Crystalline (8s,9r)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1h-1,2,4-triazol-5-yl)-8,9-dihydro-2h-pyrido[4,3,2-de]phthalazin-3(7h)-one tosylate salt

Abstract

Provided herein are (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt forms, including crystalline forms, and methods of their preparation. Pharmaceutical compositions comprising a (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt are also provided, as are methods of using (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt to treat a disease or condition, such as a cancer.

What is claimed: 
     
         1 . A (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt. 
     
     
         2 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the salt is in a substantially pure crystalline form. 
     
     
         3 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the salt is a crystalline form exhibiting at least one of
 a solid state  13 C NMR spectrum with peaks at 143.2, 136.0, 131.8, 123.9, 112.2, 105.2, and 100.3 ppm±0.2 ppm;   a differential scanning calorimetry thermogram having an endotherm with a maximum at between about 320° C. and about 335° C.;   a thermogravimetric analysis thermogram indicative of an unsolvated material;   a dynamic vapor sorption isotherm plot which does not exhibit a significant weight change from 0 to 95% relative humidity;   an X-ray powder diffraction pattern comprising characteristic peaks expressed in d-values (Å) of about 11.9, 5.9, 4.9, 4.4, 4.3, 3.9, and 3.7; and   an X-ray powder diffraction pattern comprising peaks at 2θ angle degrees±0.2 2θ angle degrees of 7.4, 15.1, 18.1, 20.1, 20.4, 22.6, and 24.0.   
     
     
         4 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the salt is a crystalline form exhibiting at least one of
 a solid state  13 C NMR spectrum with peaks at 143.2, 136.0, 131.8, 123.9, 112.2, 105.2, and 100.3 ppm±0.2 ppm;   an X-ray powder diffraction pattern comprising characteristic peaks expressed in d-values (Å) of about 11.9, 5.9, 4.9, 4.4, 4.3, 3.9, and 3.7; and   an X-ray powder diffraction pattern comprising peaks at 2θ angle degrees±0.2 2θ angle degrees of 7.4, 15.1, 18.1, 20.1, 20.4, 22.6, and 24.0.   
     
     
         5 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the salt is a crystalline form exhibiting an X-Ray Powder Diffraction pattern comprising characteristic peaks expressed in d-values (Å) of about 11.9, 5.9, 4.9, 4.4, 4.3, 3.9, and 3.7. 
     
     
         6 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the salt is a crystalline form exhibiting an X-Ray Powder Diffraction pattern comprising characteristic peaks expressed in 2θ angle degrees±0.2 2θ angle degrees of 7.4, 15.1, 18.1, 20.1, 20.4, 22.6, and 24.0. 
     
     
         7 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the salt is a crystalline form exhibiting a solid state  13 C NMR spectrum with peaks at 143.2, 136.0, 131.8, 123.9, 112.2, 105.2, and 100.3 ppm±0.2 ppm. 
     
     
         8 . The (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt of  claim 1 , where the crystalline form has a purity of at least about 99.5%. 
     
     
         9 . The tosylate salt of  claim 1 , where the crystalline form is substantially free of an amorphous form of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one or a salt or solvate thereof. 
     
     
         10 . A method of preparing a crystalline form of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt comprising
 step (1): in the presence of one or more step 1 solvent(s) independently selected from THF, acetone, methanol, acetonitrile, and DCM, contacting (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3 (7H)-one with p-toluenesulfonic acid at an elevated temperature;   step (2): allowing to stand under conditions sufficient to precipitate the crystalline form; and   step (3): isolating the crystalline form.   
     
     
         11 . The method of  claim 10  where the elevated temperature is about 30° C. to about 70° C. 
     
     
         12 . The method of  claim 10  where the one or more step 1 solvent(s) are independently selected from methanol and acetonitrile. 
     
     
         13 . The method of  claim 10  where the one or more step 1 solvent(s) are independently selected from DCM and acetonitrile. 
     
