Curcumin analogues and uses thereof

Details Curcumin analogues and uses thereof Curcumin analogues and uses thereof

2002-04-17

2004-09-14

Killos, Paul J. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

C568S325000, C514S541000, C514S646000

Reexamination Certificate

active

06790979

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds capable of acting as androgen receptor antagonists, pharmaceutical formulations containing the same, and methods of use thereof.
BACKGROUND OF THE INVENTION
The androgen receptor (AR) is a member of a large family of ligand-dependent transcriptional factors known as the steroid receptor superfamily. Chang et al.,
Proc. Natl. Acad. Sci. USA,
85, 7211-7215 (1988). Beato, M.,
Cell,
56, 335-344 (1989). Androgens and the AR play an important role in the growth of the normal prostate and prostate cancer. Prostate cancer represents the most common male malignancy in the United States. Landis et al.,
Cancer J. Clin.,
48, 6-29 (1998). Recently, antiandrogens such as hydroxyflutamide (HF) in combination with surgical or medical castration have been widely used for the treatment of prostate cancer. Crawford et al.,
New Engl. J. Med.,
321, 419-424 (1989). Several compounds, including cyprosterone, HF, and bicalutamide (shown below), have been used clinically in the treatment of prostate cancer.
The synthetic steroidal antiandrogen cyprosterone is one of the first antiandrogens used clinically in Europe, McLeod, D., G.,
Cancer,
71, 1046-1049 (1993) but it has many side effects. Neumann et al.,
J. Clin. Oncol.,
1, 41-65 (1982). HF and bicalutamide are both nonsteroidal antiandrogens. Bicalutamide is a newer nonsteroidal antiandrogen originally thought to have a pure antiandrogen activity without agonist activity. It has a longer half-life (6 days) and a higher binding affinity to the AR than HF. Verhelst et al.,
Clin. Endocrinol.,
41, 525-530 (1994). (a) Kelly et al.,
J. Urol. (
1993), 149, 607-609; (b) Scher et al., Prostate Cancer.
J. Clin. Oncol.,
11, 1566-1572 (1993).
Although antiandrogen hormone therapy has been widely used for the treatment for prostate cancer, some antiandrogens may act as AR agonists which may result in “antiandrogen withdrawal syndrome.” Miyamoto et al.,
Proc. Natl. Acad. Sci. USA,
95, 7379-7384 (1998). A currently accepted hypothesis postulates that mutations in androgen receptors may account for why HF, the active metabolite of flutamide, can activate androgen receptor target genes and stimulate prostate cancer growth. Miyamoto et al.,
Proc. Natl. Acad. Sci. USA,
95, 7379-7384 (1998). The same mechanism is used to explain the “flutamide withdrawal syndrome,” in which patients who experience an increase in prostate-specific antigen (PSA) while taking flutamide, have a decrease in PSA after withdrawal of treatment. Indeed, HF can activate androgen receptor target genes, such as PSA and MMTV-LTR (a reporter gene which expressed androgen-response element), in the presence of ARA70, the first identified androgen receptor co-activator. Yeh et al.,
The Lancet,
349, 852-853 (1997). Because this syndrome often leads to the failure of androgen-ablative therapy, it is desirable to develop better antiandrogens without agonist activity.
The phenolic diarylheptanoid curcumin (1) is the major pigment in turmeric. Curcumin and its analogs show potent anti-oxidant activity, anti-inflammatory activity, Nurfina et al.,
Eur. J. Med. Chem.,
32, 321-328 (1997) cytotoxicity against tumor cells, Syu et al.,
J. Nat. Prod.,
61, 1531-1534 (1998), antitumor-promoting activities, Sugiyama et al.,
Biochem. Pharmacol.,
52, 519-525 (1996). Ruby et al.,
Cancer Lett.,
94, 79-83 (1995) and antiangiogenesis activity (J. L. Arbiser et al.
Mol. Med.
4: 376 (1998)).
Two cyclic diarylheptanoids, 13-oxomyricanol and myricanone, exhibiting potent antitumor promoting effects on DMBA-initiated and TPA-induced mouse skin carcinogenesis have been reported. Ishida et al.,
Cancer Lett.,
