U.S. patent application number 12/124731 was filed with the patent office on 2008-09-11 for novel heterocyclic benzo[c]chromene derivatives useful as modulators of the estrogen receptors.
Invention is credited to Xiaojie Li, Zhihua Sui, Xuqing Zhang.
Application Number | 20080221125 12/124731 |
Document ID | / |
Family ID | 36499484 |
Filed Date | 2008-09-11 |
United States Patent
Application |
20080221125 |
Kind Code |
A1 |
Zhang; Xuqing ; et
al. |
September 11, 2008 |
NOVEL HETEROCYCLIC BENZO[C]CHROMENE DERIVATIVES USEFUL AS
MODULATORS OF THE ESTROGEN RECEPTORS
Abstract
The present invention is directed to novel heterocyclic
benzo[c]chromene derivatives, pharmaceutical compositions
containing them and their use in the treatment of disorders
mediated by one or more estrogen receptors. The compounds of the
invention are useful in the treatment of disorders associated with
the depletion of estrogen such as hot flashes, vaginal dryness,
osteopenia and osteoporosis; hormone sensitive cancers and
hyperplasia of the breast, endometrium, cervix and prostate;
endometriosis, uterine fibroids, osteoarthritis and as
contraceptive agents, alone or in combination with a progestogen or
progestogen antagonist.
Inventors: |
Zhang; Xuqing; (Exton,
PA) ; Li; Xiaojie; (Green Brook, NJ) ; Sui;
Zhihua; (Exton, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
36499484 |
Appl. No.: |
12/124731 |
Filed: |
May 21, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11334603 |
Jan 18, 2006 |
7399767 |
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12124731 |
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60646007 |
Jan 21, 2005 |
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Current U.S.
Class: |
514/255.05 ;
544/336; 544/405 |
Current CPC
Class: |
A61P 5/34 20180101; A61P
19/10 20180101; A61P 15/08 20180101; A61P 9/00 20180101; A61P 3/06
20180101; A61P 15/00 20180101; A61P 29/00 20180101; A61P 35/00
20180101; A61P 25/28 20180101; C07D 405/04 20130101; A61P 15/12
20180101; A61P 19/02 20180101; A61P 5/30 20180101; C07D 491/14
20130101; A61P 43/00 20180101; A61P 15/18 20180101; A61P 5/36
20180101 |
Class at
Publication: |
514/255.05 ;
544/405; 544/336 |
International
Class: |
A61K 31/497 20060101
A61K031/497; C07D 407/02 20060101 C07D407/02; A61P 15/00 20060101
A61P015/00; A61P 19/10 20060101 A61P019/10; A61P 35/00 20060101
A61P035/00 |
Claims
1. A compound of formula (I) ##STR00109## wherein represents a
single or double bond, X is selected from the group consisting of O
and S; ##STR00110## is pyrazine; R.sup.1 is selected from the group
consisting of hydrogen, alkyl, cycloalkyl, aryl, aralkyl,
heteroaryl and heteroaryl-alkyl; wherein the cycloalkyl, aryl,
aralkyl, heteroaryl or heteroaryl-alkyl group is optionally
substituted with one or more substituents independently selected
from halogen, hydroxy, alkyl, alkoxy, --SH, --S(alkyl), SO.sub.2,
NO.sub.2, CN, CO.sub.2H, R.sup.C, --OR.sup.C,
--SO.sub.2--NR.sup.DR.sup.E, --NR.sup.DR.sup.E,
NR.sup.D--SO.sub.2--R.sup.F, -(alkyl).sub.0-4-C(O)NR.sup.DR.sup.E,
(alkyl).sub.0-4-NR.sup.D--C(O)--R.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--OR.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E
or -(alkyl).sub.0-4-C(O)-(alkyl).sub.0-4-C(O)--OR.sup.F; wherein
R.sup.C is selected from the group consisting of alkyl, cycloalkyl,
cycloalkyl-alkyl, aryl, aralkyl, heteroaryl, heteroaryl-alkyl,
heterocycloalkyl and heterocycloalkyl-alkyl; wherein the
cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,
heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group
is optionally substituted with one or more substituents
independently selected from halogen, hydroxy, alkyl, alkoxy, --SH,
--S(alkyl), SO.sub.2, NO.sub.2, CN, CO.sub.2H, R.sup.C,
--SO.sub.2--NR.sup.DR.sup.E, NR.sup.DR.sup.E,
NR.sup.D--SO.sub.2--R.sup.F,
-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E,
-(alkyl).sub.0-4-NR.sup.D--C(O)--R.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--OR.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E
or -(alkyl).sub.0-4-C(O)-(alkyl).sub.0-4-C(O)--OR.sup.F; wherein Q
is selected from the group consisting of O, S, NH, N(alkyl) and
--CH.dbd.CH--; wherein R.sup.D and R.sup.E are each independently
selected from the group consisting of hydrogen and alkyl;
alternatively R.sup.D and R.sup.E are taken together with the
nitrogen atom to which they are bound to form a 4 to 8 membered
ring selected from the group consisting of heteroaryl or
heterocycloalkyl; wherein the heteroaryl or heterocycloalkyl group
is optionally substituted with one or more substituents
independently selected from halogen, hydroxy, alkyl, alkoxy,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano; wherein
R.sup.F is selected from the group consisting of hydrogen, alkyl,
cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,
heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
wherein the cycloalkyl, aryl, heteroaryl, heteroaryl-alkyl,
heterocycloalkyl or heterocycloalkyl-alkyl group is optionally
substituted with one or more substituents independently selected
from halogen, hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino,
dialkylamino, nitro or cyano; R.sup.2 is selected from the group
consisting of hydroxy, alkyl, cycloalkyl, aryl, aralkyl, heteroaryl
and heteroaryl-alkyl; wherein the cycloalkyl, aryl, aralkyl,
heteroaryl or heteroaryl-alkyl group is optionally substituted with
one or more substituents independently selected from halogen,
hydroxy, alkyl, alkoxy, --SH, --S(alkyl), SO.sub.2, NO.sub.2, CN,
CO.sub.2H, R.sup.C, --OR.sup.C, --SO.sub.2--NR.sup.DR.sup.E,
--NR.sup.DR.sup.E, NR.sup.D--SO.sub.2--R.sup.F,
-(alkyl).sub.0-4-C(O)NR.sup.DR.sup.E,
(alkyl).sub.0-4-NR.sup.D--C(O)--R.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--OR.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E
or -(alkyl).sub.0-4-C(O)-(alkyl).sub.0-4-C(O)--OR.sup.F;
alternatively, R.sup.1 and R.sup.2 are taken together with the
carbon atom to which they are bound to form C(O); n is an integer
selected from 0 to 4; each R.sup.3 is independently selected from
the group consisting of halogen, hydroxy, R.sup.C, amino,
alkylamino, dialkylamino, nitro, cyano, SO.sub.2, --C(O)R.sup.G,
--C(O)OR.sup.G, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --N(R.sup.G)C(O)R.sup.G,
--OSi(R.sup.G).sub.3--OR.sup.G, --SO.sub.2N(R.sup.G).sub.2,
--O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G; wherein each R.sup.G is
independently selected from hydrogen, alkyl, aryl, aralkyl and
1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein the alkyl,
aryl or aralkyl group is optionally substituted with one or more
substituents independently selected from alkyl, halogenated alkyl,
alkoxy, halogen, hydroxy, nitro, cyano, --OC(O)-alkyl or
--C(O)O-alkyl; alternatively two R.sup.G groups are taken together
with the nitrogen atom to which they are bound to form a
heterocycloalkyl group; wherein the heterocycloalkyl group is
optionally substituted with one or more substituents independently
selected from halogen, hydroxy, alkyl, alkoxy, carboxy, amino,
alkylamino, dialkylamino, nitro or cyano; m is an integer selected
from 0 to 4; each R.sup.4 is independently selected from the group
consisting of halogen, hydroxy, R.sup.C, amino, alkylamino,
dialkylamino, nitro, cyano, SO.sub.2, --C(O)R.sup.G,
--C(O)OR.sup.G, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --N(R.sup.G)C(O)R.sup.G,
--OSi(R.sup.G).sub.3--OR.sup.G, --SO.sub.2N(alkyl).sub.2,
--O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G; R.sup.5 is selected from the
group consisting of hydrogen, alkyl, halogenated alkyl, aryl,
aralkyl; alternatively, R.sup.3 and R.sup.5 combined to form six
membered ring; provided that when is a double bond, X is O,
##STR00111## is pyrazine, and R.sup.1 and R.sup.2 are taken
together with the carbon atom to which they are bound to form C(O),
then at least one of n or m is an integer selected from 1 to 4;
provided further that when is a single bond, X is O, ##STR00112##
is pyrazine, R.sup.1 is hydrogen and R.sup.2 is alkyl, then at
least one of n or m is an integer selected from 1 to 4; provided
further that when is a single bond, X is O, ##STR00113## is
pyrazine, R.sup.1 is hydrogen, R.sup.2 is alkyl, n is 1 and m is 1,
then R.sup.3 and R.sup.4 are other than methoxy or ethoxy; provided
further that when is a double bond, X is O, ##STR00114## is
pyrazine, R.sup.1 and R.sup.2 are taken together with the carbon
atom to which they are bound to form C(O), n is 0 and m is 2, then
each R.sup.4 is not hydroxy or alkoxy. provided further that when
is a double bond, X is O, ##STR00115## is pyrazine, R.sup.1 and
R.sup.2 are taken together with the carbon atom to which they are
bound to form C(O), R.sup.3 and R.sup.5 are combined into a six
membered ring, then at least one of n or m is an integer selected
from 1 to 4. and pharmaceutically acceptable salts thereof.
2. (canceled)
3. The compound of claim 1, wherein R.sup.1 is selected from the
group consisting of hydrogen, lower alkyl, aryl or aralkyl; wherein
the aryl or aralkyl group is optionally substituted with one to two
substituents independently selected from halogen, hydroxy, lower
alkyl, lower alkoxy, NO.sub.2, CN, and CO.sub.2H.
4. The compound of claim 1, wherein R.sup.2 is selected from the
group consisting of hydroxy, lower alkyl, aryl or aralkyl; wherein
the aryl or aralkyl is optionally substituted with one to two
substituents independently selected from halogen, hydroxy, lower
alkyl, lower alkoxy, NO.sub.2, CN, CO.sub.2H, R.sup.C, --OR.sup.C,
--NR.sup.DR.sup.E, -(alkyl).sub.0-4-C(O)NR.sup.DR.sup.E and
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E.
5. The compound of claim 1, wherein R.sup.1 and R.sup.2 are taken
together with the carbon atom to which they are bound to form
C(O).
6. The compound of claim 1, wherein R.sup.3 is selected from the
group consisting of halogen, hydroxy, R.sup.C, amino, (lower
alkyl)-amino, di(lower alkyl)amino, nitro, cyano, --OC(O)R.sup.G,
--OC(O)OR.sup.G, --OC(O)N(R.sup.G).sub.2,
--OSi(R.sup.G).sub.3--OR.sup.G, --O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G.
7. The compound of claim 1, wherein R.sup.4 is selected from the
group consisting of halogen, hydroxy, R.sup.C, amino, (lower
alkyl)-amino, di(lower alkyl)amino, nitro, cyano, --OC(O)R.sup.G,
--OC(O)OR.sup.G, --OC(O)N(R.sup.G).sub.2,
--OSi(R.sup.G).sub.3--OR.sup.G, --O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G.
8. The compound of claim 1, wherein R.sup.5 is selected from the
group consisting of hydrogen, lower alkyl, halogenated alkyl, aryl,
aralky.
9. (canceled)
10. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a compound of claim 1.
11-15. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application 60/646,007, filed on Jan. 21, 2005, which is
incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention is directed to novel heterocyclic
benzo[c]chromene derivatives, pharmaceutical compositions
containing them and their use in the treatment or prevention of
disorders and diseases mediated by an estrogen receptor such as hot
flashes, vaginal dryness, osteopenia, osteoporosis, hyperlipidemia,
loss of cognitive function, degenerative brain diseases,
cardiovascular diseases, cerebrovascular diseases, hormone
sensitive cancers and hyperplasia (in tissues including breast,
endometrium, and cervix in women and prostate in men),
endometriosis, uterine fibroids, osteoarthritis; and as
contraceptive agents either alone or in combination with a
progestogen or progestogen antagonist. The compounds of the
invention are selective estrogen receptor modulators.
BACKGROUND OF THE INVENTION
[0003] Estrogens are a group of female hormones essential for the
reproductive process and for the development of the uterus,
breasts, and other physical changes associated with puberty.
Estrogens have an effect on various tissues throughout a woman's
body, not only those involved in the reproductive process, such as
the uterus, breasts, and external genitalia, but also tissues in
the central nervous system, bones, the liver, skin, and the urinary
tract. The ovaries produce most of the estrogens in women's
body.
[0004] Endogenous estrogens, such as 17.beta.-estradiol and
estrone, play a central role in the development of and maintenance
of the female sex organs, mammary glands, and other sexual
characteristics. In addition to their role as female sex hormone,
estrogens are involved in the growth and function of a number of
other tissues, such as the cardiovascular system, the central
nervous system, and the skeleton, both in females and males. The
significance of the estrogens in the development of the female
reproductive system led to the development of a variety of
compounds that interact with the estrogen receptors, such as
contraceptives and agents for treatment of breast cancers. More
recently, intensive efforts have focused on the selective estrogen
receptor modulators for treatment and prevention of postmenopausal
conditions, such as osteoporosis, coronary artery disease,
depression and Alzheimer disease.
[0005] Menopause is defined as the permanent cessation of menses
due to loss of ovarian follicular function and the almost
termination of estrogen production. The midlife transition of
menopause is characterized by a decrease in estrogen that provokes
both short-term and long-term symptoms with the vasomotor,
urogenital, cardiovascular, skeletal and central nervous systems,
such as hot flushes, urogenital atrophy, increased risk of
cardiovascular disease, osteoporosis, cognitive and psychological
impairment, including an increased risk of cognitive disorders and
Alzheimer's disease (AD).
[0006] Seventy-five percent of all women experience some occurrence
of vasomotor symptoms associated with the onset of menopause such
as body sweating and hot flushes. These complaints may begin
several years before menopause and in some women may continue for
more than 10 years either relatively constant, or as instant
attacks without a definable, provoking cause.
[0007] Urogenital symptoms associated with the onset of menopause
involving the vagina include a sensation of dryness, burning,
itching, pain during intercourse, superficial bleeding and
discharge, along with atrophy and stenosis. Symptoms involving the
urinary tract include a burning sensation during urination,
frequent urgency, recurrent urinary tract infections, and urinary
incontinence. These symptoms have been reported to occur in up to
50% of all women near the time of menopause and are more frequent a
few years after menopause. If left untreated, the problems can
become permanent.
