Etoposide analogs and methods of use thereof

Details Etoposide analogs and methods of use thereof Etoposide analogs and methods of use thereof

2002-06-21

2003-05-20

Owens, Amelia (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S431000, C549S010000, C549S298000, C549S432000, C549S433000

Reexamination Certificate

active

06566393

ABSTRACT:

FIELD OF THE INVENTION
The present invention concerns etoposide or podophyllotoxin analogs such as 4-beta-[(4″-benzamido)-amino]-epipodophyllotoxins, pharmaceutical formulations containing the same, and the use thereof to treat cancer.
BACKGROUND OF THE INVENTION
Etoposide (1) and Teniposide (2) are semisynthetic glucosidic cyclic acetals of podophyllotoxin (3) currently used in the chemotherapy for various types of cancer
(Jardine. (1980)
Anticancer Agents Based on Natural Products Models;
Academic Press: New York, p. 319, Issell. (1982)
Cancer Chemother. Pharmacol.
7:73). Another epipodophyllotoxin derivative, GL-331, has been developed and tested in phase II clinical trials against various cancers (Lee et al. (1995)
Food and Drug Analysis.
3:209). Interestingly, although podophyllotoxin inhibits the assembly of microtubules, the primary action mode of its 4&bgr;-congeners, the epipodophyllotoxins, is to inhibit the catalytic activity of topoisomerase II by stabilizing the covalent topoisomerase II-DNA cleavable complex, cause DNA strands breaking and eventually lead to cell death (Osheroff et al. (1991)
BioEssays
13:269, Alton & Harris (1993)
Br. J. Haematol.
85:241-245, Cho et al. (1996)
J. Med. Chem.
39:1383-1395, MacDonald et al. (1991)
DNA Topoisomerase in Cancer;
Oxford University Press: New York, p. 119).
U.S. Pat. No. 5,300,500 to Lee et al. describes a podophyllotoxin analog of formula 4-V as follows:
There remains a need for new etoposide analogs with anticancer and antitumor activity.
SUMMARY OF THE INVENTION
A first aspect of the present invention is a compound according to Formula I:
wherein:
X is a linking group selected from the group consisting of —O—, —S—, —NH—, —CO—, —CH═N—, or CH
2
NH—, and in one preferred embodiment is —NH—; R
1
is a covalent linkage between X and Y, or is loweralkyl, loweralkenyl, or phenyl, and when phenyl is unsubstituted or is substituted from one to four times with loweralkyl, hydroxy, alkoxyl, alkylogen, or alkylamino, alkyoxycarbonyl, amino, halogen, nitro, or nitrile, and in one preferred embodiment R
1
is phenyl;
Y is —NHCO— or —CONH—;
Z is —CHR
2
—(CH
2
)
n
R
3
, where n is 0 to 2 and R
2
is —COOH, —NH
2
, —COOR
31
where R
31
is loweralkyl, COOCH
2
Ph, or —NHCOOCH
2
Ph (“Ph” meaning phenyl);
R
3
is a lower alkyl, loweralkenyl or aryl, which may be unsubstituted or substituted one or more times with loweralkyl, loweralkenyl, or hydroxy, alkoxyl, alkylamino, thioalkyl, hydroxycarbonyl, guanidino, or amido, and in one preferred embodiment R
3
is phenyl, indolyl, imidazolyl, pyridyl, pyrimidyl, or benzamidazolyl; and
D is selected from the group consisting of —CH
2
OC(═O)—; —CH
2
OC(═CH
2
)—; —CH
2
CH
2
C(═O)—; —CH
2
OC(═S)—; —CH
2
OCH
2
—; —CH
2
OCH(—OH)—; —CH
2
OCH(OCH
3
)—; —CH
2
CH
2
C(—NR
12
)— where R
12
is loweralkyl; —C(═O)CH
2
C(O)—; —CH
2
OS(═O)(═O)OCH
2
—; and —CH
2
OS(═O)OCH
2
—;
or a pharmaceutically acceptable salt thereof.
A particular embodiment of the foregoing is a compound having the structure of Formula II:
wherein:
Y is an —NHCO— or —CONH— linking group;
Z is —CHR
2
—(CH
2
)
n
R
3
, where n is 0 to 2 and R
2
is —COOH, —NH
2
, —COOCH
3
, COOCH
2
Ph, or —NHCOOCH
2
Ph;
R
3
is a lower alkyl, loweralkenyl or phenyl; and
R
5
, R
6
, R
7
, and R
8
are each independently selected from the group consisting of H, loweralkyl, hydroxy, alkoxyl, alkylogen, or alkylamino, alkyoxycarbonyl, amino, halogen, nitro, and nitrile;
or a pharmaceutically acceptable salt thereof.