     
         14 . The method of  claim 10  where the one or more step 1 solvent(s) are independently selected from acetone and THF. 
     
     
         15 . The method of  claim 10  where the step 1 solvent is acetone. 
     
     
         16 . The method of  claim 10  where the step 1 solvent is THF. 
     
     
         17 . The method of  claim 10  where the conditions sufficient to precipitate the crystalline form include cooling. 
     
     
         18 . The method of  claim 17  where the conditions sufficient to precipitate the crystalline form include cooling to 25° C. or cooler. 
     
     
         19 . The method of  claim 10  further comprising
 step (a): contacting 
 
       
         
           
           
               
               
           
         
         with 4-fluorobenzaldehyde in a mixture comprising one or more step (a) solvent(s) and titanium(III) chloride to make a first intermediate; 
         step (b): isolating by chiral separation an enantiomer of the first intermediate; and 
         step (c): contacting the isolated enantiomer of the first intermediate with hydrazine monohydrate in one or more step (c) solvent(s) to make (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one. 
       
     
     
         20 . The method of  claim 19  where the isolated enantiomer of the first intermediate is contacted with hydrazine monohydrate in one or more step (c) solvent(s) independently selected from methanol, ethanol, and acetonitrile. 
     
     
         21 . The method of  claim 19  where the one or more step (a) solvent(s) are independently selected from THF and methanol. 
     
     
         22 . The method of  claim 10  further comprising
 step (x): contacting 
 
       
         
           
           
               
               
           
         
         with hydrazine monohydrate in one or more step x solvents to yield 5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one; and 
         step (y): isolating (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one by chiral separation. 
       
     
     
         23 . The method of  claim 22  where the one or more step (x) solvent(s) is independently selected from methanol, ethanol, and acetonitrile. 
     
     
         24 . A (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt prepared according to the method of any of  claim 10 . 
     
     
         25 . The tosylate salt of  claim 24 , where the salt is a crystalline form exhibiting an X-Ray Powder Diffraction pattern comprising characteristic peaks expressed in d-values (Å) of about 7.4, 15.1, 18.1, 20.1, 20.4, 22.6, and 24.0. 
     
     
         26 . The tosylate salt of  claim 24 , where the salt exhibits a single endothermal peak on differential scanning calorimetry between room temperature and about 350° C., where the single endothermal peak maximum occurs between about 320° C. to about 335° C. 
     
     
         27 . The tosylate salt of  claim 24 , where the salt exhibits less than 2% thermal weight loss at or below a temperature of about 280° C. by thermogravimetric analysis. 
     
     
         28 . The tosylate salt of  claim 24 , where the salt exhibits a value of hysteresis less than about 1% in dynamic vapor sorption at about 25° C. from RH 0% to RH 95%. 
     
     
         29 . A pharmaceutical composition comprising a tosylate salt according to  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         30 . The pharmaceutical composition according to  claim 29 , where the composition is formulated for oral administration to a subject. 
     
     
         31 . A method of treating a cancer, or symptom thereof, comprising administering a therapeutically acceptable amount of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt to a subject with cancer. 
     
     
         32 . The method of  claim 31 , where the cancer is bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, Burkitt's lymphoma, nasopharyngeal carcinoma, EBV+ gastric cancer, endometrial cancers, gastrointestinal stromal tumor, glioblastoma, head and neck cancer, hepatocellular carcinoma, kidney cancer, leukemia, lung cancer, lymphoma, medulloblastoma, melanoma, meningioma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, small cell lung carcinoma, thyroid cancer or uterine cancer. 
     
     
         33 . The method of  claim 31 , where about 0.3 μg/kg body weight to about 3.0 μg/kg body weight of (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt are administered per day to the subject. 
     
     
         34 . The method of  claim 31  where the (8S,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one tosylate salt is a crystalline form according to any of  claims 3 - 9 .