Csf1r inhibitors for use in treating cancer

A dose, patient technology, applied in the direction of medical preparations containing active ingredients, drug combinations, organic active ingredients, etc., can solve problems such as high recurrence rate

Pending Publication Date: 2021-09-28
DECIPHERA PHARMA LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is often difficult to perform marginal resections on the diffuse form of TGCT, resulting in high recurrence rates

Method used

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  • Csf1r inhibitors for use in treating cancer
  • Csf1r inhibitors for use in treating cancer
  • Csf1r inhibitors for use in treating cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0154] Embodiment 1. The synthetic route of compound 1

[0155] Compound A: 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine

[0156]

[0157] A solution of 3-hydroxy-2-picoline (20.0 g, 183) and Na2CO3 (38.8 g, 367 mmol) in H2O (320 mL) and MeOH (200 mL) was treated with I2 (46.5 g, 183 mmol) and incubated at room temperature Stir for 1 hour. The mixture was acidified with HCl (2M), extracted with EtOAc (2x), and the combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness. This material was suspended in 1:1 EtOAc / Hex, sonicated and the solid collected via filtration and dried. The filtrate was concentrated to dryness, treated with DCM, the solid was collected via filtration and combined with the first solid to give 6-iodo-2-methylpyridin-3-ol (20.5 g, 48%). MS (ESI) m / z: 236.0 (M+H+).

[0158] 6-iodo-2-methylpyridin-3-ol (6.8g, 28.9mmol), 2,4-dichloropyridine (8.56g, 57.9mmol) and K2CO3 (4.00g, 28.9mmol) in DMA (50mL) The mixture i...

Embodiment 2

[0171] Example 2. Depletion of tumor-associated macrophages in a syngeneic mouse model of colorectal cancer

[0172]Protocols and procedures involving the following animal care and use of the syngeneic MC38 mouse xenograft model were reviewed and approved by the CrownBio Institutional Animal Care and Use Committee (IACUC) (Taicang, Jiangsu Province, China) prior to execution. During the study, animal care and use were performed according to the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC). All mice were given food and water ad libitum. All animals were observed for clinical signs at least once daily. In the first experiment, six to eight week old female C57BL / 6 mice were inoculated subcutaneously in the right lower flank with one million MC38 tumor cells in phosphate buffered saline. On day 12, when the tumor burden reached an average of 102 mm3, the mice were randomized. Groups of mice (n=10) were treated by oral gavage on days 12 to 18 a...

Embodiment 3

[0175] Example 3. Pharmacokinetic (PK) properties and depletion of circulating monocytes expressing CSF1R in treated patients

[0176] Doses of Compound 1 were administered orally and evaluated in seven dose cohorts totaling 40 patients with advanced solid tumor malignancies and TGCT. This included one dosing cohort receiving 10 mg QD; five dosing cohorts receiving a five-day loading dose regimen of up to 40 mg doses each, followed by a once-weekly or twice-weekly maintenance dosing schedule; and One cohort received a 5-day loading dose of 50 mg QD followed by 20 mg QD. Those five cohorts were: Cohort 1: 10 mg QD (n=7); Cohort 2: 5-day loading dose of 10 mg QD followed by a maintenance dose of 10 mg twice a week (twice a week or "BIW") ( 5x QD / BIW; n=3); Cohort 3: 20 mg QD 5-day loading dose followed by weekly 20 mg maintenance dose (5x QD / Q1W; n=4); Cohort 4: 20 mg QD 5-day loading dose , followed by a maintenance dose of 20 mg twice a week (5x QD / BIW; n=4); Cohort 5: 30 mg...

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Abstract

Described herein are CSF1R inhibitors for use in methods of treating cancers and other tumors related to the decreased proliferation, the depletion, or the repolarization of tumor-associated macrophages (TAMs) and treatment of associated disorders, including tenosynovial giant cell tumor (TGCT) and diffuse-type tenosynovial giant cell tumor (DTGCT).

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S.S.N. 62 / 786,105, filed December 28, 2018, U.S.S.N. 62 / 926,341, filed October 25, 2019, and U.S.S.N. The contents of each are incorporated herein by reference in their entirety. Background technique [0003] Colony-stimulating factor 1 receptor (CSF1R) and its ligand, colony-stimulating factor 1 (CSF1), together form a lineage-dependent relationship for the development and differentiation of normal macrophages from monocytes. Thus, proliferation of tumor-associated macrophages (TAMs) and maintenance of their differentiated state and immunosuppressive phenotype are dependent on CSF1R (also known as FMS) kinase activity. The role of TAMs in promoting an invasive and immunosuppressive tumor microenvironment is well established. TAMs mediate tumor growth, angiogenesis, invasion, metastasis, and immunosuppression through the secretion and response of various cytokines or other soluble ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/506A61K31/337A61K31/357A61K31/4184A61K31/437A61K31/4523A61K31/519A61K31/7068A61K45/06A61P35/00A61P35/02A61P35/04G01N33/50
CPCA61K31/506A61K45/06A61P35/00A61P35/02A61P35/04A61K31/337A61K31/357A61K31/7068A61K31/437A61K31/519A61K31/4523A61K31/4184A61K2300/00A61K9/0053A61K31/513
Inventor D·L·弗林B·D·史密斯R·R·索托K·咋田
Owner DECIPHERA PHARMA LLC
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