The method of obtaining derivatives of 2-formylbenzeneboronic acid

 

(57) Abstract:

Usage: in the chemistry of organophosphorus substances, in particular in the synthesis of intermediates for production of antiviral drugs in medicine. The inventive product derivatives of 2-formylbenzeneboronic acid in the form of the free acid or in the form of R1, R2di(same or different) alilovic esters, or salts. Reagent 1: 2-formylbenzeneboronic. Reagent 2: the three R1, R2, R3- alkylphosphate. Reaction conditions: in a medium of an organic solvent at 100 to 250°C. table 4.

The invention concerns a method of obtaining new derivatives of 2-formylbenzeneboronic acids used for preparation of viral preparations, which contain the active compounds in accordance with the invention.

For treatment caused by viruses of diseases was used up to the present time, various drugs such as nucleoside analogues, amantadine, analogues of pyrophosphate or immunomodulators (M. I. Wood, A. M. Geddes, The Lancet, 1987, 1189) [1] Known some derivatives of phosphonic acids, which possess antiviral activity. These include such compounds as postemergence acid [2] methylenediphosphonic acid, and Gina acid has a wide range of anti-virus, however, causes some toxic side effects, which were hitherto hindered the spread as medicine (M. I. Wood, A. M. Geddes, The Lancet 1987, 1189). On derivatives of ortho-phosphoryloxy-acetophenone derivatives known that they are particularly active against picornaviruses (European application 21000).

Diana and others (I. Med. Chem. 27, 1984, 691, DOS, 2922054) reported the class of compounds of type A C, where a represents an aromatic ring and With phosphonate or-keto-phosphonate, and a and C are separated from each other by a bridge of 3 to 8 methylene groups. Of this class of compounds arylalkylamine acid with methylene bridges with more than 5 carbon atoms showed antiviral activity against herpes viruses.

Arylalkylamine acid with methylene bridges with less than 5 carbon atoms, however, showed no antiviral activity. Replacement of the aromatic residues of these compounds perform at Diana al. basically using 2-chloro, 4-methoxy - or 4-caretakership.

Benzylphosphonate acid hitherto not been described as active antiviral compounds (I. C. H. Mao et al. Antimicrob. Agents Chemother. 27, 1985, 197) [3]

Unexpectedly, it was found that derivatives of 2-f is therefore the compounds of formula I, in which R means an aldehyde group or a group which can be converted to the aldehyde,

R1and R2which may be identical or different, denote a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkenylphenol or alkenylphenol group with 2-20 carbon atoms, aracelio group with 7-20 carbon atoms, cycloalkyl group with 3-8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or

R1and R2together form a cyclic fluids with 2-6 carbon atoms in the ring;

R3and R4which may be identical or different, denote a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkylamino or alkenylphenol group with 2-20 carbon atoms, cycloalkyl group with 3-8 carbon atoms, alkoxygroup with 1-4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine;

R5, R6, R7and R8which may be identical or different, denote a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkenylphenol or alkenylphenol group with 2-20 carbon atoms, oralchroma, hydrogen, fluorine, chlorine, bromine, iodine, cyanide, hydroxyl or phenyl group or a residue of formula 1A

OR19(Ia) where R19means a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkenylphenol or alkenylphenol group with 2-20 carbon atoms, aracelio group with 7-20 carbon atoms, cycloalkyl group with 3-8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium and

X, Y and Z may be the same or different and are oxygen or sulfur, or dosage form of the compounds of formula 1.

The compound of the formula I, in which R1and R2mean alkyl group with 1-10 carbon atoms, alkenylphenol or alkenylphenol group with 2-10 carbon atoms, hydrogen or aracelio group with 7 to 16 carbon atoms,

R3and R4alkyl group with 1-4 carbon atoms, alkenylphenol or alkenylphenol group with 2-4 carbon atoms or hydrogen,

R5, R6, R7and R8mean chlorine, bromine, methoxy or hydrogen and

X, Y, and Z means oxygen, are preferred.

Called "Palekastro I, in which R means an aldehyde group. In the article by H. Bundgaard (Design of Prodrugs, 1985, c. 1-92, Elsevier Verlag) defines the name of the "active form" and illustrated by examples.