[0008] Heart attack and stroke are major causes of morbility and
mortality among senior women. Female morbility from these diseases
increases rapidly after menopause. Women who undergo premature
menopause are at greater coronary risk than menstruating women of
similar age. The presence of serum estrogen has a positive effect
on serum lipids. The hormone promotes vasodilation of blood
vessels, and enhances the formation of new blood vessels. Thus the
decrease in serum estrogen levels in postmenopausal women results
in adverse cardiovascular effect. Additionally, it is theorized
that differences in the ability of blood to coagulate may account
for the observed difference in the occurrence of heart disease
before and after menopause.
[0009] The skeleton is under a continuous process of bone
degeneration and regeneration in a carefully regulated interaction
among the bone cells. These cells are directly affected by
estrogen. Estrogen deficiency results in a loss of bone structure
and a decrease of bone strength. Rapid loss of bone mass during the
year immediately following menopause leads to postmenopausal
osteoporosis and increased risk of fracture.
[0010] Estrogen deficiency is also one of the causes for the
degenerative changes in the central nervous system and may lead to
Alzheimer's disease and decline of cognition. Recent evidence
suggests an association between estrogen, menopause and cognition.
More particularly, it has been reported that estrogen replacement
therapy and the use of estrogen in women may prevent the
development of AD and improve cognitive function.
[0011] Hormone replacement therapy (HRT)--more specifically
estrogen replacement therapy (ERT)--is commonly prescribed to
address the medical problems associated with menopause, and also to
help hinder osteoporosis and primary cardiovascular complications
(such as coronary artery disease) in both a preventive and
therapeutical manner. As such, HRT is considered a medical therapy
for prolonging the average life span of postmenopausal women and
providing a better quality of life.
[0012] ERT effectively relieves the climacteric symptoms and
urogenital symptoms and has shown significant benefits in the
prevention and treatment of heart disease in postmenopausal women.
Clinical reports have shown that ERT lowered heart attack rates and
mortality rates in populations that received ERT versus similar
populations not on ERT. ERT initiated soon after menopause may also
help maintain bone mass for several years. Controlled
investigations have shown that treatment with ERT has a positive
effect even in older women up to age of 75 years.
[0013] However, there are numerous undesirable effects associated
with ERT that reduce patient compliance. Venous thromboembolism,
gallbladder disease, resumption of menses, mastodynia and a
possible increased risk of developing uterine and/or breast cancer
are the risks associated with ERT. Up to 30% of women who were
prescribed ERT did not fill the prescription, and the
discontinuation rate is between 38% and 70%, with safety concerns
and adverse effects (bloating and break-through bleeding) the most
important reasons for discontinuation.
[0014] A new class of pharmacological agents known as Selective
Estrogen Receptor Modulators or SERMs have been designed and
developed as alternatives for HRT. Raloxifene, a nonsteroidal
benzothiophere SERM is marketed in the US and Europe for the
prevention and treatment of osteoporosis under the trademark of
Evista.RTM.. Raloxifene has been shown to reduce bone loss and
prevent fracture without adversely stimulating endometrial and
mammary tissue, though raloxifene is somewhat less efficacious than
ERT for protecting against bone loss. Raloxifene is unique and
differs significantly from ERT in that it does not stimulate the
endometrium and has the potential for preventing breast cancer.
Raloxifene has also demonstrated beneficial estrogen agonist
effects on cardiovascular risk factors, more specifically through a
rapid and sustained decrease in total and low-density lipoprotein
cholesterol levels in patients treated with raloxifene. In
addition, raloxifene has been shown to reduce plasma concentration
of homocysteine, an independent risk factor for arteriosclerosis
and thromboembolic disease.
[0015] However, raloxifene has been reported to exacerbate symptoms
associated with menopause such as hot flushes and vaginal dryness,
and does not improve cognitive function in senior patients.
Patients taking raloxifene have reported higher rates of hot
flashes compared with either placebo or ERT users and more leg
cramps than placebo users, although women who took ERT had a higher
incidence of vaginal bleeding and breast discomfort than raloxifene
or placebo users.
[0016] As yet, neither raloxifene nor any of the other currently
available SERM compounds has been shown to have the ability to
provide all the benefits of currently available ERT such as
controlling postmenopausal syndrome and preventing AD, without
causing adverse side effects such as increasing risk of endometrial
and breast cancer and bleeding. Thus there exists a need for
compounds which are selective estrogen receptor modulators and
which provide all of the benefits of ERT while also addressing the
vasomotor, urogenital and cognitive disorders or conditions
associated with the decrease in systemic estrogen associated with
menopause.
SUMMARY OF THE INVENTION
[0017] The present invention is directed to a compound of formula
(I)
##STR00001##
[0018] wherein
[0019] represents a single or double bond,
[0020] X is selected from the group consisting of O and S;
##STR00002##
is a six membered heteroaryl ring structure containing one to two
nitrogen atoms;
[0021] R.sup.1 is selected from the group consisting of hydrogen,
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl;
wherein the cycloalkyl, aryl, aralkyl, heteroaryl or
heteroaryl-alkyl group is optionally substituted with one or more
substituents independently selected from halogen, hydroxy, alkyl,
alkoxy, --SH, --S(alkyl), SO.sub.2, NO.sub.2, CN, CO.sub.2H,
R.sup.C, --OR.sup.C, --SO.sub.2--NR.sup.DR.sup.E,
--NR.sup.DR.sup.E, NR.sup.D--SO.sub.2--R.sup.F,
-(alkyl).sub.0-4-C(O)NR.sup.DR.sup.E,
(alkyl).sub.0-4-NR.sup.D--C(O)--R.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--OR.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E
or -(alkyl).sub.0-4-C(O)-(alkyl).sub.0-4-C(O)--OR.sup.F;
[0022] wherein R.sup.C is selected from the group consisting of
alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl, heteroaryl,
heteroaryl-alkyl, heterocycloalkyl and heterocycloalkyl-alkyl;
wherein the cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl or
heterocycloalkyl-alkyl group is optionally substituted with one or
more substituents independently selected from halogen, hydroxy,
alkyl, alkoxy, --SH, --S(alkyl), SO.sub.2, NO.sub.2, CN, CO.sub.2H,
R.sup.C, --SO.sub.2--NR.sup.DR.sup.E, NR.sup.DR.sup.E,
NR.sup.D--SO.sub.2--R.sup.F,
-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E,
-(alkyl).sub.0-4-NR.sup.D--C(O)--R.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--OR.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E
or -(alkyl).sub.0-4-C(O)-(alkyl).sub.0-4-C(O)--OR.sup.F;
[0023] wherein Q is selected from the group consisting of O, S, NH,
N(alkyl) and --CH.dbd.CH--;
[0024] wherein R.sup.D and R.sup.E are each independently selected
from the group consisting of hydrogen and alkyl; alternatively
R.sup.D and R.sup.E are taken together with the nitrogen atom to
which they are bound to form a 4 to 8 membered ring selected from
the group consisting of heteroaryl or heterocycloalkyl; wherein the
heteroaryl or heterocycloalkyl group is optionally substituted with
one or more substituents independently selected from halogen,
hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino,
nitro or cyano;
[0025] wherein R.sup.F is selected from the group consisting of
hydrogen, alkyl, cycloalkyl, cycloalkyl-alkyl, aryl, aralkyl,
heteroaryl, heteroaryl-alkyl, heterocycloalkyl and
heterocycloalkyl-alkyl; wherein the cycloalkyl, aryl, heteroaryl,
heteroaryl-alkyl, heterocycloalkyl or heterocycloalkyl-alkyl group
is optionally substituted with one or more substituents
independently selected from halogen, hydroxy, alkyl, alkoxy,
carboxy, amino, alkylamino, dialkylamino, nitro or cyano;
[0026] R.sup.2 is selected from the group consisting of hydroxy,
alkyl, cycloalkyl, aryl, aralkyl, heteroaryl and heteroaryl-alkyl;
wherein the cycloalkyl, aryl, aralkyl, heteroaryl or
heteroaryl-alkyl group is optionally substituted with one or more
substituents independently selected from halogen, hydroxy, alkyl,
alkoxy, --SH, --S(alkyl), SO.sub.2, NO.sub.2, CN, CO.sub.2H,
R.sup.C, --OR.sup.C, --SO.sub.2--NR.sup.DR.sup.E,
--NR.sup.DR.sup.E, NR.sup.D--SO.sub.2--R.sup.F,
-(alkyl).sub.0-4-C(O)NR.sup.DR.sup.E,
(alkyl).sub.0-4-NR.sup.D--C(O)--R.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--OR.sup.F,
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E
or -(alkyl).sub.0-4-C(O)-(alkyl).sub.0-4-C(O)--OR.sup.F;
[0027] alternatively, R.sup.1 and R.sup.2 are taken together with
the carbon atom to which they are bound to form C(O);
[0028] n is an integer selected from 0 to 4;
[0029] each R.sup.3 is independently selected from the group
consisting of halogen, hydroxy, R.sup.C, amino, alkylamino,
dialkylamino, nitro, cyano, SO.sub.2, --C(O)R.sup.G,
--C(O)OR.sup.G, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --N(R.sup.G)C(O)R.sup.G,
--OSi(R.sup.G).sub.3--OR.sup.G, --SO.sub.2N(R.sup.G).sub.2,
--O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G;
[0030] wherein each R.sup.G is independently selected from
hydrogen, alkyl, aryl, aralkyl and
1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein the alkyl,
aryl or aralkyl group is optionally substituted with one or more
substituents independently selected from alkyl, halogenated alkyl,
alkoxy, halogen, hydroxy, nitro, cyano, --OC(O)-alkyl or
--C(O)O-alkyl;
[0031] alternatively two R.sup.G groups are taken together with the
nitrogen atom to which they are bound to form a heterocycloalkyl
group; wherein the heterocycloalkyl group is optionally substituted
with one or more substituents independently selected from halogen,
hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino,
nitro or cyano;
[0032] m is an integer selected from 0 to 4;
[0033] each R.sup.4 is independently selected from the group
consisting of halogen, hydroxy, R.sup.C, amino, alkylamino,
dialkylamino, nitro, cyano, SO.sub.2, --C(O)R.sup.G,
--C(O)OR.sup.G, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --N(R.sup.G)C(O)R.sup.G,
--OSi(R.sup.G).sub.3--OR.sup.G, --SO.sub.2N(alkyl).sub.2,
--O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G;
[0034] R.sup.5 is selected from the group consisting of hydrogen,
alkyl, halogenated alkyl, aryl, aralkyl;
[0035] alternatively, R.sup.3 and R.sup.5 combine to form a six
membered ring;
[0036] provided that when is a double bond, X is O,
##STR00003##
is a six membered heteroaryl ring structure containing one to two
nitrogen atoms, and R.sup.1 and R.sup.2 are taken together with the
carbon atom to which they are bound to form C(O), then at least one
of n or m is an integer selected from 1 to 4;
[0037] provided further that when is a single bond, X is O,
##STR00004##
is a six membered heteroaryl ring structure containing one to two
nitrogen atoms, R.sup.1 is hydrogen and R.sup.2 is alkyl, then at
least one of n or m is an integer selected from 1 to 4;
[0038] provided further that when is a single bond, X is O,
##STR00005##
is a six membered heteroaryl ring structure containing one to two
nitrogen atoms, R.sup.1 is hydrogen, R.sup.2 is alkyl, n is 1 and m
is 1, then R.sup.3 and R.sup.4 are other than methoxy or
ethoxy;
[0039] provided further that when is a double bond, X is O,
##STR00006##
is a six membered heteroaryl ring structure containing one to two
nitrogen atoms, R.sup.1 and R.sup.2 are taken together with the
carbon atom to which they are bound to form C(O), n is 0 and m is
2, then each R.sup.4 is not hydroxy or alkoxy.
[0040] provided further that when is a double bond, X is O,
##STR00007##
is a six membered heteroaryl ring structure containing one to two
nitrogen atoms, R.sup.1 and R.sup.2 are taken together with the
carbon atom to which they are bound to form C(O), one of R.sup.3
groups and R.sup.5 group are combined into a six membered ring
cyclic structure, then at least one of n or m is an integer
selected from 1 to 4;
[0041] and pharmaceutically acceptable salts thereof.
[0042] Illustrative of the invention is a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and
any of the compounds described above. An illustration of the
invention is a pharmaceutical composition made by mixing any of the
compounds described above and a pharmaceutically acceptable
carrier. Illustrating the invention is a process for making a
pharmaceutical composition comprising mixing any of the compounds
described above and a pharmaceutically acceptable carrier.
[0043] Exemplifying the invention are methods of treating a
disorder mediated by one or more estrogen receptors in a subject in
need thereof comprising administering to the subject a
therapeutically effective amount of any of the compounds or
pharmaceutical compositions described above.
[0044] Illustrating the invention is a method of contraception
comprising administering to a subject in need thereof co-therapy
with a therapeutically effective amount of a compound of formula
(I) with a progestogen or progestogen antagonist.
[0045] Another example of the invention is the use of any of the
compounds described herein in the preparation of a medicament for
treating: (a) hot flashes, (b) vaginal dryness, (c) osteopenia, (d)
osteoporosis, (e) hyperlipidemia, (f) loss of cognitive function,
(g) a degenerative brain disorder, (h) cardiovascular disease, (i)
cerebrovascular disease (j) breast cancer, (k) endometrial cancer,
(l) cervical cancer, (m) prostate cancer, (n) benign prostatic
hyperplasia, (o) endometriosis, (p) uterine fibroids, (q)
osteoarthritis and for (r) contraception in a subject in need
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0046] The present invention is directed to a compound of formula
(I)
##STR00008##
[0047] wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
##STR00009##
m, and n are as defined above, useful for the treatment of
disorders mediated by an estrogen receptor. More particularly, the
compounds of the present invention are useful for the treatment and
prevention of disorders mediated by the estrogen-.alpha. and
estrogen-.beta. receptors. More preferably, the compounds of the
present invention are tissue selective estrogen receptor
modulators.
[0048] The compounds of the present invention are useful in the
treatment of disorders associated with the depletion of estrogen,
hormone sensitive cancers and hyperplasia, endometriosis, uterine
fibroids, osteoarthritis and as contraceptive agents, alone or in
combination with a progestogen or progestogen antagonist.
[0049] More particularly, the compounds of the present invention
are useful in the treatment of a condition or disorder selected
from the group consisting of hot flashes, vaginal dryness,
osteopenia, osteoporosis, hyperlipidemia, loss of cognitive
function, degenerative brain diseases, cardiovascular diseases,
cerebrovascular diseases, cancer or hyperplasia of the breast
tissue, cancer or hyperplasia of the endometrium, cancer or
hyperplasia of the cervix, cancer or hyperplasia of the prostate,
endometriosis, uterine fibroids and osteoarthritis; and as a
contraceptive agent. Preferably, the disorder is selected from the
group consisting of osteoporosis, hot flashes, vaginal dryness,
breast cancer, and endometriosis.
