The method of obtaining oleandomycin and oleandomycin
(57) Abstract:Usage: medicine, Antibacterials. The inventive product - oleandomycin formula I listed in the description text. The compounds of formula I exhibit antibacterial activity, while MJC = from 0.2 to 16.0 μg/ml Reagent 1: oleandomycin formula III described in the text descriptions. Reagent 2 : 4 - 6-molar excess chloridrate hydroxylamine. Process conditions: excess pyridine at room temperature, 2 - 40 hours The invention relates to new Akimov oleandomitsina possessing antibacterial activity, and the way they are received.Oleandomitsin is a 14-membered macrolide antibiotic with a spectrum similar to the spectrum of erythromycin (1).The aim of the invention is the creation of new derivatives oleandomycin with high antibacterial activity.The invention encompasses oleandomycin formula I
in which R1represents CH3, R2hydrogen, or R1and R2together form an epoxy group
R3is a HE and icon ~~ means a single bound is the following compound Ia-Ie
IA R1=R2= O, R3=OH ~~ = single bond
IB R1=R2= O, R3and ~~ = double bond
IC R1= R2= CH2, R3= -OH ~~ = single bond
Id R1= -H, R2= -CH3, R3= -OH ~~ = single bond
Ie R1= -CH3, R2= -H, R3= -OH ~~ = single bond Oleandomycin formula I are new compounds.These compounds are produced by the interaction of oleandomycin formula (II).in which R1, R2, R3and ~~ have specified values, with an excess of hydroxylamine hydrochloride.In particular, the compounds Ia-Ic, as defined above, can be obtained by reaction of compounds IIa-IIc:
IIA R1=R2= O, R3=-OH ~~ = single bond
IIB R1=R2= O, R3and ~~ = double bond
IIc R1= R2= CH2, R3= -OH ~~ = single bond
IId R1= -H, R2= -CH3, R3= -OH ~~ = single bond
IIe R1= -CH3, R2= -H, R3= -OH ~~ = single bond with an excess of hydroxylamine hydrochloride.This reaction can be carried out with 4-6-molar excess of hydroxylamine hydrochloride in the presence of excess pyridine, SL">Termination of the reaction is determined by thin layer chromatography (TLC) on silikagelevye plates 60F254in the following system:
A) CHCl3(CH3OH) conc. HN4OH (6:1; 0,1)
B) CH2Cl2(CH3OH) conc. NH4OH (90:0:1,5)
Unloading is carried out by extraction of halogenated solvents such as chloroform or methylene chloride, at pH around 7.0-8.5 and ultimately by evaporation to dryness of the organic extract.Getting 8-meilleurmobile.com formula Id and Ie carried out using as starting compound 8-methyleneindoline anomers of formula II and IIE, which without pre-separation was directly subjected to the reaction oxymorphine. Was obtained the crude product, consisting of a mixture of anomeric Asimov formulas (Id) and (Ic), which were separated by chromatography in a column of silica gel with elution with a mixture of CH2Cl2CH3OH (85:15).Antibacterial activity was determined by the number of standard and clinically isolated strains. The results are expressed as the minimum inhibitory concentration (MIC, μg/ml) and presented in table.1 and 2.P R I m e R 1. In the solution alexanderalexander at room temperature in a stream of nitrogen for 2 hours In the reaction mixture injected water (400 ml), and extracted with dichloromethane by gradient extraction at pH value of 5 and 7. The organic extract (pH 7.0) and evaporated under reduced pressure to dryness and the residual product is evaporated, dried in vacuum at 40aboutWith, the result of 9.1 g (70,0%) of product.Rf (A) Of 0.51.(C) 0,32.M+702.Ultraviolet spectrum (Meon): the peak at 290 nm disappears ( With = 0). Range NAMR (Dimethylsulfoxide-d6) h/min 2,23 [6H, c (CH3)2N] of 3.33 (3H, s, 3 - core).10,82 ( = NOH), disappears as a result of ion exchange CD2O.Range13C-NMR (CDCl3) h/min: 175,8 (s-1, lactone), 159, 6 (-C= N-), The 104.3 (C-1'), 99,3 (C-1'), to 51.1 (C - 8 - CH2), 40,3 [C-3'-N(CH)]
MIC (μg/ml) (clinical isolates)
Strept. pneumoniae 0,5 Strept. serol. group AND 0.5