159. 135-140 (2000). In the present study, a number of novel curcumin analogues have been prepared and evaluated for antagonistic activity against the AR in the presence of androgen receptor coactivator, ARA70, using two human prostate cancer cell lines, PC-3 and DU-145. PC-3 cells are androgen-independent tumor cells that do not express functional AR. DU-145 cells are androgen-independent tumor cells that also do not express functional AR.
SUMMARY OF THE INVENTION
According to embodiments of the present invention, the present invention relates to a compound according to formula I:
wherein:
R
1
and R
2
are each independently selected from the group consisting of alkoxy, nitro, amino, and dialkylamino;
R
3
and R
4
are each independently selected from the group consisting of hydroxy, alkoxy, and —OR
7
C(O)R
8
, wherein R
7
is lower alkylene and R
8
is alkoxy;
or R
1
and R
3
together are alkylenedioxy;
or R
2
and R
4
together are alkylenedioxy;
R
5
and R
6
are each independently selected from the group consisting of H, halogen, and nitro;
X
1
is N, or X
1
is C bonded to a H, alkoxy or nitro; and
X
2
is N, or X
2
is C bonded to a H, alkoxy or nitro.
According to still other embodiments of the present invention, the present invention relates to a compound according to formula II:
wherein:
R
11
and R
12
are each independently selected from the group consisting of alkoxy, nitro, amino, and dialkylamino;
R
13
and R
14
are each independently selected from the group consisting of hydroxy, alkoxy, and —OR
18
C(O)R
19
, wherein R
18
is lower alkylene and R
19
is alkoxy.
or R
11
and R
13
together are alkylenedioxy;
or R
12
and R
14
together are alkylenedioxy;
R
15
and R
16
are each independently selected from the group consisting of H, halogen, and nitro;
R
17
is —R
20
C(O)OR
21
, wherein R
20
is alkylene and R
21
is H or alkyl;
X
3
is N, or X
3
is C bonded to a H, alkoxy or nitro; and
X
4
is N, or X
4
is C bonded to a H, alkoxy or nitro.
According to yet other embodiments of the present invention, the present invention relates to compounds according to the formula III:
wherein:
R
25
and R
26
are each independently H or lower alkyl;
R
27
, R
28
, R
29
and R
30
are each alkoxy;
R
31
is H or lower alkyl.
According to still other embodiments of the present invention, the present invention relates to a method of treating cancer, comprising administering to a subject in need thereof a treatment effective amount of a compound according to the formulas above. Examples of cancers that may be treated include, but are not limited to, skin cancer, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, endometrial cancer, ovarian cancer, central nervous system cancer, liver cancer and prostate cancer.
According to yet other embodiments of the present invention, the present invention relates to a method of inducing androgen receptor antagonist activity, the method comprising contacting a cancer cell with an androgen receptor antagonist effective amount of a compound according to the formulas above.
According to other embodiments of the present invention, the present invention relates to a method of inducing androgen receptor antagonist activity in a subject afflicted with an androgen-related affliction. Examples of androgen-related afflictions include, but are not limited to, baldness, hirsutism, behavioral disorders, acne, and uninhibited spermatogenesis wherein inhibition of spermatogenesis is so desired.


REFERENCES:
patent: WO 01/30335 (2001-05-01), None
patent: WO 01/40188 (2001-06-01), None
McDonald, R et al, Anti-Cancer Drug Design (2001), 16(6) 261-270.*
Parveen, I., et al.,Labeled Compounds of Interest as Antitumor Agents, Chem. Abstract., vol. 133, No. 281645 (2000).
Martono, S.,Inhibitory Effects of Curcumin and its Analogs on In Vitro Rat Liver Glutathione S-Transferases Activity, Chem. Abstract., vol. 128, No. 110377 (1996).
Gorbitz, C.H. et al.,Structural Studies of Curcuminoids, V. Crystal Structures of 1,7,-bis(3,4-dimethoxyphenyl)-4-benzyl-1, 6-heptadiene-3, 5-dione, Chem. Abstract., vol. 107, No. 6988 (1986).
Pedersen et al.,Synthesis of Naturally Occuring Curcuminoids and Related Compounds; Chem. Abstract., vol. 103, No. 178092 (1985).
Choshi et al.,Synthesis of Dibenzoylmethane Derivatives and Inhibition of Mutagenici

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