Sotuletinib HCl

Sotuletinib HCl CAS: 2222138-31-8 (HCl) Chemical Formula: C20H23ClN4O3S Molecular Weight: 434.939 7W3V82OQ0P Synonym: Sotuletinib HCl; Sotuletinib hydrochloride, Sotuletinib monohydrochloride, BLZ945; BLZ 945; BLZ-945; IUPAC/Chemical Name: 4-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)oxy)-N-methylpicolinamide hydrochloride

2-PYRIDINECARBOXAMIDE, 4-((2-(((1R,2R)-2-HYDROXYCYCLOHEXYL)AMINO)-6-BENZOTHIAZOLYL)OXY)-N-METHYL-

Sotuletinib, also known as BLZ945, is a potent and selective CSF-1R kinase inhibitor. BLZ945 showed effects of CSF1R inhibition on other tumor-infiltrating immune cells. BLZ945 attenuates the turnover rate of TAMs while increasing the number of CD8+ T cells that infiltrate cervical and breast carcinomas. BLZ945 decreases the growth of malignant cells in the mouse mammary tumor virus-driven polyomavirus middle T antigen (MMTV-PyMT) model of mammary carcinogenesis. BLZ945 prevents tumor progression in the keratin 14-expressing human papillomavirus type 16 (K14-HPV-16) transgenic model of cervical carcinogenesis. Sotuletinib (BLZ945) is an experimental drug in development for the treatment of amyotrophic lateral sclerosis (ALS). It works as a colony-stimulating factor 1 (CSF1) receptor inhibitor.^[1][2][3]

• OriginatorCelgene Corporation; Novartis
• ClassAmides; Amines; Antineoplastics; Benzothiazoles; Cyclohexanols; Ethers; Pyridines; Small molecules
• Mechanism of ActionMacrophage colony stimulating factor receptor antagonists

• Phase IIAmyotrophic lateral sclerosis
• Phase I/IISolid tumours

• 05 Dec 2022Novartis Pharmaceuticals terminates a phase I/II trials in Solid tumours (Combination therapy, Late-stage disease, Metastatic disease) in Taiwan, Japan, Israel (PO) in US, Israel, Italy, Japan, Singapore, Spain, Taiwan and Switzerland (EudraCT2015-005806-12) (NCT02829723)
• 14 Feb 2022Adverse events and pharmacodynamics data from preclinical macaque model study in brain disorders presented at the 29th Conference on Retroviruses and Opportunistic Infections
• 03 Dec 2020Chemical structure information added

An orally bioavailable inhibitor of colony stimulating factor 1 receptor (CSF-1R; CSF1R), with potential antineoplastic activity. CSF1R inhibitor BLZ945 selectively binds to CSF1R expressed on tumor-associated macrophages (TAMs), blocks the activity of CSF1R, and inhibits CSF1R-mediated signal transduction pathways. This inhibits the activity and proliferation of TAMs, and reprograms the immunosuppressive nature of existing TAMs. Altogether, this reduces TAM-mediated immune suppression in the tumor microenvironment, re-activates the immune system, and improves anti-tumor cell responses mediated by T-cells. CSF1R, also known as macrophage colony-stimulating factor receptor (M-CSFR) and CD115 (cluster of differentiation 115), is a cell-surface receptor for its ligand, colony stimulating factor 1 (CSF1); this receptor is overexpressed by TAMs in the tumor microenvironment, and plays a major role in both immune suppression and the induction of tumor cell proliferation. n

WO2007/121484

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007121484&_cid=P11-LQVRBH-85896-1

WO2018069892

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018069892&_cid=P20-MDBQ1H-27683-1

WO2017137958 PATENT The free base and salts of the compound of formula (I) may be prepared for example, according to the procedures given in International Patent Application No. PCT/US2007/066898 filed on Apr. 18, 2007 and published as WO2007/121484 on Oct. 25, 2007. The compound of formula (I) has the chemical name: 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzothiazol-6-yloxy)-N-methylpicolinamide and is also known as BLZ945. https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007121484&_cid=P22-LQW9F8-32135-1 Step 1. Preparation of 4-(2-((lR,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide To the solution of N-methyl-4-(2-(methylsulfinyl)benzo[d]thiazol-6-yloxy)picolinamide (15 mg, 43 μmole) in 400 μL of NMP was added (lR,2R)-cyclohexane-1,2-diamine (17 mg, 150 μmole). The reaction solution was stirred at 105°c for 24 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give 4-(2-((lR,2R)-2-aminocyclohexylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (12 mg, 30 μmole) as white powder. ES/MS m/z 398.1(MH⁺). PATENT  US-2020093801 https://patents.google.com/patent/US20200093801A1 PATENT https://patentscope.wipo.int/search/en/detail.jsf?docId=CN399167134&_cid=P20-LQW13I-15704-1 CN116139135 PATENT US20200190057 https://patentscope.wipo.int/search/en/detail.jsf?docId=US296503858&_cid=P20-LQW1AX-19566-1 PATENT CN110475555 https://patentscope.wipo.int/search/en/detail.jsf?docId=CN277663395&_cid=P20-LQW1CS-20349-1

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References

////////Sotuletinib HCl, BLZ945,  BLZ 945, BLZ-945, O=C(NC)C1=NC=CC(OC2=CC=C3N=C(N[C@H]4[C@H](O)CCCC4)SC3=C2)=C1.[H]Cl