Called an alkyl group with 1-10 carbon atoms, it should be understood for example the following residues: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 2,2-dimethyl-1-propyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. Under the designation Alchemilla group with 2-10 carbon atoms for instance, one should understand the following connections: ethynyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonanol or decenyl. Called Alchemilla group with 2-10 carbon atoms should be understood, for example, the following connections: ethinyl, PROPYNYL, butynyl, pentenyl, hexenyl, heptenyl, nonini, octenyl or decenyl. Under aranceles group with 7 to 16 carbon atoms should be understood, for example, the following residues: phenylmethyl, phenylethyl. phenylbutyl, phenylpropyl, fenilpentil, phenylgesic, finalgather, phenylethyl, feilner or feildel. Under cycloalkyl group with 3-8 carbon atoms should be understood remains as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Alkoxygroup with 1-4 carbon atoms that ostatnie concerned, in addition, the method of producing compounds of the formula I, in which R means an aldehyde group, which is characterized in that the compound of formula II

where R3and R4may be the same or different, represent a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkylamino or alkenylphenol group with 2-20 carbon atoms, cycloalkyl group with 3-8 carbon atoms, alkoxygroup with 1-4 carbon atoms, hydrogen, fluorine, chlorine, bromine or iodine;

R5, R6, R7and R8which may be identical or different, denote a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkenylphenol or alkenylphenol group with 2-20 carbon atoms, aracelio group with 7-20 carbon atoms, cycloalkyl group with 7-20 carbon atoms, alkoxygroup with 1-4 carbon atoms, hydrogen, fluorine, chlorine, bromine, iodine, cyanide, hydroxyl or phenyl group or a residue of the formula Ia, in

OR19which R19means a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkenylphenol or alkenylphenol group with 2-20 carbon atoms, aracelio group with 7-20 atoms ugley or triethylamine and

T means chlorine, bromine, iodine, methylsulfonate,phenylsulfonyl or tosylchlora, is subjected to the interaction with the compound of the formula III

P where R1and R2which may be identical or different, denote a linear or branched alkyl group with 1-20 carbon atoms, a linear or branched alkenylphenol or alkenylphenol group with 2-20 carbon atoms, aracelio group with 7-20 carbon atoms, cycloalkyl group with 3-8 carbon atoms, hydrogen, sodium, potassium, calcium, magnesium, aluminum, lithium, ammonium or triethylammonium or

R1and R2together form a cyclic fluids with 2-6 carbon atoms in the ring;

R9means a linear or branched alkyl group with 1-4 carbon atoms and

X, Y and Z, which may be identical or different, denote oxygen or sulphur.

The invention relates, furthermore, the method of obtaining the compounds of formula I in which R is transferred to the aldehyde group, which is characterized in that the compound of the formula I, in which R is an aldehyde, thus subjected to the interaction that appears to be translated to the aldehyde group.

Under the title "translatable to the aldehyde group" should be understood and, the aldehyde group can thus be subjected to change, what will be the compound of the formula I, in which R is transferred to the aldehyde group of the formula Ib, IC or 1d.

R16Min which R10and R11which may be identical or different, denote a linear or branched alkyl group with 1-10 carbon atoms or

R10and R11together form a cyclic acetal with 2-3 carbon atoms in the ring,

R12-R16which may be identical or different, denote a linear or branched alkyl group with 1-10 carbon atoms or alkyl group with 6, 10 or 14 carbon atoms;

Y represents oxygen or sulfur;

M a hydroxyl group, a linear or branched alkyl group with 1-10 carbon atoms, aracelio group with 7-20 carbon atoms, aryl group with 6, 10 or 14 carbon atoms or a residue of formula I or I I f

OTHER17OR18in which R17straight or branched alkyl group with 1-10 carbon atoms, amino, pyridine or aryl group with 6, 10 or 14 carbon atoms and

R18amino group, a pyridine group, a linear or branched alkyl group with 1-10 carbon atoms, arylene formula I, in which R means an aldehyde group, carried out by the interaction of the compounds of formula II with the compound of the formula III expediently at temperatures between 100 and 250aboutWith, preferably between 120 and 180about(U.S. patent N 4299615; [4] Houben-Weyl. Methods org.chemistry, volume XII/I, page 423; volume E2, page 300). The interaction can be carried out in a suitable solvent, amide as hexamethylphosphoric acid, dimethylformamide, dimethylsulfoxide, N,N'-dimethyl-N,N'-propylenimine or N,N'-dimethyl-N, N'-etilenmocevina. The reaction can also be performed without solvent. Cleaning is carried out, as a rule, by conventional methods, preferably by chromatography through silica gel with a suitable eluent, by distillation or by recrystallization from a suitable solvent.

