Sigma-2 receptors as biomarkers of tumor cell proliferation

Details Sigma-2 receptors as biomarkers of tumor cell proliferation Sigma-2 receptors as biomarkers of tumor cell proliferation

2001-04-27

2003-12-30

Jones, Dameron L. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

C424S001110, C424S001650, C424S009200, C534S014000, C540S450000

Reexamination Certificate

active

06669925

ABSTRACT:

BACKGROUND OF THE INVENTION
Breast cancer is characterized by a proliferative potential that can vary considerably from patient to patient. The rate of cell proliferation has been shown in breast tumors to predict the response to radiation therapy and chemotherapy. Presently, measures of cell proliferation are obtained by histological or flow-cytometric analysis. Both methods are limited by sampling procedures and only 60-70% of patient samples are suitable for flow cytometric analysis.
It was recently demonstrated that sigma-2 (&sgr;2) receptors are expressed in high density in a number of human and rodent breast cancer cell lines (
Cancer Research
, 55, 408 (1995)). However, their expression is heterogenous, and their function is unknown.
Compounds suitable for noninvasive methods that can accurately assess the proliferative status of breast cancer are disclosed, e.g., in U.S. application Ser. No. 60/013717, filed Mar. 30, 1996; in U.S. application Ser. No. 09/142935, filed Sep. 17, 1998; and in U.S. application Ser. No. 09/528398, filed Mar. 20, 2000. However, additional sigma-2 receptor ligands (e.g., therapeutic agents or imaging agents) are needed. Preferred ligands will demonstrate high selectivity for &sgr;
2
versus &sgr;
1
, receptors or show increased binding for sigma receptors.
A continuing need exists for noninvasive methods that can accurately assess the proliferative status of breast cancer and for novel therapeutic agents useful for treating cancer.
SUMMARY OF THE INVENTION
It has surprising been discovered that compounds of the invention demonstrate high selectivity for &sgr;
2
versus &sgr;
1
receptors or show increased binding for sigma receptors, over sigma receptors. In addition, it has surprisingly been discovered that compounds of the present invention having two to ten, and preferably 2 to 3 carbon atoms separating the aryl group and the nitrogen atom of the bicyclic ring, demonstrate high selectivity for &sgr;
2
versus &sgr;
1
receptors or show increased binding for sigma receptors, over the corresponding compounds having only one carbon atom separating the aryl group and the nitrogen atom of the bicyclic ring.
The present invention provides a compound of formula (I):
wherein
R is aryl-Y—;
Y is a divalent (C
2
-C
10
)alkyl, (C
2
-C
10
)alkenyl, or (C
2
-C
10
)alkynyl chain optionally comprising one or more —O—, —S—, or N(Z) in the chain and is optionally substituted on carbon with one or more oxo (═O);
aryl is optionally substituted with one or more halo, OH, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)C(O), (C
1
-C
6
)alkyl-S, NH
2
, SH, N(Z)
2
;
A is NH, O or S;
B is NH, O or S;
C is O or S;
D is CH or N;
E is CH or N;
F is CH or N; and
X is (CH
2
)
2
, (CH
2
)
3
or CH═CH;
each Z is H or (C
1
-C
6
)alkyl;
wherein the ring comprising F═D—E is optionally substituted with one or more halo, OH, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)C(O), (C
1
-C
6
)alkyl-S, NH
2
, SH, N(Z)
2
, wherein Z is H or (C
1
-C
6
)alkyl, or methylene dioxy (—OCH
2
O—);
or a pharmaceutically acceptable salt thereof
The present invention also provides a compound of formula (I):
wherein
R is aryl-Y—;
Y is a divalent (C
2
-C
10
)alkyl, (C
2
-C
10
)alkenyl, or (C
2
-C
10
)alkynyl chain optionally comprising one or more —O—, —S—, or N(Z) in the chain and is optionally substituted on carbon with one or more oxo (═O);
