Synthesis and anticancer activity of some novel tetralin-6-yl-pyrazoline, 2-thioxopyrimidine, 2-oxopyridine, 2-thioxo-pyridine and 2-iminopyridine derivatives

The title compounds were prepared by reaction of 6-acetyltetralin (1) with different aromatic aldehydes 2a-c, namely 2,6-dichlorobenzaldehyde, 2,6-diflouro-benzaldehyde, and 3-ethoxy-4-hydroxybenzaldehyde, to yield the corresponding a,b-unsaturated ketones 3a-c. Compound 3b was reacted with hydrazine hydrate to yield the corresponding 2-pyrazoline 4, while compounds 3a,b reacted with thiourea to afford the 2-thioxopyrimidine derivatives 5a,b, respectively. The reaction of 1, and the aromatic aldehydes 2a-c with ethyl cyanoacetate, 2-cyano-thioacetamide or malononitrile in the presence of ammonium acetate yielded the corresponding 2-oxopyridines 6a,b, 2-thioxopyridines 7a-c or 2-iminopyridines 8a,b, respectively. The newly prepared compounds were evaluated for anticancer activity against two human tumor cell lines. Compound 3a showed the highest potency with IC(50) = 3.5 and 4.5 μg/mL against a cervix carcinoma cell line (Hela) and breast carcinoma cell line (MCF7), respectively.     

若干D环带硝基的小檗因衍生物的光环化合成

通过酰烯胺的光环化反应, 合成了六个D环带硝基的小檗因类化合物。在酰烯胺的制备中, 还得到了几个非预期的副产物, 阐明了它们的结构。     

Synthesis and Reactions of Some Substituted Heterocyclic Systems as Anti-arrhythmic Agents

Summary. A series of substituted heterocyclic systems were prepared from N ¹-[4-(2-thienylmethylene)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Condensation of the thienylmethylene derivative with guanidine hydrochloride, urea, or thiourea afforded the aminopyrimidine, pyrimidinone, and thioxopyrimidine derivatives. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. Treating of the thienylmethylene derivative with phenylhydrazine or hydrazine hydrate in dioxane afforded N-phenylpyrazoline and a pyrazoline, which was reacted with acetyl chloride in dioxane affording the N-acetyl analogue. The thienylmethylene derivative was reacted with malononitrile or ethyl cyanoacetate in the presence of ammonium acetate to yield the corresponding cyanoaminopyridine and cyanopyrimidone derivatives. Also, it was reacted with hydroxylamine hydrochloride in pyridine to give the oxime derivative, which was cyclized with acetic anhydride. On the other hand, condensation of the thienylmethylene derivative with ethyl cyanoacetate in the presence of sodium ethoxide or cyanothioacetamide gave the cyanopyrane and pyridine thione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Synthesis and Reactions of Some Substituted Heterocyclic Systems as Anti-arrhythmic Agents

A series of substituted heterocyclic systems were prepared from N ¹-[4-(2-thienylmethylene)phenyl]-5-chloro-2-methoxybenzamide, which was prepared from the corresponding 5-chloroanisic acid (2-methoxy-4-chlorobenzoic acid) as starting material. Condensation of the thienylmethylene derivative with guanidine hydrochloride, urea, or thiourea afforded the aminopyrimidine, pyrimidinone, and thioxopyrimidine derivatives. The latter was condensed with chloroacetic acid to yield a thiazolopyrimidine, which was condensed with 2-thiophenealdehyde to yield the arylmethylene derivative, however, it was also prepared directly from thiopyrimidine by the action of chloroacetic acid, 2-thiophenealdehyde, and anhydrous sodium acetate. Treating of the thienylmethylene derivative with phenylhydrazine or hydrazine hydrate in dioxane afforded N-phenylpyrazoline and a pyrazoline, which was reacted with acetyl chloride in dioxane affording the N-acetyl analogue. The thienylmethylene derivative was reacted with malononitrile or ethyl cyanoacetate in the presence of ammonium acetate to yield the corresponding cyanoaminopyridine and cyanopyrimidone derivatives. Also, it was reacted with hydroxylamine hydrochloride in pyridine to give the oxime derivative, which was cyclized with acetic anhydride. On the other hand, condensation of the thienylmethylene derivative with ethyl cyanoacetate in the presence of sodium ethoxide or cyanothioacetamide gave the cyanopyrane and pyridine thione derivative, which was treated with ethyl chloroacetate affording the ethyl carboxylate derivative. The pharmacological screening showed that many of these compounds have good anti-arrhythmic activity and low toxicity.     