The compounds of formula II and formula III can be obtained by known methods. The transfer of diapir posterboy acid in its monoether, as well as the corresponding free acids or their salts carried out for example by boiling with dilute hydrochloric acid (Houben-Weyl, Methods of org.chemistry, volume XII/I, 1963), or by interacting with trimethylsilanol (C. E. Mekenna, I. Schmidhauser, I. C. S. Chem. Commun. 1979, 739). Purification is carried out by recrystallization in a suitable Rostvertol. In the ion-exchange chromatography can be obtained the desired salt form.

Syntheses proletarienne forms of the compounds of formula I can be accomplished, for example, the fact that the aldehyde group in the compounds of formula I thus change that connections get type Asimov thiosemicarbazones, carboxylic acid hydrazones, Schiff's bases, oxazolidines, thiazolidines or acetals. Moreover, the compounds of formula I, in which R means an aldehyde group, can be subjected to reaction with the compound of the formula IVa, IVb and/or IVc, IVd, or IVe

HO()H2RH RH

R MNH2where R10-R16, M and Y have the abovementioned meanings and n is 1 or 2.

Other proletarienne forms get similar methods described in Bundgaard.

Changed to the aldehyde group of compounds of formula I in vitro or in vivo can be transferred to the active antiviral forms (aldehyde form) (H. Bundgaard, Design of Prodrugs, 1985, 1-92). Translated into active form can be accomplished by hydrolysis in an aqueous solution or as the result of enzymatic catalysis, or any other way.

Test for the activity of chemotherapeutic means for HIY infection in humans is associated with A tools you need so you can refer to infection by other retroviruses. In this case, opt for the infection of mice with virus leukemia. For that infect normal mice by intravenous injection of Friend virus leukemia serum to mice. In the case of untreated control samples as a symptom of infection within 2 weeks developing a clear enlargement of the spleen and liver. Treatment is carried out over 10 days, starting 48 h after infection. On the 14th day of the experience of the animals were killed and dissected. The spleen was removed and weighed. As the parameter measuring therapeutic efficacy used the weight of the spleen of the treated animals compared with the weight of untreated control animals.

In the case of uninfected grown in mice (20-24 g body weight) spleen weighed approximately 1% of body mass or less, while in infected animals the spleen to the end of the experiment weighed approximately 10% of the body weight.

The compound of the formula I, in which R means an aldehyde group, possess valuable pharmacological properties, in particular, antiviral activity, namely as diseases caused as DNA - and RNA-viruses, in particular, against diseases that are caused by Friend leukemia virus (H. Y. I) misogny therefore to struggle with various diseases, caused by viruses like respiratory, skin, eye, Central nervous system, AIDS in various States, as related to AIDS kompleksov (ARS), the generalized lympadenopathy (PGL) related AIDS neuralgias conditions (such as dementia or tropical paraparesis), anti-HIY-antibody-positive status, Kaposi-sarcoma or thrombopenia purpura.

The compounds of formula I and/or their proletarienne form can be used independently or with physiologically compatible auxiliary means or media in effective amounts as drugs. They can be administered, for example, orally at a dose of 1-500 mg/kg/day, preferably 5-50 mg/kg/day. The parenteral, rectal or tapicerki or in aerosol form is carried out, for example, in dosages of 0.5-500 mg/kg/day, preferably 2-100 mg/kg/day. The compound of the formula I and/or its proletarienne form is made preferably in dosage units, which at least contain an effective amount of the compounds in accordance with the invention, preferably 25-6000 mg, and particularly preferably 100-1000 mg These values are for adults with an average weight is. In many cases, sufficient and smaller amounts. For the treatment of diseases caused by RNA and DNA viruses, especially suitable: diethyl ether 2-formylbenzeneboronic acid, detritylation salt of 2-formylbenzeneboronic acid, triethylammonium salt monoethylene ether 2-formylbenzeneboronic acid, thiosemicarbazone diethyl ether 2-formylbenzeneboronic acid hydrazone nicotinic acid 2-formylbenzeneboronic acid diethyl ether or diethyl ether 2-(3,4-dimethyl-5-phenyloxazolidine-2-yl)-benzylphosphonic acid.

