The present disclosure relates to heterocyclic protein kinase inhibitors, solid state forms of the same, pharmaceutical compositions containing the same, methods of making and using these compounds and compositions to treat proliferative disease mediated by kinase activity.
One embodiment provides a citiric acid salt of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene.
One embodiment provides a fumaric acid salt of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene.
Another embodiment provides crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
Another embodiment provides crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
Another embodiment provides crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
Another embodiment provides crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
Another embodiment provides crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate having a melting point of 191° C. as determined by differential scanning calorimetry.
Another embodiment provides crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate having a melting point of 240° C. as determined by differential scanning calorimetry.
Another embodiment provides crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=21.5°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=21.5°, and 15.0°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=21.5°, 19.8°, and 15.0°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern as provided in
Another embodiment provides crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=25.8°.
In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=25.8°, and 23.8°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=25.8°, 23.8°, and 23.0°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern as provided in
Another embodiment provides crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=20.6°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=20.6°, and 24.5°.
Another embodiment provides crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=14.9°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=7.1°, and 14.9°.
One embodiment provides a benzene sulfonic acid salt of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene. Another embodiment provides crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate.
One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate. One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate. Another embodiment provides the pharmaceutical composition substantially free of any other solid state form of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate. One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate. Another embodiment provides the pharmaceutical composition substantially free of any other solid state form of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate. Another embodiment provides the pharmaceutical composition substantially free of any other solid state form of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate.
Another embodiment provides the method wherein the proliferative disease is cancer. Another embodiment provides the method wherein the cancer is a hematological or myeloproliferative cancer. Another embodiment provides the method wherein the cancer is a solid tumor. Another embodiment provides the method wherein the cancer is characterized by increased Flt3, CDK or JAK signaling.
All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The features of the invention are set forth with particularity in the appended claims. A better understanding of the features of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:
While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.
One of the major advances in cancer research has been the clinical validation of molecularly targeted drugs that inhibit the activity of protein kinases. Small-molecule kinase inhibitors that are now approved for oncology indications include imatinib, gefitinib, erlotinib, sorafenib, sunitinib and dasatinib (Baselga J., Science, 2006, 312, 1175-1178). A number of kinases such as JAK2, FLT3 and CDK2 are promising kinase targets for pharmacological intervention in solid tumours, hematological malignancies, myeloproliferative disorders and non-malignant proliferative disorders like keloids. The Janus kinases (JAK) are a family of cytoplasmic tyrosine kinases consisting of JAK1, JAK2, JAK3 and Tyk2. They play a pivotal role in the signaling pathways of numerous cytokines, hormones and growth factors (Rawlings J S et al, J. Cell Sci., 2004, 117, 1281-1283). Their intracellular substrates include the family of proteins called Signal Transducer and Activator of Transcription (STAT). The JAK-STAT pathways, through the proper actions of the ligands, regulate important physiological processes such as immune response to viruses, erythropoiesis, lactation, lipid homeostasis, etc. However, dysfunctional signaling caused by a myriad of factors result in pathophysiological conditions such as allergies, asthma, rheumatoid arthritis, severe combined immune deficiency, hematological malignancies, etc. In particular, mutations in JAK2 have been associated with myeloproliferative disorders (including polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis) and a wide range of leukemias and lymphomas (Percy M J of al, Hematol. Oncol., 2005, 23, 91-93). Importantly, the myeloproliferative disorders belong to an area of unmet medical need where some treatment modalities have not been updated over the past few decades (Schafer Al, Blood, 2006, 107, 4214-4222).
The myeloproliferative disorders (MPDs) belong to a group of hematological malignancies arising from clonal expansion of mutated progenitor stem cells in the bone marrow. The association of one MPD, chronic myeloid leukemia, with the Philadelphia chromosome has been well documented. The Philadelphia negative MPDs include Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Chronic Idiopathic Myelofibrosis (MF). No effective treatment is currently available. The recent discovery that a single acquired somatic mutation in JAK2 appears responsible for many of the features of these MPDs promises to impact the diagnosis and treatment of patients with these disorders and to spur additional research into the origins of dysregulated cell growth and function. Until recently, most MPDs have been considered to be rare or orphan diseases but studies underway suggest a much higher prevalence.
Essential Thrombocythemia is a chronic MPD characterized by an increased number of circulating platelets, profound marrow megakaryocyte hyperplasia, splenomegaly and a clinical course punctuated by hemorrhagic or thrombotic episodes or both. Current treatment options include low dose aspirin, or platelet lowering agents such as anagrelide, interferon or hydroxyurea. These treatments have severe side effects that compromise the quality of life of patients.
Polycythemia Vera is a chronic progressive MPD characterized by an elevated hematocrit, an increase in the red cell mass, and usually by an elevated leukocyte count, an elevated platelet count and an enlarged spleen. The most common cause of morbidity and mortality is the predisposition of PV patients to develop life threatening arterial and venous thromboses. Treatment options include: phlebotomy with low dose aspirin or myelosuppressive therapy options such as hydroxyurea, interferon or anagrelide. Again, these treatments are not ideal due to severe side effects.
