Antitumor agents

Details Antitumor agents Antitumor agents

1999-08-31

2001-11-27

Low, Christopher S. F. (Department: 1654)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S681000, C514S691000, C530S330000, C530S331000, C560S306000, C560S300000

Reexamination Certificate

active

06323181

ABSTRACT:

BACKGROUND OF THE INVENTION
A listing of human cancers for which chemotherapy has exerted a predominant role in increasing life span, approaching normal life expectancy, includes Burkitt's lymphoma, acute lymphocytic leukemia and Hodgkin's disease, along with about 10-15 other tumor types. For example, see A. Golden et al.,
Eur. J. Cancer
, 17, 129 (1981) (Table 1). While the cure rate of these cancers illustrates the level of success of screening systems in selecting antitumor agents that are effective in man, these responsive tumors represent only a small fraction of the various types of cancer and, notably, there are relatively few drugs highly active against solid tumors such as ovarian cancer, breast cancer, lung cancer and the like. Such drugs include cyclophosphamide, adriamycin, 5-FU, hexamethylmelamine and the like. Thus, patients with many types of malignancies remain at significant risk for relapse and mortality.
After relapse, some patients can be reinduced into remission with their initial treatment regimen. However, higher doses of the initial chemotherapeutic agent or the use of additional agents are frequently required, indicating the development of at least partial drug resistance. Recent evidence indicates drug resistance can develop simultaneously to several agents, including ones to which the patient was not exposed. The development of multiple-drug resistant (mdr) tumors may be a function of tumor mass and constitutes a major cause of treatment failure. To overcome this drug resistance, high-dose chemotherapy with or without radiation and allogenic or autologous bone marrow transplantation can be employed. The high-dose chemotherapy may employ the original drug(s) or be altered to include additional agents. The development of new drugs, non-cross resistant with mdr phenotypes, is required to further the curative potential of current regimens and to facilitate curative interventions in previously treated patients.
The in vitro anti-tumor activity of a novel class of natural products called illudins has been examined by Kelner, M. et al.,
Cancer Res
., 47, 3186 (1987). Illudin M was purified and submitted for evaluation to the National Cancer Institute Division of Cancer Treatment (NCI DCT) in vivo drug screening program. Illudin M significantly increased the life span of rats with Dunning leukemia, but had a low therapeutic index in solid tumor systems. The extreme toxicity of illudins has prevented any applications in human tumor therapy. Recently, synthetic analogs of the illudins have been developed which exhibit promising antitumor activity, including those analogs disclosed in U.S. Pat. Nos. 5,439,936 and 5,523,490.
However, despite these developments, there exists a continuing need for chemotherapeutic agents which inhibit tumor growth, especially solid tumor growth, and which have an adequate therapeutic index to be effective for in vivo treatment.
SUMMARY OF THE INVENTION
The invention provides a compound of formula I:
wherein
R
1
is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or —(CH
2
)
n
—(X)—(Y);
n is 0 to 4;
X is oxy (—O—), thio (—S—), —N(R
a
)—, or absent;
Y is (C
3
-C
6
)cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a 1 to 15 membered branched or unbranched carbon chain optionally comprising 1,2, or 3 non-peroxide oxy, thio, or —N(R
a
)—; wherein said chain may optionally be substituted on carbon with 1,2, or 3, oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(R
b
)(R
c
), (C
3
-C
6
)cycloalkyl, aryl, heteroaryl, saccharides, amino acids, or peptides; and wherein said chain may optionally be saturated or unsaturated;
R
2
is carboxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, halo(C
