Novel fluoro-substituted benzo- and benzothieno fused pyrano[2,3-c]pyrazol-4(1H)-ones

A straightforward, two-step synthesis of fluoro substituted chromeno[2,3-c]pyrazol- and [1]benzothieno[2′,3′:5,6]pyrano[2,3-c]pyrazol-4(1H)-ones, respectively, is presented. Hence, treatment of 1-substituted or 1,3-disubstituted 2-pyrazolin-5-ones with fluoro substituted 2-fluorobenzoyl chlorides or 3-chloro-6-fluoro-1-benzothiophene-2-carbonyl chloride using calcium hydroxide in refluxing 1,4-dioxane gave the corresponding 4-aroylpyrazol-5-ols, which were cyclized into the fused ring systems. 5-Fluorochromeno[2,3-c]pyrazol-4(1H)-one was obtained upon treatment of the 1-(4-methoxybenzyl) protected congener with trifluoroacetic acid. Treatment of 5-fluorochromeno[2,3-c]pyrazol-4(1H)-ones with methylhydrazine afforded novel tetracyclic ring systems such as 2-methyl-7-phenyl-2,7-dihydropyrazolo[4′,3′:5,6]pyrano[4,3,2-cd]indazole. Detailed NMR spectroscopic investigations (¹H, ¹³C, ¹⁵N, ¹⁹F) with the obtained compounds were undertaken.     

吡唑并[4',3':5,6]吡喃并[2,3-d]嘧啶化合物的合成与生物活性

应用串联氮杂Wittig反应设计合成了一系列新的2-烷氨(芳氧)基-3,8-二苯基-5-芳基-6-甲基-5,8-二氢-4H-吡唑并[4',3':5,6]吡喃并[2,3-d]嘧啶-4(3H)-酮衍生物。通过氢核磁共振谱仪(1H NMR)、傅里叶变换红外光谱仪(FTIR)和元素分析等方法对所合成的化合物进行了结构表征,用X射线单晶衍射确证了化合物2-二正丙基氨基-3,8-二苯基-5-(4-甲基苯基)-6-甲基-5,8-二氢-4H-吡唑并[4',3':5,6]吡喃并[2,3-d]嘧啶-4(3H)-酮(Ⅲi)晶体结构。室内的杀菌和杀虫活性测试结果表明:目标化合物具有一定的杀菌活性,其中部分化合物对黄瓜灰霉菌(Botrytis cinereapers)在50 mg/L剂量下抑制率达到90%以上,显示了优异的杀菌活性;对水稻褐飞虱无明显的杀虫活性,但发现对粘虫具有较高的杀灭效果,大多数抑制率达到90%以上。     

Synthesis of 1,2,4-triazolo[4,3-c]-, tetrazolo[1,5-c]-, and 1,2,4-triazino[5,6-c]pyrano[4'3':4,5]pyrrolo-[3,2-e]pyrimidine derivatives

4-Hydrazinopyrano[4',3':4,5]pyrrolo[2,3-d]pyrimidines served as precursors in the synthesis of new heterocyclic systems, namely, 1,2,4-triazolo[4,3-c]-, tetrazolo[1,5-c]-, and 1,2,4-triazino[5,6-c] pyrano[4',3':4,5]-pyrrolo[3,2-e]pyrimidines.A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Republic of Armenia, 375014 Yerevan. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 700-703, May, 1995. Original article submitted January 10, 1995; revision submitted April 20, 1995.     

Reactions of 6-Amino-5-Cyano-3-Methyl-1,4-Diphenyl-1H 4H-Pyrano[2,3-C]Pyrazole and its Methanimidate

Reaction of 6-amino-5-cyano-3-methyl-1,4-diphenyl- 1H,4H-pyrano[2,3-c]pyrazole 1 with triethyl orthoformate in acetic anhydride gave its methanimidate 2, which reacts with primary aliphatic and aromatic amines to give 4,6-dihydro-3-methyl-1,4-diphenyl-6- (alkyl)pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine-5(lH)- imine 3 and the starting compound 1 , respectively. Treatment of 1 with o-aminophenol gave 5-(2-benzoxalyl)- 1,4-dihydro-3-methyl-1,4-diphenylpyrano[2,3-c]pyrazol- 6-amine 9.     

Synthesis and antiplatelet activities of N-arylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives.

