Yeni bazı biyolojik etkili flavonoid sentezleri üzerinde araştırmalar (B halkasında moleküler modifikasyon)

Abstract

187 VI. ÖZET: Bu çalışmada, Flavon çekirdeğinin B halkasının m- veya p-konumunda `1,4- Dihidropiridin` halka sistemi içeren yeni bazı flavonoid türevlerinin sentezlerini gerçekleştirebilmek özere 2 bölümde toplam 7 basamak reaksiyon uygulanmıştır, 1. Bölüm: 3' (veya 4')-Formil Flavon sentezi: Adı geçen Flavon karboksaldehit türevleri, o- veya p-toluik asitten hareketle 6 ayrı basamak reaksiyon sonucunda elde edilmişlerdir. Sentezi sağlanan 3' (veya 40-formil flavon türevleri ile bunların elde edilişi sırasında sentezi sağlanan 3' (veya 4')-bromometil flavon türevleri de orijinal bileşikler olarak sentez edilmişlerdir. 2. Bölüm: 1,4-DHP halka sisteminin sentezi: Elde edilen flavon karboksaldehit türevlerinden hareketle, Hantzsch sentez yöntemi uygulanarak 1,4-DHP halka sisteminin teşekkülü sağlanmıştır. Böylece 1,4-DHP halkasının 3. ve 5. konumlarındaki sübstitüentlerle bu halkanın flavon çekirdeğindeki konumu yönünden birbirinden farklılanan 24 yeni türev sentez edilmiştir. Bu bileşikler kimyasal isimleri ve kod. numaraları ile birlikte aşağıda verilmiştir: 1 m: Dimetil 1,4-dihidro-2,Mimetil-4-[3'-(4H-4-okso-1 -benzopiran-2-il)fenil]-3,5-piridîndilçarbobilat 2m: Metil etil l^-dihidro-Z^imetil^-P'^H^-okso-l-benzopiran^-iDfenill-B^-piridindikarbobilat 3m: Metil allH 1,4-dihldro-2,6<limeti!-4-[3X4H^^ 4m: Metil tert-butil 1,4- dihidro- 2,6- dimetil- 4- [ 3'- ( 4H-4-okso-1 - benzopiran- 2-il ) fenil ] -3,5-piridindi- karboksilat 5m: Metil 1,4-dihidro- 2,6-dimetil-3-fenil karbamoil-4- [3'- (4H-4-okso-1-benzopiran-2-il) fen»] -5-piridîn- karboksilat 6m: Dietll 1,4-dihidro-2,6-dimetil-4-[3'-(4H-4-okso-1 -benzopiran-2-il)fenil]-3,5-piridindikarboksilat 7m: Etil allil 1,4-dihidro-2,6-dimetil-4-[3'-(4H-4-okso-1-benzopiran-2-ll)fenil]-3,5-piridindikarboksilat 8m: Etil tert-butil 1,4-dihldro-2,6-dirrKtfl-4-[3M4H-4-okso-1-ben^^ 9m: Etil 1,4-dihidro-2,6-dirnetil-4-[3'-(4H-4-okso-1-benzopiran-2-il)fenill-3,5-piridin karboksilat asetanilid 1 0m: Diallil 1,4-dlhîdro-2,6-dimeHI-4-[3'-(4H-4-okso-1 -benzopiran-2-il)fenil]-3,5-piridindikarboksilat188 1 İm: Ditert-butil 1,4-dihidro-2,6-dimetil-4-[3'-(4H-4-okso-l-benzopiran-2-ll)fenil]-3,5-piridindikarboksIlat 12m: 1,4-Dihidro- 2,6-dfmetît-4- p'-(4H-4-okso-1-benzopiran-2-il) fenill-3,5-piridIn- N,N'-difenil karboks- amid I p: Dtmetll 1,4-dihidro-2,6-dimetil-4-[4'-(4H-4-okso-1 -benzopiran-2-il)fenil]-3,5-plridindikarboksilat 2p: Metil etil 1,4^ihidro-2,6^lmeöl-4-t4'-(4H-4-ofcso-1-benzopiran-2-il)fenil]-3,5-pfridindikarboteilat 3p: Metil allil 1,4-dlhidrQ-2,6-dimetil-4-[4M4H-4-ola»-1-be^^ 4p: Metil tert-butil 1,4- dlhldro- 2,6- dlmetil- 4- [ 4'- ( 4H-4-okso-1- benzopiran- 2-il ) fenil ] -3,5-piridindi- karboksilat 5p: Metil 1,4-dihidro- 2,6-dimerJI-3-fenil karbamoil-4- [4'- (4H-4-okso-1-benzopiran-2-il) fenil] -5-piridln- karboksilat 6p: Dietil 1,4-dihldro-2f6-dimeti!