Studies On The Design,Synthesis Of Aromatic Acid Derivatives, Pyrazolopyrimidinones And Their Pharmacological Activities

In this thesis, the basic research on the development of new anti-platelet aggregation and sedation-hypnosis agents was reported. Forty-three compounds were designed and synthesized, including 40 newly reported compounds. Among those new compounds, there are 13 aromatic acid derivatives and 27 pyrazolo[l,5-a]pyrimidines. The preparation technique of Picotamide and Zaleplon has been investigated in detail. The pharmacological activity of anti-platelet aggregation of aromatic acid derivatives, the sedation-hypnosis activity of pyrazolo[l,5-a]pyrimidines, and the structures activity relationship (SAR) of these compounds have also been explored.Thromboxane A2 (TXA2) is a product formed from arachidonic acid pathway, catalyzed by TXA2 synthase. TXA2 exhibits two major activities: stimulation of platelet function and smooth muscle contraction, inducing platelet aggregation vasoconstriction and bronchoconstriction. The discovery of the dual biological effects mediated by TXA2 and prostaglandin endoperoxide H2 (PGH2) in the early 1980's has stimulated the research interest in searching for TXA2 synthase inhibitors and TXA2/PGH2 receptor antagonists. Some compounds such as Picotamide have been found to have both properties of agonist and antigonist. This class of drugs exhibits a beneficial effect on different models of thrombosis than others in vitro or in vivo.Two new antiplatelet aggregation drugs, Picotamide and Indobufen, have been prepared. On the basis of pharmaceutical theory for drug design, the synthetic interest was focused on the preparation of Picotamide analogs, which carry both amide or sulfonamide and aromatic acids functionalities. The preliminary studies were conducted by attaching the sulfonamide or amido group onto the 1,3-possition of the Picotamide aryl ring. Thirteen new derivatives have been successfully prepared for their antipletelet studies in vitro. The design and synthesis of a series of aromatic acid derivatives, resembling Picotamide, are described. The structures of synthesized compounds were confirmed by IR, 1H-NMR, and HRMS (EI) spectroscopy.The activity of antiplatelet aggregation of new aromatic acid derivatives has been tested in vitro. The results show that the compounds C33f and D34f offer some advantages over drugs such as Picotamide and Indobufen. The rest of compo- unds give better antiplatelet aggregation value than that of Aspirin.The gamma aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system. The receptors for GABA have been defined pharmacologically as GABAA, GABAB, and GABAC. Pharmacological therapy has played an important role in the management of insomnia. Although traditional drugs are highly effective for initiating and maintaining sleep, tolerance and withdrawal effects as well as impairment of daytime performance are commonly troublesome and limit their use. The increased knowledge of GABA and its receptors allows for the development of new hypnotic sedatives, which can be increasingly selective for the various subunits of the GABA receptors. This development has resulted in the discovery of new agents with very favorable hypnotic profiles and side-effect profiles. These agents are expected to provide improved treatment options for medical practitioners. The pyrazolopyrimidines, the latest in this area, seem to offer some above-mentioned advantages over other agents.Zaleplon, which is a nonbenzodiazepine sedative-hypnotic with a pyrazolopyrimidine structure, is structurally different from that of the benzodiazepines. Zaleplon has the similar structure of Zolpidem and Zopiclon, and is the first agent to show selectivity for (binding to) the GABA receptor. Zaleplon was recently launched as the first drug with the structure of pyrazolopyrimidine onto Denmark and Swedish market for the treatment of sedatives hypnotic.Zaleplon has been considered as an ideal hypnotic drug due to its rapid absorption, rapid onset, adequate duration of action and minimum or no residual effect on daytime perfor...