CN-122029162-A - Pharmaceutically acceptable salts of CD47-SIRP alpha pathway inhibitors

Abstract

The present disclosure relates to pharmaceutically acceptable salts of compounds of formula (I), particularly alkali metal salts or alkaline earth metal salts, crystalline forms thereof, and methods of preparing the same. The present disclosure also relates to formulations useful for pharmaceutical use for treating a variety of diseases or conditions mediated by CD47, particularly cancer or other proliferative diseases. (I)。

Inventors

• S. N. Setalamaya Seti
• P. G.N. Sassi Kumar
• M.R. Ala
• R. B. Cha Wan

Assignees

• 奥瑞基尼肿瘤有限公司

Dates

Publication Date

20260512

Application Date

20241018

Priority Date

20231019

Claims (20)

1. 1. A pharmaceutically acceptable salt of a compound of formula (I): ; Wherein the pharmaceutically acceptable salt is an alkali metal salt or an alkaline earth metal salt.
2. 2. The pharmaceutically acceptable salt of claim 1, wherein the alkali metal salt is a sodium salt or a potassium salt.
3. 3. The pharmaceutically acceptable salt of claim 1, wherein the alkaline earth metal salt is a calcium or magnesium salt.
4. 4. The pharmaceutically acceptable salt of claim 1, wherein the alkaline earth metal salt is a calcium salt.
5. 5. The pharmaceutically acceptable salt of claim 4, wherein the stoichiometric ratio of the compound of formula (I) to calcium is 2:1.
6. 6. The pharmaceutically acceptable salt of claims 3-5, wherein the calcium is present in an amount of about 1% to about 5% by weight of the salt.
7. 7. The pharmaceutically acceptable salt of claims 3-5, wherein the calcium is present in an amount of about 1.5% to about 4% by weight of the salt.
8. 8. The pharmaceutically acceptable salt of claims 3-5, wherein the calcium is present in an amount of about 2% to about 3% by weight of the salt.
9. 9. The pharmaceutically acceptable salt of claim 1, wherein the alkali metal salt is a sodium salt.
10. 10. The pharmaceutically acceptable salt of claim 9, wherein the sodium is present in an amount of about 1% to about 10% by weight of the salt.
11. 11. The pharmaceutically acceptable salt of claim 9, wherein the sodium is present in an amount of about 5% to about 10% by weight of the salt.
12. 12. The pharmaceutically acceptable salt of claim 9, wherein the sodium is present in an amount of about 8% to about 10% by weight of the salt.
13. 13. The pharmaceutically acceptable salt of any one of claims 9 to 12, wherein the alkali metal salt is a monosodium salt or a disodium salt.
14. 14. A process for preparing the pharmaceutically acceptable salt of claim 1, the process comprising the steps of: a) Providing a mixture comprising a compound of formula (I) and a solvent a; b) Reacting said mixture with a cation source and precipitating a salt of said compound of formula (I) by using a solvent B, and C) Isolating a salt of the compound of formula (I); Wherein the solvent a and the solvent B are independently selected from tetrahydrofuran, acetonitrile, methanol, anisole, diethyl ether, ethanol, 1, 4-dioxane, acetonitrile, acetone, methylene chloride, isopropanol, methyl tert-butyl ether (MTBE), n-heptane, water, and mixtures thereof.
15. 15. The method of claim 14, wherein the solvent a is water.
16. 16. The method of claim 14, wherein in step (a) the compound of formula (I) is in the free acid form.
17. 17. The method of claim 14, wherein the compound of formula (I) in step (a) is a sodium salt of the compound of formula (I).
18. 18. The method of claim 17, further comprising treating the mixture of step (a) with a metal ion exchange resin under aqueous conditions to remove sodium ions from the mixture.
19. 19. The method of any one of claims 14 to 18, wherein the precipitation in step (B) is performed by adding the solvent B.
20. 20. The method of claim 19, wherein the solvent B is ethanol.

