5-Cyano-6-aryluracil and 2-thiouracil derivatives as potential chemotherapeutic agents. IV

A series of 5-cyano-6-aryluracils and 2-thiouracils 1a-h has been prepared and alkylated to 1,3-dialkyluracils 2a-d and 2-alkylthiouracils, 3, 4 and 6 , by electrophilic substitution with alkyl halides. Reaction of 1b with dibromoethane and 1,3-dibromopropane gave the corresponding bicyclic products, 7-aryl-6-cyano-2,3-dihydrothiazolo[3,2-a]pyrimidin-5-ones 5a,b and 8-aryl-7-cyano-3,4-dihydro-2H-pyrimido[2,3-b][1,3]thiazin-6-ones 5c-g . Nucleophilic substitution on 6 with hydrazine led to 7 which on refluxing with formic acid gave 5-aryl-6-cyano-8-methyl-s-triazolo[3,4-b]pyrimidin-7-ones ( 9 ), while with acetic and propionic acids only 2-acylhydrazino-3-methyl-4-oxo-5-cyano-6-arylpyrimidines 8a,b were isolated. The hydrazine 7 undergoes cyclization with acetylacetone and methyl dimethylmercaptoacrylate providing 2-(pyrazol-1-yl)-3-methyl-4-oxo-5-cyano-6-substituted pyrimidines 10 , and 11 . Some of the compounds were screened for antibacterial-, antifungal- and antiviral activities and a few of them showed significant chemotherapeutical activities.     

An efficient synthesis and reactions of novel indolylpyridazinone derivatives with expected biological activity

Reaction of 4-anthracen-9-yl-4-oxo-but-2-enoic acid (1) with indole gave the corresponding butanoic acid 2. Cyclocondensation of 2 with hydrazine hydrate, phenyl hydrazine, semicarbazide and thiosemicarbazide gave the pyridazinone derivatives 3a-d. Reaction of 3a with POCl(3) for 30 min gave the chloropyridazine derivative 4a, which was used to prepare the corresponding carbohydrate hydrazone derivatives 5a-d. Reaction of chloropyridazine 4a with some aliphatic or aromatic amines and anthranilic acid gave 6a-f and 7, respectively. When the reaction of the pyridazinone derivative 3a with POCl(3) was carried out for 3 hr an unexpected product 4b was obtained. The structure of 4b was confirmed by its reaction with hydrazine hydrate to give hydrazopyridazine derivative 9, which reacted in turn with acetyl acetone to afford 10. Reaction of 4b with methylamine gave 11, which reacted with methyl iodide to give the trimethylammonium iodide derivative 12. The pyridazinone 3a also reacted with benzene- or 4-toluenesulphonyl chloride to give 13a-b and with aliphatic or aromatic aldehydes to give 14a-g. All proposed structures were supported by IR, (1)H-NMR, (13)C-NMR, and MS spectroscopic data. Some of the new products showed antibacterial activity.     

Synthesis and reactions of halo-, nitro-, and arylazo-substituted 3-aminotropolones. Formation of 8H-cyclohept[d]oxazol-8-one derivatives

3-Acetamidotropolone ( 1a ) reacted with bromine and fuming nitric acid to afford respectively 3-acetamido-7-bromo- ( 1b ) and -5,7-dibromotropolone ( 1c ) and 3-acetamido-5-nitrotropolone ( 1d ). Azo-coupling reaction of 1a gave 3-acetamido-5-(4-methylphenylazo)tropolone ( 1f ). Bromination of 1d and 1f gave 7-bromo-substituted compounds 1e and 1g , respectively. The compounds 1b-g were hydrolyzed to afford 3-aminotropolones 4b-g , which reacted with triethyl orthoformate to give the corresponding 8H-cyclohept[d]oxazol-8-ones 5b-g . Heating of 3-acetamidotropolones 1a-d with polyphosphoric acid gave 2-methyl-8H-cyclohept[d]oxazol-8-ones 6a-d .     

