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 c and medicinal agent eliciting effect against pathogenic microorganisms

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.

4 cl, 7 dwg, 1 tbl, 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 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 by conversion of 7-chloro-8-cyan-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and (1S,6S)-2,8-diazabicyclo[4.3.0]nonane 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 after removal of 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 by chance there is a uniform crystalline modification, it is not clear how it can be extracted and combined to determine the hinnon. 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 of it is used for the production of medicinal substances.

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 detect low bulk density and poor fluidity. In addition, for processing hygroscopic substances require special working tools and devices in order to have reproducible results, for example, in the content of biologically active substances or stability of the produced solid products.

The task of the invention to provide 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-quinoline-carboxylic what isatou crystalline modification, having rentgenodiffraction powder recorded in the following table reflexes (2 theta) with high or medium intensity (more than 15% relative intensity).

Rentgenodiffraction powder CCDC crystalline modification

2θ (2 theta)

5,7

12,6

15,5

17,2

20,2

26,4

27

Characteristic rentgenodiffraction powder CCDC crystalline modifications are also presented in figure 1.

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

CCDC crystalline modification differs in that it has a melting point of 235 to 237° With defined using differential thermal analysis (DTA). The characteristic chart DTA presented in figure 2.

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

CCDC crystalline modification With further differs in that it can be obtained in the following way. CCDC crystalline modifications To get maintaining an unknown modification CCDC or amorphous CCDC in a few days the ri room temperature and a relative humidity of at least 92% to constant weight, thus obtained slurry product is dried and then heated to a temperature exceeding the transition temperature.

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 modification can be determined using DTA dried substance. Typically, it is between 150 and 180° C.

CCDC crystalline modification 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 can definitely and purposefully to produce a stable solid dosage form CCDC.

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

Roentgenokymogram powder on the I characteristics CCDC crystalline modification 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 modifications were made to the 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 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 rentgenodiffraction is, which it basically is amorphous.

Example

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. Refluxed 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 with a mixture of 4650 ml of ethanol and 45 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 with rentgenodiffraction presented on Figure 5.

500 mg obtained according to this method, the solids incubated at room temperature for 11 days at a relative humidity of 95% (installed through a saturated solution and then treated with Na2HPO4×12H2O in water). Receive 695 mg of product.

20 mg of the resulting solid is dried for 24 hours at a temperature of 100° With in a vacuum drying Cabinet above the P2O5. Obtain 134 mg of a solid substance having rentgenodiffraction (6), characteristic of amorphous material, the 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 180° C. Obtain 27 mg of solid substances, rentgenodiffraction powder which is 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 characterized by x-ray-diffraction pattern with the following reflexes (2 theta) with high and medium intensity:

2θ(2J)

5,7

12,6

15,5

17,2

20,2

26,4

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, characterized in that it is defined using the DTA melting point 235-237°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) of crystalline modification according to claim 1 or 2, characterized in that she received exposure on the CCDC unknown modification or amorphous CCDC consider Inoi humidity not less than 92% to cessation of weight gain and subsequent drying of the resulting product by heating to a temperature lying above the temperature of transformation, 150°to 180°C.

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



 

Same patents:

FIELD: organic chemistry, medicine.

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):

in the crystalline modification B and a medicinal agent based on thereof that elicits effect against pathogenic microorganisms. Indicated modification of compound of the formula (I) shows stability and insignificant absorption of air moisture ant doesn't convert to another crystalline modification or amorphous form being even in the prolonged storage.

EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

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EFFECT: improved and valuable properties of compound.

4 cl, 4 dwg, 6 ex

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where 1 R=NO2, R1=H;

2 R=CF3, R1=H;

3 R=CN, R1=H;

4 R=R1=CN

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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

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EFFECT: valuable properties of agent.

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2 ex

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30 cl, 11 tbl, 161 ex

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3 ex

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EFFECT: improved preparing method.

3 ex

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5 cl, 4 ex, 3 tbl

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EFFECT: improved and valuable properties of compound.

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EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

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EFFECT: valuable properties of agent.

4 cl, 4 dwg, 6 ex

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