147193-96-2

Upstream product

• 5292-43-3 bromoacetic acid tert-butyl ester 
• 147193-89-3 2-(2-trichloroacetylpyrrol-1-yl)malonic acid diethyl ester 
• 67451-43-8 2-(pyrrol-1-yl)malonic acid diethyl ester 

Downstream Products

• 147193-99-5 2-(4-bromo-2-fluorobenzyl)-4-ethoxycarbonyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-acetic acid 
• 147193-59-7 AS-3201 
• 147194-02-3 2-(4-bromo-2-fluorobenzyl)-4-carbamoylmethyl-1,3-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid ethyl ester 

Relevant academic research and scientific papers

Novel, highly potent aldose reductase inhibitors: (R)-(-)-2-(4-bromo-2- fluorobenzyl)-1,2,3,4-tetrahydropyrrolo[1,2-α]pyrazine-4-spiro-3'- pyrrolidine-1,2',3,5'-tetrone (AS-3201) and its congeners

A series of novel tetrahydropyrrolo[1,2-α]pyrazine derivatives were synthesized and evaluated as aldose reductase inhibitors (ARIs) on the basis of their abilities to inhibit porcine lens aldose reductase (AR) in vitro and to inhibit sorbitol accumulation in the sciatic nerve of streptozotocin- induced diabetic rats in vivo. Of these compounds, spirosuccinimide-fused tetrahydropyrrolo-[1,2-α]pyrazine-1,3-dione derivatives showed significantly potent AR inhibitory activity. In the in vivo activity of these derivatives, 2-(4-bromo-2-fluorobenzyl)-1,2,3,4-tetrahydropyrrolo-[1,2-α]pyrazine-4- spiro-3'-pyrrolidine-1,2',3,5'-tetrone (23t) (SX-3030) showed the best oral activity. The enantiomers of 23t were synthesized, and the biological activities were evaluated. It was found that AR inhibitory activity resides in the (-)-enantiomer 43 (AS-3201), which was 10 times more potent in inhibition of the AR (IC50 = 1.5 x 10-8 M) and 500 times more potent in the in vivo activity (ED50 = 0.18 mg/kg/day for 5 days) than the corresponding (+)-enantiomer 44 (SX-3202). From these results, AS-3201 was selected as the candidate for clinical development. The absolute configuration of AS-3201 was also established to be (R)-form by single- crystal X, ray analysis. In this article we report the preparation and structure-activity relationship (SAR) of tetrahydropyrrolopyrazine derivatives including a novel ARI, AS-3201.

Tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same

Tetrahydropyrrolo[1,2-a]pyrazine-4-spiro-3'-pyrrolidine derivatives of the formula: STR1 wherein R1 and R2 are independently hydrogen, halogen, trifluoromethyl, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, or nitro, and R3 is hydrogen, halogen or alkyl having 1 to 6 carbon atoms, and pharmaceutically acceptable salts thereof, processes for preparation thereof, and pharmaceutical composition containing the same. Said compounds and their salts show excellent aldose reductase inhibitory activity and are useful for the prevention and treatment of diabetic complications.