A series of new 1- and 2-arylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-one derivatives were synthesized and examined for their antiplatelet activities. Some of these compounds showed significant inhibitory activities. Among them, 1-phenylmethyl-3,4-dimethylpyrano[2,3-c]pyrazol-6(1H)-one (4a), 2-(2'-methoxyphenyl)methyl-3,4-dimethylpyrano[2,3-c]pyrazol-6(2H)- one (3e) and 2-(3'-methoxyphenyl)methyl-3,4-dimethylpyrano[2,3-c]pyrazol-6-(2H) - one (3f) were the most effective. These inhibitors acted in a concentration-dependent manner. The antiplatelet effect of compound 3f is due to the inhibition of thromboxane A2 formation and the blockade of thromboxane A2/prostaglandin endoperoxide receptor in washed rabbit platelets.     

Novel Synthesis of Thieno[2,3-c]Pyridazine and Pyrimido[4',5':4,5]thieno[2,3-c]pyridazine Derivatives

Abstract

Novel series of thieno[2,3-c]pyridazines and pyrimido[4′,5′:4,5] thieno-[2,3-c]pyridazines have been synthesized from the readily accessible 4-cyano-5,6-dimethylpyridazin-3(2H)-thione 3b.     

Synthesis and cytotoxic activity of benzo[a]pyrano[3,2-h] and [2,3-i]xanthone analogues of psorospermine, acronycine, and benzo[a]acronycine

Condensation of 2-hydroxy-1-naphthalenecarboxylic acid with phloroglucinol afforded 9,11-dihydroxy-12H-benzo[a]xanthen-12-one (6). Construction of an additional dimethylpyran ring onto this skeleton, by alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement, gave access to 6-hydroxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (12) and 5-hydroxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (13), which were methylated into 6-methoxy-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (14) and 5-methoxy-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (15), respectively. Osmium tetroxide oxidation of 14 and 15 gave the corresponding (+/-)-cis-diols 16 and 17, which afforded the corresponding esters 18-21 upon acylation. Similarly, condensation of 2-hydroxy-1-naphthalenecarboxylic acid with 3,5-dimethoxyaniline gave 11-amino-9-methoxy-12H-benzo[a]xanthen-12-one (23) which was converted into 11-amino-9-hydroxy-12H-benzo[a]xanthen-12-one (24) upon treatment with hydrogen bromide in acetic acid. Alkylation with 3-chloro-3-methyl-1-butyne followed by Claisen rearrangement afforded 6-amino-3,3-dimethyl-3H,7H-benzo[a]pyrano[3,2-h]xanthen-7-one (25) and 5-amino-2,2-dimethyl-2H,6H-benzo[a]pyrano[2,3-i]xanthen-6-one (26). The new benzopyranoxanthone derivatives only displayed marginal antiproliferative activity when tested against L1210 and KB-3-1 cell lines. The only compounds found significantly active against L1210 cell line, 16 and 20, belong to the benzo[a]pyrano[3,2-h]xanthen-7-one series, which possess a pyran ring fused angularly onto the xanthone basic core.     

An efficient synthesis of novel pyridothieno-fused thiazolo[3,2-a]pyrimidinones via Pictet–Spengler reaction

An efficient method for the synthesis of novel pyrido[3',2':4',5']thieno[3',2':2,3]pyrido [4,5:d][1,3]thiazolo[3,2-a]pyrimidine-4-one derivatives (5) has been developed using a Pictet-Spengler reaction between 2-(3-aminothieno[2,3-b]pyridin-2-yl)thiazolo[3,2-a] pyrimidin-5-one (3), which could be obtained from the condensation of 7-(chloromethyl)-5H-thiazolo[3,2-a]pyrimidin-5-one (1) with 3-cyanopyridine-2-thione (2) via Thorpe-Ziegler isomerization, and aromatic aldehydes under NH₂SO₃H as catalysis in good yields.     

Synthesis of novel polycyclic ring systems containing two pyrano[2,3-<Emphasis Type="Italic">c</Emphasis>]pyrazol-4-(1H)one moieties

Novel penta-or heptacyclic ring systems containing two pyrano[2,3-c]pyrazol-4(1H)-one units are prepared in one or two steps from the reaction of 3-methyl-1-phenyl-2-pyrazolin-5-one and bis(o-chlorocarbonyl chlorides) derived from benzene-or 1,10-phenanthroline. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1251–1255, August, 2007.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 6. Naphthothienonaphthyridines

Five novel polycyclic heterocyclic ring systems are reported via photocyclization. The specific final products in these ring systems are: naphtho[1′,2′:4,5]thieno[2,3-c][1,8]naphthyridin-6(5H)-one ( 5 ), naphtho-[1′,2′:4,5]thieno[2,3-c][1,6]naphthyridin-6(5H)-one ( 6 ), naphtho[1′,2′:4,5]thieno[2,3-c]-1,5-naphthyridine ( 9 ), naphtho[1′,2′:4,5]thieno[2,3-c][1,2,4]triazolo[4,3-a]-1,5-naphthyridine ( 12 ), and naphtho[2′,1′:4,5]thieno[2,3-c]-1,5-naphthyridine ( 17 ). The direction of photocyclization to produce 9 was established from a zero quantum two-dimensional nmr spectroscopy experiment (ZQCOSY) using 6-chloronaphtho[1′,2′:4,5]thieno[2,3-c]-1,5-naphthyridine ( 8 ) as the model compound.     

