الفهرس 
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Abstract
Title:Synthesis of Some Novel Pyrrolizines and Indolizines of Anticipated Pharmacological Activity.
Keywords:Pyrrolizine, Diazepinopyrrolizine,Pyrimidopyrrolizine, Indolizine, Diazepinoindolizine, Pyrimidopyrrolizine, Anticancer agents, EGFR-TK inhibition.
In the present work, design and synthesis of several substituted diazepinoindolizinesXa-cand XIIa-c, diazepinopyrrolizines XIa-c, pyrrolizinesXIIIa-c and XVa-c, indolizines XIVa-c and XVIa-c, pyrimidopyrrolizines XVIIa-c and pyrimidoindolizineXVIII were discussed.Reaction of the starting materials Va-cand VIa-cwith chloroacetyl chloride, afforded the 2-chloroacetamido derivatives VIIa-c and VIIIa-c, which undergo intramolecular cyclization into diazepino[5,6-b]pyrrolizinesIXa-c and diazepino[5,6-b]indolizines Xa-cwhich were alkylated with ethyl chloroacetate to give ethyl acetate derivatives XIa-c and XIIa-c. Reaction of 2-chloroacetamido derivatives VIIa-c and VIIIa-c with piperidine gave the 2-(piperidin-1-yl)acetamido derivativesXIIIa-c and XIVa-c. The target compounds XVa-c, XVIa-c, XVIIa-c and XVIII were obtained from the reaction of compounds Va-c and VIa-c with 4-nitrobenzaldehyde and triethyl orthoacetate. The rational for these compounds was discussed. characterization of the chemical structure of the new compounds was done using spectral and elemental analyses.
This thesis consists of the following parts:
1- Introduction:
In this chapter, a brief literature review concerning the pyrrolizine and indolizine nucleus was presented, different pharmacological activities of some pyrrolizine and indolizine derivatives and some methods adopted for their preparation.
2- Aim and bases of the present investigation:
It includes the research objectives and rationale upon which the newly synthesized compounds were designed.
3- Discussion:
In this part, various experimental methods and conditions of reactions adopted for the preparation of the designed compounds are discussed. In addition, it deals with the confirmation of the newly synthesized compounds by different methods including microanalytical data, infrared, mass, 1H NMR and 13C NMR spectra.
4- Experimental:
This part presents the practical procedures used for the synthesis of the reported and new intermediates as well as new final compounds. Also, it summarizes their spectral and microanalytical data.
Synthesis of the following compounds was found to be essential for our study
Known intermediates:
1- 2-Chloro-N-phenylacetamide (IIa).
2- 2-Chloro-N-(4-methylphenyl)-acetamide(IIb).
3- 2-Chloro-N-(4-chlorophenyl)-acetamide (IIc).
4- 2-Pyrrolidin-2-ylidene-malononitrile (IVa).
5- 2-Piperidin-2-ylidene-malononitrile (IVb).
6- 6-Amino-7-cyano-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (Va).
7- 6-Amino-7-cyano-N-(4-methylphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (Vb).
8- 6-Amino-N-(4-chlorophenyl)-7-cyano-2,3-dihydro-1H-pyrrolizine-5-carboxamide (Vc).
9- 2-Amino-1-cyano-N-phenyl-5,6,7,8-tetrahydroindolizine-3-carboxamide (VIa).
10- 6-(2-Chloroacetylamino)-7-cyano-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (VIIa).
11- 6-(2-Chloroacetylamino)-7-cyano-N-(4-methylphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (VIIb).
12- 6-(2-Chloroacetylamino)-N-(4-chlorophenyl)-7-cyano-2,3-dihydro-1H-pyrrolizine-5-carboxamide (VIIc).
13- (2-Chloroacetamido)-1-cyano-N-phenyl-5,6,7,8 tetrahydro indolizine-3-carboxamide (VIIIa).
14- 2,5-Dioxo-4-phenyl-1,2,3,4,5,7,8,9-octahydro-[1,4]diazepino[5,6-b]pyrrolizine-10-carbonitrile (IXa).
15- 2,5-Dioxo-4-(4-methylphenyl)-1,2,3,4,5,7,8,9-octahydro-[1,4] diazepino[5,6-b]pyrrolizine-10-carbonitrile (IXb).
16- 4-(4-Chlorophenyl)-2,5-dioxo-1,2,3,4,5,7,8,9-octahydro-[1,4] diazepino[5,6-b]pyrrolizine-10-carbonitrile (IXc).
Newly synthesized compounds:
Include 29 new compounds classified into seven series.
1. The first series includes:
• 2-Amino-1-cyano-N-(4-methylphenyl)-5,6,7,8-tetrahydroindolizine-3-carboxamide (VIb).
• 2-Amino-N-(4-chlorophenyl)-1-cyano-5,6,7,8-tetrahydroindolizine-3-carboxamide (VIc).
2. The second series includes:
• (2-Chloroacetamido)-1-cyano-N-(4-methylphenyl)-5,6,7,8 tetrahydro indolizine-3-carboxamide (VIIIb).
• (2-Chloroacetamido)-1-cyano-N-(chlorophenyl)-5,6,7,8 tetrahydro indolizine-3-carboxamide (VIIIc).
3. The third series includes:
• 2,5-Dioxo-4-phenyl-2,3,4,5,7,8,9,10-octahydro-1H-[1,4]diazepino[5,6-b]indolizine-11-carbonitrile (Xa).
• 2,5-Dioxo-4-(4-methylphenyl)-2,3,4,5,7,8,9,10-octahydro-1H-[1,4]diazepino[5,6-b]indolizine-11-carbonitrile (Xb).