Chronic Idiopathic Myelofibrosis (MF) is a chronic malignant hematological disorder characterized by an enlarged spleen, varying degrees of anemia and low platelet counts, red cells in the peripheral blood that resemble tear drops, the appearance of small numbers of immature nucleated red cells and white cells in the blood, varying degrees of fibrosis of the marrow cavity (myelofibrosis) and the presence of marrow cells outside the marrow cavity (extramedullar hematopoiesis or myeloid metaplasia). Current treatment is directed at alleviation of constitutional symptoms, anemia and symptomatic splenomegaly. Treatment options include hydroxyurea, interferon, thalidomide with prednisone, and allogeneic stem cell transplant. MF has the worst prognosis among the Philadelphia negative MPD and represents an area of greatest unmet medical need.
In addition, due to its role in the angiotensin II signaling pathway, JAK2 is also implicated in the etiology of cardiovascular diseases like congestive heart failure and pulmonary hypertension (Berk B C et al, Circ. Res, 1997, 80, 607-616). Furthermore, a putative role for JAK2 has been demonstrated in keloid pathogenesis and may constitute a new approach for keloid management (Lim C P et al, Oncogene, 2006, 25, 5416-5425). Yet another potential application for JAK2 inhibitors lies in the treatment of retinal diseases as JAK2 inhibition was found to offer protective effects on photoreceptors in a mouse model of retinal degeneration (Samardzija M et al, FASEB J., 2006, 10, 1096).
A family of Class III receptor tyrosine kinases (RTK), including c-Fms, c-Kit, fms-like receptor tyrosine kinase 3 (FLT3), and platelet-derived growth factor receptors (PDGFRfct and (3), play an important role in the maintenance, growth and development of hematopoietic and non-hematopoietic cells. Overexpression and activating mutations of these RTKs are known to be involved in the pathophysiology of diverse human cancers from both solid and hematological origins (Hannah A L, Curr. Mol. Med., 2005, 5, 625-642). FLT3 mutations were first reported as internal tandem duplication (FLT3/ITD) of the juxtamembrane domain-coding sequence; subsequently, point mutations, deletions, and insertions surrounding the D835 coding sequence have been found (Parcells B W et al, Stem Cells, 2006, 24, 1174-1184). FLT3 mutations are the most frequent genetic alterations reported in acute myeloid leukemia (AML) and are involved in the signaling pathway of autonomous proliferation and differentiation block in leukemia cells (Tickenbrock L et al, Expert Opin. Emerging Drugs, 2006, 11, 1-13). Several clinical studies have confirmed that FLT3/ITD is strongly associated with a poor prognosis. Because high-dose chemotherapy and stem cell transplantation cannot overcome the adverse effects of FLT3 mutations, the development of FLT3 kinase inhibitors could produce a more efficacious therapeutic strategy for leukemia therapy.
Cyclin-dependent kinases (CDKs) are serine-threonine kinases that play important roles in cell cycle control (CDK1, 2, 4 and 6), transcription initiation (CDK7 and 9), and neuronal function (CDK5) (Knockaert M et al, Trends Pharmacol. Sci., 2002, 23, 417-425). Aberrations in the cell cycle CDKs and their cyclin partners have been observed in various tumour types, including those of the breast, colon, liver and brain (Shapiro G I, J. Clin. Oncol., 2006, 24, 1770-1783). It is believed that the pharmacological inhibition of CDK1, 2, 4, 6 and/or 9 may provide a new therapeutic option for diverse cancer patients. In particular, the simultaneous inhibition of CDK1, 2 and 9 has recently been shown to result in enhanced apoptotic killing of lung cancer (H1299) and osteosarcoma cells (U2OS), compared with inhibition of single CDK alone (Cai D et al, Cancer Res, 2006, 66, 9270-9280).
Accordingly, compounds that are kinase inhibitors have the potential to provide further biologically active compounds that would be expected to have useful, improved pharmaceutical properties in the treatment of kinase related conditions or disorders such as cancer and other proliferative disorders.
Provided herein is 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene (Chemical Abstracts Number [937270-47-8]; also known as TG02 or SB1317) and referred to herein as Compound I.
Compound I is a potent in vitro inhibitor of CDK2, FLT3, JAK2 and JAK V617F with an IC50 less than 1 μM. In cell-based assays, Compound I exhibits a GI50 less than 1 μM in HL60, Colo205, HEL92.1.7, MV4-11 and DU145 cell lines. The synthesis and biological activity of Compound I was reported in WO 2007/058628 which is incorporated by reference in its entirety. It has been found, however, that the physiochemical properties of Compound I are poor, for example the solubility in water has been determined to be less than 0.001 mg/mL, thus limiting the utility of Compound I as a therapeutic agent.
One embodiment provides a citiric acid salt of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene.
One embodiment provides a fumaric acid salt of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene.
Another embodiment provides crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
Another embodiment provides crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
Another embodiment provides crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
Another embodiment provides crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
Another embodiment provides crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate having a melting point of 191° C. as determined by differential scanning calorimetry.
