Monohydrate hydrochloride 1-cyclopropyl-7-([s,s]-2,8 - diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy - 4-oxo-3-quinoline-carboxylic acid and a pharmaceutical composition with antibacterial activity

 

(57) Abstract:

Monohydrate hydrochloride 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0] non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-henrikromby acid of formula 1, in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D. and x-ray diffraction pattern has a line at an angle 2 = 26,7, exhibits antibacterial activity. Preferred crystallizing in the form of prisms monohydrate gives dehydrates form of connection is excellent fluidity and flowability. 2 S. and 2 C.p. f-crystals, 8 ill., 5 table.

The invention relates to a new derived chinainternational acids with antibacterial activity, in particular the hydrochloride monohydrate 1-cyclopropyl-7-([S, S]-2,8-diazabicyclo[4.3.0]non-8-yl)- 6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid formula

< / BR>
in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D. and x-ray diffraction pattern has a line at an angle 2 = 26,7.

1-Cyclopropyl-7-([S, S] -2,8-diazabicyclo[4.3.0] non-8-yl)-6 - fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid and its anhydrous salt, such as anhydrous hydrochloride (hereinafter CDHG) are chemotherapeutic removal to be used as protective equipment. They show little toxicity and is particularly effective against intestinal bacteria and particularly against antibiotic-resistant strains: S. aureus, Ps. aeruginosa, Enterococcus faecalis and E. coli, receive them in the form of internal salts of Quaternary ammonium bases described in the application for the European patent N 550903 and in the International application N 591808.

Anhydrous form CDHG may not, however, quite satisfied in the manufacture of various dosage forms. CDHG hygroscopic and absorbs moisture under adverse storage conditions and galenical processing of biologically active substances in dosage forms. This violates the dosing accuracy and harms the quality of medicines. Cause physical instability CDHG are additional changes in the crystal structure of the anhydrous form, when CDHG stored in aqueous suspensions or when humidity environment. Therefore, it is very important to use if possible a stable crystalline form to obtain a dosage form CDHG.

It was found that CDHH can be turned into a new water-containing crystalline modification, which differs from the known anhydrous form of increased stability in osobennosti drugs.

Upon receipt of the monohydrate of the biologically active substance crystallizes from aqueous media in the form of a strongly twisted needles. Unexpectedly, the crystal shape can be changed under certain conditions of crystallization. Thus obtained prisms represent the preferred form of the present invention, since they do not overlap and have a much more fluidity than monohydrate in the form of needles. This is very valuable when getting medicines. When using hygroscopic bulk biologically active substance is achieved satisfactory precision in obtaining drugs, which increases security and makes the risk to patients is minimal.

Monohydrate CDHG above formula in accordance with the invention get when anhydrous crystalline CDHG process sufficient for good mixing and education monohydrate amount of water at a temperature of 80oC to absorb the stoichiometric amount of water of crystallization and a complete transformation of the crystals thus obtained crystals are separated and to remove the absorbed water is dried to constant weight mo is relatively humidity. Monohydrate from aqueous media with a water content of more than 10% crystallizes as needles.

The preferred crystalline form of the monohydrate in the form of prisms can be obtained by suspendirovanie anhydrous crystalline CDHG in mixtures of ethanol/water, particularly preferably in ethanol/water with a maximum water content of 10%, you need a good mixing of the solid phase with the added amount of water to absorb the required amount of water of crystallization and a complete transformation of the crystals, for example, by stirring the suspension or shaking, rocking, rotating the reaction vessel, etc., If the water content in the mixture of ethanol/water is a maximum of 10%, monohydrate crystallizes in the form of prisms.

Provided that the amount of water is sufficient for the formation of stoichiometric monohydrate and to achieve good mixing CDHG with added to water, it is possible for the formation of monohydrate in the form of needles to use any large amount of water as the absorption of water of crystallization ends with what is happening in the transformation of the crystals education monohydrate, and then no other hydrate is no longer obtained. Alsoobe is or a slight decrease in solubility. Getting monohydrate is preferably carried out at room temperature, it is possible, however, to conduct the reaction at elevated temperature, for example from 30oC to 60oC or at lower temperatures, for example from 5oC to 20oC. Receiving monohydrate is also possible from the anhydrous form at a relative humidity of more than 30%. This method is not suitable, however, to obtain the preferred crystalline monohydrate in the form of prisms.

Department of monohydrate crystals from an excess of solvent occurs using conventional methods, for example by filtration, decanting, centrifuging and the like methods. It is advisable to dry the separated crystals of the monohydrate at room temperature or at higher temperatures up to 50oC at a relative humidity of at least 30%.

Monohydrate CDHG in accordance with this invention has a characteristic IR spectrum (Fig. 1), in which there are characteristic absorption bands of water of crystallization in the region of stretching vibrations of the group HE (3600 - 3100 cm-1), which are absent in the case of anhydrous crystalline modification. Spectrum differs from the spectrum of anhydrous CDHG and other CAH both modifications.

