Thomas Kappe

Benzimidazole condensed ring system. IX. Potential antineoplastics. New synthesis of some pyrido[1,2-α]benzimidazoles and related derivative

Summary Some pyrido[1,2-a]benzimidazoles were prepared in order to investigate their in vitro antineoplastic and anti-HIV activities. Two compounds (9b, NSC 658526 and 15, NSC 664715) showed a variable degree of antineoplastic activity against some of the cell lines tested. Compound 9a (NSC 649900) exhibited a good in vitro antineoplastic activity with subpanel disease selectivity, particularly against most of the cell lines of leukemia and some cell lines from colon, melanoma and renal cancer panels.

Synthesen von Heterocyclen, 95. Mitt.: Chinolizine und Indolizine I: Eine Synthese von 2-Hydroxychinolizinonen-(4)

An der Methylgruppe substituierte α-Picoline, insbesondere 2-Pyridylessigsaurederivate, reagieren mit unsubstit. oder monosubstit. Malonsaure-bis-trichlorphenylestern, Malonsaurechloriden oder Kohlensuboxid zu 2-Hydroxychinolizinonen-(4), die katalytisch zu 2-Hydroxy-6,7,8,9-tetrahydrochinolizinonen-(4) hydriert werden konnen.

Halogenation reactions in position 3 of quinoline-2,4-dione systems by electrophilic substitution and halogen exchange

Summary3-Substituted 4-hydroxy-2(1H)-quinolones3,5,7 are halogenated with bromine or sulfuryl chloride to yield the quinolinediones9 or10. Reaction of3,5,7 with chloroform gives the dichloromethyl quinolinediones11. Halogen exchange leads from the chloro quinolinediones10 to fluoro quinolinedones12 and to azido quinolinediones13. Similarly the dichloro quinolinedione10 an reacts to the difluoro quinolinedione14, which is reduced to the 3-fluoro-4-hydroxyquinolone16 and reacts again with sulfuryl chloride to give the mixed 3-chloro-3-fluoroquinolinedione15.Zusammenfassung3-Substituierte 4-Hydroxy-2-chinolone3,5,7 reagieren mit elementarem Brom oder Sulfurylchlorid zu den 3-Halogen-chinolindionen9 oder10. Mit Chloroform reagieren die Hydroxychinolone3,5,7 zu den 3-Dichlormethylchinolondionen11. Halogenaustausch an10 führt zu den 3-Fluorchinolindionen12 und zu 3-Azidochinolindionen13. Ähnlich reagiert 3,3-Dichlorochinolindion10 an zu 3,3-Fluorchinolindion14, das zum 3-Fluor-4-hydroxychinolon16 reduziert werden kann und in weiterer Folge mit Sulfurylchlorid zum gemischten 3-Chlor-3-fluor-chinolindion15 reagiert.

Malonates in Cyclocondensation Reactions

The use of malonates such as diethyl malonates 9, (chlorocarbonyl)ketenes 15 and bis(2,4,6-trichlorophenyl) malonates 18 as reagents for cyclocondensation with 1,3-dinucleophiles to give six-membered heterocycles is described. Further attempts to use malonates such as bis(trimethylsilyl) malonates 19 and bis(carbamimidoyl) malonates 29 as new cyclocondensation agents are described .

Synthese von Benzofuranen durch Cyclodehydrierung von Phenylmalonylheterocyclen

Phenylmalonyl heterocyclic compounds such as the quinolones1a–c or3, benzoquinolizinones6a, b and the phenalenones8a, b can be converted to benzofuranes (2a–c, 7a, b and9a, b) by cyclodehydrogenation with Pd/C in boiling diphenyl ether. 2-Phenylchinchonic acid (10) reacts under the same conditions to the dimeric benzofuroquinoline12: the decarboxylated quinoline11 however gives the monomer13.

Benzimidazole condensed ring systems. XI. Synthesis of some substituted cycloalkyl pyrido[1,2-a]benzimidazoles with anticipated antineoplastic activity

As part of a research project on the synthesis of a number of pyrido[1,2-a]benzimidazole derivatives with possible antineoplastic activity, and as a result of the interesting antineoplastic activity recorded for one such compound (NSC 649900), some new cycloalkylpyrido[1,2-a]benzimidazoles were prepared and evaluated for such activity. Compound (7c, NSC 682011) exhibited a good in vitro antineoplastic activity especially against most of the leukaemia cell lines. This compound has been selected by the NCI for further testing in a new in vivo anticancer hollow fibre assay.

Eine einfache Synthese von 11H-Indolo[3,2-c]chinolin-6-onen

Abstract11H-Indolo[3,2-c]quinolin-6-ones, which are containing the γ-carboline ring system, can be easily synthesized from 4-azido-3-phenyl-2(1H)-quinolones, which are obtained in a two step reaction from 4-hydroxy-3-phenyl-2(1H)-quinolones. Cyclization of the azides can be realized by irradiation or thermal reaction.