Reactions of trinitromethyl-1,3,5-triazines with triphenylphosphine in the presence of hydrogen donors and a dipolarophile

2-Dialkylamino-4-methoxy-6-trinitromethyl-1,3,5-triazines reacted with triphenylphosphine in toluene in the presence of primary aliphatic alcohols as proton donors to give the corresponding 6-[hydroxyimino (nitro)methyl)-1,3,5-triazines. Analogous reactions in the presence of prop-2-yn-1-ol at elevated temperature resulted in the formation of [3 + 2]-dipolar cycloaddition products, 3-(1,3,5-triazinyl)-5-hydroxymethylisoxazoles.     

Reaction of 2-methoxy-3H-azepine with NBS: efficient synthesis of 2-substituted 2H-azepines

[reaction: see text] The reaction of 2-methoxy-3H-azepines, in the presence or absence of a nucleophile, with N-bromosuccinimide (NBS) gave a regioselective 1,4-adduct from which the corresponding 2H-azepine derivatives were formed via base-promoted hydrogen bromide elimination, generally in moderate to quantitative yield. Competitive formation of 4-bromo-2-methoxy-3H-azepine by electrophilic substitutuion or 3H-azepin-2-yl 2H-azepin-2-yl ether by transetherification was minimized at lower reaction temperatures. Quantitative substitution of 2-(2',4',6'-trichlorophenoxy)-2H-azepine derivatives, formed in moderate yield from the respective 3H-azepine and NBS in the presence of 2,4,6-trichlorophenol (TCP), by various nucleophiles gave the corresponding 2-substituted 2H-azepine. Among these nucleophiles were alkanethiol and alkylamine that are not tolerated in the reaction of 3H-azepine and NBS.     

Synthesis,Characterization, and Screening for Anti‐inflammatory and Antimicrobial Activity of Novel Indolyl Chalcone Derivatives

Because of the great biological importance of substituted indole derivatives, in the present study, a series of pyrazolylindole, thiazolylindole, and pyrimidinylindole derivatives have been synthesized with good yield. The precursor indolyl chalcone 2a – d was prepared by reaction of 3‐chloro‐1H‐indole‐2‐carbaldehyde 1 with different ketones. Then, compounds 3b – d , 4 , and 5a – d have been synthesized by the reaction of chalcones 2a – d with hydrazine, phenylhydrazine, and thiosemicarbazide. When the chalcone derivative 2b subjected to react with hydroxylamine hydrochloride gave isoxazolylindole derivative 6b . N‐thiazolidine pyrazolyl indole 7 was obtained by reacting compound 5a with ethyl chloroacetate. On the other hand, when chalcone derivative 2b allowed to react with urea and thiourea gave the corresponding pyrimidinylindole derivatives 8 and 9 . Finally, when chalcone derivative 2b reacted with ethyl cyanoacetate or malononitrile gave pyridinylindole derivatives 10 and 11 . The structures of the all synthesized compounds were elucidated on the basis of spectral analysis infrared, NMR, and mass spectroscopy. Some of the synthesized compounds were screened for their antimicrobial and anti‐inflammatory activity. Compound 4b was the highest antibacterial activity against all strains of bacteria with values higher than those of the corresponding reference antibiotics (ciprofloxacin and levofoxacin, respectively) and almost the same as (gemifloxacin, moxifloxacin, clindamycin, gentamycin, and streptomycin). Compounds 4 , 5 , 6 , and 7 showed high anti‐inflammatory activity compared with the standard drug indomethacin.     

