Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-09
2001-10-16
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C435S184000
Reexamination Certificate
active
06303604
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to substituted O
6
-benzylguanines and 6(4-benzyloxypyrimidines, pharmaceutical compositions comprising such compounds, and methods of using such compounds. The subject compounds are particularly useful in inactivating the human DNA repair protein O
6
-alkylguanine-DNA alkyltransferase.
BACKGROUND OF THE INVENTION
The inactivation of the human DNA repair protein O
6
-alkylguanine-DNA alkyltransferase (AGT) by O
6
-benzylguanine leads to a dramatic enhancement in the cytotoxic response of human tumor cells and tumor xenografts to chemotherapeutic drugs whose mechanism of action involves modification of DNA quanine residues at the O
6
-position (Dolan et al.,
Proc. Natl. Acad. Sci. U.S.A.,
87, 5368-5372 (1990); Dolan et al.,
Cancer Res.,
51, 3367-3372 (1991); Dolan et al.,
Cancer Commun.,
2, 371-377 (1990); Mitchell et al.,
Cancer Res.,
52, 1171-1175 (1992); Friedman et al.,
J. Natl. Cancer Inst.,
84, 1926-1931 (1992); Felker et al.,
Cancer Chem. Pharmacol.,
32, 471-476 (1993); Dolan et al.,
Cancer Chem. Pharmacol.,
32, 221-225 (1993); Dolan et al.,
Biochem. Pharmacol.,
46, 285-290 (1993)). The AGT inactivating activity of a large number of O
6
-benzylguanine analogs have been compared with the aim of obtaining information about the types of substituent groups and the sites at which they could be attached to O
6
-benzylguanine without significantly lowering its AGT-inactivating activity (Moschel et al.,
J. Med. Chem.,
35, 4486-4491 (1992); Chae et al.,
J. Med. Chem.,
37, 342-347 (1994)). While these studies led to the production of a variety of analogs that were at potent or somewhat less potent than O
6
-benzylguanine, none of the analogs were better than O
6
-benzylguanine.
Thus, there remains a need for additional compounds which are capable of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O
6
-position of guanine. The present invention provides such compounds and associated pharmaceutical compositions and treatment methods. These and other objects and advantages of the present invention, as well as additional inventive features, will be apparent from the description of the invention provided herein.
BRIEF SUMMARY OF THE INVENTION
The present invention provides 8-substituted O
6
-benzylguanine derivatives and 4(6)-substituted 2-amino-5-nitro-6(4)-benzyloxypyrimidine and 2-amino-5-nitroso-6(4)-benzyloxypyrimidine derivatives which have been found to be effective AGT inactivators, as well as pharmaceutical compositions comprising such derivatives along with a pharmaceutically acceptable carrier. The present invention further provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent which causes cytotoxic lesions at the O
6
-position of guanine, by administering to a mammal an effective amount of one of the aforesaid derivatives, 2,4-diamino-6-benzyloxy-s-triazine, 5-substituted 2,4-diamino-6-benzyloxypyrimidines, or 8-aza-O
6
-benzylguanine, and administering to the mammal an effective amount of an antineoplastic alkylating agent which causes cytotoxic lesions at the O
6
-position of guanine.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides a compound of the formula
wherein R
1
is a substituent selected from the group consisting of amino, hydroxy, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, and C
1
-C
4
acylamino (although, as explained in further detail below, other substituents can be placed at this 2-position), R
2
is a substituent selected from the group consisting of hydrogen, C
1
-C
4
alkyl, C
1
-C
4
aminoalkyl, C
1
-C
4
hydroxyalkyl, C
1
-C
4
alkylaminoalkyl, C
1
-C
4
dialylaminoalkyl, C
1
-C
4
cyanoalkyl, C
1
-C
4
carbamoylalkyl, C
1
-C
4
pivaloylalkyl, C
1
-C
4
carboalkoxyalkyl, ribose, 2′-deoxyribose, the conjugate acid form of a C
1
-C
4
