Diterpene derivatives and anti-inflammatory analgesic agents...

Details Diterpene derivatives and anti-inflammatory analgesic agents... Diterpene derivatives and anti-inflammatory analgesic agents...

2000-09-15

2003-07-15

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

C514S557000, C548S247000, C560S117000, C562S499000, C568S665000, C568S817000, C585S021000

Reexamination Certificate

active

06593363

ABSTRACT:

TECHNICAL FIELD
The present invention relates to diterpene derivatives and anti-inflammatory analgesic agents comprising the same. More specifically, the present invention relates to diterpene derivatives prepared from the components which are extracted from Acanthopanax Koreanum and represented by Chemical Formula
1
:
wherein, R
1
and R
2
individually represent hydrogen or hydroxy, or they form a double bond in the cycle, R
3
represents vinyl, hydroxyethyl, methoxyethyl, acetyloxyethyl, methoxymethoxyethyl, methoxyethoxymethoxyethyl, methoxyiminoethyl or isoxazolinyl group, R
4
represents hydroxymethyl, carboxyl, carboxymethyl, carboxyvinyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxybutadienyl, carboxyallyl, carboxyhomoallyl, carbamoyl, methylcarbamoyl, hydroxycarbamoyl, carbazoyl, N-pipsylcarbamoylmethyl, N-pipsylcarbamoylethyl, N-pipsylcarbamoylbutadienyl or N-methanesulfonylcarbamoylethyl group; and anti-inflammatory analgesic agents comprising the same.
BACKGROUND ART
Acanthopanax Koreanum is a special product which grows spontaneously in Cheju-do in the Republic of Korea. It is a deciduous shrub belong to the family of Japanese angelica tree, and taking-out of the tree from Cheju-do is restricted. The bark of the tree and the bark of the root have been known to have effective analgesic action on pain of bones and sinews from ancient times in the field of Chinese medicines. Among the people, wine was made from the bark or root-bark of Acanthopanax Koreanum, and the win has been used for treatment of neuralgia, paralysis, hypertension and rheumatism.
Recently, the present inventors found the fact that (−)-pimara-9(11),15-diene-4-carboxylic acid among the diterpene components extracted from root-bark and bark of Acanthopanax Koreanum, and novel derivatives synthesized therefrom inhibits the stage where arachidonic acid is converted to PGE
2
, an inflammation mediator, thereby having excellent anti-inflammatory action, and the discovery was filed as a patent application (Korean Patent No. 112194).
DISCLOSURE OF THE INVENTION
The present inventors have continuously performed intensive studies in order to discover an excellent inhibitor against production of PGE
2
(prostagladin E
2
), and as a result, could additionally develop a compound having more excellent anti-inflammatory action, and complete the present invention.
The object of the present invention is to provide diterpene derivatives represented by Chemical Formula 1.
Another object of the present invention is to provide an anti-inflammatory analgesic agent comprising the diterpene derivative represented by Chemical Formula 1.
The present invention relates to diterpene derivatives represented by Chemical Formula 1 and anti-inflammatory analgesic agents comprising the same.
wherein, R
1
, R
2
, R
3
and R
4
are the same as defined previously.
The compound of Chemical Formula 1 is prepared from the components extracted from Acanthopanax Koreanum, and the process for preparation is described in detail here-in-below:
First, root-bark and bark of Acanthopanax Koreanum is cut into pieces and the pieces are heat-extracted with alcohol in a water bath, and the extract is filtered. After concentrating the combined filtrate of the alcohol extract, water is added, and the mixture is extracted with diethyl ether. The ether extract is concentrated to dryness, and the residue is fractioned by silica gel column chromatography using a mixture of ethyl acetate and hexane as an eluent, to give (−)-pimara-9(11),15-diene-4-carboxylic acid (R
4
=COOH) of Chemical Formula 2, the main component of the fractions. In the description of compounds of Chemical Formulas 2 to 48 below, the definitions of R
1
to R
4
in the parentheses are described in order to show how the substituents R
