Crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid for the treatment of disease

Abstract

The present invention relates to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid, pharmaceutical compositions and dosage forms comprising the crystalline forms, methods of making the crystalline forms and methods for their use for the treatment, prevention or management of diseases ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay.

1 - 16 . (canceled) 
     
     
         17 . A method for treating cancer comprising administering to a patient having cancer a crystal form of the compound of formula (I): 
       
         
           
           
               
               
           
         
         which has an X-ray powder diffraction pattern comprising at least three peak positions (° 2θ±0.2) when measured using Cu Kα radiation, 
         selected from the group consisting of 4.96, 6.39, 10.10, 11.54, 12.62, 12.81, 13.92, 14.16, 14.55, 14.88, 15.07, 15.58, 16.27, 16.61, 18.74, 18.94, 19.28, 19.94, 20.27, 20.74, 20.97, 21.22, 21.93, 22.58, 22.80, 23.00, 23.79, 24.14, 24.46, 25.44, 25.64, 26.07, 26.34, 26.74, 27.06, 27.79, 28.42, 29.09 and 30.48, comprising obtaining said crystal form of the compound of formula (I) and subsequently administering said crystal form of the compound of formula (I) to said patient. 
       
     
     
         18 . The method of  claim 17 , wherein the crystal form has the following unit cell parameters when measured at 150 K: a=24.2240 Å; b=3.74640 Å; c=27.4678 X; α=90°; β=92.9938°; γ=90°; V=2489.38(17) Å 3 ; Z=8; calculated density (d calc , g cm −3 ) is 1.517 g cm −3 ; and the space group is P2 1 /n (no. 14). 
     
     
         19 . The method of  claim 17 , wherein the crystal form has an X-ray powder diffraction pattern comprising at least one peak position (° 2θ±0.2) when measured using Cu Kα radiation, selected from the group consisting of 10.10, 11.54, 14.55, 14.88 and 15.07. 
     
     
         20 . The method of  claim 19 , wherein the crystal form has a differential scanning calorimetry thermogram which has an endothermic event with a peak temperature at 244° C. 
     
     
         21 . The method of  claim 19 , wherein the crystal form has a thermogravimetric analysis thermogram which has a mass loss of less than 1% of the total mass of the sample upon heating from 33° C. to 205° C. 
     
     
         22 . The method of  claim 18 , wherein the crystal form is non-hygroscopic. 
     
     
         23 . The method of  claim 17 , wherein the crystal form is characterized by  13 C CP/MAS solid-state NMR signals at the following positions: 172.6, 167.0, 131.3, 128.4 and 117.1 ppm, when externally referenced to glycine at 176.5 ppm. 
     
     
         24 . The method of  claim 17 , wherein the crystal form has an X-ray powder diffraction pattern comprising peak positions (° 2θ±0.2) when measured using Cu Kα radiation, of 10.10, 11.54, 14.55, 14.88 and 15.07. 
     
     
         25 . The method of  claim 17 , wherein the crystal form has a purity of greater than 90%. 
     
     
         26 . The method of  claim 17 , wherein the cancer is a solid tumor or hematological cancer. 
     
     
         27 . The method of  claim 17 , wherein the cancer is associated with one or more tumor suppressor genes. 
     
     
         28 . The method of  claim 27 , wherein the tumor suppressor gene is one or more genes selected from a group consisting of APC, ATM, BRAC1, BRAC2, MSH1, pTEN, Rb, CDKN2, NF1, NF2, WT1, and p53 genes. 
     
     
         29 . The method of  claim 28 , wherein the tumor suppressor gene is a p53 gene. 
     
     
         30 . The method of  claim 29 , wherein nonsense mutations have been identified in the p53 gene and have been implicated in the cancer. 
     
     
         31 . The method of  claim 17 , wherein the cancer is a solid tumor, sarcoma, carcinomas, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, menangioma, melanoma, neuroblastoma, retinoblastoma, a blood-born tumor, acute lymphoblastic leukemia, acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemic leukemia, acute megakaryoblastic leukemia, acute myelomonocytic leukemia, acute nonlymphocyctic leukemia, acute undifferentiated leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, hairy cell leukemia, or multiple myeloma.