Antiarrhythmic Activities of Some Newly Synthesized Tricyclic and Tetracyclic Thienopyridine Derivatives

3,5-Bis(4-chlorobenzylidene)-1-ethylpiperidin-4-one (1b) was condensed with malononitrile or cyanothioacetamide to yield pyranopyridine 2 and thiopyridopyridine 3b, respectively. Treatment of compound 3b with methyl iodide or ethyl chloroacetate in the presence of a base catalyst gave the corresponding compounds 4 and 5. Compound 3b was reacted with 2-chloro-N-arylacetamide derivatives to yield compounds 7a,b, which were reacted with benzoyl chloride or sodium nitrite to give the corresponding tetracyclic compounds 8a,b and 9a,b, respectively. Compound 2 was treated with acetic anhydride or formic acid to yield the corresponding N-acetylpyranopyridine 10 and pyranopyrimidine 11. Treatment of compound 2 with triethyl ortho-formate gave compound 12, which was cyclized with hydrazine hydrate to give N-aminopyrimidine 13. Some of the synthesized compounds showed high antiarrhythmic activities comparable with Procaine amide and Lidocaine as positive controls.


Introduction
The search for new heterocyclic compounds and novel methods for their synthesis is a major topic in contemporary organic synthesis.As part of our program in this area, we have synthesized some pyridine and thiazolopyrimidine derivatives of biological interest as anticancer activity [1][2][3][4][5].On the other hand, thienopyrimidine and thioxopyrimidine derivatives have promising biological [6,7] and inhibitor of VEGFR-2 kinase activity [8,9].Recently, some new pyridine, pyrimidine and their derivatives have been synthesized and used as analgesic, anticonvulsant and anti-parkinsonian agents [10][11][12][13][14][15].In addition, Atheral et al [16] have synthesized a novel series of thieno [2,3-d]pyrimidines which can be used in combating fungi in plant and inhibited the growth of cancer cells [17,18].In continuation of our previous work we synthesized some new tricyclic and tetracyclic heterocyclic compounds containing tetrahydropyridopyridine nucleus and tested their antiarrhythmic activities.

Results and Discussion
3,5-Bis(benzylidene)-1-ethylpiperidin-4-ones 1a-c and pyranopyridine derivative 2 were used as starting materials and prepared according to the published method [3].Compounds 1a-c were reacted with cyanothioacetamide in refluxing ethanol containing drops of Et 3 N to give pyridinethione derivatives 3a-c, which were reacted with methyl iodide in sodium ethoxide solution with stirring at room temperature to yield the methylmercaptopyridine derivative 4. Similarly, compound 3b was reacted with ethyl chloroacetate in refluxing ethanol in the presence of drops of Et

Pharmacological Screening
The newly synthesized compounds were pharmacologically screened for their Antiarrhythmic potency (Table 1).
Procaine amide, 5 mg/kg iv and lidocaine 5 mg/kg i.v.led to an increase in LD 100 by 65%, which corresponds to a LD 100 of approximately 9 μg/100 mg. From

Structural Activity Relationship (SAR)
• The naphthyridine moiety and a high degree of aromaticity is essential for antiarrhythmic activity.
• Hetero-aromaticity increases the anti-arrhythmic activity • Fused ring systems give anti-arrhythmic activity but to a lower extent.

Experimental
All melting points were taken on a Electrothermal IA 9000 series digital melting point apparatus.Elemental analytical data (in accordance with the calculated values) were obtained from the microanalytical unit, Cairo University, Cairo, Egypt.The IR spectra (KBr) were recorded on a Pye Unicam SP-1000 spectrophotometer.The 1 H NMR and 13  Spectrometer using TMS as an internal standard.The mass spectra were performed using a VC 2AB-3F spectrometer (70 eV).All reactions were followed by TLC (silica gel, aluminium sheets 60 F 254 , Merck).