Synthetic studies of the antitumor antibiotic streptonigrin. I. Synthesis of the A-B ring portion of streptonigrin

Bromination of 6-methoxy-5,8-quinolinedione gave the 7-bromo derivative in quantitative yield. Treatment of the bromo compound with sodium azide followed by hydrogenation yielded 7-amino-6-methoxy-5,8-quinolinedione, the A-B ring portion of the antitumor antibiotic strep tonigrin. The corresponding 2-methyl homolog was prepared in a similar manner from 6-methoxy-2-methyl-8-nitroquinoline, which in turn, was obtained by a Skraup synthesis from 2-nitro-anisidine and crotonaldehyde.     

Heterocyclic quinones. XIV. Pharmacomodulation in a series of 11H-indolo[3,2-c]quinolinediones: synthesis and cytotoxicity of 8-substituted 11H-indolo[3,2-c]quinoline-7,10-diones

4-Chloro-8-methoxy-11H-indolo[3,2-c]quinoline could be obtained from 8-chloro-2,3-dihydro-1H-quinolin-4-one and 4-methoxyphenylhydrazine by applying Fischer's indole synthesis. Its nitration led to the 7-nitro derivative which was reduced to 7-amino-4-chloro-8-methoxy-11H-indolo[3,2-c]quinoline when Raney nickel was employed as a catalyst and to 7-amino-8-methoxy-11H-indolo[3,2-c]quinoline when palladium charcoal was used. Oxidation of the amines by potassium nitrosodisulfonate produced the corresponding 11H-indolo[3,2-c]quinoline-7,10-diones. Displacement of the methoxy group by (N,N-diethylamino)ethylamine or by N-methylpiperazine afforded the 8-aminoquinones. The quinones unsubstituted at the 4-position were more cytotoxic than the previously described 2-methoxy-11H-indolo[3,2-c]quinoline-1,4-diones.     

New 2-methyl-6-alkylamino-5,8-quinolinequinones and 1,2,3,4-tetrahydro derivatives

The syntheses of six new 2-methyl-6-alkylamino-5,8-quinolinequinones, three 1,2,3,4-tetrahydro-5,8-quinolinequinones, and 7-(2′,6′,10′-trimethylundecyl)-6-hydroxy-5,8-quinolinequinone are described as potential antimetabolites of coenzyme Q and as potential antimalarial agents. The six 2-methyl-6-alkylamino-5,8-quinolinequinones were prepared by a six-step synthesis. 2-Methyl-6-methoxy-8-nitroquinoline was prepared from 2-nitro-4-methoxyaniline and crotonaldehyde by a Skraup reaction. Raney nickel reduction gave 2-methyl-6-metboxy-8-aminoquinoline, which upon diazotization followed by dithionite reduction yielded 2-methyl-6-methoxy-5,8-diaminoquinoline. Subsequent dichromate oxidation gave 2-methyl-6-methoxy-5,8-quinolinequinone, which yielded the corresponding 2-methyl-6-alkylamino-5,8-quinolinequinone in good yield when treated with the appropriate alkylamine. The telrahydro-5,8-quinolinequinones were prepared by catalytic hydrogenation of the appropriate 5,8-quinolinequinones at elevated H₂ pressure followed by air oxidation of the reduction product. 7-(2′,6′,10′-Trimethylundecyl)-6-hydroxy-5,8-quinolinequinone was synthesized by radical alkylation of 6-hydroxy-5,8-quinolinequinone by thermal decomposition of di-3,7,11-trimethyldodecanoyl peroxide, which was prepared by a multistep procedure from farnesol. Of the five new 2-methyl-6-alkylamino-5,8-quinoline-quinones tested against P. berghei in mice (blood schizonticidal test), only 2-methyl-6-cycloheptylamino-5,8-quinolinequinone was active (T-C = 6.1 at 320 mg./kg.). Both 7-(2′,6′,10′-trimelhytundecyl)-6-hydroxy-5,8-quinolinequinone and the tetrahydro derivatives were inactive in this same test system.     