[0050] In the compound of formula (I), the relative orientation of
the groups R.sup.1 and R.sup.2 is not intended to be fixed, rather
both possible orientations of the groups are intended to be
included within the definition of the compound of formula (I).
[0051] In an embodiment of the present invention are compounds of
formula (I) wherein X is O. In another embodiment of the present
invention are compounds of formula (I) wherein X is S.
[0052] In an embodiment of the present invention
##STR00010##
is selected from the group consisting of pyridinyl, oxy-pyridinyl,
pyrimidinyl, oxy-pyrimidinyl, pyrazinyl or oxy-pyrazinyl. More
preferably
##STR00011##
is selected from the group consisting of pyridinyl or pyrimidinyl.
More preferably
##STR00012##
still is selected from the group consisting of m-pyridinyl,
p-pyridinyl and p-dimethoxy-pyrimidinyl.
[0053] In an embodiment of the present invention R.sup.1 is
selected from the group consisting of hydrogen, lower alkyl, aryl
or aralkyl; wherein the aryl or aralkyl group is optionally
substituted with one to two substituents independently selected
from halogen, hydroxy, lower alkyl, lower alkoxy, NO.sub.2, CN, and
CO.sub.2H. More preferably, R.sup.1 is selected from the group
consisting of hydrogen and lower alkyl. More preferably still,
R.sup.1 is selected from the group consisting of hydrogen and
methyl.
[0054] In an embodiment of the present invention R.sup.2 is
selected from the group consisting of hydroxy, lower alkyl, aryl or
aralkyl; wherein the aryl or aralkyl is optionally substituted with
one to two substituents independently selected from the group
consisting of halogen, hydroxy, lower alkyl, lower alkoxy,
NO.sub.2, CN, CO.sub.2H, R.sup.C, --OR.sup.C, --NR.sup.DR.sup.E,
-(alkyl).sub.0-4-NR.sup.DR.sup.E and
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E.
[0055] Preferably, R.sup.2 is selected from the group consisting of
hydroxy, lower alkyl, aryl and aralkyl; wherein the aryl or aralkyl
is optionally substituted with one to two substituents
independently selected from halogen, hydroxy, lower alkyl, lower
alkoxy, NO.sub.2, CN, CO.sub.2H, R.sup.C, --OR.sup.C or
--NR.sup.DR.sup.E;
[0056] wherein R.sup.C is selected from the group consisting of
alkyl, cycloalkyl, cycloalkyl-alkyl, aryl or aralkyl; wherein the
cycloalkyl, cycloalkyl-alkyl, aryl or aralkyl group is optionally
substituted with one or more substituents independently selected
from halogen, hydroxy, alkyl, alkoxy, NO.sub.2, CN, CO.sub.2H,
R.sup.C, NR.sup.DR.sup.E, -(alkyl).sub.0-4-C(O)--NR.sup.DR.sup.E or
-(alkyl).sub.0-4-(Q).sub.0-1-(alkyl).sub.0-4-NR.sup.DR.sup.E;
[0057] wherein Q is selected from the group consisting of O, S, NH,
N(alkyl) and --CH.dbd.CH--;
[0058] wherein R.sup.D and R.sup.E are each independently selected
from the group consisting of hydrogen and alkyl; alternatively
R.sup.D and R.sup.E are taken together with the nitrogen atom to
which they are bound to form a 4 to 8 membered ring selected from
the group consisting of heteroaryl or heterocycloalkyl; wherein the
heteroaryl or heterocycloalkyl group is optionally substituted with
one or more substituents independently selected from halogen,
hydroxy, alkyl, alkoxy, carboxy, amino, alkylamino, dialkylamino,
nitro or cyano.
[0059] More preferably, R.sup.2 is selected from the group
consisting of hydroxy, aryl, 4-(1-heterocycloalkyl-alkoxy)-phenyl,
4-(di(alkyl)amino-alkoxy)-phenyl, 4-(di(alkyl)amino)-phenyl and
4-aralkyloxy-phenyl. More preferably still, R.sup.2 is selected
from the group consisting of hydroxy, phenyl,
4-(1-piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl,
4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepinyl-ethoxy)-phenyl,
4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl,
4-(dimethylamino)-phenyl, 4-benzyloxy-phenyl and
4-(1-piperidinyl-n-propoxy)-phenyl. More preferably still, R.sup.2
is selected from the group consisting of phenyl,
4-(1-piperidinyl-ethoxy)-phenyl, 4-(1-pyrrolidinyl-ethoxy)-phenyl,
4-(4-morpholinyl-ethoxy)-phenyl, 4-(1-azepinyl-ethoxy)-phenyl,
4-(diethylamino-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl,
4-(dimethylamino)-phenyl and 4-(1-piperidinyl-n-propoxy)-phenyl.
More preferably still, R.sup.2 is selected from the group
consisting of phenyl, 4-(1-piperidinyl-ethoxy)-phenyl,
4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl,
4-(1-azepinyl-ethoxy)-phenyl, 4-(diethylamino-ethoxy)-phenyl,
4-(dimethylamino-ethoxy)-phenyl and 4-(dimethylamino)-phenyl. More
preferably still, R.sup.2 is selected from the group consisting of
phenyl, 4-(1-piperidinyl-ethoxy)-phenyl,
4-(1-pyrrolidinyl-ethoxy)-phenyl, 4-(4-morpholinyl-ethoxy)-phenyl,
4-(1-azepinyl-ethoxy)-phenyl, 4-(dimethylamino-ethoxy)-phenyl and
4-(dimethylamino)-phenyl.
[0060] In an embodiment of the present invention are compounds of
formula (I) wherein R.sup.1 and R.sup.2 are taken together with the
carbon atom to which they are bound to form C(O).
[0061] In an embodiment of the present invention R.sup.3 is
selected from the group consisting of halogen, hydroxy, R.sup.C,
amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro, cyano,
--OC(O)R.sup.G, --OC(O)OR.sup.G, OC(O)N(R.sup.G).sub.2,
OSi(R.sup.G).sub.3--OR.sup.G, --O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G.
[0062] Preferably, R.sup.3 is selected from the group consisting of
hydroxy, R.sup.C, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --OSi(R.sup.G).sub.3--OR.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G.
[0063] More preferably, R.sup.3 is selected from the group
consisting of halogen, hydroxy, lower alkoxy, (lower alkyl-di(lower
alkyl))-silyloxy, --OC(O)-(lower alkyl),
--OC(O)--C(phenyl)-OC(O)-(lower alkyl),
--OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one) and
--OC(O)--C(CH.sub.3)(CF.sub.3)-phenyl. More preferably still
R.sup.3 is selected from the group consisting of fluoro, hydroxy,
methoxy, t-butyl-dimethyl-silyloxy, --OC(O)-t-butyl,
--OC(O)--C(phenyl)-OC(O)CH.sub.3,
--OC(O)-(1,7,7-trimethyl-2-oxabicyclo[.2.1]heptan-3-one) and
--OC(O)--C(CH.sub.3)(CF.sub.3)-phenyl. More preferably still,
R.sup.3 is selected from the group consisting of hydroxy and
--OC(O)-t-butyl.
[0064] In an embodiment of the present invention R.sup.G is
selected from hydrogen, lower alkyl, aryl, aralkyl and
1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one; wherein the alkyl,
aryl or aralkyl group is optionally substituted with one to two
substituents independently selected from lower alkyl, halogenated
lower alkyl, lower alkoxy, halogen, hydroxy, nitro, cyano,
--OC(O)-(lower alkyl) and --C(O)O-(lower alkyl).
[0065] In another embodiment of the present invention two R.sup.G
groups are taken together with the nitrogen atom to which they are
bound to form a 5 to 6 membered heterocycloalkyl group; wherein the
heterocycloalkyl group is optionally substituted with one to two
substituents independently selected from halogen, hydroxy, lower
alkyl, lower alkoxy, carboxy, amino, (lower alkyl)-amino, di(lower
alkyl)amino, nitro or cyano.
[0066] In an embodiment of the present invention R.sup.4 is
selected from the group consisting of halogen, hydroxy, R.sup.C,
amino, (lower alkyl)-amino, di(lower alkyl)amino, nitro, cyano,
--OC(O)R.sup.G, --OC(O)OR.sup.G, --OC(O)N(R.sup.G).sub.2,
--OSi(R.sup.G).sub.3--OR.sup.G, --O-(alkyl).sub.1-4-C(O)R.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G.
[0067] Preferably R.sup.4 is selected from the group consisting of
hydroxy, R.sup.C, --OC(O)R.sup.G, --OC(O)OR.sup.G,
--OC(O)N(R.sup.G).sub.2, --OSi(R.sup.G).sub.3--OR.sup.G and
--O-(alkyl).sub.1-4-C(O)OR.sup.G.
[0068] More preferably, R.sup.4 is selected from the group
consisting of hydroxy, lower alkoxy, (lower alkyl-(di(lower
alkyl))-silyloxy, --OC(O)-(lower alkyl),
--OC(O)--C(phenyl)-OC(O)-(lower alkyl),
--OC(O)-(1,7,7-trimethyl-2-oxabicyclo[2.2.1]heptan-3-one) and
--OC(O)--C(CH.sub.3)(CF.sub.3)-phenyl. More preferably still,
R.sup.4 is selected from the group consisting of hydroxy, methoxy,
t-butyl-dimethyl-silyloxy, --OC(O)-t-butyl,
--OC(O)--C(phenyl)-OC(O)CH.sub.3,
--OC(O)-(1,7,7-trimethyl-2-oxabicyclo[.2.1]heptan-3-one) and
--OC(O)--C(CH.sub.3)(CF.sub.3)-phenyl. More preferably still,
R.sup.4 is selected from the group consisting of hydroxy and
--OC(O)-t-butyl.
[0069] In another embodiment of the present invention R.sup.5 is
selected from the group consisting of hydrogen, lower alkyl,
halogenated alkyl, aryl, aralky. More preferably, R.sup.5 is
selected from the group consisting of hydrogen, methyl, ethyl,
chloromethyl, bromomethyl. More preferably still, R.sup.5 is
selected from the group consisting of methyl and bromomethyl.
[0070] A particularly preferred embodiment of the present invention
is directed to the following compound:
##STR00013##
[0071] In an embodiment of the present invention, m is an integer
selected from 0 to 2. Preferably, m is an integer selected from 0
to 1. More preferably m is 1.
[0072] In an embodiment of the present invention, n is an integer
selected from 1 to 2. Preferably, n is 1.
[0073] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of compounds
according to this invention or of their pharmaceutically acceptable
salts. Suitable pharmaceutically acceptable salts of the compounds
include acid addition salts which may, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of the invention
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts, e.g., sodium or potassium
salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and salts formed with suitable organic ligands, e.g.,
quaternary ammonium salts. Thus, representative pharmaceutically
acceptable salts include the following:
[0074] acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate,
bitartrate, borate, bromide, calcium edetate, camsylate, carbonate,
chloride, clavulanate, citrate, dihydrochloride, edetate,
edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide,
isothionate, lactate, lactobionate, laurate, malate, maleate,
mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
mucate, napsylate, nitrate, N-methylglucamine ammonium salt,
oleate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate,
sulfate, subacetate, succinate, tannate, tartrate, teoclate,
tosylate, triethiodide and valerate.
[0075] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0076] Where the compounds according to this invention have at
least one chiral center, they may accordingly exist as enantiomers.
Where the compounds possess two or more chiral centers, they may
additionally exist as diastereomers. It is to be understood that
all such isomers and mixtures thereof are encompassed within the
scope of the present invention. Furthermore, some of the
crystalline forms for the compounds may exist as polymorphs and as
such are intended to be included in the present invention. In
addition, some of the compounds may form solvates with water (i.e.,
hydrates) or common organic solvents, and such solvates are also
intended to be encompassed within the scope of this invention.
[0077] As used herein, the term "degenerative brain disease" shall
include cognitive disorder, dementia, regardless of underlying
cause and Alzheimer's disease.
[0078] As used herein, the term "cardiovascular disease" shall
include elevated blood lipid levels, coronary arthrosclerosis and
coronary heart disease.
[0079] As used herein, the term "cerebrovascular disease" shall
include abnormal regional cerebral blood flow and ischemic brain
damage.
[0080] As used herein, the term "progestogen antagonist" shall
include mifepristone (RU-486), J-867 (Jenapharm/TAP
Pharmaceuticals), J-956 (Jenapharm/TAP Pharmaceuticals), ORG-31710
(Organon), ORG-33628 (Organon), ORG-31806 (Organon), onapristone
(ZK98299) and PRA248 (Wyeth).
[0081] As used herein, unless otherwise noted, "halogen" shall mean
chlorine, bromine, fluorine and iodine.
[0082] As used herein, unless otherwise noted, the term "alkyl"
whether used alone or as part of a substituent group, include
straight and branched chain compositions of one to eight carbon
atoms. For example, alkyl radicals include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the
like. Unless otherwise noted, "lower" when used with alkyl means a
carbon chain composition of 1-4 carbon atoms. Similarly, the group
"-(alkyl).sub.0-4-", whether alone or as part of a large
substituent group, shall me the absence of an alkyl group or the
presence of an alkyl group comprising one to four carbon atoms.
Suitable examples include, but are not limited to --CH.sub.2--,
--CH.sub.2CH.sub.2--, CH.sub.2--CH(CH.sub.3)--,
CH.sub.2CH.sub.2CH.sub.2--, --CH.sub.2CH(CH.sub.3)CH.sub.2--,
CH.sub.2CH.sub.2CH.sub.2CH.sub.2--, and the like.
[0083] As used herein, unless otherwise noted, "alkoxy" shall
denote an oxygen ether radical of the above described straight or
branched chain alkyl groups. For example, methoxy, ethoxy,
n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
[0084] As used herein, unless otherwise noted, "aryl" shall refer
to unsubstituted carbocyclic aromatic groups such as phenyl,
naphthyl, and the like.
[0085] As used herein, unless otherwise noted, "aralkyl" shall mean
any lower alkyl group substituted with an aryl group such as
phenyl, naphthyl and the like. Suitable examples include benzyl,
phenylethyl, phenylpropyl, naphthylmethyl, and the like.
[0086] As used herein, unless otherwise noted, the term
"cycloalkyl" shall mean any stable 3-8 membered monocyclic,
saturated ring system, for example cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0087] As used herein, unless otherwise noted, the term
"cycloalkyl-alkyl" shall mean any lower alkyl group substituted
with a cycloalkyl group. Suitable examples include, but are not
limited to cyclohexyl-methyl, cyclopentyl-methyl, cyclohexyl-ethyl,
and the like.