The compound of formula I in accordance with the invention and/or its proletarienne form can be issued also in combination with other substances, in particular, antiviral compounds and stimulants of the immune system, as interferons. The compound of the formula I and/or its proletarienne form is further characterized by active substances.

The invention comprises, in addition, the use of active substances in the manufacture of medicinal preparations used in the treatment and prevention of these diseases. Another subject of the invention are pharmaceutical preparations which contain one or more act is the quality of medicinal products the active substance used either as such, or preferably in combination with suitable pharmaceutical auxiliary means or media in the form of tablets, pills, capsules, suppositories, emulsions, suspensions or solutions, the active substance is up to 95%, preferably 10-75%

Suitable excipients or carriers for the respective drugs are, for instance, along with solvents, geleobrazovanie, bases for suppositories, tablets and other carriers of active substances, antioxidants, dispersing funds, emulsifiers, antispyware, preservatives and substances imparting taste, substances that contribute to the dissolution of the dye.

The active substance can be entered orally, parenterally, intravenously or rectally, along with oral introduction preferably also intravenous administration of the aerosol.

For oral forms of application active substance is mixed with appropriate additives as carriers, stabilizers or inert diluents and the conventional methods turn the mixture into suitable forms such as tablets, coated tablets, capsules, aqueous or oil solutions. As the inert wears is whether starches, in particular corn starch. This can be done in the manufacture of both dry and wet granulation. As oily carriers or solvents should be borne in mind, for example, vegetable or animal oils as sunflower oil or cod-liver oil.

For subcutaneo or intravenous administration, the active substance is transferred into a solution, suspension or emulsion with the aid of solvents, emulsifiers or other auxiliaries. As a suitable solvent, for example, physiological saline, alcohols, like ethanol, propanol, glycerol, solutions of sugar, as glucose or mannitol, or a mixture of solvents.

P R I m e R 1. Getting diethyl ether 2-formylbenzeneboronic acid (A).

47.9 g (0,31 mol) of 2-chloromethylbenzene together 51.5 g (0,31 mol) of triethylphosphite heated to 160aboutC. When this is distilled to ethylchloride. The product was then purified by fractional distilleries.

Output: 64,59 (81%), So Kip. 130aboutC/0.3 mm

1N-DMR (270 MHz, CDCl3(TMS): of 1.23 (t, 6H, P-O-CH2-CH3), of 3.78 (d, 2H, CH2-P), JR-N24 Hz, Android 4.04 (dg, 4H, P-O-CH2-CH3), 7,19-of 7.97 (m, 4H, Ar-H).

P R I m m e R 2. Getting detritylation salt of 2-forms is you (With).

5.0 g (20 mol) of diethyl ether 2-formylbenzeneboronic acid is mixed with 100 ml of 6 M HCl and boiled for 6 hours at the boiling temperature of phlegmy. Water and HCl is distilled off under vacuum, washed three times with toluene. The remaining brown mass chromatographic through silica gel (CH2Cl2) methanol/triethylamine 75/24 (I). Get the connection and in the form of an oily product. They can be separated by chromatography through diethylaminoethylRthe Sephadex A25 (Et3NH+form, company pharmacy Freiburg, Germany). They vary in value uderzhivaemoi (Rf value). Elute with a gradient by triethylammonium 0.3 to 1.0 M

(In): Rf 0.1, yield 2.4 g (30,),1N-DMR (270 MHz, DMSO/TMS): 1,07 (t, N, N-CH2-CH3), 2,86 (g, N, N-CH2-CH3), 3,23 (d, 2H, CH2-P) JP-H23 Hz, 7,24 for 7.78 (m, 4H, Ar-H), 10,31 (s, 1H, CHO).

(C): Rf Of 0.3. Yield 1.4 g (21%),1N-DMR (270 MHz, DMSO/TMS): 1,01-1,17 (m, 12H, N-CH2-CH3and P-O-CH2-CH3), 2,88 (g, 6H, N-CH2-CH3), with 3.27 (d, 2H, CH2-P) JR-N23 Hz) 3,68 (dg, 2H, P-O-CH2-CH3),7,18-7,78 (m, 4H, Ar-H), 10,31 (s, 1H, CHO).