<Emphasis Type="Italic">N</Emphasis>-(4-methoxy-3-nitrobenzyl) derivatives of some nitrogen-containing heterocycles

A number of nitrogen heterocycles reacted with 4-methoxy-3-nitrobenzyl chloride in dimethyl-formamide in the presence of potassium carbonate to give the corresponding N-(4-methoxy-3-nitrobenzyl) derivatives. The reaction of 5-fluoro-1,3-bis(4-methoxy-3-nitrobenzyl)pyrimidine-2,4(1H,3H)-dione with aqueous methylamine afforded N,N′-bis(4-methylamino-3-nitrobenzyl)urea, whereas analogous reaction with 1-(4-methoxy-3-nitrobenzyl)-2-(methylsulfanyl)-1H-benzimidazole resulted in substitution of the methoxy group by methylamino.     

Derivatives of 1-aryl-5-methoxyindoles

By fusion with potassium hydroxide, derivatives of 1-aryl-3-ethoxycarbonyl-5-methoxy-2-methylindole are converted into the corresponding indole-3-carboxylic acids. When the indole-3-carboxylic acids are heated to their melting points, they are readily converted into derivatives of 1-arylindoles with unsubstituted -positions. A similar cycle of conversions has been carried out for 3-ethoxycarbonyl-5-methoxy-2-methyl-1-phenylbenzoindole. The reactions of derivatives of 1-aryl-5-methoxy-2-methylindoles with formaldehyde and dimethylamine hydrochloride gives Mannich bases.     

双分子维生素B_(12)模型分子的合成及表征

维生素B_(12)经醇解得到的七甲基钴啉酯1作为起始原料，经酸性水解分别得 到b,c,d,e,f-单酸钴啉酯2b～2f, 2b～2f与3-咪唑基丙胺盐酸盐反应合成了相应的 酰胺钴啉酯衍生物3b～3f, 3b～3f在乙酸的作用下合成了双分子络合维生素B_(12) 模型化合物双-单腈六甲基-N-（3-咪唑基）丙酰胺钴啉酯高氯酸盐5b～5f，并对其 化学结构进行了表征。     

Alkyl Esters of 2-[5-Chloro(bromo)-6-methoxy-4-methylpyrimidinyl-2-oxy]alkanoic Acids

The reaction of a mixture of formaldehyde and sodium cyanide or of lactic acid nitrile with trimethyl(6-methoxy-4-methylpyrimidinyl-2)ammonium chloride give the 2-(6-methoxy-4-methylpyrimidinyl-2-oxy)alkanoic acid nitriles. They were subsequently converted to the corresponding alkyl esters by a Pinner reaction and then to their 2-(5-halo-6-methoxy-4-methylpyrimidinyl-2-oxy) derivatives using N-halosuccinimides.     

含噻二唑官能基的对叔丁基硫桥杯[4]芳烃衍生物的合成及结构

以对叔丁基硫桥杯[4]芳烃(1)为原料, 在碳酸钾存在下与碘甲烷反应, 生成1,3-二取代桥杯[4]芳烃(2), 其分别与1,2-二溴乙烷, 1,3-二溴丙烷在碳酸钾的存在下进行烷基化反应, 生成硫桥杯[4]芳烃衍生物3和4. 在氢氧化钠存在下,其与过量的含不同官能团的2-巯基-1,3,4-噻二唑反应, 生成下缘含1,3,4-噻二唑基的硫桥杯[4]芳烃衍生物5a, 5b, 6a和6b, 并通过了¹H NMR, ¹³C NMR, IR, MS和元素分析的确证. 同时, X射线分析确定了硫桥杯[4]芳烃3和5a的晶体结构.     