[0088] As used herein, unless otherwise noted, the terms "acyloxy"
shall mean a radical group of the formula --O--C(O)--R where R is
alkyl, aryl or aralkyl, wherein the alkyl, aryl or aralkyl is
optionally substituted. As used herein, the term "carboxylate"
shall mean a radical group of the formula --C(O)O--R where R is
alkyl, aryl or aralkyl, wherein the alkyl, aryl or aralkyl is
optionally substituted.
[0089] As used herein, unless otherwise noted, "heteroaryl" shall
denote any five or six membered monocyclic aromatic ring structure
containing at least one heteroatom selected from the group
consisting of O, N and S, optionally containing one to three
additional heteroatoms independently selected from the group
consisting of O, N and S; or a nine or ten membered bicyclic
aromatic ring structure containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heteroaryl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
[0090] Examples of suitable heteroaryl groups include, but are not
limited to, pyrrolyl, furyl, thienyl, oxazolyl, imidazolyl,
purazolyl, isoxazolyl, isothiazolyl, triazolyl, thiadiazolyl,
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furazanyl,
indolizinyl, indolyl, isoindolinyl, indazolyl, benzofuryl,
benzothienyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl,
quinolinyl, isoquinolinyl, isothiazolyl, cinnolinyl, phthalazinyl,
quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, and the
like.
[0091] As used herein, unless otherwise noted, the term
"heteroaryl-alkyl" shall mean any lower alkyl group substituted
with a heteroaryl group. Suitable examples include, but are not
limited to pyridyl-methyl, isoquinolinyl-methyl, thiazolyl-ethyl,
furyl-ethyl, and the like.
[0092] As used herein, the term "heterocycloalkyl" shall denote any
five to seven membered monocyclic, saturated or partially
unsaturated ring structure containing at least one heteroatom
selected from the group consisting of O, N and S, optionally
containing one to three additional heteroatoms independently
selected from the group consisting of O, N and S; or a nine to ten
membered saturated, partially unsaturated or partially aromatic
bicyclic ring system containing at least one heteroatom selected
from the group consisting of O, N and S, optionally containing one
to four additional heteroatoms independently selected from the
group consisting of O, N and S. The heterocycloalkyl group may be
attached at any heteroatom or carbon atom of the ring such that the
result is a stable structure.
[0093] Examples of suitable heteroaryl groups include, but are not
limited to, pyrrolinyl, pyrrolidinyl, dioxalanyl, imidazolinyl,
imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, dioxanyl,
morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl,
indolinyl, chromenyl, 3,4-methylenedioxyphenyl,
2,3-dihydrobenzofuryl, and the like.
[0094] As used herein, unless otherwise noted, the term
"heterocycloalkyl-alkyl" shall mean any lower alkyl group
substituted with a heterocycloalkyl group. Suitable examples
include, but are not limited to piperidinyl-methyl,
piperazinyl-methyl, piperazinyl-ethyl, morpholinyl-methyl, and the
like.
[0095] When a particular group is "substituted" (e.g., cycloalkyl,
aryl, heteroaryl, heterocycloalkyl), that group may have one or
more substituents, preferably from one to five substituents, more
preferably from one to three substituents, most preferably from one
to two substituents, independently selected from the list of
substituents. Additionally when aralkyl, heteroaryl-alkyl,
heterocycloalkyl-alkyl or cycloalkyl-alkyl group is substituted,
the substituent(s) may be on any portion of the group (i.e. the
substituent(s) may be on the aryl, heteroaryl, heterocycloalkyl,
cycloalkyl or the alkyl portion of the group.)
[0096] With reference to substituents, the term "independently"
means that when more than one of such substituents is possible,
such substituents may be the same or different from each other.
[0097] Under standard nomenclature used throughout this disclosure,
the terminal portion of the designated side chain is described
first, followed by the adjacent functionality toward the point of
attachment. Thus, for example, a
"phenylC.sub.1-C.sub.6alkylaminocarbonylC.sub.1-C.sub.6alkyl"
substituent refers to a group of the formula
##STR00014##
[0098] Unless otherwise noted, when naming substituents such as
R.sup.3 group, the following numbering of the core structure will
be applied. The capital letters A, B, C and D will be used to
designate specific rings of the tetracyclic core structure.
##STR00015##
[0099] Abbreviations used in the specification, particularly the
Schemes and Examples, are as follows [0100] Ac=Acetyl group
(--C(O)--CH.sub.3) [0101] AD=Alzheimer's disease [0102] CSA=Camphor
sulfonic acid [0103] DCC=1,3-Dicyclohexylcarbodiimide [0104]
DCM=Dichloromethane [0105] DEAD=Diethylazodicarboxylate [0106]
DIAD=Diisopropylazodicarboxylate [0107] Dibal-H=Diisobutyl aluminum
hydride [0108] DIC Diisopropylcarbodiimide [0109] DIPEA or
DIEA=Diisopropylethylamine [0110] DMAP=N,N-Dimethylaminopyridine
[0111] DMF=Dimethyl formamide [0112] ERT=Estrogen replacement
therapy [0113] Et=ethyl (i.e. --CH.sub.2CH.sub.3) [0114]
EtOAc=Ethyl acetate [0115] FBS=Fetal bovine serum [0116] HPLC=High
pressure liquid chromatography [0117] HRT=Hormone replacement
therapy [0118] IPA=Isopropyl alcohol [0119] iPr.sub.2NH
Diisopropylamine [0120] LAH=Lithium aluminum hydride [0121]
LDA=Lithium Diisopropylamide [0122] LHMDS or LiHMDS or =Lithium
Hexamethyldisilazinamide [0123] (TMS).sub.2NLi or LiN(TMS).sub.2
[0124] KHMDS=Potassium Hexamethyldisilazinamide [0125]
MeOH=Methanol [0126] NaHMDS=Sodium Hexamethyldisilazinamide [0127]
NBS=N-Bromosuccinimide [0128] NCS=N-chlorosuccinimide [0129]
PBS=Phosphate buffered solution [0130] Ph=Phenyl [0131] PIV or
Piv=Pivaloyl [0132] P(Ph).sub.3=Triphenylphosphine [0133]
PPTS=Pyridinium p-toluenesulfonate [0134] Rochelle Solution=Aqueous
solution of potassium sodium tartrate tetrahydrate [0135] Pybrop
[0136] SEM=2-(Trimethylsilyl)ethoxy methyl [0137]
SEMCl=2-(Trimethylsilyl)ethoxy methyl chloride [0138]
SERM=Selective estrogen receptor modulator [0139]
TBAF=Tetra(n-butyl)ammonium fluoride [0140]
TBDMS=Tert-butyldimethylsilane [0141] TBS=Tert-butyl-dimethyl-silyl
[0142] TBSCl=Tert-butyl-dimethyl-silyl chloride [0143] TEA or
Et.sub.3N=Triethylamine [0144] TFA=Trifluoroacetic acid [0145]
THF=Tetrahydrofuran [0146] TIPSCl=Triisopropylsilyl chloride [0147]
TIPSOTf=Triisopropylsilyl trifluoromethane sulfonate [0148]
TMS=Trimethylsilyl [0149] TsOH=Tosic acid
[0150] The term "subject" as used herein, refers to an animal,
preferably a mammal, most preferably a human, who has been the
object of treatment, observation or experiment.
[0151] The term "therapeutically effective amount" as used herein,
means that amount of active compound or pharmaceutical agent that
elicits the biological or medicinal response in a tissue system,
animal or human that is being sought by a researcher, veterinarian,
medical doctor or other clinician, which includes alleviation of
the symptoms of the disease or disorder being treated. Wherein the
present invention directed to co-therapy comprising administration
of one or more compound(s) of formula I and a progestogen or
progestogen antagonist, "therapeutically effective amount" shall
mean that amount of the combination of agents taken together so
that the combined effect elicits the desired biological or
medicinal response. For example, the therapeutically effective
amount of co-therapy comprising administration of a compound of
formula I and progestogen would be the amount of the compound of
formula I and the amount of the progestogen that when taken
together or sequentially have a combined effect that is
therapeutically effective. Further, it will be recognized by one
skilled in the art that in the case of co-therapy with a
therapeutically effective amount, as in the example above, the
amount of the compound of formula I and/or the amount of the
progestogen or progestogen antagonist individually may or may not
be therapeutically effective.
[0152] As used herein, the term "co-therapy" shall mean treatment
of a subject in need thereof by administering one or more compounds
of formula I with a progestogen or progestogen antagonist, wherein
the compound(s) of formula I and progestogen or progestogen
antagonist are administered by any suitable means, simultaneously,
sequentially, separately or in a single pharmaceutical formulation.
Where the compound(s) of formula I and the progestogen or
progestogen antagonist are administered in separate dosage forms,
the number of dosages administered per day for each compound may be
the same or different. The compound(s) of formula I and the
progestogen or progestogen antagonist may be administered via the
same or different routes of administration. Examples of suitable
methods of administration include, but are not limited to, oral,
intravenous (iv), intramuscular (im), subcutaneous (sc),
transdermal, and rectal. Compounds may also be administered
directly to the nervous system including, but not limited to,
intracerebral, intraventricular, intracerebroventricular,
intrathecal, intracisternal, intraspinal and/or peri-spinal routes
of administration by delivery via intracranial or intravertebral
needles and/or catheters with or without pump devices. The
compound(s) of formula I and the progestogen or progestogen
antagonist may be administered according to simultaneous or
alternating regimens, at the same or different times during the
course of the therapy, concurrently in divided or single forms.
[0153] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combinations of the specified ingredients in
the specified amounts.
[0154] Compounds of formula (I) wherein X, R1, R2, R3, R4, R5, m,
n, and
##STR00016##
are as described above may be prepared according to the processes
outlined in Scheme 1.
##STR00017## ##STR00018##
[0155] More particularly, a suitably substituted compound of
formula (II) is reacted with a compound of formula (III), a known
compound, in the presence of an organic base such as NaH, NaOMe,
t-BuOK, and the like, in an organic solvent such as THF, dioxlane,
DMF, and the like, under the catalysis of copper(I) salt such as
CuBr, CuI, CuCl, and the like, at a temperature in the range of
about 60 to about 120.degree. C., to yield the corresponding
compound of formula (IV).
[0156] The compound of formula (IV) is reacted with an inorganic
base such as NaOH, KOH or LiOH and the like in a mixed solvent such
as such as THF, MeOH, EtOH mixed with water and the like at a
temperature in the range of 80 to about 120.degree. C., to yield
the corresponding compound of formula (V).
[0157] The compound of formula (V) is reacted with a suitably
substituted compound of formula (VI), and where X is O or S, a
known compound or compound prepared by known methods, in the
presence of DCC, DIC, Pybrop and the like, an organic base such as
TEA, DIPEA, pyridine, and the like, in an organic solvent such as
THF, dioxlane, DCM and the like, at an elevated temperature in the
range of about 40 to about 60.degree. C., to yield the
corresponding compound of formula (VII).
[0158] One skilled in the art will recognize that it may be
necessary and/or desirable to protect one or more of the R.sup.3
and/or R.sup.4 groups at any of the steps within the process
described above. This may be accomplished using known protecting
groups and know protection and de-protection reagents and
conditions, for example such as those described in Protective
Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press,
1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1991.
[0159] Accordingly, the compound of formula (VII) is reacted with
diisobutyl-aluminum hydride, L-selectride, and the like, in an
organic solvent such as toluene, benzene, THF, methylene chloride,
and the like, at a reduced temperature in the range of about 0 to
about -80.degree. C., to yield the corresponding compound of
formula (VIII).
[0160] The compound of formula (VIII) is reacted with a suitably
substituted compound of formula (IX), wherein MQ is lithium or a
magnesium halide such as MgCl, MgBr or MgI, prepared from the
corresponding known alkyl or aryl halide by known methods, in an
organic solvent such as THF, diethyl ether, dioxane, hexane, and
the like, to yield the corresponding compound of formula (X).
Without separation, the compound of formula (X) was then treated
with a protic acid such as HCl, H.sub.2SO.sub.4, p-toluene sulfonic
acid, camphor sulfonic acid (CSA), TFA, and the like or a Lewis
acid such as BF.sub.3 etherate, AlCl.sub.3, SnCl.sub.4, and the
like, in a solvent such as toluene, methylene chloride,
acetonitrile and the like, to yield the corresponding compound of
formula (XI).
[0161] Alternatively, the compound of formula (X) is treated with a
reagent such as triphenylphosphine, tributylphosphine, and the
like, or an azodicarboxamide such as DEAD, DIAD, and the like, in a
solvent such as toluene, THF, and the like, to yield the
corresponding compound of formula (XI).
##STR00019##
Compounds of formula (XI*) wherein R.sup.2 is
-(aryl)-O-(alkyl).sub.0-4-NR.sup.DR.sup.E may be prepared by
reacting a suitably substituted compound of formula (XI), wherein
the R.sup.2 group is -(aryl)-O-(alkyl).sub.0-4-Hal (Hal is selected
from Cl, Br or I) with a catalytic amount of iodine salt such as
NaI, KI, NH.sub.4NI, and the like and amine source NHR.sup.DR.sup.E
such as dimethyl amine, diethyl amine, pyrrolidine, piperidine,
morphiline and the like, in a solvent such as DMF, DMSO, DMA and
the like, to yield the corresponding compound of formula (X). For
example, a compound of formula (X*) wherein R.sup.2, is
-(aryl)-O-(alkyl).sub.0-4-NR.sup.DR.sup.E may be prepared according
to the process outlined in Scheme 2.
[0162] One skilled in the art will recognize that it may be
necessary and/or desirable to protect one or more of the R.sup.3
groups at any of the steps within the process described above. This
may be accomplished using known protecting groups and know
protection and de-protection reagents and conditions, for example
such as those described in Protective Groups in Organic Chemistry,
ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P.
G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley
& Sons, 1991.
[0163] Where the processes for the preparation of the compounds
according to the invention give rise to mixture of stereoisomers,
these isomers may be separated by conventional techniques such as
preparative chromatography.
[0164] The compound of formula (XII) may be selectively
hydrogenated to yield the corresponding compound of formula (XIII),
as shown in Scheme 3.
##STR00020##
[0165] Accordingly, the compound of formula (XII) is reacted with
hydrogen gas, at a pressure in the range of about 20 to about 100
psi, in the presence of a metal catalyst such as Pd on C, Pt on C,
Raney nickel, Pd(OH).sub.2, and the like, to yield the
corresponding compound of formula (XIII), as predominately the cis
isomer.