P R I m e R 3. Getting detritylation salt 2-formylbenzeneboronic acid (In).

To 2.0 g (8 mmol) of the compound in 10 ml of absolute dioxane is added dropwise to relax is mperature. Evaporated several times mixed with water and lyophilizers. The crude product is purified by chromatography as in example 2.

Yield 1.98 g (62%).

P R I m e R 4. Thiosemicarbazone diethyl ether 2-formylbenzeneboronic acid.

2.0 g (8 mmole) of the compound, and 0.78 g of thiosemicarbazide dissolved in 200 ml of absolute ethanol or suspended. Add 2 ml of acetic acid and boiled for 3 hours at the boiling temperature of phlegmy. During long-term cooling, distilled product 1.

Yield 1.8 g (68%), So pl. 195-197aboutC,1N-DMR (270 MHz, Dl3)TMS of 1.16 (t, 6H, CH2-CH3), to 3.38 (d, 2H, CH2-P, JR-N23 Hz, 3,94 (dg, 4H, CH2-CH3), 7.23 percent-7,39 (m, 3H, A-H) of 8.40 (s, 1H, Ar-H), 11,37 (s, 1H, Ar-CH=N).

P R I m e R 5. Hydrazone nicotinic acid diethyl ester 2-formylbenzeneboronic acid.

2.0 g (8 mmol) of compound a and 1.07 g (mmol) nicotinic acid hydrazide are dissolved in 30 ml of absolute ethanol. After adding 1 ml of acetic acid is boiled for 8 hours at the boiling temperature of phlegmy. The solvent is evaporated, the residue chromatographic through silica gel (eluent CH2Cl2) ethyl alcohol of 9.5/0.5 to Rf of 0.45. Food E get in crystalline form.

Yield 2.2 g (73% ), So pl. 136-1416 (m, 4H, CH2-CH3), 7,11-7,49 (m, 4H, Ar-H), 7,70-9,23 (m, 5H, Py-H), 10,17 and at 11.25 (s, 1:3, 1H, NH).

P R I m e R 6. Diethyl ether 2-(3,4-dimethyl-5-phenyloxazolidine-2-yl)-benzyl - phosphonic acid.

2.0 g (8 mmol) of compound a and 1,32 (8 mmol) of (-)-ephedrine dissolved in 100 ml of benzene and 24 h boil with the water trap at the boiling temperature of phlegmy. After that, the solvent is evaporated, the residue chromatographic through silica gel (eluent CH2CL2) ethanol and 9.5 (0,5) Rf of 0.55. Product E is obtained as oil.

Yield: 2.4 g (75%),1N-DMR (270 MHz, Dl3/TMS): 0,80 (d, 3H, CH-CH3), 1,25 (m, 6H, O-CH2-CH3), and 2.27 (s, 3H, N-CH3), 3,18 (dg, 1H, CH-CH3), 3,20 and of 3.28 (dd, 1H, Ph-CH-CH), 3,59 is 3.76 (m, 2H, CH2-P) to 4.01 (m, 4H, O-CH2-CH3), 5,19 (s, 1H, Ar-CH, 0 - N), 7,16 was 7.45 (m, 8H, Ar-H), 7,89-7,98 (m, 1H, Ar-H).

P R I m e R 7. Free from diseases named laboratory mice weighing about 15 g administered intraperitoneally infected Herpex simplex type 1, and then immediately processed the named table.1 compounds administered intraperitoneally, orally or subcutane. Processing was carried out twice a day over 2.5 days, starting after infection. The results of the processing were determined depending on the illness and the degree of survival compared with neobarb directorial methylhydroxyethylcellulose (viscosity 300 PS in 2% solution). Experiments were performed with groups of 5 mice on the drug.

The chemotherapeutic action of compounds And can be seen from the table.1.

P R I m e R 8. Cell culture hela and Vero cells were inoculated in micromicrofarad plates and were infected with myxoviruses (influenza A2). After 2 h after infection were added In connection With infected culture cells at different dilutions. 48-72 h after infection was determined therapeutic effect depending on cytopathogenic effect microscopically and photometrically after making neutral red (test for staining on Pintero) (Pinter N. B. Interferon, 1966). The minimum concentration at which about half of the infected cells showed no cytopathogenic effect, took over the minimum concentration of inhibition (OLS). The results are shown in table.2.

