Platinum (II) antitumor compounds

Details Platinum (II) antitumor compounds Platinum (II) antitumor compounds

2002-05-15

2004-05-18

Nazario-Gonzalez, Porfirio (Department: 1621)

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

Organic compounds

Heavy metal containing

C514S492000

Reexamination Certificate

active

06737537

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to platinum (II) compounds effective for treating tumor cells and particularly effective to induce apoptosis in leukemia cells, breast cancer cells, prostate cancer cells, and brain cancer cells.
BACKGROUND OF THE INVENTION
Cancer is a major disease that continues as one of the leading causes of death at any age. In the United States alone, it is anticipated that more than a half a million Americans will die of cancer in 2000. Currently, radiotherapy and chemotherapy are two important methods used in the treatment of cancer.
Considerable efforts are underway to develop new chemotherapeutic agents for more potent and specific anti-cancer therapy, presenting effective and efficient cytotoxicity against tumor cells, with minimal interference with normal cell function. Accordingly, there is an urgent need for the development and analysis of novel, effective anti-cancer agents.
The use of platinum (II) compounds as anti-cancer agents has been reported. For example, Cleare et al, Bioorganic Chem., 2, 187-210 (1973) discloses Pt
2
I
2
(EA)
2
and Pt
2
Cl
2
(EA)
2
; Friedman et al discloses cis-Pt(NH
2
ETOH)
2
Cl
2
; Zimmerman et al, Inorganica Chimica Acta, 292 (1999) 127-130 discloses Pt
2
I
2
(EA)
2
and Pt
2
Cl
2
(EA)
2
; U.S. Pat. No. 4,661,516 discloses cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H
2
O; U.S. Pat. No. 4,758,588 discloses cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H
2
O; U.S. Pat. No. 5,011,959 discloses 1,1,-cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H
2
O; and U.S. Pat. No. 5,132,323 discloses 1,1,-cyclopropanedicarboxylato(trans-R,R-DACH) Pt(II)H
2
O. The present invention describes new platinum (II) compounds which are particularly effective for treating cancer cells.
SUMMARY OF THE INVENTION
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to platinum (II) compounds including one or more analogues of formula (I):
wherein:
R
1
and R
2
are independently halo,
R
3
, R
4
, R
5
and R
6
are independently selected from the group consisting of: hydrogen, hydroxy, (C
1
-C
6
) alkyl, (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, and
a) when R
1
=R
2
R
7
and R
8
are independently selected from the group consisting of: hydroxy, (C
3
-C
6
) alkyl, (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, and (C
3
-C
6
) hydroxyalkyl, or when taken together form a group of the formula:
wherein m is 1 to 5 and R
10
and R
11
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl; or
b) when R
1
≠R
2
,
R
7
and R
8
are independently selected from the group consisting of: hydroxy, (C
1
-C
6
) alkyl, (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, or when taken together form a group of the formula:
wherein m is 1 to 6 and R
10
and R
11
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl;
or a pharmaceutically acceptable salt or ester thereof.
In a second aspect, the invention relates to platinum (II) compounds of formula (I) above, wherein:
R
1
and R
2
when taken together form a group of the formula:
wherein: n is 1 to 6, and
a) when n=1 to 2,
R
12
and R
13
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, and
R
7
and R
8
are independently selected from the group consisting of: hydroxy, (C
1
-C
6
) alkyl, (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, or when taken together form a group of the formula:
wherein m is 1 to 5 and R
10
and R
11
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, or m is 6 and R
10
and R
11
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl; or
b) when n=3 to 6,
R
12
and R
13
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, and
R
7
and R
8
are independently selected from the group consisting of: hydroxy, (C
1
-C
6
) alkyl, (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, or when taken together form a group of the formula:
wherein m is 1 to 6 and R
10
and R
11
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl;
or a pharmaceutically acceptable salt or ester thereof.
Moreover, the present invention also relates to pharmaceutical compositions containing the aforementioned inventive compound(s) in combination with a pharmaceutically acceptable carrier.
The invention further provides a method of inducing apoptosis in a population of cells, including contacting the population of cells with the aforementioned inventive compound and/or composition(s) comprised of formula (I), wherein:
R
1
and R
2
are halo or when taken together form a group of the formula:
wherein n is 1 to 6, and R
12
and R
13
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl;
R
3
, R
4
, R
5
and R
6
are independently selected from the group consisting of: hydrogen, hydroxy, (C
1
-C
6
) alkyl, (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy and (C
1
-C
6
) hydroxyalkyl; and
R
7
and R
8
are independently selected from the group consisting of: hydrogen, hydroxy, (C
1
-C
6
) alkyl (C
3
-C
6
) cycloalkyl, (C
2
-C
6
) alkenyl, (C
3
-C
6
) cycloalkenyl, aryl which may be unsubstituted or substituted with a halo, hydroxy, or (C
1
-C
6
) alkyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl, or when taken together form a group of the formula:
wherein m is 1 to 6, and R
10
and R
11
are independently selected from the group consisting of: hydrogen, halo, hydroxy, (C
1
-C
6
) alkyl, (C
2
-C
6
) alkenyl, (C
1
-C
6
) alkoxy, and (C
1
-C
6
) hydroxyalkyl;
or a pharmaceutically acceptable salt or ester thereof.
In yet another aspect, the invention provides a method of treating a subject with a tumor, wherein the method comprises administering to the subject a therapeutically effective amount of the aforementioned compound(s) or composition(s).
Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrict

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