-4-[4'-(4H-4-okso-1 -benzoplran-2-il)fenil] -3,5-piridindikarboksilat 7p: Etil allil 1,4-dihidro2,6-dimetil-4-[4'-(4H-4-okso-1-benzopiran-2-il)fenil]-3,5-plridindikarboksilat 8p: Etil tert-butil 1,4-dihidro-2,6-dimeHl-4-[4M4H-4-okso-1-benzopiran-2-il)fenil]-3,5-piridindlkarboksilat 9p: Etil 1,4-dihidrc^2f6-dimetil-4-[4'-(4H-4-ol(so-1-berızopiran-2-ll)fenill-3,5-piridin karboksilat asetanilid 10pt Diallll 1,4-dlhidro-2,6-dlme«l-4-[4'-(4H-4-ok50-1 -benzoplran-2-ll)fenin-3,5-plridindlkarboksilat I I p: Ditert-butil 1,4-dihidro-2,6-dimetil-4-[4'-(4H-4-okso-1 -benzopiran-2-il)fenill-3,5-piridindikarboksilat 12p: 1,4-Dihidro- 2,6-dimetil-4- [4'-(4H-4-okso-1-benzopiran-2-il) fenilI-3,5-piridin- N,N'-difenil karboks- amid Böylece sentezi gerçekleştirilen flavonoid türevi toplam 28 kimyasal bileşiğin saflık kontrolleri bazı fizikokimyasal özelliklerine dayanarak sağlanmış ve kimyasal yapıları elemanter analiz, UV, İR, H NMR ve Mass spektral verileri ile kanıtlanmıştır. Ayrıca 7p bileşiğinin X-lşınları kırınımı yapı analizi gerçekleştirilerek biyolojik etkide önemli bazı yapısal parametreleri incelenmiştir. Alınan sonuçlar kalsiyum kanal blokör etkili ilaçların prototipi olan `Nifedipin` ile konformasyon açısından karşılaştırılmış ve büyük bir uygunluk görülmüştür. 6m ve 6p izomerleri, Nifedipin referans alınarak, kalsiyum kanal blokör etki yönünden incelendiğinde elde edilen biyolojik ön deney sonuçları, bu türevlerin kalsiyum kanal blokör aktivitelerinin nifedipin ile kıyaslanabilir düzeyde olduğunu ortaya koymuştur.

189 VII. SUMMARY: In this study, synthesis of new flavonoid derivatives, which possess 1,4-dihydro- pyridine moiety at m- or p- positions of flavone ring were realised. For this purpose, totally seven steps reaction were carried out at the two different sections. Section 1 : Synthesis of 3' (or 4')-Formyl tlavones: The title flavonecarboxyaldehyde were obtained starting from o- (or p)-toluic acids by the six different reaction steps. All of these final compounds 3' (or 4')-fbrmylflavones and their intermediates 3' (or 4')-bromomethylflavones were synthesized as originally. Section 2: Synthesis of the 1,4-Dihydropyridine: This ring synthesis was realised starting from prepared flavonecarboxy aldehydes at the section 1, by the Hantzsch procedure. 24 New derivatives which are consisted different substituents at the third and fifth positions of 1,4-DHP and flavone rings were prepared. Their chemical names and code numbers are given below. 1m: Dimethyl 1,4-dihydro- 2,6-dimethyl- 4- [3'-(4H- 4-oxo- 1-benzopyran-2-yl) phenyll - 3,5- pyrldinedi- carboxylate 2m: Methyl ethyl 1,4-dlhydro- 2,6-dlmethyl- 4- [3M4H-4-oxo-1-benzopyran«2-yl)phenyl] -3,5- pyrldlnedl- carboxylate 3m: Methyl allyl 1,4-dlhydro- 2,6-dirnethyl-4-[3'-(4H-4-oxo-1-benzopyran-2-yDphenyl]-3,5-pyrldinedi- carboxylate 4m: Methyl t-butyl 1,4-dlhydro-2,6-dimethyl-4-[3'-(4H-4-oxo-1-benzopyran-2-yl)phenyl]-3,5-pyrldinedl- carboxylate 5m: Methyl 1,4-dlhydro-2,6-dlmethyl-3-phenyl carbamoyl-4-[3'-(4H-4-oxo-1-benzopyran-2-yl)phenylI-5- pyridinecarboxylate 