Streptonigrin and related compounds III. Synthesis and microbiological activity of destrioxyphenylstreptonigrin and analogues

Synthesis of three tricyclic analogues of streptonigrin, based on the 2-(2′-pyridyl)quinoline-5,8-dione system and with the characteristic substitution pattern of rings A and C of streptonigrin is described. The C-ring precursor, in the form of a substituted 2-acetylpyridine was condensed with either 3-hydroxy-5-methoxy-2-nitrobenzaldehyde or 3-hydroxy-4-methoxy-2-nitrobenzaldehyde, followed by reductive cyclization and oxidation to the corresponding quinones 12 and 29 . The 7-amino substitution was introduced in 12 via bromination and azidation. The 6-amino substitution was introduced through direct reaction of 29 with sodium azide. Destrioxyphenylstreptonigrin 2 was twice as active and the 6-amino-7-inethoxy analogue 4 was as active as streptonigrin in a microbiological assay. A 4′-bromo analogue of 2 was 60% as active as streptonigrin.     

Streptonigrin and related compounds IV. Precursors for the a-ring

The synthesis of streptonigrin or its tricyclic (ABC) analogues by the Friedlander condensation requires a 2-nitrobenzaldehyde with all the necessary functionalities. A number of alternative syntheses are examined. It is shown that oxidation of 8-amino-5,6-dimethoxy-2,2-pyridylquinoline leads to 8-amino-2,2-pyridylqunoline-5,6-dione instead of 6-methoxy-2,2-pyridylquinoline-5,8-dione. The synthesis of two useful precursors: 4-bromo-3-hydroxy-5,6-dimethoxy-2-nitrobenzaldehyde and 4-bromo-3-hydroxy-5-methoxy-2-nitrobenzaldehyde is described.     

5,8-isoquinolinediones. II. Chemical and electrochemical behavior of the 5,8-isoquinolinedione system

We have devised two general synthetic schemes to 5,8-isoquinolinediones and have investigated the chemical and electrochemical behavior of these compounds. The 1,4-addition reactions of these quinones with amines was shown to occur at the 7-position and a number of 7-amino-5,8-isoquinolinediones. were synthesized. The 1,4-addition of hydrogen bromide was also studied. The ethylenic double bond of the 5,8-quinone system underwent Diels-Alder additions to yield the oxidized forms of the adducts. The nucleophilic displacement of the methoxy group in 7-methoxy-5,8-isoquinoline was accomplished with both potassium hydroxide and morpholine. A Polarographic study of the half-wave potentials of substituted 5,8-isoquinolinediones showed a linear correlation between the change in the half-wave potential of the quinone system (ΔE° 1/2) resulting from the introduction of different substituents, and the substituent constants (σ_p-x).     

Polycyclic pyridazines. II [3]. Synthesis of pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azine derivatives from dimethyl pyrazolo[3,4-d]pyrid-azine-5,6-dicarboxylates as the key intermediates

The synthesis of the novel pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine ring system and some of its derivatives has been accomplished such as 4-amino-1-phenyl-5,8-dioxo-, 4-amino-5,8-dioxo-, 1-phenyl-5,8-dioxo-, 5,8-dioxo-, 5,8-dichloro-1-phenyl-, 5-ethoxy-1-phenyl- and 8-ethoxy-1-phenylpyrazolo[4′,3′:5,6]pyrido[2,3-d]pyrid-azines.     

Unequivocal syntheses of 6-methyl- and 6-phenylisoxanthopterin

Although 6-methyl- ( 1 ) and 6-phenylisoxanthopterin ( 2 ) have previously been synthesized, the requirement of high purity necessary for immunological testing has necessitated our development of the first reported synthesis of these compounds by unequivocal methods. In the process of so doing four new pyrazines, ethyl 3-amino-5-chloro-6-methyl-2-pyrazinecarboxylate ( 11 ), N,N-dimethyl-N'-(6-chloro-3-cyano-5-phenylpyrazin-2-yl)methanimidamide ( 16 ), 2-amino-3-ethoxycarbonyl-5-phenylpyrazine 1-oxide ( 19 ), and ethyl 3-amino-5-chloro-6-phenyl-2-pyrazinecarboxylate ( 20 ) were synthesized. Four new pteridines, 7-methoxy-6-methyl-2,4-pteridinediamine ( 7 ), 7-methoxy-6-phenyl-2,4-pteridinediamine ( 17 ), 2-amino-7-ethoxy-6-methyl-4(3H)-pteridinone ( 12 ), and 2-amino-7-ethoxy-6-phenyl-4(3H)-pteridinone ( 21 ) have also been synthesized enroute to these isoxanthopterins.     