Potential antineoplastics. Synthesis and cytotoxicity of certain 4-chloro-3-(2-chloroethyl)-2-methylquinolines and related derivatives

Summary In an extension of our work in the field of nitrogen heterocycles with potential cytotoxic activity, the synthesis of some substituted 4-chloro-3-(2-chloroethyl)-2-methylquinolines ( 10–13 ) from their parent 3-[1-(phenylamino)ethylioene]-dihybro-2(3H)-furanomes ( 6–9 ) is reported. The conversion of 10–13 to some thieno-, furo- and pyrrolo [3,2- c ]quinotines ( 14–27, 31–33 ) is also described. The compounds were evaluated for their toxicty in brine shrimp ( Artemia salina ), and their cytotoxicity against some clinically isolated human tumor in vitro. Several compounds exhibined good toxic activity against Artemia salina , which the furnace ( 6 , NSC 680781) displayed good antineoplastic activity and high selectivity against some cell lines from leukemia, lung cancer, colon and melanoma panels. This compound has been selected by the NCI for further testing in a new in vivo anticancer hollow fiber assay.

Isatoic Anhydrides and Their Uses in Heterocyclic Synthesis

Publisher Summary This chapter focuses the use of Isatoic Anhydrides (IA) as a starting material for heterocyclic compounds. Other fields of application are not included: for example, reactions leading to open-chain anthranilic acid derivatives, use in the manufacture of agricultural chemicals, dyes, pigments, cross-linking agents and chain stoppers in resins and other uses in polymer and rubber chemistry, use as a modifier in protein and carbohydrate substrates (wool, paper, textiles), use as a petroleum additive (fuel and lubricants), use as a blowing agent for polymer foams, a flameproofing agent, and a corrosion inhibitor, use in metal finishing, for foods and beverages, soaps and detergents, perfumes, cosmetics, and use in pharmaceuticals and medicines. The chapter discusses the synthesis of IA and related compounds that includes three types of reactions. IA enters into condensation and substitution reactions with ease. The hetero ring is highly susceptible to cleavage and can be N-substituted with or without ring opening. The chapter discusses the formation of anthranilic acid amides and hydrazides and reactions to heterocycles.

REACTIONS OF 3-ACYL-4-HYDROXY-2(1H)-QUINOLONES WITH NITROGEN BASES

3-Acyl-4-hydroxy-2-quinolones 1 react with amines to yield 3-aminomethylene quinolinediones 2. With hydroxylamine the corresponding oximes 3 are obtained, which cyclize on heating via a thermal Beckmann rearrangement to oxazolo[5,4-c]quinolones 4. The oxazoles can be ringopened in the presence of acids to give 3-acylamino-4-hydroxyquinolones 5. The hydrazones 6, obtained from 3-acyl-4-hydroxy-2-quinolones 1 and hydrazines, cyclize either to pyrazolo[4,3-c]quinolones 7 or give mixtures of 7 and the dimeric azino-diethylidenequinolones 8. INTRODUCTION 4-Hydroxy-2-quinolines, their oxygen derivatives and the monocyclic debenzo derivatives having aliphatic acyl groups in position 3 have found great interest in the last years because of their biological properties (4). Reaction of the keto group of this class of compounds with nitrogen bases such as amines, hydroxylamines and hydrazines offers an entry to nitrogen containing carbonyl derivatives. Some of them have caused great interest because of their biological (5) or technical properties (6). RESULTS AND DISCUSSION We have shown recently, that 3-acyl-4-hydroxyquinolones of type 1 could be aminated in an equilibrium process at the keto moiety of the 3-acyl substituent by reaction with aqueous ammonia or amines with acetic acid as catalyst (7). The isomeric 4-amino-3-acylquinolones could be excluded by synthesis of the corresponding compounds via an independent pathway. Aliphatic and aromatic amines could be shown to react with 1a-f in ethanol as solvent also by using dimethylaminopyridine as basic catalyst to obtain the 4-hydroxy-3-iminoethyl-2-quinolones 2a-l in good yields. H NMR spectroscopic studies have shown that compounds of this type deriving from 3-carbaldehydes (instead of 3-acyl groups in 2) exist mainly in the tautomeric enaminoketone form (8) by using the aldehydic/olefinic proton as probe. The lack of this proton in 2 does not allow a similar assignment, and the carbonyl frequencies of the 4-oxo group in infrared spectra, which are usually a good hint for discussion of tautomers (9), are not helpful because of hydrogen bondings between the 4-hydroxy/4-oxo group with the imino/amino group, resp. Investigations by deuterium isotope effects on C NMR chemical