Triphenylalkene derivatives and their use as selective...

Details Triphenylalkene derivatives and their use as selective... Triphenylalkene derivatives and their use as selective...

2000-11-15

2003-06-10

Rotman, Alan L. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S331000, C514S396000, C514S428000, C514S644000, C514S648000, C514S651000, C514S720000, C514S724000, C546S192000, C546S229000, C546S232000, C546S234000, C546S239000, C546S240000, C548S300100

Reexamination Certificate

active

06576645

ABSTRACT:

FIELD OF INVENTION
This invention relates to triphenylalkene derivatives and their use as selective estrogen receptor modulators (SERMs).
BACKGROUND OF INVENTION
The publications and other materials used herein to illuminate the background of the invention, and in particular, cases to provide additional details respecting the practice are incorporated by reference.
Estrogens have been known as female sex hormones. However, lately many tissue-specific properties for estrogens have been described in organs, which are not classically considered to be estrogen-sensitive or estrogen-responsive. During the menopause the secretion of estrogens is dramatically decreased. Subsequently elderly women develop commonly climacteric symptoms including hot flushes, sweating, insomnia, depression, headache, vaginal dryness, cardiovascular symptoms, urinary incontinence, swelling feeling, breast tenderness and fatigue. In long-term estrogen deficiency induces cardiovascular disorders and osteoporosis which increase the risk of bone fractures and hospitalizations, which are very expensive to the society. Estrogens are increasingly used for the treatment of climacteric symptoms, but on the other hand estrogen use increases the risk of uterine and breast cancers (Lobo, 1995). Estrogens are shown to be beneficial also in the prevention of Alzheimer's disease (Henderson, 1997) and in the lowering of LDL-cholesterol values and thus preventing cardiovascular diseases (Grodstein & Stampfer, 1998). New therapies which would have the benefits of estrogens, but not the carcinogenic risks are requested. Selective estrogen receptor modulators (SERMs) have been developed to fulfill these requirements (Macgregor & Jordan, 1998). However, the presently used SERMs have properties which are far from optimal. E.g. raloxifen use is limited by its strong antiestrogenic properties, which cause and worsen the climacteric symptoms, although the effects on the bone are beneficial (Khovidhunkit & Shoback, 1999). It would be most desirable to develop tissue-specific estrogens, which could be used in women in the treatment of climacteric symptoms, osteoporosis, Alzheimer's disease and/or cardiovascular diseases without the carcinogenic risk. At the best new SERMs could be given to men to protect against osteoporosis, cardiovascular diseases and Alzheimer's disease without estrogenic adverse events (gynecomastia, decreased libido etc.).
OBJECT AND SUMMARY OF THE INVENTION
One object of the present invention is to provide novel selective estrogen receptor modulators.
Another object of the present invention is to provide a pharmaceutical composition comprising an amount effective to produce a tissue specific estrogenic and/or antiestrogenic effect of said novel selective estrogen receptor modulator compound, or a stereoisomer, or a non-toxic pharmaceutically acceptable salt or ester thereof, and a pharmaceutically compatible acceptable carrier therefor.
An additional object of the present invention is to provide a method of producing a tissue specific estrogenic and/or antiestrogenic effect in a subject in which such an effect is desired which comprises administering to said subject said novel selective estrogen receptor modulator compound, or a stereoisomer, or a non toxic pharmaceutically acceptable salt or ester thereof in an amount sufficient to produce the desired effect.
Thus, according to one aspect this invention concerns novel selective estrogen receptor modulator compounds of the general formula:
wherein R1 and R2, which are the same or different are
a) H, halogen, OCH
3
, OH; or
where X is O, NH or S; and n is an integer from 1 to 4; and
R4 and R5, which are the same or different, are a 1 to 4 carbon alkyl, H, —CH
2
C≡CH or —CH
2
CH
2
OH; or
R4 and R5 form an N-containing five- or six-membered ring or heteroaromatic ring; or
c) —Y—(CH
2
)
n
CH
2
—O—R6
where Y is O, NH or S and n is an integer from 1 to 4; and
R6 is H, —CH
2
CH
2
OH, or —CH
2
CH
2
Cl; or
d) 2,3-dihydroxypropoxy, 2-methylsulfamylethoxy, 2-chloroethoxy, 1-ethyl-2-hydroxyethoxy, 2,2-diethyl-2-hydroxyethoxy or carboxymethoxy; and
R3 is H, halogen, OH or —OCH
3
;
stereoisomers thereof and non-toxic pharmaceutically acceptable salts and esters and mixtures thereof, provided that
in the 4-position of the phenyl
where R4 and R5
i) are the same, either methyl or ethyl; or
ii) form an N-containing five-membered ring;
then R1 and R3 cannot simultaneously be H; and
 in the 4-position of the phenyl
where R4 and R5, which are the same or different, are methyl or H; or
when R2 is —O—CH
2
CH
2
—OH or —O—CH
2
COOH in the 4-position of the phenyl, then R1 and R3, cannot simultaneously be H, or OH in the 4-position of the phenyl; and
if R1 is OH in the 4-position of the phenyl, R3 cannot be H.
According to another aspect the invention concerns a pharmaceutical composition comprising an amount effective to produce a tissue specific estrogenic and/or antiestrogenic effect of said novel selective estrogen receptor modulator compound, or a stereoisomer thereof, or a non-toxic pharmaceutically acceptable salt or ester thereof, and a pharmaceutically compatible acceptable carrier therefor.
According to an additional aspect the invention concerns a method of producing a tissue specific estrogenic and/or antiestrogenic effect in a subject in which such an effect is desired which comprises administering to said subject said novel selective estrogen receptor modulator compound, or a stereoisomer thereof, or a non-toxic pharmaceutically acceptable salt or ester thereof in an amount sufficient to produce the desired effect.
Additional embodiments and advantages of the invention will be set forth in part in the description as follows, and in part will be obvious from the description, or may be learned by practice of the invention. The embodiments and 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 not restrictive of the invention, as claimed.
DETAILED DESCRIPTION OF THE INVENTION
This invention relates to the use of novel selective estrogen receptor modulators (SERMs) and their pharmaceutical preparations in men and women for the treatment of degenerative diseases and symptoms due to estrogen deficiency. Typically SERMs act as estrogens in bone and cardiovascular system while they are antiestrogenic in breast tissue. SERMs may have agonistic and antagonistic effects in other tissues also. Depending on their chemical structure and hormonal properties some compounds can be especially suited for elderly women for the prevention of osteoporosis whereas others (which are not feminizing estrogens) may also be used in men in the prevention of osteoporosis, cardiovascular diseases and Alzheimer's disease. Some compounds are specifically suited for the treatment of climacteric symptoms in menopausal women. It is the common property of the described novel compounds that they are antiestrogenic in the mammary gland and inhibit the proliferation of breast cancer cells. They are also weak estrogens in the uterus and do not induce uterine cancers, the side effect of the well known SERM, tamoxifen.
The new SERMs of the present invention thus have tissue-specific estrogenic and/or antiestrogenic effects in vitro and in vivo and are useful in the prevention and treatment of osteoporosis, cardiovascular diseases and Alzheimer's disease in men and women, as well as in the treatment of climacteric symptoms and breast cancer in women.
The compounds of formula (I) can be prepared by a process which comprises reaction of a compound of the formula
where R7 is the same as R1 or R2 as defined before or is a protected such group, R
3
′ is R3 as defined before or a protected OH, R8 is benzyl or tetrahydropyranyl, with an organometallic compound of the formula
where R9 is H , R1 or R2 as defined before or is a protecte

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