[0166] Alternatively, the compound of formula (XII) is reacted with
a hydride such as LAH, Cu hydride, SmI.sub.2, Stryker's Reagent
([(Ph.sub.3P)CuH].sub.6), and the like, in an solvent such as THF,
diethyl ether, and the like, at a temperature in the range of about
-20 to about 60.degree. C., to yield the corresponding compound of
formula (XIII), as predominately the trans isomer.
[0167] Alternatively, the compound of formula (XII) is reacted with
triethyl silane, in the presence of an acid such as TFA, BF.sub.3
etherate, Tin tetrachloride, and the like, in an organic solvent
such as methylene chloride, toluene, and the like, to yield the
corresponding compound of formula (XIII), as a mixture of cis and
trans isomers.
[0168] Compounds of formula (M) may be prepared according to the
processes outlined in Scheme 4.
##STR00021##
[0169] The compound of formula (VII*) is reacted with bromine or a
source of bromine or chlorine such as NBS, NCS, and the like, in
the presence of a base such as LHMDS, LDA, KHMDS, NaHMDS, and the
like, at a reduced temperature in the range of about 30 to about
-78.degree. C., to yield the corresponding compound of formula
(XIV).
[0170] Alternatively, the compound of formula (VII*) is reacted
with a radical brominating agent such as NBS, CBrCl.sub.3,
NaBrO.sub.3 in combination with NaHSO.sub.3, and the like or a
radical chlorinating agent, such as NCS, SO.sub.2Cl.sub.2, Cl.sub.2
gas, t-butyl hypochloride, and the like, preferably a radical
brominating agent such as NBS, in the presence of a radical
initiator such as benzoyl peroxide, AIBN, and the like and/or in
the presence of a light source, such as a tungsten lamp, a 120 Watt
light bulb, bright sunshine, and the like, optionally at an
elevated temperature in the range of about 50-120.degree. C., to
yield the corresponding compound of formula (XIV).
[0171] The compound of formula (XIV) is reacted with a
de-methylating reagent such as TMS iodide, BBr.sub.3, AlCl.sub.3
with ethanethiol, and the like, in an chlorinated solvent such as
methylene chloride, chloroform, dichloroethane, and the like,
followed by a weak base treatment, such as K.sub.2CO.sub.3,
Na.sub.2CO.sub.3, 1 N NaOH, 1N KOH and the like to yield the
corresponding compound of formula (M).
[0172] Alternatively, the compound of formula (XIV) is reacted with
a de-methylating reagent such as pyridine hydrochloride, pyridine
hydrobromide, pyridine hydroiodide, and the like, optionally in an
organic solvent such as xylene, acetic acid, and the like, at an
elevated temperature in the range of about 170 to about 220.degree.
C., followed by a weak base treatment, such as K.sub.2CO.sub.3,
Na.sub.2CO.sub.3, 1 N NaOH, 1N KOH and the like to yield the
corresponding compound of formula (M).
[0173] One skilled in the art will recognize that it may be
necessary and/or desirable to protect one or more of the R.sup.3
and/or R.sup.4 groups at any of the steps within the process
described above. This may be accomplished using known protecting
groups and know protection and de-protection reagents and
conditions, for example such as those described in Protective
Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press,
1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in
Organic Synthesis, John Wiley & Sons, 1991.
[0174] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and/or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known from the
art.
[0175] The utility of the compounds of the instant invention to
treat disorders mediated by an estrogen receptor may be determined
according to the procedures described in Examples 1-43, and
herein.
[0176] The present invention therefore provides a method of
treating disorders mediated by an estrogen receptor in a subject in
need thereof which comprises administering any of the compounds as
defined herein in a quantity effective to treat said disorder. The
compound may be administered to a patient by any conventional route
of administration, including, but not limited to, intravenous,
oral, subcutaneous, intramuscular, intradermal and parenteral. The
quantity of the compound which is effective for treating a disorder
mediated by an estrogen receptor is between 0.01 mg per kg and 20
mg per kg of subject body weight.
[0177] The present invention also provides pharmaceutical
compositions comprising one or more compounds of this invention in
association with a pharmaceutically acceptable carrier. Preferably
these compositions are in unit dosage forms such as tablets, pills,
capsules, powders, granules, sterile parenteral solutions or
suspensions, metered aerosol or liquid sprays, drops, ampoules,
autoinjector devices or suppositories; for oral parenteral,
intranasal, sublingual or rectal administration, or for
administration by inhalation or insufflation. Alternatively, the
composition may be presented in a form suitable for once-weekly or
once-monthly administration; for example, an insoluble salt of the
active compound, such as the decanoate salt, may be adapted to
provide a depot preparation for intramuscular injection. For
preparing solid compositions such as tablets, the principal active
ingredient is mixed with a pharmaceutical carrier, e.g.
conventional tableting ingredients such as corn starch, lactose,
sucrose, sorbitol, talc, stearic acid, magnesium stearate,
dicalcium phosphate or gums, and other pharmaceutical diluents,
e.g. water, to form a solid preformulation composition containing a
homogeneous mixture of a compound of the present invention, or a
pharmaceutically acceptable salt thereof. When referring to these
preformulation compositions as homogeneous, it is meant that the
active ingredient is dispersed evenly throughout the composition so
that the composition may be readily subdivided into equally
effective dosage forms such as tablets, pills and capsules. This
solid preformulation composition is then subdivided into unit
dosage forms of the type described above containing from 5 to about
1000 mg of the active ingredient of the present invention. The
tablets or pills of the novel composition can be coated or
otherwise compounded to provide a dosage form affording the
advantage of prolonged action. For example, the tablet or pill can
comprise an inner dosage and an outer dosage component, the latter
being in the form of an envelope over the former. The two
components can be separated by an enteric layer which serves to
resist disintegration in the stomach and permits the inner
component to pass intact into the duodenum or to be delayed in
release. A variety of material can be used for such enteric layers
or coatings, such materials including a number of polymeric acids
with such materials as shellac, cetyl alcohol and cellulose
acetate.
[0178] The liquid forms in which the novel compositions of the
present invention may be incorporated for administration orally or
by injection include, aqueous solutions, suitably flavoured syrups,
aqueous or oil suspensions, and flavoured emulsions with edible
oils such as cottonseed oil, sesame oil, coconut oil or peanut oil,
as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include
synthetic and natural gums such as tragacanth, acacia, alginate,
dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinyl-pyrrolidone or gelatin.
[0179] The method of treating a disorder mediated by an estrogen
receptor described in the present invention may also be carried out
using a pharmaceutical composition comprising any of the compounds
as defined herein and a pharmaceutically acceptable carrier. The
pharmaceutical composition may contain between about 5 mg and 1000
mg, preferably about 10 to 500 mg, of the compound, and may be
constituted into any form suitable for the mode of administration
selected. Carriers include necessary and inert pharmaceutical
excipients, including, but not limited to, binders, suspending
agents, lubricants, flavorants, sweeteners, preservatives, dyes,
and coatings. Compositions suitable for oral administration include
solid forms, such as pills, tablets, caplets, capsules (each
including immediate release, timed release and sustained release
formulations), granules, and powders, and liquid forms, such as
solutions, syrups, elixers, emulsions, and suspensions. Forms
useful for parenteral administration include sterile solutions,
emulsions and suspensions.
[0180] Advantageously, compounds of the present invention may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three or four times daily.
Furthermore, compounds for the present invention can be
administered in intranasal form via topical use of suitable
intranasal vehicles, or via transdermal skin patches well known to
those of ordinary skill in that art. To be administered in the form
of a transdermal delivery system, the dosage administration will,
of course, be continuous rather than intermittent throughout the
dosage regimen.
[0181] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. Moreover, when desired or
necessary, suitable binders, lubricants, disintegrating agents and
coloring agents can also be incorporated into the mixture. Suitable
binders include, without limitation, starch, gelatin, natural
sugars such as glucose or beta-lactose, corn sweeteners, natural
and synthetic gums such as acacia, tragacanth or sodium oleate,
sodium stearate, magnesium stearate, sodium benzoate, sodium
acetate, sodium chloride and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite,
xanthan gum and the like.
[0182] The liquid forms may include suitably flavored suspending or
dispersing agents such as the synthetic and natural gums, for
example, tragacanth, acacia, methyl-cellulose and the like. For
parenteral administration, sterile suspensions and solutions are
desired. Isotonic preparations which generally contain suitable
preservatives are employed when intravenous administration is
desired.
[0183] The compound of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles, and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phophatidylcholines.
[0184] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamidephenol,
polyhydroxyethylaspartamidephenol, or polyethyl-eneoxidepolylysine
substituted with palmitoyl residue. Furthermore, the compounds of
the present invention may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyepsilon caprolactone, polyhydroxy
butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and cross-linked or amphipathic block copolymers
of hydrogels.
[0185] Compounds of this invention may be administered in any of
the foregoing compositions and according to dosage regimens
established in the art whenever treatment of a disorder mediated by
an estrogen receptor is required.
[0186] The daily dosage of the products may be varied over a wide
range from 5 to 1,000 mg per adult human per day. For oral
administration, the compositions are preferably provided in the
form of tablets containing, 1.0, 5.0, 10.0, 15.0, 25.0, 50.0, 100,
250 and 500 milligrams of the active ingredient for the symptomatic
adjustment of the dosage to the patient to be treated. An effective
amount of the drug is ordinarily supplied at a dosage level of from
about 0.01 mg/kg to about 20 mg/kg of body weight per day.
Preferably, the range is from about 0.1 mg/kg to about 10 mg/kg of
body weight per day, and especially from about 0.5 mg/kg to about
10 mg/kg of body weight per day. The compounds may be administered
on a regimen of 1 to 4 times per day.
[0187] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation, the mode of administration, and the advancement of the
disease condition. In addition, factors associated with the
particular patient being treated, including patient age, weight,
diet and time of administration, will result in the need to adjust
dosages.
[0188] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds which are readily
convertible in vivo into the required compound. Thus, in the
methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
disorders described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0189] The following Examples are set forth to aid in the
understanding of the invention, and are not intended and should not
be construed to limit in any way the invention set forth in the
claims which follow thereafter.
EXAMPLE 1
1-[2-Hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone
##STR00022##
[0191] To a solution of 1-(2,4-dihydroxy-phenyl)-ethanone (10.91 g,
71.7 mmoL) in acetone (200 mL) at room temperature was added
K.sub.2CO.sub.3 (9.9 g, 71.7 mmoL) followed by SEMCl (12.7 mL, 71.7
mmoL). The result mixture was then slightly heated at 50.degree. C.
for 2 hours. The solid was removed by filtration. The filtrate was
concentrated to give the crude product, which was then purified by
silica gel chromatography using 4:1 hexanes:ethyl acetate as eluent
to afford the title product as white solid.
[0192] .sup.1H NMR (CDCl.sub.3, .delta.) 12.60 (s, 1H), 7.62 (d,
J=8.5 Hz, 1H), 6.62 (s, 1H), 6.55 (d, J=8.5 Hz, 1H), 5.24 (s, 2H),
3.75 (t, J=11.5 Hz, 2H), 2.58 (s, 3H), 0.95 (t, J=11.5 Hz, 2H),
0.02 (s, 9H). MS, MH.sup.+, 282.
EXAMPLE 2
5-Bromo-2,4-bis-(2-trimethylsilanyl-ethoxymethoxy)-pyrimidine
##STR00023##
[0194] To a solution of 5-bromo-1H-pyrimidine-2,4-dione (5.6 g,
29.3 mmoL) in CH.sub.2Cl.sub.2 (20 mL) at room temperature was
added Et.sub.3N (4.2 mL, 29.9 mmoL) followed by SEMCl (4.87 mL,
29.9 mmoL). The result reaction mixture was stirred for 4 hours.
Solvent was removed to afford a colorless oil, which was then
purified by column chromatography using hexanes:ethyl acetate (4:1
ratio) as eluent to afford the title compound as a slight yellow
oil.
[0195] .sup.1H NMR (CDCl.sub.3, .delta.) 7.65 (s, 1H), 7.25 (s,
1H), 5.46 (s, 2H), 5.15 (s, 2H), 3.70 (t, J=9.5 Hz, 2H), 3.62 (t,
J=9.5 Hz, 2H), 0.95 (t, J=9.5 Hz, 4H), 0.03 (s, 9H), 0.02 (s,
9H).
EXAMPLE 3
2-(6-Methoxy-pyridin-3-yl)-malonic acid diethyl ester
##STR00024##
[0197] Sodium hydride (60%, 36.2 mmoL, 1.45 g) was added into a
solution of 5-bromo-2-methoxy-pyridine (16.5 mmoL, 2.13 mL),
copper(I) bromide (32.9 mmoL, 4.72 g) and diethyl malonate (32.9
mmoL, 5.0 mL) in 1,4-dioxlane (20 mL) slowly at room temperature.
After the addition, the resulting mixture was heated to 100.degree.
C. and stirred overnight. The mixture was then passed through a pad
of Celite to remove brown solid. The filtrate was then concentrated
in vacuo to afford a brown oil, which was then purified by column
chromatography using hexanes:ethyl acetate (4:1.about.2:1 ratio) as
eluent to afford the title compound as a slight yellow oil.
[0198] .sup.1H NMR (CDCl.sub.3, .delta.) 8.10 (s, 1H), 7.74 (d,
J=8.5 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H), 4.55 (s, 1H), 4.25 (m, 4H),
3.95 (s, 3H), 1.25 (m 6H). MS, MH.sup.+, 268.
EXAMPLE 4
2-(2,4-Dimethoxy-pyrimidin-5-yl)-malonic acid diethyl ester
##STR00025##
[0200] The title product was prepared as a yellow oil according to
the procedure described in Example 3 using
5-Iodo-2,4-dimethoxy-pyrimidine as the starting material.
[0201] .sup.1H NMR (CDCl.sub.3, .delta.) 8.28 (s, 1H), 4.32 (m,
4H), 4.05 (s, 3H), 4.01 (s, 3H), 1.35 (m, 6H), MS, MH.sup.+,
298.
EXAMPLE 5
2-[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-pyrimidin-5-yl]-malonic
acid diethyl ester
##STR00026##
[0203] The title product was prepared as a yellow oil according to
the procedure described in Example 3 using
5-bromo-2,4-bis-(2-trimethylsilanyl-ethoxymethoxy)-pyrimidine as
the starting material.
[0204] .sup.1H NMR (CDCl.sub.3, .delta.) 7.30 (s, 1H), 7.25 (s,
1H), 5.40 (s, 2H), 5.18 (s, 2H), 4.68 (s, 1H), 4.25 (m, 4H), 3.65
(m, 4H), 1.75 (m, 6H), 1.05 (m, 4H), 0.03 (s, 9H), 0.02 (s, 9H).
MS, MH.sup.+, 531.
