Polymorphs of 6-n-(l-ala-l-ala)-trovafloxacin

 

(57) Abstract:

Polymorphs of 6-N-(L-Ala-L-Ala) trovafloxacin formula I are monohydrate polymorph PIIM, having a powder x-ray diffraction, are shown in table. 1 in the graphics part, or pseudomorphs PII.PS, having a powder x-ray diffraction, are shown in table. 2 in the graphics part. 2 C. and 8 C.p. f-crystals, 4 PL.

The present invention relates to a prodrug of trovafloxacin formula I:

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selected from the group consisting of polymorph PII and monohydrate PII.M and his pseudomorpha PII.PS, and to methods for their preparation. Further, the present invention relates to methods of using and pharmaceutical compositions comprising the compounds of the present invention, for the treatment of bacterial infections in mammals.

Antibacterial activity of trovafloxacin disclosed in U.S. patent N 5164402 ('402 patent) and 5229396 ('396 patent), issued November 17, 1992, and July 20, 1993, respectively. These patents belong to the authors of this application. In the above patents also described polymorph PI compounds of formula I and methods of its receipt.

Brief description of the invention

In the first embodiment, the present image is the group consisting of:

a) polymorph PII, powder diffraction of x-rays which takes the form shown in table. 3 in the graphics part;

b) monohydrate PII.M, powder x-ray diffraction which takes the form shown in table. 1 in the graphics part;

c) pseudomorpha PII.PS, powder x-ray diffraction which takes the form shown in table. 2 in the graphics part.

In accordance with a second embodiment of the invention, a method for obtaining prodrugs R, as described previously, which includes the processing of PI prodrugs of formula I (powder x-ray diffraction is presented in table. 4 in the graphics part) dry ethanol.

In accordance with another aspect of the above options in the present invention, a method for obtaining monohydrate, PII.M, as indicated previously, polymorph PII, which includes:

a) processing polymorpha PI water solvent;

b) processing polymorpha PII water or

(C) processing pseudomorpha PII.M, PII.PS water.

In another aspect of the above variant of the invention, a method for obtaining pseudomorpha, PII.PS, as indicated previously, monohydrate PII.M, which includes a vacuum drying monohydro the material an effective amount of the compounds of formula I, as indicated previously, together with a pharmaceutically acceptable diluent or carrier.

In yet another embodiment of the present invention, a method for treating a bacterial infection in a mammal, which includes an introduction to the specified mammal an effective amount (for treatment of this bacterial infection) the compounds of formula I, as described earlier.

In the third embodiment of the present invention proposed a prodrug of trovafloxacin consisting of polymorph PII, characterized by a powder x-ray diffraction, described earlier, which is obtained in the processing polymorpha PI, characterized by given previously by x-ray diffraction, dry ethanol.

In accordance with another aspect of the present invention proposed a prodrug of trovafloxacin consisting of monohydrate PII.M polymorpha PII characterized the earlier powder x-ray diffraction, get:

a) processing polymorph PI (characterized by the earlier powder diffraction rentgenovskih rays) with an organic solvent containing water;

b) processing polymorph PII water or

(C) the treatment is of trovafloxacin, consisting of his pseudomorpha PII.PS (characterized by powder x-ray diffraction, presented earlier), which is obtained by vacuum drying the monohydrate PII.M.

Detailed description of the invention

The present invention relates to a prodrug of trovafloxacin having the following formula I:

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selected from the group consisting of polymorph PII and monohydrate PII.M and his pseudomorpha PII. PS, and to pharmaceutical compositions, including PII, PII. M or PII.PS, and to methods of their use. The present invention relates also to methods for PII, PII.M and PII.PS that is presented to illustrate in the following reaction scheme 1.

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In accordance with scheme 1 polymorph I turn in polymorph Pll, treating it with dry ethanol. This transformation is usually carried out at room temperature. Polymorph PI can be obtained in accordance with the method of example 49 patent '402 or located on the simultaneous consideration of the patent application U.S. N RS 9186 (the disclosure of which is included here for reference). Application PC 9186 submitted together with this application. Then polymorph PII can be turned into a monohydrate PII.M, treating it with water. Water can be in the form of liquid and vapor.

The obtained crystals are dried to a water content of about 2.7% to obtain the target product.

Monohydrate PII.M can be turned into pseudomorph PII.PS vacuum drying. Pseudomorph can again be turned into a monohydrate, treating it with water (in liquid form), as described previously in relation to the transformation of PII to PII.M.

Antibacterial compounds of formula I, i.e. polymorph PII, monog the least and intermediate compounds of the present invention, suitable for the treatment of animals and people having a wide range of bacterial infections. They are particularly useful for the treatment of Gram-positive bacterial strains.

