7-aryl-6(Z)-heptatrienoic acid retinamides

Details 7-aryl-6(Z)-heptatrienoic acid retinamides 7-aryl-6(Z)-heptatrienoic acid retinamides

1999-12-14

2001-10-30

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S170000, C564S174000, C554S035000, C514S617000, C514S622000

Reexamination Certificate

active

06310247

ABSTRACT:

BACKGROUND OF THE INVENTION
Retinoic acids (RA)s modulate the growth and differentiation of normal and malignant cells in vitro and in vivo and have been extensively studied for their potential use as therapeutic and preventative agents of a variety of malignancies. All-trans RA and 13-cis RA, which function through the nuclear retinoic acid receptors (RAR) &agr;, &bgr; and &ggr;, are known to cause differentiation of certain tumor cells in vitro. 9-cis RA and its analogs, which bind to a group of receptors known as the retinoic acid X &agr;, &bgr; and &ggr; receptors (RXR), as well as to the RAR &agr;, &bgr; and &ggr; receptors, have been shown to cause tumor regression. The ability of all-trans RA and 13-cis RA to induce apoptosis has been shown to be very limited, however, the 4-hydroxyphenyl amide of all-trans RA (4-HPR) has been shown to inhibit tumor formation and tumor growth via apoptosis [JBC 271, 22441 (1996) A. N. Fanjul et al; BBRC 224, 837 (1996) A. Dipietrantonio, etal; Cancer Res. 55, 853 (1995) M. Ponzoni, etal].
Apoptosis, or programmed cell death, is one of the most common forms of eukaryotic cell death and is characterized by loss of contact with neighboring cells, chromatin condensation, membrane blebbing, condensation of cytoplasm, and activation of an endogenous endonuclease which generates the characteristic DNA fragments (one of the benchmarks of cellular apoptosis), and finally generation of apoptotic bodies that are phagocytosed by other cells. Apoptosis is a normal process and is involved in building, sculpting and maintaining tissues during development and throughout life. Apoptosis is also an important defense mechanism against viral infection and the emergence of cancer. The development of cancer appears to involve both excess cell proliferation and the resistance to normal apoptosis stimuli. A number of tumor promoters have been shown to induce resistance to apoptosis [FASEB Journal 8, 864 (1994) S. C. Wright, etal]
While retinoic acids have been found to be effective in treating carcinomas, many retinoic acids and other retinoid compounds are very toxic, producing deleterious adverse effects such as hypervitaminosis A which limit their use in the prevention and treatment of cancer. In treating breast cancer the situation is further complicated by cancer cells which are capable of changing their sensitivity to compounds used in treatment. Cells which are initially positive for estrogen receptor (ER+) can become negative for estrogen receptor (ER−) following anti-estrogen therapies. The retinoic acids and retinoids, like most chemotherapeutic agents, are active only against ER+breast carcinoma cells and not active against estrogen receptor negative ER—breast carcinoma cells. [Can Res 50, 1997 (1990) J. A. Fontana, et al; Mol Cell Endocrinol 91, 149 (1993) B. Van der Burg, et al] Thus compounds which show activity against both ER− and ER+ breast carcinoma cells are very important for treatment of breast cancer.
A preliminary measure for possible antitumor/anticancer therapeutic activity is the induction of apoptosis, or programmed cell death, in immortalized carcinoma cells. A number of existing chemotherapeutic agents (e.g. 5FU, Adriamycin, Taxol), as well as radiation therapy, induce apoptosis in human carcinoma cells in vitro[Cancer 79, 12 (1997) K. Sugamura, etal; Cancer Lett. 93, 147 (1995) S. M. Tu, et al; Ann NY Acad. Sci 784, 550 (1996) R. M. Gangemi, etal]. Another measure of antitumor or anticancer activity is the inhibition of cell growth, or cell cycle arrest, which prevents cells from dividing, though not necessarily killing the cells. It has been shown that a specific retinoic acid amide, all trans 4-hydroxyphenyl retinamide (4-HPR), is capable of inhibiting cell growth and inducing apoptosis in both ER+ and ER− breast carcinoma cells. [Cancer Lett. 107, 65 (1996) T. T. Y. Wang, et al].
