8-cyano-1-cyclopropyl-7-(1s,6s)-2,8-diazabicyclo- [4.3.0]-nonane-8-yl)-6- fl uoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid with crystalline modification a and drug eliciting effect against pathogenic microorganisms
FIELD: organic chemistry, antibacterial agents.
SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S)-2,8-diazabicyclo-[4.3.0]-nonane-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of the formula (I): with the crystalline modification A and a drug eliciting effect against pathogenic microorganisms. The prepared crystalline modification shows stability and doesn't transform to another crystalline modification or amorphous form being even at prolonged storage.
EFFECT: improved and valuable properties of compound.
4 cl, 4 dwg, 6 ex
The present invention relates to certain crystalline modifications of known substituted quinoline-carboxylic acids, more particularly to an 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid crystalline modification And and drug with activity against pathogenic bacteria.
8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid of the formula (I) will hereinafter be referred to as CCDC
CCDC is known from DE-a 19633805 or application WO 97/31001. It is obtained respectively by reacting 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid with (1S,6S)-2,8-diazabicyclo-[4.3.0]nananom in a mixture of dimethylformamide and acetonitrile in the presence of a base. After mixing with water CCDC is extracted from water with dichloromethane and by removing the extractant is released. The resulting powder, which is no definite crystalline modification does not show. The powder, on the contrary, for the most part amorphous, and may contain a mixture of different crystalline modifications. If you accidentally formed a single crystalline modification, it is not clear how it can be extracted and combined in a certain way. To prepare Lakers the public funds available, however, the condition that for biologically active substances, which can exist in different crystalline modifications, clearly indicates what kind of crystalline modification of it is used for the production of medicines.
This is partly amorphous powder, method of manufacturing the above was briefly described, in addition, hygroscopic. Amorphous solids and particularly hygroscopic solids are difficult processing in herbal medicines, as they, for example, can have a low bulk density and poor fluidity. In addition, when using hygroscopic substances require special operating equipment and devices, in order to obtain reproducible results, for example, in the content of biologically active substances or stability of the produced solid products.
The objective of the invention is the provision of a specific crystalline modification CCDC, which on the basis of their physical properties, in particular properties of crystals and behaviour in relation to water does not show the above-mentioned disadvantages in the manufacture of galenic forms.
The problem is solved by the proposed 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (CCDC) crystal m the modification And, with x-ray diffraction the diffraction pattern with the following reflexes (2 theta) with high and medium intensity:
2Θ (2 theta)
The characteristic x-ray diffractogram of the powder CCDC modification And presented in figure 1.
According to this invention, CCDC crystal modifications And different from other forms of CCDC, it is also near future properties. These properties can be used separately or in conjunction with other parameters to characterize the proposed CCDC crystalline modification A.
CCDC crystal modifications And different, for example, that has a melting point 249-252° With defined using differential thermal analysis (DTA). The characteristic chart DTA presented in figure 2.
CCDC crystalline modification And further differs in that it is measured in KBR infrared spectrum is shown in figure 3.
CCDC crystalline modification And further differs in the way it is received, namely, that CCDC unknown modification or amorphous CCDC is dissolved in water or mixture of alcohol and water when heated, then add the alcohol, and after cooling to room temperature the precipitated solid is separated.
As alcohol is preferably used, this is ol and isopropanol.
Unexpected was that the CCDC crystalline modification And is stable and becomes even during prolonged storage in different crystalline modification or amorphous form. In addition, compared with the amorphous CCDC crystalline modification And less likely to absorb water from the air. For these reasons, it is well suited for the manufacture of tablets and other solid dosage forms. Due to its stability it gives such dosage forms long desired stability during storage. Therefore, the crystalline modification And allows a specific and targeted way to produce stable solid medicines on the basis of CCDC.
CCDC crystalline modification And has an effective activity against pathogenic bacteria in the field of medicine and veterinary medicine. Its wide range of applications corresponds to the range of application of the CCDC.
X-ray diffractogram for characteristics CCDC crystalline modification And was received on the transmission diffractometer STADI-P with metaconstitutional detector (PSD2) company STOE.
