Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02170479 2007-02-14
,~ .
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BBNZOTHIOPH$NE COMPOUNDS, INTERMEDIATES, COMPOSITIONS,
AND METHODS
This invention relates to the fields of
pharmaceutical and organic chemistry and provides novel
benzothiophene compounds which are useful for the treatment
of the various medical indications associated with post-
menopausal syndrome, and uterine fibroid disease,
endometriosis, and aortal smooth muscle cell proliferation.
The present invention further relates to intermediate
compounds useful for preparing the pharmaceutically active
compounds of the present invention, and pharmaceutical
compositions.
mPost-menopausal syndrome" is a term used to
describe various pathological conditions which frequently
affect women who have entered into or completed the
physiological metamorphosis known as menopause. Although
numerous pathologies are contemplated by the use of this
term, three major effects of post-menopausal syndrome are the
source of the greatest long-term medical concern:
osteoporosis, cardiovascular effects such as hyperlipidemia,
and estrogen-dependent cancer, particularly breast and
uterine cancer.
Osteoporosis describes a group of diseases which
arise from diverse etiologies, but which are characterized by
the net loss of bone mass per unit volume. The consequence
of this loss of bone mass and resulting bone fracture is the
failure of the skeleton to provide adequate structural
support for the body. One of the most common types of
osteoporosis is that associated with menopause. Most women
lose from about 20% to about 60% of the bone mass in the
trabecular compartment of the bone within 3 to 6 years after
the cessation of menses. This rapid loss is generally
associated with an increase of bone resorption and formation.
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However, the resorptive cycle is more dominant and the result
is a net loss of bone mass. Osteoporosis is a common and
serious disease among post-menopausal women.
There are an estimated 25 million women in the
United States, alone, who are afflicted with this disease.
The results of osteoporosis are personally harmful and also
account for a large economic loss due its chronicity and the
need for extensive and long term support (hospitalization and
nursing home care) from the disease sequelae. This is
especially true in more elderly patients. Additionally,
although osteoporosis is not generally thought of as a life
threatening condition, a 20% to 30% mortality rate is related
with hip fractures in elderly women. A large percentage of
this mortality rate can be directly associated with post-
menopausal osteoporosis.
The most vulnerable tissue in the bone to the
effects of post-menopausal osteoporosis is the trabecular
bone. This tissue is often referred to as spongy or
cancellous bone and is particularly concentrated near the
ends of the bone (near the joints) and in the vertebrae of
the spine. The trabecular tissue is characterized by small
osteoid structures which interconnect with each other, as
well as the more solid and dense cortical tissue which makes
up the outer surface and central shaft of the bone. This
inter-connected network of trabeculae gives lateral support
to the outer cortical structure and is critical to the bio-
mechanical strength of the overall structure. In post-
menopausal osteoporosis, it is, primarily, the net resorption
and loss of the trabeculae which leads to the failure and
fracture of bone. In light of the loss of the trabeculae in
post-menopausal women, it is not surprising that the most
common fractures are those associated with bones which are
highly dependent on trabecular support, e.g., the vertebrae,
the neck of the weight bearing bones such as the femur and
the fore-arm. Indeed, hip fracture, collies fractures, and
vertebral crush fractures are hall-marks of post-menopausal
osteoporosis.
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At this time, the only generally accepted method
for treatment of post-menopausal osteoporosis is estrogen
replacement therapy. Although therapy is generally
successful, patient compliance with the therapy is low
primarily because estrogen treatment frequently produces
undesirable side effects.
Throughout premenopausal time, most women have less
incidence of cardiovascular disease than age-matched men.
Following menopause, however, the rate of cardiovascular
disease in women slowly increases to match the rate seen in
men. This loss of protection has been linked to the loss of
estrogen and, in particular, to the loss of estrogen's
ability to regulate the levels of serum lipids. The nature
of estrogen's ability to regulate serum lipids is not well
understood, but evidence to date indicates that estrogen can
upregulate the low density lipid (LDL) receptors in the liver
to remove excess cholesterol. Additionally, estrogen appears
to have some effect on the biosynthesis of cholesterol, and
other beneficial effects on cardiovascular health.
It has been reported in the literature that post-
menopausal women having estrogen replacement therapy have a
return of serum lipid levels to concentrations to those of
the pre-menopausal state. Thus, estrogen would appear to be
a reasonable treatment for this condition. However, the
side-effects of estrogen replacement therapy are not
acceptable to many women, thus limiting the use of this
therapy. An ideal therapy for this condition would be an
agent which would regulate the serum lipid level as does
estrogen, but would be devoid of the side-effects and risks
associated with estrogen therapy.
The third major pathology associated with post-
menopausal syndrome is estrogen-dependent breast cancer and,
to a lesser extent, estrogen-dependent cancers of other
organs, particularly the uterus. Although such neoplasms are
not solely limited to a post-menopausal women, they are more
prevalent in the older, post-menopausal population. Current
chemotherapy of these cancers has relied heavily on the use
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of anti-estrogen compounds such as, for example, tamoxifen.
Although such mixed agonist-antagonists have beneficial
effects in the treatment of these cancers, and the estrogenic
side-effects are tolerable in acute life-threatening
situations, they are not ideal. For example, these agents
may have stimulatory effects on certain cancer cell
populations in the uterus due to their estrogenic (agonist)
properties and they may, therefore, be contraproductive in
some cases. A better therapy for the treatment of these
cancers would be an agent which is an anti-estrogen compound
having negligible or no estrogen agonist properties on
reproductive tissues.
In response to the clear need for new
pharmaceutical agents which are capable of alleviating the
symptoms of, inter alia, post-menopausal syndrome, the
present invention provides new benzothiophene compounds,
pharmaceutical compositions thereof, and methods of using
such compounds for the treatment of post-menopausal syndrome
and other estrogen-related pathological conditions such as
those mentioned below.
Uterine fibrosis (uterine fibroid disease) is an
old and ever present clinical problem which goes under a
variety of names, including uterine fibroid disease, uterine
hypertrophy, uterine lieomyomata, myometrial hypertrophy,
fibrosis uteri, and fibrotic metritis. Essentially, uterine
fibrosis is a condition where there is an inappropriate
deposition of fibroid tissue on the wall of the uterus.
This condition is a cause of dysmenorrhea and
infertility in women. The exact cause of this condition is
poorly understood but evidence suggests that it is an
inappropriate response of fibroid tissue to estrogen. Such a
condition has been produced in rabbits by daily
administrations of estrogen for 3 months. In guinea pigs,
the condition has been produced by daily administration of
estrogen for four months. Further, in rats, estrogen causes
similar hypertrophy.
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The most common treatment of uterine fibrosis
involves surgical procedures both costly and sometimes a
source of complications such as the formation of abdominal
adhesions and infections. In some patients, initial surgery
is only a temporary treatment and the fibroids regrow. In
those cases a hysterectomy is performed which effectively
ends the fibroids but also the reproductive life of the
patient. Also, gonadotropin releasing hormone antagonists
may be administered, yet their use is tempered by the fact
they can lead to osteoporosis. Thus, there exists a need for
new methods for treating uterine fibrosis, and the methods of
the present invention satisfy that need.
Endometriosis is a condition of severe
dysmenorrhea, which is accompanied by severe pain, bleeding
into the endometrial masses or peritoneal cavity and often
leads to infertility. The cause of the symptoms of this
condition appear to be ectopic endometrial growths which
respond inappropriately to normal hormonal control and are
located in inappropriate tissues. Because of the
inappropriate locations for endometrial growth, the tissue
seems to initiate local inflammatory-like responses causing
macrophage infiltration and a cascade of events leading to
initiation of the painful response. The exact etiology of
this disease is not well understood and its treatment by
hormonal therapy is diverse, poorly defined, and marked by
numerous unwanted and perhaps dangerous side effects.
One of the treatments for this disease is the use
of low dose estrogen to suppress endometrial growth through a
negative feedback effect on central gonadotropin release and
subsequent ovarian production of estrogen; however, it is
sometimes necessary to use continuous estrogen to control the
symptoms. This use of estrogen can often lead to undesirable
side effects and even the risk of endometrial cancer.
Another treatment consists of continuous
administration of progestins which induces amenorrhea and by
suppressing ovarian estrogen production can cause regressions
of the endometrial growths. The use of chronic progestin
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therapy is often accompanied by the unpleasant CNS side
effects of progestins and often leads to infertility due to
suppression of ovarian function.
A third treatment consists of the administration of
weak androgens, which are effective in controlling the
endometriosis; however, they induce severe masculinizing
effects. Several of these treatments for endometriosis have
also been implicated in causing a mild degree of bone loss
with continued therapy. Therefore, new methods of treating
endometriosis are desirable.
The present invention relates to compounds of
formula I
R3 -( CH2 ) n O oz
2
R1 S R
wherein
R1 is -H, -OH, -0(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6
alkyl), or -OS02(C2-C6 alkyl);
R2 is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6
alkyl), -OS02(C2-C6 alkyl) or halo;
R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-l-
pyrrolidinyl, dimethyl-l-pyrrolidinyl, 4-morpholino,
dimethylamino, diethylamino, diisopropylamino, or 1-
hexamethyleneimino;
n is 2 or 3; and
z is -O- or -S-;
or a pharmaceutically acceptable salt thereof.
Further provided by the present invention are the
following intermediate compounds which are useful for
preparing pharmaceutically active compounds of the present
invention, some of which are also pharmaceutically active:
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R9
` R2a
R 1 a S
I I
O
R6
Z
R2a
Rla
R11
II
R3 - ( CH2 ) ,, -O ~ I
~
Z
/ I R2a
Rla ` 11
0
wherein
Rla is -H or -OR7 in which R7 is a hydroxy
protecting group;
R2a is -H, halo, or -OR8 in which R8 is a hydroxy
protecting group;
R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-i-
pyrrolidinyl, dimethyl-l-pyrrolidinyl, 4-morpholino,
dimethylamino, diisopropylamino, or 1-hexamethyleneimino;
R6 is -H or a hydroxy protecting group which can be
selectively removed;
R9 is a leaving group;
R11 is non-existent or = 0;
n is 2 or 3; and
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X-9712 -8-
Z is -0-.or -s-;
or a pharmaceutically acceptable sal.t thereof.
Also provided.is a process for preparing compourids
of the formula
R3-(CH2)n-Q ~ .~
Z
` ` ~ . R2a
~ ~. ..~ /
Rla S
wherein
RlA is -H or -OR?a in wh.a,4* Rl8 i$ -H or a hydroxy
1.0 :protec:ti.ng group;
~RU iS -H., ha3.o, or -0R8& in which R8& is -H or a
hydreixy protecting group;
R3 is 1:-piperidinyl, 1-pyrrolidinyl, methyl-l-
pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino,
dimetYiyl.amino, diethylairtino, diisopzo,pyl,amiriaj or 1-
hexamethy leneim ino; .
n is 2 or 3-, and
Z is -0- or -S-;
or a pharmlacoutical ].y acceptable salt: thereof,. comprising
a1 oaxidizirig- the sulfur .,atom- of a formula IV
compound
R2a
S /
~la
IV
wherein
A?a and R2a are as previously def ined; azid
R9 is a leaving-group;
2i70479
X-9712 -9-
b) reacting the product of step a), a compound of
formula XIV
R9
R2a
s ~
Ria 0
XIV
with a nucleophilic group of the formula
::;~, 0-(CH2)-R3
R12
wherein R12 is -OH or -SH;
c) reducing the product of step b), a compound of
formula XVI
R3-(CH2)n-O /
~
` R2a
~ s
Rla
0
XVI
to provide a compound of the formula
2170479
X-9712 -10-
R3 - ( CH2 ) n-O / t
~
Z
/ I ` R2a
Rla ~ S ` /
d) optionally removing the Rla and/or R2a hydroxy
protecting groups, when present, of the product of step c);
and
e) optionally forming a salt of the product of
step c) or step d).
The present invention further relates to
pharmaceutical compositions containing compounds of formula
I, optionally containing estrogen or progestin, and the use
of such compounds, alone, or in combination with estrogen or
progestin, for alleviating the symptoms of post-menopausal
syndrome, particularly osteoporosis, cardiovascular related
pathological conditions, and estrogen-dependent cancer. As
used herein, the term "estrogen" includes steroidal compounds
having estrogenic activity such as, for example, 17b-
estradiol, estrone, conjugated estrogen (Premarin ), equine
estrogen 17b-ethynyl estradiol, and the like. As used
herein, the term "progestin" includes compounds having
progestational activity such as, for example, progesterone,
norethylnodrel, nongestrel, megestrol acetate, norethindrone,
and the like.
The compounds of the present invention also are
useful for inhibiting uterine fibroid disease and
endometriosis in women, and aortal smooth muscle cell
proliferation, particularly restenosis, in humans.
One aspect of the present invention includes
compounds of formula I
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R3 - ( CH2 ) n C ~ '
z
` ~ -
R Z
R1 S
wherein
R1 is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6
alkyl), or -OS02(C2-C6 alkyl);
R2 is -H, -OH, -O(C1-C4 alkyl), -OCOC6H5, -OCO(C1-C6
alkyl), -OS02(C2-C6 alkyl), or halo;
R3 is 1-piperidinyl, 1-pyrrolidinyl, methyl-l-
pyrrolidinyl, dimethyl-l-pyrrolidinyl, 4-morpholino,
dimethylamino, diethylamino, diisopropylamino, or 1-
hexamethyleneimino;
n is 2 or 3; and
z is -0- or -S-;
or a pharmaceutically acceptable salt thereof.
General terms used in the description of compounds
herein described bear their usual meanings. For example,
"C1-C6 alkyll refers to straight or branched aliphatic chains
of 1 to 6 carbon atoms including moieties such as methyl,
ethyl, propyl, isopropyl, butyl, n-butyl, pentyl, isopentyl,
hexyl, isohexyl, and the like. Similarly, the term C1-C4
alkoxy" represents a C1-C4 alkyl group attached through an
oxygen molecule and include moieties such as, for example,
methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
The starting material for one route for preparing
compounds of formula I of the present invention, compounds of
formula III, are prepared essentially as described by C. D.
Jones in U.S. Pats. No. 4,418,068, and 4,133,814_ Formiula
III has the structure
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I ` R2a
R7 O / S
III
wherein R7 and R2a are as defined above.
The R7 and R8 hydroxy protecting groups are
moieties which generally are not found in the final,
therapeutically active compounds of formula I, but which are
intentionally introduced during a portion of the synthetic
process to protect a group which otherwise might react in the
course of chemical manipulations, and is then removed at a
later stage of the synthesis. Since compounds bearing such
protecting groups are of importance primarily as chemical
intermediates (although some derivatives also exhibit
biological activity), their precise structure is not
critical. Numerous reactions for the formation, removal, and
possibly, reformation of such protecting groups are described
in a number of standard works including, for example,
Protective Groups in Organic Chemistry, Plenum Press (London
and New York, 1973); Green, T.W., Protective Groups in
Organic Synthesis, Wiley (New York, 1981); and The Peptides,
Vol. I, Schrooder and Lubke, Academic Press, (London and New
York, 1965).
Representative hydroxy protecting groups include,
for example, -C1-C4 alkyl, -C1-C4 alkoxy, -CO-(C1-C6 alkyl),
-S02-(C4-C6 alkyl), and -CO-Ar in which Ar is benzyl or
optionally substituted phenyl. The term "substituted phenyl"
refers to a phenyl group having one or more substituents
selected from the group consisting of C1-C4 alkyl, C1-C4
alkoxy, hydroxy, nitro, halo, and tri(chloro or fluoro)
methyl. The term "halo" refers to bromo, chloro, fluoro, and
iodo.
For compounds of formula III, preferred R7 and R8
(R2a) substituents are methyl, isopropyl, benzyl, and
methoxymethyl. Compounds in which R7 and R8 each are methyl
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are prepared via the procedure described in the above-
referenced Jones patent. Another preferred hydroxy
protecting group is methoxymethyl. However, a formula IV
compound, as shown below, is first prepared bearing the
preferred methyl or other hydroxy protecting group(s). These
protecting groups are then removed, forming phenolic
moieties, which are then reprotected with methoxymethyl
protecting groups.
Compounds of formula III are also prepared in which R7
hydroxy protecting groups are selectively removed, leaving
the R8(R2a) hydroxy protecting group as part of the final
product. The same is true in which the R8(R2a) hydroxy
protecting group is selectively removed, leaving the R7
hydroxy protecting group in place. For example, R7 is
isopropyl or benzyl and R8(R2a) is methyl. The isopropyl or
benzyl moiety is selectively removed via standard procedures,
and the R8 methyl protecting group is left as part of the
final product.
The first steps of the present process for
preparing certain compounds of formula I include selectively
placing a leaving group at the 3 position of a formula III
compound, coupling the reaction product of the first step
with a 4-(protected-hydroxy)phenol, and removing the phenol's
hydroxy protecting group. The present process is depicted in
Scheme I below.
Scheme I
I ` R2a
R7 O / S
III
wherein R7 and R2a are as defined above
24170479
X-9712 -14-
R9
as R2a
R7 O h
Iv
wherein R9 is a leaving group
R6
/ I
~
0
j R2a
h
R7 0 IIa
wherein R6 is a hydroxy protecting group which can be
selectively removed
HO
O
R
2a
R7 0
t):s
IIb
In the first step of Scheme I, an appropriate
leaving group is selectively placed at the 3-position of the
formula III starting material via standard procedures.
Appropriate R9 leaving groups include the sulfonates such as
methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate,
ethanesulfonate, isopropanesulfonate, 4-methoxybenzene-
sulfonate, 4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate,
triflate, and the like, halogens such as bromo, chloro, and
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iodo, and other related leaving groups. However, to insure
proper placement of the leaving group, the named halogens are
preferred, and bromo is especially preferred.
The present reaction is carried out using standard
procedures. For example, when the preferred halogenating
agents are used, an equivalent of such a halogenating agent,
preferably bromine, is reacted with an equivalent of the
formula III substrate, in the presence of a suitable solvent
such as, for example, chloroform or acetic acid. The
reaction is run at a temperature from about 40 C to about
80 C.
The reaction product from the above process step, a
compound of formula IV, is then reacted with a 4-(protected-
hydroxy)phenol to form compounds of formula IIa in which R6
is a selectively removable hydroxy protecting group.
Generally, the 4-hydroxy protecting moiety of the phenol may
be any known protecting group which can be selectively
removed without removing, in this instance, the R7 and, when
present, R8 moieties of a formula IIa compound. Preferred R6
protecting groups include methoxymethyl, when R7 and/or R8 are
not methoxymethyl, and benzyl. Of these, benzyl is
especially preferred. The 4-(protected-hydroxy)phenol
reactants are commercially available or can be prepared via
standard procedures.
This coupling reaction is known in the art as an
Ullman reaction and is run according to standard procedures
(see, e.g., Advanced Organic Chemistry: Reactions,
Mechanisms, and Structure, Fourth Edition, 3-16, (J. March,
ed., John Wiley & Sons, Inc. 1992); Jones, C.D., J. Chem.