This compound is also known to inhibit cell growth and to induce apoptosis in many other tumor cell types including lung carcinoma cell and hematopoetic malignancies. 4-HPR is effective in inducing apoptosis in cells that are resistant to retinoids that activate RARs efficiently.[Carcinogenesis 16, 2477 (1995) M. S. Sheikh, etal; Cancer Res. 53, 6036 (1993) D. Delia, etal] 4-HPR is capable of tumor regression in vivo [Clin. Cancer Res. 4, 1345 (1998) C. P. Zou, etal; Otolaryngol Head Neck Surg 118, 464 (1998) R. L. Scher, etal; Cancer Lett 47, 187 (1989) K. Dowlatshahi, etal], and acts as a potent chemopreventative agent against a number of malignancies [Cancer Res. 39, 1339 (1979) R. C. Moon, etal; Cancer Res. 54, 2032S (1994) A. Costa, etal; Anticancer Res. 17, 499 (1997) L. N. Chan, etal]. In vitro, 4-HPR appears to induce apoptosis and cause inhibition of cell growth in both ER+ and ER− breast carcinoma cell lines. The major toxicity seen in the clinic with 4-HPR was night vision impairment.
Aromatic 6-cis trienoic acids have been reported to induce apoptosis in carcinoma cells and were reported to have low toxicity (WO96/20913). However, it has been determined that one such compound is inactive against ER− and ER+ carcinoma cells in that it does not induce apoptosis ((2E,4E,6Z)-
7-[3,5
-bis(trifluoromethyl)phenyl-3,7-dimethyl-2,4,6-heptatrienoic acid). Therefore, such compounds would seem to be of little interest.
Surprisingly, the 7-aryl-6-cis heptatrienoic acid retinamides of this invention are effective against both ER+ and ER− breast carcinoma cells in vitro, reduce the number of tumors in the NMU rat tumor model, and do not exhibit the toxic or adverse effects generally associated with retinoids.
SUMMARY OF THE INVENTION
The invention comprises compounds of the formula
wherein R
1
and R
2
are independently hydrogen, halogen, alkyl, alkoxy, or trihalomethyl; R
3
is hydrogen or alkyl; and R
4
is hydrogen except when R
3
is alkyl then R
4
may be alkyl; R
5
, R
6
, and R
8
and R
9
are independently halogen, hydrogen, hydroxy, alkyl, or alkyloxy; and R
7
is hydrogen alkyl; which are free of 6-trans isomers.
These 6Z (e.g. 7-aryl-6-cis) heptatrienoic acid retinamide compounds are effective in inducing apoptosis in premalignant and malignant cells. The compounds inhibit the proliferation of cells derived from cancerous solid tumors, especially non-small-cell lung carcinoma, rectal carcinoma, and breast carcinoma, thus are useful for the treatment of cancer forming solid tumors, especially non-small-cell lung carcinoma,colorectal carcinoma and breast carcinoma.
The compounds described herein are particularly effective at inducing apoptosis in ER− breast carcinoma cells as well as ER+ cells. Furthermore, the 6-cis retinamide compounds of this invention are effective in inducing apoptosis in carcinoma cells that were once ER+ and have become ER−. Finally, these compounds are effective at dosage levels low enough to avoid deleterious or toxic side effects.
DETAILED DESCRIPTION OF THE INVENTION
The invention comprises compounds of the formula
wherein R
1
and R
2
are independently hydrogen, halogen, alkyl, alkoxy, or trihalomethyl; R
3
is hydrogen or alkyl; and R
4
is H except when R
3
is alkyl then R
4
may be alkyl; R
5
, R
6
, and R
8
and R
9
are independently halogen, hydrogen, hydroxy, alkyl, or alkyloxy; and R
7
is hydrogen or alkyl; which are free of 6-trans isomers.
Although the preferred R
7
is hydrogen, in any compound of this invention R
7
may be alkyl such as methyl. Similarly, although preferred compounds are those of formula 2 below where the positions occupied by R
5
, R
6
, and R
8
and R
9
in formula 1 are all hydrogen, in any compound of this invention, any one or more of these substituents may be halogen or hydroxy or alkyl or alkoxy, in any combination.
Compounds of particular interest are compounds of formula 2
where R
1
, R
2
, R
3
, and R
4
are as above.
Other compounds of interest include compounds of formula 1 where R
3
is alkyl su

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