Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-01-31
2001-01-16
Aulakh, Charanjit S. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000
Reexamination Certificate
active
06175023
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the semisynthesis of paclitaxel derivatives, and more particularly, the present invention relates to the semisynthesis of 9-dihydrotaxanes using 9-dihydro-13-acetylbaccatin III as the initial compound.
BACKGROUND OF THE INVENTION
Paclitaxel (taxol) is a well known chemotherapeutic agent having efficacy against a broad range of cancers. It has been shown to be clinically effective against ovarian and breast cancer, and has exhibited promising activity against a number of other types of cancers such as liver, peritoneal, cervical, prostate, colon and esophageal.
Conventionally, taxol is obtained by extraction from the bark of the Pacific
Taxus brevifolia
. However, the isolation of taxol from the tree bark is a difficult, low-yield and expensive process. Further, the scarcity of the yew has prompted, scientists to explore alternate routes.
Although paclitaxel is a promising drug for the treatment of ovarian and breast cancers, the low water solubility of paclitaxel can be problematic. In a quest for new derivatives with potentially enhanced solubility, one of the sites on the molecule where attention has been directed is the ketone function at the C-9 position, or conversion at the C-10 acetate group on the taxane nucleus to a hydroxyl group.
Previous attempts to improve water solubility have also relied on the preparation of water soluble pro-drugs, which are converted to paclitaxel under physiological conditions, or novel drug formulations.
An alternative method of increasing water solubility of palitaxel would be to replace one of the hydroxyl groups with an amino group; salts of the resulting amine would have improved water solubility.
In the search for alternative solutions, the discovery of new taxol derivatives having broader spectrum, enhanced in vivo activity and improved water solubility and stability have been reported. Among the compounds reported, those belonging to the 9-dihydrotaxane family show great promise. Thus far, only limited members of that family, including 9-dihydrotaxol and 9-dihydrotaxotere, have been successfully synthesized. The ability to synthesize a greater number of 9-dihydrotaxane compounds having superior pharmacologic properties would be a valuable asset.
SUMMARY OF THE INVENTION
In accordance with one aspect of one embodiment of the present invention, there is provided an improved method of synthesizing 9-dihydrotaxane compounds.
In accordance with a further aspect of one embodiment of the present invention, there is provided a compound having the formula:
wherein R
1
is Ac or H; R
2
is O—Si (C
2
H
5
)
3
, NH
2
, O-Tosyl, or NH
NH
2
; R
3
is C
5
H
11
or Phenyl; and R
4
is OH or NH
2
.
In a further aspect of one embodiment of the present invention, there is provided a compound having the formula:
wherein R
1
is Ac or H and R
2
is O—Si(C
2
H
5
)3, NH
2
, O-Tosyl, or NHCH
2
CH
2
NH
2
In a still further aspect of one embodiment of the present invention, there is provided a compound having the formula:
wherein R
1
is H and R
2
is O—Si(C
2
H
5
)
3
, O—Tosyl, NH
2
or NH
NH
2
Regarding a further aspect of one embodiment of the present invention, there is provided a process for preparing 9-dihydrotaxane, comprising the steps of:
(a) protecting the C-7 hydroxy group of 9-dihydro-13-acetylbaccatin III with a suitable protecting group;
(b) deacetylating the product of step (a) at the C-13 position; and
(c) adding a suitable side chain to the C-13 position of the product obtained in step (b).
