Caffeine Derivatives. I. The 8-Ethers of Caffeine

Abstract

The temperature at which the sulfur is kept affects the yields: at 300°the reaction was slow (5% conversion per passage) while at 400°the ultimate yield was 41% and an inconveniently large amount of sulfur distilled over. Dilution of the isopfene with carbon bisulfide (1:1) increased the yield Of crude 3-uléthylthiophene at 350°to 51%.Thiophene.-Crude 50% butadiene6 yielded 6% of thiophene when bubbled through molten sulfur at temperatures ranging from 320 to 420°, The same yield was obtained when pure liquid butadiene (from the tetrabromide) was dropped into the apparatus from a chilled separatory funnel. The thiophene boiled at 82-84°, had a density ¿is 1.05, gave a blue indophenin reaction, and with mercuric chloride yielded 2-chloro-mercurithiophene which did not depress the meltirrg point of authentic material. Carbon bisulfide was again noted as a by-product.2,3-Dimethylthiophene.-A distillate fraction boiling at 45-160°was obtained from the pyrolysis products of a mixture of crepe rubber and zinc oxide. This fraction had previously been shown to contain about 4% of 3methyl l,3-pefttadíene, mixed with mono-olefins and hydromatic compounds. One hundred grams of this ma-(6) We are indebted to Dr. B. T. Brooks for a generous supply of this material.

Analgesic activity of new 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives with carboxylic, ester or amide moieties

“…The methyl 2-(1,3-dimethyl-2,6,8-trioxo-2,3,8,9-tetrahydro-1H-purin-7(6H)-yl)acetate (8) was synthesized by acidic hydrolysis of 4 following by esterification with methanol. Benzylamides (9, 10) and arylpiperazinamides (11)(12)(13)(14) were prepared in a reaction of 6 and 7 with respective amine (benzylamine or 1-arylpiperazine derivatives), using 1,1 0 -carbonylimidazole (CDI) as carbonyl group activating agent in DMF medium. The structures of the newly synthesized compounds 4-14 were confirmed by 1 H NMR spectra, LC/MS and elemental analyses.…”

“…In the writhing syndrome test, the investigated compounds (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) showed diversified analgesic properties (Tables 1a and 1b).…”

“…In this paper we described the synthesis and analgesic/anti-inflammatory activity of new 8-alkoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives with ester (4, 5), carboxylic (6, 7) or amide (9)(10)(11)(12)(13)(14) terminal groups (Scheme 1). We also obtained 8-oxo-purine-2,6-dione analog (8) with an additional acid function in the form of an enol group.…”

“…We also obtained 8-oxo-purine-2,6-dione analog (8) with an additional acid function in the form of an enol group. Furthermore to investigate the influence of an alkoxy substituent in the 8 position of purine-2,6-dione system on analgesic activity the described earlier: 8-bromo-1,3,7-trimethyl-1H-purine-2,6(3H,7H)-dione (8-bromocaffeine) 15 [11] and several 7-methyl substituted analogs of new series (16)(17)(18)(19) [12,13] were resynthesized (Scheme 2). The obtained compounds (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) were evaluated for their potential analgesic and anti-inflammatory activity in two in vivo models (writhing syndrome test and formalin test).…”

Synthesis, biological evaluation and Structure Activity Relationships (SARs) study of 8-(substituted)aryloxycaffeine

“…Anyway, in 1934, Ralph C. Huston (Huston and Allen, 1934) synthesized 8-substituted (-O-phenyl)caffeine by using Fisher's method (Fischer, 1884), which was later repeated by W. Wiglicerus (Wislicenus and Ko¨rber, 1902), and H. Biltz (Wislicenus and Ko¨rber, 1902), consisted simply in heating 8-halocaffeine in methyl or ethyl alcohol solution containing an excess of sodium or potassium alcoholate. Recently, Masakazu Sono et al (Sono et al, 1994) used electrochemical oxidation of caffeine using KF as electrode in 1.5 V in 2.5 h in MeOH and obtained 43% of 8-methoxycaffeine.…”