α,β-Unsaturated nitriles in heterocyclic synthesis. II. Synthesis of Pyrazolo[3,4-b]pyridine and Pyrazolo[1,5-a]pyrimidine derivatives of antipyrine

5-Amino-3-antipyrinyl-pyrazole ( 1 ) reacted with cinnamonitriles 2a and 2c , d to afford 5-amino-4-benzylidene-pyrazole derivatives 3a , b . Compound 1 reacted with two moles of 2a to yield pyrazolo[3,4-b]pyridine derivative 7a which could be also obtained from the reaction of 3a with 2a . The reaction of 1 with α-cyanochalcone 2e resulted in the formation of pyrazolo-[1,5-a]pyrimidine derivative 8 .     

5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-芳磺酸酯新型化合物的合成及生物活性

三唑类化合物具有广泛的生物活性。以2-羟基-5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶为原料,在缚酸剂存在下,于室温分别和苯磺酰氯、对甲苯磺酰氯进行酯化反应,合成了两个新型的5,7-二甲基-1,2,4-三唑并[1,5-a]嘧啶-2-芳磺酸酯化合物a和b。产物经质谱、红外光谱、核磁共振谱确证。初步生物活性表明,该化合物具有一定的杀菌活性和除草活性,其中a有较高除草活性,而b对禾本科植物有较好的促进生长活性。     

2-巯基-5，7-二甲基-1，2，4-三唑并[1，5—α]嘧啶的合成

2-巯基-5,7-二甲基-1,2,4-三唑并[1,5—α]嘧啶是合成三唑并嘧啶类衍生物的重要中间体。实验研究了以5-氨基-3-巯基-1,2,4-嘧啶为原料,与乙酰丙酮环合制备2-巯基-5,7-二甲基-1,2,4-三唑并[1,5-α]嘧啶的工艺条件,研究结果表明,在AMZ与乙酰丙酮物质的量比为1：1．1、反应温度为120℃、反应时间为10h时,2-巯基-5,7-二甲基-1,2,4-三唑并[1,5-α]嘧啶的收率达到80％。     

2-氨基-5,7-二甲氧基-1,2,4-三嗪并[1,5-a]嘧啶的合成及工艺优化

2-氨基-5,7-二甲氧基-1,2,4-三嗪并[1,5-a]嘧啶的合成及工艺优化。以4,6-二甲氧基嘧啶-2-胺为主要原料,经两步反应制得2-氨基-5,7-二甲氧基-1,2,4-三嗪并[1,5-a]嘧啶;并考察了第二步合成工艺。通过熔点测定和1HNMR确证了2-氨基-5,7-二甲氧基-1,2,4-三嗪并[1,5-a]嘧啶;找到了最佳合成工艺,总收率81%。该合成方法具有反应条件温和、成本低、适合工业生产等优点。     

s-triazolo[4,3-a][1,3]diazacycloalkans. V. Synthesis of new derivatives of 3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo[4,3-a]pyrimidine

1-Ethoxycarbonyl-2-methylthio-1,4,5,6-tetrahydropyrimidine ( 1 ) reacting with acylhydrazines, affords 2-acyl derivatives of 3-oxo-2,3,5,6,7,8-hexahydro-s-triazolo [4,3-a] pyrimidine ( 2 ) or 2-acylhydrazine derivatives of 1 . The acylation of 2 and its 2-phenyl derivative 3 with isothiocyanates give corresponding 3-oxo-2,3,5,6,7,8 nexahydro-s-triazolo [4,3-a] pyrimidine 11a, b, 13a, e and 14 .     

Studies on aminoazoles: Synthesis of Pyrazolo[1,5-a]-pyrimidines and their aza derivatives

The reaction of 4-arylazo-3-aminopyrazol-5-ones ( 1a – i ) with α,β-unsaturated nitriles, active methylene reagents and nitrile imines are reported. They lead to new polyfunctional derivatives of pyrazolo[1,5-a]pyrimidine ( 5a – c , 6 , 10a – i , 13a – c , 14a – c , 17a – d , 15 ), pyrazolo-[5,1-c]-1,2,4-triazine ( 22a – i ) and pyrazolo[5,1-c]-1,2,4-triazole ( 25a – c ). The structures of these products and the mechanisms of their formation are reported.     