Soc. Perk. Trans. I, 4:407 (1992)].
In general, equivalent amounts of the two aryl
substrates, in the presence of up to an equimolar amount of a
copper(I) oxide catalyst and an appropriate solvent, are
heated to reflux under an inert atmosphere. Preferably, an
equivalent of a formula IV compound in which R9 is bromo is
reacted with an equivalent amount of 4-benzyloxyphenol in the
presence of an equivalent of cuprous oxide.
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Appropriate solvents for this reaction are those
solvents or mixture of solvents which remain inert throughout
the reaction. Typically, organic bases, particularly a
hindered base such as, for example, 2,4,6-collidine, are
preferred solvents.
The temperature employed in this step should be
sufficient to effect completion of this coupling reaction,
and will influence the amount of time required therefore.
When the reaction mixture is heated to reflux under an inert
atmosphere such as nitrogen, the time-to-completion usually
will be from about 20 to about 60 hours.
Following coupling, which forms a formula IIa
compound, formula IIb compounds are prepared by selectively
removing the R6 hydroxy protecting group of a formula IIa
compound via well known reduction procedures. It is
imperative that the selected procedure will not affect the R7
and, when present, R8 hydroxy protecting groups.
When R6 is the preferred benzyl moiety, and R7 and,
when present, R8 each are methyl, the present process step is
carried out via standard hydrogenolysis procedures.
Typically, the formula IIa substrate is added to a suitable
solvent or mixture of solvents, followed by the addition of a
proton donor to accelerate the reaction and an appropriate
hydrogenation catalyst.
Appropriate catalysts include noble metals and
oxides such as palladium, platinum, and rhodium oxide on a
support such as carbon or calcium carbonate. Of these,
palladium-on-carbon, particularly 10% palladium-on-carbon, is
preferred.
Solvents for this reaction are those solvents or
mixture of solvents which remain inert throughout the
reaction. Typically, ethylacetate and C1-C4 aliphatic
alcohols, particularly ethanol, is preferred.
For the present reaction, hydrochloric acid serves
as an adequate and preferred proton donor.
When run at ambient temperature and a pressure
ranging form about 30 psi to about 50 psi, the present
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reaction runs quite rapidly. Progress of this reaction may
be monitored by standard chromatographic techniques such as
thin layer chromatography.
Compounds of formula IIa and Iib are novel, are
encompassed within the genus described herein as formula II
compounds, and are useful for preparing the pharmaceutically
active compounds of formula I.
Upon preparation of a formula IIb compound, it is
reacted with a compound of formula V
R3 - ( CH2 ) n - Q
V
wherein R3 and n are as defined above, and Q is a bromo or,
preferably, a chloro moiety, to form a compound of formula
VI. The formula VI compound is then deprotected to form a
compound of formula Ia. These steps of the present process
are shown in Scheme II below
Scheme II
HO
/I
O
` ~
R2a
R7OI~
IIb
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R3 - ( CH2 ) n-
/
O
f R 2 a
R7O s
I
R3 - ( CH2 ) n-
/ I
~
O
R2b
~ s
HO
Ia
wherein R3, R7, R2a, and n are as defined above, and R2b is
-H, -OH, or halo.
In the first step of the process shown in Scheme
II, the alkylation is carried out via standard procedures.
Compounds of formula V are commercially available or are
prepared by means well known to one of ordinary skill in the
art. Preferably, the hydrochloride salt of a formula V
compound, particularly 2-chloroethylpiperidine hydrochloride,
is used.
Generally, at least about 1 equivalent of formula
IIb substrate are reacted with 2 equivalents of a formula V
compound in the presence of at least about 4 equivalents of
an alkali metal carbonate, preferably cesium carbonate, and
an appropriate solvent.
Solvents for this reaction are those solvents or
mixture of solvents which remain inert throughout the
2170479
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reaction. N,N-dimethylformamide, especially the anhydrous
form thereof, is preferred.
The temperature employed in this step should be
sufficient to effect completion of this alkylation reaction.
Typically, ambient temperature is sufficient and preferred.
The present reaction preferably is run under an
inert atmosphere, particularly nitrogen.
Under the preferred reaction conditions, this
reaction will run to completion in about 16 to about 20
hours. Of course, the progress of the reaction can be
monitored via standard chromatographic techniques.
As an alternative for preparing compounds of
formula VI, a formula IIb compound is reacted with an excess
of an alkylating agent of the formula
Q - (CH2)n - Q,
wherein Q and Q' each are the same or different leaving
group, in an alkali solution. Appropriate leaving groups are
the aforementioned leaving groups used in the preparation of
compounds of formula IV.
A preferred alkali solution for this alkylation
reaction contains potassium carbonate in an inert solvent
such as, for example, methyethyl ketone (MEK) or DMF. In
this solution, the 4-hydroxy group of the benzoyl moiety of a
formula IIb compound exists as a phenoxide ion which
displaces one of the leaving groups of the alkylating agent.
This reaction is best when the alkali solution
containing the reactants and reagents is brought to reflux
and allowed to run to completion. When using MEK as the
preferred solvent, reaction times run from about 6 hours to
about 20 hours.
The reaction product from this step is then reacted
with 1-piperidine, 1-pyrrolidine, methyl-l-pyrrolidine,
dimethyl-l-pyrrolidine, 4-morpholine, dimethylamine,
diethylamine, diisopropylamine, or 1-hexamethyleneimine, via
standard techniques, to form compounds of formula VI.
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Preferably, the hydrochloride salt of piperidine is reacted
with the alkylated compound of formula IIb in an inert
solvent, such as anhydrous DMF, and heated to a temperature
in the range from about 60 C to about 110 C. When the
mixture is heated to a preferred temperature of about 90 C,
the reaction only takes about 30 minutes to about 1 hour.
However, changes in the reaction conditions will influence
the amount of time this reaction needs to be run for
completion. Of course, the progress of this reaction step
can be monitored via standard chromatographic techniques.
Compounds of formula VI, in which R7 and when
present, R8 each are C1-C4 alkyl, preferably methyl, and in
which R2a is -H or halo, are novel and are pharmaceutically
active for the methods herein described. Accordingly, such
compounds are encompassed by the definition herein of
compounds of formula I.
Certain preferred compounds of formula I are
obtained by cleaving the R7 and, when present, R8 hydroxy
protecting groups of formula VI compounds via well known
procedures. Numerous reactions for the formation and removal
of such protecting groups are described in a number of
standard works including, for example, Protective Groups in
Organic Chemistry, Plenum Press (London and New York, 1973);
Green, T.W., Protective Groups in Organic Synthesis, Wiley,
(New York, 1981); and The Peptides, Vol. I, Schrooder and
Lubke, Academic Press (London and New York, 1965). Methods
for removing preferred R7 and/or R8 hydroxy protecting groups,
particularly methyl and methoxymethyl, are essentially as
described in the Examples, infra.
Compounds of formula Ia are novel, are
pharmaceutically active for the methods herein described, and
are encompassed by formula I as defined herein.
Compounds of formula I in which R1 is -H are
prepared via the synthetic route shown below in Scheme IIi.
Using this route, a 3-position leaving group (R9) is placed
on commercially available thianaphthene (formula VII) to form
2170479
X-9712 -21-
a compound of formula VIII, which is then coupled with a 4-
(protected-hydroxy)phenol, providing compounds of formula IX.
Scheme III
Co
VII
R9
wI ` ~
~ S
VIII
R6
~ I
~
qc$
wherein R6 is a hydroxy protecting group which can be
selectively removed and R9 is a leaving group.
The compound of formula VII is commercially
available. Preparation of formulae VIII and IX compounds,
including the definition of R6 and R9 substituents, as well as
preferred reactants and conditions, unless otherwise herein
stated, are the same as described above and shown in Scheme
I, supra.
2170479
X-9712 -22-
Compounds of formula IX are then arylated via
Suzuki coupling [see, e.g., Suzuki, A., Pure and Appl. Chem.,
.E(2):213-222 (1994)]. Using one Suzuki coupling option, a
formula IX compound is selectively halogenated at the 2-
position, and then coupled with an arylboronic acid compound
of formula XIa (Route A of Scheme IV below).
Preferably, however, an arylboronic acid of formula
Xb is formed from a compound of formula IX, and then reacted
with a halo-arene of formula XIb to give novel intermediates
of formula Iic (Route B of Scheme IV below). Such novel
intermediates are useful for preparing pharmaceutically
active compounds of the present invention (formula Ib
compounds) via alkylation and deprotection.
2170479
X-9712 -23-
Scheme IV
R6
/I
0
w~ ` ~
~ S
IX
Route A Route B
R60 R6
/~
0 0
X B(OH)2
S
()~ =
Xa Xb
~ B(OH)2
R2a (/
R2aAyxl
XIa XIb
R60 R5
0 0
()f R2a (:): \ R2a
ls s S
IIc Iic
2170479
X-9712 -24-
t I
~
HO
/I
~
0
R2a
~ ~
IId
R3-(CH2)n-
/I
=
0
s\ R 2 a
~ a
XII
R3 - (CH2 ) r,-
/I
=
Osl~
0
O~S\ R2b
~ ~
Ib
wherein
R2a, R2b, R3, R6 and n are as defined above;
2170479
X-9712 -25-
X is iodo, bromo, or fluoro, in the order of
preference; and
X' is iodo, bromo, or fluoro, in the order of
preference, or triflate.
The first step in Route A in Scheme IV is the 2-
position iodination or bromination of a formula IX compound
using standard procedures. Generally, a formula IX compound
is reacted with a slight excess of n-butyllithium in hexane,
in an appropriate solvent and under an inert atmosphere such
as nitrogen, followed by the dropwise addition of a slight
excess of the desired halogenating agent in an appropriate
solvent. Preferably, the halogenating agent for this step is
iodine, but the use of bromine, N-bromosuccinimide is also
permitted.
Appropriate solvents include an inert solvent or
mixture of solvents such as, for example, diethyl ether,
dioxane, and tetrahydrofuran (THF). Of these,
tetrahydrofuran, particularly anhydrous THF, is preferred.
The present selective, 2-position halogenation
reaction optionally is run at a temperature from about -75 C
to about 85 C.
The product of the above reaction, a halo-arene of
formula Xa, is then coupled with an arylboronic acid of
formula XIa, via standard Suzuki coupling procedures, to
provide compounds of formula Iic. Compounds of formula XIa,
in which R2a.is -H, halo, or -OR8 (R8 is a hydroxy protecting
group as defined, supra) are derived from commercially
available compounds via procedures well known tc one of
ordinary skill in the art (see, e.g., March J.; and Suzuki,
A., supra).
In the present coupling reaction, a slight excess
of a formula XIa compound is reacted with each equivalent of
a formula Xa compound in the presence of a palladium catalyst
and an appropriate base in an inert solvent such as toluene.
Although various palladium catalysts drive Suzuki
coupling reactions, the catalyst selected usually is reaction
2170479
X-9712 -26-
specific. Thus, the use of tetrakistriphenylphosphine
palladium in the present reaction is highly preferred.
Likewise, various bases may be used in the present
coupling reaction. However, it is preferred to use an alkali
metal carbonate, particularly 2ki sodium carbonate.
The temperature employed in this step should be
sufficient to effect completion of the coupling reaction.
Typically, heating the reaction mixture to reflux for a
period from about 2 to about 4 hours is adequate and
preferred.
In Route B of Scheme IV, a 2-position arylboronic
of formula Xb is prepared using well known procedures.
Generally, a compound of formula IX is treated with a slight
excess of n-butyllithium in hexanes, in an appropriate
solvent and under an inert atmosphere such as nitrogen,
following by the dropwise addition of an appropriate
trialkylborate.
Appropriate solvents include an inert solvent or
mixture of solvents such as, for example, diethyl ether,
dioxane, and tetrahydrofuran (THF). THF, particularly
anhydrous THF, is preferred.
The preferred trialkylborate used in the present
reaction is triisopropyl borate.
The product of this reaction, a compound of formula
Xb, is then reacted with a aryl halide or aryl triflate of
formula XIb, via standard Suzuki coupling procedures, to
provide compounds of formula Iic. The preferred reaction
conditions for the present reaction are as described for the
reaction of compounds of formulae XIa and Xa, in Scheme IV,
which also provide compounds of formula IIc.
The transformation of compounds of formula IIc to
formula Ia compounds is carried out as described above for
the conversion of formula IIa compounds to compounds of
formula Ia.
Compounds of formulae IIc and Iid are novel, and
are useful for the preparation of pharmaceutically active
compounds of the present invention.
2i 70479
X-9712 -27-
Compounds of formulae XII and Ib also are novel,
are useful for the methods herein described, and are
encompassed by formula I as herein defined.
Compounds of formula I in which either R1 or R2 is
-H and the other R1 or R2 substituent is -OH also are prepared
from compounds of formula I in which both R1 or R2 are -OH.
The dihydroxy compound of formula I is converted to a mixture
of 6- and 4'- monotriflates, and the triflate moiety is
reduced to hydrogen [see, Saa, J.M., g~ Li., J. Org. Chem.,
U:991 (1990)]. The resulting mixture of monohydroxy
derivatives, either as the free base or pharmaceutically
acceptable salt, preferably the hydrochloride salt, can then
be separated by standard crystallization techniques.
In general, a dihydroxy compound of formula I is
treated with about 4 to about 6 equivalents of a amine base,
such as triethylamine, in a non-reactive solvent followed by
the addition of 1 equivalent of trifluoromethanesulfonic
anhydride. A statistical mixture of mono- and di-triflates
are produced and separated by standard chromatographic
techniques. A preferred solvent for this step is anhydrous
dichloromethane.
When run at a temperature range from about 0 C to
about 25 C, the present reaction is completed within from
about 1 to about 5 hours.
The isolated mixture of mono-triflated compounds is
then hydrogenated, in a non-reactive solvent, in the presence
of from about 3 to about 6 equivalents of an amine base,
preferably triethylamine, and a hydrogenation catalyst such
as palladium-on-carbon, which is preferred. Preferred
solvents for this reaction include ethyl acetate and ethanol
or, alternatively, a mixture thereof. When this step of the
present reaction is run under about 40 psi of hydrogen gas,
at ambient temperature, the reaction time is from about 2
hours to about 5 hours.
The resulting mixture of monohydroxy derivatives of
formula I have different solubilities in ethyl aceate and the
6-hydroxy-4'-hydrogen derivatives can be partially separated
2170479
X-9712 -28-
from the 6-hydrogen-4'-hydroxy derivatives by selective
crystallization. Further separation, which provides pure
monohydroxy compounds of formula I, can be achieved by
conversion of the enriched mixtures to the hydrochloride
salts followed by crystallization from ethyl acetate-ethanol.
A more direct method for the preparation of
compounds of formula I in which either R1 or R2 is -H and the
other R1 or R2 substituent is -OH, as well as an alternative
method for the preparation of compounds of formula I in which
either R1 or R2 is -H and the other R1 or R2 substituent is
-O-(C1-C4 alkyl) uses a compound of the formula
R3 - ( CH2 ) n-
/ I
=
z
j()~~ ` / R2c
R1c S
wherein
R3 and n are defined above;
R1c is -OH or -O-(C1-C4 alkyl); and
R2c is -OH or -0-(C1-C4 alkyl);
providing when R1c is -OH, R2c is -O-(C1-C4 alkyl), and when
R1c is -O-(C1-C4 alkyl) R2c is -OH.
In this process, the hydroxy moiety of such a
compound is converted to a triflate derivative by treatment
with trifluoromethane sulfonic anhydride. The triflate
moiety is then reduced under standard conditions, preferably
by catalytic hydrogenation. The hydroxy protecting moiety is
then removed via standard procedures, as in those herein
described, providing compounds of formula I in which either
R1 or R2 is -H and the other R1 or R2 substituent is -OH.
Another alternative, and preferred, method for the
preparation of compounds of the present invention is shown in
Scheme V. In the present process, the sulfur atom of a
formula IV compound (infra) is oxidized to form a sulfoxide
(formula XIV), which is then reacted with a nucleophilic
group to introduce the oxygen or sulphur atom linker of
2170479
X-9712 -29-
formula I and formula II compounds. The sulfoxide moiety of
formula XVI compounds is then reduced to provide certain
compounds of the present invention.
Scheme V
R9
/ I ~ R2a
Rla ~ S
IV
R9
` I ~ R2a
Rla 11
O
XIV
2170479
X-9712 -30-
1
` I OR6 ~' O- ( CH2 ) n-R3 H S ~ OR6 ` ' O- ( CH2 ) n-R3
HO HO"v ~ ~ HS
XVa XVb XVc XVd
R6 R3-(CH2)n-0~ R6 R3-(CH2)n-0
~~ p ~~ p
O S
Rla I S = / R2c Rla ~ S = / R2Rla a S = I R2c Rla ~ ~ = / R2c
1 IO IO ~
XVIa XVIb XVIc XVId
R6 R3 - (CH2 ) n-O R6
~ I R3-(CH2)n- C
0 0 s
S
~~ ~ `, R2a R2a 2a
R la S Rla S R S R2c
Rla Rlb
IIg Ic IIe Id
wherein each variable has its previously defined meaning.
In the first step of this process, a compound of
formula IV is selectively oxidized to the sulfoxide. A
number of known methods are available for the process step
(,-ee, e.g., Madesclaire, M., Tetrahedron, 42 (20); 5459-5495
(1986); Trost, B.M., gt~ ~Ll., Tetrahedron Letters, 22 (14);
1287-1290 (1981); Drabowicz, J., gr ~., Synthetic
Communications, 11 (12); 1025-1030 (1981); Kramer, J.B., gr
al., 34th National Oraanic Svmoosium, Williamsburg, VA., June
11-15, 1995]. However, many oxidants provide only poor
conversion to the desired product as well as significant
over-oxidation to the sulfone. The present, novel process,
however, converts a formula IV compound to a sulfoxide of
2170479
X-9712 -31-
formula XIV in high yield with little or no formation of
sulfones. This process involves the reaction of a formula IV
compound with about 1 to about 1.5 equivalents of hydrogen
peroxide in a mixture of about 20% to about 50%
trifluoroacetic acid in methylene chloride. The reaction is
run at a temperature from about 10 C to about 50 C, and
usually required from about 1 to about 2 hours to run to
completion.
Next, the 3-position leaving group (R9) is
displaced by the desired nucleophilic derivative of formula
XV. Such nucleophilic derivatives are prepared via standard
methods.
In this step of the process, the acidic proton of
the nucleophilic group is removed by treatment with a base,
preferably a slight excess of sodium hydride or potassium
tertbutoxide, in a polar aprotic solvent, preferably DMF or
tetrahydrofuran. Other bases that can be employed include
potassium carbonate and cesium carbonate. Additionally,
other solvents such as dioxane or dimethylsulfoxide can be
employed. The deprotonation is usually run at a temperature
between about 0 C and about 30 C, and usually requires
about 30 minutes for completion. A compound of formula XIV
is then added to the solution of the nucleophile. The
displacement reaction is run at a temperature between 0 C
and about 50 C, and is usually run in about 1 to about 2
hours. The product is isolated by standard procedures.
when a benzyl moiety is used as a hydroxy
protecting group, hydrogenolysis of the sulfoxide moiety will
also provide removal of the benzyl protecting group,
eliminating the requirement for selectively removing such a
group at a later stage in the process.
