Pyrimido[5,4-b]quinolines. III. Synthesis of 10-alkyl-substituted 10-deazaalloxazines

A general method for the synthesis of 10-alkyl-substituted 10-deazaalloxazines (VIII) and the related chemistry are described. 4-Alkyl-substituted 3-aminoquinolines (IV) were reacted with benzoyl chloride and potassium cyanide in methylene chloride-water mixture to obtain Reissert compounds (V) which were hydrolyzed with a mixture of hydrobromic acid and acetic acid, and subsequently with 20% potassium hydroxide to give the corresponding 3-aminoquinaldic acids (VII). Cyclization with urea gave the 10-deazaalloxazines (VIII). Oxidation, hydroxylation and alkylation reactions of the 10-methyl derivatives (VIIIa,b) and of their quinaldic acid precursors are also reported.     

Pyrimido[5,4-b]quinolines. II. Reactions at the heterocyclic ring-carbon and nitrogen atoms

10-Chloro-7,8-dimethylpyrimido[5,4-b]quinolin-2,4(1H,3H)dione (I) was unreactive toward ammonia but it reacted with 2 molecules of n-butylamine, presumably via Dimroth-type ring-opening and closure, to give the N₃-butyl, N₁₀-butylamino derivative (IV). In similar reactions of 10-chloro-2,4-dimethoxy-7,8-dimethylpyrimido[5,4-b]quinoline (II) only the 4-meth-oxyl was displaced by either ammonia or n-butylamine. Alkyllithium reagents also displaced the 4-methoxyl as well as added to the 3,4 double bond of II to yield the corresponding gem-dialkyl substituted (C₄) derivatives; the C₁₀ chlorine remained unreactive. 2,4-Dimethoxy-7,8-di-methylpyrimido[5,4-b]quinoline-10-one (III) could be alkylated only in the form of the thallium salt. Treatment of the benzyl derivative of III with methylmagnesium bromide led only to the displacement of the 4-methoxyl by a methyl group.     

Novel synthesis of isoxazolo[5,4-b]quinolines

Isoxazolo[5,4-b]quinolines have been prepared by reacting 3-acyl or aroyl-2-chloro-6-alkoxy or 6,7-dialkoxyquinolines with hydroxylamine. The method is of general applicability for obtaining this class of compounds and involves the use of easily available starting materials.     

Synthesis of 2H-pyrano[2,3-b]quinolines. Part I

3,4-Dihydro-2H-pyrano[2,3-b]quinolines 5a-e and 2H-pyrano[2,3- b ]quinolines 10a-c were synthesised starting from the appropriate ω-chloro-n-valeroylanilides 2a-e . Compounds 10a-c were transformed to analogs of the novel antihypertensive agent Cromakalim ( 1 ).     

Synthesis of 10-deazariboflavin and related 2,4-Dioxopyrimido[4,5-b]quinolines

Condensation of substituted anthranilaldehydes with barbituric acid results in the formation of 2,4-dioxopyrimido[4,5-b]quinolines. Using this general synthetic approach, 7,8-dimethyl-2,4-dioxo-10-ribityl-2,3,4,10-tetrahydropyrimido[4,5-b]quinoline (10-deazariboflavin) was prepared by the condensation of barbituric acid with 4,5-dimethyl-N-ribitylanthranilaldehyde. The latter was obtained in situ by the treatment of 1-[4,5-dimethyl-N-(ribityl)anthraniloyl]-2-(p-toluenesulfonyl)hydrazine, prepared from 4,5-dimethylanthranilic acid with anhydrous sodium carbonate.     

Synthesis and Antioxidant,Anti-Inflammatory,and Analgesic Activity of Novel Polycyclic Pyrimido[4,5-b]quinolines

The behavior of the 2-methylthio-pyrimido[4,5-b]quinolin-4-one towards differently substituted amines is reported. Also, the reactivity of 3-aminothiazolo[3′,2′ :1,2]-pyrimido[4,5-b]quinoline-2-carbonitrile towards formic acid, urea, thiourea, formamide, and carbon disulfide is discussed. Some of the synthesized derivatives possess biological activities as anti-inflammatory and analgesic agents. Some of these selective biologically active compounds were screened for antioxidant properties.     