2-[4-(4-氟苄基)哌嗪-1-基甲基]吡唑并[1,5-a]吡啶的合成及其体外受体结合分析

以吡唑并[1,5-a]吡啶-2-甲醛和N-甲酰基哌嗪为原料,经过还原胺化反应、水解反应、N-烷基化反应,合成了2-[4-(4-氟苄基)哌嗪-1-基甲基]吡唑并[1,5-a]吡啶,总收率29.5%,用1HNMR、19FNMR、ESI-MS对中间体及目标化合物进行了结构表征,并通过体外受体结合实验,测定目标化合物对多巴胺D4受体的亲和常数为1.2nmol/L,对D2、D3受体的亲和常数分别为3 900、1 890 nmol/L,显示对多巴胺D4受体具有较高的亲和性与选择性,是一种潜在的多巴胺D4受体配基。     

Amino-thieno[2,3–c]pyrazole und Amino-thieno[2,3–b]pyrrole

Amino-thieno[2,3–c]pyrazoles and Amino-thieno[2,3–b]pyrroles The synthesis of thieno[2,3–c]pyrazoles and thieno[2,3–b]pyrroles is described. From the dithioliumsalt ( 1 ) and potassium hydroxide the potassium-(2,2-dicyan-1-methylthio-ethen-1-yl)-thiolate ( 2 ) is formed. This reacts with hydrazine hydrate to form the 3-amino-5-thioxo-pyrazol-4-carbonitrile ( 3 ) S-Alkylation with α-chlorocarbonyl compounds yielding ( 6a–c ) leads via Thorpe-Ziegler-cyclization to 3,4-diamino-thieno[2,3–c]pyrazoles ( 9 ) if the position 1 is alkylated ( 8 ). Acetyl acetone yields 2-mercapto-pyrazolo[1,5–a]pyrimidine ( 5 ). After S-alkylation ( 10a–d ) are immediately cyclized to thieno [2′,3′:3,4]pyrazolo[1,5-a]pyrimidine ( 11a–d ). The ketone ( 6a ) can be cyclized to the pyrazolo [5,1–b]thiazole ( 12 ). 3 reacts with oxalyl chloride to form the 2,3-dioxo-6-thioxo-imidazo[1,2-b]pyrazole ( 13 ) of which S-phenacyl derivative ( 14 ) because the NH-proton cannot be cyclized. The 5-amino-3,4-dicyano-pyrrol-2-thiolate ( 16 ) shows the analogous behaviour. The S-alkylation is followed by cyclization, and 3,5-diamino-thieno[2,3–b]pyrroles ( 18a–b ) arise. Reaction of 5-amino-2-alkylthio-pyrrol-3,5-dicarbonitrile ( 17 ) with acetyl acetone provides pyrrolo[1,2-a]pyrimidine ( 20a–c ) which can be cyclized to form thieno[3′,2′:4,6]pyrimidines ( 21a–c ) very easily.     

Synthesis of pyrazolo[4′,3′:5,6]pyrazino[2,3-c]pyrazoles and pyrazolo[4′,3′:5,6]pyrazino[2,3-d]pyrimidines and their application to polyester fibres

4-Nitroso-1-phenyl-3-methyl-5-aminopyrazole ( 1 ) was condensed with ethylcyanoacetate ( 2 ), malononitrile ( 4a ) and 2-cyanomethylbenzimidazole ( 4b ) to yield 6-hydroxy-5-cyano, 6-amino-5-cyano and 6-amino-5-(benzimidazol-2-yl)-3-methylpyrazolo [3,4-b]pyrazines 3, 5a and 5b , respectively. 5-Cyano-6-chloro derivative 6 obtained from 3 was converted to 3-aminopyrazolo[4′,3′:5,6]pyrazino[2,3-c]pyrazoles 8a and 8b by the treatment with hydrazin hydrate ( 7a ) and phenylhydrazine ( 7b ), respectively. Compound 5a was treated with formamide ( 9a ), urea ( 9b ) and thiourea ( 9c ) to give 4-aminopyrazolo[4′,3′:5,6]pyrazino[2′3′-d]pyrimidines 10a–10c. With refluxing acetic anhydride compounds 8a, 8b and 10a gave corresponding acetamido derivatives 8c, 8d and 10d. Compound 5a was treated with ethylorthoformate ( 11 ), acetic anhydride ( 12 ) or benzoylchloride ( 13 ) to give fused benzimidazopyrazolo[4′,3′:5,6]pyrazino[2′,3′-d]pyrimidines, viz., benzimidazol[1,2-c]pyrazolo[4,3-g]pteridines ( 14a–14c ). Some of the compounds 8, 10 and 14 were applied to polyester as disperse dyes and their fastness properties were studied.     