In the next step of the present process, novel
sulfoxides of formulae XVI a, b, c, and d (collectively
formula XVI) are reduced to a benzothiophene compound of
formulae IIg, Ic, IIe, and Id, respectively. Prior to the
present reduction process, compounds of formulae IIg and Iie
can first be alkylated as herein described. Reduction of the
CA 02170479 2007-08-10
X-9712. .-32-
su].foxide compounds can-be accomplished hy using one of a
multitude of_methods known.in the art. including, for example.,
hydride reduction (lithiwn aluminum hydride).R catalytic
hydrogenation, transfer hydrogeno3ysis and trimethylsilyl
iodide-(TMS-i). in -this reduction, the choice of reagent.is
dependent upon the= compatibilitX of, other functionali:ties in
the molecule. For the compounds described in the present
invention, lithiumm aluminum hydri,de (LiA1,144) and transfer
hydrogenolysis (pa:lladi.um.blac.k/ ammonium. formate) are the
preferred reagents. For LiAlHq, reduction, appropriate
solve:nts such as, for example, diethyl ether, dioxane, and
tetrahydrofuran (THF). Of these, THR, particularly anhydrous
THF, is preferred:b For transfer. - hydrogenolysis, alcohol
solvents, particularly ethainol, is preferrecl;,:, The rea.ction
is run at., a temperature. from about 00 C to about .60 C, axid
requires.from about 0.5 hours to about-2 hours for
completionY.
When desixed, the hydraxy protecting droup or
groups of the prodticts of the proC.ess.shown in Scheme V can
be.. retnoved, .and a salt of the product of any step of the
process. Accordingly, rhe present invention provides.a
process lor preparing c0mpounds of the formula
R3-{GH2)n-p /
~
/ ~ .~.~.
R2sR.la
/
wherein
Rla is -H or t OR7a in which R7a is -H or a hyd-roxy
protecting group;
RZa fs -H, -halo, or --pR$8 in ikhich R8a is -H or a
hydroxy protecting group;
3D R3 is 1-piperid.inyl;, 2=pyrXoi..i:dinyl, methyl-l-
pyrrolidinyl, dimethyl.-1-pyrrol.i,dinyl, 4--morphol i.no,.
2170479
X-9712 -33-
dimethylamino, diethylamino, diisopropylamino, or 1-
hexamethyleneimino;
n is 2 or 3; and
Z is -0- or -S-;
or a pharmaceutically acceptable salt thereof, comprising
a) oxidizing the sulfur atom of a formula IV
compound
R9
( ` R2a
/ s
~
R1a
IV
wherein
R1a and R2a are as previously defined; and
R9 is a leaving group;
b) reacting the product of step a), a compound of
formula XIV
R9
`
R2a
s ~ ~
)01
Rla 11
0
XIV
with a nucleophilic group of the formula
0- ( CH2 ) n-R3
R12
wherein R12 is -OH or -SH;
2170479
X-9712 -34-
c) reducing the product of step b), a compound of
formula XVI
R3-(CH2)n-O
Z
/ ~ R2a
R1a ~ S
11
O
XVI
to provide a compound of the formula
R3- (CH2) n-O / I
~
Z
cczzt~' ` R2a
Rla S ` /Y
d) optionally removing the Rla and/or R2a hydroxy
protecting groups, when present, of the product of step c);
and
e) optionally forming a salt of the product of
step c) or step d).
This novel process also provides nove; compounds of
formulae XIV, and XVI a, b, c, and d, each of which is an
intermediate useful for preparing the pharmaceutically active
compounds of the present invention.
Compounds of formulae I in which Z is S are also
prepared using the process described below in Scheme VI in
which a compound of formula IVa is metallated. The resulting
product, a compound of formula XVII is reacted with a 4-
(protected hydroxy)phenyl disulfide of formula XVIII, and the
2170479
X-9712 -35-
phenol protecting group of a formula Iie compound is removed
to provide compounds of formula IIf. One will note that, in
using this process, R2 cannot be halo because of chemical
limitations.
Scheme VI
R9
I ` R2a
Rla S ` /
IVa
M
I ` R2a
Rla S /
XVII
OR6
/ S I
N
I S ~
R60 XVIII
R6
/I
Z L*NI
s
I ` R2a
S ~ ~
Rla
IIe
2170479
X-9712 -36-
HO
s
~ ` ~ R2a
~ s
Rla
IIf
wherein
R1a is -H or -OR7 and R7 is a hydroxy protecting
group;
R2a is -H, or -OR8 and R8 is a hydroxy protecting
group;
R6 is a hydroxy protecting group which can be
selectively removed;
R9 is a leaving group; and
M is a metal ion.
In the first two steps of Scheme VI, a formula IVa
compound is metallated via well known procedures. Most
commonly, and preferably, a formula IVa compound is treated
with a slight excess of n-butyllithium in hexanes in an
appropriate solvent, followed by the dropwise addition of a
solution of a disulfide compound of formula XVIII in an
appropriate solvent.
Both of these reaction steps are run under an inert
atmosphere such as nitrogen, while appropriate solvents for
both steps include one or more inert solvents such as diethyl
ether, dioxane, and THF. Of these, THF, particularly the
anhydrous form thereof, is preferred. In addition, the
present reaction steps are run at a temperature from about
-78 C to about 85 C.
In the first step of the present reaction, a
metallated compound of formula XVII is provided. The 4-
(protected-hydroxy)phenyl disulfide (a formula XVIII
compound) which is reacted with such a formula XVII compound
to give a compound of formula IIe, is prepared by protecting
2170479
X-9712 -37-
the hydroxy group of commercially available 4-
hydroxyphenylsulfide with an appropriate protecting group via
procedures known in the art. A preferred R6 protecting group
is methoxymethyl, providing R7 and R8, if either or both are
present, is a hydroxy protecting group other than
methoxymethyl. It is imperative that the R6 hydroxy
protecting group is a moiety different than those formed by
R7 and R8 hydroxy protecting groups, when present, so that the
R6 group can selectively be removed, via standard procedures,
to provide compounds of formula IIf.
To effect deprotection by removal of the R6
protecting group, a formula IIe compound in a protic solvent
or mixture of solvents is reacted in an acid media containing
at least one equivalent of acid, preferably methanesulfonic
acid, and heating from about 25 to about 110 C. Typically,
the reaction time is from about 6 to about 24 hours, but the
progress of the reaction may be monitored via standard
chromatographic techniques.
Appropriate solvents for the present reaction
include, for example, water and methanol.
Compounds of formulae Iie and IIf are novel, are
useful for preparing pharmaceutically active compounds of
formula I and are herein encompassed within the above
depiction of formula II.
Compounds of formula Id
R3-(CH2)n- / (
~
S
R2b
R1b O S
Id
wherein
Rlb is -H or -OH;
R2b is -H or -OH; and
2170479
X-9712 -38-
R3 and n, are as defined above, are prepared by
using the above-described procedures related to the process
steps shown in Schemes II and IV. Such compounds of formula
Id also are novel, are useful for the methods of the present
invention, and are herein encompassed within the above
depiction of formula I.
Compounds of formula I, in which R1 and R2 are
different hydroxy protecting groups or either R1 and R2
is a hydroxy protecting group and the other is hydroxy are
selectively prepared by using a modified 2-arylbenzothiophene
starting material of formula III above, providing that
hydroxy protecting groups designated R7 and R8 are
sufficiently different so that one protecting group is
removed while the other group remains. Such 2-
arylbenzothiophenes are prepared via procedures well known in
the art.
Particularly useful for the preparation of formula
I compounds in which R1 and R2 are different protecting groups
is Suzuki coupling as described above in Scheme IV. However,
6-(protected hydroxy) benzothiophene-2-boronic acid is
reacted with a formula xIb compound above in which R2a is -OR8
and R7 does not equal R8. This reaction allows preparation of
compounds of the present invention in which R7 and R8 are
different hydroxy protecting groups so that one protecting
group may selectively be removed and the other remains as a
moiety of the final product. Preferably, the R7 protecting
group, especially benzyl or isopropyl, is removed to form a
hydroxy moiety while the R8 protecting group, particularly
methyl, remains.
Suzuki coupling also is accomplished by using the
above-described procedures but replacing a formula XIb
compound with a compound of formula XIX
2l %0479
X-9712 -39-
Rio
R8a
XIX
wherein
R8a is C1-C6 alkyl sulfonate, preferably
methansulfonate or C4-C6 aryl sulfonate; and
R10 is a leaving group, preferably bromo or
triflate.
In this process, a 6-(protecting hydroxy)
benzothiophene-2-boronic acid as described above is reacted
with a compound of formula XIX to provide a compound of
formula XX, which is reacted with boron tribromide in
methylene chloride to provide a monohydroxy compound which is
subsequently converted to, for example, a benzyl moiety by
standard procedures (formula XXI). The 4'-sulfonate ester is
then selectively removed by basic hydrolysis or, preferably,
by treatment with LiAlH4, in an appropriate aprotic solvent
such as, for example, THF. This reaction provides a compound
of formula XXII which is finally, for example, methylated at
the 4'-position via standard procedures (formula IIIa). Of
course, one skilled in the art will recognize that various
processes can be utilized to provide formula IIIa compounds
in which the hydroxy protecting groups are other than shown
in Scheme VII below, but which can be selectively removed to
provide monohydroxy compounds of formula I of the present
invention.
2170479
X-9712 -40-
Scheme VII
)(: R8a H3 CO
XX
R8a
Bzo
o s
XXI
~
OH
Bz0 / I ` S
XXII
jo~ / OMe
Bz0 S
IIIa
Compounds of IIIa are then subjected to the various processes
herein described to provide compounds of formula I and II of
the present invention.
Other preferred compounds of formula I are prepared
by replacing 6- and/or 4'-position hydroxy moieties, when
present, with a moiety of the formula -O-CO-(C1-C6 alkyl), or
-O-S02-(C2-C6 alkyl) via well known procedures. See, e.g.,
U.S. Pat. No. 4,358,593.
For example, when an -O-CO(C1-C6 alkyl) group is
desired, a mono- or dihydroxy compound of formula I is
2170479
X-9712 -41-
reacted with an agent such as acyl chloride, bromide,
cyanide, or azide, or with an appropriate anhydride or mixed
anhydride. The reactions are conveniently carried out in a
basic solvent such as pyridine, lutidine, quinoline or
isoquinoline, or in a tertiary amine solvent such as
triethylamine, tributylamine, methylpiperidine, and the like.
The reaction also may be carried out in an inert solvent such
as ethyl acetate, dimethylformamide, dimethylsulfoxide,
dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl
ketone, and the like, to which at least one equivalent of an
acid scavenger (except as noted below), such as a tertiary
amine, has been added. If desired, acylation catalysts such
as 4-dimethylaminopyridine or 4-pyrrolidinopyridine may be
used. 5_eg, e.g., Haslam, gr~ ~., Tetrahedron, 36:2409-2433
(1980).
The present reactions are carried out at moderate
temperatures, in the range from about -25 C to about 100 C,
frequently under an inert atmosphere such as nitrogen gas.
However, ambient temperature is usually adequate for the
reaction to run.
Acylation of a 6-position and/or 4'-position
hydroxy group also may be performed by acid-catalyzed
reactions of the appropriate carboxylic acids in inert
organic solvents. Acid catalysts such as sulfuric acid,
polyphosphoric acid, methanesulfonic acid, and the like are
used.
The aforementioned R1 and/or R2 groups of formula I
compounds also may be provided by forming an active ester of
the appropriate acid, such as the esters formed by such known
reagents such as dicyclohexylcarbodiimide, acylimidazoles,
nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-
hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan,
.U:1979 (1965), and Chem. Ber., 788 and 2024 (1970).
Each of the above techniques which provide -0-CO-
(C1-C6 alkyl) moieties are carried out in solvents as
discussed above. Those techniques which do not produce an
acid product in the course of the reaction, of course, do not
2170479
X-9712 -42-
call for the use of an acid scavenger in the reaction
mixture.
When q formula I compound is desired in which the
6- and/or 4'-position hydroxy group of a formula I compound
is converted to a group of the formula -O-S02-(C2-C6 alkyl),
the mono- or dihydroxy compound is reacted with, for example,
a sulfonic anhydride or a derivative of the appropriate
sulfonic acid such as a sulfonyl chloride, bromide, or
sulfonyl ammonium salt, as taught by King and Monoir, J. Am.
Chem. Soc., .97:2566-2567 (1975). The dihydroxy compound also
can be reacted with the appropriate sulfonic anhydride or
mixed sulfonic anhydrides. Such reactions are carried out
under conditions such as were explained above in the
discussion of reaction with acid halides and the like.
Although the free-base form of formula I compounds
can be used in the methods of the present invention, it is
preferred to prepare and use a pharmaceutically acceptable
salt form. Thus, the compounds used in the methods of this
invention primarily form pharmaceutically acceptable acid
addition salts with a wide variety of organic and inorganic
acids, and include the physiologically acceptable salts which
are often used in pharmaceutical chemistry. Such salts are
also part of this invention. Typical inorganic acids used to
form such salts include hydrochloric, hydrobromic,
hydroiodic, nitric, sulfuric, phosphoric, hypophosphoric, and
the like. Salts derived from organic acids, such as
aliphatic mono and dicarboxylic acids, phenyl substituted
alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids,
aromatic acids, aliphatic and aromatic sulfonic acids, may
also be used. Such pharmaceutically acceptable salts thus
include acetate, phenylacetate, trifluoroacetate, acrylate,
ascorbate, benzoate, chlorobenzoate, dinitrobenzoate,
hydroxybenzoate, methoxybenzoate, methylbenzoate, o-
acetoxybenzoate, naphthalene-2-benzoate, bromide,
isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-l,4-
dioate, hexyne-1,4-dioate, caprate, caprylate, chloride,
cinnamate, citrate, formate, fumarate, glycollate,
2170479
X-9712 -43-
heptanoate, hippurate, lactate, malate, maleate,
hydroxymaleate, malonate, mandelate, mesylate, nicotinate,
isonicotinate, nitrate, oxalate, phthalate, terephthalate,
phosphate, monohydrogenphosphate, dihydrogenphosphate,
metaphosphate, pyrophosphate, propiolate, propionate,
phenylpropionate, salicylate, sebacate, succinate, suberate,
sulfate, bisulfate, pyrosulfate, sulfite, bisulfite,
sulfonate, benzenesulfonate, p-bromophenylsulfonate,
chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethane-
sulfonate, methanesulfonate, naphthalene-l-sulfonate,
naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate,
tartarate, and the like. Preferred salts are the
hydrochloride and oxalate salts.
The pharmaceutically acceptable acid addition salts
are typically formed by reacting a compound of formula I with
an equimolar or excess amount of acid. The reactants are
generally combined in a mutual solvent such as diethyl ether
or ethyl acetate. The salt normally precipitates out of
solution within about one hour to 10 days and can be isolated
by filtration or the solvent can be stripped off by
conventional means.
The pharmaceutically acceptable salts generally
have enhanced solubility characteristics compared to the
compound from which they are derived, and thus are often more
amenable to formulation as liquids or emulsions.
Representative preferred compounds of the present
invention include the following:
Group I:
[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b] thiophene-(S-
oxide)
[6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b] thiophene-
(S-oxide)
2170479
X-9712 -44-
[6-methoxy-2-(4-isopropoxyphenyl)-3-bromo]benzo[b] thiophene-
(S-oxide)
[2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide)
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene-(S-oxide)
[3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-methoxyphenyl)]
benzo[b]thiophene-(S-oxide)
[6-benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-
(S-oxide)
[6-isopropoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-
(S-oxide)
[6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]thiophene-
(S-oxide)
[6-methoxy-2-(4-isopropoxyphenyl)-3-bromo]benzo[b]thiophene-
(S-oxide)
[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene-(S-oxide)
[6-isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene-(S-oxide)
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene-(S-oxide)
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
isopropoxyphenyl)]benzo[b]thiophene-(S-oxide)
[6-methoxy-2-(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)
thiophenoxy]benzo[b]thiophene
2170479
X-9712 -45-
[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)thiophenoxy]
benzo[b]thiophene
Group II:
[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]
benzo[b]thiophene
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]
benzo[b]thiophene hydrochloride
[3-[4-[2-(1-pyrolidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]
benzo[b]thiophene
[3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]
benzo[b]thiophene hydrochloride
[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(phenyl)]benzo
[b]thiophene hydrochloride
[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-fluorophenyl)]
benzo[b]thiophene
[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-
benzo[b]thiophene
[6-isopropoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-
benzo[b]thiophene
2170479
X-9712 -46-
[6-methoxy-2-(4-isopropoxyphenyl)-3-(4-benzyloxy)phenoxy]-
benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-pyrolodinyl)ethoxylphenoxy]-2-(4-
methoxyphenyl)]benzo[blthiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxylphenoxyl-2-
(4-methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxyl-2-(4-
methoxyphenyl)]benzo[blthiophene hydrochloride
[6-methoxy-3-[4-[2-(morpholino)ethoxylphenoxy]-2-(4-
methoxyphenyl)]benzo[blthiophene hydrochloride
[6-methoxy-3-[4-[3-(piperidino)propoxylphenoxy]-2-(4-
methoxyphenyl)]benzo[blthiophene hydrochloride
[6-methoxy-3-[4-[3-(1-N,N-diethylamino)propoxylphenoxy]-2-(4-
methoxyphenyl)lbenzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-
hydroxyphenyl)]benzo[blthiophene
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxyl-2-(4-
hydroxyphenyl)]benzo[blthiophene oxalate
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[blthiophene hydrochloride
CA 02170479 2000-05-26
X-9712 -47~
[6-hydroxy-3-[4-[2-(I-pyrroiidirzyl)eth~.)xy]pherloxv] -2-(4-
hydroxyphenyl)]benzo(blthiophene
[6-hydroxy-3-[4-[2-(1-hexamethy~erneimir.;o)ethoxy]phenoxyl-2-
(4-hydroxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo(b]thiophene
[6-hydroxy-3-[4-[2-(morpholino)ethon,,]phenoxyJ-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
(6-hydroxy-3-(4-(3-(1-N,N-diethylamino)propoxy]phenoxy]-2-(4-
hydroxyphenyl)Jbenzo(b]thiophene hydrochloride
(6-hydroxy-3-[4-[2-(1-N,N-diisopropylam:.no)-ethoxy]phenoxyJ-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[3-(piperidino)propoxy]phenoxy]-2-(4-
hydroxyphenyl)lbenzo[blthiophene hydrochloride
[6-methoxy-3-(4-[2-(1-piperidinyl)ethoxylphenoxyl-2-(4-
methoxyphenyl)]benzo[bJthiophene hydrochloride
[6-benzyloxy-3-(4-(2-(1-piperidinyl)ethnxy]phenoxy]-2-(4-
methoxyphenyl)lbenzo[b]thiophene
[6-benzyloxy-3-[4-(2-(l-pyrrolidinyl)ethoxy]phenoxyJ-2-(4-
methoxyphenyl)Jbenzo[b)thiophene
(6-benzyloxy-3-[4-[2-(1-hexamethylimino)ethoxylphenoxyl-2-(4-
methoxyphenyl)Jbenzo[b)thiophene
[6-benzyloxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-
(4-methoxyphenyl)Jbenzo[blthiophene
A ". .