P R I m e R 9. Free from diseases of mice (laboratory) with a weight of about 16 grams intranasal were infected with influenza A2 and immediately thereafter was treated therapeutically named table.3 connections subcutane and orally. Connections were made to the animals under light anaesthesia with drops of viral suspension into the nose. Processing of data was performed twice a day over 2.5 days, starting after C is zabolevaniya and degree of survival compared with untreated infected control animals. Control animals received instead of the tested compounds water-soluble methylhydroxyethylcellulose (viscosity 300 P. with 2% solution). Experiments were performed with groups of 5 mice on the drug.

Chemotherapeutic effect is shown in table.3.

P R I m e R 10. Mice weighing 20-24 g, female mice were infected intravenously mouse serum containing the Friend virus-leukemia (FIV). After 48 h after infection has begun processing. After 10 days, mice were treated with substances listed in table.4. Once per day, these substances were administered orally or administered intraperitoneally. 14 days after infection, animals were killed by paralysis and removed the spleen. The weight of the spleen was determined. As the parameter measuring therapeutic efficacy of the weight of the spleen of the animals that were treated with compounds a and b, compared with the control untreated infected animals.

As a standard substance served as suramin, azidothymidine (AZT). The drug can be seen in the table.4.

The METHOD of OBTAINING DERIVATIVES of 2-FORMYLBENZENEBORONIC ACID of General formula

< / BR>
where R1and R2identical or different, are hydrogen, alkyl or coloradosprings interaction with trialkylphosphites General formula

< / BR>
where R1, R2and R3alkyl,

with subsequent isolation of the desired product in the form of ether or transfer it if necessary in the acid or its salt.

 

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FIELD: medicine, ophthalmology.

SUBSTANCE: one should apply an autohemocomponent preparation being supernatant liquid of patient's autoblood at increased serotonin content obtained due to irreversible thrombocytic aggregation due to the impact of 0.5 mg ATP per 1.0 ml plasma followed by a 30-min-long centrifuging at the rate of 1000, 2000 and 3000 rot./min for 20, 7 and 3 min, correspondingly. In case of no exudative phenomena on patient's eye bottom the obtained preparation should introduced at the quantity of 7-10 ml once in 48 h for 1 mo (totally, 15 injections). In case of exudative-hemorrhagic phenomena it should be introduced parabulbarly at the volume of 0.5 ml and parenterally - 7.0-10.0 ml once in 48 h for 1 mo per 15 injections, correspondingly. The preparation enables to improve visual functions due to decreased tissue hypoxia and normalization of microcirculation in visual analyzer.

EFFECT: higher efficiency of therapy.

2 cl, 7 dwg, 2 ex

FIELD: medicine, ophthalmology.

SUBSTANCE: one should apply an autohemocomponent preparation being supernatant liquid of patient's autoblood at increased serotonin content obtained due to irreversible thrombocytic aggregation due to simultaneous impact of 0.5 mg ATP per 1.0 ml plasma followed by a 30-min-long centrifuging at the rate of 1000, 2000 and 3000 rot./min for 20, 7 and 3 min, correspondingly. Preparation should introduced parabulbarly at the volume of 0.5-1.0 ml, parenterally - 7.0-10.0 ml once daily at 20 injections for 1 mo. The method enables to increase visual functions due to normalization of functional activity of photoreceptors and neurons of internal layer in retinal peripheral departments.

EFFECT: higher efficiency of therapy.

1 cl, 2 ex

FIELD: coordination compounds synthesis.

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EFFECT: increased assortment of complexes with useful medicine-destination properties.

14 cl, 4 dwg, 30 ex

FIELD: experimental medicine.

SUBSTANCE: on should introduce solution into fracture area at the following ratio of ingredients, g/l: 1-hydroxyethylidenediphosphonic acid 1.80 - 2.06, water-free calcium chloride 1.44 - 2.22, gadolinium (III) nitrate hexahydrate 0.30 - 0.40, dysprosium (III) chloride hexahydrate 0.038 - 0.076, moreover, solution's pH corresponds to 7.3 - 7.8. The present innovation enables to shorten the process of bony tissue regeneration in the site of its lesion or defect and, also, shorten the period for restoring normal physiological function of traumatized bone.

EFFECT: higher efficiency of regeneration.

22 ex, 1 tbl

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