(orl1) Antagonist Synthetic Intermediates And Snk,-860 Synthesis And Me-too, 5¦Á-reductase Inhibitors Exploration

Part IThe first part of this thesis is the synthesis of the key intermediate of non-peptide ORL1 receptor antagonists. Non-peptide ORL1 receptor antagonists show high affinity for ORL1 receptor with a selectivity greater than 600-fold over the usual opioid receptor( , , ), which indicats this kind of compounds have potential efficacy on a wide variety of disease. 1-[1-Cyclooctylmethyl-3-methoxycarbonyl -l,2,5,6-tetrahydro-pyridin-4-yl]-3-ethyl-l,3-dihydro-2H-benzimidazol-2-one is a key intermediate of non-peptide ORL1 receptor antagonists. Owing to the vast foreground of this kind of drug, we proposed a novel synthetic approach to this key intermediate and completed its synthesis via a series of reaction steps, including Michael addition, Dieckmann condensation, forrnylation, reductive alkylation, cyclization, etc. During the study, the condition of Michael addition was optimized and the polymerization of methyl acrylate was avoided. The process of synthesis of methyl 4-oxo-piperidine -3-carboxylate hydrochloride was improved. The condition of the reductive alkylation was optimized and the overall yield was greatly increased.Part IIThe second part of this thesis is the synthesis of the aldose reductase inhibitor SNK-860. SNK-860 is a potent aldose reductase inhibitor with high ARJ activity and low side effects, which makes it a promising drug for diabetic neuropathy. This drug was co-developed by Japan Energy and Sanwa Kagaku Kenkyusho Co., and is in the registration stage now. SNK-860 was synthesized from 4-fluoroanisole via eight steps including Friedel-Crafts reaction, cyclization, resolution, Bucherer-Bergs reaction, esterification, ammonolysis, etc. During our study, we found the proper condition of cyclization and the efficient purification method for the final product, as well as the safe and easy method of the after-treatment in Bucherer-Bergs reaction. Furthermore, we discovered the recrystallization solvent for separation of the diastereomer.Part IIIThe third part of this thesis is about the attempt to synthesize nonsteroid 5 a -reductase inhibitors which are used for treatment of benign prostatic hyperplasia (BPH). BPH is one of the most common diseases in elderly men. Steroidal inhibitors of 5 a -reductase are dominant drugs for the treatment BPH on the current market. However, these drugs have showed severe adverse effects in the clinical application. Recently, nonsteroidal inhibitors of 5 a -reductase have caused much attention considering their potent efficacy and beneficial safety profile in the treatment of the BPH. In recent years, a series of novel indoline derivatives which showed potent inhibitory activities for the human 5 a -reductases have been discovered. According to the structure-activity relationships, we have designed five novel indoline derivatives and have synthesized three of them. Some animal evaluations are under way.