Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-26
2001-11-06
McKane, Joseph K. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S453000, C549S024000, C549S382000
Reexamination Certificate
active
06313161
ABSTRACT:
BACKGROUND OF THE INVENTION
The estrogen hormones, estrone and estradiol, are involved in many physiological processes. The formation of these steroids is regulated by a number of enzymes. The enzyme aromatase is the rate limiting enzyme in the non-reversible conversion of the androgen hormones, testosterone and androstenedione, to the estrogen hormones, estradiol and estrone. Compounds such as aromatase inhibitors may thus regulate or inhibit androgen to estrogen conversion, and have therapeutic utility in treating clinical conditions potentiated by the presence of estrogens.
19-Nordeoxycorticosterone (19-norDOC) is known to induce mineralocorticoid hypertension. In the biosynthetic formation of 19-norsteroids, such as 19-norDOC, the initial step is the adrenal hydroxylation of an appropriate steroid such as deoxycorticosterone (DOC). The inhibition of the biosynthetic formation of 19-norDOC by inhibition of 19-hydroxylation of DOC would thus serve to decrease the level of 19-norDOC present in the animal involved and reduce hypertensive effects attributable to the presence of this material.
SUMMARY OF THE INVENTION
The present invention is directed to 2,19-bridged steroidal aromatase and 19-hydroxylase inhibitor compounds, their related intermediates, a process for their preparation, and their use in the treatment of various estrogen dependent/mediated disorders. These compounds may be represented by the following formulas:
wherein
represents a single or double bond,
A is O, S, SO, or SO
2
,
R is H, ═CH
2
, ═O, or —OH,
R
1
is H or C
1-4
alkyl,
R
2
is ═O, —OH, or —O—(C
1-4
alkanoyl),
X is ═O, ═CH
2
, —OH, or —O—(C
1-4
alkanoyl), and
Y is H, —OH, or —O—(C
1-4
alkanoyl), and when Y=H, OH, or —O—(C
1-4
alkanoyl), X may not include —OH, and R may not include ═O or —OH.
Examples of the alkyl groups referred to above are methyl, ethyl and propyl. Examples of the alkanoyl groups referred to above are acetyl, propionyl and butyryl. The double bonds, as represented by the dotted lines above are selected in such a way that the compounds must contain at least one double bond, usually in the A-ring of the standard steroid skeleton, although it can also be located at the 5,6-position in the B-ring. If the double bond is located at the 5,6-position, then the other dotted lines represent single bonds. When the system is doubly unsaturated, the double bonds are located at the 4,5- and the 6,7-positions.
Since the compounds of the present invention can be considered as containing a bridged steroid structure, it is possible to name them as derivatives of the basic steroid involved. When this is done with the oxygen-bridged compounds of the present invention, the compounds can be referred to as 2,19-(methyleneoxy) steroids. This indicates that a —CH
2
O— group connects the 2- and 19-positions with the carbon attached on the &bgr;-side of the 2-position and the oxygen attached to the 19-carbon atom. The sulfur bridged compounds can be described in a similar way.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are inhibitors of aromatase and 19-hydroxylase. As aromatase inhibitors, they are useful in treating hyperestrogenemia. The compounds are useful in controlling abnormally high levels of estrogens, both when the high levels observed are relatively steady, or when there are brief surges of elevated levels occurring as part of cyclical body functions. Both females and males can be treated, although obviously, the level of estrogens which would be considered high in males would be much lower than the amount considered high in females.
These compounds are also useful as anti-fertility agents to prevent ovulation or implantation in females, or to reduce the mating behavior in males where brain aromatization is required for such behavior. These compounds further have value in treating diseases of the male, such as gynecomastia, male infertility resulting from elevated estrogen levels, and hyperestrogenemia, which may precede myocardial infarction. Other male diseases for which the compounds of this invention are applicable include the therapeutic and/or prophylactic treatment of prostatic diseases, including prostatic hyperplasia, a disease of the estrogen dependent stromal tissue, and prostatic cancer.
There is substantial clinical evidence to indicate that many tumor types are associated with elevated estrogen production. Ovariectomy, adrenalectomy and hypophysectomy are commonly employed in patients with breast cancer as a means of reducing the amount of estrogen. Non-surgical procedures include treatments with high levels of steroids, anti-estrogens and inhibitors of steroidal enzymatic pathways. Treatment with antiestrogens results in about one-third of the patients obtaining objective tumor regressions. Andrenalectomy will cause regression of breast cancer in postmenopausal women with hormonal-dependent tumors, presumably as the result of reduction in available estrogen derived from androstenedione, whose source is primarily from the adrenals. Growth of several lines of breast cancer cells have been shown to be estrogen dependent or at least estrogen mediated, and can be inhibited, by compounds which antagonize estrogen action.
Breast tumors excised from postmenopausal women contain estradiol concentrations that are 5-50 fold higher than plasma estrogen levels. The aromatase activities of breast tumors are associated with stromal fibroblasts and adipose tissue. Fibroblast and adipose tissue aromatase activity is stimulated by a variety of promoters such as glucocorticoids, phorbal esters, cytokines and growth factors that can act through associated receptors via autocrine and paracrine pathways to promote tumor growth.
The aromatase inhibitors of the present invention can effectively prevent the biologically active estrogens from reaching endocrine tumors or reduce estrogen biosynthesis in those tumors capable of endogenous estrogen synthesis, thereby producing remissions of hormonal dependent breast cancer. Thus, these compounds are useful in the treatment of breast, ovarian, uterine and pancreatic tumors as well as disease condition such as galactorrhea, McCune-Albright syndrome, benign breast disease, endometriosis, and polycystic ovarian disease.
The bioconversion of deoxycorticosterone via a 19-hydroxylase pathway to 19-nordeoxycorticosterone potentiates its mineralocorticoid activity. Mineralocorticoid excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, and hypertensive conditions. Increased excretion of 19-nordeoxycortico-sterone has been reported for hypertensive patients, including those with primary aldosteronism, Cushing's syndrome, 17&bgr;-hydroxylase deficiency, and individuals with essential hypertension. As 19-hydroxylase inhibitors, these compounds may be useful as antihypertensive agents and for management of edemous conditions often associated with sodium retention and potassium loss.
The compounds of the present invention which have a pregnane side chain are further useful in that a C
17-20
lyase enzyme can cleave the indicated side chain to give the corresponding 17-oxygenated androstene compounds which, as already indicated, are useful as aromatase inhibitors.
To achieve their desired effect, the compounds of the present invention may be administered orally, parenterally, for example, intravenously, intraperitoneally, intramuscularly, or subcutaneously, including the injection of the active ingredient directly into tissue or tumor sites, to a patient in need of treatment. The term patient is taken to mean a warm-blooded animal, for example, mammals such as humans, primates, cattle, dogs, cats, horses, sheep, mice, rats, and pigs. These compounds may also be administered in the form of a pharmaceutical preparation, and may further be incorporated into sustained delivery devices. The amount of compound administered will vary over a wide range and be any effective amount. Depending on the patient to be treated, the condition to be treated,
Burkhart Joseph P.
Johnston J. O'Neal
Peet Norton P.
Gupta Balaram
Kurys Barbara F.
Martin Lawrence L.
McKane Joseph K.
Merrell Pharmaceuticals Inc.
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