8-cyano-1-cyclopropyl-7-(1s,6s-2,8-diazabicyclo-[4,3,0]-nonane-8-yl)-6- flu oro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid of crystalline modification d and medicinal agent eliciting effect against pathogenic microorganisms

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes 8-cyclo-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):

in crystalline modification D and a medicinal agent based on thereof eliciting effect against pathogenic microorganisms. The prepared crystalline form of compound of the formula (I) shows low hygroscopicity and can be processed to galenic preparations easily and it has the highest filled density and satisfied fluidity.

EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 ex

 

The present invention refers to a crystalline modification 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, 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 D 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 the application DE-A 19 633 805 and applications WO 97/31001. It is obtained 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 polecats is in a certain form. For the preparation of drugs available, however, the condition that for biologically active substances, which can exist in different crystalline modifications, clearly indicates what kind of crystalline modification it must be prepared for the production of medicines.

This is partly amorphous powder, method of manufacturing the above was briefly described, in addition, hygroscopic. Amorphous solids and, in particular, 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 due to their physical properties, in particular properties of crystals, 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-chinainternational (CCDC) of crystalline modification D, characterized by x-ray-diffraction pattern with the following reflexes (2 theta) with high and medium intensity:

2θ (2 theta)

7,6

9,5

12,8

14,2

17,5

19

19,3

19,5

20,4

21

21,8

22,6

25,2

27,5

X-ray diffractogram of the powder CCDC crystalline modification D is also presented in figure 1.

According to this invention CCDC crystalline modification D differs from other forms of CCDC, it is also near future properties. These properties can also be used separately or in conjunction with other parameters to determine the proposed CCDC crystalline modification D.

CCDC crystalline modification D differs, for example, that has a melting point of 261 to 265°With defined using differential thermal analysis (DTA). The characteristic chart DTA presented in figure 2.

CCDC crystalline modification D differs in that it is measured in KBR infrared spectrum is shown in figure 3.

CCDC crystalline modification D get by way CCDC unknown modification or amorphous CCDC is dissolved in water to a concentration of 1-3 wt.%, the solution is kept before the deposition of solid, which is filtered off and dried, then the resulting slurry product is heated to a temperature exceeding the temperature is in transition.

Drying the water-containing product may occur with known methods. Thus, aqueous product can be dried at elevated temperature in vacuum. It is also possible to carry out drying in the presence of conventional drying means, such as phosphorus pentoxide.

The temperature necessary for the transition of the dried samples in a crystalline modification of D can be determined using DTA dried substance. Typically, it is between 130 and 160°C.

CCDC crystalline modification D proved remarkably stable and becomes even during prolonged storage in different crystalline modification or amorphous form. Therefore it is well suited for the manufacture of tablets and other solid dosage forms. Due to its stability it imparts medicinal forms the desired long-lasting stability during storage. From CCDC crystalline modification D you can definitely and purposefully to produce a stable solid dosage form CCDC.

CCDC crystalline modification D has an effective activity against pathogenic bacteria in the field of medicine and veterinary medicine. Its widespread use corresponds to the use of CCDC.

X-ray diffractogram of the powder characteristics CCDC crystalline modification of D was received on the transmission diffractometer STADI-P with mestach Stateline 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 D was carried out in air in an aluminum crucible at a rate of 10 K/min

The infrared spectrum was obtained on the device 881 firm Perkin-Elmer with the insertion of the sample in KBR.

The following examples illustrate the invention without limiting it. Used solvents and bases are particularly preferred.

Comparative example

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. One stripped off (the result) of the solution was adjusted with diluted hydrochloric acid to pH 7 and the precipitated solid is filtered off. The filtrate is shaken out three times with dichloromethane, was taken in 20 ml of the Organic phase is dried with sodium sulfate, filtered and the filtrate evaporated on a vacuum rotary evaporator at a temperature of the water bath 60°C. Obtain 2.4 g of a solid substance in a light brown colour, having shown in figure 4 x-ray diffractor the MMU, in accordance with which it is in the bulk is amorphous.

Example 1

To 1012 g of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid add a mixture of 3300 ml of ethanol, 1980 ml of N-methylpyrrolidone and 534 g diisopropylethylamine. Heat with phlegm and then pin 459 g of (1S,6S)-2,8-diazabicyclo[4.3.0]nonane. After the addition is stirred for further 3 hours with phlegm, then cooled to room temperature, filtered the solid and washed it a total of 1800 ml of ethanol.

The resulting substance is suspended in a mixture of 4650 ml of ethanol and 41 g of diisopropylethylamine and heated the reaction mixture for 3 hours with flowing phlegm. Next, the reaction mixture is cooled to room temperature, filtered, the solid is then washed it a total of 1000 ml of ethanol and dried at a temperature of 60-70°in a vacuum drying Cabinet to constant weight. Receive 1130 solid beige color, which is presented on figure 5 x-ray diffraction the diffraction pattern of the powder.

450 g of this solid and 29450 g of double-distilled water prepare a 1.5% (weight/weight) aqueous solution, which is filtered through a filter with a pore size of 0.2 microns to remove any undissolved particles. Then maintain this solution of 4 weeks at room temperature the tour is not available for light containers made of polyethylene. After this time precipitated is filtered off precipitate the solid on the filter with a pore size of 0.8 microns and dried overnight at a temperature of 75°With:

Receive 2 g of solid, which according to x-ray-diffraction pattern of the powder mainly amorphous (6) and DTA is shown in Fig.7.

30 mg of this obtained solid substance is heated for 2 hours in a stream of nitrogen at a temperature of 160°C. Obtain 28 mg of solids, x-ray powder diffractogram shown in figure 1, chart DTA is shown in figure 2, the IR spectrum is shown 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 D, characterized by x-ray-diffraction pattern with the following reflexes (2 theta) with high and medium intensity:

2θ(2 theta)

7,6

9,5

12,8

14,2

17,5

19,3

19,5

20,4

21,8

22,6

25,2

27,5

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 D according to claim 1, characterized in that it is defined using the DTA melting temperature 261-265°C.

3. 8-cyan-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo[4.3.0]nonan-8-yl)-6-ft the p-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid (CCDC) of crystalline modification according to claim 1 or D 2, characterized in that it is obtained by dissolving CCDC unknown modification or amorphous CCDC in water at a concentration of 1-3 wt.%, dropped out after some time, the solid is filtered off, dried and heated to a temperature above the temperature of transformation, from 130°160°C.

4. Drug with activity against pathogenic bacteria, characterized in that it comprises, along with the usual excipients and fillers CCDC crystalline modification D according to one of claims 1 to 3,



 

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FIELD: organic chemistry, medicine pharmacy.

SUBSTANCE: invention describes 8-cyano-1-cyclopropyl-7-(1S,6S-2,8-diazabicyclo-[4.3.0]-nonane8-yl)-6-fluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in the crystalline modification C of the formula (I):

and a medicinal agent eliciting effect against pathogenic microorganisms. This crystalline modification of compound of the formula (I) elicits low hygroscopicity, satisfied friability and can be processed easily to galenic preparations.

EFFECT: valuable properties of agent.

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EFFECT: valuable properties of agent.

4 cl, 7 dwg, 1 tbl, 1 ex

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