(57) Abstract:The invention relates to new derivatives of 4-aseankorea General formula (1),
< / BR>in which R is hydrogen or C1-3alkyl group; X is chlorine, bromine or iodine and is a single or double bond. 2 S. p. f-crystals. The invention relates to new derivatives of 4-aseankorea General formula (1)
< / BR>in which R is hydrogen or C1-3alkyl;
X is chlorine, bromine or iodine and
- single or double bond.In addition, the invention relates to a method for producing these compounds.Compounds of General formula (1) can be advantageously used for producing compounds inhibiting the enzyme 5-reductase. For the synthesis of the compound of General formula (1) is injected into the reaction with primary or secondary alkylamino mainly in the medium of dimethylformamide in an atmosphere of carbon monoxide in the presence of palladium (II) acetate, triphenylphosphine and triethylamine, and then, if desirable, the double bond derived16- 17-carboxamide catalytically hydronaut (see examples 9 and 10).Inhibitors of the enzyme 5-reductase delay the transformation of testosterone into dihydrotestosterone, so you can use them for) of hirsutism.It Is Known [J. Chem. Soc. pages 470 + -476 (1962)] that the 17-iodine-androsta-5,16-Dien-3-ol are obtained by reaction of the 17-hydrazone-derived DHEA with elemental iodine in tetrahydrofuran in the presence of triethylamine. Using pregnenolone-20-hydrazone as raw materials, such reaction conditions can be obtained 20-iodopsin-5,20-Dien-3-ol.Further development of the above method by examining the influence of grounds and water are given in other literature (Tetrahedron Letters 24, pages 1605 to 1680 (1983)). According to this publication 17-hydrazone of DHEA is also used as a raw material, but as the Foundation of applied tetramethylguanidine. The example also serves as a transformation of the derivatives of non-steroidal hydrazone.The interaction of hydrazone derivatives with N-bromo - or N-chloro-succinimide discussed in the publication (Chern. Pharm. Bull. Japan 11, pages 1413 to 1417 (1963)). In accordance with this publication is derived 17-hydrazone of epiandrosterone used as raw material, which reacts with N-bromo - or N-chlorosuccinimide. This reaction occurs completely within a few minutes, which can be seen on the termination of nitrogen excretion. After infusion in water, the reaction mixture is extracted, the x2">This method also published in the patent N 171166 (Hungary). In this way hydrazone androst-2-EN-17-one enter into reaction with N-halogenating in pyridine at a temperature of from -30oC to +20oC to obtain the final product "vinyl Gallinago type".In accordance with our invention to provide new compounds of General formula (I) includes:
a) interaction of the compounds of General formula (II)
< / BR>in which R and relationships defined above, with elemental iodine in the presence of a base in the form of tertiary amine in a halogenated or aromatic hydrocarbon solvent, or mixtures thereof, or in the solvent of the ether type,
to obtain the compounds of General formula (I) containing iodine as X; or
(b) coordination compounds of General formula (II) in which R and relationships defined above, with N-chloro - or N-bromosuccinimide, respectively, in pyridine, optionally substituted by one or more C1-4alkyl group (the group) as solvent at a temperature of from -10oC to +10oC,