Synthesis of 3-oxoisothiazolo[5,4-b] pyridines

3-Oxoisothiazolo[5,4-b]pyridines were synthesized for the first time by the reaction of 3-cyanopyridine-2-thiones or bis(3-cyanopyridyl) disulfides with concentrated sulfuric acid. It is demonstrated that 3-carbamoylpyridine-2-thiones are formed as intermediates. The 3-oxoisothiazolopyridines were converted to 3-bromoisothiazolopyridines and pyridine-2-thiones. The bromination of pyridine-2-thione was studied.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 508–512, April, 1982.     

Synthesis of 9-chloropyrazolo[4,3-b]quinolines

A series of 1-methyl-4-arylaminopyrazole-3- and -5-carboxylic acids were synthesized by the reaction of 1-methyl-4-halopyrazole-3- and -5-carboxylic acids with aromatic amines in the presence of a copper catalyst; treatment with phosphorus oxychloride converted them to the corresponding 9-chlorosubstituted 1-methyl-1H- and 2-methyl-2H-pyrazolo[4,3-b]quinolines.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1123–1125, August, 1984.     

Synthesis of 4-hydrazino-5H-pyrimido[5,4-b]indole and related compounds

This paper describes the synthesis of two 4-amino-5H-pyrimido[5,4-b]indoles 5 , 4-hydrazino-5H-pyrimido[5,4-b]indole 6 , two 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 , and tetrazolo[4,5-c]pyrimido[5,4-b]indole 10 . Starting with ethyl 3-aminoindole-2-carboxylate 1 , 5H-pyrimido[5,4-b]indol-4-one 2 was obtained (80%) by condensing with formamide. Reactions of 2 with phosphorus oxychloride and phosphorus pentasulfide gave respectively, 4-chloro-5H-pyrimido[5,4-b]indole 3 (70%) and 5H-pyrimido[5,4-b]indole-4-thione 4 (80%). Compound 3 reacted with amines (morpholine, piperidine) to give the respective 4-amino-5H-pyrimido[5,4-b]-indoles 5 , and compound 4 reacted with hydrazine to give 4-hydrazino-5H-pyrimido[5,4-b]indole 6 (80%). Two hydrazones of 6 (benzylidene, isopropylidene) 7 were also prepared (90%). Compound 6 reacted with formic and acetic acids to give (65–75%) the respective 1,2,4-triazolo[4,3-c]pyrimido[5,4-b]indoles 8 and with nitrous acid to give tetrazolo[4,5-c]pyrimido[5,4-b]indole 9 (85%). All the new compounds 2 to 9 were characterized by elemental analysis and spectral data (ir, nmr).     

Synthesis of substituted pyrrolo[3,2-f]quinolines

Reactions of 2,3,6-trimethyl- and 2,6-dimethyl-6-methoxy-5-aminoindoles with 1,3-dicarbonyl compounds represent a convenient route for obtaining substituted pyrrolo[3,2-f]quinolines, even though the presence of a methoxy group on the benzene ring sometimes lowers the reactivity of the amine, thus increasing the required reaction time and reducing the yield.M. E. Evsev'ev Mordovian State Pedagogical Institute, Saransk 430007. M. V. Lomonosov Moscow State University, Moscow 119899. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1080–1087, August, 1997.     

Synthesis of thiazolo[5,4-b]pyridine-2-carboxamides

A convenient procedure was developed for preparation of thiazolo[5,4-b]pyridine-2-carboxamides by oxidation of monothiooxamides synthesized from 3-aminopyridine.     

Synthesis of 2,10,11-Trisubstituted Indolo[3,2-b]quinolines

A new method has been developed for the synthesis of derivatives of indolo[3,2-b]quinolines-11 based on N-oxidization of 2-nitro-10-substituted indolo[3,2-b]quinolines with subsequent conversion of the mixtures obtained into 2-nitro-11-substituted indolo[3,2-b]quinolinones-11. A series of 2-nitro-11-substituted indolo[3,2-b]quinolines was prepared.     