Another embodiment provides crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate having a melting point of 240° C. as determined by differential scanning calorimetry.
Another embodiment provides crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=21.5°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=21.5°, and 15.0°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=21.5°, 19.8°, and 15.0°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern as provided in
Another embodiment provides crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=25.8°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=25.8°, and 23.8°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=25.8°, 23.8°, and 23.0°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern as provided in
Another embodiment provides crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=20.6°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=20.6°, and 24.5°.
Another embodiment provides crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate characterized by a powder x-ray diffraction pattern having reflections at 2 theta=14.9°. In a further embodiment the composition is characterized by a powder x-ray diffraction pattern having reflections at 2 theta=7.1°, and 14.9°.
One embodiment provides a benzene sulfonic acid salt of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene. Another embodiment provides crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate.
One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate. One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate. Another embodiment provides the pharmaceutical composition substantially free of any other solid state form of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate. One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate. Another embodiment provides the pharmaceutical composition substantially free of any other solid state form of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
One embodiment provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate. Another embodiment provides the pharmaceutical composition substantially free of any other solid state form of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate.
One embodiment provides a method of treating proliferative disease comprising administering a therapeutically effective amount of the pharmaceutical composition comprising a therapeutically effective amount of crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate.
Another embodiment provides the method wherein the proliferative disease is cancer. Another embodiment provides the method wherein the cancer is a hematological or myeloproliferative cancer. Another embodiment provides the method wherein the cancer is a solid tumor. Another embodiment provides the method wherein the cancer is characterized by increased Flt3, CDK or JAK signaling.
Provided herein are pharmaceutical compositions comprising citrate, fumarate or besylate addition salts of Compound I as the active ingredient and one or more pharmaceutically acceptable excipients or carriers. In various embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of crystalline citrate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate as the active ingredient and one or more pharmaceutically acceptable excipients or carriers. In various embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of crystalline citrate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene citrate as the active ingredient and one or more pharmaceutically acceptable excipients or carriers. In various embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of crystalline fumarate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate as the active ingredient and one or more pharmaceutically acceptable excipients or carriers. In various embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of crystalline fumarate pattern 2 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene fumarate as the active ingredient and one or more pharmaceutically acceptable excipients or carriers. In various embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
Provided herein are pharmaceutical compositions comprising a therapeutically effective amount of crystalline besylate pattern 1 of 14-methyl-20-oxa-5,7,14,27-tetraazatetracyclo-[19.3.1.12,6.18,12]heptacosa-1(25),2,4,6,8,10,12(26),16,21,23-decaene besylate as the active ingredient and one or more pharmaceutically acceptable excipients or carriers. In various embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable vehicle, carrier, diluent, or excipient, or a mixture thereof.
Provided herein are pharmaceutical compositions in film-coated dosage forms, which comprise a combination of an active ingredient, and one or more tabletting excipients to form a tablet core using conventional tabletting processes and subsequently coating the core. The tablet cores can be produced using conventional granulation methods, for example wet or dry granulation, with optional comminution of the granules and with subsequent compression and coating.
The pharmaceutical compositions provided herein may be provided in unit-dosage forms or multiple-dosage forms. Unit-dosage forms, as used herein, refer to physically discrete units suitable for administration to human and animal subjects and packaged individually as is known in the art. Each unit-dose contains a predetermined quantity of the active ingredient sufficient to produce the desired therapeutic effect, in association with the required pharmaceutical carriers or excipients. Examples of unit-dosage forms include ampules, syringes, and individually packaged tablets and -capsules. Unit-dosage forms may be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in segregated unit-dosage form. Examples of multiple-dosage forms include vials or bottles of tablets or capsules.
The pharmaceutical compositions provided herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
In the case wherein the patient's condition does not improve, upon the doctor's discretion the administration of the combinations may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition. In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the combinations may be given continuously or temporarily suspended for a certain length of time (i.e., a “drug holiday”). In some embodiments, once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained.
Treatment dosages generally may be titrated to optimize safety and efficacy. Typically, dosage-effect relationships from in vitro studies initially can provide useful guidance on the proper doses for patient administration. Studies in animal models also generally may be used for guidance regarding effective dosages for treatment in accordance with the present disclosure. In terms of treatment protocols, it should be appreciated that the dosage to be administered will depend on several factors, including the particular agent that is administered, the route administered, the condition of the particular patient, etc. Determination of these parameters are well within the skill of the art. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.
The compositions provided herein may be administered alone, or in combination with one or more other active ingredients.
The pharmaceutical compositions provided herein may be formulated in various dosage forms for oral, parenteral, buccal, intranasal, epidural, sublingual, pulmonary, local, rectal, transdermal, or topical administration. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, N.Y., 2002; Vol. 126).
In various embodiments, the pharmaceutical compositions provided herein may be provided in solid, semisolid, or liquid dosage forms for oral administration
As used herein, oral administration also include buccal, lingual, and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, solutions, wafers, sprinkles, elixirs, and syrups. In addition to the active ingredient(s), the pharmaceutical compositions may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, coloring agents, dye-migration inhibitors, sweetening agents, and flavoring agents.