• 4-(4-Chlorophenyl)-2,5-dioxo-2,3,4,5,7,8,9,10-octahydro-1H-[1,4]diazepino[5,6-b]indolizine-11-carbonitrile (Xc).
4. The fourth series includes:
• Ethyl 2-(10-cyano-2,5-dioxo-4-phenyl-3,4,5,7,8,9-hexahydro-[1,4]diazepino[5,6-b]pyrrolizin-1(2H)-yl)acetate (XIa).
• Ethyl 2-(10-cyano-2,5-dioxo-4-(4-methylphenyl)-3,4,5,7,8,9-hexahydro-[1,4]diazepino[5,6-b]pyrrolizin-1(2H)-yl)acetate (XIb).
• Ethyl 2-(4-(4-chlorophenyl)-10-cyano-2,5-dioxo-3,4,5,7,8,9-hexahydro-[1,4]diazepino[5,6-b]pyrrolizin-1(2H)-yl)acetate (XIc).
• Ethyl 2-(11-cyano-2,5-dioxo-4-phenyl-2,3,4,5,7,8,9,10-octahydro-1H-[1,4]diazepino[5,6-b]indolizin-1-yl)acetate (XIIa).
• Ethyl 2-(11-cyano-2,5-dioxo-4-(4-methylphenyl)-2,3,4,5,7,8,9,10-octahydro-1H-[1,4]diazepino[5,6-b]indolizin-1-yl)acetate (XIIb).
• Ethyl 2-(4-(4-chlorophenyl)-11-cyano-2,5-dioxo-2,3,4,5,7,8,9,10-octahydro-1H-[1,4]diazepino[5,6-b]indolizin-1-yl)acetate (XIIc).
5. The fifth series includes:
• 7-Cyano-N-phenyl-6-(2-(piperidin-1-yl)acetamido)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (XIIIa).
• 7-Cyano-6-(2-(piperidin-1-yl)acetamido)-N-(4-methylphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (XIIIb).
• N-(4-Chlorophenyl)-7-cyano-6-(2-(piperidin-1-yl)acetamido)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (XIIIc).
• 1-Cyano-N-phenyl-2-(2-(piperidin-1-yl)acetamido)-5,6,7,8-tetrahydroindolizine-3-carboxamide (XIVa).
• 1-Cyano-2-(2-(piperidin-1-yl)acetamido)-N-(4-methylphenyl)-5,6,7,8-tetrahydroindolizine-3-carboxamide (XIVb).
• N-(4-Chlorophenyl)-1-cyano-2-(2-(piperidin-1-yl)acetamido)-5,6,7,8-tetrahydroindolizine-3-carboxamide (XIVc).
6. The sixth series includes:
• 7-Cyano-6-((4-nitrobenzylidene)amino)-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (XVa).
• 7-Cyano-6-((4-nitrobenzylidene)amino)-N-(4-methylphenyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (XVb).
• N-(4-Chlorophenyl)-7-cyano-6-((4-nitrobenzylidene)amino)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (XVc).
• 1-Cyano-2-((4-nitrobenzylidene)amino)-N-phenyl-5,6,7,8-tetrahydroindolizine-3-carboxamide (XVIa).
• 1-Cyano-2-((4-nitrobenzylidene)amino)-N-(4-methylphenyl)-5,6,7,8-tetrahydroindolizine-3-carboxamide (XVIb).
• N-(4-Chlorophenyl)-1-cyano-2-((4-nitrobenzylidene)amino)-5,6,7,8-tetrahydroindolizine-3-carboxamide (XVIc).
7. The seventh series includes:
• 2-Methyl-4-oxo-3-phenyl-4,6,7,8-tetrahydro-3H-pyrimido[4,5-b]pyrrolizine-9-carbonitrile (XVIIa).
• 2-Methyl-4-oxo-3-(4-methylphenyl)-4,6,7,8-tetrahydro-3H-pyrimido[4,5-b]pyrrolizine-9-carbonitrile (XVIIb).
• 3-(4-Chlorophenyl)-2-methyl-4-oxo-4,6,7,8-tetrahydro-3H-pyrimido[4,5-b]pyrrolizine-9-carbonitrile (XVIIc).
• 2-Methyl-4-oxo-3-phenyl-3,4,6,7,8,9-hexahydropyrimido[4,5-b]indolizine-10-carbonitrile (XVIII).
5- Biological screening:
Evaluation of the anticancer activity of the new compounds were performed by determination of the growth inhibitory effect on lung cancer (A549), breast cancer (MCF-7), and liver cancer (Hep3B) cell lines using sulforhodamine-B (SRB) assay. The results were expressed in IC50(µmol/ml)and compared with doxorubicin as a reference anticancer drug where all the tested compounds have IC50 in the range of 0.003-2.559µmol/ml. The most potent pyrrolizine compounds werepyrimido[4,5-b]pyrrolizine-9-carbonitrileXVIIc with IC50 of 0.009 µmol/ml against A549 cell line and 2-(piperidin-1-yl)acetamideXIIIb with IC50 of 0.043 and 0.049 µmol/ml against MCF-7 and Hep3B cell lines respectively. EGFR-TK inhibition assay of the target pyrrolizine compounds revealed inhibition % in the range of 59.8-89.7%. The most potent indolizine compounds werepyrimido[4,5-b]indolizine-10-carbonitrileXVIII with IC50 of 0.028 and 0.004 µmol/ml against A549 and MCF-7 cell lines respectively and diazepino[5,6-b]indolizine-11-carbonitrileXa with IC50of 0.003 µmol/ml against Hep3B cell line.
6- References:
This part includes 190 references.
7- Arabic summary.