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Abstract
The present thesis comprises the following chapters:
Chapter I (Introduction):
An introductory part describing chemistry of thienopyrimidines and different approaches for cancer therapy, including targeted chemotherapeutic agents. Prominent examples are tyrosine kinase inhibitors, such as gefitinib, erlotinib, lapatinib and dasatinib.
Chapter II (Research Objectives):
The aim of this research is to synthesize structural analogues for gefitinib (Iressa®) and its congeners: erlotinib (Tarceva®), lapatinib and dasatinib.
In our strategy, to improve binding affinity of anilinoquinazoline framework, we introduced the following modifications for this template according to the following planes; pyrano-thienopyrimidine derivatives are cyclic oxygenated thienopyrimidines, mimicking that of gefitinib. Introduction of bulky heterocyclylsulfonamido group at aniline ring to fill pocket in the ATP binding region as lapatinib does. Therefore, enhancing the activity of both ErbB-1 and ErbB-2.
On the other hand, another series of cyano-substituted fused thiophenes was introduced. Based on the replacement of the nitrogen atom of the thiazole ring of dasatinib with a carbon atom that had an attached electron-withdrawing group (such as a cyano group). The synthetic routes, which have been followed for the preparation of target compounds, are illustrated by 6 schemes.
Chapter III (Theoretical Discussion):
A theoretical discussion of synthetic pathways that have been followed to obtain final new compounds and their mechanisms; spectral data and biological results.
Chapter IV (Experimental):
Gewald aminothiophene synthesis allows for a convenient synthetic approach to 2-aminothiophene-3-carboxylates (Ia,b) and 2-aminothiophene-3-carbonitriles (IVa,b) , which were used as starting materials for the synthesis of a large number of reactive intermediates.
The requisite aminothiophenes were synthesized from the appropriate ketone, sulfur, and the appropriate activated nitrile: ethyl cyanoacetate (scheme 1) or malononitrile (scheme 2) in the presence of an organic base through one-pot thiolation/heterocyclization reaction.
The aminothiophene esters (Ia,b) were cyclized with formamide to afford thienopyrimidin-4-one derivatives (IIa,b).
Reacting compounds (IIa,b) with a chlorinating reagent such as phosphorous oxychloride or thionyl chloride provided the 4-chlorothieno-pyrimidine derivatives (IIIa,b) (scheme 1).
On the other hand, the 2-aminothiophene-3-carbonitriles (IVa,b) were treated with chloroacetyl chloride to provide the corresponding N-chloroacetylated derivatives (Va,b) (scheme 2).
Finally, compounds (IIIa,b), (Va,b) were coupled with a variety of primary substituted aromatic amines and sulfonamides. The structures of new compounds were confirmed by both analytical and spectral data (IR, 1HNMR, MS).
Chapter V (Pharmacological Screening):
Lead compounds were evaluated for their ability to inhibit the growth of human breast carcinoma (MCF-7) and human colorectal carcinoma (HCT116) cell lines in which tyrosine kinase activity is highly expressed, using the method of Skehan et al. (1990).
The present investigation involves the synthesis of the following intermediates:-
1] Ethyl-2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylate (Ia).
2] Ethyl-2-amino-4,5-dihydro-7H-thieno[2,3-c]pyran-3-carboxylate (Ib).
3] 5,6,7,8-Tetrahydrobenzothieno[2,3-d]pyrimidin-4(3H)-one (IIa).
4] 5,6-Dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d]pyrimidin-4(3H)-one (IIb).
5] 4-Chloro-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine (IIIa).
6] 4-Chloro-5,6-dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d]pyrimidine (IIIb).
7] 2-Amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (IVa).
8] 2-Amino-4,5-dihydro-7H-thieno[2,3-c]pyran-3-carbonitrile (IVb).
9] 2-Chloroacetylamino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (Va).
10] 2-Chloroacetylamino-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (Vb).
