Antitumor drugs and methods

Details Antitumor drugs and methods Antitumor drugs and methods

2003-06-04

2004-06-08

Peselev, Elli (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S007100

Reexamination Certificate

active

06747011

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to treatment of cancer and proliferative disorders, and specifically to apoptolidin derivatives and methods of use thereof.
2. Description of Related Art
Agents that can selectively induce apoptosis in cancer cells show great promise for therapeutic use. Compounds capable of being highly specific antitumor agents by selectively leading to tumor cell arrest and apoptosis are desirable.
Apoptolidin, a structurally complex macrolide isolated by Seto and coworkers (Kim, J. W.; Adachi, H.; Shin, Y. K.; Hayakawa, Y.; Seto, H. J. Antibiot., 1997, 50, 628-630; Y. Hayakawa, J. W. Kim, H. Adachi, K. Shin-ya, K. Fujita and H. Seto, J. Am. Chem. Soc., 1998, 120, 3524), has been shown to be a highly selective inducer of apoptosis in certain cancer cell lines, including those derived from human leukemias and melanomas, and colon, renal, central nervous system, and ovarian tumors. Apoptolidin is, however, unstable under alkaline and physiological conditions and readily isomerizes to isoapoptolidin (Wender, P. A., Gulledge, A. V., Jankowski, O. D., Seto, H., Org. Lett., 2002, 4(22), 3819-3822.) This simple-equilibrium interconversion is especially disadvantageous because isoapoptolidin is significantly less potent than apoptolidin. To address this issue and to prepare highly active, stable selective apoptosis-inducing agents, we have focused our efforts on derivatives of apoptolidin which are not prone to isomerization.
BRIEF SUMMARY OF THE INVENTION
In certain embodiments, this invention is directed to derivatives of apoptolidin, including skeletal homologues, which are potent, selective and stable under physiological conditions apoptosis-inducing agents and/or which derivatives do not undergo isomerization to less potent compounds.
In certain embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof:
wherein:
n is an integer from 0 to 6,
m is an integer from 0 to 6, except that m≠0 when n=0, and
R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 0-2, and
m is 0-2, except that m≠0 when n=0.
In certain other preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 1-6
m is 0.
In more preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 1-2, and
m is 0.
In most preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 1, and
m is 0.
In certain other embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n=0,
m is 1 to 6, and
R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain more preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n=0, and
m is 1-2.
In most preferred embodiments, this invention is directed to compounds of the formula (I) and pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n=0, and
m is 1.
In other aspects, the invention is directed to pharmaceutical or veterinary compositions of the compounds of formula (I).
In certain embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I:
or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is an integer from 0 to 6,
m is an integer from 0 to 6, except that m≠0 when n=0, and
R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain preferred embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 0-2, and
m is 0-2, except that m≠0 when n=0.
In certain preferred embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 1-6, and
m is 0.
In certain more preferred embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 1-2, and
m is 0.
In most preferred embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n is 1, and
m is 0.
In certain other embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n=0,
m is 1 to 6, and
R is a substituted or unsubstituted alkyl, alkenyl, alkynyl, aryl, heterocyclyl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, or alkylthio.
In certain more preferred embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n=0, and
m is 1-2.
In most preferred embodiments, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and as active ingredient the compound of formula I or pharmaceutically acceptable esters, ethers, and/or salts thereof, wherein:
n=0, and
m is 1.
In other aspects, the invention is directed to methods to treat hyperproliferative disorders and tumors and cancers by administering the compound of formula (I) or a pharmaceutical composition thereof to a patient in the need of such treatment. “Treatment” includes both therapeutic and prophylactic effects.
In certain embodiments, this invention is directed to a method of treatment of a cancer in a patient, which method comprises administering to a patient in need of such treatment a therapeutically effective amount of the compounds or pharmaceutical compositions disclosed herein.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to derivatives of apoptolidin, including skeletal homologues, which are potent, selective and stable under physiological conditions apoptosis-inducing agents and/or which derivatives do not undergo isomerization to less potent compounds. Further, this invention relates to pharmaceutical compositions comprising compounds described herein and to their use as therapeutic agents, particularly in the treatment of cancer and cell proliferative disorders.
More specifically, the compounds o

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