2170479
~ X-9712 -48-
[6-benzyloxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[blthiophene
[6-isopropoxyoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-hexamethylimino)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(l-hexamethylimino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
2170479
X-9712 -49-
[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-hexamethylimino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-
(4-benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
isopropoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
isopropoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-
(4-isopropoxyphenyl)]benzo[b]thiophene
2170479
X-9712 -50-
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-
isopropoxyphenyl))benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
isopropoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl))benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-
(4-hydrooxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy)phenoxy)-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-
(4-hydrooxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
2170479
X-9712 -51-
[6-benzoyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
benzoyloxyphenyl)]benzo[b]thiophene hydrochloride
[6-ethylsulfonyloxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-
2-(4-ethylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-
ethylsulfonyloxyphenyl)]benzo[b]thiophene hydrochloride
[6-ethylsulfonyloxy-3-[4-[2-(l-piperidinyl)ethoxy]-phenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-(4-
triflouromethanesulfonyloxyphenyl)]benzo[b]thiophene
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
benzoyloxyphenyl)]benzo[b]thiophene hydrochloride
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
pivaloyloxyphenyl)]benzo[b]thiophene hydrochloride
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-butylsulfonyl-
oxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(l-piperidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-
2-(4-methoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-methoxyphenyl)]benzo[b]thiophene
2170479
X-9712 -52-
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-benzyloxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-
(4-methoxyphenyl)]benzo[b)thiophene
[6-benzyloxy-3-[4-[2-(1-
hexamethyleneimino)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-benzyloxy-3-[4-[2-(1-N,N-
dimethylamino)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-benzyloxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy)-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy)-2-
(4-methoxyphenyl)]benzo[b)thiophene
[6-isopropoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]-
thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-N,N-
dimethylamino)ethoxy)thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-isopropoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy)-2-(4-
methoxyphenyl)]benzo[b]thiophene
2170479
X-9712 -53-
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]-
thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-methoxyphenyl)]benzo[b)thiophene
[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl))benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]-
thiophenoxy)-2-(4-methoxyphenyl)]benzo[b)thiophene
hydrochloride
[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-methoxyphenyl)]benzo[b)thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy)thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
benzyloxyphenyl)]benzo[b)thiophene
2170479
X-9712 -54-
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxyl-
2-(4-benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-benzyloxyphenyl)]benzo[blthiophene
[6-methoxy-3-[4-[2-(1-morpholino)ethoxylthiophenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxylthiophenoxy]-2-(4-
isopropoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxylthiophenoxy]-2-(4-
isopropoxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxylthiophenoxyl-
2-(4-isopropoxyphenyl)]benzo[blthiophene
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxylthiophenoxy]-
2-(4-isopropoxyphenyl)]benzo[blthiophene
[6-methoxy-3-[4-[2-(1-morpholino)ethoxylthiophenoxy]-2-(4-
isopropoxyphenyl)]benzo[blthiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxylthiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[blthiophene
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxylthiophenoxy]-
2-(4-hydroxyphenyl)]benzo[blthiophene
2 170479
X-9712 -55-
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene
[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
2170479
X-9712 -56-
[6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-pyrrolidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]thiophenoxy]--
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-N,N-dimethylamino)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
[6-hydroxy-3-[4-[2-(1-morpholino)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-phenyl]
benzo[b]thiophene hydrochloride
The following examples are presented to further
illustrate the preparation of compounds of the present
invention. It is not intended that the invention be limited
in scope by reason of any of the following examples.
NMR data for the following Examples were generated
on a GE 300 MHz NMR instrument, and anhydrous d-6 DMSO was
used as the solvent unless otherwise indicated.
2170479
X-9712 -57-
Prevaration 1
Preparation of [3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]
-2-(4-hydroxyphenyl)]benzo[b]thiophene
[3-(4-benzyloxy)phenoxy]benzo[b]thiophene
o
a o
o
Qz
s
To a solution of 3-bromo-benzo[b)thiophene (69.62 g,
0.325 mol) in 55 mL of anhydrous collidine under N2 was added
4-benzyloxyphenol (97.6 g, 0.488 mol) and cuprous oxide (23.3
g, 0.163 mol). The mixture was heated to reflux for 24
hours. Upon cooling, the reaction mixture was diluted with
ethyl acetate (200 mL) and the crude mixture filtered through
a pad of Celite (Aldrich, Milwaukee, WI) to remove inorganic
salts. The filtrate was washed with 1.U hydrochloric acid (3
x 150 mL). The organic was dried (sodium sulfate) and
concentrated in vacuo to a liquid. Thianaphthene was removed
by distillation (10 mm Hg, 115-120 C). The remainder of the
material was chromatographed (silicon dioxide, hexanes: ethyl
acetate 85:15) to provide 12.2 g of benzo[b]thiophene and
12.95 g(35o based on recovered starting material) of [3-(4-
benzyloxy)phenoxy]benzo-[b]thiophene as an off-white solid.
mp 84-86 C. 1H NMR (CDC13) d 7.91-7.83 (m, 2H), 7.47-7.34
(m, 7H), 7.04 (q, JAB = 9.0 Hz, 4H), 6.47 (s, 1H), 5.07 (s,
2H). Anal. Calcd. for C21H1602S: C, 75.88; H, 4.85. Found:
C, 75.75; H, 5.00.
2170479
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Preparation 2
[2-Iodo-3-(4-benzyloxy)phenoxy]benzo-[blthiophene
i
0
0
CCS\ To a solution of [3-(4-benzyloxy)phenoxylbenzo[b]
thiophene (6.00 g, 18.1 mmol) in anhydrous tetrahydrofuran
(100 mL) under N2 at -78 C was added n-butyllithium (12.4
mL, 19.9 mmol, 1.6 M in hexanes) dropwise via syringe. The
solution turned from colorless to deep orange. After
stirring for 20 minutes at -78 C, the lithio species was
treated with 12 (5.03, 19.9 mmol), added dropwise via canula
as a solution in 50 mL of anhydrous tetrahydrofuran. Upon
completion of the addition, the reaction turned light yellow
in color, and was allowed to slowly warm to room temperature.
The reaction was quenched by the addition of 0.1 N sodium
sulfite solution (200 mL). The layers were separated and the
aqueous extracted with ethyl acetate (2 x 150 mL). The
organic was combined, dried (sodium sulfate), and
concentrated in vacuo to give an oil that crystallized on
standing. Recrystallization from hexanes/ethyl ether yielded
7.10 g (86%) of (2-Iodo-3-(4-benzyloxy)phenoxy)benzo[b]
thiophene as a white crystalline powder. mp 87-92 C. 1H
NMR (CDC13) d 7.72 (d, J = 8.1 Hz, 1H), 7.47-7.20 (m, 8H),
6.89 (s, 4H), 5.01 (s, 2H). Anal. Calcd. for C21H1502SI: C,
55.03; H, 3.30. Found: C, 55.29; H, 3.31.
2170479
W...
X-9712 -59-
Prevaration 3
[2-(4-tertbutyloxyphenyl)-3-(4-benzyloxy)phenoxy]
benzo[b]thiophene
i
0
o ~4-
ce>-C~-"~-O
To a solution of [2-Iodo-3-(4-benzyloxy)phenoxy]-
benzo[b]thiophene (4.50 g, 9.82 mmol) in toluene (20 mL) was
added 4-(tertbutoxy)phenyl boronic acid (2.28 g, 11.75 mmol)
followed by tetrakistriphenylphosphinepalladium (0.76 g, 0.66
mmol). To this solution was added 14.5 mL of 21 sodium
carbonate solution. The resulting mixture was heated to
reflux for 3 hours. Upon cooling, the reaction was diluted
with 150 mL of ethyl acetate. The organic was washed with
0.1.N sodium hydroxide (2 x 100 mL) and then dried (sodium
sulfate). Concentration produced a semi-solid that was
dissolved in chloroform and passed through a pad of silicon
dioxide. Concentration produced an oil that was triturated
from hexanes to yield 4.00 g (91%) of [2-(4-tertbutyloxy-
phenyl)-3-(4-benzyloxy)phenoxy]benzo[b]thiophene as a white
powder. mp 105-108 C. 1H NMR (CDC13) d 7.77 (d, J = 7.7 Hz,
1H), 7.68 (d, J= 8.6 Hz, 2H), 7.43-7.24 (m, 8H), 6.98 (d, J
= 8.6 Hz, 2H), 6.89 (q, JAB= 9.3 Hz, 4H), 4.99 (s, 2H), 1.36
(s, 9H). FD mass spec: 480. Anal. Calcd. for C31H2803S: C,
77.47; H, 5.87. Found: C, 77.35; H, 5.99.
2 i 70479
X-9712 -60-
Preparation 4
Prepared in a similar manner employing 4-
methoxyphenylboronic acid was [2-(4-methoxyphenyl)-3-
(4-benzyloxy)phenoxy]benzo[b]-thiophene
i
0
0
a-S\ o~''g3
~ ~
Yield = 73%. mp = 115-118 C. 1H NMR (CDC13) d 7.80-
7.90 (m, 3H), 7.33-7.53 (m, 8H), 6.93-7.06 (m, 6H), 5.00 (s,
2H), 3.83 (s, 3H). FD mass spec: 438. Anal. Calcd. for
C28H2203S: C, 76.69; H, 5.06. Found: C, 76.52; H, 5.09.
Preparation 5
[2-(4-tertbutyloxyphenyl)-3-(4-hydroxy)phenoxy]
benzo[b]thiophene
ao
Q
o ~L
O&O
To a s
olution of [2-(4-tertbutyloxyphenyl)-3-(4-
benzyloxy)phenoxy]benzo[b]thiophene (1.50 g, 3.37 mmol) in 30
mL of absolute ethanol containing 1% concentrated
hydrochloric acid was added 0.50 g of 10% palladium-on-
carbon. The mixture was hydrogenated at 40 psi for 1 hour,
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X-9712 -61-
after which the reaction was judged to be complete by thin
layer chromatography. The mixture was filtered through a pad
of Celite, and the filtrate concentrated in vacuo. The crude
product was dissolved in minimal ethyl acetate and passed
through a short silicon dioxide column to remove Celite
(ethyl acetate as eluant). Concentration provided a white
solid that was triturated from hexanes/ethyl ether.
Filtration provided 868 mg (73%) of [2-(4-tertbutyloxy-
phenyl)-3-(4-hydroxy)phenoxy]-benzo[b]thiophene. mp 210-
213 C. 1H NMR (DMSO-d6) d 9.13 (s, 1H), 7.94 (d, J = 7.7 Hz,
1H), 7.63 (d, J = 8.6 Hz, 2H), 7.35-7.26 (m, 3H), 7.01 (d, J
= 8.6 Hz, 2H), 6.70 (q, JAB = 8.9 Hz, 4H), 1.28 (s, 9H). FD
mass spec: 390. Anal. Calcd. for C24H2203S: C, 73.82; H,
5.68. Found: C, 73.98; H, 5.84.
Preparation 6
Prepared in a similar manner was [2-(4-methoxyphenyl)-
3-(4-hydroxy)phenoxy]benzo[b]thiophene
Ho
/
0
a OCH3
Yield = 80%. mp = 120-125 C. 1H NMR (CDC13) d 7.80-7.90
(m, 3H), 7.48 (m, 1H), 7.30-7.48 (m, 2H), 6.90-7.03 (m, 4H),
6.76-6.86 (m, 2H), 3.82 (s, 3H). FD mass spec: 348; Anal
Calcd. for C21H1603S: C, 72.39; H, 4.63. Found: C, 72.68; H,
4.82.
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X-9712 -62-
Example 1
[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
N ~~ O
/
O
` / OH
c3s\ ~
To a solution of [2-(4-tertbutyloxyphenyl)-3-(4-hydroxy)
phenoxy]benzo[b]thiophene (1.25 g, 3.20 mmol) in anhydrous
N,N-dimethylformamide (10 mL) at ambient temperature was
added cesium carbonate (5.70 g, 17.6 mmol). After stirring
for 20 minutes, 2-chloroethylpiperidine hydrochloride (1.95
g, 10.56 mmol) was added in small portions. The resulting
heterogeneous mixture was stirred vigorously for 24 hours.
The contents of the reaction were then diluted with water
(200 mL). The aqueous phase was extracted with ethyl acetate
(3 x 100 mL). The combined organic layer was then washed with
water (2 x 200 mL). Drying of the organic layer (sodium
sulfate) and concentration in vacuo gave an oil.
Chromatography (5-10% methanol/chloroform) provided 1.47 g
(91%) of 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
tertbutyloxyphenyl)]benzo[b]-thiophene that was carried on
directly to the next step without characterization.
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
tertbutyloxy-phenyl)]benzo[b]thiophene (1.37 g, 2.73 mmol)
was dissolved in triflouroacetic acid (10 mL) at ambient
temperature. After stirring for 15 minutes, the solvent was
removed in vacuo. The residue was dissolved in ethyl acetate
(20 mL) and washed with sat. sodium bicarbonate solution (3 x
10 mL). The organic layer was dried (sodium sulfate) and
concentrated whereupon a white solid precipitated formed in
solution. The product was recrystallized from ethyl acetate-
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X-9712 -63-
ethyl ether to provide 1.03 g (85%) of 3-[4-[2-(1-
piperidinyl)ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]-
thiophene as colorless crystals. mp 169-172 C. 1H NMR
(DMSO-d6) d 9.81 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.54 (d, J
= 8.5 Hz, 2H), 7.36-7.26 (m, 3H), 6.86 (s, 4H), 6.78 (d, J
8.6 Hz, 2H), 4.10 (m, 2H), 3.29 (m, 2H), 2.95-2.75 (m, 4H),
1.68-1.40 (m, 6H). Anal. Calcd. for C27H27N03S=0.55 CF3CO2H:
C, 66.40; H, 5.46; N, 2.76. Found: C, 65.99; H, 5.49; N,
2.61
Example 2
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene was converted to its
hydrochloride salt in 90% yield by treatment with
ethyl ether=hydrochloric acid in ethyl acetate
=Hci
N~,O
/
~ ,
O
cl: &OH
Data for Example 2 mp 233-240 C. 1H NMR (DMSO-d6) d
10.43 (m, 1H), 9.89 (s, 1H), 7.93-7.95 (m, 1H), 7.60-7.64 (m,
2H), 7.35-7.50 (m, 3H), 6.83-7.03 (m, 6H), 4.27-4.30 (m, 2H),
3.40-3.60 (m, 4H), 2.96-3.10 (m, 2H), 1.70-1.95 (m, 5H),
1.40-1.53 (m, 1H). FD mass spec: 446. Anal. Calcd. for
C27H27N03S=1.OHC1: C, 67.28; H, 5.86; N, 2.91. Found: C,
67,07; H, 5.66; N, 2.96.
'2170479
X-9712 -64-
Examnle 3
Prepared in an analogous manner were the following examples:
[3-[4-[2-(1-pyrolidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
G~o
0
~ /- oH
mp 150-155 C. 1H NMR (DMSO-d6) d 9.79 (s, 1H), 7.92 (d,
J = 7.8 Hz, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.36-7.26 (m, 3H),
6.84 (s, 4H), 6.78 )d, J = 8.6 Hz, 2H), 4.00 (bt, 2H), 2.92
(m, 2H), 2.85 (m, 4H), 1.73 (m, 4H). Anal. Calcd. for
C26H25N03S=0.33 CF3CO2H: C, 68.25; H, 5.44; N, 2.99. Found:
C, 68.29; H, 5.46; N, 3.19.
Examvle 4
[3-[4-[2-(1-hexamethyleneimino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
QO
Q
O
aoH
mp 189-191 C. 1H NMR (DMSO-d6) d 7.91 (d, J = 7.6 Hz,
1H), 7.52 (d, J = 8.5 Hz, 2H), 7.34-7.25 (m, 3H), 6.81 (s,
4H), 6.75 (d, J= 8.6 Hz, 2H), 3.89 (bt, 2H), 2.75 (bt, 2H),
2.68 (m, 4H), 1.48 (m, 8H). Anal. Calcd. for C28H29N03S=1.50
2170479
X-9712 -65-
H20: C, 69.11; H, 6.79; N, 2.88. Found: C, 69.25; H, 6.79;
N, 2.58.
Example 5
[3-[4-[2-(1-N,N-diethylamino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
~N 0
O
` / OH
mp 70 C. 1H NMR (DMSO-d6) d 9.91 (bs, 1H), 7.92 (d, J
7.9 Hz, 1H), 7.54 (d, J 8.6 Hz, 2H), 7.35-7.24 (m, 3H),
6.82 (s, 4H), 6.78 (d, J 8.6 Hz, 2H), 3.88 (bt, 2H), 2.76
(bt, 2H), 2.51 (m, 4H), 0.91 (m, 6H). FD mass spec: 434.
Anal. Calcd. for C26H27N03S=0.50 H20: C, 70.56; H, 6.38; N,
3.16 Found: C, 70.45; H, 6.26; N, 3.20.
Examiple 6
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
=aC1
N-"~O
Q
O
C~S\ OCH3
~ ~
mp = 228-230 C. 1H NMR (DMSO-d6) d 7.96 (d, J = 7.5 Hz,
1H), 7.66 (d, J = 8.8 Hz, 2H), 7.35-7.50 (m, 3H), 6.98 (d, J
= 8.7 Hz, 2H), 6.86-6.90 (m, 4H), 4.28-4.31 (m, 2H), 3.74 (s,
21'70479
X-9712 -66-
3H), 3.37-3.45 (m, 4H), 2.92-2.96 (m, 2H), 2.46-2.48 (m, 5H),
1.74 (m, 1H). FD mass spec: 459. Anal Calcd. for
C28H29N03S=1.OHC1: C, 67.80; H, 6.10; N, 2.82. Found: C,
68.06; H, H, 6.38; N, 2.60.