carboxyalkyl, and the carboxylate anion of a C
1
-C
4
carboxyalkyl as the sodium salt (although, as explained in further detail below, other substituents can be placed at this N
9
-position), and R
3
is a substituent selected from the group consisting of hydrogen, halo, C
1
-C
4
alkyl, C
1
-C
4
hydroxyalkyl, thiol, C
1
-C
4
alkylthio, trifluoromethylthio, C
1
-C
4
thioacyl, hydroxy, C
1
-C
4
alkoxy, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, C
1
-C
4
oxyacyl, amino, C
1
-C
4
aminoalkyl, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, C
1
-C
4
aminoacyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C
1
-C
4
alkyldiazo, C
5
-C
6
aryldiazo, trifluoromethyl, C
1
-C
4
haloalkyl, C
1
-C
4
cyanoalkyl, cyano, C
1
-C
4
alkyoxycarbonyl, C
1
-C
4
alkylcarbonyl, phenyl, phenylcarbonyl, C
1
-C
4
acyl, formyl, C
1
-C
4
alkoxymethyl, phenoxymethyl, C
1
-C
4
vinyl, C
1
-C
4
ethynyl, and SO
n
R′ wherein n is 0, 1, 2, or 3 and R′ is hydrogen, C
1
-C
4
alkyl, amino, or phenyl, with the proviso that R
1
is not amino when both R
2
and R
3
are hydrogen. Of particular interest are those compounds wherein R
1
is amino, R
2
is hydrogen or C
1
-C
4
alkyl (preferably methyl), and/or R
3
is amino, C
1
-C
4
alkyl (preferably methyl), hydroxy, halo (preferably bromine), nitro, or trifluoromethyl. Also of particular interest are those compounds wherein R
1
is hydroxy, C
1
-C
4
alkylamino (preferably methylamino), C
1
-C
4
dialkylamino (preferably dimethylamino), or C
1
-C
4
acylamino (preferably acylamino, i.e., CH
3
COHN—), R
2
is hydrogen, and/or R
3
is hydrogen or hydroxy.
The present invention also provides a compound of the formula
wherein R
1
is NO
2
or NO, and R
2
is a substituent selected from the group consisting of hydrogen, halo, C
1
-C
4
alkyl, C
1
-C
4
hydroxyalkyl, thiol, C
1
-C
4
alkylthio, trifluoromethylthio, C
1
-C
4
thioacyl, hydroxy, C
1
-C
4
alkoxy, trifluoromethoxy, oxymethanesulfonyl, oxytrifluoromethanesulfonyl, C
1
-C
4
oxyacyl, C
1
-C
4
aminoalkyl, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, C
1
-C
4
aminoacyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C
1
-C
4
alkyldiazo, C
5
-C
6
aryldiazo, trifluoromethyl, halomethyl, C
1
-C
4
haloalkyl, cyanomethyl, C
1
-C
4
cyanoalkyl, cyano, C
1
-C
4
alkyoxycarbonyl, C
1
-C
4
alkylcarbonyl, phenyl, phenylcarbonyl, C
1
-C
4
acyl, formyl, C
1
-C
4
alkoxymethyl, phenoxymethyl, C
1
-C
4
vinyl, C
1
-C
4
ethynyl, and SO
n
R′ wherein n is 0, 1, 2, or 3 and R′ is hydrogen, C
1
-C
4
alkyl, amino, or phenyl. Of particular interest are those compounds wherein R
2
is hydrogen or a C
1
-C
4
alkyl, preferably methyl, particularly when R
1
is NO
2
.
The present invention additionally provides treatment methods, which are generally administered via pharmaceutical compositions comprising one or more of the O
6
-substituted compounds of the present invention. In particular, the present invention provides a method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O
6
-position of guanine, which method comprises administering to a mammal an effective amount of one or more of the aforedescribed present inventive compounds, and administering to the mammal an effective amount of an antineoplastic alkylating agent that causes cytotoxic lesions at the O
6
-position of guanine. The present invention also includes the method of enhancing the chemotherapeutic treatment of tumor cells in a mammal with an antineoplastic alkylating agent that causes cytotoxic lesions at the O
6
-position of guanine, which method comprises (i) administering to a mammal an effective amount of
wherein R is a substituent selected from the group consisting of hydrogen, halo, C
1
-C
4
alkyl, C
1
-C
4
hydroxyalkyl, thiol, C
1
-C
4
alkylthio, trifluoromethylthio, C
1
-C
4
thioacyl, hydrox
Chae Mi-Young
Dolan M. Eileen
Moschel Robert C.
Pegg Anthony E.
Krass Frederick
Leydig , Voit & Mayer, Ltd.
The United States of America as represented by the Department of
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