aryl is optionally substituted with one or more halo, haloalkyl, OH, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)C(O), (C
1
-C
6
)alkyl-S, NH
2
, SH, N(Z)
2
;
A is NH, O or S;
B is NH, O, or S;
C is O or S;
D is CH or N;
E is CH or N;
F is CH or N; and
X is (CH
2
)
2
, (CH
2
)
3
or CH═CH;
each Z is H or (C
1
-C
6
)alkyl;
wherein the ring comprising F═D—E is optionally substituted with one or more halo, OH, (C
1
-C
6
)alkyl, haloalkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)C(O), (C
1
-C
6
)alkyl-S, NH
2
, SH, N(Z)
2
, wherein Z is H or (C
1
-C
6
)alkyl, or methylene dioxy (—OCH
2
O—);
or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound of formula (II):
wherein
m is 2-7.
The present invention also provides a compound of formula (I):
wherein
R is a —L-Det;
L is a divalent (C
2
-C
10
)alkyl, (C
2
-C
10
)alkenyl, or (C
2
-C
10
)alkynyl chain optionally comprising one or more —O—, —S—, or N(Z) in the chain and is optionally substituted on carbon with one or more oxo (═O);
A is NH, O or S;
B is NH, O, or S;
C is O or S;
D is CH or N;
E is CH or N;
F is CH or N;
X is (CH
2
)
2
, (CH
2
)
3
or CH═CH;
wherein the ring comprising F═D—E is optionally substituted with one or more halo, OH, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)C(O), (C
1
-C
6
)alkyl-S, NH
2
, SH, N(Z)
2
, wherein Z is H or (C
1
-C
6
)alkyl, or methylene dioxy (—OCH
2
O—);
Z is H or (C
1
-C
6
)alkyl;
Det is
 wherein
M is Technetium-99m or Rhenium-186;
R
1
and R
2
are each independently H or together are oxo;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound of formula (I):
wherein
R is a —L-Det;
L is a divalent (C
2
-C
10
)alkyl, (C
2
-C
10
)alkenyl, or (C
2
-C
10
)alkynyl chain optionally comprising one or more —O—, —S—, or N(Z) in the chain and is optionally substituted on carbon with one or more oxo (═O);
A is NH, O or S;
B is NH, O, or S;
C is O or S;
D is CH or N;
E is CH or N;
F is CH or N;
X is (CH
2
)
2
, (CH
2
)
3
or CH═CH;
wherein the ring comprising F═D—E is optionally substituted with one or more halo, OH, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)C(O), (C
1
-C
6
)alkyl-S, NH
2
, SH, N(Z)
2
, wherein Z is H or (C
1
-C
6
)alkyl, or methylene dioxy (—OCH
2
O—);
Z is H or (C
1
-C
6
)alkyl;
Det is
The present invention also provides a compound of formula (III):
wherein
M is Technetium-99m or Rhenium-186; and
R
1
and R
2
are each independently H or together are oxo.
The present invention also provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
The present invention also provides a method to determine the proliferative status of a cancer cell comprising:
(a) administering to a human afflicted with a solid tumor, an amount of a detectably-labeled compound of the present invention; and
(b) determining the extent to which the compound binds to cells of the tumor, the extent providing a measure of the proliferative status of the cells.
The present invention also provides a compound of the present invention for use in medical therapy or diagnosis.
The present invention also provides a radiolabeled compound of the present invention (e.g., a compound of formula (I) or (II)).
The present invention also provides the use of a compound of the present invention for the manufacture of a medicament for imaging a tumor in a mammal.
The present invention also provides an unlabeled compound of the present invention (e.g., a compound of formula (I)) useful as a therapeutic agent for treating diseases wherein sigma-2 activity is implicated and modulation (e.g., antagonism or agonism) of sigma-2 activity is designed.


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Vilner, B.J., et al., “Sigma-1 and Sigma-2 Receptors Are Exp

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