The melting temperature was obtained by means of DTA instrument DSC 820 company Mettler-Toledo. The heating of the sample CCDC crystalline modification And was carried out in air in an aluminum crucible at a rate of 10 K/min
The IR spectrum was obtained in CVG with p the physical alteration of the device FTS 60A company Biorad.
The following examples illustrate the invention. Used solvents and bases are particularly preferred.
A mixture of 3.07 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid, 1.39 g of (1S,6S)-2,8-diazabicyclo [4.3.0]nonane, 2.24 g of 1,4-diazabicyclo[2.2.2]octane (DABCO), 29.5 ml of dimethylformamide and 29.5 ml of acetonitrile is stirred for 16 hours at room temperature.
The reaction mixture is evaporated in a rotary vacuum evaporator at a bath temperature of 60° and the resulting residue is mixed with 10 ml of water. The resulting solution was adjusted with diluted hydrochloric acid to pH 7 and the precipitated solid precipitate is filtered off. The filtrate is shaken out three times with dichloromethane, was taken in 20 ml of the Organic phase is dried over sodium sulfate, filtered and the filtrate evaporated on a vacuum rotary evaporator at a temperature of the water bath at 60° C. Obtain 2.4 g of a solid substance in a light brown colour, which is shown in figure 4 x-ray diffraction the diffraction pattern, on which it is mostly amorphous.
Obtained according to this example, the solid is at a relative air humidity of 95% (installed by using having a residue of a saturated solution of Na2HPO4·12H2O) absorbs within days 17 wt.% water.
617 g CCDC any modification dissolved in 6170 ml of chloroform. Add 100 g of sodium sulfate, stirred for 5 minutes and then filtered through 50 g of diatomaceous earth, which is then washed with 100 ml of chloroform. The solvent is distilled off in a rotary vacuum evaporator to a residual pressure of 10 mbar, and get a glassy residue. To this residue is added 740 ml of water and 740 ml of ethanol and heated to 60° until then, until everything goes into solution. This solution add then in 17 liters of boiling ethanol. Allow to boil for another 5 minutes and then cooled for one hour to 35° C. the Precipitated crystals are sucked off and about 16 hours at 20° and then at 30° dried in vacuum to constant weight.
Get 530 g of solid, which is presented on Fig.1 x-ray diffraction the diffraction pattern presented in figure 2 diagram DTA presented on figure 3 IR spectrum.
Obtained according to this example, the solid is at a relative air humidity of 95% (installed by using having a residue of a saturated solution of Na2HPO4·12H2O) absorbs within days to about 3 wt.% water.
2 g CCDC unknown modification dissolved in 4 ml of water. Add 4 ml of isopropanol, and then the reaction mixture is slowly heated under stirring and then add 32 ml of isoprop the Ola. The obtained clear solution is heated to boiling point. Thus the solution begins to thicken, and the short time allocated crystals. After a three-minute phlegmy stop heating, and the mixture is left to stand without stirring for 3-4 hours. Then the solid is sucked off, washed with isopropanol and then dried in air to constant weight. Get 1,54 solids, which has x-ray of the diffraction pattern identical to the one presented in figure 1, the DTA diagram identical to the one presented in figure 2, and the infrared spectrum is identical with that presented in figure 3.
1. 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (CCDC) of crystalline modification And having x-ray diffraction the diffraction pattern with the following reflexes (2 theta) with high and medium intensity.
2. 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (CCDC) of crystalline modification according to claim 1 And having defined using DTA melting temperature 249-252°C.
3. 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (CCDC) crystalline modi the paths And according to claim 1 or 2, obtained by dissolving in water or a mixture of water - alcohol CCDC unknown modification or amorphous CCDC and deposition by heating after the addition of alcohol.
4. Drug with activity against pathogenic bacteria, characterized in that it comprises, along with the usual excipients and fillers CCDC modification And according to one of claims 1 to 3.
where 1 R=NO2, R1=H;
2 R=CF3, R1=H;
3 R=CN, R1=H;
where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims
or its pharmaceutically acceptable salts, where R1- H, CH3or CH2OH; R2- CH3CH2CH3; R3- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl, halogen; R4- H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or halogen; R5- H or halogen; R6, R7are the same or different and mean H, C1-C6alkyl, gidroksilirovanii C1-C6alkyl or C1-C6alkoxy-substituted C1-C6alkyl; X represents NH or O, which inhibit exogenously or endogenously stimulated secretion of gastric acid and therefore can be used for the prevention and treatment of gastrointestinal inflammatory diseases
FIELD: organic chemistry, medicine.
SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.
EFFECT: valuable properties of agents.
4 cl, 3 tbl, 78 ex
FIELD: medicine, pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.
EFFECT: valuable medicinal properties of compounds.
21 cl, 1 dwg, 1 tbl, 6 ex
FIELD: biotechnology, vaccines.
SUBSTANCE: vaccine comprises bacterial mass of Pasteurella multocida of serovariants A, B and D, Haemophilus pleuropneumonia of serogroups 1 and 2, and streptococcus of serogroups C and R, and also lysate-anigens of salmonellae Salmonella cholerae - suis, strain № 370 and Salmonella typhimurium № 415 mixed in the definite concentration. Vaccine elicits the high immunogenicity and provides the protection of pigs against infectious pneumonia of bacterial etiology and salmonellosis.
EFFECT: valuable veterinary properties of vaccine.
3 cl, 1 tbl, 5 ex
FIELD: veterinary science.
SUBSTANCE: the method deals with injecting oxylate once daily for 3 d at the dosage of 1 ml/30 kg body weight at repeated therapy course in 5 d at the background of antibioticotherapy. The method enables to normalize biochemical and morphological blood values and increase average daily body weight gain in sick animals.
EFFECT: higher efficiency of therapy.
2 ex, 2 tbl
FIELD: organic synthesis.
SUBSTANCE: invention provides substituted 7-acylaminocephalosporins of formula I:
(I), where W denotes CH or B; V denotes NO; R1 hydrogen or С1-С4-alkyl; R3 hydrogen or ester residue; and R2 one of the following groups: , , , , in which X, R5, R6, R'6, R7, and Hal have meanings indicated in claims, in free state, in the form of salts and/or solvates, or, if such forms are stable, in the form of internal salt, quaternary salt, or their hydrates, possessing antimicrobial activity. Invention also discloses a method for preparing such compounds and a pharmaceutical connected containing them.
EFFECT: increased choice of antimicrobial preparations.
13 cl, 10 tbl, 225 ex
SUBSTANCE: composition is constituted by effective amount of thymol obtained from plant Trychyspermum ammi, mint oil combination of mint oil containing required amounts of monoterpenes and isolated from Mentha spicata and Mentha arvensis, and typical additives. Invention also relates to preparation of the composition by mixing above ingredients and to method of treating patients by administering therapeutically effective amount of the composition.
EFFECT: created therapeutic agent overcoming drug resistance of bacteria and minimized or even eliminated secondary adverse effect of drug.
19 cl, 12 tbl, 11 ex
FIELD: pharmacology, fluorinated quinolone-based drug, in particular ofloxacine for injections.
SUBSTANCE: claimed composition contains therapeutically acceptable amount of ofloxacine and trilon-B, sodium chloride, water for injections as additives.
EFFECT: high therapeutic effectiveness; non-crystallized active agent for a long-time storage.
FIELD: biotechnology, medicine, infectious diseases, medicinal microbiology.
SUBSTANCE: invention relates to a composition designated for treatment and prophylaxis of infections caused by Neisseria microorganism that comprises the following components: (a) protein with amino acid sequence similar by 65% and above with the natural Neisseria protein of a single species (the first group of amino acid sequences is given in the text) and/or its fragment consisting of 10 and more amino acids and eliciting antigen properties; (b) the second protein with amino acid sequence similar by 65% and above with the natural Neisseria protein of another species (the second group of amino acid sequences with even numbers is given in the text), and/or its fragment consisting of 10 or more amino acids and eliciting antigen properties; in particular, the second protein represents NspA. The composition comprises additionally adjuvant. The composition is used both a medicinal agent and for manufacturing the medicinal agent. Applying the invention provides enhancing the effectiveness of prophylaxis or treatment due to the universal effect of the composition (vaccine). Invention can be used in medicine for treatment of infections.
EFFECT: valuable medicinal properties of composition.
8 cl, 137 dwg, 5 tbl, 12 ex