Analjezik-antiinflamatuvar etki göstermesi beklenen yeni kondanse oksazolinon türevlerinin sentezleri ve farmokolojik aktivitelerinin araştırılması
Synthesis of condensed oxazolinone derivatives wich are expected to have analgesic-antiinflammatory affect and investigation of their pharmacological activities
Yazar: NESRİN GÖKHAN
Danışman: PROF.DR. HAKKI ERDOĞAN
Hacettepe Üniversitesi / Sağlık Bilimleri Enstitüsü / Farmasötik Kimya Ana Bilim Dalı
Derece: Doktora, 1998
Konu: Eczacılık ve Farmakoloji = Pharmacy and Pharmacology
Dizin: Analjezikler = Analgesics ; Antiinflamatuar ajanlar = Anti inflammatory agents ; Benzoksazoller = Benzoxazoles ; Oksazol = Oxazole

Özet:
IV ÖZET Bu çalışmada 3-[2-(2-/4-piridil)]etil-(5-kloro)-6-(2,5-; 2,3-; 3,4-; 3,5-; 2,6-difloroben_ zoil)-2-benzoksazolinon ve 3-[2-(2-/4-piridil)]etil-(6-bromo)-oksazolo[4,5-b]piridin-2-on yapı_ sında 24 bileşiğin sentezi yapılarak, analjezik-antiinflamatuvar etkileri incelenmiştir. Başlan_ gıç maddesi olan 6-(diflorobenzoil)-2-benzoksazolinonlar aromatik karboksilli asitlerin poli_ fosforik asitli ortamda 2-benzoksazolinon ile reaksiyonu sonucu hazırlanmıştır. Oksazo_lo[4,5-b]piridin-2-on ise 2-amino-3-hidroksipiridinin 1,1'-karbonildiimidazol ile reaksiyonu sonucu hazırlanmış ve daha sonra bromlama yapılarak 6-bromooksazolo[4,5-b]piridin-2-on elde edilmiştir. Bu türevlerin 2-/4-vinilpiridinle Michael katımı sonucu hedef bileşiklere ulaşılmıştır. Sentezi yapılan bileşiklerin erime dereceleri, reaksiyon yüzde verimleri, kristallendirme çözücüleri, molekül formülleri ve elementel analiz sonuçlan aşağıda tablo halinde verilmiştir. Bileşiklerin fiziksel özellikleri, ince tabaka kromatografisinde Rf değerleri ve UV absorpsiyon özellikleri saptanmış, yapılan İR, 1H-NMR, 13C-NMR, kütle spektroskopisi ve elementel analiz verileri ile kanıtlanmıştır. Hazırlanan bileşiklerin analjezik etkileri Aspirin referans alınarak değiştirilmiş Koster Testi ile incelenmiştir. Bileşiklerden 4 tanesinin (Bileşik 1, 7, 23, 24) analjezik etkisi aspirinin etkisinden daha yüksektir, özellikle 3-[2-(4-piridil)]etil-6-(2,5-diflorobenzoil)-2-benzoksazolinonun (Bileşik 1) analjezik etkisi (%86.40 p<0.01) diğerlerine oranla daha yüksek bulun_ muştur. Bileşiklerin antiinflamatuvar etkileri farelerde karagenin ile oluşturulan arka pençe ödemi ile incelenmiştir. 3-t2-(2-piridil)]etil-5-kloro-6-(3,5-diflorobenzoil)-2-benzoksazolinon (Bileşik 18) serideki en etkili bileşik olarak bulunmuştur (%80.01 p<0.01). Bazı bileşiklerin gastrointestinal ülserasyon aktiviteleri de incelenmiş ve çalışılan bileşiklerden sadece 2 tanesinin (Bileşik 1 ve 2) 100 mg/kg dozda kanama yapmadığı gözlenmiştir.V Sentezi yapılan bileşiklerin erime dereceleri, reaksiyon yüzde verimleri, kristallendirme çözücüleri, molekül formülleri ve elementel analiz sonuçlan R2Y^N-CHz-CHz-Ar Oi^A, vr o ;.. %% %v**.