Description

Pharmaceutically acceptable salts of CD47-SIRP alpha pathway inhibitors The present application claims priority and benefit from indian patent application IN202341071231 filed on day 2023, 10, 19, the entire contents of which are incorporated herein by reference. Technical Field The present disclosure relates to pharmaceutically acceptable salts of compounds of formula (I), including crystalline forms thereof, and methods of preparing the same. The present disclosure also relates to pharmaceutical compositions comprising salts of the compounds of formula (I) and crystalline forms thereof, and methods of their use as therapeutic agents. Background CD47, also known as integrin-associated protein (IAP), ovarian cancer antigen (OA 3), rh-associated antigen, and MER6, is a transmembrane protein encoded by the CD47 gene in humans. CD47 belongs to the immunoglobulin superfamily, which pairs with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulated protein alpha (sirpa). CD47 is well known for its key role in preventing clearance of healthy cells by phagocytes by binding to signal-regulating protein alpha (sirpa) expressed by phagocytes. Sirpa is an inhibitory protein expressed on macrophages that once activated inhibits phagocytosis of CD47 expressing cells. The CD 47/sirpa axis is an important steady state mechanism that prevents the clearance of normal healthy cells expressing CD 47. In contrast, down-regulation of CD47 expression in damaged, senescent or redundant cells ensures that they are cleared in time. CD47 is expressed on almost all non-malignant cells, and blocking loss of CD47, CD47 expression or alterations in its membrane distribution can be used as a marker on senescent or damaged cells, especially on Red Blood Cells (RBCs). Furthermore, blocking sirpa can also engulf targets that are not normally engulfed (these cells also present pre-phagocytic signals). CD47 is a widely expressed transmembrane glycoprotein with one immunoglobulin-like domain and five transmembrane regions that function as cellular ligands for sirpa, whose binding is mediated through the NH 2 -terminal V-like domain of sirpa. Sirpa is expressed primarily in myeloid cells, including macrophages, granulocytes, myeloid Dendritic Cells (DCs), mast cells, and their precursor cells, including hematopoietic stem cells. CD47 is also constitutively upregulated in a variety of cancers, such as non-hodgkin's lymphoma (NHL), acute Myeloid Leukemia (AML), breast cancer, colon cancer, glioblastoma, glioma, ovarian cancer, bladder cancer, and prostate cancer. Tumor cells overexpress CD47, effectively helping it to evade immune surveillance and to be killed by innate immune cells. Studies have shown that CD47 can be considered a potential target for atherosclerosis treatment. Because the process of atherosclerosis formation (i.e., the formation of atheromatous plaques on the arterial wall) is associated with the upregulation of CD47, this upregulation renders malignant cells resistant to programmed cell clearance or "burial". This effect of the cytocidal effect was reversed after administration of the CD47 blocking antibody, restoring normal clearance of diseased vascular tissue, and improved atherosclerosis in various mouse models (Kojima Y, et al, nature. 2016 Aug 4; 536 (7614): 86-90). In addition, blocking CD47 with a CD47-Fc fusion protein has been reported to be effective in modulating Experimental Autoimmune Encephalomyelitis (EAE) in Multiple Sclerosis (MS) animal models, thereby providing a potential therapeutic target for the prevention and treatment of MS (Gao Q et al, J Autoimmun.2016 May; 69:74-85). International publications WO2019138367 and WO2020095256 describe inhibitors of the CD 47-sirpa signaling pathway, methods of their preparation, pharmaceutical compositions comprising them, and their use as therapeutic agents in monotherapy and in combination therapy for the treatment of a variety of conditions, particularly for the treatment of cancer and other proliferative conditions, the contents of which are incorporated herein by reference for all purposes. CD47 inhibitors are currently being developed for cancer treatment. For drug development, it is often advantageous to employ a pharmaceutical form having desirable properties in terms of its preparation, purification, reproducibility, stability, bioavailability and other characteristics to prepare a suitable pharmaceutical formulation. However, the salt or crystalline form of the CD47 inhibitor reported in the above documents is difficult to obtain because the compound is unstable under ambient conditions. WO2019138367 discloses a group of 1,2, 4-oxadiazole compounds useful as inhibitors of the CD47 signaling pathway. One disclosed 1,2, 4-oxadiazole compound is (((S) -1- (3- ((S) -1-amino-3-carboxypropyl) -1,2, 4-oxadiazol-5-yl) -4-guanidinobutyl) carbamoyl) -L-proline. There is a need to develop novel CD47 inhibiting compounds which, in add