6m: Diethyl 1,4-dihydro- 2,6-dlmethyl- 4- [3'- (4H- 4-oxo- 1- benzopyran- 2-yl) phenyl] -3,5- pyrldlnedl- carboxylate 7m: Ethyl allyl 1,4-dlhydro- 2,6- dlmethyl-4- [3'-(4H-4-oxo-1-benzopyran-2-yl) phenyl] -3,5- pyrldlnedl- carboxylate 8m: Ethyl t-butyl 1,4-dihydro- 2,6- dimethyl-4- [3'-{4H-4-oxö- 1-benzopyran-2-yl) phenyl]-3,5-pyrldlnedl- carboxylate 9m: Ethyl 1,4- dlhydro- 2,6- dlmethyl-4- [3'-(4H- 4- oxo-1 -benzopyran- 2- yl) phenyl]- 3,5- pyrldlnedl- carboxyiate acetanilld 10m: Diallyl 1,4-dlhydro- 2,6- dlmethyl-4- [3'-(4H-4-oxo- 1-benzopyran-2-yl) phenyl]-3,5-pyrldlnedl- carboxylate 11m: Dl t-butyl 1,4-dlhydro- 2,6- dlmethyl-4- [3'-(4H-4-oxo- 1 -benzopyran-2-yl) phenyl]-3,5-pyr!dlnedi- carboxylate190 12m: 1,4-dlhydro- 2,6- dimethy 1-4- [3'-(4H-4-oxo- l-benzopyran-2-yl) phenyl]-3,5-pyridine-N,N'-dlphenyl carboxamide Ipi Dimethyl 1,4-dihydro- 2,6-dimethyl- 4- [4'-(4H- 4-oxo- l-benzopyrarı-2-yl) phenyl] - 3,5- pyridinedi- carboxylate 2pt Methyl ethyl 1,4-dihydro- 2,6-dlmethyl- 4- [4'-(4H-4-oxo-1-benzopyran-2-yl)phenyl] -3,5- pyrldlnedi- carboxylate 3p: Methyl allyl 1,4-dihydro- 2,6-dlmethyl-4-[4'-(4H-4-oxo-1-benzopyran-2-yl)phenyl]-3,5-pyrldinedi- carboxylate 4pt Methyl t-butyl 1,4-dihydro-2,6-dlmethyl-4-[4'-(4H-4-oxo-l-benzopyran-2-yl)phenylI-3,5-pyr(dlnedI- carboxylate 5p: Methyl 1,4-dlhydro-2,6-dlmethyl-3-phenyl carbamoyl-4-[4'-(4H-4-oxo-1-benzopyran-2-yl)phenyl]-5- pyridinecarfaoxylate 6p: Diethyl 1,4-dlhydro- 2,6-dlmethyl- 4- [4'- (4H- 4-oxo- 1- benzopyran- 2-yl) phenyl] -3,5- pyridinedi- carboxylate 7px Ethyl allyl 1,4-dlhydro- 2,6- dlmethyl-4- [4'-(4H-4-oxo-1-benzopyran-2-yl) phenyl] -3,5- pyridinedi- carboxylate 8pî Ethyl t-butyl 1,4-dlhydro- 2,6- dimethyl-4- [4'-(4H-4-oxo- l-benzopyran-2-yl) phenyl]-3,5-pyrldlnedl- carboxylate 9p: Ethyl 1,4- dlhydro- 2,6- dlmethyl-4- [4'-(4H- 4- oxo-1 -benzopyran- 2- yl) phenyl]- 3,5- pyrldlnedl- carboxylate acetanilid 10p: Dlallyl 1,4-dlhydro- 2,6- dlmethyl-4- [4'-(4H-4-oxo- 1-benzopyran-2-yl) phenyl]-3,5-pyrldlnedl- carboxylate Up: Dl t-butyl 1,4-dlhydro- 2,6- dlmethyl-4- [4'-(4H-4-oxo- 1-benzopyran-2-yl) phenyll-3,5-pyrldlnedi- carboxylate 12ps 1,4-dlhydro- 2,6- dlmethyl-4- [4'-(4H-4-oxo- 1-benzopyran-2-yl) phenyl]-3^-pyrldlne-N,N'-diphenyl carboxamide The purities of the synthesized 28 compounds were checked some of their physicochemical parameters and chemical structures were elucidated by the UV, İR, HNMR, Mass spectral findings and elemental analyses. In addition X-Ray analyses of the compound 7p was realised and some of its structural parameters related with the biological activity was investigated. According to the obtained results; this compounds shows almost similiar conformation with the `Nifedipine` which is known as a prototype of the calcium channel blockers. Calcium channel blocker effect of the isomers 6m and 6p were investigated using `Nifedipine* as the reference compound. This pre-experiments results shows thar^ isomers 6m and 6p have comparable activity with the `Nifedipine`.