Some reactions of 4-[(2′,3′-diphenyl-6′-methoxy-5′-benzofuranyl)-methylene]- and 4-[(2′,3′-diphenyl-5′-methoxy-6′-benzofuranyl)-methylene]-2-phenyloxazolin-5-one

2,3-Diphenyl-5-formyl-6-methoxybenzofuran was reacted with hippuric acid to give 4-[(2′,3′-diphenyl-6′-methoxy-5′-benzofuranyl)methylene]-2-phenyloxazolin-5-one. The above mentioned oxazolone yielded 2,3-diphenyl-6-methoxybenzofuranylacetic acid by reaction with hydrazine hydrate, nitrous acid, benzene followed by acid hydrolysis. The reactions of the oxazolone with hydroxylamine hydrochloride and primary or secondary amines were also investigated.     

Synthesis of Azaheterocyclic Cymantrene Derivatives

The reduction of acetylcymantrene with sodium tetrahydridoborate gave cymantrenylethanol which was acylated with 4,5-dichloroisothiazole- and 5-(4-methylphenyl)isoxazole-3-carbonyl chlorides to obtain esters containing a 1,2-thia(oxa)zole fragment. The condensation of acetylcymantrene with 5-arylisoxazole-3- carbaldehydes, (5-arylisoxazol-3-yl)methoxybenzaldehydes (Ar = Ph, 4-Tol), and 4,5-dichloroisothiazole-3- carbaldehyde afforded the corresponding (E)-3-(azol-3-yl)-1-cymantrenylprop-2-en-1-ones. The resulting α,β- unsaturated ketones reacted with semicarbazide hydrochloride and thiosemicarbazide to produce substituted 4,5-dihydro-1H-pyrazole-1-carboxamides and -1-carbothioamides, and their reaction with hydroxylamine hydrochloride led to the formation of 4,5-dihydroisoxazoles containing cymantrene and 1,2-azole fragments. Heterocyclization of azolylcymantrenylpropenones with guanidine gave 2-aminopyrimidine derivatives, and dihydropyrimidine-2-thiones were obtained by their reaction with thiourea.     

Synthesis and properties of carbamoyl derivatives of 5-hydroxy-3,3,5-trimethylisoxazolidine

The reaction of 5-hydroxy-3,3,5-trimethylisoxazolidine with alkyl (or aryl) isocyanates gives N-alkyl(aryl)-carbamoyl-5-hydroxy-3,3,5-trimethylisoxazolidines, which react with methanol in the presence of p-toluenesulfonic acid to give 5-methoxy-1-carbamoyl derivatives of isoxazolidine. When arylcarbamoyl-5-hydroxy-3,3,5-trimethylisoxazolidines are heated in carbon tetrachloride, they are converted to O-arylcarbamoyl-N-(2-methyl-4-oxo-2-pentyl)hydroxylamines, the treatment of which with hydrogen chloride in benzene made it possible to isolate 1,2,6-oxadiazepin-7-ones along with the hydrochloride of the given compounds.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 746–750, June, 1979.     

Utility of (p‐Sulfonamidophenyl)azomalononitrile,and Ethyl Acetoacetate in Synthesis of Fused Azole and Azines Derivatives II

[(p‐Sulfonamidophenyl)azo]malononitrile ( 1a,b ) reacted with N‐cyclohexanemethylidene‐2‐cyanoacetohydrazide, N'‐arylmethylidene‐2‐cyanoacetohydrazide ( 3a‐c ), S‐methylthiourea and hydrazine hydrate to afford [1,2,4]triazolo‐[1,5‐a]pyridinone derivatives ( 2a,b ) & ( 4a‐c ), substituted pyrimidines 5a,b and 6a,b. The corresponding pyridazinones 7a,b were synthesized from the reaction of 1c,d with ethyl cyanoacetate. Compound 7a,b reacted with elemental sulfur to yield 8a,b . Compound 6a underwent cycloaddition with α‐cinnamonitrile 9a‐e to yield 11a‐c, 14 and 15 . Also, compound 6a reacted with β‐ketoester and 1,3‐diketones to give 16, 17 and 18 .     

