Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-10-24
2002-06-25
Trinh, Ba K. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C549S511000, C549S214000
Reexamination Certificate
active
06410756
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel taxanes, semi-synthetic and isolation methods for their production and their use an anticancer agents.
BACKGROUND OF THE INVENTION
The taxane family of terpenes are considered as an exceptionally promising group of cancer chemotherapeutic agents. Many taxane derivatives are highly cytotoxic and possess strong in vivo activities in a number of leukemic and tumor systems.
The best known taxane is paclitaxel (Bristol-Myers Squibb's Taxol®). Currently, paclitaxel and semisynthetic analog docetaxel (Rhône Poulenc Rorer's Taxotere®) have been approved for the treatment of breast and ovarian cancer, and many clinical trials are underway for a number of other indications, including lung cancer, Kaposi's sarcoma, and lymphoma.
A major problem with all of the clinical studies is the limited availability of the compounds. Paclitaxel is a natural product which can be isolated from the bark of Yew trees, but the extraction is difficult, the process is expensive and the yield of paclitaxel is low. Removal of the bark destroys Pacific or Western yew,
Taxus brevifolia
, which is listed among the world's endangered conifer species. The original method of obtaining Taxol® involved cutting down and stripping tens of thousands of trees to harvest small amounts of the compound (13,500 kg of
Taxus brevifolia
bark yields about 1 kg of paclitaxel). Alternative modes of obtaining paclitaxel have not solved the supply problem. The total chemical synthesis of paclitaxel requires more than thirty steps. Taxus plant cell culture only supplies relatively low yields of taxanes, and biosynthesis by a yew tree fungus,
Taxomyces andreanae
has not been sufficient to be economically feasible (Nature Biotech., 14:1055, 1996).
Isolation of taxanes from the stems and needles of various Taxus species offers hope that the supply of taxanes, which can be used for semi-synthesis, will become more abundant. Because of the structural complexity of paclitaxel, partial synthesis is a far more viable approach to providing adequate supplies of paclitaxel and paclitaxel precursors and derivatives than total synthesis. The first successful partial synthesis of paclitaxel was developed by Denis et al, (U.S. Pat. No. 4,924,011 re-issued as 34,277) using the starting material 10-deacetylbaccatin III which can be extracted in relatively high yield from needles of specific species of
taxus baccata.
Many derivatives of paclitaxel have also been synthesized since the realization of its utility as a therapeutic agent in the treatment of cancer. Examples include 7-deoxy-taxol analogs (as described in PCT Application No. WO 94/13655), which are useful for breast, ovarian, lung, colonic and gastric cancers, malignant melanoma and leukemia. A number of benzoate derivatives (Canadian Patent Application No. 2,095,375), have also been synthesized. Paclitaxel analogs with a ketone moiety (U.S. Pat. No. 5,440,047 and PCT Application No. WO 95/33736), have also been reported to have remarkable antitumoral and antileukemic properties. Derivatives with an epoxide residue have also been disclosed (PCT Application No. WO/94/13654) which exhibit antitumour activity. The preparation of a further group of taxane derivatives have been described in PCT Application Nos. WO 95/02400 and WO 93/21173 which are structurally very similar to paclitaxel but have somewhat increased chemotherapeutic activity when compared to paclitaxel.
Although the use of paclitaxel is successful against a number of specific tumor types, it is not universally effective. Different taxanes exhibit different efficacies to various tumor types, hence there is an urgent need for novel compounds from the taxane family that are closely related to paclitaxel in their chemical structures but which have more potent chemotherapeutic activities.
SUMMARY OF THE INVENTION
One embodiment of the present invention is to provide a new taxane and its derivatives, which have chemotherapeutic activities.
A further embodiment of the present invention is to provide a compound, hereinafter referred to as Canadensol, having the following structural Formula I:
a previously unknown constituent of the Canada yew,
Taxus canadensis.
It is another embodiment of the invention to provide analogs having in common with Canadensol the following structural Formula II:
as well as a process for preparing such compounds from the starting material baccatin III.
Wherein: R
1
in Formula II is selected from the group consisting of: C
1
-C
6
alkyl including methyl, isopropyl, isopropenyl, propenyl, butyl, cyclopropyl, substituted alkyl including halo, di-(tri-halomethyl)methyl, 3′-trihalo-n-propyl, or phenyl substituted with: one, 2 or 3 C
1
-C
4
alkyl, C
1
-C
3
alkoxy, halo, C
1
-C
3
alkylthio, trifluoromethyl, C
2
-C
6
dialkylamino, hydroxy or nitro, 2-furyl, 2-thienyl; 1-napthyl, 2-napthyl, isopropoxy, isopropenoxy, propenoxy, cyclopropoxy, di-(trihalomethyl)methoxy, 3′-trihalo-n-propanoxy, dimethylamino, ethylamino, isopropylamino, propylamino, isopropenamino, imidazol, acetyl, hydroxycarbonyl, 2-(hydroxy)ethyl, 2-(methyl)-propyl, benzyl.
Wherein: R
2
in Formula II is selected from the group consisting of: —OAc or —OH.
It is a further embodiment of the present invention to provide analogs having in common with Canadensol the following structural Formula III:
as well as a process for preparing such compounds from the starting material baccatin III.
Wherein: R
3
in Formula III is selected from the group consisting of: C
1
-C
6
alkyl including methyl, isopropenoyl, isopropenoyl, propenoyl, cyclopropanoyl, substituted alkyl including halo, di-(tri-halomethyl)acetanoyl, 3′-trihalo-n-propanoyl, 3,4-methylene-dioxyphenyl or phenyl substituted with one, 2 or 3 C
1
-C
4
alkyl, C
1
-C
3
alkoxy, halo, C
1
-C
3
alkylthio, trifluoromethyl, C
2
-C
6
dialkylamino, hydroxy or nitro, 2-furyl, 2-thienyl, 1-napthyl, 2-napthyl, isopropoxycarbonyl, isopropenoxycarbonyl, propenoxycarbonyl, cyclopropoxycarbonyl, di-(trihalomethyl)methoxycarbonyl, 3′-trihalo-n-propanoxycarbonyl, dimethylaminocarbonyl, ethylaminocarbonyl, isopropylaminocarbonyl, propylaminocarbonyl, isopropenaminocarbonyl, imidazolcarbonyl, pyruvyl, oxalyl, 2-(hydroxy)ethylcarbonyl, 2-(methyl)-propylcarbonyl, benzylcarbonyl.
Due to the immediate requirement for additional novel taxanes, a further object of the present invention is to provide a family of taxanes, represented by Formula II and Formula III. These compounds are useful for the treatment of, or in the preparation of paclitaxel derivatives for use in treatment of, cancers and leukemias. The invention also provides for pharmaceutically acceptable compositions compounds of Formula II and Formula III, for use as therapeutic agents for use as anticancer agents in the management of such disease.
It is a further embodiment of this invention to provide a simple and inexpensive semi-synthetic method for the production of these novel taxanes. Accordingly, it is an object of this invention to provide a reproducible method for the isolation and semi-synthesis of taxanes from plant matter derived from the Taxus genus of plants.
Yet a further object of the present invention is to provide, in particular a method for the isolation and semi-synthesis of a novel taxane, named Canadensol, which exhibits higher chemotherapeutic activity than paclitaxel.
It is a further object of this invention to provide a method for the production of a number of protected intermediates, that are useful in the semi-synthesis of novel taxanes.
It is yet a further embodiment of the present invention to provide for the use of the compounds exhibited in Formula I, II, and III in the treatment of various maladies, including various forms of cancer.
These and other objectives, as well as the nature, scope and utilization of this invention, will become readily apparent to those skilled in the art from following the description, the drawings and the appended claims.
REFERENCES:
patent: 4924011 (1990-05-01), Denis et al.
patent: RE34277 (
Caron Gaéton
Zamir Lolita
Zheng Yi Feng
Institut National de la Recherche Scientifique
Sterne Kessler Goldstein & Fox P.L.L.C.
Trinh Ba K.
LandOfFree
Family of Canadensol taxanes, the semi-synthetic preparation... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Family of Canadensol taxanes, the semi-synthetic preparation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Family of Canadensol taxanes, the semi-synthetic preparation... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2963484