Derivatives of (Z)-1,2-diphenylethene

Abstract

The present invention relates to the new chemical compounds containing (Z)-1,2-diphenylethene moiety in the structures, particularly the new derivatives of cis-stilbene, the new derivatives of 4,5-diphenyl-1,3-oxazole, the new derivatives of 1-methyl-4,5-diphenyl-1H-imidazole and pharmaceutically acceptable salts thereof. The invention relates also to the application of aforementioned compounds as a microtubule-interfering agents (MIAs). The new derivatives, because of their potential antimitotic and antiangio-genic activity, can be used as ingredients in the preparations used in the treatment of cancer.

Claims

1. The new 4,5-diphenyl-1,3-oxazole derivatives of the general formula 2, ##STR00008## wherein: R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5H, R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5H, and R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5H, and R.sup.6OCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6OCH.sub.3; R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NO.sub.2, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NO.sub.2, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5NO.sub.2, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NH.sub.2, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NH.sub.2, R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5NH.sub.2, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NHC(O)CH(NH.sub.2)CH.sub.2OH, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NHC(O)CH(NH.sub.2)CH.sub.2OH, and R.sup.6H; or R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5NHC(O)CH(NH.sub.2)CH.sub.2OH, and R.sup.6H.

2. A pharmaceutically acceptable salt of a 4,5-diphenyl-1,3-oxazole derivative of the general formula 2, ##STR00009## wherein: R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5H, R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5H, and R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5H, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5H, and R.sup.6OCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5H, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6SCH.sub.3; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6OCH.sub.3; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4H, R.sup.5OCH.sub.3, and R.sup.6OCH.sub.3; R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4SCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5OCH.sub.3, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NO.sub.2, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NO.sub.2, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5NO.sub.2, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NH.sub.2, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NH.sub.2, R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5NH.sub.2, and R.sup.6H; R.sup.1OCH.sub.3, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NHC(O)CH(NH.sub.2)CH.sub.2OH, and R.sup.6H; R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5NHC(O)CH(NH.sub.2)CH.sub.2OH, and R.sup.6H; or R.sup.1Br, R.sup.2SCH.sub.3, R.sup.3Br, R.sup.4OCH.sub.3, R.sup.5NHC(O)CH(NH.sub.2)CH.sub.2OH, and R.sup.6H.

3. A method of treating cancer comprising the step of administering a microtubule-interfering agent comprising a compound of claim 1 to a subject in need thereof.

4. The compounds according to claim 2, wherein the pharmaceutically acceptable salts comprise chlorides, bromides, phosphates, hydrogen sulfates (VI), sulfates (VI), acetates, citrates, tartrates, and lactates.

5. A 4,5-diphenyl-1,3-oxazole derivative of the general formula 2, ##STR00010## wherein R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R6H.

6. A pharmaceutically acceptable salt of a 4,5-diphenyl-1,3-oxazole derivative of the general formula 2, ##STR00011## wherein R.sup.1Br, R.sup.2OCH.sub.3, R.sup.3OCH.sub.3, R.sup.4OCH.sub.3, R.sup.5SCH.sub.3, and R6H.

7. A method of treating cancer comprising the step of administering a microtubule-interfering agent comprising a compound of claim 5 to a subject in need thereof.

8. The pharmaceutically acceptable salt of claim 6, comprising a chloride, a bromide, a phosphate, a hydrogen sulfate (VI), a sulfate (VI), an acetate, a citrate, a tartrate, or a lactate.

Description

DESCRIPTION OF THE FIGURES

(1) FIG. 1presents the general formulas of the new derivatives of cis-stilbene (formula 1), the new derivatives of 4,5-diphenyl-1,3-oxazole (formula 2) and the new derivatives of 1-methyl-4,5-diphenyl-1H-imidazole (formula 3).

(2) The following examples are given for the purpose of illustrating the present disclosure and should not be considered as limitation on the scope or spirit of the disclosure.