Synthesis,photochemical synthesis and antitumor evaluation of novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones

The novel derivatives of thieno[3',2':4,5]thieno[2,3-c]quinolones 6a, 6b, 7, 10a and 10b were synthesized in multistep synthesis starting from thiophene-3-carboxaldehyde and malonic acid reacting in aldol condensation or from 3-bromothiophenes or methyl 4-bromothiophene-2-carboxylate reacting in Heck reaction. They resulted in corresponding substituted thienylacrylic acids 3a-c, which were cyclized into thieno[2,3-c]thiophene-2-carbonyl chlorides 4a-c and converted into thieno[2,3-c]thiophene-2-carboxamides 5a-d. Prepared carboxamides were photochemically dehydrohalogenated into corresponding substituted thieno[3',2':4,5]thieno[2,3-c]quinolones 6a-d. Compound 7 was prepared from 6d by alkylation with N-[3-(dimethylamino)propyl]chloride hydrochloride in the presence of NaH. Compounds 10a and 10b were prepared from 6c in the multistep synthesis over acid 8 and acid chloride 9. Compounds 6a, 6b, 7, 10a and 10b were found to exert cytostatic activities against malignant cell lines: pancreatic carcinoma (MiaPaCa2), breast carcinoma (MCF7), cervical carcinoma (HeLa), laryngeal carcinoma (Hep2), colon carcinoma (CaCo-2), melanoma (HBL), and human fibroblast cell lines (WI-38). The compound 6b, which bears the 3-dimethylaminopropyl substituent on quinolone nitrogen and methoxycarbonyl substituent on position 9, exhibited marked antitumor activity. On the contrary, compound 7, which also bears the 3-dimethylaminopropyl substituent on the quinolone nitrogen but anilido substituent on position 9, exhibited less antitumor activity than the others.     

四氢苯并[4',5']噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶-4(3H)-酮的合成、晶体结构及杀菌活性

通过氮杂Wittig反应合成了一系列结构新颖的未见文献报道的取代四氢苯并[4',5']噻吩并[3',2':5,6]吡啶并[4,3-d]嘧啶-4(3H)-酮化合物6, 产物的结构通过核磁共振氢谱、质谱、红外光谱、元素分析的确证. 为进一步了解此类化合物的结构, 对化合物6c进行了X射线单晶衍射. 初步杀菌活性测定结果表明, 该类化合物具有较好的杀菌活性和选择性. 如6f在50 mg/L浓度时, 对黄瓜灰霉菌的抑制率为98%.     

Chemical and photochemical synthesis of substituted dihydro-thieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones and tetrahydro-dithieno[2,3-b:2',3'-d]thieno[2'',3''c:2'',3''c']diquinolin-6,14-dione

Some new substituted dihydrothieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones 9- 12 and tetrahydrodithieno[2,3-b: 2',3'-d]thieno[2',3'-c:2',3'-c']diquinolin-6,14-dione (17) were prepared from the corresponding new anilides 5-8 and from the corresponding dianilide 15, respectively, by a multistep combination of chemical and photochemical reactions. All the prepared compounds are of particular interest because they might serve as DNA intercalators in anticancer therapy.     

New polyheterocyclic series based on 4,5,6,7-tetrahydrothieno[2,3-c]pyridine

4,8-Dimethyl-6,7,8,9-tetrahydropyrido[4′,3′:4,5]thieno[2,3-e][1,2,4]triazolo[3,4-a]-4H-pyrimidin-5-ones, 7-methyl-2,3,6,7,8,9-hexahydropyrido[4′,3′:4,5]thieno[2,3-d]pyrrolo[1,2-a]-1H, 10H-pyrimidin-10-one, 8-methyl-1,2,3,4,7,8,9,10-octahydropyrido[4′,3′:4,5]thieno[2,3-d]-11H-pyrimidin-11-one, and 9-methyl-2,3,4,5,8,9,10,11-octahydro[4′,3′:4,5]thieno[2,3-d]azepino-[1,2-a]-1H, 12H-pyrimidin-12-one which consist four new heterocyclic ring systems were synthesized from 2-amino-3-carbethoxy-5-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.     