Alternate Synthesis of [2-(4-tertbutyloxyphenyl)-3-(4-
benzyloxy)phenoxy]benzo[b]thiophene
Prevaration 7
[3-(4-benzyloxy)phenoxy]benzo[b]thiophene-2-
boronic acid
0
0
I \ $-B(0H)2
To a-78 C solution of [3-(4-benzyloxy)phenoxy]benzo
[b]-thiophene (5.00 g, 15.1 mmol) in 20 mL of anhydrous
tetrahydrofuran under N2 was added n-butyllithium (9.90 mL,
15.8 mmol, 1.6 M in hexanes) dropwise via syringe. After
stirring for 15 minutes, B(OiPr)3 (3.83 mL, 16.6 mmol) was
added via syringe, and the resulting mixture was allowed to
warm to 0 C. The reaction was then quenched by distributing
between ethyl acetate and 1.0hl hydrochloric acid (100 mL
each). The layers were separated and the organic was
extracted with water (1 x 100 mL). The organic layer was
dried (sodium sulfate) and concentrated in vacuo to a solid
that was triturated from ethyl ether/hexanes. Filtration
provided 3.96 g (70%) of [3-(4-benzyloxy)phenoxy]
benzo[b]thiophene-2-boronic acid as a white solid. mp 115-
121 C. 1H NMR (DMSO-d6) d 8.16 (d, J = 8.5 Hz, 1H), 7.98 (d,
2 170479
X-9712 -67-
J= 9.0 Hz, 1H), 7.42-7.23 (m, 7H), 6.90 (q, JAB = 9.0 Hz,
4H), 5.01 (s, 2H). Anal. Calcd. for C21H1704SB: C, 67 04;
H, 4.55. Found: C, 67.17; H, 4.78.
[3-(4-Benzyloxy)phenoxy]benzo[b]thiophene-2-boronic acid
was reacted with 4-(-tertbutoxy)bromobenzene according to the
conditions described above for [2-iodo-3-(4-benzyloxy)
phenoxy]-benzo[b]thiophene and 4-(tertbutoxy)phenyl boronic
acid to give [2-(4-tertbutyloxyphenyl)-3-(4-
benzyloxy)phenoxy]benzo[b] thiophene in 81% yield.
Examples prepared by employing this method are:
Examiple 7
[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(phenyl)]benzo [b]thiophene hydrochloride
=acl
Qo
,
O
mp 223-226 C. 1H NMR (DMSO-d6) d 7.99 (d, J= 8.2 Hz,
1H), 7.71 (d, J = 7.3 Hz, 1H), 7.44-7.30 (m, 7H), 6.90 (s,
4H), 4.27 (m, 2H), 3.43-3.35 (m, 4H), 2.97-2.88 (m, 2H),
1.73-1.61 (m, 5H), 1.34 (m, 1H). Anal. Calcd. for
C27H27NO2S=1.0 HC1: C, 69.59; H, 6.06; N, 3.00. Found: C,
69.88; H, 6.11; N, 3.19.
2170479
X-9712 -68-
Example 8
[3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
flourophenyl)]benzo[b]thiophene
=HCi
O
/
~ /
O
CQ -a
mp 219-226 C. 1H NMR (DMSO-d6) d 10.20 (bs, 1H), 7.99
(d, J = 8.2 Hz, 1H), 7.77-7.73 (m, 4H), 7.42-7.25 (m, 5H),
6.90 (s, 4H), 4.27 (m, 2H), 3.44-3.31 (m, 4H), 2.96-2.89 (m,
2H), 1.78-1.61 (m, 5H), 1.34 (m, 1H). FD mass spec: 447.
Anal. Calcd. for C27H26N02SF=1.0 HC1: C, 67.00; H, 5.62; N,
2.89. Found: C, 67.26; H, 5.67; N, 3.03.
Prevaration 8
Synthesis of [6-Hydroxy-3-[4-[2-(1-
piperidinyl)ethoxy]-phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo-
[b]thiophene
Br
OCH3
H3CO 25
To a solution of [6-methoxy-2-(4-methoxyphenyl)]benzo
[b]thiophene (27.0 g, 100 mmol)in 1.10 L of chloroform at
60 C was added bromine (15.98 g, 100 mmol) dropwise as a
solution in 200 mL of chloroform. After the addition was
complete, the reaction was cooled to room temperature, and
2170479
X-9712 -69-
the solvent removed in vacuo to provide 34.2 g (100%) of [6-
methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene as a
white solid. mp 83-85 C. 1H NMR (DMSO-d6) d 7.70-7.62 (m,
4H), 7.17 (dd, J = 8.6, 2.0 Hz, 1H), 7.09 (d, J= 8.4 Hz,
2H). FD mass spec: 349, 350. Anal. Calcd. for C16H13O2SBr:
C, 55.03; H, 3.75. Found: C, 54.79; H, 3.76.
Examvle 9
[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)
phenoxy]-benzo[b]thiophene
i
0
0
I \ \ OCH3
H3C0 )O: ` ~
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-bromo]
benzo[b]thiophene (34.00 g, 97.4 mmol) in 60 mL of collidine
under N2 was added 4-benzyloxyphenol (38.96 g, 194.8 mmol)
and cuprous oxide (14.5 g, 97.4 mmol). The resultant mixture
was heated to reflux for 48 hours. Upon cooling to room
temperature, the mixture was dissolved in acetone (200 mL),
and the inorganic solids were removed by filtration. The
filtrate was concentrated in vacuo, and the residue dissolved
in methylene chloride (500 mL). The methylene chloride
solution was washed with 3,U hydrochloric acid (3 x 300 mL),
followed by 1H sodium hydroxide (3 x 300 mL). The organic
layer was dried (sodium sulfate), and concentrated in vacuo.
The residue was taken up in 100 mL of ethyl acetate whereupon
a white solid formed that was collected by filtration
(recovered [6-methoxy-2-(4-methoxyphenyl)]benzo-[b]thiophene
(4.62 g, 17.11 mmol]. The filtrate was concentrated in
2170479
X-9712 -70-
vacuo, and then passed through a short pad of silica gel
(methylene chloride as eluant) to remove baseline material.
The filtrate was concentrated in vacuo, and the residue
crystallized from hexanes/ethyl acetate to provide initially
7.19 g of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
benzyloxy)phenoxy]benzo[b]-thiophene as an off-white
crystalline solid. The mother liquor was concentrated and
chromatographed on silica gel (hexanes/ethyl acetate 80:20)
to provide an additional 1.81 g of product. Total yield of
[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phenoxy]-
benzo[b]thiophene was 9.00 g (24% based on recovered starting
material). The basic extract was acidified to pH = 4 with 5N
hydrochloric acid, and the resultant precipitate collected by
filtration and dried to give 13.3 g of recovered 4-
benzyloxyphenol. mp 100-103 C. 1H NMR (CDC13): d 7.60 (d, J
= 8.8 Hz, 2H), 7.39-7.24 (m, 7H), 6.90-6.85 (m, 7H), 4.98 (s,
2H), 3.86 (s, 3H) 3.81 (s, 3H). FD mass spec: 468. Anal.
Calcd. for C29H2404S: C, 74.34; H, 5.16. Found: C, 74.64; H,
5.29.
Prevaration 9
[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)-
phenoxy]benzo[b]thiophene
ao
0
~g3
g3`O )O~ $ a
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
benzyloxy)phenoxy]benzo[b]thiophene (1.50 g, 3.20 mmol) in 50
mL of ethyl acetate and 10 mL of 1% concentrated hydrochloric
acid in ethanol was added 10% palladium-on-carbon (300 mg).
The mixture was hydrogenated at 40 psi for 20 minutes, after
2i 104/y
X-9712 -71-
which time the reaction was judged complete by thin layer
chromatography. The mixture was passed through Celite to
remove catalyst, and the filtrate concentrated in vacuo to a
white solid. The crude product was passed through a pad of
silica gel (chloroform as eluant). Concentration provided
1.10 g (91%) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
hydroxy)phenoxy]benzo[b]-thiophene as a white solid. mp 123-
126 C. 1H NMR (DMSO-d6) d 9.10 (s, 1H), 7.59 (d, J = 8.8 Hz,
2H), 7.52 (d, J= 2.1 Hz, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.95
(d, J = 8.8 Hz, 2H), 6.89 (dd, J = 8.8, 2.1 Hz, 1H), 6.72 (d,
J = 9.0 Hz, 2H), 6.63 (d, J = 9.0 Hz, 2H), 3.78 (s, 3H), 3.72
(s, 3H). FD mass spec: 378. Anal. Calcd. for C22H1804S: C,
69.82; H, 4.79. Found: C, 70.06; H, 4.98.
Examvle 10
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxY7-phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene.
=aO2ccosa
N O
/
~ ,
O
OCH3
$,co
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
hydroxy)phenoxy]benzo[b]thiophene (1.12 g, 2.97 mmol) in 7 mL
of anhydrous N, N- dime thyl f ormamide under N2 was added cesium
carbonate (3.86 g, 11.88 mmol). After stirring for 10
minutes, 2-chloroethylpiperidine hydrochloride (1.10 g, 1.48
mmol) was added. The resultant mixture was stirred for 18
hours at ambient temperature. The reaction was the
distributed between chloroform/water (100 mL each). The
layers were separated and the aqueous extracted with
chloroform (3 x 50 mL). The organic was combined and washed
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X-9712 -72-
with water (2 x 100 mL). Drying of the organic (sodium
sulfate) and concentration provided an oil that was
chromatographed on silica gel (2% methanol/chloroform). The
desired fractions were concentrated to an oil that was
dissolved in 10 mL of ethyl acetate and treated with oxalic
acid (311 mg, 3.4 mmol). After stirring for 10 minutes, a
white precipitate formed and was collected by filtration and
dried to provide 1.17 g (70%) overall of [6-methoxy-3-[4-[2-
(1-piperidinyl)ethoxy]-phenoxy]-2-(4-methoxyphenyl)]benzo[b]
thiophene as the oxalate salt. mp 197-200 C (dec) . 1H NMR
(DMSO-d6) d 7.60 (d, J= 8.7 Hz, 2H), 7.55 (d, J = 1.1 Hz,
1H), 7.14 (d, J= 8.8 Hz, 1H), 7.06 (d, J= 8.8 Hz, 2H), 6.91
(dd, J= 8.8, 1.1 Hz, 1H), 6.87 (s, 4H), 4.19 (broad t, 2H),
3.78 (s, 3H), 3.72 (s, 3H), 3.32 (broad t, 2H), 3.12-3.06 (m,
4H), 1.69-1.47 (m, 4H), 1.44-1.38 (m, 2H). FD mass spec: 489
. Anal. Calcd. for C29H31N04S=0.88 H02CC02H: C, 64.95; H,
5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54.
Examvle 11
Treatment of free base with ethyl ether=hydrochloric
acid provided [6-methoxy-3-[4-[2-(1-
piperidinyl)ethoxy]-phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
=ac1
O
I
~ ,
~ ~ ~ ~ h Oc$3
83CO
mp 216-220 C. 1H NMR (DMSO-d6) d 10.20 (bs, 1H), 7.64
(d, J = 8.7 Hz, 2H), 7.59 (d, J= 1.5 Hz, 1H), 7.18 (d, J=
9.0 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.96 (dd, J = 9.0, 1.5
Hz, 1H), 6.92 (q, JAB= 9.0 Hz, 4H), 4.31 (m, 2H), 3.83 (s,
3H), 3.77 (s, 3H), 3.43 (m, 4H), 2.97 (m, 2H), 1.77 (m, 5H),
2170479
X-9712 -73-
1.37 (m, 1H). FD mass spec: 489 . Anal. Calcd. for
C29H31N04S=1.0 HC1: C, 66.21; H, 6.13; N, 2.66. Found: C,
66.,46; H, 6.16; N, 2.74.
Prepared in an analogous manner were the following examples:
Examflle 12
[6-Methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene
a-oo
)O~ OCH3
$3Co
mp 95-98 C. 1H NMR (DMSO-d6) d 7.64 (d, J = 9.0 Hz, 2H),
7.58 (d, J = 2.0 Hz, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.00 (d,
J = 9.0 Hz, 2H), 6.94 (dd, J = 9.0, 2.0 Hz, 1H), 6.86 (s,
4H), 3.97 (t, J= 6.0 Hz, 2H), 3.83 ( s, 3H), 3.76 (s, 3H),
2.73 (t, J= 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 4H). FD
mass spec: 477. Anal. Calcd. for C28H29N04S: C, 70.71; H,
6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.
2 i 70479
X-9712 -74-
Fxamnle 13
[6-Methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]
phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene
hydrochloride
QN-"~ O
O
j)~ OCH3
H3C0
mp 189-192 C. 1H NMR (DMSO-d6) d 10.55 (bs, 1H), 7.64
(d, J = 9.0 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.19 (d, J =
9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0
Hz, H), 6.86 (s, 4H), 3.94 (t, J= 6.0 Hz, 2H), 3.83 (s, 3H),
3.76 (s, 3H), 2.80 (t, J= 6.0 Hz, 2H), 2.66 (m, 4H), 1.53
(m, 8H). Anal. Calcd. for C3oH33N04S=1.0 HC1: C, 66.71; H,
6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.
Examt)le 14
[6-Methoxy-3- [4- [2- ( 1-N, N-
diethylamino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
=HCi
Tr0
O
` ` ~ ~H3
~~ s
H3C0
2170479
X-9712 -75-
mp 196-198 C. 1H NMR (DMSO-d6) d 10.48 (bs, 1H), 7.64
(d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.19 (d, J =
9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0
Hz, 1H), 6.87 (q, JAB = 9.0 Hz, 4H), 4.25 (m, 2H), 3.83 (s,
3H), 3.77 (s, 3H), 3.54 (m, 2H), 3.09 (m, 4H), 2.00 (m, 3H),
1.88 (m, 3H). Anal. Calcd. for C28H31N04S=1.5 HC1: C, 63.18;
H, 6.15; N, 2.63. Found: C, 63.46; H, 5.79; N, 2.85.
$xamvle 15
[6-Methoxy-3-[4-[2-(morpholino)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
=HC1
Qo
I ~ ` / OcH,
H3C0 S
mp 208-211 C. 1H NMR (DMSO-d6) d 10.6 (bs, 1H), 7.63
(d, J = 9.0 Hz, 2H), 7.60 (d, J= 2.0 Hz, 1H), 7.20 (J = 9.0
Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.97 (dd, J = 9.0, 2.0 Hz,
1H), 6.91 (q, JAB = 9.0 Hz, 4H), 4.29 (m, 2H), 4.08-3.91 (m,
4H), 3.82 (s, 3H), 3.77 (s, 3H), 3.59-3.42 (m, 4H), 3.21-3.10
(m, 2H). Anal. Calcd. for C28H29N05S=1.0 HC1: C, 63.09; H,
5.73; N, 2.65. Found: C, 63.39; H, 5.80; N, 2.40.
2170479
X-9712 -76-
Examvle 16
[6-Methoxy-3-[4-[3-(piperidino)propoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
ON =HC1
0
I OCH3
H3CO mp 195-200 C. 1H NMR (DMSO-d6) d 9.90 (bs, 1H), 7.64
(d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.18 (d, J =
9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J = 9.0, 2.0
Hz, 1H), 6.88 (s, 4H), 3.97 (t, J= 6.0 Hz, 2H), 3.83 (s,
3H), 3.77 (s, 3H), 3.44 (m, 2H), 3.15 (m, 2H), 2.87 (m, 2H),
2.12 (m, 2H), 1.77 (m, 5H), 1.39 (m, iH). Anal. Calcd. for
C30H33N04S=1.15 HC1: C, 66.01; H, 6.40; N, 2.73. Found: C,
66.01; H, 6.40; N, 2.73.
Examr)le 17
[6-Methoxy-3- [4- [3- ( 1-N, N-
diethylamino)propoxy]phenoxy]-2-(4-methoxyphenyl)]
benzo[b]thiophene hydrochloride
=HC1
O
/
~ /
O
JO: ` /oCH3
H3C0
2170479
X-9712 -77-
mp 164-166 C. 1H NMR (DMSO-d6) d 9.77 (bs, 1H), 7.64
(d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0 Hz, 1H), 7.18 (d, J =
9.0 Hz, 1H), 7.00 (d, J = 9.0 Hz, 2H), 6.95 (dd, J= 9.0, 2.0
Hz, 1H), 6.89 (s, 4H), 3.99 (t, J = 6.0 Hz,2H), 3.83 (s, 3H),
3.77 (s, 3H), 3.15 (m, 6H), 2.06 (m, 2H), 1.20 (t, J= 7.0
Hz, 6H). Anal. Calcd. for C29H33N04S=1.0 HC1: C, 65.96; H,
6.49; N, 2.65. Found: C, 66.25; H, 6.64; N, 2.84.
Examr)le 18
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
(4-hydroxyphenyl)]benzo[b]thiophene
O
Q
O
OH
Ho s
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride (10.00 g,
19.05 mmol) was dissolved in 500 mL of anhydrous methylene
chloride and cooled to 8 C. To this solution was added
boron tribromide (7.20 mL, 76.20 mmol). The resultant mixture
was stirred at 8 C for 2.5 hours. The reaction was quenched
by pouring into a stirring solution of saturated sodium
bicarbonate (1 L), cooled to 0 C. The methylene chloride
layer was separated, and the remaining solids were dissolved
in methanol/ethyl acetate. The aqueous layer was then
extracted with 5% methanol/ethyl acetate (3 x 500 mL). All
of the organic extracts (ethyl acetate and methylene
chloride) were combined and dried (sodium sulfate).
Concentration in vacuo provided a tan solid that was
chromatographed (silicon dioxide, 1-7% methanol/chloroform)
to provide 7.13 g (81 %) of [6-hydroxy-3-[4-[2-(1-
2170479
X-9712 -78-
piperidinyl) ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]-
thiophene as a white solid. mp 93 C. 1H NNR (DMSO-d6) d 9.73
(bs, 1H), 9.68 (bs, 1H), 7.45 (d, J= 8.6 Hz, 2H), 7.21 (d, J
= 1.8 Hz, 1H), 7.04 (d, J= 8.6 Hz, 1H), 6.84 (dd, J= 8.6,
1.8 Hz, 1H (masked)), 6.81 (s, 4H), 6.75 (d, J= 8.6 Hz, 2H),
3.92 (t, J= 5.8 Hz, 2H), 2.56 (t, J= 5.8 Hz, 2H), 2.36 (m.
4H), 1.43 (m, 4H), 1.32 (m, 2H). FD mass spec: 462. Anal.
Calcd. for C27H27N04S: C, 70.20; H, 5.90; N, 3.03. Found: C,
69.96; H, 5.90; N, 3.14.
Examvle 19
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-hydroxyphenyl)]benzo[b]thiophene is converted to
its oxalate salt in 80gs yield by the procedure
described above. Data for [6-hydroxy-3-[4-[2-(1-
piperidinyl)-ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene oxalate
= aO2ccO2H
Qo
/
~ /
O
08
gO
mp 246-249 C (dec) . 1H NMR (DMSO-d6) d 7.45 (d, J 8.6
Hz, 2H), 7.22 (d, J = 1.8 Hz, 1H), 7.05 (d, J = 8.6 Hz, 1H),
6.87 (dd, J = 8.6, 1.8 Hz, 1H (masked)), 6.84 (s, 4H), 6.75
(d, J = 8.6 Hz, 2H), 4.08 (bt, 2H), 3.01 (bt, 2H), 2.79 (m,
4H), 1.56 (m, 4H), 1.40 (m, 2H). FD mass spec 462. Anal.