(3) .sup.1H and .sup.13C-NMR spectra were recorded on a Bruker Avance II 400 and Bruker Avance III 500 spectrometers at ambient temperature and in CDCl.sub.3 as a solvent. The chemical shifts are reported in ppm relative to tetramethylsilane (TMS) as an internal standard.

Example 1

(E)-3-(2-methylthiophenyl)-2-(3,4,5-trimethoxyphenyl)prop-2-enoic acid (1)

(4) 3,4,5-trimethoxyphenylacetic acid (0.450 g, 2 mmol), 2-methylthiobenzaldehyde (0.300 g, 2 mmol) and triethylamine (0.5 ml, 3.59 mmol) were added to the 5 ml of acetic anhydride. The mixture was refluxed for 2 hours, then cooled and treated with 6 ml of conc. HCl. The precipitate was filtered off, washed several times with water and then recrystallized from 92% ethanol. 0.28 g (38.8%) of product in form of yellow needles with melting point 192-194 C. was obtained.

(5) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.23 (s, 1H), 7.26 (d, J=8.8 Hz, 1H), 7.20 (t, J=8.2 Hz, 1H), 6.87 (t, J=8.0 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.76 (s, 1H), 6.40 (s, 2H), 3.84 (s, 3H), 3.69 (s, 6H), 2.52 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) 172.59, 153.01, 140.05, 139.46, 137.81, 133.68, 132.86, 129.89, 129.76, 129.26, 125.97, 124.75, 107.42, 104.86, 60.86, 56.03, 16.30.

Example 2

(Z)-1-(2-methylthiophenyl)-2-(3,4,5-trimethoxyphenyl)ethen (2)

(6) The (E)-3-(2-methylthiophenyl)-2-(3,4,5-trimethoxyphenyl)prop-2-enoic acid (1) (0.2 g, 0.55 mmol) and copper (0.18 g, 2.86 mmol) were added to 5 ml of quinoline, then the mixture was heated at oil bath of temperature 200 C. for 2 hours. The reaction mixture was cooled down to room temperature, filtered and washed with 10 ml of diethyl ether and then treated with 5 ml of concentrated HCl. The ether layer was separated and the aqueous layer was extracted with 310 ml of diethyl ether. The combined ether layers were washed with 30 ml of saturated sodium carbonate, 30 ml of water and 30 ml of brine, dried over with anhydrous MgSO.sub.4, filtered and evaporated under vacuum to obtain 0.464 g of brown oil. The separation was carried out on a chromatographic column in the system of hexane:ethyl acetate (10:4). A 0.157 g (90.2%) of product in the form of cream-colored crystals was obtained.

(7) .sup.1H NMR (500 MHz, CDCl.sub.3) 7.28 (dd, J=9.7, 8.2 Hz, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.08 (t, J=7.2 Hz, 1H), 6.67 (d, J=12.0 Hz, 1H), 6.59 (d, J=12.0 Hz, 1H), 6.41 (s, 2H), 3.83 (s, 3H), 3.62 (s, 6H), 2.50 (s, 3H). .sup.13C NMR (126 MHz, CDCl.sub.3) 152.70, 137.72, 137.30, 136.57, 131.96, 131.33, 129.51, 127.89, 127.69, 125.28, 124.72, 106.18, 60.86, 55.72, 15.62.

Example 3

N-[(toluene-4-sulfonyl)(3,4,5-trimethoxyphenyl)methyl]formamide

(8) 3,4,5-trimethoxybenzaldehyde (4.6 g, 23.44 mmol), p-toluenesulfonic acid (3.01 g, 19.29 mmol) and (+)-camphorsulfonic acid (0.110 g, 0.47 mmol) were added to 10 ml of form amide, then the mixture was heated at 60 C. for 16 hours under vigorous stirring. After cooling, the resulting precipitate was filtered off, washed with several portions of methanol and dried. 4.37 g (59%) of white crystalline product with melting point 155-157 C. was obtained.