A further aspect of the present invention is a pharmaceutical formulation comprising a compound as described above in a pharmaceutically acceptable carrier (e.g.,an aqueous carrier).
A still further aspect of the present invention is a method of treating a cancer, comprising administering to a human or animal subject in need thereof a treatment effective amount (e.g., an amount effective to treat, slow the progression of, etc.) of a compound as described above. Examples of cancers that may be treated include, but are not limited to, skin cancer, lung cancer including small cell lung cancer and non-small cell lung cancer, testicular cancer, lymphoma, leukemia, Kaposi's sarcoma, esophageal cancer, stomach cancer, colon cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer and prostate cancer.
DETAILED DESCRIPTION OF THE INVENTION
The present invention will now be described more fully hereinafter with reference to the accompanying figures, which further illustrate the invention described herein. This invention may, however, be embodied in different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this disclosure will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art.
The terminology used in the description of the invention herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used in the description of the invention and the appended claims, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety.
The term “alkyl” or “loweralkyl” as used herein refers to C1 to C4, C6 or C8 alkyl, which may be linear or branched and saturated or unsaturated.
“Cycloalkyl” is specified as such herein, and is typically C3, C4 or C5 to C6 or C8 cycloalkyl.
“Alkenyl” or “loweralkenyl” as used herein likewise refers to C1 to C4 alkenyl, and alkoxy or loweralkoxy as used herein likewise refers to C1 to C4 alkoxy.
“Alkoxy” as used herein refers to linear or branched, saturated or unsaturated oxo-hydrocarbon chains, including for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, and t-butoxy.
The term “aryl” as used herein refers to C3 to C10 cyclic aromatic groups such as phenyl, naphthyl, and the like, and includes substituted aryl groups such as tolyl.
“Halo” as used herein refers to any halogen group, such as chloro, fluoro, bromo, or iodo.
The term “hydroxyalkyl” as used herein refers to C1 to C4 linear or branched hydroxy-substituted alkyl, i.e., —CH
2
OH, —(CH
2
)
2
OH, etc.
The term “aminoalkyl” as used herein refers to C1 to C4 linear or branched amino-substituted alkyl, wherein the term “amino” refers to the group NR′R″, wherein R′ and R″ are independently selected from H or lower alkyl as defined above, i.e., —NH
2
, —NHCH
3
, —N(CH
3
)
2
, etc.
The term “oxyalkyl” as used herein refers to C1 to C4 oxygen-substituted alkyl, i.e., —OCH
3
, and the term “oxyaryl” as used herein refers to C3 to C10 oxygen-substituted cyclic aromatic groups.
The term “alkylenedioxy” refers to a group of the general formula —OR′O—, —OR′OR′—, or —R′OR′OR′— where each R′ is independently alkyl.
“Treat” or “treating” as used herein refers to any type of treatment that imparts a benefit to a patient afflicted with a disease, including improvement in the condition of the patient (e.g., in-one or more symptoms), delay in the progression of the disease, prevention or delay of the onset of the disease, etc.
“Pharmaceutically acceptable” as used herein means that the compound or composition is suitable for administration to a subject to achieve the treatments described herein, without unduly deleterious side effects in light of the severity of the disease and necessity of the treatment.
“Inhibit” as used herein means that a potential effect is partially or completely eliminated.
The present invention is concerned primarily with the treatment of human subjects, but may also be employed for the treatment of

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