1
-C
6
)alkyl, —C(═O)NR
d
R
e
, a saccharide, an amino acid, a peptide, or (C
1
-C
6
)alkyl substituted by 1 or 2 hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or —C(═O)NR
d
R
e
;
R
3
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy;
R
4
is hydrogen or (C
1
-C
6
)alkyl; and R
5
is hydroxy, (C
1
-C
6
)alkoxy, or (C
1
-C
6
)alkanoyloxy; or R
4
and R
5
taken together are ethylenedioxy;
R
6
is hydrogen, carboxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, halo(C
1
-C
6
)alkyl, —C(═O)NR
f
R
g
, a saccharide, an amino acid, a peptide, or (C
1
-C
6
)alkyl optionally substituted by 1 or 2 hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or —C(═O)NR
f
R
g
;
R
a
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl; and
R
b
, R
c
, R
d
, R
e
, R
f
and R
g
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl; or R
b
and R
c
, R
d
and R
e
, or R
f
and R
g
, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholinio;
wherein any aryl, heteroaryl, aryloxy, or heteroaryloxy of Y, or R
3
may optionally be substituted by 1, 2, or 3 (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, (C
1
-C
6
)alkoxycarbonyl, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or —N(R
h
)(R
j
); wherein each R
h
and R
j
is independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl; or R
h
and R
j
together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino;
or a pharmaceutically acceptable salt thereof.
The invention also provides a compound of formula I wherein: R
1
is —(CH
2
)
n
—(X)—(Y); n is 0 to 4; X is oxy, thio, —N(R
a
)—, or absent; Y is a monoprotected amino acid, a diprotected amino acid, a peptide, or a 1 to 15 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 non-peroxide oxy, thio, or —N(R
a
)—; wherein said chain is substituted with 1, 2, or 3 peptides; and wherein said chain may optionally be saturated or unsaturated; R
2
is hydrogen or (C
1
-C
6
)alkyl; R
3
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkylthio, aryl, heteroaryl, aryloxy, or heteroaryloxy; R
4
is hydrogen or (C
1
-C
6
)alkyl; and R
5
is hydroxy, (C
1
-C
6
)alkoxy, or (C
1
-C
6
)alkanoyloxy; or R
4
and R
5
taken together are ethylenedioxy; R
6
is hydrogen, carboxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkoxycarbonyl, halo(C
1
-C
6
)alkyl, —C(═O)NR
f
R
g
, a saccharide, an amino acid, a peptide, or (C
1
-C
6
)alkyl optionally substituted by 1 or 2 hydroxy, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyloxy, carboxy, amino acids, peptides, saccharides, or —C(═O)NR
f
R
g
; R
a
is hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl; and R
b
, R
c
, R
d
, R
e
, R
f
and R
g
are each independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl; or R
b
and R
c
, and R
d
and R
e
, or R
f
and R
g
, together with the nitrogen to which they are attached, are pyrrolidino, piperidino, or morpholino; wherein any aryl heteroaryl, aryloxy, or heteroaryloxy of Y, or R
3
may optionally be substituted by 1, 2, or 3 (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, (C
1
-C
6
)alkanoyloxy, (C
1
-C
6
)alkoxycarbonyl, hydroxy(C
1
-C
6
)alkyl, halo(C
1
-C
6
)alkyl, hydroxy, halo, carboxy, mercapto, nitro, or —N(R
h
)(R
j
); wherein each R
h
and R
j
is independently hydrogen, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkanoyl, phenyl or benzyl; or R
h
and R
j
together with the nitrogen to which they are attached are pyrrolidino, piperidino, or morpholino; or a pharmaceutically acceptable salt thereof. Preferably, Y is (C
1
-C
6
)alkyl substituted with a peptide.
The invention also provides a compound of formula I wherein: R
1
is hydrogen, hydroxy, mercapto, amino, halo, carboxy, nitro, or —(CH
2
)
n
—(X)—(Y); n is 0 to 4; X is oxy, thio, —N(R
a
)—, or absent; Y is (C
3
-C
6
)cycloalkyl, aryl, heteroaryl, a saccharide, an amino acid, a peptide, or a 1 to 15 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 non-peroxide oxy, thio, or —N(R
a
)—; wh

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