EXAMPLE 6
(6-Methoxy-pyridin-3-yl)-acetic acid
##STR00027##
[0206] 2-(6-Methoxy-pyridin-3-yl)-malonic acid diethyl ester (5.6
g, 21.0 mmoL) prepared in Example 3 was dissolved in 2N
NaOH/THF:H.sub.2O (1:1) (20 mL). The resulting mixture was heated
to reflux for 3 hours. The reaction mixture was then adjusted to
pH=1 by concentrated HCl and stirred at room temperature for
another 1 hour. The solution was then adjusted to pH=13 by 1N NaOH
and extracted with ether. The aqueous phase was acidified to pH=5
by 1N HCl and extracted 3.times. by ethyl acetate. The combined
organic phase was then washed with brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered and concentrated to give the title
compound a white solid (2.45, 70%).
[0207] .sup.1H NMR (CDCl.sub.3, .delta.) 12.5 (br, 1H), 7.91 (s,
1H), 7.46 (d, J=8.1 Hz, 1H), 6.62 (d, J=8.1 Hz, 1H), 3.83 (s, 3H),
3.42 (s, 2H).
EXAMPLE 7
(2,4-Dimethoxy-pyrimidin-5-yl)-acetic acid
##STR00028##
[0209] The title product was prepared as a white solid according to
the procedure described in Example 6 using
2-(2,4-dimethoxy-pyrimidin-5-yl)-malonic acid diethyl ester as the
starting material.
[0210] .sup.1H NMR (CDCl.sub.3, .delta.) 10.3 (s, br, 1H), 8.15 (s,
1H), 4.05 (s, 6H), 3.48 (s, 2H),
EXAMPLE 8
[2,4-Bis-(2-trimethylsilanyl-ethoxymethoxy)-pyrimidin-5-yl]-acetic
acid
##STR00029##
[0212] The title product was prepared as a white solid according to
the procedure described in Example 6 using
2-[2,4-bis-(2-trimethylsilanyl-ethoxymethoxy)-pyrimidin-5-yl]-malonic
acid diethyl ester as the starting material.
[0213] .sup.1H NMR (CDCl.sub.3, .delta.) 9.48 (br, s, 1H), 7.45 (s,
1H), 5.45 (s, 2H), 5.18 (s, 2H), 3.98 (m, 2H), 3.65 (m, 4H), 0.98
(t, J=11.5 Hz, 4H), 0.03 (s, 9H), 0.02 (s, 9H).
EXAMPLE 9
7-Methoxy-4-methyl-3-pyridin-4-yl-chromen-2-one
##STR00030##
[0215] To a solution of 1-(2-hydroxy-4-methoxy-phenyl)-ethanone
(2.1 g, 12.0 mmoL) and .quadrature.yridine-4-yl-acetic acid HCl
salt (2.0 g, 12.0 mmoL) in CH.sub.2Cl.sub.2 (20 mL) was added
triethyl amine (3.4 mL, 24 mmoL), DMAP (180 mg, 1.2 mmoL) and DCC
(3.71 g, 8 mmoL) at room temperature. The mixture was stirred
overnight and then heated to reflux for another 2 hours. The
resulting solution was concentrated in vacuo and dissolved in
.about.100 mL ether. The solid was removed by filtration. The
filtrate was then concentrated to give the crude material, which
was then purified by silica gel chromatography using hexanes ethyl
acetate (3:1 to 1:1) as eluent to give the title product as a white
solid (1.85 g, 58%).
[0216] .sup.1H NMR (CDCl.sub.3, .delta.) 8.75 (s, 1H), 7.58 (d,
J=6.8 Hz, 1H), 7.25 (d, J=4.32, 2H), 6.90 (d, J=6.8 Hz, 1H), 6.82
(s, 1H), 3.91 (s, 3H), 2.30 (s, 3H), MS, MH.sup.+, 267.
EXAMPLE 10
4,7-Dimethyl-3-pyridin-4-yl-chromen-2-one
##STR00031##
[0218] The title product was prepared as a white solid according to
the procedure described in Example 9 using
1-(2-hydroxy-4-methyl-phenyl)-ethanone and
.quadrature.yridine-4-yl-acetic acid HCl salt as the starting
material.
[0219] .sup.1H NMR (CDCl.sub.3, .delta.) 8.72 (d, J=6.1 Hz, 2H),
7.52 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.23 (d, J=8.5 Hz, 1H), 7.20
(d, J=6.1 Hz, 2H), 2.55 (s, 3H), 2.34 (s, 3H). MS, MH.sup.+, 252,
MNa.sup.+, 274.
EXAMPLE 11
7-Methoxy-4-methyl-3-(1-oxy-pyridin-4-yl)-chromen-2-one
##STR00032##
[0221] To a solution of in CH.sub.2Cl.sub.2 was added mCPBA at
0.degree. C. The reaction was slowly warmed to room temperature and
washed with sat. Na.sub.2S.sub.2O.sub.3. The aqueous layer was
extracted 3.times. with CH.sub.2Cl.sub.2. The combined organic
phase was washed with sat. NaHCO.sub.3, brine, dried over anhydrous
Na.sub.2SO.sub.4, filtered, concentrated to give the crude
material, which was then purified by silica gel column
chromatography using hexanes:ethyl acetate (1:1 to pure ethyl
acetate) to afford the title product as a white solid.
[0222] .sup.1H NMR (CDCl.sub.3, .delta.) 8.28 (d, J=7.5 Hz, 2H),
7.58 (d, J=7.0 Hz, 1H), 7.26 (d, J=7.5 Hz, 2H), 6.92 (d, J=7.0 Hz,
1H), 6.84 (s, 1H), 3.98 (s, 3H), 2.35 (s, 3H). MS, MH.sup.+, 284,
MNa.sup.+, 306.
EXAMPLE 12
7-Hydroxy-4-methyl-3-pyridin-4-yl-chromen-2-one
##STR00033##
[0224] To a solution of
7-methoxy-4-methyl-3-pyridin-4-yl-chromen-2-one (600 mg, 2.24 mmoL)
in CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C. was added EtSH
(.about.1 mL) followed by AlBr.sub.3 (6.74 mmoL, 1.80 g). The
mixture was slowly warm to room temperature and poured into ice
sat. NaHCO.sub.3 solution. Extraction was conducted 3.times. with
CH.sub.2Cl.sub.2. The combined organic layer was washed with brine,
dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated to
give the crude material, which was then purified by silica gel
column chromatography using hexanes:ethyl acetate 1:1 as eluent to
afford the title product as pale yellow solid.
[0225] .sup.1H NMR (MeOD, .delta.) 8.61 (s, br, 1H), 7.72 (d, J=7.5
Hz, 2H), 7.45 (d, J=7.45 Hz, 2H), 7.35 (d, J=5.5 Hz, 1H), 6.86 (d,
J=5.5 Hz, 1H), 6.72 (s, 1H), 2.30 (s, 3H). MS, MH.sup.+, 254.
EXAMPLE 13
7-(tert-Butyl-dimethyl-silanyloxy)-4-methyl-3-pyridin-4-yl-chromen-2-one
##STR00034##
[0227] To a solution of
7-hydroxy-4-methyl-3-pyridin-4-yl-chromen-2-one (310 mg, 1.23 mmoL)
in DMF (5 mL) was added imidazole (84 mg, 1.23 mmoL) followed by
TBDMSCl (185 mg, 1.23 mmoL) at room temperature. The mixture was
stirred for 2 hours and partitioned between ethyl acetate and
water. The aqueous layer was extracted 2.times. with ethyl acetate.
The combined organic layer was washed with brine, dried over
anhydrous Na.sub.2SO.sub.4, filtered and concentrated to give the
crude material, which was then purified by silica gel column
chromatography using hexanes:ethyl acetate 1:1 as eluent to afford
the title product as pale yellow solid.
[0228] .sup.1H NMR (CDCl.sub.3, .delta.) 8.68 (d, J=5.8 Hz, 2H),
7.55 (d, J=8.5 Hz, 1H), 7.24 (d, J=5.8 Hz, 2H), 6.85 (d, J=8.5 Hz,
1H), 6.81 (s, 1H), 2.23 (s, 3H), 1.05 (s, 9H), 0.28 (s, 6H). MS,
MH.sup.+, 382.
EXAMPLE 14
7-Methoxy-4-methyl-3-pyridin-3-yl-chromen-2-one
##STR00035##
[0230] The title product was prepared as a white solid according to
the procedure described in Example 9 using
1-(2-hydroxy-4-methoxy-phenyl)-ethanone and
.quadrature.yridine-3-yl-acetic acid HCl as the starting
material.
[0231] .sup.1H NMR (CDCl.sub.3, .delta.) 8.65 (s, 1H), 8.60 (d,
J=6.5 Hz, 1H), 7.62.about.7.49 (m, 3H), 7.02 (d, J=7.5 Hz, 1H),
6.15 (s, 1H), 3.88 (s, 3H), 2.48 (s, 3H), MS, MH.sup.+, 267.
EXAMPLE 15
7-Methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-chromen-2-one
##STR00036##
[0233] The title product was prepared as a white solid according to
the procedure described in Example 9 using
1-(2-hydroxy-4-methoxy-phenyl)-ethanone and
(6-methoxy-pyridin-3-yl)-acetic acid as the starting material.
[0234] .sup.1H NMR (CDCl.sub.3, .delta.) 8.10 (s, 1H), 7.62 (d,
J=7.5 Hz, 1H), 7.60 (d, J=7.5 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H), 6.85
(d, J=9.2 Hz, 1H), 6.82 (s, 1H), 4.01 (s, 3H), 3.95 (s, 3H), 2.32
(s, 3H).
EXAMPLE 16
3-(6-Hydroxy-pyridin-3-yl)-7-methoxy-4-methyl-chromen-2-one
##STR00037##
[0236] To a solution of
7-methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-chromen-2-one in
CH.sub.2Cl.sub.2 (5 mL) at room temperature was added BBr.sub.3
(1.0 N, 24.2 mmoL, 24 mL) dropwise. After addition, the reaction
was slightly heated to reflux 4 hours. The reaction was quenched
with ice sat. NaHCO.sub.3, extracted with 3.times.CH.sub.2Cl.sub.2,
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to give the crude material. The crude material was
re-crystallized in 2:1 hexanes:ethyl acetate to afford the title
product as a pale reddish solid.
[0237] .sup.1H NMR (CDCl.sub.3, .delta.) 7.57 (d, J=7.5 Hz, 1H),
7.42 (d, J=6.5 Hz, 1H), 7.25 (s, 1H), 6.86 (d, J=6.5 Hz, 1H), 6.80
(s, 1H), 6.62 (d, J=7.5 Hz, 1H), 3.82 (s, 3H), 1.98 (s, 3H), MS,
MH.sup.+, 284.
EXAMPLE 17
3-[6-(tert-Butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-chr-
omen-2-one
##STR00038##
[0239] To a solution of
3-(6-hydroxy-pyridin-3-yl)-7-methoxy-4-methyl-chromen-2-one_in DMF
(5 mL) at room temperature was added imidazole (174 mg, 2.56 mmoL)
followed by TBDMSCl (384 mg, 2.56 mmoL). The reaction mixture was
stirred for 2 hours and then quenched by sat. NaHCO.sub.3. The
resulting suspension was extracted 3.times. with ethyl acetate,
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to give the crude material, which was then
purified by silica gel column chromatography using hexanes:ethyl
acetate 2:1 as eluent to afford the title product as pale yellow
solid.
[0240] .sup.1H NMR (CDCl.sub.3, .delta.) 8.08 (s, 1H), 7.61 (d,
J=6.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 6.82 (m, 4H), 3.98 (s, 3H),
2.35 (s, 3H), 1.05 (s, 9H), 0.36 (s, 6H).
EXAMPLE 18
3-(6-Methoxy-pyridin-3-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-c-
hromen-2-one
##STR00039##
[0242] The title product was prepared as a white solid according to
the procedure described in Example 9 using
1-[2-hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone
and (6-methoxy-pyridin-3-yl)-acetic acid as the starting
material.
[0243] .sup.1H NMR (CDCl.sub.3, .delta.) 8.08 (s, 1H), 7.58 (m,
2H), 7.05 (m, 2H), 6.82 (d, J=6.5 Hz, 1H), 5.28 (s, 2H), 3.98 (s,
3H), 3.76 (t, J=6.5 Hz, 2H), 2.40 (s, 3H), 0.93 (t, J=6.5 Hz, 2H),
0.00 (s, 9H).
EXAMPLE 19
3-(2,4-Dimethoxy-pyrimidin-5-yl)-7-methoxy-4-methyl-chromen-2-one
##STR00040##
[0245] The title product was prepared as a white solid according to
the procedure described in Example 9 using
1-(2-hydroxy-4-methoxy-phenyl)-ethanone and
(2,4-dimethoxy-pyrimidin-5-yl)-acetic acid as the starting
material.
[0246] .sup.1H NMR (CDCl.sub.3, .delta.) 8.15 (s, 1H), 7.62 (d,
J=7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.88 (s, 1H), 4.05 (s, 3H),
4.00 (s, 3H), 3.91 (s, 3H), 2.25 (s, 3H). MS, MH.sup.+, 329,
MNa.sup.+, 351, [2M+Na].sup.+, 679.
EXAMPLE 20
3-(2,4-Dimethoxy-pyrimidin-5-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymeth-
oxy)-chromen-2-one
##STR00041##
[0248] The title product was prepared as a white solid according to
the procedure described in Example 9 using
1-[2-hydroxy-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-ethanone
and (2,4-dimethoxy-pyrimidin-5-yl)-acetic acid as the starting
material.
[0249] .sup.1H NMR (CDCl.sub.3, .delta.) 8.15 (s, 1H), 7.54 (d,
J=10.1 Hz, 1H), 7.05 (s, 1H), 7.00 (d, J=10.1 Hz, 1H), 5.28 (s,
2H), 4.08 (s, 3H), 4.01 (s, 3H), 3.75 (t, J=11.5 Hz, 2H), 2.25 (s,
3H), 0.98 (t, J=11.5 Hz, 2H), 0.02 (s, 9H).
EXAMPLE 21
4-Bromomethyl-3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-chromen-2-one
##STR00042##
[0251] To a solution of
3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-4-methyl-chromen-2-one
(210 mg, 0.64 mmoL) in anhydrous THF (5 mL) at -78.degree. C. was
added LiHMDS (1.0 M, 1.28 mmoL, 1.28 mL) dropwise. The resulting
reddish solution was stirred at -78.degree. C. for 20 min. To this
solution was added NBS (114 mg, 0.64 mmoL) in THF (2 mL) slowly.