The active compounds can be entered separately, but they are usually injected in a mixture with a pharmaceutically acceptable carrier selected with regard to the proposed route of administration and standard pharmaceutical practice. For example, they can be administered orally or in the form of tablets containing such excipients as starch or lactose, or in capsules either alone or in a mixture with excipients, or in the form of elixirs or suspensions containing corrigentov or tinted agents. In the case of animals, they are preferably contained in animal feed or in drinking water at a concentration of from about 5 to about 5000 hours per million, preferably from about 25 to about 500 million hours They can be administered parenterally, for example intramuscularly, intravenously or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other dissolved substances, for example enough salts or glucose to make the solution isotonic. In the case of animals, the compounds of formula I is up to about 10 mg/kg/day as single daily dose or up to 3 divided doses.

The active compounds can enter people for the treatment of bacterial diseases either orally or parenterally. They can be administered orally in doses of from about 0.1 to 500 mg/kg/day, preferably 0.5 to 50 mg/kg/day as a single unit dose or up to 3 divided doses. For intramuscular or intravenous dose is from about 0.1 to 200 mg/kg/day, preferably 0.5 to 50 mg/kg/day. While intramuscularly you can enter the active compound either as a single dose or in 3 divided vines, and intravenous administration may include the introduction of via IV. Naturally, there are different variations depending on the weight and condition of the subject to treatment of the patient and the particular route of administration chosen by the experts.

Antibacterial activity of the compounds of the present invention is demonstrated by testing in accordance with replicating methodology Steers, which is the standard method of bacterial test in vitro, described E. Steers et al. Antibiotics and Chemotherapy 9, 307 (1959).

The following examples illustrate the methods and compounds of the present invention. Note, however, that the present invention is not limited to Konko-1,8-naphthiridine-2-yl]-4-azabicyclo [3.1.0]Gex-6-yl}-N'-tert - butoxycarbonyl-L-alaninate

Zwitterion of trovafloxacin (obtained by the method are on the simultaneous consideration of the application N PC 9186) (3 g) is mixed with 45 ml of dichloromethane at a temperature of approximately 25oC to obtain a white suspension. To this suspension add 2,19 g of N-tert-butyloxycarbonyl-L-alanyl-L-alanine and 1.95 g of 2-ethoxy-1-etoxycarbonyl-1,2-dihydroquinoline, and the resulting mixture is stirred for 4 hours at a temperature of approximately 25oC. the Reaction mixture is cooled to a temperature of about 5oC, and is listed in the title compound is isolated in the form of white crystals in the filter. These crystals are washed with dichloromethane (15 ml) and dried in vacuum. Yield 4.7 g, 80%.

Example 2

L-alanyl-N-{ (1,5,6) -3-[6-carboxy-8-(2,4-differenl)-3-fluoro-5,8-dihydro-5-oxo-1,8-naphthiridine-2 - yl]-3-azabicyclo[3.1.0]Gex-6-yl}-L-alanineaminotransferase

Specified in the title of the example 1 compound (10 g) and tetrahydrofuran (60 ml) is stirred to obtain a suspension at a temperature of approximately 25oC. To this suspension add methansulfonate acid (2.9 g) and the resulting reaction mixture is heated to boiling under reflux (about 66oC) for about 6 hours. The reaction mixture is cooled to about 5oC, and the floor is ω (15 ml) and dried in vacuum at 40 ° oC. Yield 9.4 g, 94%.

Example 3

L-alanyl-N-{ (1,5,6) -3-[6-carboxy-8-(2,4-differenl)-3-fluoro-5,8-dihydro-5 - oxo-1,8-naphthiridine-2-yl] -3-azabicyclo [3.1.0]Gex-6-yl}-L-alanineaminotransferase

Specified in the title of the example 1 product (10 g), acetone (80 ml) and water (1.8 ml) is stirred to obtain a suspension at a temperature of about 20oC. To this suspension add methansulfonate acid (4.4 g) and the resulting reaction mixture is heated to boiling under reflux (about 56oC) for about 4 hours.

Add additional acetone (40 ml) to the reaction mixture while boiling under reflux. The reaction mixture is cooled to about 5oC, and the resulting crystals are specified in the title of the product produce by filtration, washed with cold acetone (25 ml) and dried in vacuum to a temperature of about 35oC. Yield of 9.9 g, 93%.

