaline phosphatase activity; 3

DK 155672 B

the effect on the granuloma bag formation (Granulomsackbildung) caused by local action of vitamin A; the extremely flat course of the dose-effect curve or the change of effect sign at large doses; activating effect on the Golgi apparatus; 5 favoring the formation of mucus or goblet cells; increasing effect on the concentration of vitamin A.

b) Clinical-therapeutic effects: keratoconjunctivis sicca; Sjogren's syndrome; rhino-laryngo-pharingitis sicca; ozæna; 10 chronic bronchitis; sinobronchitis; mucoviscidosis; constitutional lung disease in young children; periodontal disease; skin and mucosal susceptibility to viruses and fungi; cortisone antagonistic effect; beneficial effect on healing of operative and mucosal wounds; erosio colli; pruritus-like disorders; reduction of 15 sense of smell and taste.

B) Effects without vitamin A grade 20 (a) Pharmacological and biochemical effects: effect on blood sugar levels with a transient decrease; increasing effect on phosphaturia, lowering effect on serum phosphate level; radiation protective effect; reducing the time required to reach the goal of maze trials in 25 inactivated animals; diminishing effect on experimentally induced fluorine and cadmium toxicosis; increasing effect on the cyclic adenosine monophosphate depletion of the kidneys; attenuating effect on the symptoms of experimentally induced lathyrism; decrease in histamine sensitivity; enhancing effect on the activity of liver enzyme tyrosine aminotransferase.

b) Therapeutic effects: weak radiation damage; vitiligo; muscle hypotonia; psychoenergetic effect; beneficial effect on involutional and gerontological conditions as well as on the mnestic functions; keloid inclinations; spondylosis ankylo-

3 S

poetica; diseases of the movement organs due to wear and tear; scle-rotic fundus; amyloidosis; morphea; fibrocytic mastopathy.

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DK 155672 B

In the veterinary medicine, the compounds of the invention have similar fields of application as in human medicine, ie. eg skin damage (peeling), wound healing and bone fractures.

The process according to the invention is characterized in that the characterizing part of the claim claims.

The process according to the invention is illustrated in the following by way of example.

Example 10 "4.68 ml (5 mmol) of phosphorus oxychloride is added dropwise with cooling and stirring in 1.8 ml of water (Biochem. Preparations 6, 76, 1958). To the solution is added, in small portions, 1.9 g (l0 mmol) of yL-glutyl-mycolamine (prepared from carbobenzyloxy-γ- (a-benzyl) -L-glu-1-s-tamilkolamine). · The mixture is heated to 60 ° with stirring. C for two hours and, after cooling, 0.72 ml of water is added with stirring and the reaction mixture is left at room temperature for two hours. Then, with stirring, 10 ml of 96% ethyl alcohol and then 10 ml of ether are added dropwise. The reaction mixture is left at 4 ° C overnight and then 5 ml of 96% ethanol is added. The precipitate is filtered off, washed first with ethanol and then washed. with ether and finally recrystallized from a mixture of ethanol and water. 1.75 g of γ-L-glutamylcolamine phosphate is obtained.

^ Biological Study γ-Glutamyl-Colamine Phosphate. a) Effect on blood sugar level

Control group 104 mg% Treatment group 93 mg%

Significance: P <0.05

20-20 rats were used for the samples. The measurements were carried out after 18 hours of fasting. The dose used was 1 µg / kg body weight for 4 days in the form of a solution by oral administration.

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DK 155672 B

5 b) Increasing effect on serum vitamin A level

Oral dose Vitamin A effect yg / 200 g body weight yg% ______ 0 (control) 8.8 5 5 12.3 1 13.4 0/3 14.3 0.1 16.0 0.05 15.5 10 0 , 01 11.2 0.005_9j2_

Significance: P <0.01 15 For the experiments, 20-20 Wistar male rats weighing 200-220 g were used.

Trial period: 6 days.

c) Effect on blood silicon level: ^ Silicon (mg / g blood) 0 hours_20 days_40 days_

Control group 0.106 + 0.011 0.136 + 0.017 0.159 + 0.022

Treatment group I 5 µg / day 0.096 + 0.009 0.311 + 0.016 ** 0.340 + 0.017 25 Treatment group vv vv II 10 µg / day 0.111 + 0.011 0.374 + 0.1211 0.365 + 0.019 ** 35

Significance: P <0.001

The results are significant from the 13th day at the significance level P <0.01 and from the 20th day at the level P <0.001.

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The experiments were performed on inbred male rabbits of body weight 2.5-3 kg. The active ingredient was administered orally in the daily doses shown in the table. The determination of silicon was performed according to Gaubatz's method (Gaubatz E., Clin. Wschrft. 14, 1753, 1935) in 5 ml of blood samples taken from the animals' ears.

DK 155672 B

6 d) The effect of γ-glutamyl-colamine phosphate and vitamin A on the granuloma-causing effect of water implantation: __

Dose Weight of dried granuloma

Vitamin Ax γ-glutamyl mg 5 Local Colamine Phosphate mg Local Oral _g g / day__

Control group I. - - “49 + 1/2

Control group II. + Solvent - “” 50 + 2.9 1 ® Treatment Group III. 2 - - 61 + 12.0

Treatment Group IV. 2 0.1 - 62 + 2.1

Treatment group V. - - 0.1 74 + 2.3

Treatment Group VI. 2 - 0.1 91 + 3.9 x Hoffmann la Roche 15,

The differences are significant as follows:

Between groups II and III P <0.05, between groups II and V P <0.001 and between groups V and VI P <0.01.

The determination of granuloma was performed on male Sprague-Dawley body weights 110-120 g by the method of Lee et al (Lee KH, Fu Ch.Ch., Spencer MR Tong TG and Poon RJ, Pharm. Sci. 62, 895, 1973). . The dorsolaterally subcutaneously implanted tampons were removed after 10 days and measured after drying at 65 ° C to constant weight.

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The investigated compound γ-glutamyl-colamine phosphate has unprotected C-terminal group and N-terminal group. Compounds of general formula I having one or two protecting groups, i. wherein R 3 "is different from hydrogen and / or where A 1 is different from hydroxy has the same biological effect as the corresponding 30 unprotected compounds, one having to expect the protecting groups to be cleaved in the organism.

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Claims (2)

R 1 -NH-CH-COA 1 (CHO) I in 2 n CO-N- (CH 2) t-OPO (OH) 2 R 10 where in A is hydroxy, C ^^ alko alkoxy or phenyl-C ^^ al alkoxy, R is hydrogen or C ^ alkyl alkyl alkyl, R ^ is hydrogen, ^ al alkoxycarbonyl or phenyl-C ^^ al alkoxycarbonyl, 15. is 1 or 2 and t is 2 or 3, or a physiologically acceptable salt thereof or an optical active isomer thereof, characterized in that a racemic or optically active compound of the general formula R1-NH-CH-COA1 (CEL) II, 2 n CO-N- (CH2) t-OH Wherein A, R, R, n and t have the meanings given above, are esterified with phosphoric acid or phosphorus oxychloride, and if necessary, the compound thus obtained is partially hydrolyzed and / or, if desired, converted to a physiologically acceptable salt or released from a salt and / or prepared in optically active form by decomposing a won racemic product. 35