147194-10-3

Upstream product

• 159345-13-8 ethyl 3-benzyloxycarbonylamino-3-ethoxycarbonyl-3-cyanopropionate 
• 144-48-9 iodacetamide 
• 3005-66-1 diethyl 2-benzyloxycarbonylaminomalonate 
• 79-07-2 Chloroacetamide 
• 147194-08-9 (RS)-ethyl 2-(benzyloxycarbonylamino)-2-cyanoacetate 

Downstream Products

• 147254-64-6 ranirestat 
• 159213-18-0 (R)-ethyl-3-amino-2,5-dioxopyrrolidine-3-carboxylate 
• 214418-25-4 (S)-3-Benzyloxycarbonylamino-2,5-dioxo-pyrrolidine-3-carboxylic acid ethyl ester 
• 159213-17-9 (R)-2-benzyloxycarbonylamino-2-ethoxycarbonylsuccinimide 

Relevant academic research and scientific papers

Process for production of 2,5 dioxopyrrolidine 3 carboxylate

The present invention provides a novel intermediate which enable to prepare tetrahydropyrrolo[1,2-a]pyrazin-4-spiro-3′-pyrrolidine derivatives such as Ranirestat being promising therapeutic agents for diabetic complications in a short process and in an economically advantageous and safe manner, and a process for preparing the same. That is, the present invention provides a process for preparing a compound of the following formula (I) wherein R1 is an amino group protected with a protecting group, etc., and R2 is a lower alkyl group, etc., comprising the following steps (1) and (2): (1) a step of converting a cyano group in a compound of the following formula (II) wherein n and m are each independently 0 or 1; provided when n is 0 and m is 1, then R2 and R3 are the same or different protecting groups for a carboxyl group; and when n is 1 and m is 0, then R2 and R3 are the same protecting groups for a carboxyl group; and R1 is as defined above, into a carbamoyl group in the presence of divalent palladium compound(s), primary amide(s) and water; and (2) a step of cyclizing the product obtained in the step (1).

METHOD FOR PRODUCING SUCCINIMIDE COMPOUND

There is provided a method for producing a succinimide compound. The method for producing a succinimide compound of formula (3) comprises reacting an aminomalonic ester compound of formula (1) with a compound of formula (2) in a solvent in the presence of

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.