to obtain the compounds of General formula (I) containing chlorine or bromine as X.According to the method (a) iodination preferably carried out at room temperature. CRP iodine is removed by treatment with an aqueous solution of hydrochloric acid, and then sodium thiosulfate. Then the solvent is distilled off and the resulting crude product is purified by chromatography and recrystallization. Iodination preferably carried out in halogenated or aromatic hydrocarbon solvent, preferably chloroform, benzene or mixtures of these solvents or in solvent of the ether type, preferably tetrahydrofuran, in the presence of a base in the form of a tertiary amine, preferably triethylamine or tetramethylguanidine at room temperature.According to the method (b) compounds of General formula (I) comprising chlorine or bromine respectively as X, preferably get by dissolving the compound of General formula (II) in pyridine and then adding parts of N-chloro - or N-bromosuccinimide to the obtained solution at a temperature of from -10oC to +10oC. After completion of the reaction, determined by the termination of the allocation of gaseous nitrogen, the crude product is precipitated by addition of water, filtered, washed with water to remove pyridine, dried and purified by chromatography and subsequent recrystallization. Halogenoalkane N-chloro - or N-bromosuccinimide respectively carried out preferably at a temperature of 0oC.Proizvodi the time.After dissolution (known from literary sources: J. Pharm. Sci. 63, pages 19 to 23 (1974); J. Med. Chem. 27, page 1690 (1984); J. Org. Chem. 46, pages 1442 to 1446 (1981)) 4-Aza-5-androstane-3,17-dione, 4-Asandros-5-ene-3,17-dione or 4-methyl-4-Aza-5-androstane-3,17-dione in ethanol, to the solution add triethylamine and hydrazinehydrate and the reaction mixture is refluxed. After completion of the reaction the excess hydrazine hydrate is added and distilled triethylamine (by evaporation of the mixture to approximately 1/10 of its original volume). The residue is precipitated by adding water, and the residue after filtration was washed with water until neutralization and dried. The resulting crude product can be used to prepare compounds of General formula (I) without any treatment.Example 1. Getting 17-hydrazone-4-Aza-5-androsten-3-one
To a suspension of 10 g (0,0346 mol) of 4-Aza-5-androsten-3,17-dione in 100 ml of ethanol, add 14 ml (0.1 mol) of triethylamine and 50 ml (1.0 mol) of hydrazine hydrate is added and the mixture refluxed for 3 h (the Progress of the reaction is controlled by thin-layer chromatography). After completion of the reaction the mixture is cooled, the solution is evaporated to 1/10 of its original volume, and the product precipitated by adding approximately 10-t to obtain the compounds according to the invention.Yield - 9,44 g (90%), tp: 254-258oC.1H-NMR (300 MHz, CDCl3) million-1: 0,86 (S, 3H, 18-CH3), OF 0.93 (S, 3H, 19-CH3), is 2.41 (m, 2H, H-2), of 3.07 (dd, 1H, H-5), of 4.77 (br, 2H, NH2), 5,74 (br, 1H, NH).Example 2. Getting 17-hydrazone-4-Asandros-5-ene-3-one
Perform the process described in Example 1, except using 4-Asandros-5-ene-3,17-dione as a raw material for obtaining the compounds according to the invention.The yield is 35%, tp: 379-382oC.IR (KBr) : 1633 (C=C), 1661 (C=N), 1693 (C=O), 3200 (NH), 3350 (NH2) cm-1.Example 3. Getting 17-hydrazone-4-methyl-4-Aza-5-androsten-3
Perform the process described in Example 1, except using 4-methyl-4-Aza-5-androsten-3,17-dione as a raw material for obtaining the compounds according to the invention.The yield is 75%, tp: 211-218oC.1H-NMR (300 MHz, CDCl3) million-1: 0,86 (S, 3H, 18-CH3), OF 0.91 (S, 3H, 19-CH3), WITH 2.93 (S, 3H, N-CH3), 3,05 [dd (J = 3,6; J = 12,6), 1H, H-5], 4,78 (v br, 2H, NH2).Example 4. Getting 17-iodine-4-Aza - 5-androst-16-EN-3-one
After dissolution of 9.1 g (0.03 mol) of 17-Gereon-4-Aza-5-androsten-Z-she's in 1200 ml of a mixture of chloroform/benzene 1:1 ratio and add 90 ml of triethylamine polythelene stirred at room temperature for 60-90 min (progress of the reaction is controlled by thin-layer chromatography). After completion of the reaction, the obtained solution is diluted with 500 ml of chloroform and successively washed with: 10% aqueous solution of hydrochloric acid, water, 5% aqueous sodium thiosulfate solution, water, 5% aqueous soda solution and finally with water and dried over anhydrous sodium sulfate. After evaporation of the solution under reduced pressure the residue purified by