Naphthoquinone antitumor compound and method

Details Naphthoquinone antitumor compound and method Naphthoquinone antitumor compound and method

1998-07-30

2001-01-16

Goldberg, Jerome D. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

57, 57, 57, 57, 57

Reexamination Certificate

active

06174918

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to 2,3-disubstituted naphthoquinone compounds and the use of such compounds as antitumor agents.
REFERENCES
Ambrogi, V., et al.,
Br. J. Pharm.
40:871 (1970).
Boyd, M., in
CANCER; PRINCIPLES AND PRACTICE OF ONCOLOGY UPDATES
(De Vita, V. T., et al., Eds.) J. B. Lippincott, Philadelphia, pp 1-12 (1989).
Driscoll, J., et al.,
Cancer Chemother. Rep.
4(2):1-27 (1974a).
Driscoll,
J., Canc. Chemo. Rep.
4(4):3-4 (1974b).
Entwistle, I. D., et al., EP 240047 B1 (1987).
Fieser, L. F., et al.,
Record Chem. Progress
7:26 (1946).
Fries, K., et al.,
Ann.
516:248 (1935).
Gilman, A. G., et al., in
THE PHARMACOLOGICAL BASIS OF THERAPEUTICS
, Eighth Ed., Pergamon Press, New York, (1990).
Greene, T. W., et al., in
PROTECTIVE GROUPS IN ORGANIC SYNTHESIS,
2nd Ed., John Wiley & Sons, New York, N.Y.(1991).
Grever, M. R. et al.,
Seminars Oncol.
19:622-638 (1992).
Griffin, J. E. and Wilson, J. D., (1991) in
HARRISON'S PRINCIPLES OF INTERNAL MEDICINE,
12th Ed., (Harrison, T. R., et al., Eds.), McGraw-Hill, Inc., New York, N.Y., p 1587.
Hoffmann-Ostenhof, O.,
Metab. Inhibitors
2:145-159 (963).
Hoover, J. et al.,
J. Am. Chem. Soc.
76:4148-52 (1954).
Larock, R., in
COMPREHENSIVE ORGANIC TRANSFORMATIONS
, VCH Publishers, New York, N.Y., pp 972-976 (1989).
Lin, A., et al.,
CANCER CHEMOTHER. REP.
4(2):23-26 (1974).
Monks, A., et al.,
J. Natl. Cancer Inst.
83:757-766 (1991).
Morton, R. A., Ed., in
BIOCHEMISTRY OF QUINONES
Academic Press, New York, N.Y. (1965).
Webb, J. L., in
ENZYME AND METABOLIC INHIBITORS
Vol. 3, Academic Press, New York, N.Y. (1966).
BACKGROUND OF THE INVENTION
Compounds containing the quinone (cyclohexadienedione) moiety are involved in a wide variety of biochemical processes including electron transport and oxidative phosphorylation (Morton). Many quinone compounds are naturally occurring, such as o-benzoquinone, fumigatin (3-hydroxy-2-methoxy-5-methyl-1,4-benzoquinone), daunorubicin, adriamycin, lapachol, and phthiocol (2-hydroxy-3-methyl-1,4-naphthoquinone). The K vitamins are all 1,4-naphthoquinone compounds or compounds that are oxidized to contain the 1,4-naphthoquinone moiety and are present in the blood as coagulation factors. Another naturally occurring 1,4-naphthoquinone compound is coenzyme Q, which occurs in many kinds of cells and is involved in electron transport.
A wide variety of quinone derivatives have been synthesized to date, and various structurally diverse quinone compounds have been reported to be biologically active. As an illustration, various quinone compounds have been reported to possess enzyme inhibitory (Hoffmann-Ostenhof), antibacterial (Ambrogi), antimalarial (Fieser), metabolite antagonist (Hoover), and antifungal (Webb, Entwistle) activities.
Various synthetic and naturally occurring quinone compounds have been reported to exhibit antitumor properties. One example of such compounds, early recognized to exhibit antitumor properties, is the mitomycins, a group of antitumor antibiotics produced by
Streptomyces caespitosus
(griseovinaceseus). Included in this class is mitomycin C, an antineoplastic agent and inhibitor of nucleic acid synthesis (Lin). The mitomycins are heterocyclic quinone compounds, and the early discovery of the biological activity of these compounds has led to the synthesis and investigation of large numbers of heterocyclic quinone derivatives.
As part of its ongoing efforts to obtain new antitumor drug candidates, since the late 1950s, the National Cancer Institute (NCI) has screened over 700,000 synthetic compounds (Griffin). As part of this effort, the NCI has screened approximately 1500 quinones falling outside of the present invention, with limited success. Of the quinone compounds tested in in vivo and in vitro model systems, only a small number exhibited antitumor activity (Driscoll, 1974a,b). Further, in reviewing relationships among members of biologically active natural product families and model analogs thereof, such as in the case of quinones, it was concluded that structurally simpler analogs of complex active materials typically resulted in inactive compounds (Driscoll, 1974a), thus indicating the difficulty in designing compounds for use as antitumor agents.
