Polymorph of rucaparib camsylate

This application is a continuation of International Patent Application No. PCT/CN2018/119486 filed on Dec. 6, 2018, which is hereby incorporated by reference in its entirety.

The present invention relates to novel crystals of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt form D and its preparation method and use.

Ovarian cancer is a cancer that originates in a woman's ovaries and produces abnormal cells that invade and metastasize to other areas. The initial symptoms of ovarian cancer are not obvious, and with the progress of the disease, many typical symptoms of cancer appear, including flatulence, abdominal distension, and pelvic pain. Cancer spreads easily to the peritoneum, lymph nodes, lungs, and liver. In 2012, 239,000 women worldwide suffered from ovarian cancer, killing 152,000 people. It is the seventh most common cancer among cancers and the eighth most common cause of death among women. Ovarian cancer is more prevalent in North America and Europe than in Africa and Asia. Polyadenylate diphosphate ribose polymerase (PARP) inhibitors are important DNA repair enzymes that recognize single-strand breaks in DNA to initiate repair. The target drug can inhibit the activity of PARP, and has the effect of enhancing radiotherapy and DNA damage chemotherapy drugs. In addition, it can also selectively kill tumor cells with DNA repair defects. Rucaparib was originally developed by Pfizer. Clovis Oncology obtained its authorization from Pfizer in 2011 and applied for marketing in the United States. It was approved by the US FDA for listing on Dec. 19, 2016 under the trade name Rubraca®. The drug is the second PARP inhibitor on the market and is approved as a monotherapy for patients with advanced ovarian cancer who have undergone BRCA mutations who have received two or more chemotherapy.

Rucaparib Camsylate is chemically named 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt with molecular formula of C 19 H 18 FN 3 O.C 10 H 16 O 4 S and a molecular weight of 555.66, also represented by the structure as follows:

For chemical raw materials to be formulated, they must have good purity, stability, physical and chemical properties, and operability. These properties are related to the crystal form of the drug. Different crystal forms have different physical and chemical properties. The stability of the drug preservation and the purpose of improving the efficacy of the drug require that the drug be made into a crystal state.

Different crystalline forms of drugs have different solubility and dissolution rates, which affect the bioavailability of drugs, as a result, they can lead to differences in clinical efficacy.

The main object of the present invention is to provide 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt (Rucaparib camsylate) new crystalline form D, and process for its preparation and a medicinal use.

A process for the preparation of 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt crystal form D comprising:

(i) dissolving 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt in an organic solution;

(ii) the solution obtained in step (i) is placed in an ultrasonic environment, and an antisolvent (a solvent having a low solubility in rucaparib camsylate) is added to precipitate the compound from the solution; and

(iii) obtaining 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt crystal form D of after liquid-solid separation.

A pharmaceutical composition may comprise t 8-fluoro-2-{4-[(methylamino)methyl]phenyl}-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indol-6-one ((1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl) methanesulfonic acid salt crystal form D as an active ingredient.

Rucaparib camsylate crystalline form D and its pharmaceutical composition use: for treating cancer.

It is used to treat cancer-related diseases. The disease is selected from breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer, which have the same “PARP gene.”

WO2011098971 patent discloses crystalline forms A, B, and C of rucaparib camsylate, but studies have found that crystal forms A, B, and C have low solubility under low pH conditions, such as pH 1.2, which affects the dissolution time of rucaparib camsylate in gastric juice. In practical applications, patients take a relatively high dose of rucaparib camsylate daily. The recommended dose is 600 mg (calculated as rucaparib free base, 300 mg twice daily), and the maximum daily is 1200 mg (calculated as rucaparib free base (600 mg twice daily), or 1030.9 mg and 2061.8 mg if calculated based on rucaparib camsylate. At such high doses, only the compound can be quickly dissolved to ensure that the compound absorbs the drug within the absorption window. For drugs that cannot be dissolved in time, they will not be absorbed by the body which will be wasted and cause unwanted side effects. Compared with the existing crystalline form A, B or C, the crystalline form D of rucaparib camsylate found in the present invention can unexpectedly increase the solubility of rucaparib camsylate in simulated gastric juice, thereby it can make high-dose rucaparib fully absorbed and produce better clinical results with the same dose.

FIG. 1 is an XPRD pattern of rucaparib camsylate form D. 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate;

FIG. 2 is a DSC plot of rucaparib camsylate Form D. Temperature in unit of ° C. in accordance with the abscissa. The Heat flow (w/g) as ordinate;

FIG. 3 is a TGA plot of rucaparib camsylate Form D. Temperature in unit of ° C. in accordance with the abscissa. The Weight (%) as ordinate;

FIG. 4 is an XPRD pattern of rucaparib camsylate form D after forced degradation treatment (elevated temperature). 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate;

FIG. 5 is an XPRD pattern of rucaparib camsylate form D after forced degradation treatment (high humid). 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate; and

FIG. 6 is an XPRD pattern of rucaparib camsylate form D after forced degradation treatment (light stability). 20 values in unit of degree in accordance with the abscissa. The intensity of diffraction peak as ordinate.

The specific embodiments of the present invention are further described in detail below with reference to the drawings and embodiments. The following examples are intended to illustrate the invention, but are not intended to limit the scope of the invention.

The X-ray powder diffraction operation and analysis steps in this patent are as follows:

The Rigaku Ultima IV powder diffractometer was used, which was irradiated with Cu-K(R) (40 kV, 40 mA) at room temperature using a D/tex Ultra detector. The scanning range is from 3° to 45° in the 2θ interval, and the scanning speed is 20°/min.

Measurement differences associated with X-ray powder diffraction analysis results are produced by a variety of factors including: (a) errors in sample preparation (e.g., sample height), (b) instrument error, (c) calibration differences, (d) operator error (including errors that occur when determining peak position), and (e) properties of the substance (e.g., preferred orientation error). Calibration errors and sample height errors often result in displacement of all peaks in the same direction. When using a flat sampler, small differences in sample height will result in large displacements of the XRPD peak position. Systematic studies have shown that a 1 mm sample height difference can result in a 20 peak shift of up to 10. These displacements can be identified from the X-ray diffraction pattern and can be eliminated by compensating for the displacement (using a system calibration factor for all peak position values) or recalibrating the instrument. As described above, the measurement errors from different instruments can be corrected by applying a system calibration factor to make the peak positions consistent.