Calcd. for C27H27N04S=0.75 HO2CCO2H: C, 64.63; H, 5.42; N,
2.64. Found: C, 64.61; H, 5.55; N, 2.62.
2170479
X-9712 -79-
Example 20
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-hydroxyphenyl)]benzo[b] thiophene was converted to
its hydrochloride sait in 91% yield by treatment of
the free base in ethyl acetate with ethyl
ether=hydrochloric acid. Data for [6-hydroxy-3-[4-[2-
(1-piperidinyl)ethoxy]-phenoxy]-2-(4-
hydroxyphenyl)]benzo [b]thiophene hydrochloride
=aci
Qo
Q
O
c \ o$
Ho s
mp 158-165 C. 1H NMR (DMSO-d6) d 9.79 (s, 1H), 9.74 (s,
1H), 7.40 (d, J= 8.6 Hz, 2H), 7.23 (d, J = 2.0 Hz, 1H), 7.04
(d, J= 8.6 Hz, 1H), 6.86 (q, Jp,B = 9.3 Hz, 4H), 6.76 (dd, J
8.6, 2.0 Hz, 1), 6.74 (d, J= 8.6 Hz, 2H), 4.26 (bt, 2H),
3.37 (m, 4H), 2.91 (m, 2H), 1.72 (m, 5 H), 1.25 (m, 1H). FD
mass spec 461. Anal. Calcd. for C27H27N04S=1.0 HC1: C, 65.11;
H, 5.67; N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.
Prepared in an analogous manner were the following examples:
CA 02170479 2007-08-10
X-9712 =80-
$xaaflla~ 11
[ 6 -Hydroxy-3 -:[4 - [2- (1-pyrrolidinyl) ethoxylphenoxy] -2-
( 4 -hydroxyphenyl ) ] benso [:b] t:bi-oDhene .
~~=~ .
0
oe
to $.
mp 99-113 C. IH-NMR E-DMSO-d6) d 9.75 Is, 111), 9'.71 (s,
1H) , 7.510 (d, J =. 9 ~0 Hz, 2H), 7,25 (d, 2,0 Hz, lfO , 7.09
Ifl td, J 9p0 Hz, 1H~, 6:.85 (s, 11), 6,80 ddd., J= 9Ø 2.0 Hz;
1i3) , 6...79 (d, .7 = 9.;0 Hz,. 2H)-, 3~i93 Im, 2H) , 2.73 (m, 2H) ,
2.53 Em* 4H)., 0,96 (t, J= 7.0 Hzs 4H),. Anal!- Calcd. for
C26xj5NO4S=0;-5 H20t C, 68.40; H,. 5.74<; N, 3.07:,: Foiund: C,
68.52; H.,. 6:,;00s N, 3.34,
$'xam~Ie a2
[4~-Hydroxy-3-[.4-[2-(I-hexamethyleneimino)ethoxy)
phenoxy) -Z - ( ~ -bydroacypheayl ) ~ benza [:b J thiophen.e
0
g0. A
titp 125-.130 C. 1E NMR-.(.IMSO-d6) d 9675 (s, 2H) , 9%71: (s,
IH), 7..50 (d, J= 9.0 Hz, 2H), 7,26 Ed, J= 2 x0 Hz, 1H) ,?r,09
(d, J= 9.0 Hz. 1H), .6::p85: (s, 3H), 6.80 (dd, J= 9.0, 2 r:0 Hz,
1H), 6x,79 (d, J- 9.0 Hz)', 3.94 (t, J= f Q0 Hz, .2H) ,-Z. 80 (t,
J= 6,.0 Hz, 2H), 2:y,.66 (mm, aH) , 1. 53 (m, 8H). Anal. Caldd,. for
217047`-)
X-9712 -81-
C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C, 70.67; H,
6.31; N, 2.93.
Example 23
[6-Hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]
phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene
0
c \ OH
so s
mp 137-141 C. 1H NMR (DMSO-d6) d 9.75 (s, 1H) , 9.71 (s,
1H), 7.49 (d, J = 9.0 Hz, 1H), 7.25 (d, j = 2.0 Hz, 1H), 7.09
(d, J= 9.0 Hz, 1H), 6.85 (s, 4H), 6.80 (dd, J= 9.0, 2.0 Hz,
1H), 6.79 (d, J= 9.0 Hz, 2H), 3.95 (t, J= 6.0 Hz, 2H), 2.74
(t, J= 6.0 Hz, 2H), 2.51 (m, 4H), 1.66 (m, 6H). Anal.
Calcd. for C26H27N04S: C, 69.46; H, 6.05; N, 3.12. Found: C,
69.76; H, 5.85; N, 3.40.
Examt)le 24
[6-Hydroxy-3-[4-[2-(morpholino)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
=ac1
rN~o
0 ~
v .~
0
ao$
ao
2170479
X-9712 -82-
mp 157-162 C. 1H NMR (DMSO-d6) d 10.60 (bs, 1H), 9.80
(s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.28 (d, J
~B = 9.0
= 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.92 (q, JA
Hz, 4H), 6.81 (dd, J = 9.0, 2.0 Hz, 1H), 6.80 (d, J = 9.0 Hz,
2H), 4.30 (m, 2H), 3.95 (m, 2H), 3.75 (m, 2H), 3.51 (m, 4H),
3.18 (m, 2H). Anal. Calcd. for C26H25N05S=HC1: C, 62.46; H,
5.24; N, 2.80. Found: C, 69.69; H, 5.43; N, 2.92.
Examnle 25
[6-Hydroxy-3-[4-[3-(1-N,N-diethylamino)
propoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo
[b]thiophene hydrochloride
=HC1
O
/
~ ,
OH
HO O s
mp 185-191 C. 1H NMR (DMSO-d6) d 9.94 (bs, 1H), 9.81
(s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27 (dd, J
= 2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80
(dd, J = 9.0, 2.0 Hz, 1H), 6.79 (d, J = 9.0 Hz, 2H), 3.99 (t,
J= 6.0 Hz, 2H), 3.14 (m, 6H), 2.08 (m, 2H), 1.20 (t, J = 6.0
Hz, 6H). Anal. Calcd. for C27H29N04S=1.30HC1: C, 63.46; H,
5.98; N, 2.74. Found: C, 63.23; H, 6.03; N, 3.14.
21170479
X-9712 -83-
Examnle 26
[6-Hydroxy-3-[4-[2-(1-N,N-diisopropylamino)-
ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene
hydrochloride
=gcl
NO
O
Og
go s
mp 128-131 C. 1H NMR (DMSO-d6) d 9.81 (bs, 1H), 9.76
(s, 1H), 9.02 (s, 1H), 7.49 (d, J= 9.0 Hz, 2H), 7.28 (m,
1H), 7.09 (d, J = 9.0 Hz, 1H), 6.90 (s, 4H), 6.79 (m, 3H),
4.19 (m, 2H), 3.68 (m, 2H), 3.50 (m, 2H). 1.31 (m, 12H).
Anal. Calcd. for C28H31N04S=1.33HC1: C, 63.92; H, 6.19; N,
2.66. Found: C, 63.82; H, 6.53; N, 2.61.
Example 27
[6-Hydroxy-3-[4-[3-(piperidino)propoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene hydrochloride
oO
~
~ ,
O
~ oR
ao s
mp 258-262 C. 1H NMR (DMSO-d6) d 9.85 (bs, 1H), 9.81
(s, 1H), 9.75 (s, 1H), 7.50 (d, J = 9.0 Hz, 2H), 7.27 (d, J
2170479
X-9712 -84-
2.0 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 6.87 (s, 4H), 6.80
(dd, J= 9.0, 2.0 Hz, 1H), 6.79 (d, J= 9.0 Hz, 2H), 3.97 (t,
J= 6.0 Hz, 2H), 3.44 (m, 2H), 3.15 (m, 2H), 2.88 (m, 2H),
2.11 (m, 2H), 1.73 (m, 5H), 1.39 (m, 1H). Anal. Calcd. for
C28H29NO4S=0.75HC1: C, 66.87; H, 5.96; N, 2.78. Found: C,
67.04; H, 5.90; N, 2.68.
Alternatively, as shown in Scheme III, supra, Example 19
was prepared using the methoxymethyl (MOM) protecting groups
in place of methoxy. The methods are directly analogous to
those just described, with the exception that the MOM groups
are removed in the final step by acid hydrolysis.
Prevaration 10
[6-Methoxy-2-(4-methoxmethyloxyphenyl)-3-(4-benzyloxy)
phenoxy]benzo[b]thiophene
0
I \ ` OCH2OCH3
H3COH2CO mp 94-96 C. 1H NMR (DMSO-d6) d 7.65 (d, J = 2.0 Hz,
1H), 7.64 (d, J = 8.6 Hz, 2H), 7.43-7.32 (m, 5H), 7.23 (d, J
= 8.8 Hz, 1H), 7.08 (d, J=8.6 Hz, 2H), 7.04 (dd, J = 8.8,
2.0 Hz, 1H), 6.92 (q, Jp,B = 9.2 Hz, 4H), 5.26 (s, 2H), 5.21
(s, 2H), 5.01 (s, 3H), 3.40 (s, 3H), 3.37 (s, 3H). FD mass
spec 528.
2170479
X-9712 -85-
Prevaration 11
[6-Methoxy-2-(4-methoxmethyloxyphenyl)-3-
(4-hydroxy)phenoxy]benzo[b]thiophene
HO
O
OCHzOCH3
H3COH6CO
mp 90-91 C. 1H NMR (DMSO-d6) d 9.15 (s, 1H), 7.65 (d, J
= 8.1 Hz, 2H), 7.63 (d, J = 2.0 Hz, 1H), 7.22 (d, J= 8.8 Hz,
1H), 7.05 (dd, J = 8.8, 2.0 Hz, 1H), 6.72 (q, JAB = 9.1 Hz,
4H), 5.26 (s, 2H), 5.21 (s, 2H), 3.40 (s, 3H), 3.37 (s, 3H).
FD mass spec 438. Anal. Calcd. for C24H2206S: C, 65.74; H,
5.06. Found: C, 65.50; H, 4.99.
Mxamnle 28
[6-Methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]
thiophene-(S-oxide)
sr
OCH3
H3CO /
11
O
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-
bromo]benzo [b]thiophene (10.0 g, 28.6 mmol) in 50 mL of
anhydrous methylene chloride was added 50 mL of
triflouroacetic acid. After stirring for 5 minutes, hydrogen
peroxide (4.0 mL, 28.6 mmol, 30% aqueous solution) was added.
The resulting mixture was stirred at ambient temperature for
2 hours. Solid sodium bisulfite (1.25 g) was added to the
dark solution followed by 15 mL of water. The mixture was
stirred vigorously for 15 minutes then concentrated in vacuo.
2170479
X-9712 -86-
The residue was partitioned between chloroform saturated
sodium bicarbonate solution (200 mL ea.). The layers were
separated and the organic layer was extracted with saturated
sodium bicarbonate solution. The organic layer was then
dried (sodium sulfate) and concentrated in vacuo to a solid
that was triturated from ethyl ether/ethyl acetate.
Filtration provided 8.20 g(800) of [6-methoxy-2-(4-
methoxyphenyl)-3-bromo]benzo [b]thiophene-(S-oxide) as a
yellow solid that can be recrystallized from ethyl acetate.
m.p. 170-173 C. 1H NMR (DMSO-d6) d 7.24 (d, J = 2.2 Hz, 1H),
7.68 (d, J= 8.8 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.26 (dd,
J= 8.5, 2.2 Hz, 1H), 7.10 (d, J = 8.8 H, 2H), 3.86 (s, 3H),
3.80 (s, 3H). Anal. Calcd. for C16H1303SBr: C, 52.62; H,
3.59. Found: C, 52.40; H, 3.55.
Examnle 29
Prepared in an analogous manner was [2-(4-
methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-oxide).
Br
` OCH3
Ao s ` h
11
0
mp 120-125 C. 1H NMR (DMSO-d6) d 8.06 (d, J = 7.6 Hz, 1H),
7.78-7.59 (m, 5H), 7.13 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H). FD
mass spec: 335. Anal. Calcd. for C15H1102SBr: C, 53.75; H,
3.31. Found: C, 53.71; H, 3.46.
211 70479
X-9712 -87-
grevaration 12
Preparation of 4-(2-(1-piperidinyl)ethoxy)-phenol.
I 0v _N
gO
To a solution of 4-benzyloxyphenol (50.50 g, 0.25 mol)
in 350 mL of anhydrous DMF was added 2-chloroethylpiperidine
(46.30 g, 0.25 mol). After stirring for 10 minutes,
potassium carbonate (52.0 g, 0.375 mol) and cesium carbonate
(85.0 g, 0.25 mol) were added. The resulting heterogeneous
mixture was stirred vigorously at ambient temperature for 48
hours. The reaction was then poured into water (500 mL) and
extracted with methylene chloride. The organic was then
extracted with 1 N sodium hydroxide several times and finally
washed with brine. The organic layer was then dried (sodium
sulfate) and concentrated in vacuo to an oil. Chromatography
(Si02, 1:1 hexanes/ethyl acetate) provided 60.0 g (77%) of 4-
[2-(1-piperidinyl)ethoxy]phenoxybenzyl ether as a colorless
oil. 1H NMR (DMSO-d6) d 7.40-7.27 (m, 5H), 6.84 (q, JAB =
11.5 Hz, 4H), 4.98 (s, 2H), 3.93 (t, J= 6.0 Hz, 2H), 2.56
(t, J= 6.0 Hz, 2H), 2.35-2.37 (m, 4H), 1.48-1.32 (m, 6H)..
FD mass spec: 311. Anal. Calcd. for C20H25N02: C, 77.14; H,
8.09; N, 4.50. Found: C, 77.34; H, 8.18; N, 4.64.
4-[2-(1-Piperidinyl)ethoxy]phenoxybenzyl ether (21.40 g,
68,81 mmol) was dissolved in 200 mL of 1:1 EtOH/EtOAc
containing 1% con. HC1. The solution was transferred to a
Parr bottle, and 5% palladium-on-carbon (3.4 g) was added.
The mixture was hydrogenated at 40 psi for 2 hours. The
mixture was then passed through a plug of Celite to remove
catalyst. The filtrate was concentrated in vacuo to a solid
that was slurried in ethyl ether and filtered to provide
12.10 g (83%) of 4-(2-(1-piperidinyl) ethoxy)-phenol. mp 148-
150 C. 1H NMR (DMSO-d6) d 8.40 (s, 1H), 6.70 (q, Jpg = 11.5
Hz, 4H), 3.93 (t, J= 6.0 Hz, 2H), 2.59 (t, J= 6.0 Hz, 2H),
2i iv4 79
X-9712 -88-
2.42-2.38 (m, 4H), 1.52-1.32 (m, 6H). FD mass spec: 221.
Anal. Calcd. for C13H19N02: C, 70.56; H, 8.09; N, 4.50.
Found: C, 70.75; H, 8.59; N, 6.54.
Example 30
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)
O
Q
O
I `
` / OCH3
H 3C0 /
O
To a solution of 4-(2-(1-piperidinyl)ethoxy)-phenol
(0.32 g, 1.43 mmol) in 5 mL of anhydrous DMF at ambient
temperature was added sodium hydride (0.57 g, 1.43 mmol, 60%
dispersion in mineral oil). After stirring for 15 minutes,
[6-methoxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-
oxide) (0.50 g, 1.37 mmol) was added in small portions.
After stirring for 1 hour, the reaction was judged complete
by TLC analysis. The solvent was removed in vacuo, and the
residue was distributed between water and 10% ethanol/ethyl
acetate. The organic was washed several times with water and
then dried (sodium sulfate). Concentration in vacuo gave an
oil that was triturated from ethyl acetate/hexanes to provide
0.62 g (89%) of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]
phenoxy)-2-(4-methoxyphenyl)]benzo [b]thiophene-(S-oxide)- as
a light yellow solid. mp 97-100 C. 1H NMR (DMSO-d6) d 7.68
(d, J = 2.1 Hz, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.06-6.92 (m,
6H), 6.85 (d, J= 8.8 Hz, 2H), 3.94 (t, J= 6.0 Hz, 2H), 3.81
(s, 3H), 3.72 (s, 3H), 2.56 (t, J= 6.0 Hz, 2H), 2.39-2.32
(m, 4H), 1.47-1.32 (m, 6H). Anal. Calcd. for C29H31N05S: C,
68.89; H, 6.18; N, 2.77. Found: C, 68.95; H, 6.04; N, 2.57.
2170479
X-9712 -89-
Example 31
Prepared in an analogous manner was [3-[4-[2-(1-
piperidinyl)ethoxy]phenoxy]-2-(4-methoxyphenyl)]
benzo[b]thiophene-(S-oxide)
O
/
/
O
\-s k\ h CH3
O
Oil. 1H NMR (DMSO-d6) d 8.03 (m, 1H), 7.65 (d, J 8.7
Hz, 2H), 7.53-7.50 (m, 2H), 7.09-6.82 (m, 7H), 3.94 (bt, J
5.9 Hz, 2H), 3.74 (s, 3H), 2.56 (bt, J= 5.9 Hz, 2H), 2.36-
2.33 (m, 4H), 1.45-1.31 (m, 6H). FD mass spec: 475. Anal.
Calcd. for C28H29N04S: C, 70.71; H, 6.15; N, 2.94. Found: C,
70.44; H, 6.43; N, 3.20.
Examvle 32
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene hydrochloride
=HC1
/
O
CH3
)OZ
HjCO ` /
2170479
X-9712 -90-
To a solution of [6-methoxy-3-[4-[2-(l-piperidinyl)
ethoxy] phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene-(S-
oxide) (Example 30) (3.00 g, 5.94 mmol) in 200 mL of
anhydrous THF under nitrogen gas at 0 C was added lithium
aluminum hydride (0.34 g, 8.91 mmol) in small portions.
After stirring for 30 minutes, the reaction was quenched by
the careful addition of 5.0 mL of 2.0 N sodium hydroxide.
The mixture was stirred vigorously for 30 minutes, and
additional 2.0 N sodium hydroxide was added to dissolve
salts. The mixture was then distributed between water and
10% sodium hydroxide. The layers were separated and the
aqueous extracted several times with 10% ethanol/ethyl
acetate. The organic layer was dried (sodium sulfate) and
concentrated in vacuo to an oil. The crude product was
dissolved in 50 mL of 1:1 ethyl acetate/ethyl ether and
treated with excess ethyl ether hydrochloride. The resulting
precipitate was collected and dried to provide 2.98 g (96%)
of [6-methoxy-3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride as a white
solid.
Example 6 was also prepared from Example 31 by the same
procedure.
Prevaration 13
6-Methoxybenzo[b]thiophene-2-boronic acid
I ` (o s),
s,co )CC~B
To a solution of 6-methoxybenzo[b]thiophene (18.13 g,
.111 mol) in 150 mL of anhydrous tetrahydrofuran (THF) at
-60 C was added n-butyllithium (76.2 mL, .122 mol, 1.6 M
solution in hexanes), dropwise via syringe. After stirring
for 30 minutes, triisopropyl borate (28.2 mL, .122 mol) was
2170479
X-9712 -91-
introduced via syringe. The resulting mixture was allowed to
gradually warm to 0 C and then distributed between 111
hydrochloric acid and ethyl acetate (300 mL each). The
layers were separated, and the organic layer was dried over
sodium sulfate. Concentration in vacuo produced a white
solid that was triturated from ethyl ether hexanes.