Studies on 5-arylidene-3-phenyl-2-methylmercaptohydantoins

The action of ammonium acetate on 5-arylidene-3-phenyl-2-methylmercaptohydantoins 1g,h in acetic acid led to the formation of the 5-arylidene-3-phenylhydantoin derivatives 4a,b . In absence of a solvent, ring opening and rearrangement took place with the formation of the 5-arylidene-N²-phenylglycocyamidine derivatives 7a-c . Compounds 7a-c reacted with methyl iodide to afford the corresponding 3-methyl derivatives 9a-c . The structures of the synthesised products were established and the mechanism proposed for the rearrangement reaction was discussed.     

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-diones

Ring transformation of 6-methyl-3,4-dihydro-2H-1,3-oxazine-2,4-dione (Ia) and its N-sub-stituted derivatives, such as 3-methyl (Ib), 3-ethyl (Ic), and 3-benzyl (Id) derivatives is described. Reaction of Ia with hydrazine hydrate gave 1-amino-6-methyluracil (II), while Id reacted with hydrazine hydrate to give 3-hydroxy-5-methylpyrazole (III). Reaction of Ia,b,d with ethyl acetoacetate in ethanol in the presence of sodium ethoxide afforded ethyl 3-acetyl-6-hydroxy-4-methyl-2(1H) pyridone-5-carboxylate derivatives (IVa,b,d). On the other hand, reaction of Ib,c,d with ethyl acetoacetate in tetrahydrofuran in the presence of sodium hydride did not give IV, but gave 3-acetyl-1-alkyl-5-(N-alkylcarbamoyl)-6-hydroxy4-methyl-2(1H) pyridone (VIb,c,d). Mechanisms for the formation of compounds IV and VI are discussed.     

叶绿素-a及其衍生物的Qy轴向氧化反应和E-环重排反应

在酸碱性条件下对叶绿素-a (1)进行空气氧化反应, 分别得到卟吩衍生物2b～4b; 通过酯交换和去金属镁离子, 将叶绿素-a转化为脱镁叶绿酸-a甲酯(MPa) (5), 其3-位碳碳双键与氯化氢的加成生成卟吩醇(6), 经碱性空气氧化和E-环重排则转化成紫红素-18衍生物7. 选用四氧化锇和高碘酸钠将5氧化成卟吩醛(8), 在丁醇中以丁醇钠作催化剂, 8的氧化和重排反应给出3-甲酰基紫红素-18酯(9)和紫红素-7三甲酯衍生物10. 异构体4的空气氧化和重排反应也生成紫红素-18酯(3), 进一步与2-甲基丁胺进行缩合反应, 得到N-烷基紫红素-18酰亚胺(11a)以及氧化重排产物3-甲酰基-N-烷基紫红素-18酰亚胺(11b). 所得叶绿素衍生物均经UV, IR, 1H NMR及元素分析证明其结构, 并对相应的反应提出可能的反应机理.     

Synthesis and Antimicrobial Activity of Novel Heterocycles Utilizing 3‐(1,4‐Dioxo‐3,4‐dihydrophthalazin‐2(1H)‐yl)‐3‐oxopropanenitrile as Precursors

The reaction of 3‐(1,4‐dioxo‐3,4‐dihydrophthalazin‐2(1H)‐yl)‐3‐oxopropanenitrile 1 and salicyladehyde furnished coumarin derivatives 4 and 5 . Coupling reaction of 1 with aryl diazonium chlorides and benzene‐1,4‐bis (diazonium) chloride gave the corresponding hydrazones 6a , b and bishydrazone 9 , respectively. Hydrazones 6 underwent intramolecular cyclization upon treating with hydrazine hydrate to give 3‐aminopyrazoles 7 . Pyranyl phthalazine 13 was prepared from the reaction of 1 with ethyl 2‐cyano‐3‐ethoxyacrylate 10 . Enaminonitrile 14 was reacted with hydrazine hydrate/phenylhydrazine and hydroxylamine to afford the corresponding pyrazoles 16 and oxime 17 . The antimicrobial evaluation revealed pyrazole derivatives 7a , b and 16a , b displayed a broad spectrum activity against most strains. 3‐Aminopyrazole derivative 7b showed potent antibacterial activity against all tested microorganisms.