1
to R
4
of Chemical Formulas 2 to 48 are characteristically altered as compared to Chemical Formula 1.
The compound of Chemical Formula 2 is subjected to chemical reactions shown in Reaction Schemes 1 to 7, to form various derivatives.
As shown in Reaction Scheme 1, the natural diterpene (R
4
=COOH) of Chemical Formula 2 is reduced, and then oxidized, using tetrapropylammonium perruthenate, PDC, PCC or Swern oxidation to give a compound (R
4
=CHO) of Chemical Formula 3. The aldehyde group of the compound of Chemical Formula 3 thus obtained is subjected to Wittig reaction using triethylphosphono acetate anion in tetrahydrofuran to obtain a double bond in the compound of Chemical Formula 6. The double bond of the conjugated ester is reduced by magnesium in methanol, or directly hydrolyzed with lithium hydroxide to obtain a compound of Chemical Formula 7 (R
4
=CH
2
CH
2
COOH) or that of Chemical Formula 8 (R
4
=CHCHCOOH). The compound of Chemical Formula 4 (R
4
=CHCHOCH
3
) obtained from Wittig reaction using methoxymethyl phosphorane is hydrolyzed by p-toluenesulfonic acid in acetone to give an aldehyde, which is oxidized by silver oxide in water and ethanol to give a compound of Chemical Formula 5 (R
4
=CH
2
COOH).
Carbonyl derivatives of the present invention can be prepared according to Reaction Scheme 2 or 3 shown below.
As shown in Reaction Scheme 2, the natural diterpene of Chemical Formula 2 (R
4
=COOH) is directly reacted with oxalyl chloride or thionyl chloride in benzene to give a compound of Chemical Formula 9 (R
4
=COCl), which is reacted with aqueous ammonia or aqueous solution of methyl amine in ethyl acetate, with hydroxylamine hydrochloride in benzene, or with hdyrazine monohydrate in dry ether, to give a compound of Chemical Formula 10 (R
4
=CONH
2
), a compound of Chemical Formula 11 (R
4
=CONHCH
3
), a compound of Chemical Formula 12(R
4
=CONHNH
2
, carbazoyl), and a compound of Chemical Formula 13 (R
4
=CONHOH), respectively.
Similarly, the acid chloride group of the compound of Chemical Formula 9 is reacted with trimethylsilyl ethanol in pyridine to give a compound of Chemical Formula 14 (R
4
=COOCH
2
CH
2
TMS) wherein the carboxylic group is protected, which is then reacted with two equivalents of borane-methyl sulfide in tetrahydrofuran and deprotected with tetrabutylammonium fluoride in dimethylformamide to give a compound of Chemical Formula 15 (R
1
=OH, R
2
=H, R
3
=CH
2
CH
2
OH, R
4
=CO
2
H). Otherwise, the compound of Chemical Formula 14 wherein the carboxylic group is protected (R
4
=COOCH
2
CH
2
TMS) is subjected to additional cyclization using nitrile oxide, which was obtained from N-chlorosuccinimide and acetaldoxime, in tetrahydrofuran, and then deprotected with tetrabutylammonium fluoride to give a compound of Chemical Formula 16 (R
1
, R
2
=double bond, R
4
=isoxazolinyl).
As shown in Reaction Scheme 3 above, the natural diterpene of Chemical Formula 2 (R
4
=COOH) is reacted with n-butyllithium in tetrahydrofuran to obtain a carboxylate salt, which is reduced by one equivalent of borane-methyl sulfide complex (BH
3
—SMe
2
) to give an objective compound of Chemical Formula 17 (R
3
=CH
2
CH
2
OH), without giving any effect on the carboxylic group. The compound of Chemical Formula 17 thus obtained is reduced on contact to give a compound of Chemical Formula 18 (R
1
=H
2
, R
2
H, R
3
=CH
2
CH
2
OH).
As shown in Reaction Scheme 4 above, the aldehyde group of the compound of Chemical Formula 19 (R
4
=CH
2
CHO), which was obtained by hydrolzying the compound of Chemical Formula 4 as in Reaction Scheme
1
, is subjected to Wittig reaction in toluene to obtain a double bond. The conjugated ester is directly hydrolyzed by lithium hydroxide, or reduced by magnesium in methanol and hydrolyzed, to provide a compound of Chemical formula 21 (R
4
=CH
2
CHCHCOOH) or a compound of Chemical Formula 23 (R
4
=CH
2
CH
2
CH
2
COOH).
As shown in Reaction Scheme 5 above, the conjugated ester group of the compound of Chemical Formula 6 (R
4
=CHCHCO
2
Et), which was obtained in Reaction Scheme 2, is reduced and then oxidi

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