* ^ ""v BJJeşiK «*- 1&J? J* VSrfflfc fcJ* W>İr*. l *> ^MfMr \ ^X ;, *m*< *& ^$*fc^ *iGte$afc * ^v v^^4%b :%* *, ! % - %%" :. *f*l;x y «C»! * -'Vv'* H«^^i^x^il^^ :v ;v* \%*...;* ^Vv x\% V % - *. s <. * V.* s *** ^ \> **Jfe^^ v: *^N -.X X %^ ^« v * ^ %^ ". %x xs «.N ^.. ^ % ^^f- *^%*<'*''*ıî>%^. *»^.V; 21-H 4-Piridil 30.72 112-4 Karbon C:64.720:64.77 tetraklorür H:4.60H:4.59N:17.42N:17.58 Karbon 0:64.720:64.80 22-H 2-Piridil 33.28 98-100 tetraklorür H:4.60H:4.56N:17.42N:17.44 Aseton-su C:48.770:48.69 23-Br 4-Piridil 53.76 137-9 (3:1) H:3.15H:3.00N:13.13N: 13.36 Etil aset.- 0:48.770:48.81 24-Br 2-Piridil 56.45 127-9 n-heksan H:3.15H:3.04l llll (2:1) |N:13.13|N:13.38 Anahtar kelimeler: 2-Benzoksazolinon, oksazolo[4,5-b]piridin-2-on, açilleme, Michael katımı, analjezik-antiinflamatuvar etki

Abstract:
VII ABSTRACT In this study, twenty four 3-[2-(2-/4-pyridyl)]ethyI-(5-chloro)-6-(2,5-; 2,3-; 3,4-; 3,5-; 2,6-difluorobenzoyl)-2-benzoxazolinone and 3-[2-(2-/4-pyridyl)]ethyl-(6-bromo)-oxazolo[4,5- b]pyridin-2-one were synthesized and screened for their analgesic-antiinflammatory activities. Starting compounds having 6-(difluorobenzoyl)-2-benzoxazolinones structure were prepared by reacting 2-benzoxazolinone with aromatic carboxylic acids in the presence of polyphosphoric acid. Oxazolo[4,5-b]pyridine-2-one was synthesized by reacting 2-amino- 3-hydroxypyridine and 1,1'-carbonyldiimidazole. 6-Bromooxazolo[4,5-b]pyridin-2-one was also yielded by bromination of the oxazolo[4,5-b]pyridine-2-one. Target compounds were obtained by reacting these derivatives with 2-/4-vinylpyridine according to Michael Reaction. Melting points, percentage yields, crystallization solvent, molecular formula and elemental analyses of the synthesized compounds are given in the table below. The physical properties, Rf values on thin layer chromatography and the UV absorption properties of the compounds were determined. The structures of the compounds were proved by IR, 1H-NMR, 13C-NMR, mass spectroscopy and elemental analysis. Analgesic activity of the synthesized compounds were tested by modified Koster Test using Aspirin as reference. Analgesic activities of four compounds (Compound 1, 7, 23, 24) were found higher than that of Aspirin. Among these compounds, analgesic activity of 3- [2-(4-pyridyl)]ethyl-6-(2,5-difluorobenzoyl)-2-benzoxazolinone (Compound 1) (%86.40 p<0.01) was found higher than those of others. Antiinflammatory activity of the compounds was tested by carregeenan hind paw edema test. It was found that 3-[2-(2-pyridyl)]ethyl-5-chloro-6-(3,5-difluorobenzoyl)-2- benzoxazolinone (Compound 18) was the most potent compound in this series. Ulcerogenic activities of the some compounds were also studied and no gastrointestinal bleeding was observed at the 100 mg/kg dose level for only two compounds of the studied compounds (Compound 1 and 2).viii Melting points, percentage yields, crystallization solvent, molecular formula and elemental analyses of the synthesized compounds R2Y^N-Ofe-CHZ-Ar £>1r °A° R^O * % ^%-> ^.>.