Determination of moisture content confirms the existence of stoichiometric monohydrate CDHG. Defined in some samples monohydrate thermogravimetric mass loss is 1 mole of water (3,9 %, Fig. 2). Shot with DSC (differential scanning calorimetry) at atmospheric pressure thermogram monohydrate (Fig. 3 shows in accordance with thermogravimetric measurements of the dissociation of water detected on a broad endothermic peak, which indicates a rearrangement of the crystal lattice of the investigated monohydrate, dissociation CDHG and water and the enthalpy of evaporation Slobodskoy water of crystallization. X-ray diffraction,13C-NMR spectra, Raman spectra and spectra in the far infrared region of the anhydrous form and monohydrate indicate specific differences (Fig. 4 - 7, Tables 2 - 5): for example, in13C-NMR spectrum detect the characteristic peak at 168,1 M. D., and x-ray diffraction pattern detect a line at an angle 2 = 26,7.

thermogram of differential scanning calorimetry and thermogravimetric analysis were obtained with the use of instruments for thermal analysis (DSC 7 and TGA 7) (Perkin-Elmer). X-ray the infrared and Raman spectra were recorded using an IR spectrometer with Fourier transform IFS 66 (IR), IFS 66v (spectra in the far infrared region) and IFS 88 (Raman spectra) (company Bruker). 13C-NMR spectra of solids were recorded using the instrument Bruker MSL 300. Microscopic images were taken using a microscope Laborlux S (produced by Leitz).

Monohydrate CDHG according to the invention manifests during storage compared with the anhydrous crystalline modification a higher physical stability and is therefore more suitable for the manufacture of various dosage forms. Preferred crystallizing in the form of prisms monohydrate gives CDHG, in addition, excellent flowability and fluidity, which is a great advantage in the manufacture of pharmaceutical preparations (Fig. 8). The object of the invention is therefore a pharmaceutical composition with anti-bacterial activity, which, along at least one media contains monohydrate CDHG in accordance with the invention in an effective amount, for example, in the form of suspensions, emulsions, tablets, pills, pills kernel, suppositories, hard or soft gelatin capsules, and the like forms. Water suspension and tablets for oral administration preferably contain monohydrate in accordance with the invention, osobie to contain other antimicrobial active substances.

As carriers of pharmaceutical composition contains conventional applied accepted method in the manufacture of drugs, AIDS and additives such as a binder for tablets, fillers, preservatives, baking powder for tablets, the means for regulating flow, softening agent, wetting agent, dispersant, emulsifier, solvent, flavoring and similar substances.

Obtaining the pharmaceutical composition is carried out in a known manner, for example by mixing, stirring, suspendirovanie, dispersion, emulsification and the like operations of biologically active substances, for example, pharmaceutical excipients and processing in a pharmaceutically suitable useful dosage forms for oral, parenteral or rectal administration.

Obtaining crystalline CDHG (needles, prisms)

Example 1 (prism)

1 g of anhydrous CDHG dissolved in 150 ml of absolute ethanol and the solution is filtered. The solution is heated at 60oC until complete evaporation of the solvent. The precipitated crystals are dried at room temperature when the ambient humidity.

Example 2 (prism)

0.1 Horites. The precipitated crystals are dried at room temperature when the ambient humidity.

Example 3 (prism)

4 g anhydrous CDHG dissolved in 300 ml of ethanol (96%). The solvent is distilled off on a rotary evaporator at 60oC and 120 mbar residual pressure. The crystals are dried in a vacuum oven for 2 hours at 80 mbar residual pressure and 105oC to achieve the environmental humidity.

Example 4 (needle)

0.3 g of anhydrous CDHG dissolved in 6 ml of a mixture of water:ethanol (1:1). The solution is heated at 70oC until complete evaporation of the solvent. The precipitated crystals are dried at room temperature in vacuum and then left overnight at room temperature at a relative humidity of 85%.

Example 5 (needle)

0.1 g anhydrous CDHG dissolved in 5 ml of methanol. The solution was kept at room temperature until complete evaporation of the solvent. The crystals are dried at room temperature in vacuum and then left overnight at room temperature at a relative humidity of 85%.

Example 6 (needle)

0.1 g anhydrous CDHG dissolved in 5 ml of water. The solution was kept at room temperature until complete evaporation of the solvent. The crystals are dried in a vacuum Ave is STI 85%.

Example 7

of 25.1 g of monohydrate CDHG (prism), 3.3 grams of Avicel PH 101 and 1.7 g of corn starch are mixed in a granulator-mixer and then granularit with 13 g of water. After processing by means of a rasp (4 mm) the granulate is dried in a mini-dryer in the fluidized bed (air intake temperature of 80oC) and sieved (0.8 mm). Additionally mix from 0.19 g of Ac-Di-Sol (modified sodium-carboxymethylcellulose cross-stitching) and 0.01 g of magnesium stearate. After that carry out pressing on the press with an eccentric (tablet size: diameter 5.5 mm, the curvature radius of 9 mm, the weight of the tablet and 68.5 mg).

