Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-04
2003-01-21
Chang, Ceila (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S213010, C514S331000, C514S428000, C514S650000, C540S585000, C540S609000, C544S105000, C546S192000, C546S205000, C546S229000, C546S233000, C548S566000, C548S570000, C548S571000, C548S575000
Reexamination Certificate
active
06509356
ABSTRACT:
TECHNICAL FIELD
The present invention relates to organic compounds having pharmacological activity, to compositions containing the compounds, and to a medical method of treatment.
More particularly, the present invention concerns a class of 1-[4-(substituted alkoxy)benzyl]naphthalene compounds having estrogenic activity; to pharmaceutical compositions containing the compounds and to a method of treating or inhibiting cancer of the breast or uterus.
BACKGROUND OF THE INVENTION
Estrogen is a generic term for estrus-producing steroid compounds. Within the “estrogen group” are the traditional steroids such as 17&bgr;-estradiol and estrone (the major estrogens in humans), as well as various metabolites such as the estratriols, sulfates and glucuronides of estradiol and estrone. Also, germane to human medicine, are the steroidal equine estrogens such as the equilins, in that they are administered to humans in preparations, such as Premarin™. Also, certain compounds known as “anti-estrogens”, e.g., tamoxifen, clomiphene, and nafoxidene, demonstrate varying degrees of estrogen agonist properties in some tissues; however they act to antagonize the natural estrogens and their function in other tissues.
Recently, these “anti-estrogens” have been categorized into three different types depending on their degree and mix of estrogen agonist/antagonist properties which is based on their ability to freeze estrogen receptors in different conformational states, cf. D. P. McDonnell, et al.,
Molecular Endocrinology,
9(6): 659-669 (1995). Most germane are the type II anti-estrogens of which compounds of the current invention belong.
Estrogens as biologically active molecules exert their properties by binding to an intracellular receptor. After the receptor and bound ligand are transported to the nucleus of a cell, the complex exerts its effect by binding to certain recognition sites on DNA and allowing certain genes to be expressed. This binding to the receptor and regulation is not completely understood at this time; however, it appears to be crucial to the varying degree of agonistic and antagonistic properties of a molecule. Thus, certain types of so-called “anti-estrogens” allow agonist activity in some tissues, but are antagonists in others. Hence, the term, “selective estrogen receptor modulators (SERMs)” has been proposed to describe these molecules, especially the type II, of which the compounds of the present invention are members.
Estrogen has long been classified as “the female sex hormone” and a voluminous literature describes its activity as such. However, in recent years, research has shown that estrogens have many other homeostatic functions, other than those related to female reproduction and function of sex tissues. Indeed, it has been shown that males possess estrogen receptors and DNA recognition sites and possess the ability to produce estrogens and many tissues, such as those involved in the cardiovascular system. The exact nature of the effects of estrogens in both men and women, outside the productive aspects, are only beginning to be explored and are currently poorly understood.
The majority of the documented activities of the estrogens have been derived from studies in women, since most women suffer from the most obvious effects of estrogen, mainly due to menopause and estrogen dependent cancers. The clinical pathologies associated with estrogen levels and their subsequent function, can be categorized into two main types, i.e., those which are due to a deprivation or lack of estrogen and those which are due to an aberrant physiological response to existing estrogen in estrogen sensitive tissues. SERMS, especially those of type II, have the property of being estrogen agonists in those cases where estrogen deprivation is a cause of pathology (mainly in non-sex related tissues) and simultaneously being antagonists of the pathologies caused by abnormal responses to endogenous estrogen (in sex related tissues).
Thus, SERMS of the type II have the potential to effectively treat a variety of estrogen dependent pathological conditions. This dual effect is an intrinsic and unique property of the molecules of the present invention.
SUMMARY OF THE INVENTION
In its principal embodiment, the present invention provides a selective estrogen modulating compound of structure 1:
or a pharmaceutically acceptable salt thereof where R
1
and R
2
are independently selected from hydrogen, alkyl of one to six carbon atoms, acyl of two to six carbon atoms, and phenacyl.
