1309684-94-3

Basic information

• Product Name: RO8994
• Synonyms: RO8994;(2'S,3R,4'S,5'R)-N-[4-(Aminocarbonyl)-2-methoxyphenyl]-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-1,2-dihydro-2-oxo-spiro[3H-indole-3,3'-pyrrolidine]-5'-carboxamide
• CAS NO: 1309684-94-3
• Molecular Formula: C₃₁H₃₁Cl₂FN₄O₄
• Molecular Weight: 613.51
• EINECS: -0
• Mol File: 1309684-94-3.mol

Chemical Properties

• Boiling Point: 753.5±60.0 °C(Predicted)
• Appearance: /
• Density: 1.41±0.1 g/cm3(Predicted)
• PKA: 12.00±0.70(Predicted)
• CAS DataBase Reference: RO8994(CAS DataBase Reference)
• NIST Chemistry Reference: RO8994(1309684-94-3)
• EPA Substance Registry System: RO8994(1309684-94-3)

Safety Data

• Hazardous Substances Data: 1309684-94-3(Hazardous Substances Data)

Usage

Uses

Used in Cancer Therapy:
RO8994 is used as an anticancer agent for its ability to inhibit the proliferation of cancer cells such as SJSA-1, RKO, and HCT116 with an average IC50 value of 20 nM. It also increases apoptosis in SJSA-1 cells in a concentration-dependent manner, which contributes to its potential as a cancer treatment.
Used in Tumor Suppression:
In an SJSA-1 osteosarcoma mouse xenograft model, RO8994 is used to reduce tumor growth and induce tumor regression when administered at doses of 1.56 and 6.25 mg/kg, respectively. This highlights its potential in directly targeting and suppressing tumor growth in vivo.

Upstream product

• 177476-76-5 4-amino-3-methoxybenzonitrile 
• 2987-16-8 3,3-dimethylbutyrylaldehyde 
• 1219086-34-6 2-[(E)-(3,3-dimethylbutylidene)amino]acetic acid tert-butyl ester 
• 1345866-83-2 4-{2-[3,3-dimethyl-but-(E)-ylideneamino]acetylamino}-3-methoxybenzoic acid methyl ester 
• 1419186-19-8 4-(2-aminoacetylamino)-3-methoxybenzoic acid methyl ester hydrochloride 
• 908027-64-5 6-chloro-3-[1-(3-chloro-2-fluorophenyl)-meth-(E)-ylidene]-1,3-dihydroindol-2-one 
• 1419186-29-0 4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid dimethyl-((R)-1-phenylethyl)amine salt 
• 41608-64-4 methyl 3-methoxy-4-aminobenzoate 
• 85070-48-0 2-fluoro-3-chlorobenzaldehyde 
• 56341-37-8 6-chloro-2-oxindole 
• 1419186-30-3 4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid methyl ester 

Relevant articles and documents

Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy

The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994.

Synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist

A practical synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist 2 is reported. Cycloaddition of dipolarophile 3 with imine 30 afforded a complex mixture of diastereomers that were isomerized to the desired stereoisomer 31 by heating the mixture in the presence of DBU. After hydrolysis, the resulting product was resolved with a chiral amine to give an enantiopure acid which was converted to the target product 2. The process has been scaled up to a multihundred-gram scale. In addition, an asymmetric synthesis of 31 catalyzed by AgOAc and a chiral phosphine ligand was developed to give enantiomerically enriched 31, which was also converted to enantiopure 2.

SPIROINDOLINONE PYRROLIDINES

There are provided compounds of the formula wherein X, Y and R1 to R8 are described herein along with the enantiomers, pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.