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Taxane derivatives synthesized in accordance with the present invention are characterized by the following chemical structure:
7-amino-9-dihydrotaxol C, wherein
R
1
is Ac
R
2
is NH
2
R
3
is C
5
H
11
R
4
is OH
7-amino-10-deacetyl-9-dihydrotaxol C, wherein
R
1
is H
R
2
is NH
2
R
3
is C
5
H
11
R
4
is OH
2′-amino-9-dihydrotaxol, wherein
R
1
is AC
R
2
is OH
R
3
is C
6
H
5
R
4
is NH
2
2′-amino-10-deacetyl-9-dihydrotaxol, wherein
R
1
is H
R
2
is OH
R
3
is C
6
H
5
R
4
is NH
2
7-amino-9-dihydrotaxol, wherein
R
1
is Ac
R
2
is NH
2
R
3
is C
6
H
5
R
4
is OH
7-amino-10-deacetyl-9-dihydrotaxol, wherein
R
1
is H
R
2
is NH
2
R
3
is C
6
H
5
R
4
is OH
7
-aminoethylamino-9-dihydrotaxol, wherein
R
1
is Ac
R
2
is NH NH
2
R
3
is C
6
H
5
R
4
is OH
9-dihydro-13-acetylbaccatin IIII is used as the starting material in the preparation of the above 9-dihydrotaxanes. 9-dihydro-13-acetylbaccatin III can be extracted from the Taxus species, preferably
Taxus canadensis.
In overview, plant material such as stems and needles are collected, ground and extracted with methanol. The extraction continues for 24 hours at room temperature, and is filtered. The extract is concentrated to about 10% of its original volume by evaporation, and an equal amount of water is added to the concentrate. The aqueous solution is extracted several times with hexane to give an aqueous layer and a non-aqueous layer. The aqueous layer is extracted several times with chloroform or dichloromethane. The chloroform or dichloromethane extract is concentrated to dryness, and the residue is dissolved in a mixture of chloroform, methanol and acetone in a ratio of approximately 10:1:0.5 and fractionated by dry column chromatography to obtain several fractions containing taxol and 9-dihydro-13-acetylbaccatin III. The fractions are combined and extracted with methanol. The methanol extract is concentrated to dryness, and the residue is dissolved in methanol to crystallize out the 9-dihydro-13-acetylbaccatin III.
The processes of the present invention, as illustrated below in Schemes 1 to 4(b), include the steps of:
(a) protecting the C-7 hydroxy group of 9-dihydro-13-acetylbaccatin III with a suitable protecting group;
(b) deacetylating the product of step (a) at the C-13 position; and
(c) adding a suitable side chain to the C-13 position or the product obtained in step (b).
The processes may further include the step of removing the protecting group of the product obtained in step (c).
Referring to Scheme 1,7-amino-9-dihydrotaxol C may be obtained by adding a protecting group, for example a Tosyl group such as tosyl chloride to 9-dihydro-13-acetylbaccatin IIII at the C-7 position in the presence of a suitable catalyst, preferably a substituted amine such as tetrabutylammonium iodide, and a non-polar solvent such as dichloromethane. Compared to the prior art method, it was found that the tetrabutylammonium iodide/dichloromethane combination improves the yield of the desired product. Other advantages such as a short reaction time, an easy purification of the product and a relatively small amount of byproducts being produced were also noted. Advantageously, the above reagents are less toxic which can be beneficial in large scale production. The mixture is stirred at room temperature until the reaction is completed, following which it is extracted with a non-polar solvent such as dichloromethane. The organic phase is concentrated to dryness under vacuum and purified by a chromatography method, preferably normal flash column chromatography, eluting with suitable solvent systems such as dichloromethane and methanol in a ratio of 97:3 to yield the intermediate 7-O-tosyl-9-dihydro-13-acetylbaccatin III.
The 7-O-tosyl-9-dihydro-13-acetylbaccatin III intermediate is deacetylated at the C-13 position by reaction with an alkyl lithium, for example methyl lithium, or using Red-Al. The resulting mixture is partitioned between a solvent system consisting of a buffer such as sodium hydrogencarbonate of ammonium chloride and a non-polar solvent such as dichloromethane. The organic layer is concentrated to dryness, and the crude product is purified by, for example flash column chromatography, using a solvent system such as dichloromethane and methanol in a ratio of 97:3 to yield the intermediate 7-O-tosyl-9-dihydrobaccatin III.
The 7-O-tosyl-9-dihydrobaccatin III intermediate is further treated with 2′-ethoxyethyl-N-hexanoyl-(2R,3S)-3-phenyl-isoscrine in the presence o
(Marks & Clerk)
Aulakh Charanjit S.
Liu Jian
Sharpe Paul S.
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