> %% % %N*' v^ x» %V^-N %v" * %^PWdlw8fr'^'>«\*'^ Co*npoü«d H? *t/8^ > Ar* l tâ* l «JVJ &&İ&İ ı ; * **.'" v *'; *V 0r'- «e *. \\v>**v > ^ »og^^a^B^ v.. C*%^%.-.'.'.** \ ^% "^K. ^."1 vx-i *N s "-^"."."%"' î: * -."N%% \^*.. % ". vN.^^ \\SV^"^* ^^ '"«.*^îfvv *« ^V» ^<«^':X'W 1-H 2,5- 4-Pyridyl 64.00 154-5 Ethanol- C:66.32C:66.32 Difluorowater H:3.71H:3.75(3:1) N:7.37N:7.30 Ethanol- C:66.32C:66.19 2-H 2,5- 2-Pyridyl 72.73 116-7 water H:3.71H:3.70Difluoro(3:1) N:7.37N:7.21 Ethylacet.- 0:66.32C:66.22 3-H 2,3- 4-Pyridyl 73.68 139-40 n-hexane H:3.71H:3.70Difluoro(2:1) N:7.37N:7.46 Ethylacet.- 0:66.320:66.24 4-H 2,3- 2-Pyridyl 64.73 107-8 n-hexane H:3.71H:3.71Difluoro(2:1) N:7.37N:7.54 Ethanol- 0:66.320:66.30 5-H 3,4- 4-Pyridyl 64.00 154-5 water H:3.71H:3.77Difluoro(3:1) N:7.37N:7.48 Ethanol- 0:66.320:66.27 6-H 3,4- 2-Pyridyl 65.26 134-5 water H:3.71H:3.81Difluoro(3:1) N:7.37N:7.21 Ethanol- C:66.320:66.22 7-H 3,5- 4-Pyridyl 72.63 170-2 water H:3.71H:3.77Difluoro(3:1) N:7.37N:7.30 Ethanol- 0:66.320:66.05 8-H 3,5- 2-Pyridyl 80.00 117-8 water 1-1:3.71H:2.68Difluoro(3:1) N:7.37N:7.27 Acetone- 0:66.320:66.67 9-H 2,6- 4-Pyridyl 81.57 130-2 water(3:1) H:3.71H:3.56DifluoroN:7.37N:7.40 Acetone- 0:66.320:66.18 10-H 2,6- 2-Pyridyl 81.57 166-8 water(3:1) H:3.71H:4.02DifluoroN:7.37N:7.48 Ethanol- 0:60.81C:60.94 11-Ol 2,5- 4-Pyridyl 63.70 132-4 water H:3.16H:3.55Difluoro(3:1) N:6.75N:6.73 Ethanol- 0:60.810:60.92 12-Ol 2,5- 2-Pyridyl 79.15 121-2 water H:3.16H:2.60Difluoro(3:1) N:6.75N:6.70 Dioxane- 0:60.810:60.71 13-Ol 2,3- 4-Pyridyl 39 104 water(1:1) H:3.16H:3.15l l Difluoro l| l || N:6.75 |N:7.52ix I IIIII Dioxane- l C:60.81j C:60.46 14-Cl 2,3- 2-Pyridyl 73.35 113-4 water(1:1) H:3.16 H:2.92DifluoroN:6.75N:6.92 Ethanol- C:60.810:60.64 15-Cl 3,4- 4-Pyridyl 46.33 138-40 water H:3.16H:3.20Difluoro(3:1) N:6.75N:6.80 Ethanol- C:60.81C:60.32 16-Cl 3,4- 2-Pyridyl 52.12 113-4 water H:3.16H:3.21Difluoro(3:1) N:6.75N:6.62 Ethanol- C:60.81C:61.10 17-Cl 3,5- 4-Pyridyl 57.23 135 water(3:1) H:3.16H:3.05DifluoroN:6.75N:6.81 Ethanol- C:60.81C:60.77 18-Cl 3,5- 2-Pyridyl 53.08 138 water(3:1) H:3.16H:3.31DifluoroN:6.75N:6.75 Ethanol- C:60.81C:60.83 19-Cl 2,6- 4-Pyridyl 42.95 153-4 water(3:1) H:3.16H:3.19DifluoroN:6.75N:6.83 Ethanol- C:60.81C:60.56 20-Cl 2,6- 2-Pyridyl 62.25 98-9 water(3:1) H:3.16H:3.07j l Difluoro |l | ll N:6.75| N:6.82 «VV-o XM Clfc-CHz-Ar t s i * " lAaölpsfe e«ıaj*<»»**t & Af o metâ ^ «4* l ?*»4ot: ^ * / ; UİI««% I * ^ CateötatedffeMft^ 21-H 4-Pyridyl 30.72 112-4 Carbon C:64.72C:64.77 tetra H:4.60H:4.59chloride N:17.42N:17.58 Carbon C:64.72C:64.80 22-H 2-Pyridyl 33.28 98-100 tetra H:4.60H:4.56chloride N:17.42N:17.44 Acetone- C:48.77C:48.69 23-Br 4-Pyridyl 53.76 137-9 water(3:1) H:3.15H:3.00N:13.13N:13.36 Ethyl C:48.77C:48.81 24-Br 2-Pyridyl 56.45 127-9 acetate.-n- H:3.15H:3.04 hexane N:13.13N:13.38l llll (2:1) ||Key vvords : 2-Benzoxazoiinone, oxazolo[4,5-b]pyridin-2-one, acylation, Michael addttion, analgesic-antiinflammatory activity