Streptonigrin and lavendamycin partial structures. Preparation of 7-amino-2-(2′-pyridyl)quinoline-5,8-quinone-6′-carboxylic acid: A probe for the minimum,potent pharmacophore of the naturally occurring antitumor-antibiotics

The preparation of 7-amino-2-(2′-pyridyl)quinoline-5,8-quinone-6′-carboxylic acid (4) constituting a potential minimum, potent pharmacophore of streptonigrin (1) and lavendamycin (2) , two structurally-related naturally-occurring antitumor-antibiotic, is detailed. In contrast to observations associated with streptonigrin and lavendamycin in which the C-6′ acid potentiates the antitumor, antimicrobial, and cytotoxic activity of the naturally-occurring, substituted 7-aminoquinoline-5,8-quinone AB ring systems, the C-6′ carboxylic acid of 4 diminishes the observed antimicrobial and cytotoxic properties of 7-amino-2-(2′-pyridyl)quinoline-5,8-quinone.     

Preparation of 7-alkylamino-2-methylquinoline-5,8-diones

Several novel 7-alkylamino-2-methylquinoline-5,8-diones (2) were synthesized from 2,5-dimethoxyaniline in five steps via the Skraup reaction followed by demethylations, oxidative bromination, amination, and debromination. We have achieved an unusual hydrobromic acid catalyzed debromination reactions of several 6-bromo-7-alkylamino-2-methylquinoline-5,8-diones, giving 7-alkylamino-2-methylquinoline-5,8-diones in good yields.     

Synthesis of polycyclic pyridazinediones as chemiluminescent compounds

Reactions of 1,3-disubstituted 5-aminopyrazole-4-carbonitrile derivatives 3a-o with dimethyl acetylenedicarboxylate in the presence of potassium carbonate in dimethyl sulfoxide gave the corresponding dimethyl 1,3-disubstituted pyrazolo[3,4-b]pyridine-5,6-dicarboxylates 4a-o which were allowed to react with excess hydrazine hydrate under ethanol refluxing conditions followed by heating at 250-300° to give 1,3-disubstituted 4-amino-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 7a-s in good yields. Similarly, 1,3-disubstituted 4-hydroxy-1H-pyrazolo[4′3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-diones 10a-c were obtained from alkyl 1,3-disubstituted 5-aminopyrazole-4-carboxylates 8a-c . These tricyclic pyridazine derivatives were alternatively synthesized from 4-hydroxypyrrolo[3,4-e]pyrazolo[3,4-b]pyridine-5,7-diones 13a-c prepared by reactions of 5-aminopyrazoles (8e-g) with methyl 1-methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carboxylate (11a) followed by the Gould/Jacobs reaction. 1-Methyl-4-methylthio-2,5-dioxo-1H-pyrrole-3-carbonitrile smoothly reacted with 2-aminobenzimidazoles to give the corresponding 5-amino-3-methyl-1H-pyrrolo[3′4′:4,5]pyrimido[1,2-a]benzimidazole-1,3(2H)-diones 16a-e , which were readily converted to the desired 12-aminopyridazino[4′,5′:4,5]pyrimido-[1,2-a]benzimidazole-1,4(2H,3H)-diones 17a-e in good yields. Other pyridazinopyrimidine derivatives were also obtained by the reaction of the corresponding 2-aminoheterocycles with the maleimide in good yields. Substituted anilines reacted 11b in refluxing methanol to give the corresponding methyl 4-phenylamino-1-methyl-2,5-dioxo-1H-pyrrole-3-carboxylates 25a-e which were converted in good yields to 2-methylpyrrolo[3,4-b]quinoline derivatives 26a-e by heating in diphenyl ether. Reaction of 26a-c with hydrazine hydrate gave 10-hydroxypyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 27a-e in good yields. The desired 10-aminopyridazino[4,5-b]pyridazine-1,4(2H,3H)-diones 30a-e were obtained in good yields by the chlorination of 4a-e with phosphorus oxychloride followed by aminolysis with 28% ammonium hydroxide. Some pyridazino[4,5-a][2.2.3]cyclazine-1,4(2H,3H)-diones 37a,b as luminescent compounds were synthesized via several steps from indolizine derivatives. The key intermediates, dimethyl 6-dimethylamino[2.2.3]cyclazine-1,2-dicarboxylates 34, 36 , were synthesized by the [8 + 2] cycloaddition reaction of the corresponding 7-dimethylaminoindolizines 33, 35 with dimethyl acetylenedicarboxylate in the presence of Pd-C in refluxing toluene. Some were found to be more efficient than luminol in light production. 4-Amino-3-methylsufonyl-1-phenyl-1H-pyrazolo[4′,3′:5,6]pyrido[2,3-d]pyridazine-5,8(6H,7H)-dione (7r) , 10-hydroxypyridazino[4,5-b]-quinoline-1,4(2H,3H)-diones 27a-e , and 10-aminopyridazino[4,5-b]quinoline-1,4(2H,3H)-diones 30a-e showed the greatest chemiluminescence intensity in the presence of hydrogen peroxide peroxidase in a solution of phosphate buffer at pH 8.0.     