Synthesis and Chemistry of 4-Aroyl-3-oxo- and 3-Chloropyridazine Derivatives

4H,5H-6-Phenyl (1a) and 6-p-phenoxyphenyl (1b) pyridazin-3(2H)-ones were reacted with aromatic aldehydes to give 4-arylmethylpyridazm-3(2H)-ones (2a-g), Oxidation of (2a-g) with various oxidising agents (selenium dioxide in ethanol or chromium trioxide in acetic acid) gave 4-aroyl-6-arylpyridazin-3(2H)-ones (3a-g). Chlorination of (3a-g) with phosphorous oxychloride afforded 4-aroyl-6-aryl-3-chloropyridazine (4a-g). 1H-3-Aryl-5-phenylpyrazolo[3,4-c]pyridazines (5a-d) were obtained by heating (4a-d) with excess hydrazine hydrate. Hydroxyamination of (3e-g) with iydroxylamine gave aryl-4(6-p-phenoxyphenyl-2,3-dihydro-3-oxo)pyridazinyl oxime (6a-c). Silylation of oximes (6b & 6c) gave (7a & 7b) as acyclic compound instead of the expected seven - membered - ring compound (8).     

Studies on ketene and its derivatives. Part 119. Reactions of haloketenes with 2-arylideneaminopyridines

Reactions of haloketenes with 2-arylideneaminopyridines were examined. Reaction of dichloroketene with 2-benzylideneaminopyridines gave 2,2-dichloro-3-phenyl-3-(2-pyridylamino)propanoic acids and 3-chloro-2-phenylpyrido[1,2-a]pyrimidin-4(4H)-ones. Similar reaction of dichloroketene with 2-(2-furfurylideneamino)-pyridines gave 3-chloro-2-(2-furyl)pyrido[1,2-a]pyrimidin-4-(4H)-ones. Chloroketene and chlorophenylketene also reacted with 2-arylideneaminopyridines to give pyrido[1,2-a]pyrimidin-4(4H)-ones. Ring transformations of pyrido[1,2-a]pyrimidin-4-(4H)-ones were carried out to give 1,8-naphthyridin-4(1H)-ones and imidazo[1,2-a]-pyridines.     

Enaminones as building blocks for the synthesis of substituted pyrazoles with antitumor and antimicrobial activities

Novel N-arylpyrazole-containing enaminones 2a,b were synthesized as key intermediates. Reactions of 2a,b with active methylene compounds in acetic acid in the presence of ammonium acetate afforded substituted pyridine derivatives 5a-d. Enaminones 2a,b also reacted with aliphatic amines such as hydrazine hydrate and hydroxylamine hydrochloride to give bipyrazoles 8a,b and pyrazolylisoxazoles 9a,b, respectively. On the other hand, treatment of 2a,b with a heterocyclic amine and its diazonium salt yielded the respective [1,2,4]triazolo[4,3-a]pyrimidines 12a,b and pyrazolylcarbonyl[1,2,4]triazolo-[3,4-c][1,2,4]triazines 14a,b. Moreover, 2-thioxo-2,3-dihydro-1H-pyrido[2,3-d]pyrimidin-4-one (17) was prepared via reaction of enaminone 2a with aminothiouracil (15). Cyclocondensation of 17 with the appropriate hydrazonoyl chlorides 18a-c gave the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5-ones 21a-c. The cytotoxic effects of compounds 2b, 14a and 17 against human breast cell line (MCF-7) and liver carcinoma cell line (HEPG2) were screened and in both lines they showed inhibition effects comparable to those of 5-fluorouracil, used as a standard. The antimicrobial activity of some products chosen as representative examples was also evaluated.     

Preparation of 5-sulfonylpyrimidines from β-keto, β-cyano-, and β-ethoxycarbonyl-β-sulfonylenamines

β-Keto-β-sulfonylenamines 2a,b reacted with benzamidine or guanidines to give 2,4-disubstituted 5-methanesulfonylpyrimidines 3a-d , whose methanesulfonyl groups were substituted by n-butyllithium or alkylmagnesium bromides to yield 2,4-disubstitued 5-alkylpyrimidines 6a-d. 2-Substituted 4-amino-5-sulfonylpyrimidines 7a,b, 8 and 2-substituted 5-benzenesulfonylpyrimidin-4-ones 9a,b were similarly obtained from β-cyano-β-sulfonylenamines 2c,d and β-ethoxycarbonyl-β-sulfonylenamine ( 2e ), respectively.     