Synthesis of condensed tricyclic pyrazolo[3,4-b]thieno[2,3-d]pyridine and related isostere derivatives

In this paper we report the synthesis of an isosteric series of new heterotricyclic derivatives, corresponding to pyrazolo[3,4-b]thieno[2,3-d]pyridine ( 1 ), pyrazolo[3,4-b]furano[2,3-d]pyridine ( 2 ) and pyrazolo[3,4-b]pyrrolo[2,3-d]pyridine ( 3 ). These functionalized compounds were obtained, in high overall yield, by an ‘one-pot’ reaction of the chloroester intermediate 4 , possessing the pyrazolo[3,4-b]pyridine system, with an adequate α-hetero-acetyl ester derivative, in SNAr/Dieckman cyclization type consecutive reactions.     

Synthesis of 2-substituted 3-oxoisothiazolo[5,4-b]pyridines

Starting with 2-chloro-3-pyridinecarboxylic acid 1 , three different routes to prepare 3-oxoisothiazolo-[4,5-b]pyridines 10 were studied.     

Synthesis of substituted 1H-pyrrolo[3,2-c]quinolines

1H-2-Phenylpyrrolo[3,2-c]quinoline (1a) is made by thermal cyclization of quinol-4-yl hydrazone. Subsequent substitution of the C-3 hydrogen atom of the pyrrole ring of 1a with chlorine and a formyl group is easily achieved by reacting 1a with trichloroacetyl chloride and phosphorus oxychloride in DMF, respectively.     

Synthesis and biological activities of substituted dihydrobenzo[h]-pyrimido[4,5-b]quinolines as tetracyclic 5-deaza nonclassical folates

Novel tetracyclic compounds 1–4 have been synthesized via a regiospecific cyclocondensation reaction between substituted 6-aminopyrimidines 5– 7 and chlorovinyl aldehydes 13 and 14 . The linear structures of these compounds were established by ¹H nmr and ¹³C nmr spectral data and also by synthesis of the compounds via an unambiguous route. The growth of Manca human lymphoma cells was inhibited 50% by 1 and 4 at 4.5 × 10^?6 M and 1.2 × 10^?6 M respectively. These compounds also inhibited human dihydrofolate reductase (DHFR)by 50% at 4.4 × 10^?6 M and 1.4 × 10^?6 irrespectively and L. casei DHFR at 1.9 × 10^?5 M and 1.1 × 10^?5 M respectively. Compound 16 , a positional isomer of 1 , was the most potent of the compounds studied, it inhibited the growth of Manca human lymphoma cells by 50% at 9 × 10^?8 M. The IC₅₀ values of 16 for the inhibition of human DHFR and L. casei DHFR were 8 × 10^?8 M and 1.9 × 10^?5 M respectively.     

Synthesis of substituted imidazo[5,1-b]benzimidazoles

Some chemical characteristics and reactions of 3-phenyl-4-methylimidazo[5,1-b]benzimidazole (I) have been examined. It has been shown that I undergoes electrophilic substitution (hydroxymethylation, acetylation, nitrosation, and the Mannich and Vilsmeier reactions), the substituent entering at the 1-position. Cyanoethylation of I gives 1-cyanoethyl-3-phenyl-4-methylimidazo[5,1-b]benzimidazole.For part III, see [3].     

Synthesis of substituted thieno[2,3-b]pyrroles

A relatively simple route for synthesis of substituted thieno[2,3-b]pyrroles from readily available starting material and data for structural assignment are reported.     

Nicotinic acid-supported cobalt ferrite-catalyzed one-pot synthesis of substituted chromeno[3,4-b]quinolines

One-pot synthesis of substituted chromeno[3,4-b]quinoline derivatives was developed by three-component reaction of aldehydes, dimedone or 1,3-cyclohexadione, and 4-aminocoumarin in the presence of nicotinic acid-supported cobalt ferrite [CoFe₂O₄@SiO₂@Si(CH₂)₃Cl@NA] as a novel magnetic catalyst in chloroform at reflux conditions. Nicotinic acid-supported cobalt ferrite was characterized via Fourier transform infrared spectroscopy, X-ray diffraction, thermal gravimetric analysis, scanning electron microscopy, high-resolution transmission electron microscopy, energy-dispersive X-ray spectroscopy, and vibrating sample magnetometry. Moreover, the catalyst could be easily recovered by magnetic separation and recycled up to five times without significant loss of its catalytic activity. The products formed in excellent yields over appropriate reaction times under environmentally friendly conditions. High efficiency and easy isolation of the catalyst from products by simple magnetic attraction are some of the considerable advantages of this procedure.