Synthesis and central nervous system stimulant activity of 5,8-methanoquinazolines fused with imidazole,thiadiazole, pyrimidine and 1,3,5-triazine

5,8-Methanoquinazolines fused with imidazoles 4a-4b , thiadiazoles 5–6 , pyrimidines 7, 9, 11 and 12 , and 1,3,5-triazine 13 were prepared starting from (5R,8S)-2-amino-8,9,9-trimethyl-5,6,7,8-tetrahydro-5,8-methanoquinazoline 3 . Most compounds possessed central nervous system stimulant activities.     

Simple preparation of 7-alkylamino-2-methylquinoline-5,8-diones: regiochemistry in nucleophilic substitution reactions of the 6- or 7-bromo-2-methylquinoline-5,8-dione with amines

7-Alkylamino-2-methylquinoline-5,8-diones (7) were prepared from 6-bromo-2-methylquinoline-5,8-dione (2) not from 7-bromo-2-methylquinoline-5,8-dione (1). The chemistry of the transformation of 6-bromo-2-methylquinoline-5,8-dione (2) and various alkylamines, such as piperidine, 2-methylaziridine, benzylamine, n-butylamine, cyclohexylamine, t-butylamine, and ammonia, to 7-alkylamino compounds 7 as well as the transformation of 7-bromo compound 1 and the alkylamines to 6-alkylamino-2-methylquinoline-5,8-diones 11 was studied. The efficient and simple synthetic routes of the key intermediates, 6- and 7-bromo-2-methylquinoline-5,8-diones (2 and 1), from 5,8-dihydroxy-2-methylquinoline (15) and 5,7-dibromo-8-hydroxy-2-methylquinoline (9), respectively, were developed. We also proposed the mechanism for the unusual regioselectivity on the nucleophilic amination of 6- and 7-bromo-2-methylquinoline-5,8-diones (2 and 1).     

Synthesis of 6-cyanopyrido[2,3-d]pyrimidinones in the reaction of 6-amino-4-pyrimidinones with arylidene derivatives of malonodinitrile

This paper describes the synthesis of a new series of 7-amino-5-aryl-6-cyano-5,8-dihydropyrido-[2,3-d]pyrimidin-4(3H)-ones 3 from the reaction of 6-amino-4-pyrimidinones 1 with arylidene derivatives of malonodinitrile 2 . The structure of the final compounds was determined on the basis of nmr measurements, especially by ¹H, ¹H-, ¹H, ¹³C COSY, DEPT, HMBC and HMQC experiments.     

Synthesis of 1-functionalized-6-hydroxy-4-methyl and 6,11-dihydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinones

Using 2-methoxy- and 2,5-dimethoxyacetophenones 8a and 8b as starting materials, 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ) and its 6-bromo derivative 7 were obtained via multistep sequences. Whereas Diels-Alder condensation of the former compound with homophthalic anhydride ( 22 ) led to a mixture of the two possible isomers: 1-chloro-11-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 23 ) and 1-chloro-6-hydroxy-4-methylnaphtho[2,3-g]isoquinoline-5,12-quinone ( 24 ), this last tetracyclic chloroquinone was specifically obtained from 6-bromo-1-chloro-4-methylisoquinoline-5,8-quinone ( 7 ) and homophthalic anhydride. The 6,11-dihydroxy derivative was then prepared by ammonium nitrate oxidation or photochemically by cycloaddition of benzocyclobutenedione ( 28 ) and 1-chloro-4-methylisoquinoline-5,8-quinone ( 6 ). Chloro compounds were easily substituted by diamines to provide corresponding 1-amino substituted hydroxy tetracyclic quinones.     

