CA-3124401-C - CRYSTALLINE AND SALT FORMS OF AN ORGANIC COMPOUND AND PHARMACEUTICAL COMPOSITIONS THEREOF

Abstract

Provided herein are various salts, including tris(hydroxymethyl)aminomethane salts and sodium salts, as well as various crystalline forms of the compound represented by the structural formula: Also provided are pharmaceutical compositions comprising these salts and crystalline forms, methods for their manufacture, and uses thereof for treating conditions, including but not limited to conditions that would benefit from inhibition of dihydroorotate dehydrogenase (DHODH).

Inventors

• Syed Altaf
• Abira Ramakrishnan
• Jacob Sizemore
• Shijie Zhang

Assignees

• LES LABORATOIRES SERVIER

Dates

Publication Date

20260505

Application Date

20191220

Priority Date

20181221

Claims (1)

1. CLAIMS 1. A tris(hydroxymethyl)aminomethane salt of a compound represented by the formula of Compound 1: 2. The tris(hydroxymethyl)amino methane salt of claim 1, wherein the salt is an anhydrate. 3. The tris(hydroxymethyl)aminomethane salt of claim 1 or 2, wherein the salt is crystalline Form A characterized by X-ray powder diffraction peaks at 20 angles (± 0.2°) 4.4°, 15.6°, and 18.9°. 4. The tris(hydroxymethyl)amino methane salt of claim 3, wherein the crystalline Form A is further characterized by X-ray powder diffraction peaks at 20 angles(± 0.2°) 11.5°, 16.4°, 19.6° and25.5°. 5. The tris(hydroxymethyl)aminomethane salt of claim 3 or 4, wherein the crystalline Form A is further characterized by at least one X-ray powder diffraction peaks at 20 angles (± 0.2°) selectedfrom8.7°, 15.2°, 18.6°,21.4°and25.1°. 6. The tris(hydroxymethyl)aminomethane salt of claim 1 or 2, wherein the crystalline form is crystalline Form B characterized by X-ray powder diffraction peaks at 20 angles (± 0.2°) 6.0°, 7.0°, and 7.2°. 7. The tris(hydroxymethyl)aminomethane salt of claim 6, wherein the crystalline Form Bis further characterized by at least one X-ray powder diffraction peak at 20 angles(± 0.2°) selected from 9.3° and 12.5°. 84 Date rec;ue/Date received 2024-06-14 88648345 8. The tris(hydroxymethyl)aminomethane salt of claim 6 or 7, wherein the crystalline Form B is further characterized by at least one X-ray powder diffraction peaks at 20 angles (± 0.2°) selected from 15.6° and 19.0°. 9. The tris(hydroxymethyl)aminomethane salt of claim 1 or 2, wherein the crystalline form is crystalline Form C characterized by X-ray powder diffraction peaks at 20 angles (± 0.2°) 4.5°, 13.5°, and 18.0°. 10. The tris(hydroxymethyl)aminomethane salt of claim 9, wherein the crystalline Form C is further characterized by at least one X-ray powder diffraction peak at 20 angles(± 0.2°) selected from 14.3°, 18.3°, and 23.5°. 11. The tris(hydroxymethyl)aminomethane salt of claim 9 or 10, wherein the crystalline Form C is further characterized by at least one X-ray powder diffraction peaks at 20 angles (± 0.2°) selected from 16.3°, 19.0°, 21.2°, 22.5°, and22.8°. 12. A pharmaceutical composition comprising the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11 and one or more pharmaceutically acceptable excipients. 13. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11, or the pharmaceutical composition of claim 12 in the manufacture of a medicament for treating cancer, wherein the tris(hydroxymethyl)aminomethane salt, or the pharmaceutical composition is optionally combined with an additional therapeutic agent. 14. The use of claim 13, wherein the cancer is selected from lung cancer, breast cancer, triple negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, cancer of the head or neck, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, 85 Date rec;ue/Date received 2024-06-14 88648345 squamous cell cancer, an environmentally induced cancer, and a PTEN mutant cancer; and biliary tract cancer or cancer of the ampulla of Vater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, cancer of the ovary, and cancer of the upper aerodigestive tract. 15. The use of claim 13, wherein the cancer is a hematological cancer selected from acute myeloid leukemia, multiple myeloma, B -pro lymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma cancer of the bladder, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B cell lymphoma, and triple hit diffuse large B cell lymphoma; angioimmunoblastic lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, blastic NK-cell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, W aldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelo:fibrosis, and polyeythemia rubra vera. 16. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11, or the pharmaceutical composition of claim 12 in the manufacture of a medicament for treating cancer, wherein the cancer is responsive to inhibition of dihydroorotate dehydrogenase. 17. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11, or the pharmaceutical composition of claim 12 in the manufacture of a medicament for treating a condition or a disease selected from a viral- mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder. 18. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11 or the pharmaceutical composition of claim 12 in the manufacture of a medicament for inhibiting growth and/or metastasis of tumor cells, wherein the tumor cells are responsive to inhibition of dihydroorotate dehydrogenase. 86 Date rec;ue/Date received 2024-06-14 88648345 19. The pharmaceutical composition of claim 12 for use in treating cancer in a subject, wherein the tris(hydroxymethyl)aminomethane salt or the pharmaceutical composition is optionally combined with an additional therapeutic agent. 20. The pharmaceutical composition for use of claim 19, wherein the cancer is selected from lung cancer, breast cancer, triple negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, cancer of the head or neck, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, an environmentally induced cancer, and a PTEN mutant cancer; and biliary tract cancer or cancer of the ampulla of Yater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, cancer of the ovary, and cancer of the upper aerodigestive tract. 21. The pharmaceutical composition for use of claim 19, wherein the cancer is a hematological cancer selected from acute myeloid leukemia, multiple myeloma, B-prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma cancer of the bladder, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B cell lymphoma, and triple hit diffuse large B cell lymphoma; 87 Date rec;ue/Date received 2024-06-14 88648345 angioimmunoblastic lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, blastic NKcell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelofibrosis, and polyeythemia rubra vera. 22. The pharmaceutical composition of claim 12 for use in treating cancer in a subject, wherein the cancer is responsive to inhibition of dihydroorotate dehydrogenase. 23. The pharmaceutical composition of claim 12 for use in treating a condition or a disease selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder in a subject. 24. The pharmaceutical composition of claim 12 for use in inhibiting growth and/or metastasis of tumor cells, wherein the tumor cells are responsive to inhibition of dihydroorotate dehydrogenase. 25. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11 for the treatment of cancer in a subject, optionally in combination with an additional therapeutic agent. 26. The use of claim 25, wherein the cancer is selected from: lung cancer, breast cancer, triple negative breast cancer, melanoma, glioblastoma, prostate cancer, colon cancer, pancreatic cancer, bone cancer, cancer of the head or neck, skin cancer, cutaneous or intraocular malignant endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, solid tumors of childhood, cancer of the kidney or ureter, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, an environmentally induced cancer, and a PTEN mutant cancer; and 88 Date rec;ue/Date received 2024-06-14 88648345 biliary tract cancer or cancer of the ampulla of Yater, non-small cell lung cancer, bronchoalveolar carcinoma, liver cancer, cancer of the ovary, and cancer of the upper aerodigestive tract. 27. The use of claim 25, wherein the cancer is a hematological cancer selected from: acute myeloid leukemia, multiple myeloma, B-prolymphocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, follicular lymphoma, diffuse large B cell lymphoma, anaplastic large cell lymphoma, mantle cell lymphoma, lymphocytic lymphoma cancer of the bladder, primary CNS lymphoma, and T-cell lymphoma; chemotherapy-resistant acute myeloid leukemia, cytarabine-resistant acute myeloid leukemia, acute monocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, diffuse mixed cell lymphoma, myelodysplastic syndrome, myelodysplastic/myeloproliferative neoplasms, primary effusion lymphoma, erythroleukemia, chronic myeloid leukemia, chronic monocytic leukemia, double hit diffuse large B cell lymphoma, and triple hit diffuse large B cell lymphoma; angioimmunoblastic lymphoma, Burkitt's lymphoma, Burkitt-like lymphoma, blastic NKcell lymphoma, cutaneous T-cell lymphoma, lymphoblastic lymphoma, MALT lymphoma, mediastinal large B-cell lymphoma, nodal marginal zone B-cell lymphoma, small lymphocytic lymphoma, thyroid lymphoma, follicular lymphoma, Waldenstrom's macroglobulinemia, essential thrombocythemia, chronic idiopathic myelofibrosis, and polyeythemia rubra vera. 28. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11 for the treatment of cancer in a subject, wherein the cancer is responsive to inhibition of dihydroorotate dehydrogenase. 29. Use of the tris(hydroxymethy l)aminomethane salt of any one of claims 1-11 for the treatment of a condition or a disease selected from a viral-mediated disease, transplant rejection, rheumatoid arthritis, psoriasis, an autoimmune disease, or an inflammatory disorder in a subject. 30. Use of the tris(hydroxymethyl)aminomethane salt of any one of claims 1-11 for the inhibition of growth and/or metastasis of tumor cells, wherein the tumor cells are responsive to inhibition of dihydroorotate dehydrogenase. 89 Date rec;ue/Date received 2024-06-14

