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US-12624049-B2 - Salt and crystal forms of 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-z-yl)thieno[2.3-b]pyridin-6(7H)-one

US12624049B2US 12624049 B2US12624049 B2US 12624049B2US-12624049-B2

Abstract

A novel salt form of Compound (I) represented by the following structural formula, and its corresponding pharmaceutical compositions, are disclosed. Particular single crystalline forms of 1:1 Compound (I) tartrate salt are characterized by a variety of properties and physical measurements. Methods of preparing specific crystalline forms are also disclosed. The present disclosure also provides methods of treating cancer in a subject.

Inventors

  • Mark R. Bray
  • Sze-Wan Li

Assignees

  • UNIVERSITY HEALTH NETWORK

Dates

Publication Date
20260512
Application Date
20210510

Claims (12)

  1. 1 . A tartrate salt of Compound (I) represented by the following structural formula: wherein the molar ratio between Compound (I) and tartaric acid is 1:1, wherein the tartrate salt is in a single crystalline form, characterized by an X-ray powder diffraction pattern which comprises at least three peaks chosen from 11.9°, 15.4°, 16.9°, 17.2°, and 25.6°±0.2 in 2θ.
  2. 2 . The tartrate salt of claim 1 , wherein the tartrate salt is in a single crystalline form, characterized by an X-ray powder diffraction pattern which comprises peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 25.6°, 26.3°, and 30.7°=0.2 in 2θ.
  3. 3 . The tartrate salt of claim 1 , wherein the tartrate salt is in a single crystalline form, characterized by an X-ray powder diffraction pattern which comprises peaks at 11.9°, 14.0°, 15.4°, 16.9°, 17.2°, 22.1°, 25.6°, 26.3°, 30.7°, and 34.0°±0.2 in 2θ.
  4. 4 . The tartrate salt of claim 1 , wherein the tartrate salt is in a single crystalline form, characterized by an X-ray powder diffraction pattern which further comprises peaks at 8.7° and 12.9°±0.2 in 2θ.
  5. 5 . The tartrate salt of claim 1 , wherein the tartrate salt is in a single crystalline form, characterized by a differential scanning calorimeter (DSC) peak phase transition temperature of 189±2° C.
  6. 6 . The tartrate salt of claim 1 , wherein water uptake is less than 4% of the mass of the tartrate salt at 90% relative humidity (RH) as measured under the following conditions: i) drying between 0.5 and 1.5 mg of the tartrate salt under a nitrogen atmosphere at 0% relative humidity for 2 hours; ii) increasing or decreasing the relative humidity in steps of 10% from 0% to 90% then to 0%; iii) maintaining the relative humidity at each step until the mass change compared to the mass of the original tartrate salt per minute is less than 0.01 (%/min), provided that minimum and maximum duration time at each step is 10 minutes and 180 minutes, respectively; and iv) measuring the mass of the tartrate salt at 90% relative humidity and wherein steps i)-iv) are carried out at 25° C.
  7. 7 . The tartrate salt of claim 6 , wherein water uptake is less than 1% of the mass of the tartrate salt at 90% relative humidity (RH).
  8. 8 . The tartrate salt of claim 1 , wherein water uptake is less than 1% of the mass of the tartrate salt at 30% relative humidity (RH) as measured under following conditions: i) drying between 0.5 and 1.5 mg of the tartrate salt under a nitrogen atmosphere at 0% relative humidity for 2 hours; ii) increasing or decreasing the relative humidity in steps of 10% from 0% to 90% then to 0%; iii) maintaining the relative humidity at each step until the mass change compared to the mass of the original tartrate salt per minute is less than 0.01 (%/min), provided that minimum and maximum duration time at each step is 10 minutes and 180 minutes, respectively; and iv) measuring the mass of the tartrate salt at 30% relative humidity and wherein steps i)-iv) are carried out at 25° C.
  9. 9 . The tartrate salt of claim 8 , wherein water uptake is less than 0.1% of the mass of the tartrate salt at 30% relative humidity (RH).
  10. 10 . A solid pharmaceutical composition comprising the tartrate salt of claim 1 , and a pharmaceutically acceptable carrier or diluent.
  11. 11 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of the tartrate salt of claim 1 , wherein the cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, prostate cancer, leukemia, lymphomas, brain cancer, head and neck cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, or renal cancer.