Synthesis and reaction of 6-substituted 3-methoxycarbonyl-4-methylthio-2H-pyran-2-one derivatives

Reaction of aryl and styryl methyl ketones 1a-m with dimethyl bis(methylthio)methylenemalonate ( 2 ) in the presence of potassium hydroxide in dimethyl sulfoxide gave the corresponding methyl 6-aryl- and 6-styryl-4-methylthio-2-oxo-2H-pyran-3-carboxylates 3a-m . 6-Aryl derivatives 3a-d,g were treated with sodium methoxide in methanol to give the corresponding 6-aryl-4-methoxy-2H-pyran-2-ones 8a-d and 9. Phenylcoumalin ( 7a ) and paracotoin ( 7b ) were synthesized by the desulfurization of 6-aryl-4-methylthio-2H-pyran-2-ones 4a,b. Similarly, anibine ( 8e ) was also synthesized from 3g . Treatment of 3 with hydrogen peroxide or 3-chloroperoxybenzoic acid gave the corresponding 4-methylsulfiny-2H-pyran-2-ones 10a-f in good yields. Displacement reactions of 10a-f with nucleophilic reagents are also described.     

新型环烷烯并嘧啶并噻唑-3-酮类化合物的合成

以环戊酮、环庚酮为起始原料合成的环烷烯并[1,2-d]嘧啶-2-硫酮(2)与氯乙酸、芳香醛反应, 合成具有潜在抗癌活性的稠合杂环化合物5-芳基-2,8-二芳亚甲基-2,3,6,7-四氢-5H,8H-环戊烯并[1,2-d]噻唑并[3,2-a]嘧啶-3-酮(3)以及5-芳基-2,10-二芳亚甲基-2,3,6,7,8,9-六氢-5H,10H-环庚烯并[1,2-d]噻唑并[3,2-a]嘧啶-3-酮(4). 3和4的结构经¹H NMR, IR, MS分析确认.     

Furopyridines. XII . Reaction of 3-bromo, 2-phenylthio and 2-phenylthio-3-bromo derivatives of furo[2,3-b]-, furo[3,2-b]-, furo[2,3-c]- and furo[3,2-c]pyridine with several alkyllithiums

This paper describes reactions of 3-bromo- 1a-d , 2-phenylthio- 5a-d and 2-phenylthio-3-bromofuropyridines 6a-d with n-butyl-, t-butyl- and methyllithium and lithioacetonitrile. Lithiation of compounds 1a-d with n-butyl- or methyllithium gave the parent furopyridines 2a-d and o-ethynylpyridinols 3a-d. Reaction of compounds 5a-d with methyllithium afforded o-(phenylthioethynyl)pyridinols 7a-d , which were also yielded by reaction of compounds 6a-d with t-butyl- or methyllithium. The phenylthio group in compounds 7a-d were substituted with t-butyl group by the reaction with excess t-butyllithium. In contrast, 2-phenylthio group in compounds 5a-d and 6a-d was substituted with cyanomethyl group by reaction with lithioacetonitrile to give compounds 11a-d and 10b, c respectively.     

Iminophosphorane-mediated efficient synthesis of new tricyclic 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a]pyrimidin-9-ones

The carbodiimides 2, obtained from aza-Wittig reactions of iminophosphorane 1 with aromatic isocyanates, reacted with hydrazine to give selectively 6-amino-7H-1,2,3-triazolo[4,5-d]pyrimidin-7-ones 5. Compounds 5 were further transformed to iminophosphoranes 6 by reaction with triphenylphosphine, hexachloroethane and triethylamine. A tandem aza-Wittig reaction of iminophosphorane 6 with isocyanate or acyl chloride generated previously unreported 3,5-dihydro-1,2,3-triazolo[4,5-d]-1,2,4-triazolo[1,5-a]pyrimidin-9-ones 10 or 12 in satisfactory yield. X-ray structure analysis of 10 g verified the proposed structure and the reaction selectivity.     