Filtration provided 16.4 g (71%) of 6-methoxybenzo[b]
thiophene-2-boronic acid as a white solid. mp 200 C (dec).
1H NMR (DMSO-d6) d 7.83 (s, 1H), 7.78 (d, J = 8.6 Hz, 1H),
7.51 (d, J= 2.0 Hz, 1H), 6.97 (dd, J= 8.6, 2.0 Hz, 1H),
3.82 (s, 3H). FD mass spec: 208.
Preparation 14
[6-Methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]
thiophene
` OSO~2CH3
ja~a
H3C0 S 20 To a solution of 6-methoxybenzo[b]thiophene-2-boronic
acid (3.00 g, 14.4 mmol) in 100 mL of toluene was added 4-
(methanesulfonyloxy)phenylbromide (3.98 g, 15.8 mmol)
followed by 16 mL of 2.0 N sodium carbonate solution. After
stirring for 10 minutes, tetrakistriphenylphosphinepalladium
(0.60 g, 0.52 mmol) was added, and the resulting mixture was
heated to reflux for 5 hours. The reaction mixture was then
allowed to cool to ambient temperature whereupon the product
precipitated from the organic phase. The aqueous phase was
removed and the organic layer was concentrated in vacuo to a
solid. Trituration from ethyl ether yielded a solid that was
filtered and dried in vacuo to provide 3.70 g(770) of [6-
methoxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as
a tan solid. mp 197-201 C. 1H NMR (DMSO-d6) d 7.82-7.77 (m,
3H), 7.71 (d, J = 8.8 Hz, 1H), 7.54 (d, J = 2.3 Hz, 1H), 7.40
(d, J= 8.7 Hz, 2H), 6.98 (dd, J= 8.7, 1.5 Hz, 1H), 3.80 (s,
2170479
X-9712 -92-
3H), 3.39 (s, 3H). FD mass spec 334. Anal. Calcd. for
C16H1404S2: C, 57.46; H, 4.21. Found: C, 57.76; H, 4.21.
Prevaration 15
Prepared in an analogous manner to Preparation 14 was
[6-methoxy-2-(4-benzyloxyphenyl)]benzo[b]thiophene
I ` ` oBn
HaCO ~ 8
Yield = 73 %. mp 217-221 C. 1H NMR (DMSO-d6) d 7.63-7.60
(m, 3H), 7.59-7.26 (m, 7H), 7.02 (d, J = 8.7 Hz, 2H), 6.96
(dd, J= 8.8, 2.2 Hz, 1H), 5.11 (s, 2H), 3.88 (s, 3H). FD
mass spec 346. Anal. Calcd. for C22H1802S: C, 76.27; H, 5.24.
Found: C, 76.00; H, 5.25.
Prevaration 16
[6-Hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]
thiophene
( oSO2C$3
Ho S
To a solution of [6-methoxy-2-(4-methanesulfonyloxy-
phenyl)Jbenzo[b]thiophene (9.50 g, 28.40 mmol) in anhydrous
methylene chloride (200 mL) at room under nitrogen gas was
added boron tribromide (14.20 g, 5.36 mL, 56.8 mmol). The
resulting mixture was stirred at ambient temperature for 3
hours. The reaction was quenched by slowly pouring into
excess ice water. After vigorously stirring for 30 minutes,
the white precipitate was collected by filtration, washed
several times with water, and then dried in vacuo to provide
8.92 g (98%) of [6-hydroxy-2-(4-methanesulfonyloxyphenyl)]
benzo[blthiophene as a white solid. mp 239-243 C. 1H NMR
2 i 70479
X-9712 -93-
(DMSO-d6) d 9.70 (s, 1H), 7.76 (d, J = 8.7 Hz, 2H), 7.72 (s,
1H), 7.62 (d, J = 8.7 Hz, 1H), 7.38 (d, J = 8.7 Hz, 2H), 7.24
(d, J = 1.7 Hz, 1H), 6.86 (dd, J = 8.7, 1.7 Hz, 1H), 3.38 (s,
3H). FD mass spec 320. Anal. Calcd. for C15H1204S2: C, 56.23;
H, 3.77. Found: C, 56.49; H, 3.68.
Prevaration 17
[6-Benzyloxy-2-(4-methanesulfonyloxyphenyl)]benzo
[b]thiophene
`
OSOzCB3
)O~
Bno S ` /
To a solution of [6-hydroxy-2-(4-methanesulfonyloxy-
phenyl)] benzo[b]thiophene (3.20 g, 10.0 mmol) in 75 mL of
anhydrous DMF was added Cs2CO3 (5.75 g, 17.7 mmol) followed by
benzylchloride (1.72 mL, 11.0 mmol). The resulting mixture
was stirred vigorously for 24 hours. The solvent was removed
in vacuo, and the solid residue was suspended in 200 mL of
water. The white precipitate was collected by filtration and
washed several times with water. Upon drying in vacuo, the
crude product was suspended in 1:1 hexanes:ethyl ether. The
solid was collected to provide 3.72 g (91%) of [6-benzyloxy-
2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a white
solid. mp 198-202 C. 1H NMR (DMSO-d6) d 7.81-7.78 (m, 3H),
7.72 (d, J = 8.7 Hz, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.47-7.30
(m, 7H), 5.15 (s, 2H), 3.39 (s, 3H). FD mass spec 410.
Prer)aration 18
[6-Benzyloxy-2-(4-hydroxyphenyl)]benzo[b]thiophene
oH
Bno / S ` /
2170479
X-9712 -94-
To a solution of [6-benzyloxy-2-(4-methanesulfonyloxy-
phenyl)]benzo[b]thiophene (12.50 g, 30.50 mmol) in 300 mL of
anhydrous THF under nitrogen gas at ambient temperature was
added lithium aluminum hydride (2.32 g, 61.0 mmol) in small
portions. The mixture was then stirred at ambient
temperature for 3 hours and then quenched by carefully
pouring the mixture into an excess of cold 1.0 N hydrochloric
acid. The aqueous phase was extracted with ethyl acetate.
The organic was then washed several times with water and then
dried (sodium sulfate) and concentrated in vacuo to a solid.
Chromatography (silicon dioxide, chloroform) provided 8.75 g
(87%) of [6-benzyloxy-2-(4-hydroxyphenyl)]benzo[b] thiophene
as a white solid. mp 212-216 C. lH NMR (DMSO-d6) d 9.70 (s,
1H), 7.63 (d, J = 8.7 Hz, 1H), 7.56 (d, J = 2.2 Hz, 1H),
7.51-7.30 (m, 8H), 7.00 (dd, J = 8.7, 2.2 Hz, 1H), 6.80 (d, J
= 8.6 Hz, 2H), 5.13 (s, 2H). FD mass spec 331. Anal. Calcd.
for C21H1602S: C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.
Examiple 19
[6-Benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene
I \ ` OCH3
BIIO / s
To a solution of [6-benzyloxy-2-(4-hydroxyphenyl)]
benzo[b] thiophene (8.50 g, 26.40 mmol) in 200 mL of
anhydrous DMF under nitrogen gas at ambient temperature was
added sodium hydride (1.66 g, 41.5 mmol) in small portions.
Once gas evolution had ceased, iodomethane (3.25 mL, 52.18
mmol) was added dropwise. The reaction was stirred for 3
hours at ambient temperature. The solvent was then removed
in vacuo, and the residue distributed between water/ethyl
acetate. The layers were separated, and the organic phase
was washed several times with water. The organic layer was
then dried (sodium sulfate) and concentrated in vacuo to
provide 9.00 g (98%) of [6-benzyloxy-2-(4-methoxyphenyl)]
2170479
X-9712 -95-
benzo[blthiophene as a white solid. mp 180-185 C. 1H NMR
(DMSO-d6) d 7.67-7.58 (m, 5H), 7.46-7.29 (m, 5H), 7.02 (dd, J
= 8.8, 2.2 Hz, 1H), 6.98 (d, J = 8.7 Hz, 2H), 5.13 (s, 2H),
3.76 (s, 3H). FD mass spec 346. Anal. Calcd. for C22H1802S:
C, 76.27; H, 5.24. Found: C, 76.54; H, 5.43.
Prevaration 20
[6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo-
[b]thiophene
Br
OC$3
Bno / S
[6-Benzyloxy-2-(4-methoxyphenyl)]benzo[b]thiophene (10.0
g, 28.9 mmol) was placed in 200 mL of chloroform along with
10.0 g of solid sodium bicarbonate at ambient temperature.
To this suspension was added bromine (1.50 mL, 29.1 mmol)
dropwise over 30 minutes as a solution in 100 mL of
chloroform. Upon completion of the addition, water (200 mL)
was added and the layers were separated. The organic phase
was dried (sodium sulfate) and concentrated in vacuo to a
white solid. Crystallization from methylene chloride/
methanol provided 10.50 g (85%) of [6-benzyloxy-2-(4-
methoxyphenyl)-3-bromo]benzo-[b]thiophene as a white solid.
mp 146-150 C. 1H NMR (DMSO-d6) d 7.70 (d, J = 2.2 Hz, 1H),
7.65-7.60 (m, 3H), 7.47-7.30 (m, 5H), 7.19 (dd, J = 8.8, 2.2
Hz, 1H), 7.06 (d, J = 8.7 Hz, 2H), 5.17 (s, 2H), 3.78 (s,
3H). FD mass spec 346. Anal. Calcd. for C22H1702SBr: C,
62.13; H, 4.03. Found: C, 61.87; H, 4.00.
2170479
X-9712 -96-
Prevaration 21
Prepared in an analogous manner was [6-methoxy-2-(4-
benzyloxyphenyl)-3-bromo]benzo-[b]thiophene
Br
I ` OBn
H3CO/ s
Yield = 91%. mp 125-127 C. 1H NMR (DMSO-d6) d 7.64-7.61 (m,
4H), 7.46-7.31 (m, 5H), 7.15-7.09 (m, 3H), 5.15 (s, 2H), 3.82
(s, 3H). FD mass spec 346. Anal. Calcd. for C22H1702SBr: C,
62.13; H, 4.03. Found: C, 62.33; H, 3.93.
Prepared in a manner analgous to Example 28 are Examples 33-
34.
Example 33
[6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]
thiophene-(S-oxide)
Br
` OCH3
/
Bno I I
Isolated as a yellow solid by crystallization from ethyl
acetate. mp 202-205 C. 1H NMR (DMSO-d6) d 7.80 (d, J = 2.2
Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.55(d, J = 8.4 Hz, 1H)
7.47-7.32 (m, 6H), 7.10 (d, J = 8.7 Hz, 2H), 5.23 (s, 2H),
3.80 (s, 3H). FD mass spec 441. Anal. Calcd. for C22H1703SBr:
C, 59.87; H, 3.88. Found: C, 59.59; H, 3.78.
2i7U479
X-9712 -97-
Example 34
[6-Methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]
thiophene-(S-oxide)
Br
\N I `
OBn
HjCO / II
O
Isolated as a yellow solid by chromatography (Si02,
CHC13). mp 119-123 C. 1H NMR (DMSO-d6) d 7.73 (d, J = 2.2
Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.55 (d, J = 8.5 Hz, 1H)
7.46-7.31 (m, 5), 7.26 (dd, J= 8.5, 2.2 Hz, 1H), 7.18 (d, J
= 8.8 Hz, 2H), 5.16 (s, 2H), 3.86 (s, 3H). FD mass spec 441.
Anal. Calcd. for C22H17O3SBr: C, 59.87; H, 3.88. Found: C,
60.13; H, 4.10.
Prepared in a manner analagous to Example 30 are Examples 35-
36.
Examvle 35
[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide)
Qo
z
O
I ` OCH3
Bn0 / iI
O
Yellow oil. 1H NMR (DMSO-d6) d 7.76 (d, J = 2.2 Hz, 1H),
7.62 (d, J = 8.8 Hz, 2H), 7.44-7.30 (m, 5H), 7.12 (dd, J
8.6, 2.2 Hz, 1H), 7.03-6.93 (m, 5H), 6.85 (d, J = 8.8 Hz,
'Z4 170479
X-9712 -98-
2H), 5.18 (s, 2H), 3.94 (bt, J= 5.8 Hz, 2H), 3.73 (s, 3H),
2.56 (bt, J= 5.8 Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.32 (m,
6H). FD mass spec 592. Anal. Calcd. for C35H35N05S: C, 72.26;
H, 6.06; N, 2.41. Found: C, 72.19; H, 5.99; N, 2.11.
Examt)le 36
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-benzyloxyphenyl)]benzo[b]thiophene-(S-oxide)
O
O
` OBn
$gC'O
fl
0
Yellow solid. mp 89-93 C. 1H NMR (DMSO-d6) d 7.68 (d, J
= 2.2 Hz, 1H), 7.62 (d, J= 8.8 Hz, 2H), 7.42-7.28 (m, 5H),
7.08-6.92 (m, 6H), 6.86 (d, J= 8.8 Hz, 2H), 5.09 (s, 2H),
3.94 (bt, J= 5.8 Hz, 2H), 3.81 (s, 3H), 2.56 (bt, J= 5.8
Hz, 2H), 2.37-2.34 (m, 4H), 1.45-1.31 (m, 6H). FD mass spec
592. Anal. Calcd. for C35H35N05S=0.25 EtOAc: C, 71.62; H,
6.18; N, 2.32. Found: C, 71.32; H, 5.96; N, 2.71.
Prepared in a manner analagous to Example 11 are Exampes 37-
38.
2i7~479
X-9712 -99-
Examvle 37
[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene
O
N
/
/
O
i OCg3
Bno
Isolated in 95% overall yield starting from [6-
benzyloxy-2-(4-methoxyphenyl)-3-bromo]benzo[b]thiophene-(S-
oxide). Purified by chromatography (Si02, 1-5%
methanol/chloroform) to provide an off-white solid. mp 105-
108 C. 1H NMR (DMSO-d6) d 7. 62 (d, J = 2.2 Hz, 1H) , 7.59 (d,
J = 8.8 Hz, 2H), 7.45-7.30 (m, 5H), 7.15 (dd, J = 8.6 Hz,
1H), 7.00-6.94 (m, 3H), 6.82 (s, 4H), 5.13 (s, 2H), 3.92 (bt,
J = 5.8 Hz, 2H), 3.72 (s, 3H), 2.55 (bt, J = 5.8 Hz, 2H),
2.37-2.34 (m, 4H), 1.44-1.31 (m, 4H). FD mass spec 565.
Anal. Calcd. for C35H35N04S: C, 74.31; H, 6.24; N, 2.48.
Found: C, 74.35; H, 6.07; N, 2.76.
Examiple 38
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-benzyloxyphenyl)]benzo[b]thiophene
Qo
/
O
I ` ` /OBn
8S
3C0 /
2170,479
X-9712 -100-
Yield = 91%. mp 106-110 C. 1H NMR (DMSO-d6) d 7.59 (d,
J = 8.8 Hz, 2H), 7.54 (d, J = 2.2 Hz, 1H), 7.42-7.28 (m, 5H),
7.13 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.82 (s,
4H), 5.08 (s, 2H), 3.92 (bt, J = 5.8 Hz, 2H), 3.78 (s, 3H),
2.55 (bt, J = 5.8 Hz, 2H), 2.37-2.33 (m, 4H), 1.44-1.31 (m,
4H). FD mass spec 565. Anal. Calcd. for C35H35N04S: C, 74.31;
H, 6.24; N, 2.48. Found: C, 74.26; H, 6.17; N, 2.73.
Example 39
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene
N~~O
O
OCH3
so
To a solution of [6-benzyloxy-3-[4-[2-(1-piperidinyl)
ethoxy]phenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene (8.50
g, 15.0 mmol) in 300 mL of 5:1 ethanol/ethyl acetate was
added palladium black (1.50 g), ammonium formate (3.50 g,
55.6 mmol), and 30 mL of water. The resulting mixture was
heated to reflux and monitored by TLC. After approximately 3
hours, the reaction was judged complete and the solution was
cooled to ambient temperature. The reaction was filtered
through a pad of Celite to remove catalyst, and the filtrate
was concentrated in vacuo to a solid. The concentrate was
distributed between saturated sodium bicarbonate solution and
5% ethanol/ethyl acetate. The layers were separated, and the
organic phase was dried (sodium sulfate) and concentrated in
vacuo. The crude product was chromatographed (silicon
dioxide, 1-5% methanol/chloroform) to provide 6.50 g (91%) of
[6-hydroxy-3-[4-[2-(1-piperidinyl) ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene as foam that converted to
2170479
X-9712 -101-
solid upon trituration with hexanes. mp 174-176 C. 1H NMR
(DMSO-d6) d 9.77 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.23 (d, J
= 2.0 Hz, 1H), 7.07 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.8 Hz,
2H), 6.81 (s, 4H), 6.76 (dd, J = 8.6, 2.0 Hz, 1H), 3.91 (bt,
J= 5.9 Hz, 2H), 3.71 (s, 3H), 2.55 (bt, J = 5.9 Hz, 2H),
2.38-2.33 (m, 4H), 1.46-1.28 (m, 6H). FD mass spec 475.
Anal. Calcd. for C28H29N04S: C, 70.71; H, 6.15; N, 2.94.
Found: C, 70.46; H, 5.93; N, 2.71.
Example 40
Prepared in an analogous manner to Example 39 was [6-
methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
hydroxyphenyl)]benzo[b]thiophene
O
O
J D o$
s,co S
Yield = 88%. mp 147-150 C. 1H NMR (DMSO-d6) d 9.72 (s,
1H), 7.51 (d, J = 2.0 Hz, 1H), 7.48 (d, J = 8.6 Hz, 2H), 7.11
(d, J= 8.8 Hz, 1H), 6.88 (dd, J= 8.8, 2.2 Hz, 1H), 6.81 (s,
4H), 6.76 (d, J= 8.6, 2H), 3.91 (bt, J= 5.9 Hz, 2H), 3.77
(s, 3H), 2.55 (bt, J = 5.9 Hz, 2H), 2.38-2.33 (m, 4H), 1.46-
1.28 (m, 6H). FD mass spec 475. Anal. Calcd. for C28H29N04S:
C, 70.71; H, 6.15; N, 2.94. Found: C, 71.00; H, 6.17; N,
2.94.
Alternatively, Examples 39 and 40 can be prepared by the same
transfer hydrogenolysis procedure directly in 90% yield from
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
benzyloxyphenyl)]benzo[b]thiophene-(S-oxide) and [6-
~~170~79
X-9712 -102-
benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo [b]thiophene-(S-oxide), respectively.
