Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing
Reexamination Certificate
2000-08-22
2003-03-18
Jones, Dameron L. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
C424S001110, C424S001650, C534S014000
Reexamination Certificate
active
06534037
ABSTRACT:
TECHNICAL FIELD
The present invention relates to non-steroidal compounds which can bind to steroid receptors, and more particularly to compounds that can bind to both a steroid receptor and a radionuclide for either diagnostic or therapeutic purposes.
BACKGROUND OF THE INVENTION
Steroids are produced by many human tissues and exert significant impacts on the health and activity of humans. For example, progesterone is secreted from the corpus Iuteum, and in concert with estradiol, acts to maintain the uterine endometrium for egg implantation in females. Testosterone, another so-called sex hormone, is secreted by Leydig cells of testis, and after bioconversion to dihydrotestosterone, effects production of sperm proteins in Sertoli cells and is central to the development of secondary sex characteristics in males. Aldosterone, secreted from glomerulosa cells of the adrenal cortex, causes sodium ion uptake via conductance channels and thereby raises blood pressure and fluid volume during periods of stress.
After secretion, steroids are transported through the blood to receptor sites. Typically, steroids are bound to a protein during transport. Corticosteroid binding globulin protein, sex hormone binding protein, androgen binding protein and albumin are the most common binding proteins. Regardless of their bound form, steroids become unbound near their target cells and then enter the target cells to bind with a receptor. Depending on the cell, steroid receptors appear to be located within either the cell's cytoplasm or nucleus, and possibly at both locations. In structural terms, the receptor is a protein which, upon binding to a steroid, undergoes a change in conformation and activity. For instance, a steroid may induce a receptor protein to bind to a specific region of DNA, where that region then becomes accessible to RNA polymerase with subsequent stimulation of transcription.
The foregoing brief summary of steroids and steroid receptors serves to illustrate the importance of this biological system to humans and, in fact, to most animals. Further discussion of steroids and their action can be found in many texts including, to name a few, Gower, D. B.
Steroid Hormones
Croom Helm Biology in Medicine Series, Year Book Medical Publishers, Chicago, Ill. (1979); Peters, H. et al.
The Ovary
University of California Press, Berkeley, Calif. (1980); Hadley, M. C.
Endocrinology
Prentice-Hall, Inc., Englewood Cliffs, N.J. (1984); Norman, A. W. et al.
Hormones
Academic Press, Inc. New York, N.Y. (1987); Zeelen, F. J.
Pharmacochemistiy Library,
15:
Medicinal Chemistry of Steroids
Elsevier, Amsterdam, Netherlands (1990); Bohl, M. et al.
Molecular Structure and Biological Activity of Steroids
, CRC Press, Boca Raton, Fla. (1992); and Parker, M. G.
Steroid Hormone Action
IRL Oxford, United Kingdom (1993).
Knowledge about the location and activity of steroid receptors is generally important to understanding the biochemistry of life and disease. Research is pressing forward to supplement current knowledge, which may be applied to diagnostic as well as therapeutic procedures. Diagnostic techniques which afford quantitative information about the population of receptor sites in a tissue are particularly useful in monitoring health of the tissue. Relevant to therapeutic procedures, one goal of medicinal chemists is to provide caregivers with tools to modulate the activity of steroid receptors.
One general approach to identifying biological receptors, whether for steroids or any of a host of other biologically important molecules, has been to design chemicals which may be termed “receptor analogs” that both bind to a receptor and carry with them a “functional agent”. For diagnostic purposes, the functional agent may be a “marker”, which is an atom or molecular fragment that can be visualized or otherwise detected in some way. For example, the marker may be a radionuclide that emits a radioactive species which can be detected by a molecular nuclear medical technique such as scintigraphic imaging. This approach allows a technician to administer a receptor analog to a subject and, after waiting an appropriate time for binding to occur, make an image of the subject which shows the location(s) where binding has occurred. In some instances, the intensity of the image may be used to develop a quantitative understanding of receptor activity. For example, cancerous cells tend to have a higher density of receptor sites than non-cancerous cells of the same type, due to an increased expression of the receptor gene. Thus, identification of a high density of steroid receptor sites may provide some indication of cancer.
