Organic compounds -- part of the class 532-570 series – Organic compounds – Sulfonate esters
Reexamination Certificate
1999-10-14
2001-07-03
Ramsuer, Robert W. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Sulfonate esters
C514S518000, C560S020000, C560S106000, C560S109000, C560S144000
Reexamination Certificate
active
06255517
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a thymol derivative represented by following Chemical Formula 1:
wherein, R
1
is a hydroxy group which may be protected with acetyl group or isobutyryl group, methyl group or —OR
6
(R
6
is benzyl, 4-nitrobenzyl, 4-methyl benzyl, 4-toluenesulfonyl or 4-methoxybenzyl); R
2
represents hydrogen, acetyl, isobutyryl, palmitoyl, benzoyl, 4-nitrobenzoyl, 4-methylbenzoyl, phenylacetyl, 4-nitrophenylacetyl, 4-fluorophenylacetyl, 4-methoxyphenylacetyl, methanesulfonyl, 4-methoxybenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-fluorobenzenesulfonyl, o-toluenesulfonyl, 2-nitro-o-toluenesulfonyl or p-toluenesulfonyl; R
3
and R
4
together forms an epoxy group, diol or olefin; and R
5
represents a hydroxy group which may be protected by acetyl group or isobutyryl group, methyl group or hydrogen; and
pharmaceutically acceptable salts or esters thereof, and anti-cancer agents comprising the same as an active component.
BACKGROUND OF THE INVENTION
The compound represented by Chemical Formula 38, which is a mother compound of a thymol derivative, was extracted from long tabacco grass (
Carpesium divaricatum
S.). It was firstly isolated and identified by Ferdinand et al. in 1961 (Chem. Ber., 102, 864-871, 1969). The intermediates of thymol were synthesized by Baliman, et al. (Tetrahedron Lett., 20, 2827-2828, 1972).
These thymol derivative are compounds of monoterpene derivatives, and it has been reported that terpene type compounds including monoterpenes generally show anti-tumor activity (The Journal of Biological Chemistry, 266(26), 17679-17685, Carcinogenesis 13(7), 1261-1264). The researches on the pharmacological mechanism of these compounds and developments for anti-cancer agents based on such researches have been actively performed up to the present.
SUMMARY OF THE INVENTION
As a result of intensive studies to develop compounds having excellent anti-tumor activity, the present inventors synthesized various thymol derivative of the present invention by using m-cresol and 2,4-dihydroxyacetophenone as starting material, and found that the compounds has excellent anti-tumor activity.
The present invention relates to a thymol derivative represented by following Chemical Formula 1:
wherein, R
1
is a hydroxy group which may be protected with acetyl group or isobutyryl group, methyl group or —OR
6
(R
6
is benzyl, 4-nitrobenzyl, 4-methyl benzyl, 4-toluenesulfonyl or 4-methoxybenzyl); R
2
represents hydrogen, acetyl, isobutyryl, palmitoyl, benzoyl, 4-nitrobenzoyl, 4-methylbenzoyl, phenylacetyl, 4-nitrophenylacetyl, 4-fluorophenylacetyl, 4-methoxyphenylacetyl, methanesulfonyl, 4-methoxybenzenesulfonyl, 4-nitrobenzenesulfonyl, 4-fluorobenzenesulfonyl, o-toluenesulfonyl, 2-nitro-o-toluenesulfonyl or p-toluenesulfonyl; R
3
and R
4
together forms an epoxy group, diol or olefin; and R
5
represents a hydroxy group which may be protected by acetyl group or isobutyryl group, methyl group or hydrogen; pharmaceutically acceptable salts and esters thereof, and anti-cancer agents comprising the same as the active component.
DETAILED DESCRIPTION OF THE INVENTION
Hereinafter, the processes for preparing the compounds represented by Chemical Formula 1 are more specifically described by referring to the reaction schemes.