3,4,5-trimethoxyphenyl(tosyl)methyl isocyanide

(9) N-[(toluene-4-sulfonyl)(3,4,5-trimethoxyphenyl)methyl]formamide (4.17 g, 11 mmol) was suspended in 100 ml of dimethoxyethane and the mixture was cooled down to 10 C. Then, phosphorus oxychloride (3.07 ml, 33 mmol) was added and then triethylamine (7.67 ml, 55 mmol) dissolved in 10 mL of DME, was slowly added dropwise. The flask content was then stirred at 5 C. for 2 hours, then poured into ice/water mixture (250 ml) and subsequently extracted with 360 ml of ethyl acetate. The combined ethyl acetate extracts were washed with 10% solution of NaHCO.sub.3, brine, and then dried with anhydrous MgSO.sub.4, filtered and evaporated under reduced pressure. 3.0 g (75.5%) of the product were obtained as pale yellow crystals with melting point 104-105 C.

(10) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.65 (d, J=8.1 Hz, 2H), 7.33 (d, J=8.1 Hz, 2H), 6.49 (s, 2H), 5.53 (s, 1H), 3.87 (s, 3H), 3.78 (s, 6H), 2.47 (s, 3H).

4-(3,4,5-trimethoxyphenyl)-5-(2-methylthiophenyl)oxazole (158)

(11) 3,4,5-trimethoxyphenyl(tosyl)methyl isocyanate (0.433 g, 1.2 mmol), 2-methylthiobenzaldehyde (0.152 g, 1.0 mmol) and anhydrous K.sub.2CO.sub.3 (0.33 g, 2.4 mmol) were added to a mixture of 10 ml of ethanol and 3 ml of DME, and then refluxed for 2 hours. After cooling down to room temperature, the mixture was concentrated under reduced pressure. Afterwards, it was treated with 50 ml of ethyl acetate, washed with water, brine solution, dried with anhydrous MgSO.sub.4, filtered and evaporated under reduced pressure. The residue (0.645 g) was purified by means of column chromatography in a system of hexane:ethyl acetate (1:1). 0.222 g (60%) of the cream-coloured crystalline product was obtained.

(12) .sup.1H NMR (400 MHz, CDCl.sub.3) 8.00 (s, 1H), 7.49-7.43 (m, 1H), 7.38 (d, J=7.6 Hz, 1H), 7.35 (d, J=7.3 Hz, 1H), 7.23 (t, J=8.1 Hz, 1H), 6.80 (s, 2H), 3.82 (s, 3H), 3.66 (s, 6H), 2.40 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) 153.09, 150.17, 143.75, 140.98, 137.57, 135.88, 131.54, 130.61, 127.68, 126.61, 125.57, 124.85, 103.35, 60.80, 55.69, 15.61.

Example 4

1-methyl-4-(3,4,5-trimethoxyphenyl)-5-(2-methylthiophenyl)imidazole (211)

(13) 2-methylthiobenzaldehyde (0.152 g, 1.0 mmol), 33% solution of methylamine in ethanol (0.62 ml, 5 mmol) and acetic acid (0.3 ml, 5.25 mmol) were added to 15 ml of ethanol and refluxed for 2 hours. After cooling down to room temperature, 3,4,5-trimethoxypheny(tosyl)methyl isocyanide (example 3) dissolved in 10 ml of DME was added followed by anhydrous K.sub.2CO.sub.3 (0.552 g, 4 mmol). The mixture was refluxed for 3 hours and next, after cooling, concentrated under reduced pressure. Afterwards, it was treated with 50 ml of ethyl acetate, washed with water, brine solution, dried with anhydrous MgSO.sub.4, filtered and evaporated under reduced pressure. The residue (0.578 g) was purified by column chromatography in ethyl acetate:methanol (19:1). 0.158 g (44.3%) of the product in the form of yellow oil was obtained.

(14) .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (s, 1H), 7.49-7.43 (m, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.28-7.22 (m, 2H), 6.76 (s, 2H), 3.79 (s, 3H), 3.62 (s, 6H), 3.43 (s, 3H), 2.38 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) 152.87, 141.79, 138.21, 137.22, 136.33, 132.04, 130.01, 128.98, 126.34, 124.97, 124.47, 102.40, 60.75, 55.52, 31.67, 14.8.