Synthese neuer Thieno [2′,3′; 4,5]imidazo[1,2-a]pyridiniumsalze

Syntheses of New Salts of Thieno[2′,3′;4,5]imidazo[1,2-a]pyridines Mesomeric 1-[2-amino-1-cyano-2-thio-]ethene-pyridinium ylides 1 are cyclizized to imidazo[1,2-a]pyridinium ylides 2 in the presence of HgO. S-alkylation of 2 leads to derivatives of 1-R¹-2-thio-3-cyano-imidazo[1,2-a]pyridinium halides 3 or 4 . Alkylation products from 2 with α-haloketones are cyclizized to thieno[2′,3′ 4,5]imidazo[1,2-a]pyridinium salts 5 .     

Anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates as p53 activators in cervical cancer cells

A library of new anthranilamide-pyrazolo[1,5-a]pyrimidine conjugates were designed, synthesized, and evaluated for their anticancer activity in cervical cancer cells such as HeLa and SiHa that possess low levels of p53. All 24 conjugates showed antiproliferative activity, while some of them exhibit significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G(2) /M arrest in HeLa cells and G(1) cell-cycle arrest in SiHa cells. Immunocytochemistry assays revealed that these compounds cause nuclear translocation of p53, thereby indicating the activation of p53. In cervical cancer cells, the p53 protein is degraded by E6 oncoprotein. Immunoblot and RT-PCR analyses proved the presence of mitochondria-mediated apoptosis with involvement p53 target genes such as BAX, Bcl2, and p21 (CDKI). Moreover, these compounds increased the phosphorylated forms of p53 and provide signals for apoptosis induction. Interestingly, one of the conjugates, (2-phenyl-7-(3,4,5-trimethoxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl)(4-(2-(thiophen-2-ylmethylamino)benzoyl)piperazin-1-yl)methanone, is the most promising candidate in this series and has the potential to be taken up for further detailed studies.     

Heterocyclic Synthesis with Nitriles: Synthesis of some novel pyrrolo [2,1-b]thiadiazoline,pyrrolo[2,1-b]thiadiazolo[3,2-a]pyrimidine and pyridine derivatives

α-(Bromothiocyanatomethyl)benzylidenemalononitrile ( 1 ) reacts with the hydrazides 2a – c , cyanoacethoydrazide ( 2d ,) cyanoacetamide ( 3a ) and cyanoacetanilides 3b – d to afford pyrrolo[2,1-b]thiadiazolines 5a – c , pyrrolo[2,1-b]thia-diazolo[3,2-a]pyrimidine ( 8 ) and the pyridone derivatives 11a – d . Structures and conceivable mechanisms are discussed.     

Synthesis of pyrazolo[4′,3′:5,6]pyrido[1,2-a]benzimidazole derivatives and study of their fluorescence properties

Synthesis of pyrazolo[4′,3′ :-5,6′pyrido]1,2-a benzimidazoles was achieved by the condensation of 1-chloro-2-formyl-3-methyl pyrido[1,2-a]benzimidazole-4-carbonitrile and 1-chloro-3-methyl pyrido[1,2-a]benzimidazole-2,4-dicarbonitrile with hydrazine hydrate and phenyl hydrazine. The fluorescence properties of the resulting compounds were studied. Some of the compounds when applied on polyester fibres as fluorescent brighteners gave excellent results.     

Thieno[2,3-d]pyrimidine 3-oxides. Synthesis and N-oxide reactions of 4-Phenyl- and 4-Aminothieno[2,3-d]pyrimidine 3-oxides

Two 4-phenylthieno[2,3-d]pyrimidine 3-oxides, 2a , 2b and two 4-aminothieno[2,3-d]pyrimidine 3-oxides, 12a, 12b , have been prepared. The two former are easily reduced with PCl₃ to the corresponding 3-desoxy derivatives and undergo the Polonovski rearrangement. It has not been possible to observe such reactions with 12a and 12b which instead seem to yield phosphorous acid derivatives and N-acetylated products, respectively.     

5,7-二甲基-N-芳基-1,2,4-三唑[1,5-a]嘧啶-2-磺酰胺的合成

以5-氨基-3-巯基-1,2,4-三唑为原料,经氧氯化后分别与6个芳胺反应,得到5氨基-N-芳基1,2,4-三唑-3-磺酰胺,继而和乙酰丙酮于乙酸中环合,制得6个取代的1,2,4-三唑[1,5-a]嘧啶-2-磺酰胺衍生物,同时讨论了胺解反应和环合反应的影响因素。所有目标产物的结构均经IR和1HNMR谱验证。     

Chinoxaline. XXIV. Synthese von 4-substituierten 1,2,3-Triazolo[1,5-a]chinoxalinen

Quinoxalines. XXIV. Synthesis of 4-Substituted 1,2,3-Triazolo [1, 5-a] quinoxalines 3-Substituted quinoxaline-2-carbaldehydes 1 react with tosylhydrazide to give 3-substituted quinoxaline-2-carbaldehyde tosylhydrazones 2 . The treatment of 2 with a boiling solution of sodium methoxide or ethoxide – the so called Bamford-Stevens reaction – leads to 4-substituted 1,2,3-triazolo[1,5-a]quinoxalines 4 in high yields. Some of these compounds were also obtained by thermolysis of 2 .     