chromatography on silikagelevye column using first chloroform and then a mixture of chloroform/acetone in a ratio of 95:5 as solvents. The resulting product will recrystallized from ethanol to obtain compounds according to the invention.Yield: 5.9 g (50%), tp: 278-282oC.1H-NMR (300 MHz, CDCl3) million-1: TO 0.73 (S, 3H, 18-CH3), OF 0.91 (S, 3H, 19-CH3), and 3.1 (dd, 1H, H-5), 6,18 (m, 1H, H-16), 6,9 (br, 1H, NH).Using a similar number tetramethylguanidine instead of triethylamine in the above reaction, get the connection according to the invention with a yield of 65% and above physical characteristics.Example 5. Getting 17-iodine-4-Asandros-5,16-Dien-3-one
Perform the process described in Example 4, except 17-hydrazone-4-Asandros-5-ene-3-one as the P CLASS="ptx2">1H-NMR (300 MHz, CDCl3) million-1: 0,78 (S, 3H, 18-CH3), OF 1.13 (S, 3H, 19-CH3), 4,9 [dd (J= 2,4; J=5,1), 1H, H-6], 6,15 [dd (J=3,2; J=1,7), 1H, H-16], of 8.27 (br, 1H, NH).Example 6. Getting 17-iodine-4-methyl-4-Aza-5-androst-16-EN-3-one
Perform the process described in Example 4, except that 17-hydrazone-4-methyl-4-Aza-5-androsten-3-one as starting material and the reaction is carried out in benzene. Get the connection according to the invention with a yield of 57%, tp: 176-181oC.1H-NMR (300 MHz, CDCl3) million-1: 0,74 (S, 3H, 18-CH3), TO 0.92 (S, 3H, 19-CH3), TO 2.94 (S, 3H,N-CH3), 3,07 [dd (J=3,7; J=12,6), 1H, H-5], 6,13 [dd (J=3,2; J=1,7), 1H, H-16].Example 7. Getting 17-chloro-4-methyl-4-Aza-5-androst-16-EN-3-one
A solution of 4 g (0,0126 mol) 17-hydrazone-4-methyl-4-Aza-5-androsten-3-one in 40 ml of anhydrous pyridine is cooled to ABOUToC and a solution of 3.2 g (0,024 mol) N-chlorosuccinimide in 40 ml of pyridine are added dropwise under vigorous stirring. After the termination of allocation of gaseous nitrogen, the reaction mixture was additionally stirred for 15 min and then added dropwise to 800 ml of water. After the seal precipitate the crude product is filtered off, washed with water until neutralization and dried over pjatiokisi phosphorus under reduced pressure and CGA chloroform as solvent. After recrystallization evaporated from petroleum ether residue receive the connection according to the invention to yield 2.15 g (535), tp: 139-140oC.1H-NMR (300 MHz, CDCl3) million-1: 0,88 (S, 3H, 18-CH3), OF 0.93 (S, 3H, 19-CH3), 2,89 (S, 3H, N-CH3), and 3.0 (dd, 1H, H-5), of 5.53 (m, 1H, H-16).Example 8. Getting 17-bromo-4-methyl-4-Aza-5-androst-16-EN-3-one
Perform the process described in Example 7, using 17-hydrazone-4-methyl-4-Aza-5-androsten-3-one as a raw material and N-bromosuccinimide as a reagent, to obtain compounds according to the invention. Yield: 55%, tp: 159-161oC.1H-NMR (300 MHz, CDCl3) million-1: OF 0.82 (S, 3H, 18-CH3), OF 0.91 (S, 3H, 19-CH3), OF 2.86 (S, 3H, N-CH3), and 3.0 (dd, 1H, H-5), of 5.68 (m, 1H, H-16).Example 9. Obtaining 3-oxo-4-Aza - 5-androst-16-ene-17-(N-tert-butyl-carboxamide)
To a solution of 3.99 g (0.01 mol) of 17-iodine-4-Aza-5-androst-16-ene-Z-she's in 150 ml of dimethylformamide was added 0,224 g (0.001 mol) of palladium (II) acetate, 0,524 g (0.002 mol) of triphenylphosphine, 10 ml of triethylamine and 15 ml (0.14 mol) of tributylamine, and the mixture was heated to 60oC in an atmosphere of carbon monoxide within 90 to 120 min (the course of the reaction was controlled by thin-layer gas chromatography). After reaccreditation washed with water, 5% aqueous solution of hydrochloric acid, saturated aqueous solution of soda and water solution of sodium chloride to neutralize and finally dried over anhydrous sodium sulfate. After evaporation of the solvent the residue is chromatographically purified on silikagelevye column, using ethyl acetate as solvent, to obtain a combined according to the invention. Yield: 3,16 g (85%, tp: 292-297oC.1H-NMR (300 MHz, CDCl3) / mn-1: 0,93 (S, 3H, 19-CH3), 1,0 (S, 3H, 18-CH3), AND 1.4 (S, 3H, C(CH3)3), of 2.15 (m, 2H, H-15a + H-15b), and 2.4 (m, 2H, H-2), is 3.08 [dd (J=4,5; J=7,0), 1H, H-5], of 5.48 (br s, 1H, NH), 5,6 (br s, 1H, NH), 6,18 [dd (J=1,7; J=1,4), 1H, H-16].Example 10. Obtaining 3-oxo-4-Aza - 5-androsten-17-(N-tert-BUTYLCARBAMATE)