Example 8

196,6 g svezhesmolotogo (up to microns) monohydrate CDHG (needle) is mixed with 88 g of Avicel in the granulator-mixer (powder mixture); 3.6 g of polyvinylpyrrolidone dissolved in 25 97,2 g of water (liquid granulation). Powdery mixture granularit together with fluid granulation. After processing a rasp (3 mm) the granulate is dried in a rapid dryer (temperature supply air 90oC) and sieved (1 mm). Additionally mixed with 1.8 g of Ac-Di-Sol (modified sodium-carboxymethylcellulose cross-stitching) and 0.1 g of magnesium stearate. Afterwards press the">

1. Monohydrate hydrochloride 1-cyclopropyl-7-([S, S] -2,8-diazabicyclo[4.3.0] non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid formula

< / BR>
in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D. and x-ray diffraction pattern has a line at an angle 2 = 26,7.

2. Monohydrate under item 1 in crystalline form in the form of prisms.

3. Pharmaceutical composition with antibacterial activity, containing the hydrochloride of 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinoline-carboxylic acid as an active start and at least one pharmaceutically acceptable carrier, wherein the effective beginning it contains an effective amount of the monohydrate specified hydrochloride formula

in13C-NMR spectrum of which has a characteristic peak at 168,1 M. D. and x-ray diffraction pattern has a line at an angle 2 = 26,7.

4. The pharmaceutical composition according to p. 3, characterized in that it contains monohydrate in crystalline form in the form of prisms.

 

Same patents:

The invention relates to new nitrogen-containing heterocyclic compounds which possess valuable biological properties, in particular derived cycloalkane-indole-azaindole, mixtures of their isomers, or individual isomers and their pharmaceutically acceptable salts, derivatives of carboxylic acid as starting compounds and pharmaceutical compositions inhibiting the release associated with apolipoprotein B - 100 lipoproteins

The invention relates to new derivatives of imidazopyridines formula I

< / BR>
where R denotes a group of the formula Ia

< / BR>
R1means F, R2-SO2NHCOR5, R3- A, R4group of the formula CnH2nR9; R5- A, - CtH2t(C3-C8cycloalkyl), - CtH2t-Ar; R9-COOA, Ar-CO-NR6R7, -CO-Ar; R6and R7respectively N And ArCnH2nor R6and R7together mean alkylenes chain with C-5, R8means1-C6-alkyl, AND - C1-C6-alkyl, AG - unsubstituted phenyl group, t is 0, 1, 2 or 3, n=1, 2, 3, 4 or 5 or their salts, and method of production thereof, pharmaceutical composition and method for producing the composition

The invention relates to new nitrogen-containing heterocyclic compounds with valuable biological properties, in particular to new derivatives of 1,4-dihydropyridines with a cyclic bridge in positions 1,2, having biological activity

The invention relates to new nitrogen-containing heterocyclic compounds with biological activity, in particular to substituted derivatives of pyrazole and means of having a weed-killing activity

The invention relates to new biologically active compounds, methods of treating diseases with their use and pharmaceutical compositions based on these compounds

The invention relates to compounds of the following formula I which inhibit the enzyme glycinamide ribonucleotide the formyl transferase (GARFT)

The invention relates to disubstituted polycyclic compounds, their derivatives, pharmaceutical preparations and methods of use in treating mammals disorders mental and/or neurological dysfunction and/or depressions such as diseases associated with degeneration of the nervous system, and not only their

The invention relates to (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S, 4S)-2-[(3R)-3-methylaminomethyl-1-ylcarbonyl] pyrrolidin-4-ylthio]-1-karbapin-2-em-3-carboxylic acid or its pharmaceutically acceptable salts, method of treatment a pharmaceutical composition based on it

The invention relates to novel crystalline salts of joining acids cafema General formula (I), where n = 1 or 2, m = 0.4 to 2.6 and X is the anion hydroxycarbonic acid, exhibiting antibacterial activity

The invention relates to new derivatives of 1-methylcarbamate General formula (I) described in the claims

The invention relates to medicine, in particular to pharmacology concerns anti-allergic and anti-inflammatory agents of the formula I, with low toxicity

The invention relates to iododerma biologically active compositions containing iodine and halides of nitrogenous bases of the formula I, where the values of the radicals a, b, C, R, X and m are specified in the claims

The invention relates to a pharmaceutical dosage form for oral administration containing a proton pump inhibitor and one or more means of nonsteroidal anti-inflammatory therapy in the form of a metered dose of the drug, in which the proton pump inhibitor is protected intersolubility coating, means non-steroidal anti-inflammatory therapy, to a method for producing a dosage form and method for the treatment of side effects in the gastrointestinal tract as a result of treatment by means of a non-steroidal anti-inflammatory therapy

Antibacterial // 2157686
The invention relates to the field of medicine

The invention relates to the field of organic chemistry and medicine and relates to new quinoline derivatives of General formula I, where R represents unsubstituted C1-C3-alkyl or C2-C3alkenyl; R1is cyano, which are agonists alpha-2-adrenergic receptors and can be used when obtaining drugs suitable for the treatment of nasal congestion, glaucoma, diarrhea, asthma
Up!