In further embodiments, the pharmaceutical compositions provided herein may be provided as compressed tablets, tablet triturates, chewable lozenges, rapidly dissolving tablets, multiple compressed tablets, or enteric-coating tablets, sugar-coated, or film-coated tablets. Enteric-coated tablets are compressed tablets coated with substances that resist the action of stomach acid but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach.
The tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular forms, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled-release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are especially useful in the formation of chewable tablets and lozenges.
The pharmaceutical compositions provided herein may be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. The hard gelatin capsule, also known as the dry-filled capsule (DFC), consists of two sections, one slipping over the other, thus completely enclosing the active ingredient. The soft elastic capsule (SEC) is a soft, globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. The liquid, semisolid, and solid dosage forms provided herein may be encapsulated in a capsule. Suitable liquid and semisolid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils, or triglycerides.
In other embodiments, the pharmaceutical compositions provided herein may be provided as non-effervescent or effervescent, granules and powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable carriers and excipients used in the non-effervescent granules or powders may include diluents, sweeteners, and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and a source of carbon dioxide.
In various embodiments, the pharmaceutical compositions provided herein may be formulated as a modified release dosage form. As used herein, the term “modified release” refers to a dosage form in which the rate or place of release of the active ingredient(s) is different from that of an immediate dosage form when administered by the same route. Modified release dosage forms include delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. The pharmaceutical compositions in modified release dosage forms can be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion-exchange resins, enteric coatings, multilayered coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be modified by varying the particle size of the active ingredient(s). Examples of modified release include, but are not limited to, those described in U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,972,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; and 6,699,500.
In other embodiments, the pharmaceutical compositions provided herein in an immediate release dosage form are capable of releasing not less than 75% of the therapeutically active ingredient or combination and/or meet the disintegration or dissolution requirements for immediate release tablets of the particular therapeutic agents or combination included in the tablet core, as set forth in USP XXII, 1990 (The United States Pharmacopeia.).
The term “therapeutically effective amount” or “effective amount” is an amount sufficient to effect beneficial or desired clinical results. An effective amount can be administered in one or more administrations. An effective amount is typically sufficient to palliate, ameliorate, stabilize, reverse, slow or delay the progression of the disease state.
The examples and preparations provided below further illustrate and exemplify the compounds of the present disclosure and methods of preparing such compounds. It is to be understood that the scope of the present disclosure is not limited in any way by the scope of the following examples and preparations.
The present disclosure is further illustrated by the following examples, which should not be construed as limiting in any way. The experimental procedures to generate the data shown are discussed in more detail below. The disclosure has been described in an illustrative manner, and it is to be understood that the terminology used is intended to be in the nature of description rather than of limitation.
X-Ray Powder Diffraction patterns were collected on a Bruker AXS C2 GADDS diffractometer or a Bruker D8 diffractometer.
X-Ray Powder Diffraction patterns collected on a Bruker AXS C2 GADDS diffractometer were performed using Cu Ka radiation (40 kV, 40 mA), automated XYZ stage, laser video microscope for auto-sample positioning and a HiStar 2-dimensional area detector. X-ray optics consists of a single Göbel multilayer mirror coupled with a pinhole collimator of 0.3 mm. The beam divergence, i.e. the effective size of the X-ray beam on the sample, was approximately 4 mm. A θ-θ continuous scan mode was employed with a sample-detector distance of 20 cm which gives an effective 2θ range of 3.2-29.7°. Typically the sample would be exposed to the X-ray beam for 120 seconds. The software used for data collection was GADDS for WNT 4.1.16 and the data were analysed and presented using Diffrac Plus EVA v 9.0.0.2 or v 13.0.0.2. Samples run under ambient conditions were prepared as flat plate specimens using powder as received without grinding. Approximately 1-2 mg of the sample was lightly pressed on a glass slide to obtain a flat surface.
X-Ray Powder Diffraction patterns collected on a Bruker D8 diffractometer were performed using Cu Ka radiation (40 kV, 40 mA), θ-2θ goniometer, and divergence of V4 and receiving slits, a Ge monochromator and a Lynxeye detector. The instrument is performance checked using a certified Corundum standard (NIST 1976). The software used for data collection was Diffrac Plus XRD Commander v2.5.0 and the data were analysed and presented using Diffrac Plus EVA v 11,0.0.2 or v 13.0.0.2. Samples were run under ambient conditions as flat plate specimens using powder as received. Approximately 20 mg of the sample was gently packed into a cavity cut into polished, zero-background (510) silicon wafer. The sample was rotated in its own plane during analysis. The details of the data collection are:
Data were collected on a Bruker AXS 1K SMART CCD diffractometer equipped with an Oxford Cryosystems Cryostream cooling device. Structures were solved using either the SHELXS or SHELXD programs and refined with the SHELXL program as part of the Bruker AXS SHELXTL suite. Unless otherwise stated, hydrogen atoms attached to carbon were placed geometrically and allowed to refine with a riding isotropic displacement parameter. Hydrogen atoms attached to a heteroatom were located in a difference Fourier synthesis and were allowed to refine freely with an isotropic displacement parameter.
