Heterocyclisierungen unter Verwendung cyclischer Hydrazinium- und Hydrazoniumdithiokohlensäurediester-Salze zu zwei- und dreikernigen S,N-Heterocyclen
Ziel dieser Arbeit war es, ausgehend von cyclischen Dithiocarbazidsäureestern vom N-Boc geschützten 3-Amino-2-thioxo-2,3-dihydrothiazol-Typ, über Kondensation mit CH- und NH-aciden Verbindungen an die durch Methylierung des Thioxo-Schwefels aktivierte Position 2 und anschließenden Ringschluss über d...
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Format: | Doctoral Thesis |
Language: | German |
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Philipps-Universität Marburg
2006
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Online Access: | PDF Full Text |
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The intention of this thesis was the synthesis of novel S,N-heterobi- and –tricycles starting from cyclic dithiocarbacic acid esters like N-boc protected 3-amino-2-thioxo-2,3-dihydrothiazoles. After activation of the C-2 carbon by methylating the thioxo-sulfur with methyl iodide the so created electrophilic agent was condensed with different C- and N-nucleophiles followed by cyclisation with participation of the exocyclic nitrogen. The pharmacological properties were tested. Starting with 7 novel derivatives of N-(2-thioxo-2,3-dihydrothiazole-3-yl)-carbamidacid-tert-butylesters these have been developed to novel lead structures for biological evaluation. The procedure was as follows: After activating position 2 of the N-(2-thioxo-2,3-dihydrothiazole-3-yl)-carbamidacid-tert-butylesters with methyliodide, simple or double activated, phenylogous and vinylogous C-nucleophiles could be condensed with C-2 resulting in keten-N,S-acetales. After this step, cyclisation via reaction between the N-amino function and keto-, ester- or nitrilo-groups of the C-nucleophile could be performed in a simple way by acidic katalysis with p-toluenesulfonic acid under loss of the N-protection group in acceptable yield. Using 4-chloracetic acid ester as a CH-acidic compound, two novel thiazolo[3,2-b]pyridazine-derivatives were obtained. Creation of this bicycle type has not been described in literature so far. Treatment of the condensed products with vinylogous C-nucleophiles under cyclisating conditions did not result in the formation of the expected thiazolo[3,2-b][1,2]diazepines but yielded pyrazolo[5,1-b]thiazoles under splitting of malonodinitrile. Hydrazones can be obtained by refluxing the N-boc protected 3-amino-2-thioxo-2,3-dihydrothiazoles with aldehydes in the presenceof a catalytic amount of p-toluenesulfonic acid. Hydrazoniumdithiocarbonic acid diester iodides with an 3,4,5-trimethoxyphenyl residue leads after condensing with vinylogous C,H-acid compounds to pyrazolo[5,1-b]thiazole derivatives resulting from oxidative C,C-bonding with oxygen as oxidant. The same reaction with simple, double activated C-nucleophiles leads to 1,3-rearrangements under N,N-bond cleavage. Coupling of the hydraziniumdithiocarbonic acid diester salts has been carried out with some hydrazides and thiosemicarbazide as N-nucleophiles. Cyanamide was able to condense with electrophile C-2 position of several activated N-boc-3-amino-2-thioxo-2,3-dihydrothiazoles even after deprotonating of cyanamide with Na-methylate in a first step. The so obtained 2-cyanimino derivatives could be cyclisised to 2-aminothiazolo[3,2-b][1,2,4]triazoles in the same way as described for creating of pyrazolo[5,1-b]thiazoles. A melting reaction with urea and the novel 6-amino-3-tert-butylpyrazolo[5,1-b]thiazol-7-yl)phenylmethanone leads to a novel S,N-heterotricycle which was unknown before. Typical side reactions and side products of the methylthio activation of cyclic dithiocarbazidacidesters have been discovered. Those are N-methylation of the exocyclic nitrogen and the regression of the 2-thioxo residue from the hydrazinium dithiocarbonic diester salts by demethylation of the methylthio group under treatment with triethylamine. The activation of position 2 gets lost. Another important side reaction is the formation of stable betain structures of the used hydrazine- respective ureide substructure by deprotonating the exocyclic nitrogen. Positive in vitro results of pharmacological activity against some protozoes, especially Plasmodium falciparum and Leishmania donovani have been found. The range of a few test compounds is in the lower µM range (best fit: 1.2 µM P. falciparum K1 strain) by low toxicity. Some of the novel compounds also show a good antimicrobial and antifungical activities.