P R I m m e R 2. Angerielingerie.com Ib.Anhydroerythromycin (IIb) (2.2 g 0,0033 mol) was dissolved in dry pyridine (4 ml), was injected NH2OH HCl (1.2 g of 0.017 mol) and the reaction mixture stirred at room temperature in a stream of nitrogen for 18 hours, the Pyridine was removed by evaporation under reduced pressure and by entering water. Water was added to a suspension of chloroform, the pH value was brought to 8.3 by UB>) and evaporated to dryness, and the resulting received 21 g (93,0%) of a white solid.Rf (A) 0,52
M+68.Range 'H-NMR (Dimethylsulfoxide-d6) ppm: 2,21 [6H, c (CH3)2N-], 3,34 (SN, s, 3"-och3), 10,97 (1H, s, =NOH), disappears as a result of exchange with D2O.Range13C-NMR (CDCl3) ppm: 174,8 (S-I, lactone) 157,3 (-C = N-), 104,6 (I'), of 99.5 (C-I), to 130.1 (C-II), 135,0 (C-10), A 51.2 (C-8-CH2), 40,3 [C-3'-N(CH3)2]
MIC (μg/ml) (clinical isolates)
Strept. pneumoniae 2,0; Strept.serol. group And 1.0.P R I m e R 3. 8-Methylene-Oleandomycin IC.8-Methylenedianiline (IIc) (2,7 with 0,004 mol) dissolved in dry pyridine (19 ml) and injected hydroxylamine hydrochloride (1.35 g 0,019 mol). The reaction mixture was stirred at room temperature in a stream of nitrogen for 2 hours After extraction with dichloromethane at pH of 5 and 7, the product is recovered by evaporation of the extract (pH 7.0) dry (2.0 g 73,0%).Rf (A) 0,58
Range 'H-NMR (Dimethylsulfoxide-d6) ppm: 2,29 [6H, c (CH3)2N-], 3,34 (CH, c., 3" - OCH3) 10,28 (1H, s, =NOH), disappears as a result of exchange with D2O.Range13C-NMR (CDCl3) ppm: 176,6 (s-1 lactone) 163,4 (-C=N-t. serol. group AND 1.0
P R I m e R 4. 8-Methyl-oleandomycin Id and Ie.8-Methyl-oleandomitsin (mixture of anomers IId and IIE).(1.2 g 0,0018 mole) is dissolved in dry pyridine (4 ml) and injected NH2OH HCl (0.6 g, 0,0086 mol) and the reaction mixture stirred at room temperature in a stream of nitrogen. Thin layer chromatography indicates complete conversion of compound IId (Rf(A) is (0.67) after 5 h product Id (Rf(A) = 0,48), while the original compound IIe (Rf(A) = 0,63) gives the product Ie (Rf(A) = 0,57) after 40 hours Performing gradient extraction with methylene chloride at pH = 7.5 to receive the product as a mixture of isomers (0.7 g 57%), which may be divided into a column of silica gel with elution CH2Cl/CH3OH (85:15).These isomers have the following physicochemical properties:
____< / BR>Rf (A)0; 48
M+688.Range 'H-NMR (Dimethylsulfoxide-d6) ppm; 2,42 [6H, c (CH3)2N] of 3.43 (3H, c., 3"-OCH3), the 10.40 (1H, c., =NOH), disappears as a result of exchange with D2O.Range13C-NMR (CDCl3) ppm: 176,8 (C-1, lactone), 165,5 (-C=N-), 104,7 (C-I'), of 99.5 (C-I), 40,4 [C-3"-N(CH3)2].Ie
Rf (A) 0,57
Range H-NMR (Dimethylsulfoxide-d6) ppm;
Spectrum 13 C-NMR (CDCl3) ppm: 176,2 (S-I, lactone), 168,6 (-C=N-), 104,2 (C-1'), to 98.5 (C-1') 40,4 [C-3'-N(CH3)2]. Activity: 657 u/mg Sarcinalutea ADS. 1. The method of obtaining oleandomycin General formula
< / BR>where R1is hydrogen or methyl;
R2is methyl or hydrogen, or R1and R2together form an epoxy group, or = CH2;
R3the hydroxy - group;
~ ~ simple or double bond,
characterized in that conduct the reaction oleandomycin derivatives of General formula
< / BR>where R1, R2, R3and ~~ have specified values, with 4 - 6-molar excess of hydroxylamine hydrochloride in the presence of excess pyridine in a stream of nitrogen at room temperature for 2 to 40 hours, followed by separation of the target product.2. Oleandomycin General formula
< / BR>where R1is methyl;
R2is hydrogen or R1and R2together form an epoxy ring;
R3the hydroxy - group;
~~ - a simple link, or R3and ~~ together form a double bond.
FIELD: medicine, neurology.
SUBSTANCE: the present innovation describes arylalkylamines that specifically affect certain types of receptor-operated Ca2+-canals, their application and pharmaceutical compositions for treating neurological disorders or diseases.
EFFECT: higher efficiency.
55 cl, 29 ex, 11 tbl
SUBSTANCE: method involves rectally introducing mixture produced on base of 5% Novocain solution containing isoniazid, rifamycin, ethambutol in therapeutic doses daily during 21 days. The mixture is pretreated in ultrasonic field during 5 min at 2 MHz frequency.
