Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-26
2004-06-08
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C540S451000
Reexamination Certificate
active
06747021
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the fields of pharmaceutical and organic chemistry and provides a cryptophycin compound useful in the treatment of cancer.
BACKGROUND OF THE INVENTION
Neoplastic diseases, characterized by the proliferation of cells not subject to the normal control of cell growth, are a major cause of death in humans and other mammals. Clinical experience in cancer chemotherapy has demonstrated that new and more effective drugs are desirable to treat these diseases. Such clinical experience has also demonstrated that drugs which disrupt the microtubule system of the cytoskeleton can be effective in inhibiting the proliferation of neoplastic cells.
The microtubule system of eukaryotic cells is a major component of the cytoskeleton and is in a state of dynamic assembly and disassembly. Heterodimers of tubulin are polymerized to form microtubules. Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The dynamic state of microtubules is critical to their normal function. With respect to cell division, tubulin is polymerized into microtubules that form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle's use has been fulfilled. Accordingly, agents that disrupt the polymerization or depolymerization of microtubules, and thereby inhibit mitosis, comprise some of the most effective cancer chemotherapeutic agents in clinical use.
The cryptophycins are novel macrolides first isolated from blue-green algae (Nostoc sp. Strain GSV224) which have been shown to be potent tumor selective cytotoxins in vivo. Cryptophycins have been synthesized by a convergent method in which four fragments, Fragment A, Fragment B, Fragment C, and Fragment D (Golakati, et al.,
Journal of the American Chemical Society,
117(49), 12031 (1995)) are coupled together to form the final product (U.S. Pat. No. 6,013,626). Such methods have been used to prepare the original cryptophycins, isolated from Nostoc sp., as well as new cryptophycins.
Certain cryptophycin compounds, and methods for their preparation, are known in the literature. U.S. Pat. No. 4,845,085 and U.S. Pat. No. 4,845,086, for example, report novel semi-synthetic compounds formed by converting the epoxide of a particular cryptophycin to a carbon-carbon double bond. These compounds have potential as agents for mycotic infections.
U.S. Pat. No. 4,868,208 reports novel semi-synthetic antifungal compounds formed by subjecting a cryptophycin compound to hydrolysis or alcoholysis.
WO 95/17093, WO 96/39829, and WO 96/40184 report novel Cryptophycin compounds for inhibiting the proliferation of hyperproliferative cells.
WO 97/07798 reports a series of cryptophycin compounds that can be useful for disrupting the microtubulin system, as antineoplastic agents, as antifungals, and for the treatment of cancer.
WO 97/08334 reports novel cryptophycin compositions that exhibit a broad spectrum of antineoplastic activity similar to presently used antineoplastic agents such as vinblastine, taxol, and adriamycin.
WO 97/23211, WO 97/31632, WO 98/08506, WO 98/08505, and WO 98/08829 report novel cryptophycin compounds which can be useful for disrupting the microtubulin systems, as antineoplastic agents, and for the treatment of cancer.
Cryptophycin molecules are known to be somewhat toxic. Accordingly, it would be desirable to have cryptophycin molecules with lower toxicity that nonetheless retain the anti-cancer activity of the original cryptophycin molecules. Additionally, cryptophycin compounds having even greater solubility and stability are desired for most pharmaceutical uses. Surprisingly, applicants have now discovered the compound of this invention provides remarkably greater aqueous solubility as well as a superior ability to disrupt the microtubule system to any other compounds disclosed in WO 98/08505. This compound also has a lower toxicity than other cryptophycin molecules. Because of the lower toxicity, higher dosing levels may be achieved for a higher degree of cancer treatment.
As noted in WO 98/08505, such compounds can be prepared using total synthetic methods and are therefore well suited for development as pharmaceutically useful agents.
SUMMARY OF THE INVENTION
The present invention provides a compound of Formula I:
or a pharmaceutically acceptable salt thereof.
This invention also provides a pharmaceutical formulation that comprises, in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I.
The present invention provides a method for the treatment of hyperproliferative conditions such as cancer, neoplasm, and hyperproliferative cell growth in mammals comprising administering to a mammal in need of such treatment a pharmaceutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention provides a method for disrupting a microtubulin system in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I.
This invention also provides the use of the compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of hyperproliferative conditions such as cancer, neoplasm, and hyperproliferative cell growth in mammals. Additionally, this invention provides a pharmaceutical formulation adapted for the treatment of hyperproliferative conditions such as cancer, neoplasm, and hyperproliferative cell growth containing the compound of Formula I, or a pharmaceutically acceptable salt thereof.
This invention further provides the use of the compound of Formula I, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for disrupting a microtubulin system. Additionally, this invention provides a pharmaceutical formulation adapted for disrupting a microtubulin system containing the compound of Formula I or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The compound of Formula I is also known as Cryptophycin-309. We have found that Cryptophycin-309 exhibits lower toxicity than other cryptophycins but retains the anti-cancer activity of previously known cryptophycin molecules. Because of the lower toxicity, higher dosing levels may be achieved allowing for a higher degree of cancer treatment.
As used herein, the term “mammal” shall refer to the Mammalia class of higher vertebrates and includes, but is not limited to, a human. The term “treating” as used herein includes prophylaxis of the named condition or amelioration or elimination of the condition once it has been established. The compound of Formula I claimed herein can be useful for veterinary health purposes as well as for the treatment of a human patient.
The present invention provides methods for disrupting a microtubulin system in a mammal and for the treatment of hyperproliferative conditions such as cancer, neoplasm, and hyperproliferative cell growth in mammals by administering to a mammal in need of such treatment a pharmaceutically effective amount of a compound of Formula I. The preferred mammal is human.
Because the compound of Formula I is an amine, it is basic in nature and accordingly reacts with any of a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. It is preferable to convert the free amine to a pharmaceutically acceptable acid addition salt for ease of handling and administration. Acids commonly employed to form such salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen-phosphate, dihydrogenphosphate, metaphosphate, pyrophosphate,
Corbett Thomas Hughes
Liang Jian
Moore Richard Elliott
Eli Lilly and Company
Kifle Bruck
Merchant & Gould P.C.
LandOfFree
Cryptophycin compound does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Cryptophycin compound, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Cryptophycin compound will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3322959