Synthesis And Analysis Of Several Series Of Pharmaceuticals For Treatment Of Diabetes Ⅱ

Diabetes is a chronic disease which is very harmful to people's health. It is the third factor leading human to death, inferior to cardiovascular diseases and tumor. For chemists and pharmacists it should be done to invent some new high efficiency antidiabetic drugs without obvious toxicity and side effect. In this thesis, we summarize the reason, the treatment and the market. Using computer-assisted drug design, the synthesis and analysis of target molecules are accomplished aiming at the proteins PPAR( and PPAR(. In virtue of parallel high throughput screening (HTS) by cells in vitro, the biological activity of target molecules are screened to find new drugs with high biological activity and new pharmacological mechanism. The main content and achievement of this thesis are followed:1. The synthesis and analysis of 2-{4-[2-(5,6,7,8- tetrahydro -5,5,8,8- tetramethyl -2- naphthoxy) ethoxy] benzyl} malonic acid derivatives. Making use of the easily available and cheap reagents, such as 2,5-dimethyl-2,5-hexanediol, phenol, 1,2-dibromoethane, 4-hydroxylbenzaldehyde, dimethyl malonate etc, in virtue of Knoevenagel, Williamson reactions, Pa-C catalyzed hydrogenation with mild conditions and high yields, we synthesize 5 dimethyl 2-{4-[2-( 5,6,7,8- tetrahydro -5,5,8,8- tetramethyl-2- naphthoxy) ethoxy] benzyl} malonate derivatives through 6～9 steps. The synthetic pathway has some characteristics of green chemistry with total yield of 22%. Structural analysis is done and affirmed by UV, NMR, IR and MS. Through biological screening, it is found that PPARα activities of the target compounds are almost equal to or slightly high than that of Rosiglitazone while their PPARγ activities are only 50-60% of Rosiglitazone, required to be modified.2. The synthesis and analysis of 2-{4-[2-(5,6,7,8-tetrahydro-2- naphthoxy) ethoxy] -benzyl} malonic acid derivatives. Using similar methods, we synthesize 5 dimethyl 2-{4-[2-(5,5,8,8-tetramethyl-2-naphthoxy)- ethoxy]-benzyl} malonate derivatives by 4～7 steps. The total yield is about 32%. The target molecules are analyzed by UV, NMR, IR and MS. Their biological activities on PPARα and PPARγ are universal higher 2-4.5 and 1.3 times than Rosiglitazone, respectively. 3. The synthesis and analysis of L-tyrosine derivatives substituted by three-ring group. Employing the easily available and cheap reagents such as L-tyrosine methyl ester, 1,2-dibromoethane, Benzoylacetone and carbazole in virtue of dehydration, Williamson synthesis and phase transfer catalysis with mild conditions and high yield, we synthesize 3 L-tyrosine derivatives substituted by three-ring group. The total yield is about 3.4%. The target molecules are analyzed by UV, NMR, IR and MS. The biological screening shows that their PPARα and PPARγ activities are universal higher 1-3.2 and about 0-0.9 times than Rosiglitazone, respectively. 4. The synthesis and analysis of three-ring substituted derivatives of ethoxy- benzyl- malonic acid. Starting with the easily available and cheap reagents such as 1,2-dibromoethane, 4-hrdroxylbenzaldehyde, dimethyl malonate etc, in virtue of Knoevenagel, Williamson syntheses, plus phase transfer catalysis and Pa-C catalysed hydrogenation with mild conditions and high yield, we synthesize the target compounds by 4～7 steps reaction. The total yield is about 18%. The target molecules are analyzed by UV, NMR, IR and MS. Biological experiments shows that the PPARα activities of the targets are high than Rosiglitazone at low concentration and their PPARγ activity is only 50% of Rosiglitazone. The structures need to be improved.