Crystal forms of a 9-aminomethyl substituted tetracycline compound and a preparation method thereof

1. Crystal forms of a compound represented by formula (1), (4S,4aS,5aR,12aS)-9-(3-azabicyclo[3.1.0]hexan-3-ylmethyl)-4,7-bis(dimethylamino)-3,10,12,12a-tetrahydroxy-1,11-dioxo-1,4,4a,5,5a,6,11,12a-octahydrotetracene-2-carboxamide,

which are characterized by having X-ray powder diffraction patterns comprising the following characteristic peaks expressed by 2θ degree, when measured using Cu-Ka radiation:

Crystal form I: 10.6°±0.2°, 13.3°±0.2°, 15.9°±0.2°, 24.0°±0.2°;

Crystal form II: 10.2°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 24.1°±0.2°;

Crystal form VII: 11.7°±0.2°, 15.1°±0.2°, 15.9°±0.2°, 17.9°±0.2°.

2. Crystal forms of the compound represented by formula (1) of claim 1 , which are characterized by having X-ray powder diffraction patterns comprising the following characteristic peaks expressed by 2θ degree, when measured using Cu-Ka radiation:

Crystal form I: 9.0°±0.2°, 10.6°±0.2°, 13.3°±0.2°, 15.9°±0.2°, 23.6°±0.2°, 24.0°±0.2°;

Crystal form II: 9.3°±0.2°, 10.2°±0.2°, 14.0°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 24.1°±0.2°;

Crystal form VII: 11.7°±0.2°, 15.1°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 20.1°±0.2°, 21.8°±0.2°.

3. Crystal forms of the compound represented by formula (1) of claim 1 , which are characterized by having X-ray powder diffraction patterns comprising the following characteristic peaks expressed by 2θ degree, when measured using Cu-Ka radiation:

Crystal form I: 9.0°±0.2°, 10.6°±0.2°, 13.3°±0.2°, 14.3°±0.2°, 15.9°±0.2°, 18.0°±0.2°, 20.0°±0.2°, 21.3°±0.2°, 23.6°±0.2°, 24.0°±0.2°;

Crystal form II: 9.3°±0.2°, 10.2°±0.2°, 14.0°±0.2°, 15.9°±0.2°, 17.9°±0.2°, 20.8°±0.2°, 23.0°±0.2°, 24.1°±0.2°, 24.8°±0.2°, 27.7°±0.2°;

Crystal form VII: 11.0°±0.2°, 11.7°±0.2°, 13.8°±0.2°, 14.3°±0.2°, 15.1°±0.2°,15.9°±0.2°, 17.9°±0.2°, 20.1°±0.2°, 21.8°±0.2°, 25.6°±0.2°.

4. Crystal forms of the compound represented by formula (1) of claim 1 , which are characterized in that:

Crystal form I has an X-ray powder diffraction pattern substantially as shown in FIG. 1 ;

Crystal form II has an X-ray powder diffraction pattern substantially as shown in FIG. 3 ;

Crystal form VII has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .

5. Crystal forms of the compound represented by formula (1) of claim 1 , which are characterized in that:

Crystal form I has an endothermic peak in the range of 180-220° C. in its differential scanning calorimetry curve;

Crystal form II has an endothermic peak in the range of 195-215° C. in its differential scanning calorimetry curve;

Crystal form VII has an endothermic peak in the range of 165-205° C. in its differential scanning calorimetry curve.

6. A process for preparing crystal forms I, II, and VII of the compound represented by formula (1) according to claim 1 , wherein:

the compound represented by formula (1) is placed in anhydrous acetonitrile for slurry-washing or in tetrahydrofuran for stirring, a solid separates from the mixture, and crystal form I is obtained through filtration;

the compound represented by formula (1) is placed in a lower alcohol, ethyl acetate, acetone, or a mixed solution of methanol and water in a ratio of 1:1-9:1 (v/v) for slurry-washing, or dissolved in tetrahydrofuran under an atmosphere of isopropanol or n-heptane, a solid separates from the mixture, and crystal form II is obtained through filtration;

the compound represented by formula (1) is placed in a mixed solution of acetonitrile and water in a ratio of 1:1-9:1 (v/v) for slurry-washing, filtered, and dried in vacuum to produce crystal form VII.

7. A pharmaceutical composition, wherein said pharmaceutical composition contains crystal form I, II, VII of the compound represented by formula (1) or a combination thereof according to claim 1 , and pharmaceutically acceptable carrier(s).

8. The pharmaceutical composition of claim 7 , wherein said crystal form has a content of not lower than 94.5%.

9. A pharmaceutical formulation containing crystal form I, II, VII of the compound represented by formula (1) or a combination thereof according to claim 1 , and one or more pharmaceutically acceptable carriers and/or diluents, which is in any pharmaceutically acceptable dosage form.

10. A method for treating a disease caused by tetracycline-sensitive bacteria and/or tetracycline-resistant bacteria, comprising:

administering to a recipient in need thereof, an amount of a medicament comprising the crystal form of the compound represented by formula (1) of claim 1 , a pharmaceutically acceptable salt, solvate thereof,

wherein said disease caused by tetracycline-sensitive bacteria and/or tetracycline-resistant bacteria is selected from infection, cancer, diabetes and other diseases that have been found to be treatable by other tetracycline compounds, wherein said crystal form is selected from crystal form I, II, VII or a combination thereof.