The reaction was stirred for 2 hours at -78.degree. C. and then
quenched with sat. NaHCO.sub.3, warmed to room temperature. THF was
removed in vacuo and the residue was partitioned between
CH.sub.2Cl.sub.2 and water. The aqueous phase was extracted
3.times. with CH.sub.2Cl.sub.2. The combined organic layer was
washed with brine, dried over anhydrous Na.sub.2SO.sub.4, filtered
and concentrated to afford a yellow solid, which was then purified
by silica gel column chromatography using hexanes:ethyl acetate
(4:1 to 2:1) to afford the title product as a white solid.
[0252] .sup.1H NMR (CDCl.sub.3, .delta.) 8.28 (s, 1H), 7.68 (d,
J=7.5 Hz, 1H), 6.95 (dd, J=7.5, 1.5 Hz, 1H), 6.85 (d, J=1.5 Hz,
1H), 4.35 (abq, J=12.5 Hz, 2H), 4.08 (s, 3H), 4.00 (s, 3H), 3.95
(s, 3H).
EXAMPLE 22
2,8-Dihydroxy-11H-6,12-dioxa-1,3-diaza-chrysen-5-one
##STR00043##
[0254] To a solution of
4-bromomethyl-3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-chromen-2-one
(200 mg, 0.492 mmoL) in ClCH.sub.2CH.sub.2Cl (5 mL) at room
temperature was added BBr.sub.3 (1.0 N, 2.50 mmoL, 2.5 mL). The
result reaction mixture was stirred at room temperature for 30 min
and then heated to reflux overnight. The reaction was cooled down
and the solvent was removed in vacuo. The residue was dissolved in
10% K.sub.2CO.sub.3 in MeOH:acetone (.about.1:1, 10 mL) at
0.degree. C., stirring was kept for another 2 hours. The solvent
was evaporated to dryness, the residue was dissolved in water (15
mL) and then acidified with dilute hydrochloric acid to about pH 4.
The precipitated brown solid was isolated by filtration, washed
with water and dried to yield the title compound.
[0255] .sup.1H NMR (d.sub.6-DMSO, .delta.) 11.6 (s, 1H), 8.68 (s,
1H), 7.58 (d, J=8.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 6.80 (s, 1H),
5.74 (s, 2H).
EXAMPLE 23
7-Methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-2H-chromen-2-ol
##STR00044##
[0257] A solution of
7-methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-chromen-2-one (430
mg, 1.45 mmol, 1 eq) in toluene (5 mL) was cooled to -78.degree. C.
in a 100 mL 3-neck round bottom flask under nitrogen. To the
reaction mixture was slowly added a toluene solution of
diisobutylaluminum hydride (1.5 mL of 1.0 M, mmol, 1.1 eq), with
the temperature of the reaction mixture maintained at less than
-70.degree. C. The reaction was stirred for 1 hour, quenched with
addition of methanol (0.5 mL). The resulting solution was diluted
with dichloromethane, the solution washed with a saturated solution
of Rochelle salt, then washed with brine, dried on anhydrous sodium
sulphate, filtered and evaporated to yield the crude compound as a
yellow solid. The solid was purified by column chromatography using
a hexane:ethyl acetate mixture (1:1) to yield the title product as
a yellow solid.
[0258] .sup.1H NMR (CDCl.sub.3, .delta.) 8.18 (s, 1H), 7.60 (d,
J=7.2 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.62
(m, 1H), 6.58 (s, 1H), 5.86 (d, J=6.5 Hz, 1H), 4.05 (d, J=6.5 Hz,
1H), 4.01 (s, 3H), 3.82 (s, 3H), 2.10 (s, 3H). MS, MH.sup.+, 282,
MNa.sup.+, 314.
EXAMPLE 24
3-[6-(tert-Butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-2H--
chromen-2-ol
##STR00045##
[0260] The title product was prepared as a yellow solid according
to the procedure described in Example 23 using
3-[6-(tert-butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-ch-
romen-2-one as the starting material.
[0261] MS, MH+, 400.
EXAMPLE 25
3-(6-Methoxy-pyridin-3-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-2-
H-chromen-2-ol
##STR00046##
[0263] The title product was prepared as a yellow solid according
to the procedure described in Example 23 using
3-(6-methoxy-pyridin-3-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)--
chromen-2-one as the starting material.
[0264] .sup.1H NMR (CDCl.sub.3, .delta.) 8.18 (s, 1H), 7.60 (m,
1H), 7.29 (d, J=6.0 Hz, 1H), 6.75 (m, 3H), 5.87 (d, J=5.8 Hz, 1H),
5.20 (s, 2H), 3.95 (s, 3H), 3.71 (t, J=6.5 Hz, 2H), 2.10 (s, 3H),
0.93 (t, J=6.5 Hz, 2H), 0.00 (s, 9H).
EXAMPLE 26
7-Methoxy-4-methyl-3-pyridin-4-yl-2H-chromen-2-ol
##STR00047##
[0266] The title product was prepared as a yellow solid according
to the procedure described in Example 23 using
7-methoxy-4-methyl-3-pyridin-4-yl-chromen-2-one as the starting
material.
[0267] .sup.1H NMR (CDCl.sub.3, .delta.) 8.52 (d, J=5.5 Hz, 2H),
7.33 (d, J=5.5 Hz, 2H), 7.30 (d, J=7.0 Hz, 1H), 6.62 (m, 2H), 5.98
(s, 1H), 5.92 (br, s, 1H), 3.85 (s, 3H), 2.18 (s, 3H). MS,
MH.sup.+, 270.
EXAMPLE 27
7-(tert-Butyl-dimethyl-silanyl)-4-methyl-3-pyridin-4-yl-2H-chromen-2-ol
##STR00048##
[0269] The title product was prepared as a yellow solid according
to the procedure described in Example 23 using
7-(tert-butyl-dimethyl-silanyloxy)-4-methyl-3-pyridin-4-yl-chromen-2-one
as the starting material.
[0270] .sup.1H NMR (CDCl.sub.3, .delta.) 8.48 (d, J=6.5 Hz, 2H),
7.33 (d, J=6.5 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 6.55 (m, 2H), 5.75
(s, 1H), 5.65 (br, s, 1H), 2.04 (s, 3H) 1.05 (s, 9H), 0.28 (s, 6H).
MS, MH.sup.+, 354.
EXAMPLE 28
3-(2,4-Dimethoxy-pyrimidin-5-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymeth-
oxy)-2H-chromen-2-ol
##STR00049##
[0272] The title product was prepared as a yellow solid according
to the procedure described in Example 23 using
3-(2,4-dimethoxy-pyrimidin-5-yl)-7-methoxy-4-methyl-chromen-2-one
as the starting material.
[0273] .sup.1H NMR (CDCl.sub.3, .delta.) 8.15 (s, 1H), 7.28 (d,
J=8.5 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.72 (d, J=6.0 Hz, 1H), 5.88
(d, J=9.5 Hz, 1H), 5.20 (s, 2H), 4.02 (s, 3H), 4.00 (s, 3H), 3.71
(t, J=9.5 Hz, 1H), 1.98 (s, 3H), 0.95 (t, J=9.5 Hz, 2H), 0.02 (s,
9H).
EXAMPLE 29
2-(tert-Butyl-dimethyl-silanyloxy)-5-{2-[4-(2-chloro-ethoxy)-phenyl]-7-met-
hoxy-4-methyl-2H-chromen-3-yl}-pyridine
##STR00050##
[0275] In a single neck, 100 mL round bottom flask was dissolved
and stirred 1-(2-chloro-ethoxy)-4-iodo-benzene (530 mg, 1.88 mmol,
5.0 eq), in tetrahydrofuran (5 mL) under nitrogen, and the mixture
cooled to -78.degree. C. After 5 minutes of stirring, a hexane
solution of n-BuLi (0.75 mL of 2.5 M, 1.88 mmol, 5.0 eq) was added
via syringe. The reaction mixture was then stirred for 30 min at
about -78.degree. C. A tetrahydrofuran solution of
3-[6-(tert-butyl-dimethyl-silanyloxy)-pyridin-3-yl]-7-methoxy-4-methyl-2H-
-chromen-2-ol (150 mg, 0.376 mmol, 1 eq, in 2 mL), prepared as in
Example 24, was then added, the cooling bath was removed and the
reaction mixture was allowed to warm to room temperature overnight.
After about 18 hours, the reaction was worked-up with addition of
saturated ammonium acetate solution and extraction with ethyl
ether. The combined organic extracts were washed with brine and
water, dried with anhydrous sodium sulphate, filtered and
evaporated to yield a sticky semisolid residue. To this solid was
added 0.2 mL HCl in 10 mL toluene at room temperature. The mixture
was stirred for 2 hours at room temperature. The reaction was
worked-up with sodium bicarbonate washing and extraction with ethyl
acetate three times. The combined organic extracts were washed with
brine and water, dried with anhydrous sodium sulphate, filtered and
evaporated to yield a brown oil. The title product was isolated as
a white semisolid foam via chromatography on silica gel eluted with
1:1 hexanes:ethyl acetate as eluent.
[0276] .sup.1H NMR (CDCl.sub.3, .delta.) 7.75 (s, 1H), 7.15 (d,
J=6.5 Hz, 1H), 7.10 (d, J=8.5 Hz, 2H), 7.01 (d, J=6.5 Hz, 1H), 6.60
(d, J=8.5 Hz, 2H), 6.55 (d, J=6.5 Hz, 1H), 6.25 (d, J=7.1 Hz, 1H),
6.11 (s, 1H), 5.61 (s, 1H), 4.02 (t, J=9.5 Hz, 2H), 3.78 (s, 3H),
3.55 (t, J=9.5 Hz, 2H), 1.95 (s, 3H), 0.78 (s, 3H), 0.02 (s, 6H).
MS, MH.sup.+, 424.
EXAMPLE 30
5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymet-
hoxy)-2H-chromen-3-yl]-2-methoxy-pyridine
##STR00051##
[0278] The title product was prepared as a white solid according to
the procedure described in Example 29 using
3-(6-methoxy-pyridin-3-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)--
2H-chromen-2-ol as the starting material.
[0279] .sup.1H NMR (CDCl.sub.3, .delta.) 8.00 (s, 1H), 7.35-7.15
(m, 6H), 6.80 (d, J=6.5 Hz, 2H), 6.70 (m, 2H), 6.50 (s, 1H), 5.70
(s, 1H), 5.18 (s, 2H), 4.15 (t, J=4.5 Hz, 2H), 3.90 (s, 3H), 3.75
(t, J=6.5 Hz, 2H), 2.10 (s, 3H), 1.25 (t, J=4.5 Hz, 2H), 0.95 (t,
J=6.5 Hz, 2H), 0.00 (s, 9H).
EXAMPLE 31
5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymet-
hoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine
##STR00052##
[0281] The title product was prepared as a white solid according to
the procedure described in Example 29 using
3-(2,4-dimethoxy-pyrimidin-5-yl)-4-methyl-7-(2-trimethylsilanyl-ethoxymet-
hoxy)-2H-chromen-2-ol as the starting material
[0282] .sup.1H NMR (CDCl.sub.3, .delta.) 7.82 (s, 1H), 7.27 (d,
J=6.5 Hz, 1H), 7.22 (d, J=9.5 Hz, 2H), 6.82 (d, J=9.5 Hz, 2H), 6.62
(d, J=6.5 Hz, 1H), 6.48 (s, 1H), 5.85 (s, 1H), 5.21 (s, 2H), 4.15
(t, J=8.5 Hz, 2H), 4.03 (s, 3H), 4.01 (s, 3H), 3.76 (t, J=10.5 Hz,
2H), 3.70 (t, J=10.5 Hz, 2H), 1.99 (s, 3H), 0.95 (t, J=8.5 Hz, 2H),
0.03 (s, 9H). MS, MH.sup.+, 586.
EXAMPLE 32
4-Methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-3-pyridin-4-yl-2H-chromen--
7-ol
##STR00053##
[0284] To a solution of 4-[2-(piperidin-1-yl)-ethoxy]-iodobenzene
(2.56 g, 7.73 mmol, 3 eq), in tetrahydrofuran (10 mL) under argon
at -78.degree. C. was added dropwise isopropylmagnesium bromide
(3.6 mL of 2.13 M, 7.73 mmol, 3 eq). The reaction mixture was then
stirred for 2 hours at about -78.degree. C. A tetrahydrofuran
solution of
7-(tert-butyl-dimethyl-silanyl)-4-methyl-3-pyridin-4-yl-2H-chromen-2-ol
(950 mg, 2.58 mmol, 1 eq, in 5 mL), prepared as in Example 27, was
then added, the cooling bath was removed and the reaction mixture
was allowed to warm to room temperature overnight. After about 18
hours, the reaction was worked-up with addition of saturated
ammonium acetate solution (15 mL) and extraction with ethyl ether
(2.times.). The combined organic extracts were washed with brine
and water, dried with anhydrous sodium sulphate, filtered and
evaporated to yield a sticky semisolid residue. To this solid in
THF at room temperature was added 0.5 mL HCl in MeOH. The mixture
was stirred for 30 min and quenched with sat. NaHCO.sub.3,
partitioned between CH.sub.2Cl.sub.2 and water. The aqueous layer
was extracted 3.times. with CH.sub.2Cl.sub.2. The combined organic
phase was washed with brine, dried over anhydrous Na.sub.2SO.sub.4,
filtered and concentrated to afford the crude material. The title
product was isolated as a viscous, colorless, semisolid foam via
chromatography on silica gel eluted with 3%
methanol/dichloromethane.
[0285] .sup.1H NMR (CDCl.sub.3, .delta.) 7.45 (d, J=6.4 Hz, 1H),
7.25 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.0 Hz, 2H), 6.81 (d, J=8.0 Hz,
2H), 6.62 (d, J=8.5 Hz, 2H), 6.40 (d, J=6.4 Hz, 1H), 6.25 (s, 1H),
5.78 (s, 1H), 4.05 (t, =9.5 Hz, 2H), 2.73 (t, J=9.5 Hz, 2H), 2.55
(m, 4H), 2.08 (s, 3H), 1.55.about.1.45 (m, 6H). MS, MH.sup.+,
443.
EXAMPLE 33
2-Methoxy-5-[(7-methoxy-4-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-2H-
-chromen-3-yl]-pyridine
##STR00054##
[0287] The title product was prepared as a pale yellow solid
according to the procedure described in Example 32 using
7-Methoxy-3-(6-methoxy-pyridin-3-yl)-4-methyl-2H-chromen-2-ol as
the starting material.
[0288] .sup.1H NMR (CDCl.sub.3, .delta.) 7.98 (s, 1H), 7.55 (d,
J=5.5 Hz, 1H), 7.32 (d, J=5.5 Hz, 1H), 7.20 d, J=8.5 Hz, 2H), 7.05
(d, J=5.5 Hz, 1H), 6.70 (d, J=8.5 Hz, 2H), 6.58 (d, J=6.5 Hz, 1H),
6.32 (s, 1H), 5.78 (s, 1H), 4.10 (t, J=10.5 Hz, 2H), 3.95 (s, 3H),
3.78 (s, 3H), 2.75 (t, J=10.5 Hz, 2H), 2.55 (m, 4H), 2.10 (s, 3H),
1.75 (m, 6H). MS, MH+, 487, MNa+, 509.