Nuclear Magnetic Resonance (NMR)
1H NMR spectra were collected on a Bruker 400 MHz instrument equipped with an auto-sampler and controlled by a DRX400 console. Automated experiments were acquired using ICON-NMR v4.0.4 (build 1) running with Topspin v 1.3 (patch level 8) using the standard Bruker loaded experiments. For non-routine spectroscopy, data were acquired through the use of Topspin alone. Samples were prepared in d6-DMSO, unless otherwise stated. Off-line analysis was carried out using ACD SpecManager v 9.09 (build 7703).
Differential Scanning Calorimetry (DSC)
DSC data were collected on a TA Instruments Q2000 equipped with a 50 position auto-sampler. The calibration for thermal capacity was carried out using sapphire and the calibration for energy and temperature was carried out using certified indium. Typically 0.5-3 mg of each sample, in a pin-holed aluminium pan, was heated at 10° C.·min−1 from 25° C. to 250° C. A purge of dry nitrogen at 50 was maintained over the sample. The instrument control software was Advantage for Q Series v2.8.0.392 and Thermal Advantage v4.8.3 and the data were analysed using Universal Analysis v4.3A.
Thermo-Gravimetric Analysis (TGA)
TGA data were collected on a TA Instruments Q500 TGA, equipped with a 16 position auto-sampler. The instrument was temperature calibrated using certified Alumel. Typically 5-15 mg of each sample was loaded onto a pre-tared platinum crucible and aluminium DSC pan, and was heated at 10° C.·min−1 from ambient temperature to 250° C. A nitrogen purge at 60 was maintained over the sample. The instrument control software was Advantage for Q Series v2.8.0.392 and Thermal Advantage v4.8.3
Polarised Light Microscopy (PLM)
Samples were studied on a Leica LM/DM polarised light microscope with a digital video camera for image capture. A small amount of each sample was placed on a glass slide, mounted in immersion oil and covered with a glass slip, the individual particles being separated as well as possible. The sample was viewed with appropriate magnification and partially polarised light, coupled to a X false-colour filter.
Gravimetric Vapour Sorption (GVS)
Sorption isotherms were obtained using a SMS DVS Intrinsic moisture sorption analyser, controlled by SMS Analysis Suite software. The sample temperature was maintained at 25° C. by the instrument controls. The humidity was controlled by mixing streams of dry and wet nitrogen, with a total flow rate of 200 ml·min−1. The relative humidity was measured by a calibrated Rotronic probe (dynamic range of 1.0-100% RH), located near the sample. The weight change, (mass relaxation) of the sample as a function of % RH was constantly monitored by the microbalance (accuracy ±0.005 mg). Typically 5-20 mg of sample was placed in a tared mesh stainless steel basket under ambient conditions. The sample was loaded and unloaded at 40% RH and 25° C. (typical room conditions). A moisture sorption isotherm was performed as outlined below (2 scans giving 1 complete cycle). The standard isotherm was performed at 25° C. at 10% RH intervals over a 0.5-90% RH range. The sample was recovered after completion of the isotherm and re-analysed by XRPD.
Thermodynamic Aqueous Solubility
Aqueous solubility was determined by suspending sufficient compound in water to give a maximum final concentration of 210 mg·ml−1 of the parent free-form of the compound. The suspension was equilibrated at 25° C. for 24 hours then the pH was measured. The suspension was then filtered through a glass fibre C filter into a 96 well plate. The filtrate was then diluted by a factor of 101. Quantitation was by HPLC with reference to a standard solution of approximately 0.1 mg·ml−1. in DMSO. Different volumes of the standard, diluted and undiluted sample solutions were injected. The solubility was calculated using the peak areas determined by integration of the peak found at the same retention time as the principal peak in the standard injection.
Analysis was performed on an Agilent HP1 100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SR1.
Chemical Purity Determination by HPLC
Purity analysis was performed on an Agilent HP1 100 series system equipped with a diode array detector and using ChemStation software vB.02.01-SR1.
Ion Chromatography (IC)
Data were collected on a Metrohm 861 Advanced Compact IC (for anions) using IC Net software v2.3. Accurately weighed samples were prepared as stock solutions in DMSO and diluted 1:9 with either DMSO or water prior to testing. Quantification was achieved by comparison with standard solutions of known concentration of the ion being analysed.
pKa Determination and Prediction
Data were collected on a Sirius GlpKa instrument with a D-PAS attachment. Measurements were made at 25° C. in aqueous solution by UV and in methanol water mixtures by potentiometry. The titration media was ionic-strength adjusted (ISA) with 0.15 M KCl (aq). The values found in the methanol water mixtures were corrected to 0% co-solvent via a Yasuda-Shedlovsky extrapolation. The data were refined using Refinement Pro software v2.2. Prediction of pKa values was made using ACD pKa prediction software v12.
