This paper describes the synthesis of a new series of 6‐amino‐4‐aryl‐5‐cyanopyrazolo[3,4‐b]pyridines 4 and 4‐aryl‐5‐cyano‐6H‐pyrazolo[3,4‐b]pyridin‐6‐ones 5 from the reaction of 5‐amino‐3‐methyl‐1‐phenylpyrazole 1 with arylidene derivatives of malonodinitrile 2 and ethyl cyanoacetate 3. The structure of the final compounds was determined on the basis of nmr measurements, especially by 1H, 1H‐, 1H, 13C‐COSY, DEPT and X‐ray diffraction.
Several 3(2H)‐pyridazinones with amino groups at the 5‐position of the pyridazine nucleus have been prepared. The 6‐aryl‐5‐halo‐3(2H)‐pyridazinones obtained from mucochloric and mucobromic acid lead to the corresponding 5‐alkylamino‐3(2H)‐pyridazinones, which were tested as platelet aggregation inhibitors.
2H)-Pyridazin-3-ones substituted at 5-position were prepared via Palladium-catalyzed cross-coupling reactions starting from bromopyridazinones and several vinyl and alkynyl coupling reagents according to Stille, Heck and Sonogashira conditions. MOM was employed as efficacious protecting group.(2H)-Pyridazin-3-one derivatives have attracted particular attention during the last decade due to the importance of their biological activity. Especially, 6-aryl-(2H)-pyridazin-3-ones as well as their 4,5-derivatives show various pharmacological activities such as reduction of blood pressure, inhibition of platelet aggregation activities, antithrombotic properties, and others. 2 Imazodan and pimobendam 3 are PDE III inhibitors, developed as promising cardiotonic agents. Other pyridazinones such as zardaverine 4 show combined PDE-3/PDE-4 activity and have been investigated for the treatment of asthma. Recently, Coates and McKillop reported the synthesis of 6-(o-hydroxyphenyl)-(2H)-pyridazin-3-ones as key intermediates in the preparation of the prizidilol, which combines b-blocking and vasodilatory properties. 4Since a few years ago, we have been involved in the development of efficient strategies to functionalize the pyridazinone system. 1 We have focused our attention on searching for platelet aggregation inhibitors. Particularly our studies on 5-amino 5 and 5-oxygenated 6 pyridazinones have led to the development of new platelet antiaggregation agents with non cAMP-PDE-3 based mechanism of action. 7 These results motivated us to study other 5-substituted pyridazinones that may possess this activity. 8 Palladium-catalyzed coupling reactions have been reported to be effective and versatile for, among others, alkenylation or alkynylation of aryl/vinyl halides. 9 Starting from 5-bromo-6-phenyl-(2H)-pyridazin-3-one we have investigated this approach for the preparation of vinyl and alkynyl derivatives at the C-5 position as a practical, highly efficient route to new pyridazinones. Only a few reports have been published on palladium-catalyzed reactions of pyridazines. Starting from halogenated (iodo and bromo) precursors Yamanaka 10 and Oshawa 11 have reported on the preparation of alkynyl derivatives of pyridazines via palladium-catalyzed cross-coupling reactions. Recently, Wermuth 12 described an efficient synthesis of 3-alkynyl pyridazines from pyridazine triflates using Pd(0) crosscoupling reactions. However, to our knowledge, there is no report in the literature for palladium cross-coupling reactions in the pyridazinone system.We present here a highly efficient synthesis of 5-alkynyl and 5-alkenylpyridazinones by using palladium coupling reactions between MOM-protected 5-bromo-6-phenyl-(2H)-pyridazin-3-ones and several alkynes and vinyltrialkylstannanes. Disappointingly all attempts at performing the cross-coupling reaction with N-unprotected pyridazinones were completely unsuccessful. However, use of protecting groups such as the MOM with a slightly electron-withdrawing properties resulted in successful couplings in high y...
6-Phenyl-5-hydroxymethyl-4,5-dihydro-3(2H)-pyridazinone (1) and 6-thienyl-5-hydroxymethyl-4,5-dihydro-3(2H)-pyridazinone (2) inhibit platelet aggregation induced by thrombin (IC50 = 0.25 and 0.26 mM, respectively) or by the calcium ionophore ionomycin (IC50 = 0.42 and 0.43 mM, respectively). Pyridazinones 1 and 2 also show concentration-dependent attenuation of the increases in platelet cytosolic free calcium concentration induced by thrombin and ionomycin, suggesting that their antiaggregatory activity may be due to their capacity to inhibit the passage of calcium through the cytoplasmic membrane. This effect may be implicated in other pharmacological activities of 6-aryl-5-substituted-pyridazinones.
A highly efficient procedure for introducing aryl or heteroaryl rings at position 5 of the 6-phenyl-(2H)-pyridazin-3-one system using a Suzuki cross-coupling reaction has been developed in the search for new platelet aggregation inhibitors.
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