EXAMPLE 34
5-{7-Methoxy-4-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-2H-chromen-3--
yl}-pyridin-2-ol
##STR00055##
[0290] To (80 mg, 0.15 mmoL, 1.0 eq) in DMF (2 mL) was added
catalytic amount of KI (15 mg, 0.09 mmoL, 0.6 eq) and piperidine
(30 mg, 0.30 mmoL, 2.0 eq). The reaction mixture was heated at
50.degree. C. for 2 hours. CH.sub.2Cl.sub.2 and water were added,
the organic layer was separated and the aqueous layer re-extracted
with dichloromethane. The combined organic extracts were washed
with brine, dried (anhydrous sodium sulphate), filtered and
evaporated in vacuo. The residue was purified by chromatography on
silica gel using 2% methanol/dichloromethane as an eluent to yield
the title product as a crystalline solid.
[0291] .sup.1H NMR (CDCl.sub.3, .delta.) 8.01 (s, 1H), 7.81 (d,
J=6.5 Hz, 1H), 7.42 (d, J=6.5 Hz, 1H), 7.30 (d, J=7.5 Hz, 1H), 7.20
(d, J=7.5 Hz, 2H), 6.68 (d, J=7.5 Hz, 2H), 6.42 (d, J=6.5 Hz, 1H),
6.25 (s, 1H), 5.72 (s, 1H), 4.23 (t, J=9.5 Hz, 2H), 3.98 (s, 3H),
3.68 (t, J=9.5 Hz, 2H), 2.70 (m, 4H), 2.15 (s, 3H), 1.68 (m 6H).
MS, MH.sup.+, 473, MNa.sup.+, 495.
EXAMPLE 35
3-(2,4-Dimethoxy-pyrimidin-5-yl)-4-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-p-
henyl]-2H-chromen-7-ol
##STR00056##
[0293] The title product was prepared as a white solid according to
the procedure described in Example 34 using
5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxyme-
thoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and piperidine as
the starting material.
[0294] .sup.1H NMR (CDCl.sub.3, .delta.) 7.82 (br, s, 1H), 7.24 (d,
J=8.2 Hz, 2H), 7.18 (d, J=8.0 z, 1H), 6.80 (d, J=8.2 Hz, 2H), 6.48
(d, J=8.0 Hz, 1H), 6.18 (s, 1H), 5.78 (s, 1H), 4.18 (t, J=9.5 Hz,
2H), 4.05 (s, 3H), 3.98 (s, 3H), 2.95 (t, J=9.5 Hz, 2H), 2.75 (m,
4H), 1.98 (s, 3H), 1.68 (m, 6H), MS, MH.sup.+, 504, MNa.sup.+,
526.
EXAMPLE 36
2-[4-(2-Diethylamino-ethoxy)-phenyl]-3-(2,4-dimethoxy-pyrimidin-5-yl)-4-me-
thyl-2H-chromen-7-ol
##STR00057##
[0296] The title product was prepared as a white solid according to
the procedure described in Example 34 using
5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxyme-
thoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and diethyl amine
as the starting material.
[0297] .sup.1H NMR (CDCl.sub.3, .delta.) 7.82 (s, 1H), 7.25 (d,
J=7.5 Hz, 2H), 7.15 (s, 1H), 6.72 (d, J=7.5 Hz, 2H), 6.52 (d, J=6.5
Hz, 1H), 6.48 (d, J=6.5 Hz, 1H), 6.28 (s, 1H), 5.75 (s, 1H), 4.05
(s, 3H), 4.01 (s, 3H), 4.08 (t, J=9.5 Hz, 2H), 2.95 (t, J=9.5 Hz,
2H), 2.60 (q, J=10.5 Hz, 4H), 1.95 (s, 3H), 1.15 (t, J=10.5 Hz,
6H). MS, MH.sup.+, 492, MNa.sup.+, 514.
EXAMPLE 37
3-(2,4-Dimethoxy-pyrimidin-5-yl)-4-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)--
phenyl]-2H-chromen-7-ol
##STR00058##
[0299] The title product was prepared as a white solid according to
the procedure described in Example 34 using
5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxyme-
thoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and pyrrolidine as
the starting material.
[0300] .sup.1H NMR (CDCl.sub.3, .delta.) 7.72 (s, 1H), 7.25 (d,
J=10.5 Hz, 2H), 7.18 (d, J=8.5 Hz, 1H), 6.85 (d, J=10.5 Hz, 2H),
6.38 (d, J=8.5 Hz, 1H), 6.12 (s, 1H), 5.78 (s, 1H), 4.25 (t, J=10.5
Hz, 2H), 4.01 (s, 3H), 3.95 (s, 3H), 3.51 (t, J=10.5 Hz, 2H), 3.30
(m, 4H), 2.10 (m, 4H), 1.96 (s, 3H). MS, MH.sup.+, 490, MNa.sup.+,
512.
EXAMPLE 38
3-(2,4-Dimethoxy-pyrimidin-5-yl)-4-methyl-2-[4-(2-morpholin-4-yl-ethoxy)-p-
henyl]-2H-chromen-7-ol
##STR00059##
[0302] The title product was prepared as a white solid according to
the procedure described in Example 34 using
5-[2-[4-(2-Chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxyme-
thoxy)-2H-chromen-3-yl]-2,4-dimethoxy-pyrimidine and morpholine as
the starting material.
[0303] .sup.1H NMR (CDCl.sub.3, .delta.) 7.80 (s, 1H), 7.23 (d,
J=6.5 Hz, 2H), 7.10 (s, 1H), 6.72.about.6.48 (m, 4H), 6.25 (s, 1H),
5.85 (s, 1H), 4.02 (s, 3H), 3.98 (s, 3H), 3.90 (t, J=8.5 Hz, 2H),
3.75 (d, J=9.5 Hz, 4H), 3.56 (t, J=9.5 Hz, 4H), 2.90 (t, J=8.5 Hz,
2H), 2.01 (s, 3H). MS, MH.sup.+, 506.
EXAMPLE 39
3-(6-Methoxy-pyridin-3-yl)-4-methyl-2-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-
-2H-chromen-7-ol
##STR00060##
[0305] The title product was prepared as a white solid according to
the procedure described in Example 34 using
5-[2-[4-(2-chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxyme-
thoxy)-2H-chromen-3-yl]-2-methoxy-pyridine and piperidine as the
starting material.
[0306] .sup.1H NMR (CDCl.sub.3, .delta.) 7.95 (s, 1H), 7.40 (m,
2H), 7.35-7.15 (m, 3H), 6.65 (m, 3H), 6.40 (m, 1H), 6.25 (s, 1H),
5.75 (s, 1H), 4.00 (t, J=2.1 Hz, 2H), 3.90 (s, 3H), 2.75 (m, 2H),
2.60 (m, 4H), 2.00 (s, 3H), 1.65 (m, 4H), 1.45 (m, 2H).
EXAMPLE 40
3-(6-Methoxy-pyridin-3-yl)-4-methyl-2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl-
]-2H-chromen-7-ol
##STR00061##
[0308] The title product was prepared as a white solid according to
the procedure described in Example 34 using
5-[2-[4-(2-chloro-ethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxyme-
thoxy)-2H-chromen-3-yl]-2-methoxy-pyridine and pyrrolidine as the
starting material.
[0309] .sup.1H NMR (CDCl.sub.3, .delta.) 7.90 (s, 1H), 7.30-7.10
(m, 5H), 6.65 (m, 3H), 6.30 (m, 1H), 6.20 (s, 1H), 5.70 (s, 1H),
4.00 (t, J=2.1 Hz, 2H), 3.90 (s, 3H), 2.90 (m, 2H), 2.60 (m, 4H),
2.00 (s, 3H), 1.75 (m, 4H).
[0310] Following the procedures described in the Schemes and
Examples above, representative compounds of the present invention
were prepared, as listed in Tables 1.
TABLE-US-00001 TABLE 1 ##STR00062## ID No ##STR00063## R.sup.4
R.sup.5 R.sup.1/R.sup.2 Calc. MW. 1 ##STR00064## 8-methoxy methyl
.dbd.O 267.28 2 ##STR00065## 8-methyl methyl .dbd.O 251.28 3
##STR00066## 8-methoxy methyl .dbd.O 283.28 4 ##STR00067##
8-hydroxy methyl .dbd.O 253.25 5 ##STR00068##
8-(t-butyl-dimethyl-silyloxy) methyl .dbd.O 367.51 6 ##STR00069##
8-methoxy methyl .dbd.O 267.28 7 ##STR00070## 8-methoxy methyl
.dbd.O 297.31 8 ##STR00071## 8-methoxy methyl .dbd.O 283.28 9
##STR00072## 8-methoxy methyl .dbd.O 397.54 10 ##STR00073## 8-SEM
methyl .dbd.O 413.54 11 ##STR00074## 8-methoxy methyl .dbd.O 328.32
12 ##STR00075## 8-SEM methyl .dbd.O 444.55 13 ##STR00076##
8-methoxy bromomethyl .dbd.O 407.22 14 ##STR00077## 8-hydroxy
##STR00078## .dbd.O 284.22 15 ##STR00079## 8-methoxy methyl H/OH
299.32 16 ##STR00080## 8-methoxy methyl H/OH 399.56 17 ##STR00081##
8-SEM methyl H/OH 415.55 18 ##STR00082## 8-methoxy methyl H/OH
269.30 19 ##STR00083## 8-(t-butyl-dimethylsilyloxy) methyl H/OH
369.53 20 ##STR00084## 8-SEM methyl H/OH 446.57 21 ##STR00085##
8-methoxy methyl ##STR00086## 538.15 22 ##STR00087## 8-SEM methyl
##STR00088## 554.15 23 ##STR00089## 8-SEM methyl ##STR00090##
585.16 24 ##STR00091## 8-hydroxy methyl ##STR00092## 442.55 25
##STR00093## 8-methoxy methyl ##STR00094## 486.60 26 ##STR00095##
8-methoxy methyl ##STR00096## 472.58 27 ##STR00097## 8-hydroxy
methyl ##STR00098## 503.59 28 ##STR00099## 8-hydroxy methyl
##STR00100## 491.58 29 ##STR00101## 8-hydroxy methyl ##STR00102##
489.56 30 ##STR00103## 8-hydroxy methyl ##STR00104## 505.56 31
##STR00105## 8-hydroxy methyl ##STR00106## 472.58 32 ##STR00107##
8-hydroxy methyl ##STR00108## 458.55
EXAMPLE 41
MCF-7 Cell Proliferation Assay
[0311] This assay was run according to the procedure described by
Welshons, et al., (Breast Cancer Res. Treat., 1987, 10(2), 169-75),
with minor modification.
[0312] Briefly, MCF-7 cells (from Dr. C. Jordan, Northwestern
University) were maintained in RPMI 1640 phenol red free medium
(Gibco) in 10% FBS (Hyclone), supplemented with bovine insulin and
non-essential amino acid (Sigma). The cells were initially treated
with 4-hydroxyltamoxifen (10.sup.-8 M) and let stand at 37.degree.
C. for 24 hours. Following this incubation with tamoxifen, the
cells were treated with compounds at various concentrations.
[0313] Compounds to be tested in the agonist mode were added to the
culture media at varying concentrations. Compounds to be treated in
the antagonist mode were prepared similarly, and 10 nM
17.beta.-estradiol was also added to the culture media. The cells
were incubated for 24 hours at 37.degree. C. Following this
incubation, 0.1 .quadrature.Ci of .sup.14C-thymidine (56 mCi/mmol,
Amersham) was added to the culture media and the cells were
incubated for an additional 24 hours at 37.degree. C. The cells
were then washed twice with Hank's buffered salt solution (HBSS)
(Gibco) and counted with a scintillation counter. The increase in
the .sup.14C-thymidine in the compound treated cells relative to
the vehicle control cells were reported as percent increase in cell
proliferation.
[0314] Representative compound of the present invention were tested
according to the procedure described above, with results as listed
in Table. 2.
TABLE-US-00002 TABLE 2 ID No Agonist (No.) (nM) Antagonist (No.)
(nM) 27 NA 843 28 NA 3640 29 NA 1264 30 NA >10000 31 NA 533 32
NA 662 NA INDICATES NO DETECTED ACTIVITY AT TEST CONCENTRATION.
EXAMPLE 42
Alkaline Phosphatase Assay in Human Endometrial Ishikawa Cells
[0315] This assay was run according to the procedure described by
Albert et al., Cancer Res, (9910), 50(11), 330-6-10, with minor
modification.
[0316] Ishikawa cells (from ATCC) were maintained in DMEM/F12 (1:1)
phenol red free medium (Gibco) supplemented with 10% calf serum
(Hyclone). 24 hours prior to testing, the medium was changed to
DMEM/F12 (1:1) phenol red free containing 2% calf serum.
[0317] Compounds to be tested in the agonist mode were added to the
culture media at varying concentrations. Compounds to be treated in
the antagonist mode were prepared similarly, and 10 nM
17.beta.-estradiol was also added to the culture media. The cells
were then incubated at 37.degree. C. for 3 days. On the fourth day,
the media was remove, 1 volume of 1.times. Dilution Buffer
(Clontech) was added to the well followed by addition of 1 volume
of Assay Buffer (Clontech). The cells were then incubated at room
temperature for 5 minutes. 1 volume of freshly prepared
Chemiluminescence Buffer (1 volume of chemiluminescent substrate
(CSPD) in 19 volume Chemiluminescent Enhancer with final
concentration of CSPD at 1.25 mM; Sigma Chemical Co.) was added.
The cells were incubated at room temperature for 10 minutes and
then quantified on a luminometer. The increase of chemiluminescence
over vehicle control was used to calculate the increase in alkaline
phosphatase activity.
[0318] Representative compound of the present invention were tested
according to the procedure described above, with results as listed
in Table 3.
TABLE-US-00003 TABLE 3 ID No Agonist (No.) (nM) Antagonist (No.)
(nM) 27 NA 488 28 NA >10000 29 NA 581 30 NA >10000 31 NA 38
32 NA 72.5 NA INDICATES NO DETECTED ACTIVITY AT TEST
CONCENTRATION;
EXAMPLE 43
[0319] As a specific embodiment of an oral composition, 100 mg of
the compound 11, prepared as in Example 11 is formulated with
sufficient finely divided lactose to provide a total amount of 580
to 590 mg to fill a size 0 hard gel capsule.
[0320] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *