Fluorinated chromenes. Synthesis of 6,7-dimethoxy-2-methyl-2-trifluoromethyl-2H-chromene

Preparation of the title compound, a trifluoromethyl analog of the natural insect antijuvenile hormone 6,7-dimethoxy-2,2-dimethyl-2H-chromene (precocene II), from 3,4-dimethoxyphenol and 1,1,1-trifluoro-4,4-dimethoxy-2-methyl-2-butyl mesylate is described.     

Fragmentation of enamides derived from 6,7-dimethoxy-4-methyl-2H-1,3-benzothiazin and 3,4-dihydro-6,7-dimethoxy-1-methylixopuinoline

The electron impact mass spectra of several enamides have been examined. The enamides were prepared by reaction of aroyl halides with 6,7-dimethoxy-4-methyl-1,3-benzothiazin, and with 3,4-dihydro-6,7-dimethoxy-l-methylisoquinoline. The fragmentation pathways that have been proposed are supported by ion composition determinations and by mass-analysed ion kinetic energy spectrometry experiments carried out on the molecular ions and major fragment ions. The spectra are characterized by a loss of carbon monoxide from the molecular ion of each compound, a process which is accompanied by migration of the aryl group.     

Synthesis of 6,7-dimethoxy-1-halobenzyl-1,2,3,4-tetrahydroisoquinolines

Some 6,7-dimethoxy-1-halobenzyl-1,2,3,4-tetrahydroisoquinolines were synthesized from 2-(3,4-dimethoxyphenyl)ethylamine and halophenylacetic acids in three steps in good yield.     

Synthesis of novel 1,2-functionally-substituted 6,7-dimethoxy-4-spirocyclo-pentanetetrahydroisoquinolines

1-[(3,4-Dimethoxyphenyl)cyclopentyl]methylamine has been used in the synthesis of 6,7-dimethoxy-4-spirocyclopentane-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid N-methylamide which is employed in the preparation of novel derivatives with substituents in positions 1,2,6, and 7.     

Periphery-modified crown ethers. Synthesis of bis-5,8-dimethoxy-1,4-methanonaphthalene-fused crown ethers

The easily accessible and multi-functionalized 5,8-dimethoxy-6,7-dihydroxy methyl-1,4-dihydro-1,4-methanonaphthalene (1) has been utilized as the basic building material to synthesize the symmetric bis-methanonaphthalene-fused crown ethers 14a-d (BMN-16-crown-4, BMN-22-crown-6, BMN-28-crown-8, and BMN-34-crown-10), that are constructed based on the connection between the α,β-bis-benzylic carbon atoms of diol 1 and oligoethylene glycols (9a-d) via two synthetic routes keyed upon the method of Williamson ether synthesis.     

Studies on cardiotonic agents. V. Synthesis of 1-(6,7-dimethoxy-4-quinazolinyl)piperidine derivatives carrying various 5-membered heterocyclic rings at the 4-position

A series of 1-(6,7-dimethoxy-4-quinazolinyl)piperidines carrying various 5-membered heterocycles at the 4-position was synthesized and examined for cardiotonic activity in anesthesized dogs. The (4-oxo-2-thioxo-3-imidazolindinyl)amino derivatives showed the most potent inotropic activity. Marked loss of activity was observed in the 2,4-dihydro-3-thioxo-3H-1,2,4-triazolyl, the 2,4-dihydro-3-oxo-3H-pyrazolyl and the (2,3-dihydro-2-thioxo-3H-1,3,4-thiadiazol-5-yl)amino derivatives. The synthesis and structure-activity relationships are discussed.     

Studies on cardiotonic agents. IV. Synthesis of novel 1-(6,7-dimethoxy-4-quinazolinyl)piperidine derivatives carrying substituted hydantoin and 2-thiohydantoin rings

A series of novel 1-(6,7-dimethoxy-4-quinazolinyl)piperidines carrying substituted hydantoin and 2-thiohydantoin rings was synthesized and examined for cardiotonic activity in anesthetized dogs. Introduction of isopropyl and sec-butyl group at the 5-position of the hydantoin and thiohydantoin rings led to potent inotropic activity. Effects of insertion of an alkyl chain between the piperidine and the hydantoin rings were also examined. The structural requirements necessary for optimal cardiotonic activity within the series were investigated.     

Nitroimidazoles. V . Synthesis of 1-methyl-2-(2-methyl-4-thiazolyl)nitroimidazoles

Reaction of readily available 2-methyl-4-formylthiazole ( 1 ) with glyoxal and ammonia gave 2-(2-methyl-4-thiazolyl)imidazole ( 2 ). Nitration of 2 with a mixture of nitric acid-sulfuric acid at 100° yielded 2-(2-methyl-4-thiazolyl)-4,5-dinitroimidazole ( 3 ) as the sole reaction product, while nitration at 65° afforded 2-(2-methyl-4-thiazolyl)-4-(or 5)-nitroimidazole ( 4 ). N-Methylation of compound 4 in the presence of base gave 1-methyl-2-(2-methyl-4-thiazolyl)4-nitroimidazole ( 6 ), whereas N-methylation with diazomethane afforded 1-methyl-2-(2-methyl-4-thiazolyl)-5-nitroimidazole ( 5 ). N-Methylation of compound 3 yielded 1-methyl-2-(2-methyl-4-thiazolyl)-3,5-dinitroimidazole ( 7 ) in high yield.     

Synthesis and structure-active relationship of 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline anticonvulsants

We have previously disclosed that some 6,7-dimethoxyisoquinoline derivatives are able to produce anticonvulsant effects in different animal models of epilepsy. Following these studies this paper describes the synthesis of a small series of new 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines strictly related to previously reported analogues. This novel series of isoquinolines was designed on the basis of well defined structure-active relationship (SAR) information already acquired for this class of anticonvulsant agents. The pharmacological effects of the new synthesized compounds were evaluated against audiogenic seizures in Dilute Brown non-Agouti (DBA/2) mice. The preliminary pharmacological screening led to the identification of a new active molecule the 2-acetyl-1-(4'-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6d) that displayed significant anticonvulsant activity. Computational studies helped to rationalize these obtained pharmacological results.     

Synthesis and absorption spectra of 2-substituted 5,8-dimethoxy-4H-1-benzothiopyran-4-one 1,1-dioxides

2,3-Dibromo-5,8-dimethoxy-4H-1-benzothiopyran-4-one (thiochromone) 1,1-dioxide which was a starting material to prepare sulfone analogues of 1,4-naphthoquinone dyes was easily prepared from 5,8-dimethoxythiochroman-4-one by oxidation and bromination. The reactions of 2,3-dibromo-5,8-dimethoxythiochromone 1,1-dioxide 4 with aliphatic and aromatic amines in ethanol below 20° gave 2-substituted derivatives 12a-e and at higher reaction temperature the amination gave 2-arylamino derivatives 13c-e debrominated at C -3. The visible absorption spectra of these derivatives were investigated by the PPP MO method.     

4-取代-2-甲基-6,7-亚甲二氧基-3-喹啉酸乙酯的合成及表征

喹啉及其衍生物是合成抗疟药物和某些金属萃取剂的重要原料[1,2]。文献[3,4]曾报道2,3 二取代喹啉衍生物的合成方法。本文以1,2 亚甲二氧基苯为原料,通过酰化、硝化、还原和催化缩合,得到四种4 取代 2 甲基 6,7 亚甲二氧基 3 喹啉酸乙酯Ⅳ,产率为74～87%。化合物Ⅳa-Ⅳd分别通过IR、1HNMR谱、元素分析和质谱表征。合成路线如图1所示。R=a,CH3;b,C2H5;c,CH2CH2CH3;d,CH(CH3)2。图1　4 取代 2 甲基 6,7 亚甲二氧基 3 喹啉酸乙酯合成路线Fig.1　Syntheticroutenof4 substitrtedethyl 2 methyl 6,7 methylenedioxy 3 quinolinecar…     

Synthesis and antitumor activity of 6- and 2- （ 1-acyl sulfanylalkyl）-5,8-dimethoxy- 1,4-naphthoquinones

Sixteen novel 6- and 2-（1-acylsulfanylalkyl）-5,8-dimethoxy-l,4-naphthoquinones were designed and synthesized. Their cytotoxicities were evaluated in vitro against BEL-7402, HT-29 and SPC-Al cell lines. The pharmacological results showed that most of the prepared compounds displayed the excellent selectivity for HT-29 cell line. Compound lab exhibited the most potent antitumor activity among the tested compounds.     