Log P Determination
Data were collected by potentiometric titration on a Sirius GlpKa instrument using three ratios of octanol:ionic-strength adjusted (ISA) water to generate Log P, Log Pion, and Log D values. The data were refined using Refinement Pro software v2.2. Prediction of Log P values was made using ACD v12 software.
The synthesis of Compound I free base has been reported in WO 2007/058628 which is incorporated by reference in its entirety. Additional synthetic routes to Compound I are presented below.
As illustrated in Scheme 1,2,4-dichloropyrimidine (1) was subjected to a palladium (II)-mediated cross-coupling reaction with 3-hydroxyphenylboronic acid (2) to give the 4-substituted pyrimidine 3. Alkylation with 1-bromo-3-butene followed by condensation with aniline 7 afforded the tricyclic alkene 8. Subjecting compound 8 to the ring closing metathesis reaction provided Compound I which was isolated as the hydrochloride salt.
Scheme 2 illustrates the synthesis of aniline 7. 3-Nitrobenzaldehyde is subjected to a reductive amination with N-methylallylamine to give amine 6. Reduction of the nitro group with SnCl2 afforded aniline 7.
An alternative synthesis of Compound I is presented in Scheme 3, alkylation of 3-hydroxyphenylboronic acid with 1-bromo-3-butene followed by palladium (II)-mediated cross-coupling reaction with 2,4-dichloropyrimidine 2-chloropyrimidine compound 4. Condensation with aniline 7 afforded tricyclic diene 8. Subjecting compound 8 to the ring closing metathesis reaction provided Compound I which was isolated as the citrate salt.
The Table below is a summary of the characterisation of the free base of compound I.
1H-NMR (400 MHz,
Additionally to these characterisation data, single crystals were obtained by slow evaporation of a free base solution in TI-IF at RT. The crystal structure of anhydrous Form 1 of the free base was solved and the comparison between the simulated XRPD diffractogram and the experimental Pattern 1 of the free base showed a good match, except one additional peak at circa 6.2° (20) which could be due to a crystalline impurity (see the superimposition of simulated and experimental XRPD patterns in
The NMR spectrum of Compound I is given in
The HPLC chromatogram of Compound I is given in
A XRPD of Compound I after stability study (40° C./75% R.H.) is illustrated in
A HPLC chromatogram of Compound I post-stability study is given in
An optical microscopy photograph of Compound I is provided in
The recording of the TGA/DSC @ 10° C./min is provided in
The GVS at 25° C. curves are provided in
A high resolution XRPD of Compound I is provided in
A XRPD of Compound I after GVS study is illustrated in
pKa and logP determinations were performed as described above. The pKa values for Compound I were calculated and measured, and the correlation between both values was in good agreement.
A preliminary screen of solvents for crystallization with hydrochloric acid and tartaric acid indicated that tetrahydrofuran, methyl ethyl ketone (MEK) and water:ethanol (1:1/v:v) were good solvents for obtaining crystalline products. Taking in consideration the pKa values, a number of acids were selected to carry out the salt screen. These acids are shown in the Table 6.
No salt formation and/or no crystalline solids were obtained for the samples containing 1 eq. of phosphoric acid, L-glutamic acid, L-lactic acid and acetic acid.
The free base (50 mg, 0.134 mmol) was weighted into 2 cm3 vials and the appropriate solvent was added; 15 volumes in THF and 50 volumes in MEK and water:ethanol mixture. The samples were then warmed, under shaking, up to 50° C. for 2 hours to obtain homogeneous solutions.
Each sample was then treated with 1 eq. of the corresponding acid (or 2 eq. for the HCl salt) and subjected to a series of heat-cool cycles from RT to 50° C. (8 hour cycles). After 12 hours of maturation, the samples which did not yield any solid were cooled down 4° C.
After 2 days, the solids were isolated by filtration under vacuum at RT to be characterised by XRPD analysis. Each new crystalline solid phase detected was characterised by 1H NMR and TGA-DSC analyses in order to determine if salt formation had occurred and whether the material was a solvate. At this stage, each salt identified was then analysed by HPLC to determine the chemical purity prior to being stored in the humidity chamber (40° C./75% R.H.) to assess its stability. The experimental results are summarised in Table 7.
The salt formation has been successfully obtained for nine counter-ions, during the main screen, resulting in 13 new XRPD patterns as listed below (in addition to Pattern 2 of the hydrochloride):
HCl Pattern 2 and 6 (crystallised with 2 eq. of HCl)
Sulfate Pattern 1
Mesylate Pattern 1
Besylate Pattern 1
Maleate Pattern 1 and 2
Fumarate Pattern 1 and 2
Citrate Pattern 1 and 2
Malate Pattern 1
Succinate Pattern 1 and 2
The most promising results were obtained for the Fumarate Pattern 2 and the Citrate Pattern 1. These mono-salts produced anhydrous crystalline forms with a good yield and with a good crystallinity. Furthermore, both were not sensitive to humidity after 2 weeks (at least) of storage in the humidity chamber at 40° C./75% R.H.