The group designated X is —(CH
2
)
n
where n is an integer of one to 6, inclusive.
Y is absent or is selected from the group consisting of 1,4-piperazinylene; ureido; N-(lower alkyl)ureido; N′-(lower alkyl)ureido; and N,N′-(di-lower alkyl ureido.
The substitutent Z is selected from the group consisting of 1-, 2- or 3-pyrrolidinyl; 1-, 2-, or 3-[1-(lower alkyl)pyrrolidinyl]; 1- 2-, 3- or 4-piperidinyl; 1-, 2-, 3- or 4-[1-lower alkyl)piperidinyl]; N,N-dialkyl in which the alkyl groups are independently from one to four carbon atoms; 1-azepinyl; 1- or 2-naphthylamino; 4-morpholinyl; dimethyl-4-morpholinyl; 3-azaspiro[5.5]undecan-3-yl; pyrrolidinon-1-yl; unsubstituted phenyl; and phenyl substituted with one or two groups independently selected from acyl of two to four carbon atoms, alkyl of one to four carbon atoms, halo, and alkoxy of one to four carbon atoms.
All of the above definitions are with the proviso that n is not 2 or 3 when Z is 1-pyrrolidinyl, 1-piperidinyl, 1-azepinyl, 4-morpholinyl, N,N-dimethylamino or N,N-diethyl-amino.
In a second embodiment, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound as defined above in combination with a pharmaceutically acceptable carrier.
In another embodiment, the present invention comprises a method of treating or inhibiting estrogen-dependent cancers in women, particularly cancer of the breast and uterus, comprising administering to a woman in need of such treatment an effective amount of a compound as defined above.
DETAILED DESCRIPTION
As used throughout this specification and the appended claims, the following terms have the meanings ascribed to them.
“Alkyl of one to six carbon atoms” means a univalent radical derived by the removal of one hydrogen atom from methane, ethane, or a straight or branched hydrocarbon of three to six carbon atoms and is typified by methyl, ethyl, n- or iso-propyl, n-, sec- iso- or tert-butyl, n-pentyl, 2-methylbutyl, n-hexyl, 2-methylpentyl, 2,3-dimethylbutyl, and the like.
“Acyl” denotes an alkyl group as defined above, attached to the parent molecular moiety through a carbonyl group.
“Lower alkyl” denotes an alkyl group as defined above containing one to four carbon atoms.
The term “alkoxy” refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom.
The term “1,4-piperazinylene” denotes a divalent radical of the structure:
and the term “ureido” means the divalent radical represented by the structure
The term “N-(lower alkyl)ureido”, as used herein, means a ureido group in which the lower alkyl group is attached to the nitrogen nearest the group denoted “X” in structure 1 above, thus:
and “N′-(lower alkyl)ureido” means a ureido group in which the lower alkyl group is attached to the nitrogen nearest the group denoted “Z” in structure I above, thus:
Compounds contemplated as falling within the scope of the present invention include, but are not limited to, the following representative examples.
Compounds of the present invention in which Y is absent, and Z is alkyl or dialkyl include:
6-hydroxy-2-(4-hydroxyphenyl)-1-[4-(N-methylamino)methoxy-benzyl]naphthalene;
6-hydroxy-2-(4-hydroxyphenyl)-1-[4-(N,N-dimethylamino)-methoxybenzyl]naphthalene;
6-hydroxy-2-(4-hydroxyphenyl)-1-[4-(N-isopropylamino)-methoxybenzyl]naphthalene;
6-hydroxy-2-(4-hydroxyphenyl)-1-[4-(N,N-diisopropylamino)-methoxybenzyl]naphthalene;
6-hydroxy-2-(4-hydroxyphenyl)-1-
Dodge Jeffrey Alan
Glasebrook Andrew Lawrence
Lugar, III Charles Willis
Birch Gary M.
Chang Ceila
Eli Lilly and Company
Sales James J.
Voy Gilbert T.
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