In the United States, cancer is the second leading cause of death. Based on current statistics, an individual born in the United States has a greater than 1 in 3 chance of developing cancer in his or her lifetime. Since the mid-1950s, it has been recognized that cancer chemotherapy can be used to cure certain cancers. Although many cancers can be cured by surgical resection, chemotherapy is often used as an adjunct to surgical therapy, and is used primarily in the treatment of nonoperable or metastatic malignancy. In view of the high number of deaths each year resulting from cancer, a continuing need exists to identify effective chemotherapeutic drugs, and particularly compounds exhibiting high antitumor activity and selectivity, for use as anticancer agents.
SUMMARY OF THE INVENTION
The present invention provides a method for inhibiting tumor cell growth in a subject by administering a 1,4-naphthoquinone compound represented by the formula:
where R
1
is lower alkyl, halogenated lower alkyl, phenyl, benzyl, phenethyl, or —(CH
2
)
m
COOX, where m is 2 or 3 and X is H, methyl, or ethyl; R
2
is halo or NHY, where Y is hydrogen, lower alkyl, halogenated lower alkyl, hydroxylated lower alkyl, lower dialkylaminoalkyl, phenyl, benzyl, or phenethyl; R
3
is lower alkyl, halogenated lower alkyl, phenyl, benzyl, phenethyl, or —(CH
2
)
m
COOX, where m and X are as defined for R
1
above; and R
4
is hydrogen, lower alkyl, lower aminoalkyl, halogenated lower alkyl, phenyl, benzyl, or phenethyl.
In one embodiment, a 2-amido-3-substituted-1,4-naphthoquinone of formula (I) is administered where R
1
is phenyl or benzyl and R
2
is Cl. Compounds for administration according to the present invention are 2-amido-3-chloro derivatives having as R
1
a substituted phenyl group, where R
1
is 4-fluorophenyl, 4-methoxyphenyl, 3,5-dimethoxyphenyl, 2-fluorophenylmethyl, or 4-fluorophenylmethyl.
Additional compounds for administration by the present method are those represented by formula (I) where R
1
is phenyl and R
2
is NHY, where Y is hydrogen, methyl or ethyl, halogenated methyl or ethyl, hydroxyethyl, or —(CH
2
)
2
NZ
2
, where Z is methyl or ethyl. In a preferred embodiment, the compound is a 3-amino derivative where R
1
is 3,5-dimethoxyphenyl and R
2
is NH(C
2
H
5
).
In yet another embodiment, compounds for use in inhibiting tumor cell growth are 2-amido-3-amino-1,4-naphthoquinones of formula (I), where R
1
is lower alkyl or halogenated lower alkyl, and R
2
is NHY, where Y is lower alkyl or halogenated lower alkyl. Representative compounds are those where R
1
is methyl and R
2
is NHCH (CH
2
CH
3
)
2
or NHCH
2
CH
2
N(CH
3
)
2
.
Additional 2-amido-3-substituted-1,4-naphthoquinones of formula (I) for use in the present treatment method are those where R
1
is lower alkyl, halogenated lower alkyl, or —(CH
2
)
m
COOX, and R
2
is NHY, where Y is phenyl or benzyl. In one embodiment, R
1
is methyl, and Y is (4-methoxyphenyl)methyl or (4-chlorophenol)methyl. In another embodiment, R
1
is —(CH
2
)
2
COOCH
3
or —(CH
2
)
2
COOCH
2
CH
3
, and R
2
is NHY, where Y is unsubstituted phenyl or 4-methoxyphenyl.
In another embodiment of the present invention, a 1,2-disubstituted naphth[2,3-d]imidazole-4,9-dione of formula (II) is administered, for inhibiting tumor cell growth in a subject. 1,2-disubstituted naphth[2,3-d]imidazole-4,9-dione compounds for administration according to the present method are those where R
3
is phenyl or benzyl, and R
4
is H. Additional compounds for use in the present invention are those where R
3
and R
4
are both lower alkyl groups. In a preferred embodiment, R
3
is methyl and R
4
is ethyl. In another embodiment, R
3
is methyl and R
4
is 2-chloroethyl.
Additional compounds represented by formula (II), for use in the present method are those wher

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