Example 4

L-alanyl-N-{ (1,5,6) -3-[6-carboxy-8-(2,4-differenl)-3-fluoro-5,8-dihydro - 5-oxo-1,8-naphthiridine-2-yl]-3-azabicyclo[3.1.0]Gex-6-yl}-N'-tert - butoxycarbonyl-L-alaninate

7-{ (1,5,6) -6-amino-3-naphthiridine-2-yl]-3-azabicyclo[3.1.0]Gex-3-yl} -6-fluoro-1- (2,4-differenl)-1,4-dihydro-4-oxo-1,8-naphthalen-3-carboxylic acid methanesulfonate (40 g) is mixed with dichloramine (7.9 g), N-tert.-butyl-oxycarbonyl-L-alanyl-L-alanine (23.7 g) and 2-ethoxy - and 1-etoxycarbonyl-1,2-dihydroquinoline (21,24 g) and the resulting reaction mixture is stirred for about 16 hours at a temperature of approximately 25oC. the Reaction mixture is cooled to about 5oC for 1 hour, and is listed in the title product is isolated in the form of white crystals by filtration. The obtained crystal was washed with dichloromethane (80 ml) and dried in vacuum. Output 42.6 g, 83%.

Example 5

Polymorph PII L-Ala-N-{(1,5,6) -3-[6-carboxy-8-(2,4-differenl)-3-fluoro - 5,8-dihydro-5-oxo-1,8-naphthiridine-2-yl]-3-azabicyclo-[3.1.0]Gex-6-yl} - L-alanineaminotransferase

Specified in title product of example 2 or 3 was stirred in a dry (water content less than about 0.1%) ethanol (2.0 ml) for 48 hours at a temperature of approximately 25oC. Specified in the title of the product emit filtering.

This product is characterized by the diffraction pattern of the scattering of x-rays that you specified earlier.

Example 6

The monohydrate polymorph II (PII.M)

A. the Product specified in the title of the example 2 or 3 (4 g), heated to boiling under reflux (about 78oC) in ethanol containing water ( 5%) (40 ml) for about 1 hour. Add dopolnennuyu the mixture is cooled to a temperature of about 25oC to obtain a slurry of crystals. These crystals are filtered and dried to a water content of 2.7% to obtain the title product. Output 90%.

C. the Product specified in the title of the example 2 or 3 (20 g), heated to a temperature of approximately 45oC in ethyl acetate (300 ml). Then slowly add 21 ml of oxen to obtain a suspension. This suspension is heated to the boiling temperature under reflux, and azeotrope to remove water (19 ml). The resulting solution is cooled to about 25oC to obtain a slurry of crystals. These crystals are filtered and dried to a water content of about 2.7% to obtain the title product. A yield of 99%.

Specified in the title of the product is characterized by the above mentioned diffraction pattern of the scattering of x-rays.

Example 7

Pseudomorph PII.PS Monohydrate polymorph II

The product that is listed in the title of example 6 and dried in vacuum until then, until completely remove the water, getting listed in title product. Specified in the title of the product is characterized by the above mentioned powder x-ray diffraction.

1. Polymorphs of 6-N-(L-Ala-L-Ala)-trovafloxacin formula

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where specified the percent in table.1 in the graphics part,

or pseudomorphs R. PS, having a powder x-ray diffraction, are shown in table.2 in the graphics part.

2. Polymorphs of trovafloxacin under item 1, characterized in that it consists of a monohydrate R.M.

3. Polymorphs of trovafloxacin under item 1, characterized in that it consists of pseudomorpha R.PS.

4. Polymorphs of trovafloxacin under item 2, characterized in that contain water around 2.7%.

5. Polymorphs of trovafloxacin under item 1, characterized in that it consists of a monohydrate polymorph R.M, characterized by specified previously by x-ray diffraction, and which is obtained by processing polymorpha PI, characterized specified previously by x-ray diffraction, dry ethanol or an organic solvent containing water to obtain polymorpha R characterized specified previously by x-ray diffraction; processing polymorpha R water or processing pseudomorpha R.M, R.PS water.

6. Polymorphs of trovafloxacin under item 5, characterized in that it consists of its pseudomorph R.PS, characterized specified previously by x-ray diffraction, which is obtained by vacuum drying the monohydrate R.M.

7. The method of obtaining monohydrate, PIU x-rays, are given in table.3 in the graphics part,

processing polymorpha PI, having a powder x-ray diffraction, are shown in table.4 in the graphics part,

dry ethanol or an organic solvent containing water, and processing polymorpha R water, or processing pseudomorpha R.M, R.PS water.

8. The method according to p. 7, characterized in that the organic solvent is selected from the group consisting of C1-C6-alkyl esters of C1-C6-alkanovykh acids and C1-C6-alkanols.

9. The method according to p. 8, characterized in that said solvent is ethyl acetate.

10. The method according to p. 7, characterized in that it further includes a vacuum drying monohydrate R.M to get its pseudomorph R.PS.

 

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