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

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.

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.

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

CN116139135

PATENT

US20200190057

PATENT

CN110475555

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References

1. ^ Pognan, François; Buono, Chiara; Couttet, Philippe; Galarneau, Jean-René; Timsit, Yoav; Wolf, Armin (29 October 2022). “Liver enzyme delayed clearance in rat treated by CSF1 receptor specific antagonist Sotuletinib”. Current Research in Toxicology. 3: 100091. doi:10.1016/j.crtox.2022.100091. ISSN 2666-027X.
2. ^ Thongchot, Suyanee; Duangkaew, Supani; Yotchai, Wasan; Maungsomboon, Sorranart; Phimolsarnti, Rapin; Asavamongkolkul, Apichat; Thuwajit, Peti; Thuwajit, Chanitra; Chandhanayingyong, Chandhanarat (2 December 2022). “Novel CSF1R-positive tenosynovial giant cell tumor cell lines and their pexidartinib (PLX3397) and sotuletinib (BLZ945)-induced apoptosis”. Human Cell. 36 (1): 456–467. doi:10.1007/s13577-022-00823-0.
3. ^ Martinez-Gonzalez, Loreto; Martinez, Ana (1 February 2023). “Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis”. Expert Opinion on Investigational Drugs. 32 (2): 141–160. doi:10.1080/13543784.2023.2178416.

////////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