1401033-86-0

Basic information

• Product Name: AMG 925
• Synonyms: AMG 925;1-[7,8-Dihydro-2-[[9-(trans-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl]amino]-1,6-naphthyridin-6(5H)-yl]-2-hydroxyethanone;2-Hydroxy-1-(2-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-;Ethanone, 1-[7,8-dihydro-2-[[9-(trans-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl]amino]-1,6-naphthyridin-6(5H)-yl]-2-hydroxy-
• CAS NO: 1401033-86-0
• Molecular Formula: C₂₆H₂₉N₇O₂
• Molecular Weight: 471.57
• Mol File: 1401033-86-0.mol
• Article Data: 3

Chemical Properties

• Boiling Point: 712.3±70.0 °C(Predicted)
• Appearance: /
• Density: 1.48±0.1 g/cm3(Predicted)
• Solubility: insoluble in DMSO; insoluble in H2O; insoluble in EtOH
• PKA: 13.41±0.10(Predicted)
• CAS DataBase Reference: AMG 925(CAS DataBase Reference)
• NIST Chemistry Reference: AMG 925(1401033-86-0)
• EPA Substance Registry System: AMG 925(1401033-86-0)

Safety Data

• Hazardous Substances Data: 1401033-86-0(Hazardous Substances Data)

Usage

Description

AMG 925 is a dual inhibitor of FMS-related tyrosine kinase 3 (FLT3) and cyclin-dependent kinase 4 (Cdk4; IC50s = 1 and 3 nM, respectively). It is selective for FLT3 and Cdk4 over Cdk1 (IC50 = 2.22 μM). AMG 925 also binds to FLT3ITD, FLT3D835Y, FLT3D835H, FLT3K663Q, and FLT3N841I (Kds = 1-4 nM). It inhibits proliferation of MOLM-13, COLO 205, and U937 cancer cells (IC50s = 19, 55, and 52 nM, respectively). AMG 925 (50, 75, and 150 mg/kg) reduces intratumor levels of pSTAT5 and pRb and inhibits tumor growth in a MOLM-13 acute myeloid leukemia (AML) mouse xenograft model.

Uses

AMG 925 is a FLT3 and CDK4 Dual Kinase Inhibitor with Preferential Affinity for the Activated State of FLT3.

references

[1] keegan k, li c, li z, ma j, ragains m, coberly s, hollenback d, eksterowicz j, liang l, weidner m, huard j, wang x, alba g, orf j, lo mc, zhao s, ngo r, chen a, liu l, carlson t, quéva c, mcgee lr, medina j, kamb a, wickramasinghe d, dai k. preclinical evaluation of amg 925, a flt3/cdk4 dual kinase inhibitor for treating acute myeloid leukemia. mol cancer ther. 2014 apr;13(4):880-9.

Upstream product

• 79-14-1 glycolic Acid 
• 1401033-82-6 9-((1r,4r)-4-methylcyclohexyl)-N-(5,6,7,8-tetrahydro-1,6-naphthyridin-2-yl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine 
• 1588959-28-7 C₁₆H₂₀ClN₅ 
• 1588959-18-5 C₁₁H₁₇BrN₄ 
• 1588959-12-9 C₁₁H₁₅BrClN₃ 
• 2523-55-9 trans-4-methylcyclohexanamine 
• 1401034-47-6 2-(2-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-oxoethyl acetate 
• 1401034-46-5 tert-butyl 2-((9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate 
• 1401034-45-4 9-((1r,4r)-4-methylcyclohexyl)-9H-pyrido[4′,3′:4,5]pyrrolo[2,3-d]pyrimidin-2-amine 
• 1401034-44-3 5-(3-fluoropyridin-4-yl)-N⁴-((1R,4R)-4-methylcyclohexyl)pyrimidine-2,4-diamine 
• 1401034-43-2 5-iodo-N⁴-((1R,4R)-4-methylcyclohexyl)pyrimidine-2,4-diamine 
• 1401034-42-1 N⁴-((1r,4r)-4-methylcyclohexyl)pyridine-2,4-diamine 
• 33483-65-7 trans-4-methylcyclohexylamine hydrochloride 
• 766545-20-4 2-chloro-5,6,7,8-tetrahydro[1,6]naphthyridine hydrochloride 

Downstream Products

• 1401034-19-2 2-hydroxy-1-(2-((9-((1R,4R)-4-methylcyclohexyl)-9H-pyrido[4',3':4,5]pyrrolo[2,3-d]pyrimidin-2-yl)amino)-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)ethanone hydrochloride 

Relevant articles and documents

Multi-kilo delivery of AMG 925 featuring a buchwald-hartwig amination and processing with insoluble synthetic intermediates

The development of a synthetic route to manufacture the drug candidate AMG 925 on kilogram scale is reported herein. The hydrochloride salt of AMG 925 was prepared in 23% overall yield over eight steps from commercially available raw materials, and more than 8 kg of the target molecule were delivered. The synthetic route features a Buchwald-Hartwig amination using BrettPhos as ligand and conducted to afford 12 kg of product in a single batch. In addition, this work highlights the challenges associated with the use of poorly soluble process intermediates in the manufacture of active pharmaceutical ingredients. Creative solutions had to be devised to conduct seemingly routine activities such as salt removal, pH adjustment, and heavy metal scavenging due to the low solubility of the process intermediates. Finally, a slurry-to-slurry amidation protocol was optimized to allow for successful scale-up.

FUSED TRICYCLIC DUAL INHIBITORS OF CDK 4/6 AND FLT3

Compounds of Formula I are useful inhibitors of CDK 4, CDK6, and FLT3. Such compounds are useful in treating cancer and various other disease conditions. Compounds of Formula I have the following structure: where R1 is a group of Formula IA, Formula IB, Formula IC, or Formula ID and the definitions of the other variables are provided herein.