In addition to, the synthesis of the following final new compounds:
I] 4-[4-(N-(Substituted)sulfamoyl)]anilino-5,6,7,8-tetrahydrobenzothieno [2,3-d]pyrimidines:
1] 4-[4-(N-(Diaminomethylene)sulfamoyl)]anilino-5,6,7,8-tetrahydrobenzothieno [2,3-d]pyrimidine (VIa).
2] 4-[4-(N-(Thiazol-2-yl)sulfamoyl)]anilino-5,6,7,8-tetrahydrobenzothieno[2,3-d] pyrimidine (VIIa).
3] 4-[4-(N-(5-Methylisoxazol-3-yl)sulfamoyl)]anilino-5,6,7,8-tetrahydrobenzo-thieno[2,3-d]pyrimidine (VIIIa).
4] 4-[4-(N-(4-Methylpyrimidin-2-yl)sulfamoyl)]anilino-5,6,7,8-tetrahydrobenzo-thieno[2,3-d]pyrimidine (IXa).
5] 4-[4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl)]anilino-5,6,7,8-tetrahydro-benzothieno[2,3-d]pyrimidine (Xa).
II] 4-(Hydroxy)anilino-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidines:
1] 4-(3-Hydroxy)anilino-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine (XIa).
2] 4-(4-Hydroxy)anilino-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidine (XIIa).
III] 4-[4-(N-(Substituted)sulfamoyl)]anilino-5,6-dihydro-8H-pyrano [4’,3’:4,5]thieno[2,3-d]pyrimidines:
1] 4-[4-(N-(Diaminomethylene)sulfamoyl)]anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5] thieno[2,3-d]pyrimidine (VIb).
2] 4-[4-(N-(Thiazol-2-yl)sulfamoyl)]anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5] thieno[2,3-d]pyrimidine (VIIb).
3] 4-[4-(N-(5-Methylisoxazol-3-yl)sulfamoyl)]anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d]pyrimidine (VIIIb).
4] 4-[4-(N-(4-Methylpyrimidin-2-yl)sulfamoyl)]anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d]pyrimidine (IXb).
5] 4-[4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl)]anilino-5,6-dihydro-8H-pyrano [4’,3’:4,5]thieno[2,3-d]pyrimidine (Xb).
IV] 4-(Hydroxy)anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d] pyrimidines:
1] 4-(3-Hydroxy)anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d]pyrimidine (XIb).
2] 4-(4-Hydroxy)anilino-5,6-dihydro-8H-pyrano[4’,3’:4,5]thieno[2,3-d]pyrimidine (XIIb).
V] 2-[4-(N-(Substituted)sulfamoyl)anilino]acetamido-3-cyano-4,5,6,7-tetra-hydrobenzo[b]thiophene derivatives:
1] 2-[4-(N-(Diaminomethylene)sulfamoyl)anilino]acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XIIIa).
2] 2-[4-(N-(Thiazol-2-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XIVa).
3] 2-[4-(N-(5-Methylisoxazol-3-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XVa).
4] 2-[4-(N-(4-Methylpyrimidin-2-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XVIa).
5] 2-[4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XVIIa).
VI] 2-(Hydroxyanilino)acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b] thiophenes:
1] 2-(3-Hydroxyanilino)acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XVIIIa).
2] 2-(4-Hydroxyanilino)acetamido-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene (XIXa).
VII] 2-[4-(N-(Substituted)sulfamoyl)anilino]acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran derivatives:
1] 2-[4-(N-(Diaminomethylene)sulfamoyl)anilino]acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XIIIb).
2] 2-[4-(N-(Thiazol-2-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XIVb).
3] 2-[4-(N-(5-Methylisoxazol-3-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XVb).
4] 2-[4-(N-(4-Methylpyrimidin-2-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XVIb).
5] 2-[4-(N-(4,6-Dimethylpyrimidin-2-yl)sulfamoyl)anilino]acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XVIIb).
VIII] 2-(Hydroxyanilino)acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c] pyran:
1] 2-(3-Hydroxyanilino)acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XVIIIb).
2] 2-(4-Hydroxyanilino)acetamido-3-cyano-4,5-dihydro-7H-thieno[2,3-c]pyran (XIXb).