The Besylate Pattern 1 was also an anhydrous form and stable after 2 weeks of storage in the humidity chamber at 40° C./75% R.H. However, its stoichiometry was not clearly determined by integration of the 1H NMR signals.
The free base of Compound I (650 mg, 1.74 mmol) was dissolved at 50° C. in 50 volumes of MEK (31.25 mL). After homogenisation, the solution was treated with 1 eq. of citric acid (1.745 mL of a 1 M solution in THF). The reaction mixture was then subjected to maturation cycles from room temperature to 50° C. (8 hour cycles) for a 12 hour period. The resulting solid was filtered under vacuum and dried at room temperature to provide 960 mg (97%) of product. XPRD analysis indicates the product is citrate pattern 1 polymorph of Compound I. Citrate Pattern 1 is an anhydrous polymorphic form melting at 191° C. (according the DSC). This salt is also stable in the solid state, at ambient conditions and is not sensitive to humidity (no transformation observed in GVS at 25° C. and after 2 weeks, at least, in the humidity chamber at 40° C./75% R.H.). The aqueous solubility was significantly higher than that of the free base (0.16 mg/mL).
The 1H NMR spectrum of the citrate pattern 1 polymorph of Compound I is given in
The HPLC chromatogram of the citrate pattern 1 polymorph of Compound I is given in
A high resolution XRPD of the citrate pattern 1 polymorph of Compound I is provided in
An optical microscopy photograph of the citrate pattern 1 polymorph of Compound I is provided in
The recording of the TGA/DSC at 10° C./min of the citrate pattern 1 polymorph of Compound I is provided in
The GVS at 25° C. curves of the citrate pattern 1 polymorph of Compound I are provided in
A XRPD of the citrate pattern 1 polymorph of Compound I after GVS study is illustrated in
Table 8 is a summary of the characterisation of the citrate pattern 1 polymorph of Compound I.
1H NMR (400 MHz,
The free base of Compound I (650 mg, 1.74 mmol) was dissolved at 50° C. in 50 volumes of MEK (31.25 mL). After homogenisation, the solution was treated with 1 eq. of fumaric acid (3.490 mL of a 0.5 M solution in THF/methanol). The reaction mixture was then subjected to maturation cycles from room temperature to 50° C. (8 hour cycles) for a 12 hour period. The resulting solid was filtered under vacuum and dried at room temperature to provide 830 mg (97%) of product. XPRD analysis indicates the product is fumarate pattern 2 polymorph of Compound I. Fumarate pattern 2 is an anhydrous polymorphic form melting at 240° C. (according the DSC). Fumarate pattern 2 is stable in the solid state, at ambient conditions (temperature and pressure) and is not sensitive to high level of humidity (no transformation observed in GVS at 25° C. and after 2 weeks, at least, in the humidity chamber at 40° C./75% R.H.). Furthermore, the aqueous solubility was significantly higher than that of the free base (0.029 mg/mL).
The 1H NMR spectrum of the fumarate pattern 2 polymorph of Compound I is given in
The HPLC chromatogram of the fumarate pattern 2 polymorph of Compound I is given in
A high resolution XRPD of the fumarate pattern 2 polymorph of Compound I is provided in
An optical microscopy photograph of the fumarate pattern 2 polymorph of Compound I is provided in
The recording of the TGA/DSC at 10° C./min of the fumarate pattern 2 polymorph of Compound I is provided in
The GVS at 25° C. curves of the fumarate pattern 2 polymorph of Compound I are provided in
A XRPD of the fumarate pattern 2 polymorph of Compound I after GVS study is illustrated in
Table 9 is a summary of the characterisation of the fumarate pattern 2 polymorph of Compound I.
1H NMR (400 MHz,
The free base of Compound I (100 mg, 0.268 mmol) was dissolved at 50° C. in 15 volumes of THF. After homogenisation, the solution was treated with 1 eq. of benzenesulfonic acid (0.268 mL of a 1 M solution in THF). The reaction mixture was then subjected to maturation cycles from room temperature to 50° C. (8 hour cycles) for a 12 hour period. The resulting solid was filtered under vacuum and dried at room temperature to provide 53 mg of product. XPRD analysis indicates the product is a mixture of besylate pattern 1 and form 1 of the free base of Compound I.
Changing the solvent to MEK and using 2 equivalents of benzenesulfonic acid followed by maturing the reaction mixture at room temperature also afforded the product as a mixture of besylate pattern 1 and form 1 of the free base of Compound I.
Changing the solvent to MEK and using 1 equivalents of benzenesulfonic acid followed by maturation cycles from room temperature to 50° C. (8 hour cycles) for a 12 hour period and obtaining a sample product by hot filtration at 50° C. afforded a product as besylate pattern 1. Upon cooling to room temperature, filtration and drying, the product was obtained as a mixture of besylate pattern 1 and form 1 of the free base of Compound I.
A XRPD of the besylate pattern 1 polymorph of Compound I and form 1 of the free base is illustrated in
A XRPD of the besylate pattern 1 polymorph of Compound I obtained by hot filtration and the mixture of the besylate pattern 1 polymorph of Compound I and form 1 of the free base obtained by room temperature filtration is illustrated in
An initial polymorphism screen was performed for the fumarate and citrate salts using 10 common class II and III organic solvents (with and without addition of water), plus pure water. 20-25 mg of salt (Fumarate Pattern 2 or Citrate Pattern 1) was weighed into a 2 cm3 vial and 20 volumes of the appropriate solvent was added. The samples were subjected to a series of heat/cool cycles (room temp −50° C., 8 hour cycles). After 3 days, the samples were filtered and the solids were characterised by XRPD analysis. The results for Fumarate Pattern 2 are presented in Table 10 and results for Citrate Pattern 1 are presented in Table 11.
No transformation of Fumarate Pattern 2 and Citrate Pattern 1 was observed after 3 days of maturation in dried solvents.
Fumarate Pattern 2 transformed to Fumarate Pattern 1 after 3 days of maturation in water, toluene:water, ethyl-acetate:water, and TBME:water. Fumarate Pattern 1 was previously detected, during the salt screen from salt formation in a water:ethanol mixture. This salt was partially characterised by TGA-DSC (see
Citrate Pattern 1 transformed to Citrate Pattern 2 after 3 days of maturation in water, toluene:water, ethyl-acetate:water, THF:water, acetonitrile:water, TBME:water and nitromethane:water. Citrate Pattern 2 was also previously detected as a mixture with Form 1 of the free base, during the main salt screen from a water:ethanol mixture. Furthermore, Citrate Pattern 1 transformed to a new solid phase (Citrate Pattern 3) after slurrying in DCM:water (95:5 v/v).
The free base of Compound I (200 mg) was dissolved in 50:50 v/v water:ethanol (10 mL) at 60° C. with stirring in a 25 mL conical flask. After complete dissolution, fumaric acid (1.128 mL of a 0.5 M solution in 50:50 (v/v) methanol:THF) was added dropwise to the warm solution and the reaction mixture was maturated in a maturation chamber from room temperature to 50° C. (8 hour cycles) with shaking for 12 hours. The reaction mixture was filtered under vacuum and dried for 12 hours at room temperature to give a yellow solid. The 1H NMR is presented in
The free base of Compound I (200 mg) was dissolved in 50:50 v/v water:ethanol (10 mL) at 60° C. with stirring in a 25 mL conical flask. After complete dissolution, a seed crystal of Citrate Pattern 2 was added followed by citric acid (0.564 mL of a 1.0 M solution in THF) added dropwise to the warm solution and the reaction mixture was maturated in a maturation chamber from room temperature to 50° C. (8 hour cycles) with shaking for 12 hours. The reaction mixture was filtered under vacuum and dried for 12 hours at room temperature to give a yellowish solid. The 1H NMR is presented in
Purpose:
To compare the rate of hydration of fumarate pattern 2 against citrate pattern 1. Test medium was prepared by dissolving methocel (4 g) in water (196 mL) to afford a 2% (w/w) solution. After stirring for 12 hours to ensure a homogenous solution is obtained, Tween 80 (800 mg) and water (600 mL) was added and the mixture stirred for an additional 12 hours to homogenise.
For the 1 mg/mL concentration experiments, the anhydrous polymorph (30 mg of either citrate pattern 1 or fumarate pattern 2) was placed into a 40 mL glass tube. Test medium (30 mL) was added and each sample was maturated at the indicated temperature and condition (−20° C., 4° C., room temperature with stirring and room temperature without stirring). A parallel series of samples was prepared with the addition of a hydrated polymorph seed crystal (either citrate pattern 2 or fumarate pattern 1). The samples were monitored over time by XRPD to determine the rate of hydration of the anhydrous polymorph.
For the 10 mg/mL concentration experiments, the anhydrous polymorph (50 mg of either citrate pattern 1 or fumarate pattern 2) was placed into a 20 mL glass tube. Test medium (5 mL) was added and each sample was maturated at the indicated temperature and condition (−20° C., 4° C., room temperature with stirring and room temperature without stirring). A parallel series of samples was prepared with the addition of a hydrated polymorph seed crystal (either citrate pattern 2 or fumarate pattern 1). The samples were monitored over time by XRPD to determine the rate of hydration of the anhydrous polymorph.
The results from the stability study are presented in Table 12 and indicate the kinetics of hydration of the citrate salt are slower than for the fumarate salt. Seeding and stirring are two parameters which increase the kinetics of transformation with seeding reducing the nucleation time and stirring accelerating the permanent dissolution-recrystallisation phenomenon.
A pharmaceutical composition comprising 100 mg of active ingredient per capsule is prepared according to the formula and process described below.
The ingredients are dry blended to homogenity and the bulk composition dispensed into the hard gelatin capsule shells using a Minicap 100 semi-automatic capsule filler.
This application claims the benefit of U.S. Provisional Application No. 61/301,771, filed Feb. 5, 2010, which is incorporated herein by reference in its entirety.
Filing Document | Filing Date | Country | Kind | 371c Date |
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PCT/US11/23810 | 2/4/2011 | WO | 00 | 2/21/2013 |
Number | Date | Country | |
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61301771 | Feb 2010 | US |