New syntheses of pyrazolo[3,4-d]pyrimidine,pyrazolo[3,4-d]pyridazine,isoindolinedione and pyrazole derivatives

Phenacylmalononitriles 2 react with hydrazines, acetic-hydrochloric acid and with diazotised primary aromatic amines to afford phenacylpyrazole ( 5a,b ), aminofurans ( 6a,b ) and aminopyrazole derivatives ( 3a,d ) respectively. The synthesised derivatives ( 3d, 6a ) were the key materials for the synthesis of isoindolinedione, ( 7a – c ) pyrazolopyrimidine ( 9, 10 ), and pyrazolopyridazine derivatives ( 11 ). The structures of the newly synthesised heterocycles were established on the basis of elemental analyses and spectral data besides synthesis via other routes.     

Chinoxaline. XXVI. Synthese von bis-azolo[a,c]kondensierten Chinoxalinen. I. Darstellung aus 4-substituierten 1,2,3-Triazolo[1,5-a]chinoxalinen

Quinoxalines. XXVI. Synthesis of Bis-azolo[a,c]-fused Quinoxalines. I. Synthesis from 4-Substituted 1,2,3-Triazolo[1,5-a]quinoxalines The synthesis of bis-azolo-fused quinoxalines of type. 6 is described. The new bisazolo-fused compounds 9, 10a, b, 12 , and 16 were synthesized from the 4-substituted 1,2,3-triazolo-[1,5-a]quinoxalines 7, 8, 11 , and 13 by intramolecular cyclization reactions. The structures were determined by microanalysis, i.r., ¹H-n.m.r., and mass spectra.     

Synthese von Pyrrolo[1,2-a]chinazolinonen,Indolo[1,2-a]chinazolinonen,Pyrrolo[1,2-a]thieno[3,2-e]pyrimidinonen,Benzothieno[3,2-e]-pyrrolo[1,2-a]pyrimidinonen und 6H-Cyclohepta[4,5]thieno-[3,2-e]pyrrolo[1,2-a]pyrimidinonen

A Synthesis of Pyrrolo[1,2-a]quinazolinones, Indolo[1,2-a]-quinazolinones, Pyrrolo[1,2-a]thieno[3,2-e]pyrimidinones, Benzothieno[3,2-e]pyrrolo[1,2-a]pyrimidinones and 6H-Cyclohepta[4,5]-thieno[3,2-e]pyrrolo[1,2-a]pyrimidinones α-Cyano-γ-halo-crotonnitriles ( 1 ) synthesized (e.g. via Knoevenagel reaction and by subsequent halogenation) react with primary arylamines ( 2 ) to substituted 1-aryl-2-amino-3-cyano-pyrroles ( 3 ). We found that the reaction yields pyrrolo[1,2-a]quinazolin-5-ones ( 6 ) in a one-pot procedure if anthranilic esters ( 4 ) and compounds of the general formula 5 are used. The analogous treatment with 2-amino-3-ethoxy-carbonyl-thiophene derivatives ( 8 ) leads to pyrrolo[1,2-a]thieno-[3,2-e]pyrimidin-5-ones, benzothieno[3,2-e]pyrrolo[1,2-a]pyrimidinones and 6H-Cyclohepta[4,5]-thieno[3,2-e]pyrrolo[1,2-a]pyrimidinones as thiadiazastereoid analogs 9 . This reaction is suitable for the synthesis of various heterocyclic ring systems.     

2-{[5-（取代吡唑-5-基）-1，3，4-噁二唑-2-基]甲巯基）-5，7-二甲基-1，2，4-三唑[1，5-a]嘧啶类化合物合成及生物活性

设计并合成了七个2-{[5-（取代吡唑-5-基）-1,3,4-噁二唑-2-基]甲巯基）-5,7-二甲基-1,2,4-三唑[1,5-a]嘧啶类化合物,均为未见文献报道的新化合物。目标产物的结构经元素分析、IR、MS和^1H NMR测定确证,初步生物活性测试表明标题化合物具有一定的除草活性。