Synthesis of thieno[2,3-d]thia[1]pyrano[4,3-b]pyrrole derivatives

It is shown that 2-methyl-3-carbethoxy-4H,8H,5,6-dihydrothieno[2,3-d]thia[1]pyrano [4,3-b]pyrrole and 8-methyl-9-carbethoxy-10H,5,6-dihydrothieno[2,3-d]thia[1]chromeno[4,3-b]pyrrole and their S,S-dioxides, respectively, are obtained in the reaction of 2-methyl-3-carbethoxy-4-thienylhydrazine with tetrahydro-4-thiopyrone, tetrahydro-4-thiopyrone S, S-dioxide, 4-thiochromanone, and 4-thiochromanone S,S-dioxide in the presence of an acid catalyst.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 195–196, February, 1979.     

Structural effects on the electronic properties of extended fused-ring thieno[3,4-b]pyrazine analogues

The synthesis and characterization of the extended thieno[3,4-b]pyrazine analogues acenaphtho[1,2-b]thieno[3,4-e]pyrazine (3a), 3,4-dibromoacenaphtho[1,2-b]thieno[3,4-e]pyrazine (3b), 3-octylacenaphtho[1,2-b]thieno[3,4-e]pyrazine (3c), dibenzo[f,h]thieno[3,4-b]quinoxaline (4), and thieno[3',4':5,6]pyrazino[2,3-f][1,10]phenanthroline (5) are reported. Comparison of structural, electrochemical, and photophysical properties to those of simple thieno[3,4-b]pyrazines are provided in order to provide structure-function relationships within this series of compounds.     

The synthesis of novel polycyclic heterocyclic ring systems via photocyclization. 19. Thieno[3′,2′:4,5]thieno[2,3-c]-naphtho[1,2-f]quinoline,thieno[3′,2′:4,5]thieno[2,3-c]naphtho-[1,2-f][1,2,4]triazolo[4,3-a]quinoline and thieno[3′,2′:4,5]-thieno[2,3-c]naphtho[1,2-f]tetrazolo[1,5-a]quinoline

Photocyclization of 3-chloro-N-(3-phenanthryl)thieno[2,3-b]thiophene-2-carboxamide ( 5 ) yielded only one of the two possible structural isomers, thieno[3′,2′:4,5]thieno[2,3-c]naphtho[1,2-f]quinolin-6(5H)-one ( 6 ), which was further elaborated to afford the unsubstituted ring system 10 , its triazole 11 and tetrazole 12 . The structural confirmation of 10 was achieved by the total assignment of its ¹H and ¹³C nmr spectra by the concerted utilization of two-dimensional nmr spectroscopic methods.     

Synthesis and Properties of Derivatives of the new Heterocyclic System Benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine

Derivatives of a new heterocyclic system - benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine have been obtained by successive reactions in three stages - alkylation of 3-cyanopyridine-2(1H)-thiones with 2-chloromethylbenzylimidazole to give 2-benzimidazolylmethylthio-3-cyanopyridines, closing the thiophene ring in the latter to form 3-amino-2-(benzimidazolyl-2)thieno[2,3-b]pyridines, and cyclization of the pyrimidine ring by acylation with carboxylic acid anhydrides or chlorides.     

Synthesis and antimicrobial activity of new derivatives of pyrano[4',3':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine and new heterocyclic systems

Taking into account previously obtained biological results on some polyheterocyclic compounds (containing different heteroatoms) and in particular on several 8-amino-5-isopropyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines Ia-v we have carried out the synthesis of twentyone 8-amino-5-isobutyl-2,2-dimethyl-10-(methylthio)-1,4-dihydro-2H-pyrano[4’’,3’’:4’,5’]pyrido[3’,2’:4,5]thieno[3,2-d]pyrimidines 6. Therefore we have slightly modified the structure of the previously studied I introducing at C-5 an isobutyl group instead of the previously examined isopropyl ones in order to see if this variation (changing a little the lipophilicity) will affect the biological activity. Furthermore thieno[3,2-d]pyrimidine-8-thione 7 and their S-alkylated 8 were synthesized. Finally by alkylation of 5-isobutyl-2,2-dimethyl-10-thioxo-1,4,10,11-tetrahydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidin-8(9H)-one 3 with alkyl dichlorides (bifunctional reagents) we realized the cyclization of a thiazole or thiazine ring on the [b] side of the pyrimidine ring with formation of the new condensed pentaheterocyclic systems: pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d][1,3]thiazolo[3,2-a]pyrimidin-8-one 11 and pyrano[4''',3''':4'',5'']pyrido[3'',2'':4',5']thieno[3',2':4,5]pyrimido[2,1-b][1,3]thiazin-8-one 12. It was found that some of the synthesized compounds showed interesting antimicrobial activity (by agar diffusion method) against some gram-positive and gram-negative bacilli strains.