A suspension of 1 g of palladium-carbon catalyst in 6 ml of water is added to the solution containing 1 g of 3-oxo-4-Aza-5-androst-16-ene-17-(N-tert-BUTYLCARBAMATE)and 40 ml of formic acid in a nitrogen atmosphere. The heterogeneous mixture was stirred at room temperature for 4-5 hours Restoring control thin-layer chromatography. After completion of the reaction the catalyst is filtered off and washed with a mixture of chloroform/methanol in a ratio of 1:1. After evaporation of the combined solution dry octatetraene. Yield: 90%, tp: 283-286oC. 1. Derivative 17-halogen-4-aseankorea General formula
< / BR>where R is hydrogen or C1WITH3-alkyl;
X is chlorine, bromine or iodine;
a single or double bond.2. A compound selected from the group consisting of 17-iodine-4-Aza-5-androst-16-EN-3-one, 17-iodine-4-Aza-androst-5,16-Dien-3-one, 17-iodine-4-methyl-4-Aza-5-androst-16-EN-3-one, 17-chloro-4-methyl-4-Aza-5-androst-16-EN-3-one and 17-bromo-4-methyl-4-Aza-5-androst-16-EN-3-one.
< / BR>where R1radical containing nitroxyl group >NO, and R2=R1or H, which possess antiviral activity against RNA-containing viruses (human immunodeficiency virus and vesicular stomatitis virus) and DNA-containing virus (cytomegalovirus)
SUBSTANCE: method involves carrying out hernia removal in intralaminar way. Posterior longitudinal ligament defect is covered with Tacho-Comb plate after having done disk cavity curettage. Subcutaneous fat fragment on feeding pedicle is brought to dorsal surface of radix and dural sac.
EFFECT: enhanced effectiveness of treatment; reduced risk of traumatic complications.
FIELD: medicine, obstetrics, gynecology.
SUBSTANCE: at the background of therapy conducted one should introduce derinate immunomodulator into the body of pregnant woman additionally nasally per 1-2 drops of 0.25%-solution into each nasal canal 5-8 times daily for 3-5 d and - parenterally per 5.0 ml of 1.5%-solution once daily for 3-8 d along with preparation that improves microcirculation and along with antioxidant at a certain sequence, moreover, derinate should be introduced 30-40 min after application of microcirculation-improving preparation, and antioxidant - 20-30 min after derinate's introduction. The present innovation favors decreased edemas, decreased body weight, stabilization of Macluer-Aldrich test that in its turn enables to avoid perinatal losses, decrease the risk for the development of fetoplacental insufficiency and intrauterine fetal infection.
EFFECT: higher efficiency of therapy.
1 ex, 2 tbl
FIELD: medicine, otolaryngology.
SUBSTANCE: the present innovation deals with introducing neomycin sulfate antibiotic in granules prepared by the following technique. Tablet of neomycin sulfate 1.0g should be put into a vial with 100 ml distilled water till tablet's decomposition. Then vial's content should be shaken and kept till suspension sedimentation. In a day one should take 1 ml of supernatant liquid to be put into another vial and diluted with distilled water at 1:100 ratio. This procedure should be repeated 4 times more, moreover, during the last procedure one should apply alcohol for dilution. Then one should transfer the drop of alcoholic solution into a vial with granules out of milk sugar to then shaken and kept open for 1 d till granules" drying up. The suggested preparation should be applied per 1 granule under the tongue, moreover, multiplicity and duration of the above-suggested intake should be matched individually by patient's sensitivity and obtaining the clinic effect. The method enables to improve the value of tonic threshold audiometry by about 30-50 dB, decrease perception threshold of vocal range frequencies and widen the range towards high frequencies.