  12. 12 . A method of treating a subject with cancer, comprising administering to the subject an effective amount of the tartrate salt of claim 1 , and an effective amount of second anti-cancer agent, wherein the cancer is breast cancer, colorectal cancer, lung cancer, ovarian cancer, uterine cancer, prostate cancer, leukemia, lymphomas, brain cancer, head and neck cancer, pancreatic cancer, melanoma, hepatocellular carcinoma, or renal cancer; wherein the second anti-cancer agent is ipilumab, nivolumab, pembrolizumab, pidilizumab, BMS 936559, MPDL3280A, MSB0010718C, MED14736, paclitaxel, docetaxel, 5-fluorouracil, trastuzumab, lapatinib, bevacizumab, letrozole, goserelin, tamoxifen, cetuximab, panitumumab, gemcitabine, capecitabine, irinotecan, oxaliplatin, carboplatin, cisplatin, doxorubicin, epirubicin, cyclophosphamide, methotrexate, vinblastine, vincristine, melphalan, cytarabine, etoposide, daunorubicin, bleomycin, mitomycin, or adriamycin.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. § 371 national stage filing of of International Application No. PCT/CA2021/050645, filed May 10, 2021, which claims priority to U.S. Provisional Application No. 63/022,867, filed May 11, 2020. The entire contents of the aforementioned applications are incorporated herein by reference. BACKGROUND Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted Ste20 serine/threonine kinase. It has been reported that HPK1 can be a novel target for cancer immunotherapy (Sawasdikosol et al., Immunol Res. 2012 December; 54(1-3):262-5). Specifically, targeted disruption of HPK1 alleles confers T cells with an elevated Th1 cytokine production in response to TCR engagement. HPK1 (−/−) T cells proliferate more rapidly than the haplotype-matched wild-type counterpart and are resistant to prostaglandin E2 (PGE(2))-mediated suppression. Most strikingly, mice that received adoptive transfer of HPK1 (−/−) T cells became resistant to lung tumor growth. Also, the loss of HPK1 from dendritic cells (DCs) endows them with superior antigen presentation ability, enabling HPK1 (−/−) DCs to elicit a more potent anti-tumor immune response when used as cancer vaccine. U.S. Pat. No. 10,501,474, the entire teachings of which are incorporated herein by reference, discloses highly potent inhibitors of HPK1. The structure of one of the inhibitors disclosed in U.S. Pat. No. 10,501,474, referred to herein as “Compound (I)” is shown below: The chemical name of Compound (I) is 4-amino-5-(6-(4-methylpiperazin-1-yl)-1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyridin-6(7H)-one. The successful development of pharmaceutically active agents, such as Compound (I), typically requires the identification of a solid form with properties that enable ready isolation and purification following synthesis, that are amendable to large scale manufacture, that can be stored for extended periods of time with minimal absorption of water, decomposition or transformation into other solid forms, that are suitable for formulation and that can be readily absorbed following administration to the subject (e.g., are soluble in water and in gastric fluids). SUMMARY The present disclosure relates to a tartrate salt of Compound (I), wherein the molar ratio between Compound (I) and tartaric acid is 1:1. Because of the two carboxylic acid groups on tartaric acid and the multiple basic nitrogen atoms in Compound (I), multiple possible stoichiometries are possible. For example, Compound (I) forms both a 1:1 tartaric acid salt and a 1:0.5 tartaric acid salt. The 1:1 tartaric acid salt of Compound (I) is referred to herein as “1:1 Compound (I) tartrate” or “1:1 Compound (I) tartrate salt”. It has now also been found that 1:1 Compound (I) tartrate salt can be crystallized under well-defined conditions to provide non-hygroscopic crystalline forms (see Example 6). The tartrate salt also has improved solubility in water and in simulated gastric fluids (see Example 7 and Table 7), has an extended shelf life (see Example 8), and is suitable for large scale synthesis (see Example 5). A salt screening with thirteen different acids (see Examples 1 to 3) with different Compound (I)/acid molar ratios was performed. Among 20 obtained salt forms (Examples 1 and 2), only mono hydrochloric, mesylate, tartrate and maleate salts showed modest to good crystallinity by X-ray powder diffraction (XRPD). Further evaluation of these four salts in different solvent system shows that the crystallinity of the mesylate and maleate salts is modest (see Example 3). In addition, different polymorphic forms were isolated for mono hydrochloric, mesylate, and maleate salts when different solvent systems were used. Notably, the di-hydrochloric salt does not have or has very low crystallinity as demonstrated in Examples 1 and 4. Compared to the mono hydrochloric salt, 1:1 Compound (I) tartrate salt has the additional advantage that it is non-hygroscopic. Moreover, as shown in Example 9 below, compared to the free base and the mono HCl salt, the 1:1 Compound (I) tartrate salt in crystalline form results in improved plasma concentrations in dogs, following oral administration. This is a significant advantage because the new solid form can be administered orally to result in effective plasma levels of the drug. In one aspect, the present disclosure provides a tartrate salt of Compound (I), wherein the molar ratio between Compound (I) and tartaric acid is 1:1. In another aspect, the present disclosure provides a pharmaceutical composition comprising 1:1 Compound (I) tartrate salt and a pharmaceutically acceptable carrier or diluent. In yet another aspect, the present disclosure provides a method of treating a subject with cancer, comprising administering to the subject an effective amount of 1:1 Compound (I) tartrate salt disclosed herein or the corresponding pharmaceutical composition. The present disclosure also provides a method of trea