EFFECT: improved bacteriostatic blood and prostate secret activity.
SUBSTANCE: method involves applying cannabinoid receptor agonists for treating for transitory relaxation of lower esophageal sphincter and states like gastroesophageal reflux disease, regurgitation, preventing reflux or insufficient mass increase caused by the relaxation.
EFFECT: enhanced effectiveness of treatment.
18 cl, 3 tbl
FIELD: medicine, phthisiology.
SUBSTANCE: method involves firstly the achievement of lymphotropicity of three chemopreparations by addition of 5% glucose and aloe to solutions of these chemopreparations. Then the conduction paravertebral anesthesia is carried out at the level and at side of administration of preparations. Then three chemopreparations are administrated separately in different intercostals sites, 1-3 times per a week, course of 4-12 injections by subcutaneous paravertebral route, parasternal route in I-X intercostals - in projection of regional lymphatic collectors. Method allows reducing the duration of intensive phase in tuberculosis treatment up to 1-3-6 months, to prevent the development of drug-resistant tuberculosis and adverse effects of chemopreparations and to relieve the residual changes of tuberculosis. Invention can be used in treatment of infiltrative, destructive and drug-resistant pulmonary tuberculosis.
EFFECT: improved and enhanced method of treatment.
FIELD: medicine; physiotherapy.
SUBSTANCE: two to here days after surgical operation, vibration massage is made by means of vibration apparatus on thorax area of root of lung being opposite to that one which was subject to operation. Vibration massage is made daily at frequency of 90-100 Hz and amplitude of 0,4-0,5 mm during 3-5 minutes for 13-14 days. Starting from the fourth f the fifth day after operation, when both drainages are removed from post-resection pleural cavity, electric-vibration acupressure is made in parallel on skin covers all around total area of thorax by means of massaging device. Vibration-acupressure is made daily at the second part of day after I-II row chemical preparations are given to patient. Frequency of procedure is 35-40 Hz and amplitude 0,5-0,6 mm. Duration of influence is increased gradually from 3 to 13-14 minutes during 11-12 days.
EFFECT: reduced number of pleural-pulmonary complications; uniform ventilation of all parts of segments of lung subjected to operation.
2 ex, 3 tbl
FIELD: organic chemistry, medicine, pharmacy.
SUBSTANCE: invention relates to novel ester compounds represented by the formula (1): wherein values for R1, R2, A, X, R3, R4, Alk1, Alk2, l, m, D, R8 and R9 are determined in the invention claim. Also, invention relates to inhibitor of matrix metalloproteinase (MTP), a pharmaceutical composition able to inhibit activity of MTP selectively, agents used in treatment or prophylaxis of hyperlipidemia, arteriosclerosis, coronary artery diseases, obesity, diabetes mellitus or hypertension wherein the pharmaceutical composition is prepared in capsulated formulation, and to a biphenyl compound of the formula (100) given in the invention description.
EFFECT: valuable medicinal properties of compounds.
53 cl, 78 tbl, 17 ex
FIELD: medicine, phthisiology.
SUBSTANCE: method involves the combined oral and rectal administration of chemopreparations. Ethambutol and pyrazinamide are administrated by oral route in the doses 1.2 g and 1.5 g, respectively. Mixture of chemopreparations as an ultraemulsion is used for rectal administration that is prepared 1 h before administration. The mixture comprises isoniazid (10 mg/kg), rifampicin (600 mg), kanamycin (1 g) and lecithin (20 ml). Therapy is carried out in intensive treatment phase 5 times per a week up to three months and in supporting phase 2 times per a week up to closing destruction cavities. Method provides rapid regression of pulmonary tuberculosis process, to improve tolerance of chemopreparations based on their selective accumulation in lymphatic system of lungs and specific schedule of administration of these chemopreparations. Invention can be used in treatment of destructive form of pulmonary tuberculosis.
EFFECT: improved method of treatment.
1 tbl, 1 ex
FIELD: pharmaceutical industry, in particular biocide agent.
SUBSTANCE: claimed gel includes hydroxyethyl cellulose, polyguanidine compound (e.g. polyhexamethylene guanidine succinate or poly-(4,9-dioxadodecan guanidine) succinate), glycerol, trilon B, polyethylene glycol, citric acid, perfume composition, and water. Additionally it contains neonol, calcium pantothenate and chamomile extract in specific component ratio.
EFFECT: gel with increased biocidal action.