2-氨基噻吩并[2,3-d]嘧啶-4(3H)-酮衍生物的合成

丁醛(1)、氰乙酸乙酯、硫磺在三乙胺作用下制得2-氨基-4-乙基噻吩-3-羧酸乙酯(2), 2再与三苯基膦、六氯乙烷及三乙胺反应, 以84%的产率得到膦亚胺3. 应用膦亚胺3与芳基异氰酸酯的氮杂Wittig反应, 生成的碳二亚胺4, 再与仲胺作用得到中间体5, 而后在醇钠的催化下关环制得2-二烷氨基噻吩并[2,3-d]嘧啶-4(3H)-酮衍生物6, 产率为58%～82%.     

Furopyridines. XV . Synthesis and properties of ethyl 2-(3-furo[2,3-b]-, -[3,2-b]-, -[2,3-c]- and -[3,2-c]pyridyl)acetate

Ethyl 2-(3-furopyridyl)acetates 10a-d were synthesized from furopyridin-3(2H)-ones 4a-d by the Wittig-Horner reaction with diethyl cyanomethylphosphonate, hydrolysis and the subsequent esterification. Reaction of compounds 10a-d with lithium diisopropylamide (IDA) gave the corresponding methylene-lithiated intermediate, and the subsequent reaction with benzaldehyde, acetone and iodomethane afforded the methylene-alkylated product respectively, while N,N-dimethylacetamide did not give any reaction product. The 2-position of 10a, b and d is alkylated by the lithiation with excess of LDA and the successive reaction with an electrophile.     

Synthesis and Reactions of Some New Heterocyclic Compounds Containing Cycloalka[e]thieno[2,3‐b]pyridine Moiety

Hydrolysis of ethyl 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxylates ( 3a-d) gave the corresponding o-aminocarboxylic acids 4a-d . Heating the latter compounds ( 4a-d) with acetic anhydride furnished the oxazinone derivatives 5a-d which, in turn, underwent recyclization reaction to give the corresponding pyrimidinones 6a-d upon treatment with ammonium acetate in acetic acid. Reaction of 3-amino-4-aryl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides ( 3f,h ) with triethyl orthoformate gave pyrimidinone derivatives 7a,b . Reaction of 3-amino-4-phenyl-cycloalka[e]thieno[2,3-b]pyridine-2-carboxamides 3e,h with aromatic aldehydes furnished tetrahydropyridothienopyrimidinones 8a-d . Chlorination of 7a,b and 6a-d by using phosphorous oxychloride produced 4-chlorocycloalka[5′,6′]pyrido[3′,2′:4,5]thieno[3,2-d]pyrimidine derivatives 9a-f which were used as key intermediates in the synthesis of several new cycloalkapyrido-thienopyrimidines 10a-f ˜ 14a-f . Moreover, some cycloalkapyridothienotriazinones 15a,b-17a,b were synthesized.     

Syntheses of optically active tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones and hexahydroimidazo[1,2-a]pyridin-2(3H)-ones

The reactions of (2S)-2-amino-2-substituted-N-(4-nitrophenyl)acetamides 16a-c, succindialdehyde (13), and benzotriazole afforded enantiopure (3S,5R,7aR)-5-(1H-1,2,3-benzotriazol-1-yl)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 17a-c, which were converted by sodium borohydride into (3S,7aR)-3-substituted-1-(4-nitrophenyl)tetrahydro-1H-pyrrolo[1,2-a]imidazol-2-ones 18a-c. Chiral (2S)-2-amino-2-substituted-N-(4-methylphenyl)acetamides 12a-d, easily prepared in two steps from N-Boc-alpha-amino acids 10a-d, similarly reacted with glutaraldehyde (20) and benzotriazole to generate 5-benzotriazolyl-3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 21a-d, which were converted by sodium borohydride directly into optically active 3-substituted-hexahydroimidazo[1,2-a]pyridin-2(3H)-ones 22a-d.     