EFFECT: higher efficiency of therapy.
FIELD: medicine, oncology.
SUBSTANCE: invention relates to a method for treatment of chronic lympholeukosis. Method involves intravenous drop and jet administration of antitumor chemopreparations and carrying out the autochemotherapy. At the 1-st and 8-th day of treatment cyclophosphan in the dose 750 mg/m2, vincristine in the dose 1.4 mg/m2 and doxorubicin in the dose 30 mg/m2 incubated with 200 ml of autoblood are administrated to patients. From the 1-st to 14-th day of treatment prednisolone is used every day in the therapeutic dose. The treatment course is repeated in 30-35 days depending on blood indices and patient state. The total treatment of courses is 4-5. Method provides reducing cardiotoxicity of doxorubicin and cumulative toxicity of chemopreparations that allows carrying out administration of antitumor chemopreparations in the full volume to patients of elderly age groups.
EFFECT: improved method for treatment.
FIELD: medicine, oncohematology.
SUBSTANCE: the present innovation deals with treating elderly patients with chronic lympholeukosis accompanied with cardiovascular failure. The method deals with applying chemopreparations and cytoprotector. Moreover, 1 wk before the onset of chemotherapeutic therapy one should prescribe preductal at the dosage of 105 mg daily. At this background one should sample blood out of elbow vein at the volume of 200 ml into a vial with glugicir to centrifuge it, isolate plasma, divide into two portions, add into the 1st vial - cyclophosphan 600-800 mg/sq. m, vincristin 1.4 mg/sq. m, into the 2nd vial - adriamycin 50 mg/sq. m to be incubated for 30 min at 37 C and intravenously injected by drops for patients. Simultaneously, the intake of prednisolone should be prescribed at the dosage of 60 mg/sq. m since the 1st d and during the next 5 d and preductal at the dosage of 105 mg daily during a week, and then 2 wk more at the dosage of 60 mg daily. All the procedures should be repeated in above-mentioned sequence 4-6 times. The method enables to decrease toxic manifestations of chemotherapy while applying adequate dosages of cytostatics, anthracycline antibiotics, among them, at no great manifestations of their toxicity due to preductal's cardioprotective action.
EFFECT: higher efficiency of therapy.
1 ex, 5 tbl
FIELD: medicine, immunology, nucleic acids.
SUBSTANCE: invention relates to a method for stimulation of the immune response using nucleic acids-containing immunostimulating compositions, oligonucleotide-containing composition and to a method for treatment or prophylaxis of allergy or asthma. For stimulation of the immune response thymidine-enriched nucleic acid comprising poly-T sequences and/or comprising above 60% of thymidine-containing nucleotide residues is administrated. Invention provides the development of new method for stimulation of the immune response due to administration of the proposed immunostimulating nucleic acid.
EFFECT: valuable medicinal properties of nucleic acid.
27 cl, 12 dwg, 12 ex
FIELD: veterinary science.
SUBSTANCE: the suggested method should be performed under conditions of experimental modeling dystrophic process due to intraosseous introduction of glucosamine hydrochloride at the dosage of 15-25 mg/kg 1-2 times weekly during a month. The method provides high local concentrations of medicinal preparation, at its steady entering the circulation by leaving aside hepatic barrier and, as a result, optimization of chondroprotector action of glucosamine hydrochloride and better treatment of articular alterations induced in the course of an experiment in animals.
EFFECT: higher efficiency of correction.
8 dwg, 1 ex
FIELD: veterinary science.
SUBSTANCE: the suggested method should be implemented under conditions of experimental modeling dystrophic process due to intramuscular injection of glucosamine hydrochloride at the dosage of 15-25 mg/kg once or twice weekly for 1 mo. The method provides good effect in treating a lesion induced in the course of an experiment due to matching adequate dosages and a certain mode of injecting chondroprotector in animals.
EFFECT: higher efficiency of correction.