Method 1
As can be seen from following Scheme 1, the phenolic hydroxyl group of compound of Chemical Formula 2, as the starting material, is acetylated with acetyl chloride to give compound of Chemical Formula 3, which is then subjected to Fries reaction to obtain compound of Chemical Formula 4 wherein acetyl group has been introduced. By using methyl magnesium bromide, compound of Chemical Formula 5 is formed therefrom. Then, the phenolic hydroxyl group is protected by using acetic anhydride, and the tertiary hydroxyl group is simultaneously removed to give compound of Chemical Formula 6. The ester group of compound (6) is hydrolyzed to give compound of Chemical Formula 7, of which the phenolic hydroxyl group is then subjected to esterification by using isobutyric acid, to obtain compound of Chemical Formula 8. Then, a hydroxyl group is introduced to the allylic position of the double bond by using selenium dioxide as a catalyst, to form compound of Chemical Formula 9. When various acids are combined with the newly made hydroxyl group, various compounds represented by Chemical Formula 10 are obtained. The compound (10) is then subjected to epoxidation reaction to provide desired compound of Chemical Formula 11.
Scheme 1.
Method 2
As can be seen from following Scheme 2, a hydroxyl group is introduced to the allylic position of the double bond of compound (6) obtained from Method 1, by using selenium dioxide as a catalyst, to form compound of Chemical Formula 12. When various acids are combined with the newly made hydroxyl group, various compounds represented by Chemical Formula 13 are obtained. The compound (13) is then subjected to epoxidation reaction to provide desired compound of Chemical Formula 14.
Method 3
As can be seen from following Scheme 3, a compound (13), which was obtained as an intermediate from Method 2, is oxidized with osmium tetraoxide to provide a compound represented by Chemical Formula 15.
Method 4
As can be seen from following Scheme 4, the compound of Chemical Formula 3 obtained from Method 1, as the starting material, is subjected to Fries reaction to obtain compound of Chemical Formula 16 of which the para position is acetylyzed. By using methyl magnesium bromide, compound of Chemical Formula 17 is formed therefrom. Then, the phenolic hydroxyl group of compound (17) is acetylated by using acetic anhydride, and the tertiary hydroxyl group is simultaneously removed to give compound of Chemical Formula 18. Then, a hydroxyl group is introduced to the allylic position of compound (18) by using selenium dioxide as a catalyst, to form compound of Chemical Formula 19. When various acids are combined with the newly made hydroxyl group, various compounds represented by Chemical Formula 20 are obtained. The compound (20) is subjected to epoxidation reaction to provide desired compound represented by Chemical Formula 21.
Method 5
As can be seen from following Scheme 5, the compound of Chemical Formula 23 is prepared, from the compound of Chemical Formula 22, by using methyl magnesium bromide. Then, the phenolic hydroxyl group of thus obtained compound (23) is acetylated by using acetic anhydride, and the tertiary hydroxyl group is simultaneously removed to give compound of Chemical Formula 24. Then, a hydroxyl group is introduced to the allylic position of the double bond of the compound (24) by using selenium dioxide as a catalyst, to form compound of Chemical Formula 25. When various acids are combined with the newly made hydroxyl group, various compounds represented by Chemical Formula 26 are obtained. The compound (26) is subjected to epoxidation reaction to provide desired compound represented by Chemical Formula 27.
Method 6
As can be seen from following Scheme 6, the compound of Chemical Formula 29 is prepared, from the compound of Chemical Formula 28, by using methyl magnesium bromide. Then, the phenolic hydroxyl group of thus obtained compound (29) is acetylated by using acetic anhydride, and the tertiary hydroxyl group is simultaneously removed, to give compound of Chemical Formula 30. Then, a hydroxyl group is introduced to the allylic position of the double bond of the compound (30) by using selenium dioxide as a catalyst, to form compound of Chemical Formula 31. When various acids are combined with the newly made hydroxyl group, various compounds represented by Chemical Formula 32 are obtained. The compound (32) is then subjected to epoxidation reaction to provide desired compound represented by Chemical Formula 33.
Method 7
As can be seen from following Scheme 7, the compound of Chemical Formula 34 is prepared, from the compound of Chemical Formula 13, by using potassium cyanide. Then, the phenolic hydroxyl group of thus obtained compound (34) is subjected to alkylation by using various alkyl hali
Baek Hyung Geun
Jung Young Hoon
Kim Dae Keun
Lee Kang Ro
Lee Min Jung
Meyer Jerald L.
Nath Gary M.
Nath & Associates PLLC
Ramsuer Robert W.
Zee Ok Pyo
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