3 tbl, 3 ex
FIELD: medicine, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to using compound of the formula Z-linker-Z' (1) representing antagonist of chemokinine receptor CXCR4 for preparing a medicinal agent used in mobilization and collection of cell-precursors and/or stem cells in subject. The claimed invention describes also methods for increasing amount of cell-precursors and stem cells in animals using compounds that bind chemokinine receptor CXCR4. Using compound of the formula (1) allows enhancing effectiveness in treatment of HIV and to alleviate unfavorable effects on bone marrow in the process of chemotherapy carrying out.
EFFECT: improved methods for activation.
19 cl, 12 tbl, 1 dwg, 4 ex
FIELD: pharmaceutical industry and technology, pharmacy.
SUBSTANCE: invention relates to development of method for preparing rifabutin-containing antibacterial composition. Method involves separate mixing one part of rifabutin with special additives and filling agent and another part of rifabutin with lacking amount of filling agent and their following combining, powdering the mixture with magnesium stearate at stirring and making capsules. Method allows simplifying technology in preparing the preparation in capsulated form owing to optimal technological indices of the prepared composition mixture. The composition shows high stability in storing and therapeutic effectiveness.
EFFECT: valuable pharmaceutical and medicinal properties of composition.
2 tbl, 1 ex
FIELD: organic chemistry, chemical technology, antibiotics.
SUBSTANCE: invention relates to a method for preparing fumarate salt of compound of the formula (II) wherein R1 represents hydrogen atom or lower alkyl group; R2 represents lower alkyl group. Method involves interaction of compound of the formula (I) wherein R1 represents hydrogen atom or lower alkyl group with chloroformate. Then all carbamate groups are removed followed by alkylation of nitrogen atom at 3'-position of desosamine ring to obtain compound of the formula (II) and conversion of this compound to fumarate salt. Interaction of compound of the formula (I) with chloroformate is carried out in the presence of cyclic ether or carboxylic acid ester. Carbamate groups are removed in the presence of sodium hydrocarbonate. Crystallization and re-crystallization of compound of the formula (II) fumarate salt is carried out from alcohol-containing solvent, in particular, from isopropyl alcohol. Method provides increasing yield and enhancing purity of the end product.
EFFECT: improved preparing and purifying method.
28 cl, 11 ex
FIELD: production of macrolide road-spectrum antibiotic tylosine.
SUBSTANCE: claimed method includes tylosine deposition from organic tylosine base concentrate with organic solvent (hexane). Deposition is carried out by addition of organic tylosine base concentrate to hexane at velocity of 3-5 ml/min per 50 ml of concentrate.
EFFECT: method for production of tylosine base in granulated form with homogeneous composition.
2 cl, 6 ex
FIELD: medicine, pharmacy.
SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.
EFFECT: improved and valuable properties of compounds.
6 cl, 5 tbl, 19 ex
FIELD: antibiotics, chemical technology.
SUBSTANCE: invention relates to a method for preparing erythromycin oxime in homogenous conditions by oximylation of erythromycin A with hydroxylamine hydrochloride in dry methanol using triethylamine as a base. Method provides enhancing yield and quality of product.
EFFECT: improved method for preparing.
FIELD: organic chemistry, antibiotics, chemical technology.
SUBSTANCE: invention relates to a novel crystalline form E of erythromycin derivative fumarate salt represented by the formula (I)
and to a method for its preparing. Indicated crystalline form E shows strong roentgen diffraction peaks at diffraction angles (2θ) 5.6° and 10.4° that was established by roentgen diffractometry with Cu-Kα-radiation. Also, invention proposes crystalline form D of erythromycin derivative fumarate salt represented by the formula (I) showing average particles size 90 mcm or above and/or the content of residual solvent 1500 ppm or less. Method for preparing indicated crystalline form D involve suspending indicated crystalline form E in mixture ethyl acetate and water in the ratio = (99:1)-(97:3) at temperature from -20°C to 20°C. Invention provides reducing the content of residual solvent and elimination of difficulties in making tablets.
EFFECT: improved preparing methods.
14 cl, 1 tbl, 5 dwg, 6 ex
FIELD: organic chemistry, antibiotics, pharmacy.
SUBSTANCE: invention describes crystalline forms A, C and D of erythromycin derivative of the formula (VII): . Crystalline forms are prepared by recrystallization of crude fumarate crystal from an alcoholic solvent (form A) and, additionally, from ethyl acetate (form C) or, additionally, from an aqueous ethyl acetate (form D). Also, invention relates to methods for preparing intermediate compounds. Prepared crystalline forms possess the better quality, in particular, high stability that is important in preparing pharmaceutical preparations.
EFFECT: improved preparing methods.
16 cl, 8 dwg, 13 ex
SUBSTANCE: invention relates to azithromycin as a stable monohydrate comprising from 4.0% to 6.5% of water and to a method for its preparing. Invention provides preparing the stable form of azithromycin monohydrate.
EFFECT: improved preparing method.
3 cl, 2 tbl, 2 ex