Photoinduced Molecular Transformations. Part 142. One-step syntheses of 1H-benz[f]indole-4,9-diones and 1H-indole-4,7-diones by a new regioselective photoaddition of 2-amino-1,4-naphthoquinones and 2-amino-1,4-benzoquinones with alkenes

The 2,3-dihydro-1H-benz[f]indole-4,9-diones 3a–d , h were formed in a one-step reaction in 13–82% yield by an unprecedented [3 + 2] regioselective photoaddition of 2-amino-1,4-naphthoquinone ( 1 ) with various electronrich alkenes 2 (Scheme 1, Table). The [3 + 2] photoadducts derived from 1 with vinyl ethers and vinyl acetate gave 1H-benz[f]indole-4,9-diones 4e , f , i , in 33–72% yield, by spontaneous loss of the corresponding alcohol or AcOH from the resulting adducts; 4i has a kinamycin skeleton. The [3 + 2] photoaddition also took place on irradiation of the differently substituted amino-1,4-benzoquinones 6 , 7 , and 12 and excess alkenes 2 in benzene, giving 1H-indole-4,7-dione derivatives 13 and 14 (Scheme 3), 15a and 16 (Scheme 4), and 18 (Scheme 4), respectively. The initial products in these photoadditions were proved to be hydroquinones, the air oxidation of which yielded the heterocyclic quinones; 2,3-dihydro-2-methoxy-2-methyl-5-phenyl-1H-indole-1,4,7-triyl triacetate ( 19 ) was isolated after treatment of the crude photoaddition mixture obtained from 2-amino-5-phenyl-1,4-benzoquinone ( 7 ) and 2-methoxyprop-1-ene ( 2f ) with Ac₂O and pyridine under N₂. A pathway leading to the annelated hydroquinones involving ionic intermediates arising from an electron transfer in these photoadditions is proposed (Scheme 5).     

1,2,4-Triazines, 9. The synthesis of novel 4-amino-1,6-dihydro-1,2,4-triazinones

3-Alkylthio-4-amino-1,6-dihydro-1,2,4-triazin-5(4H)-ones were synthesized by the reduction of 3-thio-4-amino-1,2,4-triazine-3,5(2.H,4H)-diones and successive S-alkylation. The regiospecific alkylation on the N-1 position or the exo amino group leads to a variety of 1,6-dihydro-1,2,4-triazin-5(4H)-one derivatives. An alternative synthesis of 3-thio-4-amino-1,6-dihydro-1,2,4-triazine-3,5(2H,4H)-diones was accomplished through the cyclization of 1-thiocarbohydrazidoacetamide derivatives.     

Synthesis of 2-aminochromones. Studies on the nucleophilic displacement of sulphinyl and sulphonyl groups in the 2-position of 5,8-dimethoxychromone

The synthesis is described of a number of N-substituted 2-amino-5,8-dimethoxychromones ( 1 ) by replacement of the sulphoxide group in 2-ethylsulphinyl-5,8-dimethoxychromone ( 5a ) with the appropriate amine. Analogous substitution of 2-ethylsulphonyl-5,8-dimethoxychromone ( 5b ) is also possible but limited by the instability of the sulphone. Replacement reactions of 5a involving oxygen, sulphur, and phosphorus nucleophiles are also described.     

Chemistry of naphthazarin derivatives: XV. Bromination of naphthazarin and its derivatives

Bromination of a number of naphthazarin (5,8-dihydroxy-1,4-naphthoquinone) derivatives having different substituents in the aromatic ring with molecular bromine in carbon tetrachloride was studied. Preparative procedures for the synthesis of 2-bromo-5,8-dihydroxy-7-methoxy-1,4-naphthoquinone, 2-bromo-6,7-dichloro-5,8-dihydroxy-1,4-naphthoquinone, 2-bromo-3,5,8-trihydroxy-1,4-naphthoquinone, and 2-bromo-6,7-dichloro-3,5,8-trihydroxy-1,4-naphthoquinone were developed.     

Cyclic homologs of xanthines. I. Imidazo[4,5-e][1,4]diazepine-5,8-diones

A useful synthetic approach to variously alkylated 4,5,7,8-tetrahydro-6.H-imidazo[4,5-e][1,4]diazepine-5,8-diones is reported. These compounds are potentially interesting cyclic homologs of pharmacologically important alkylxanthines.