92137-91-2

Upstream product

• 14149-34-9 3-phenyl-2,6-piperidine-dione 
• 140-29-4 phenylacetonitrile 
• 30698-33-0 methyl 2-cyano-2-(4-nitrophenyl)acetate 
• 100-00-5 4-chlorobenzonitrile 
• 119023-00-6 methyl 4-cyano-4-(4-nitrophenyl)butanoate 
• 91137-66-5 2-phenylpentanedinitrile 
• 147795-57-1 ethyl α-cyano-α-(p-nitrophenyl)acetate 

Downstream Products

• 19733-55-2 3-(4-nitrophenyl)piperidine 
• 19733-56-3 3-(4-aminophenyl)piperidine 
• 875798-79-1 3-(4-aminophenyl)piperidine-1-carboxylic acid tert-butyl ester 
• 92137-90-1 3-(4-Amino-phenyl)-piperidine-2,6-dione 

Relevant academic research and scientific papers

PROCESSES FOR THE PREPARATION OF NIRAPARIB AND INTERMEDIATES THEREOF

The present invention relates to novel procedures and novel intermediates useful in the synthesis of Niraparib or any salt thereof.

SYNTHESIS OF FLUORINATED DERIVATIVES OF GLUTETHIMIDE AND AMINOGLUTETHIMIDE

Aminoglutethimide (1), used in the treatment of hormone dependent breast cancer, interacts with enzyme complexes desmolase and aromatase.Its action is not specific and its metabolism gives rise to toxic and non-inhibitory metabolites.The work described here explores the impact of fluorine substitution within the glutethimide (2) framework, on the enzyme inhibitory properties of aminoglutethimide.Four new fluorinated derivatives (5), (6), (8) and (9) have been prepared, in which fluorine substituents have been introduced into the phenyl ring and the ethyl side chain. 4-Fluoroglutethimide (5) and 3-trifluoroglutethimide (6) were synthesised from the corresponding fluorophenylacetonitriles (10) and (14) via sequential monoethylation, Michael addition to methyl propenoate and cyclisation.An alternative strategy, devised for the synthesis of (8), involved the monoarylation of ethyl cyanoacetate, and gave rise to the intermediate (29).Incorporation of fluorine was carried out by SF4 fluorination of the cyanoketoester (33), which was subsequently converted to the difluoroaminoglutethimide (8).For the synthesis of trifluoromethyl glutethimide (9), the trifluoromethyl group was introduced by alkylation of phenylcyanoacetate (16) with 2-iodo-1,1,1-trifluoroethane.Preliminary in vitro enzyme inhibition results have been obtained for compounds (5), (6) and (8).

Aromatase Inhibitors. Synthesis and Evaluation of Mammary Tumor Inhibiting Activity of 3-Alkylated 3-(4-Aminophenyl)piperidine-2,6-diones

The synthesis and biological evaluation of 3-alkyl-substituted 3-(4-aminophenyl)piperidine-2,6-diones as inhibitors of estrogen biosynthesis are described .In vitro compounds 4-14 showed a stronger inhibition of human placental aromatase compared to aminoglutethimide (AG, compound 3), which recently has become used for the treatment of hormone-dependent breast cancer.The most active derivative, compound 10, showed a 93-fold stronger inhibition than AG.With the exception of 5, 7, and 8, all other compounds exhibited similar or decreased inhibition of bovine adrenal desmolase compared to AG.Compounds 4 and 6-12 showed a stronger inhibition of the plasma estradiol concentration of pregnant mare serum gonadotropin (PMSG) primed Sprague-Dawley (SD) rats compared to the parent compound.Compounds 4, 6-8, 10, and 12 inhibited the testosterone-stimulated tumor growth of ovariectomized 9,10-dimethyl-1,2-benzanthracene (DMBA) tumor-bearing SD rats more strongly than AG.Being stronger and more selective inhibitors of the estrogen biosynthesis than AG, some of the newly developed derivatives of AG might be better candidates for the treatment of the hormone-dependent human breast cancer.