Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-08-14
2002-08-20
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S254000
Reexamination Certificate
active
06436945
ABSTRACT:
TECHNICAL FIELD OF THE INVENTION
The present invention relates to substituted O
6
-benzylguanines, O
6
-benzyl-8-azaguanines, 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 guanine 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 as 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 7- and 8-substituted O
6
-benzylguanine derivatives, 7,8-disubstituted O
6
-benzylguanine derivatives, 7,9-disubstituted benzylguanine derivatives, 8-aza-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 I
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
dialkylaminoalkyl, C
1
-C
4
cyanoalkyl, C
1
-C
4
carbamoylalkyl, C
1
-C
4
pivaloylalkyl, C
1
-C
6
alkylcarbonyloxy C
1
-C
4
alkyl, C
1
-C
4
alkoxyalkyl carbonyl alkyl, 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, methanesulfonyloxy, trifluoromethanesulfonyloxy, C
1
-C
4
acyloxy, 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, halomethyl, C
1
-C
4
cyanoalkyl, cyanomethyl, cyano, C
1
-C
4
alkyloxycarbonyl, C
1
-C
4
alkylcarbonyl, phenyl, phenylcarbonyl, formyl, C
1
-C
4
alkoxymethyl, phenoxymethyl, C
2
-C
4
vinyl, C
2
-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, and with the proviso that R
1
is not amino or methylamino when R
2
is ribose or 2′-deoxyribose and R
3
is hydrogen. It is to be understood that the substituents are defined herein such that the group farthest from the point of attachment of the substituent is named first. By way of illustration, C
1
-C
6
alkylcarbonyloxy C
1
-C
4
alkyl includes pivaloyloxymethyl.
Suitable compounds of the above formula include those compounds wherein R
1
is selected from the group consisting of amino, hydroxy, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, and C
1
-C
4
alkylcarbonylamino, R
2
is selected from the group consisting of hydrogen, C
1
-C
4
alkyl, and C
1
-C
6
alkylcarbonyloxy C
1
-C
4
alkyl, and R
3
is selected from the group consisting of amino, halo, C
1
-C
4
alkyl, hydroxy, and trifluoromethyl. Other suitable compounds include those wherein R
1
is selected from the group consisting of amino, hydroxy, methylamino, dimethylamino, and acetylamino, R
2
is selected from the group consisting of hydrogen, methyl, and pivaloyloxymethyl, and R
3
is selected from the group consisting of amino, bromo, methyl, hydroxy, and. trifluoromethyl. Examples of suitable compounds include 8-amino-O
6
-benzylguanine, 8-methyl-O
6
-benzylguanine, 8-hydroxy-O
6
-benzylguanine, 8-bromo-O
6
-benzylguanine, 8-trifluoromethyl-O
6
-benzylguanine, O
6
-benzylxanthine, O
6
-benzyluric acid, N
2
-acetyl-O
6
-benzyl-8-oxoguanine, O
6
-benzyl-N
2
-methylguanine, O
6
-benzyl-N
2
,N
2
-dimethylguanine, 6-benzyl-8-trifluoromethyl-9-methylguanine, O
6
-benzyl-8-bromo-9-methylguanine, and O
6
-benzyl-8-bromo-9-(pivaloyloxymethyl)guanine.
The present invention also provides a compound of the formula II
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
alkyloxy, trifluoromethoxy, methanesulfonyloxy, trifluoromethanesulfonyloxy, C
1
-C
4
acyloxy, C
1
-C
4
aminoalkyl, C
1
-C
4
alkylamino, C
1
-C
4
dialkylamino, trifluoromethylamino, ditrifluoromethylamino, aminomethanesulfonyl, amino C
1
-C
4
alkylcarbonyl, aminotrifluoromethylcarbonyl, formylamino, nitro, nitroso, C
1
-C
4
alkyldiazo, C
5
-C
6
aryldiazo, trifluoromethyl, C
1
-C
4
haloalkyl, cyanomethyl, C
1
-C
4
cyanoalkyl, cyano, C
1
-C
4
alkyloxycarbonyl, C
1
-C
4
alkylcarbonyl, phenyl, phenylcarbonyl, formyl, C
1
-C
4
alkoxymethyl, phenoxymethyl, C
2
-C
4
vinyl, C
2
-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. Suitable compounds include tho
Chae Mi-Young
Dolan M. Eileen
Moschel Robert C.
Pegg Anthony E.
Leydig , Voit & Mayer, Ltd.
Rao Deepak R
Raymond Richard L.
The United States of America as represented by the of Health and
LandOfFree
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