Solid phase synthesis of arylretinamides

Details Solid phase synthesis of arylretinamides Solid phase synthesis of arylretinamides

2002-07-08

2004-02-24

O'Sullivan, Peter (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S155000, C564S158000, C564S182000, C554S104000, C554S105000, C554S106000, C554S107000, C554S108000, C554S109000, C554S110000, C554S111000, C554S112000, C554S114000, C560S104000, C562S430000, C562S453000, C562S457000

Reexamination Certificate

active

06696606

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds, particularly arylretinamides, for treating or preventing cancer in a mammalian subject and methods of making such arylretinamides.
BACKGROUND
Breast cancer kills thousands of women annually. While surgical intervention has saved the lives of many women, radical and partial mastectomies often prove physically and emotionally debilitating. Moreover, patients who have undergone surgery and subsequent chemotherapy often experience recurrence.
Drugs for preventing or treating breast cancer, as well as other cancers, are desirable, and many research efforts have focused on the development of such drugs. One such drug is retinoic acid, a metabolite of vitamin A. Retinoic acid and certain amide analogs of this compound display cancer preventive activity and, thus, have been proposed as cancer chemopreventive agents (Moon et al. Cancer Res. (1979) 39, 1339-1346). Similarly, other retinoic acid analogs such as retinyl acetate, 13-cis-retinoic acid, and glucuronide analogs of retinoic acid also display cancer preventive activity, including breast cancer preventative activity (Hill, D. L. et al. Ann. Rev. Nutrition (1992) 12, 161-181 and Mehta, R. G. et al. Oncology (1991) 48, 1505-1509).
Unfortunately, retinoic acid and most of its closely related analogs exhibit relatively high toxicity, thus impeding their use in humans (Biesalski, H. K. Toxicology (1989) 57, 117-161). Use of most of these compounds results in side effects such as teratogenicity, hepatotoxicity, scaly skin, hair loss and headaches. Accordingly, researchers have continued to pursue the synthesis of retinoic acid analogs with increased potency and/or reduced toxicity for application as cancer preventative agents.
It has also been found that N-(4-hydroxyphenyl) retinamide (hereinafter “4-HPR”), an analog of retinoic acid, displays chemopreventive activity in breast cancer (Moon et al. Cancer Res. (1979) 39, 1339-1346). Indeed, 4-HPR, when combined with calcium glucarate, synergistically exerts an increased breast cancer chemopreventive activity in carcinogen-induced rat mammary tumors (Abou-Issa, H. M. et al.(1988) Proc. Natl. Acad. Sci. USA 85, 4181-4184). However, 4-HPR still displays teratogenic potential as evidenced by studies in the rat, mouse and the rabbit. (See Kenel, M. F., Krayer, J. H., Merz, E. A. and Pritchard, J. R. (1988) “Teratogenicity of N-(4-hydroxyphenyl)-all-trans retinamide in rats and rabbits.” Teratogenesis, Carcinogenesis and Mutagenesis 8:1-11; Kochhar, D. M. Shealy, Y. F., Penner, J. D. and Jiang, H. (1992) “Retinamides: hydrolytic conversion of retinoylglycine to retinoic acid in pregnant mice contributes to teratogenicity.” Teratology 45:175-185.) Furthermore, 4-HPR impairs night vision in human patients (Kaiser-Kupfer, M. I., Peck, G. K., Caruso, R. C., Jaffe, J D., DiGiovanna, J. J., Gross, E. G. (1986) “Abnormal retinal function associated with fenretinide, a synthetic retinoid.” Arch Ophthalmol.104:69-70.; Costa, A., Malone, W., Perloff, M., Buranelli, F., Campa, T., Dossena, G., Magni, A., Pizzichetta, M., Andreoli, C., DelVecchio, M., Formelli, F., and Barbier, A. (1989) “Tolerability of the synthetic retinoid Fenretinide (HPR).” Eur. J. Cancer Clin. Oncol. 25:805-808).