Description

CRYSTALLINE AND SALT FORMS OF AN ORGANIC COMPOUND AND PHARMACEUTICAL COMPOSITIONS THEREOF RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No. 62/784,083, filed December 21, 2018; U.S. Provisional Application No. 62/791,571, filed January 11, 2019; and U.S. Provisional Application No. 62/882,712, filed August 5, 2019. BACKGROUND [0002] Dihydroorotate dehydrogenase (DHODH) is an enzyme that catalyzes one of the steps in the de novo pyrimidine nucleotide biosynthetic pathway. It catalyzes the only oxidation/reduction reaction in that pathway, which is the step of converting OHO ( dihydroorotate) to orotate with the aid of flavin cofactor and an electron acceptor. Inhibitors of dihydroorotate dehydrogenase have been found to possess wider applications as chemotherapeutic agents. [0003] 1-methyl-5-(2' -methyl-[l, 1 '-biphenyl]-yl)-1H-benzo[d][l,2,3]triazole-7- carboxylic acid, hereinafter also referred to as "Compound l" (structural formula shown below), has been characterized as an inhibitor of DHODH. See e.g., International Patent Application Publication No. WO 2014/128669 and US Patent No. 9,630,932. [0004] Compound 1 was developed to treat conditions and disorders that would benefit from inhibition of DHODH, such as but not limited to solid cancers, hematological cancers, viral-mediated diseases, transplant rejection, rheumatoid arthritis, psoriasis, autoimmune diseases, and inflammatory disorders. Given its therapeutic benefits, and the great promise for treating a plethora of different diseases, there is a need to develop alternative forms of Compound 1 in an effort to facilitate isolation, manufacturing, and l Date rec;ue/Date received 2024-06-14 WO 2020/132471 PCT/0S2019/067897 formulation development for various routes of administration, as well as to enhance storage stability. SUMMARY [0005] As described in greater detail in the following paragraphs, it has now been found that the Tris salt of Compound 1 has superior properties relative to the free acid and other salt forms of the compound. It has also been found that the Tris salt Form C is superior to other Tris salt forms. [0006] During the salt screening studies described herein, over 50 different salt hits of Compound 1 which included 10 counterions and five different solvents were evaluated. 12 different crystalline forms were identified (see Table 8). Of these crystalline salt forms, the Tris salt form was found to be superior. Specifically, Tris salt Form A and Tris salt Form C of Compound 1 stood out as leading crystalline salt forms with sharp XRPD peaks (see Example 3, Table 8 and FIG. 6). Good crystallinity of drug substance typically translates to better physical and chemical stability and is therefore a desirable characteristic of an active pharmaceutical ingredient (API). Moreover, the thermogravimetric analysis (TGA) data reflects negligible weight loss for the Tris salt Form A and Tris salt Form C of Compound 1 (see Table 9), therefore indicating minimal residual solvents and an anhydrate polymorph, which is often preferred over solvated / hydrated forms for oral solid dosage form development. The differential scanning calorimetry (DSC) data for the Tris salt Form A and Tris salt Form C of Compound 1 (see Table 9) further indicates one sharp melting endotherm prior to decomposition, indicates a low likelihood of polymorphic changes and low possibility of phase transformations that are often undesirable from the perspective of physical stability of the APL [0007] Comparing the Tris salt Form A and Tris salt Form C of Compound 1, thermodynamic stability studies using slurry competition experiments indicated that Tris salt Form C is more thermodynamically stable (see Example 5). Furthermore, Tris salt Form C of Compound 1 was also found to be less hygroscopic than its Tris salt Form A counterpart, making it more easily disintegrate in solvents during formulation development. [0008] Comparing the pharmacokinetic properties of the free acid and the Tris salt of Compound 1, the Tris salt form is clearly superior in terms of achieving a higher maximum concentration (i.e., higher Cm.ax) within a shorter time period (i.e., lower Tm.ax) (see Example 8 and Table 13). Although initial forms of the free acid having low crystallinity and purity show comparable exposure to the Tris salt as indicated by AUC values (see Table 13 and 2 WO 2020/132471 PCT/0S2019/067897 FIG. lOA), such high AUC values could not reproduced with a near-final form of the free acid having improved crystallinity and purity, and despite particle size reduction (see Table 13 and FIG. 10B). [0009] The PK data indicates that the Tris salt of Compound 1 shows excellent exposure, as well as faster and higher absorption compared to the free acid form. The relatively clean DSC profile with the sharp melting endotherm for Tris salt Form C of Compound 1, coupled with excellent thermodynamic properties and low hygroscopicity, is an indicati