Studies on cardiotonic agents. III. Synthesis of 1-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3-substituted 2-imidazolidinone and 2-imidazolidinethione derivatives

A series of 1-[1-(6,7-dimethoxy-4-quinazolinyl)-4-piperidinyl]-3-substituted 2-imidazolidinone and 2-imidazolidinethione derivatives was synthesized and examined for cardiotonic activity in anesthetized dogs. Alkylation of the 2-imidazolidinone (1) afforded the N-alkylated products, while alkylation of the 2-imidazolidinethione (12) afforded the S-alkylated derivatives accompanied with a small quantity of the N-alkylated products. The N-alkylated derivatives showed generally potent activity, and the S-alkylated ones exhibited weak activity. Insertion of an alkyl group between the piperidine and the imidazolidinone moiety generally resulted in a fall in activity.     

Synthesis and biological properties of 3-methyl-10-propargyl-5,8-dideazafolic acid

The synthesis of N³-methyl-10-propargyl-5,8-dideazafolic acid ( 1b ) is described. Ring closure of methyl-5-methylanthranilate with chloroformamidine hydrochloride gave a high yield of pure 2-amino-4-hydroxy-6-methylquinazoline treatment of which with iodomethane/sodium hydroxide provided the corresponding 3-methylquinazoline (6) which was converted to its 2-pivaloylamino derivative. This synthetic approach, next involving functionalisation of the 6-methyl group, was not further pursued because of difficulty encountered in removing the pivaloyl group. Methyl 5-methylanthranilate was treated with p-toluenesulfonyl chloride and the product then N-methylated. The tosyl group was cleaved with hydrogen bromide/phenol and the resulting methylamine ring-closed with chloroformamidine hydrochloride to provide 2-amino-1,4-dihydro-1,6-dimethyl-4-oxoquinazoline ( 11 ). The 2-pivaloylamino derivative of 11 was prone to hydrolytic deamination when attempts were made to remove the pivaloyl group and further elaboration of this heterocycle, with the intention of obtaining N¹-methyl-10-propargyl-5,8-dideazafolic acid was, too, not attempted. Di-t-butyl N-(4-propargylamino)benzoyl)-L-glutamate was therefore prepared and coupled with 2-amino-6-bromomethyl-4-hydroxyquinazoline hydrobromide. The resulting antifolate diester was N-monomethylated. Removal of the t-butyl groups with trifluoracetic acid afforded the target compound 1b and its structure was proved by degradation to the quinazoline 6 . Its IC₅₀ for L1210 thymidylate synthase (TS) was 26 μM; the control value for 10-propargyl-5,8-dideazafolic acid ( 1a ) was 0.02 μM. Thus the substitution of the lactam hydrogen in 1a by a methyl group reduced the TS inhibition by 1300-fold. Compound 1b was poorly cytotoxic to L1210 cells in culture (ID₅₀ > 100 μM). An unperturbed lactam group in this class of antifolate is important for binding to TS.     

2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one: Synthesis and investigation of serine protease inactivation

Summary 2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one was prepared by thermal treatment of 2-(3-benzoylthioureido)-4,5-dimethoxybenzoic acid and by benzoylation of 2-amino-6,7-dimethoxy-4H-3,1-benzoxazin-4-one. The inactivation of chymotrypsin and human leukozyte elastase by the title compound and 2-benzoylamino-4H-3,1-benzoxazin-4-one is reported.

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2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-on: Synthese und Untersuchung der Inaktivierung von Serin-Proteasen

Zusammenfassung 2-Benzoylamino-6,7-dimethoxy-4H-3,1-benzoxazin-4-on wurde durch thermische Behandlung von 2-(3-Benzoylthioureido)-4,5-dimethoxybenzoesäure und durch Benzoylierung von 2-Amino-6,7-dimethoxy-4H-3,1-benzoxazin-4-on hergestellt. Über die Inaktivierung von Chymotrypsin und humaner Leukozyten-Elastase durch die Titelverbindung und 2-Benzoylamino-4H-3,1-benzoxazin-4-on wird berichtet.