Thus, there still remains a long-felt need to have stable chemopreventive drugs for the prevention and treatment of various cancers, including breast cancer.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds for treating or preventing cancer, particularly breast cancer in a subject. The compounds are new arylretinamides and pharmaceutical compositions that contain one of more of the present arylretinamides. The arylretinamides have structure A, B, or C below:
wherein
R
2
is H, OH, NO
2
, CH
2
OH, a halide, or an alkyl comprising 1-4 carbon atoms,
R
3
is H, OH, NO
2
, CO
2
CH
3
, CO
2
CH
2
CH
3
, CO
2
(CH
2
)
2
CH
3
, CO
2
(CH
2
)
3
CH
3
, CO
2
H, CH
2
OH, a halide, or an alkyl comprising 1-4 carbon atoms;
R
4
is H, OH, OCH
3
, OCH
2
CH
3
, O(CH
2
)
2
CH
3
, O(CH
2
)
3
CH
3
, SO
2
CH
3
, SO
2
CH
2
CH
3
, SO
2
(CH
2
)
2
CH
3
, SO
2
(CH
2
)
3
CH
3
, NH
2
, NHCOCH
3
, NHCOCH
2
CH
3
, NHCO(CH
2
)
2
CH
3
, NHCO(CH
2
)
3
CH
3
, NHCOCF
3
, N
3
, NCS, a halide, an alkyl comprising 1-4 carbon atoms, or NHCOCH
2
X, wherein X is a halide;
R
5
is H, NO
2
, C(CH
3
)
3
, C(CH
2
CH
3
)
3
, C((CH
2
)
2
CH
3
)
3
, C((CH
2
)
3
CH
3
)
3
, CO
2
CH
3
, CO
2
CH
2
CH
3
, CO
2
(CH
2
)
2
CH
3
, CO
2
(CH
2
)
3
CH
3
, a halide, or an alkyl comprising 1-4 carbon atoms, and
R
6
is H, CO
2
H, CO
2
CH
3
, CO
2
CH
2
CH
3
, CO
2
(CH
2
)
2
CH
3
, CO
2
(CH
2
)
3
CH
3
, a halide or an alkyl comprising 1-4 carbon atoms;
provided however that when R
2
, R
3
, R
4
, R
5
, and R
6
are all H, R
4
is not OH or OCH
2
CH
3
; and also provided that when R
3
, R
5
, and R
6
are all H, and R
2
is OH, R
4
is not CO
2
CH
3
.
wherein the OH group is at position 2, 4, or 5 when the retinamido group is at linked to position 1, and the OH group is at position 3 when the rentinamido group is linked to position 2.
wherein R
7
is C
1
to C
4
alkyl.
The present arylretinamides find use in the treatment of cancer in a mammalian subject, including a human subject. Use for treating a particular cancer is initially shown employing an apoptosis assay in a cancer cell line that serves as an experimental model for the particular cancer. Examples of such cell lines include the human breast cancer cell line MCF7 and the human neuroblastoma cell line LA1-15n.
In another aspect the present invention provides methods of treating cancer in a mammalian subject. The present methods comprise administering a biologically effective amount of one or more of present arylretinamides to a mammalian subject, particularly a human subject, who is at risk of or has been diagnosed as having cancer.
In another aspect, the present invention provides a method for synthesizing arylretinamides. The method is a solid phase synthetic scheme and comprises reacting hexachloroacetone with a solvent-suspended resin-bound triphenylphosphine to provide a suspension comprising an activated chlorinating reagent; reacting retinoic acid with the activated chlorinating reagent to provide retinoyl chloride; adding pyridine and a select arylamine to the resulting mixture; and stirring the resulting mixture for a time and at a temperature sufficient for the select arylamine to react with the retinoyl chloride and provide the arylretinamide. Preferably, the method further comprises the step of purifying the arylretinamide from the suspension.


REFERENCES:
patent: 4108880 (1978-08-01), Gander et al.
patent: 4190594 (1980-02-01), Gander et al.
patent: 5399757 (1995-03-01), Maryanoff
patent: 5731320 (1998-03-01), Wagner et al.
patent: 6117845 (2000-09-01), Clagett-Dame et al.
Abstract, Publ. No. JP 4-54119A, “5-Lipoxygenase Inhibitor” by Hirozumi, et al., Feb. 1992, col. 2, p. 127, cols. 1 and 2, p. 131.
Abstract, “Solid-phase assisted synthesis of a library of N-(4-hydroxyphenyl)retinamide (4-HPR) analogs” By Mershon, et al., Aug. 2001 American Chemical Society Meeting.
Abstract, “Solid Phase-Assisted Synthesis and Screening of a Library of N-(4-Hydroxyphenyl)Retinamide Analogs” by Mershon, et al., Jun. 2002 FASEB Summer Research Conference.
Abstract, “Photo/affinity label analogs of N-(4-hydroxyphenyl)retinamide” by Barnett, et al., Aug. 2002 American CHemical Society Meeting.

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