Saturated heterocycles, 248. Synthesis of 2,4-dioxo and 4-oxo-2-thioxo derivatives of octahydrocyclopenta[d]pyrimidines

Unsubstituted and 1-benzyl-substituted cis-cyclopenta[d]pyrirnidine-2,4-diones and cis-2-thioxo-cyclopenta[d]pyrimidin-4-ones 9a,b and 10a,b were prepared from the corresponding cis-2-amino-1-cyclopentanecarboxylates 3 and 5 with potassium cyanate and thiocyanate. It was found that the cis derivatives 7a-h readily underwent ring closure, resulting in 3-substituted cis-2,4-cyclopenta[d]pyrimidinediones and cis-2-thioxocyclopenta[d]pyrimidin-4-ones 11a-d and 12a-d , whereas the trans counterparts 8a-d failed to cyclize, but gave hydrolysed amino acid derivatives 13a,b and 14 . This difference in the reactivities of the cis and trans isomers is a further example of the difficulty of preparing cyclopentane trans-fused six-membered 1,3-heterocycles by ring closure.     

Synthese und Eigenschaften von Thiazolo[3,2-a]pyrimidinen und Thiazolo [3,2-a] pyrrolo [2,3-d]pyrimidinen

From the alkali-catalysed reaction of thiouracil with bromoacetaldehyde diethyl acetal three products are isolated in nearly the same quantity: 2-(2, 2-diethoxyethylthio)-uracil ( 2 ) and two cyclization products: 3 , a thiazolo[3, 2-a]pyrimidin-5-one, and 4 , athiazolo[3, 2-a]pyrimidin7-one. By warming with acid both 2 and 4 yield 3 . Rearrangement of 4 to 3 proceeds also by heating the hydrochloride. Similar cyclizations leading to thiazolo[3, 2-d]pyrrolo[2, 3-d]pyrimidin-5-ones are also described. Bromine substitutes 3 in position 6. The bromo derivative 6 on treatment with primary or secondary amines affords 7-amino compounds.     

Reactions of 3-acetyl-2-aminotropones and 2-acetyl-7-aminotropones with hydrazine

3-Acetyl-2-aminotropone ( 1a ) reacted with hydrazine to afford its hydrazone ( 3a ) and 3-methyl-1,8-dihydrocycloheptapyrazol-8-one ( 4 ), while methylamino- and pyrrolidinyl-substituted compounds 1b and 1c gave only the cyclized compound ( 4 ). Reactions of 2-acetyl-7-aminotropones 2a-d gave their hydrazones 5a-d and the hydrazone 6 . The hydrazones 3a and 5b were heated in acetic acid to give 4 and 3-methyl-8-methylamino-1,2-diazaazulene ( 7 ), respectively. Several reactions of 4 and 6 were also described.     

Synthesis,reactions and biological evaluation of some 1,2,4-triazine derivatives

6-Substituted benzyl-4-phenyl-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazin-5-ones 3a-d were prepared and converted into their corresponding 3-methylthio derivatives 4a-d . Reaction of compounds 4a-d with hydrazine hydrate gave the corresponding 4-amino-3-anilino-4,5-dihydro-1,2,4-triazin-5-ones 5a-d . 6-Substituted benzyl-4-phenyl-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 9a-c were synthesized and allowed to react with hydrazine hydrate to give the corresponding 6-substituted benzyl-4-amino-2,3,4,5-tetrahydro-1,2,4-triazin-3,5-diones 10a-c . The biological evaluation of some of these triazines is described. All compounds were screened for antiviral, antibacterial, antimycobacterial, antifungal and antiyeast activity. No important biological activity was found.     

Tautomeric structure of dihydropyrazolo[1,5-a]-pyrimidin-7-one in a solution. A facile synthesis of novel 6-quinoxalinyldihydropyrazolo[1,5-a]pyrimidin-7-ones by ring transformation

6-Quinoxalinyldihydropyrazolo[1,5-a]pyrimidin-7-ones 4a-d were synthesized by the ring transformation of 3-(N,N-dimethylcarbamoyl)furo[2,3-b]quinoxaline hydrochloride 5 . Compounds 4a-d were found to exist as the 4,7-dihydro-7-oxo form E in dimethyl sulfoxide based on the nmr spectral data.