Receptor analogs may be used in therapeutic as well as diagnostic applications. For instance, the functional agent of the receptor analog may be, or can be made toxic to surrounding tissue. Upon administration to a subject, the therapeutic receptor analog will bind to receptors in or on targeted cell types, and if those cell types are cancerous, then the cancer cells may be killed. For instance, the receptor analog may have a structure similar to a steroid, and thus bind to steroid receptors, however the analog has a functional agent that is a radionuclide which is toxic to nearby cells.
The approach of using steroid receptor analogs for diagnostic and therapeutic purposes has been described. However, to date, known steroid receptor analogs have not provided the desired degree of receptor binding properties, including specificity for specific receptor binding sites and strength of binding. See, e.g., Hom R. K. et al.
Nucl. Med
. &
Biology
24:485-498 1997; Hom R. K. et al. Presentation from XIIth International Symposium on Radiopharmaceutical Chemistry, Uppsala, Sweden, Jun. 15-19, 1997, pp. 510-511. Hom R. K. et al.
J. Org. Chem.
62:6290-6297, 1997; Labaree, D. C.
J Nucl. Med.
38(3):402-409 March 1997; Avril, N. et al.
J Nucl. Med.
38(8):1186-1191 August 1997; Top, S. et al. U.S. Pat. No. 5,554,602, issued Sep. 10, 1996; Bonasera, T. A. et al.
J. Nucl. Med.
37(6):1009-1015 June 1996; Katzenellenbogen, J.
J. Nucl. Med.
36(6, Supp):8S-13S June, 1995; Choe, Y. S. et al.
J. Nucl. Med.
36(65, Proceedings):39P, May, 1995; O'Neil, J. P. et al.
Bioconjugate Chem.
5:182-193 1994; Chi, D. Y. et al.
J. Med. Chem.
37:928-937 1994; Chi, D. Y. et al.
J.A.C.S.
115:7045-7046 1993; DiZio, J. P. et al.
J. Nucl. Med.
33(4):558-569 April 1992; and DiZio, J. P. et al.
Bioconjugate Chem.
2:353-366 1991.
Therefore, there is a need in the art for effective receptor analogs, which demonstrate specificity to an intended steroid receptor, and can deliver functional agents to the steroid receptor. The present invention fulfills this need and further provides other related advantages as disclosed herein.
SUMMARY OF THE INVENTION
A compound of the formula (I)
wherein,
A) R
1
and R
2
together are a steroid receptor binding group where,
i) R
1
and R
2
are independently selected from
where A1, A2, A3, A4, A7 and A8 are independently selected from —CH—, —CX—, —C(OH)— AND N, where X is halide, with the proviso that not more than three of A1, A2, A3 and A4 are simultaneously N, and not more than one of A7 and A8 are simultaneously N;
A5 and p are independently selected from (A5/p): O/1, S/1, Se/1, C(═O)O/1, N/2, P/2, and Si/3, where R3 at each occurrence is independently selected from H, C1-C10hydrocarbyl, and a protecting group for A5, or A5—(R3)p may together form —NO2, hydrogen or halogen;
A
6
is selected from S, O and NH;
R
4
is selected from H, —OH, halide and C
1
-C
3
alkyl;
R
5
is selected from H, —OH, halide and C
1
-C
3
alkyl; and
R
6
is selected from H, —OH, —SH, halide, C
1
-C
3
alkyl, C(═O)CH
3
, thio and oxo;
B) C
1
and C
2
are joined together by
i) a double bond, or
ii) a single bond, where
a. the single bond may form part of a 3- to 5-membered carbocyclic or heterocyclic ring, the heterocyclic ring containing one heteroatom selected from oxygen, nitrogen and sulfur; or
b. C1 and C2 are independently substituted with H, halogen, or C1-C3alkyl; or
Gleave D. Mark
Kasina Sudhakar
Jones Dameron L.
NeoRx Corporation
Seed Intellectual Property Law Group PLLC
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