Example 41
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene (Example 39) was
converted to its hydrochloride salt in 85% yield by
treatment with ethyl ether/hydrochloride in ethyl
acetate followed by crystallization from ethanol/ethyl
acetate
HCI
O
0
O
OCH3
Ho S
mp 156-160 C. 1H NMR (DMSO-d6) d 10.28 (bs, 1H), 9.85 (s,
1H), 7.56 (d, J = 8.8 Hz, 2H), 7.25 (d, J = 2.0 Hz, 1H), 7.06
(d, J = 8.7 Hz, 1H), 6.93 (d, J = 8.8 Hz, 2H), 6.87 (q, JAB _
9.3 Hz, 4H), 4.27 (bt, J= 5.9 Hz, 2H), 3.71 (s, 3H), 3.44-
3.31 (m, 4H), 2.98-2.88 (m, 2H), 1.74-1.60 (m, 5H), 1.36-1.29
(m, 1H) FD mass spec 475. Anal. Calcd. for C28H29N04S=1.0
HC1: C, 65.68; H, 5.90; N, 2.73. Found: C, 65.98; H, 6.11; N,
2.64.
2170479
X-9712 -103-
Examvle 42
Prepared in a manner analogous to Example 41 was [6-
hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride
=HCI
-'\,O
0 N
Q
O
oH
s,co s
mp 215-217 C. 1H NMR (DMSO-d6) d 10.28 (bs, 1H), 9.80 (s,
1H), 7.52 (d, J = 2.2 Hz, 1H), 7.47 (d, J= 8.6 Hz, 2H), 7.12
(d, J= 8.4 Hz, 1H), 6. 91-6. 80 (m, 5H) , 6.78 (d, J= 8.6 Hz,
2H), 4.27 (bt, J = 5.8 Hz, 2H), 3.78 (s, 3H), 3.43-3.34 (m,
4H), 2.97-2.91 (m, 2H), 1.78-1.61 (m, 5H), 1.36-1.29 (m, 1H).
FD mass spec 475. Anal. Calcd. for C28H29N04S=1.0 HC1: C,
65.68; H, 5.90; N, 2.73. Found: C, 65.87; H, 5.79; N, 2.99.
Examnle 43
[6-Benzoyloxy-3-[4-[2-(1-piperidinyl)-ethoxy]phenoxy]-
2-(4-benzoyloxyphenyl)]benzo[b]thiophene hydrochloride
=aci
o
O
O ( ~k `
A0 k\
~ o s h
o
/
2170479
X-9712 -104-
To a solution of Example 20 (0.50 g, 1.08 mmol) in 20 mL
of anhydrous tetrahydrofuran at 0 C was added triethylamine
(1.00 mL). To this mixture was added benzoylchloride (0.28
mL, 2.35 mmol). After stirring at 0 C for 2 hours, the
reaction was quenched by distributing between ethyl
acetate/saturated sodium bicarbonate solution (100 mL each).
The layers were separated and the organic was dried (sodium
sulfate) and concentrated in vacuo to a white solid. The
crude product was dissolved in 10 mL of ethyl acetate and
treated with ethyl ether=hydrochloric acid. A white
precipitate formed that was collected by filtration. Drying
provided 390 mg (50%) of [6-benzoyloxy-3-[4-[2-(1-
piperidinyl) ethoxy]phenoxy]-2-(4-benzoyloxyphenyl)]benzo
[b]thiophene hydrochloride as a white solid. mp 200-204 C.
1H NMR (DMSO-d6) d 9.95 (bs, 1H), 8.18 (m, 1H), 8.16 (m, 2H),
8.12 (dd, J= 10.0, 2.0 Hz, 2H), 7.87 (dd, J = 7.0, 2.0 Hz,
2H), 7.78 (m, 2H), 7.64 (m, 2H), 7.42 (d, J = 7.0 Hz, 2H),
7.34 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (s, 4H), 4.32 (m, 2H),
3.45 (m, 4H), 2.99 (m, 2H), 1.75 (m, 5H), 1.39 (m, 1H). Anal.
Calcd. for C41H35N06S=1.5HC1: C, 67.97; H, 5.08; N, 1.93.
Found: C, 68.05; H, 5.24; N, 2.01.
By the same procedure was prepared:
Examnle 44
[6-Ethylsulfonyloxy-3-[4-[2-(1-piperidinyl)ethoxy]-
phenoxy]-2-(4-ethylsulfonyloxypher_yl)]
benzo[b]thiophene hydrochloride
=ac
N-'\,O
/
O
` OS (O)zEt
Et(O)zS0 S ` /
~170479
X-9712 -105-
Yield = 72%. mp 110-115 C. 1H NMR (DMSO-d6) d 10.15
(bs, 1H), 8.15 (d, J= 2.0 Hz, 1H), 7.85 (d, J = 7.0 Hz, 2H),
7.43 (m, 3H), 7.34 (dd, J = 9.0, 2.0 Hz, 1H), 6.97 (m, 4H),
4.31 (m, 2H), 3.57 (m, 4H), 3.44 (m, 4H), 2.97 (m, 2H), 1.76
(m, 5H), 1.40 (m, 7H). Anal. Calcd. for C31H35NO8S3=1.5HC1:
C, 54.57; H, 5.32; N, 2.05. Found: C, 54.36; H, 5.37; N,
2.05.
By a similar procedure employing triflouromethanesulfonic
anhydride was:
Example 45
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
(4-triflouromethanesulfonyloxyphenyl)]
benzo[b]thiophene
N~~O
O
JO~ ` / OSOzCF3
H3C0
Yield = 81%. Oil. 1H NMR (DMSO-d6) d 7.82 (d, J = 8.7 Hz,
2H), 7.60 (d, J = 2.0 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.17
(d, J = 8.8 Hz, 1H), 6.93 (dd, J = 8.8, 2.0 Hz, 1H), 6.84 (s,
4H), 3.92 (bt, J= 5.7 Hz, 2H), 3.79 (s, 3H), 2.56 (bt, J
5.7 Hz, 2H), 2.36-2.30 (m, 4H), 1.44-1.31 (m, 6H). FD mass
spec: 607. Anal. Calcd. for C29H28NO6F3S2: C, 57.32; H,
4.64; N, 2.30. Found: C, 57.16; H, 4.52; N, 2.01.
Prepared from Example 1 by similar procedures were:
2110419
X-9712 -106-
Example 46
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
benzoyloxyphenyl)]benzo[b]thiophene hydrochloride
=aci
aoo
0 -
0
Yield = 85%. mp 190-198 C. 1H NMR (DMSO-d6) d 10 . 48
(br s, 1H), 8.00-8.10 (m, 2H), 7.80-8.00 (m, 3H), 7.60-7.53
(m, 4H), 7.40-7.56 (m, 6H), 6.93 (s, 2H), 4.37-4.43 (m, 2H),
3.00-3.05 (m, 2H), 2.53-2.63 (m, 6H), 1.75-1.95 (m, 3H),
1.40-1.50 (m, 1H). FD mass spec: 550. Anal. Calcd. for
C34H31N04S=1.OHC1: C, 74.29; H, 5.68; N, 2.55. Found: C,
74.52; H, 5.80; N, 2.59.
Examvle 47
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
pivaloyloxyphenyl)]benzo[b]thiophene hydrochloride
=HCl
N~~O
O
0,
0
Yield = 90%. mp = 193-197 C. 1H NMR (DMSO-d6) d 10.10
(br s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.85 (d, J = 8.6 Hz,
1H), 7.40-7.53 (m, 3H), 7.15 (d, J= 6.7 Hz, 2 H), 7.00 (s,
2170479
X-9712 -107-
5H), 4.33-4.40 (m, 2H), 3.45-3.60 (m, 4H), 3.00-3.10 (m, 2H),
1.70-1.90 (m, 6H), 1.40 (s, 9H). FD mass spec: 529. Anal.
Calcd. for C32H35N04S-1.OHC1: C, 67.89; H, 6.41; N, 2.47.
Found: C, 68.94; H, 6.61; N, 1.72.
Examvle 48
3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
butylsulfonyl-oxyphenyl)]benzo[b]thiophene
hydrochloride
=acl
N~~O
os(o)zn8u
Yield = 85% white solid. mp = 98-104 C. 1H NMR (DMSO-
d6) d 10.20 (br s, 1H), 8.02 (d, J 8.0 Hz, 1H), 7.82 (d, J
8.7 Hz, 2H), 7.40-7.55 (m, 5H), 7.00 (s, 4H), 4.30-4.40 (m,
2H), 3.46-3.66 (m, 6H), 3.00-3.10 (m, 2H), 1.70-1.95 (m, 6H),
1.40-1.60 (m, 4H), 0.87 (t, J= 7.3 Hz, 3H). FD mass spec:
565. Anal. Calcd. for C31H35N05S2=1.OHC1: C, 61.83; H, 6.03;
N, 2.33. Found: C, 61.55; H, 6.15; N, 2.25.
Prevaration 21
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-
thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene
/ oca,oca,
S` s~ ~
H3coHZco
Preparation of 4-(methoxymethyloxy)phenyldisulfide.
2170479
X-9712 -108-
To a solution of 4-hydroxyphenyldisulfide (650 mg, 2.60
mmol) in 10 mL of anhydrous N,N-dimethylformamide at 10 C
was added sodium hydride (230 mg, 5.75 mmol, 60% dispersion
in mineral oil). After stirring for 15 minutes,
chloromethylmethyl ether (0.44 mL, 5.75 mmol) was added via
syringe. The reaction was warmed to ambient temperature and
stirred for 0.5 hours. The mixture was distributed between
brine/ethyl acetate (20 mL each). The layers were separated
and the aqueous phase extracted with ethyl acetate (2 x 20
mL). The organic was dried (sodium sulfate) and concentrated
to a yellow oil (993 mg, 100%). An analytical sample of 4-
(methoxymethyloxy)-phenyldisulfide was prepared by
chromatography (silicon dioxide, 4% ethyl acetate/hexanes).
1H NMR (DMSO-d6) d 7.40 (d, J = 6.9 Hz, 4H), 7.00 (d, J = 6.9
Hz, 4H), 5.15 (s, 4H), 3.32 (s, 6H). FD mass spec: 338.
Anal. Calcd. for C16H1804S2: C, 56.78; H, 5.36. Found: C,
57.08; H, 5.44.
Sxample 49
[6-Methoxy-2-(4-methoxyphenyl)-3-(4-
methoxymethyleneoxy)thiophenoxy]benzo[b]thiophene
H 3COfi,CO
s
J OCH3
H3CO
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-
bromo]benzo[b)thiophene (1.82 g, 5.2 mmol) in 10 mL of
anhydrous tetrahydrofuran under N2 at -60 C was added n-
butyllithium (3.15 mL, 5.0 mmol, 1.6 M solution in hexanes)
dropwise via syringe. The resulting mixture was warmed to
-20 C for 10 minutes, then cooled back to -60 C. 4-
(methoxymethyloxy)-phenyldisulfide (800 mg, 2.36 mmol) in 5
2170479
X-9712 -109-
mL of anhydrous tetrahydrofuran was added to the lithio
species, and the resultant mixture was allowed to gradually
warm to 00 C. After stirring for 20 minutes, the reaction
was quenched by distributing between brine/ethyl acetate (50
mL each). The layers were separated, and the aqueous phase
was extracted with ethyl acetate(2 x 50 mL). The organic
layer was combined, dried (sodium sulfate), and concentrated
in vacuo to an oil. Chromatography (silicon dioxide, 5%
ethyl acetate/hexanes) provided 287 mg (27%) of [6-methoxy-2-
(4-methoxyphenyl)-3-(4-methoxymethyleneoxy)thiophenoxy]
benzo[b]thiophene as a colorless oil. 1H NMR (DMSO-d6) d 7.59
(d, J = 8.4 Hz, 2H), 7.58 (d, J = 2.0 Hz, 1H), 7.52 (d, J =
8.8 Hz, 1H), 7.03- 6.85 (m, 7H), 5.06 (s, 2H), 3.79 (s, 3H),
3.76 (s, 3H). FD mass spec: 438. Anal. Calcd. for C24H2204S2:
C, 65.73; H, 5.06. Found: C, 65.93; H, 5.10.
Examvle 50
[6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)
thiophenoxy]benzo[b]thiophene
Ho
~ ~ -
~H3
H3CO
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
methoxymethyleneoxy)thiophenoxy]benzo[b]thiophene (233 mg,
0.53 mmol) in 10 mL of a 1:1:2 mixture of methanol:water:
tetrahydrofuran was added methane sulfonic acid (0.2 mL, 2.66
mmol). The mixture was heated to reflux for 5 hour. Upon
cooling to ambient temperature, the reaction mixture was
diluted with water. The aqueous phase was extracted with
ethyl acetate (2x). The organic layer was washed with sat
sodium bicarbonate solution several times. The organic layer
2170479
X-9712 -110-
was dried (sodium sulfate) and concentrated in vacuo to
provide 206 mg (99%) of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
hydroxy)thiophenoxy]benzo-[b]thiophene as a colorless oil.
1H NMR (DMSO-d6) d 9.43 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H),
7.61 (d, J = 2.0 Hz, 1H), 7.59 (d, J= 8.8 Hz, 1H), 7.08 (d,
J= 8.4 Hz, 2H), 7.02 (dd, J = 8.8, 2.0 Hz, 1H), 6.90 (d, J
8.6 Hz, 2H), 6.63 (d, J = 8.6 Hz, 2H). FD mass spec: 395.
Anal. Calcd. for C22H1803S2: C, 66.98; H, 4.60. Found: C,
67.26; H, 4.78.
Example 51
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-
2-(4-methoxyphenyl)]benzo[b]thiophene
fN O
Q
s
I / r::-(I)--- OC$,
H3Co
To a solution of [6-methoxy-2-(4-methoxyphenyl)-3-(4-
hydroxy)thiophenoxy]benzo[b]thiophene (242 mg, 0.61 mmol) in
8.0 mL of anhydrous N,N-dimethylformamide was added cesium
carbonate (820 mg, 2.5 mmol) followed by 2-
chloroethylpiperidine hydrochloride (194 mg, 1.05 mmol). The
resulting mixture was stirred for 48 hours at ambient
temperature and then distributed between brine/ethyl acetate.
The layers were separated, and the aqueous phase was
extracted with ethyl acetate (3x). The organic layer was
dried (sodium sulfate) and concentrated in vacuo to an oil.
Chromatography (silicon dioxide, 0-2% methanol/chloroform)
provided 244 mg (92 %) of [6-methoxy-3-[4-[2-(1-piperidinyl)
ethoxy]thiophenoxy]-2-(4-methoxyphenyl)]benzo-[b]thiophene as
an amber oil.
Example 52
2170479
X-9712 -111-
A sample of [6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-
thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene was
converted to its hydrochloride salt according to the
standard procedure in 72% yield
c =HCl
O
Q
S
` /~H3
H3c0 )O~
mp 198-201 C. 1H NMR (DMSO-d6) d 7.63 (d, J= 8.6 Hz,
2H), 7.62 (d, J = 2.0 Hz, 1H), 7.58 (d, J= 8.2 Hz, 1H), 7.07
(d, J= 8.6 Hz, 2H), 7.02 (dd, J = 8.2, 2.0 Hz, 1H), 6.92 (q,
JAB = 9.0 Hz, 4H), 4.24 (bt, 2H), 3.82 (s, 3H), 3.80 (s, 3H),
3.49-3.39 (m, 4H), 2.93 (m, 2H), 1.82-1.62 (m, 5H), 1.38 (m,
1H). Anal. Calcd. for C29H32N03S2=1.0 HC1: C, 64.28; H, 5.95;
N, 2.58. Found: C, 64.09; H, 6.08; N, 2.78.
Example 53
[6-8ydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-
thiophenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene
N-~\1O
S
\ oH
Ho S
To a solution of [6-methoxy-3-[4-[2-(1-piperidinyl)
ethoxyl-thiophenoxy]-2-(4-methoxyphenyl)]benzo[b]thiophene
hydrochloride (160 mg, 0.29 mmol) in 15 mL of anhydrous
2170479
X-9712 -112-
methylene chloride at 0 C under N2 was added boron
tribromide (0.15 mL). The resulting dark solution was
stirred for 1 hour at 0 C and then immediately poured into a
stirred solution of ethyl acetate/sat sodium bicarbonate
solution (50 mL each). The layers were separated, and the
aqueous phase was washed with ethyl acetate (3 x 30 mL). The
organic was dried (sodium sulfate) and concentrated in vacuo
to a white solid. Chromatography (silicon dioxide, 0-5%
methanol/ chloroform) provided 91 mg (60%) of [6-hydroxy-3-
[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-2-(4-
hydroxyphenyl)]benzo[b]-thiophene as a white solid. mp 123-
127 C. 1H NMR (DMSO-d6) d 9.79 (s, 1H), 9.71 (s, 1H), 7.46
(d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.9 Hz, 1H), 7.26 (d, J
2.0 Hz, 1H), 6.91 (d, J= 8.8 Hz,2H), 6.82-6.76 (m, 5H),
3.91 (t, J= 8.8 Hz, 2H), 2.56 (t, J= 5.8 Hz, 2H), 2.40 (m,
4H), 1.41-1.28 (m, 6H). FD mass spec: 478. Anal. Calcd. for
C27H27N03S2: C, 67.90; H, 5.70; N, 2.93. Found: C, 68.14; H,
5.84; N, 2.65.
Example 54
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
G =Eci
000 c oH
ao S
mp 180-190 C. 1H NMR (DMSO-d6) d 9.86 (s, 1H), 9.79 (s,
1H), 7.46 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.7 Hz, 1H), 7.29
(d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H), 6.86-6.81 (m,
5H), 4.27 (m, 2H), 3.41-3.37 (m, 4H), 2.96-2.84 (m, 2H),
1.77-1.60 (m, 5H), 1.35-1.28 (m, 1H). FD mass spec: 477.
Anal. Calcd. for C27H27N03S2=2.2 HC1: C, 58.13; H, 5.28; N,
2.51. Found: C, 58.11; H, 5.10; N, 2.61.
2170479
.~..
X-9712 -113-
Prepared by the same procedures were:
Examvle 55
[6-Methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy]thiophenoxy]-
2-(4-methoxyphenyl)]benzo[b]thiophene hydrochloride
=sc1
~ i
~ z
s
)0~ ` , OC83
H3CO s
mp 215-218 C. 1H NMR (DMSO-d6) d 7.61-7.58 (m, 3H), 7.52
(d, J = 8.8 Hz, 1H), 7.04-6.95 (m, 5H), 6.86 (d, J 8.8 Hz,
2H), 4.22 (bt, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.47-3.42 (m,
4H), 3.01 (m, 2H), 1.94-1.80 (m, 4H). FD mass spec: 491.
Anal. Calcd. for C28H29N03S2=1.OHC1: C, 63.67; H, 5.73; N,
2.65. Found: C, 63.47; H, 5.78; N, 2.65.
Examvle 56
[6-Hydroxy-3-[4-[2-(1-pyrolodinyl)ethoxy]thiophenoxy]-
2-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride
=aci
GN~
s
og
Ho S
mp 137-140 C(dec). 1H NMR (DMSO-d6) d 9.86 (s, 1H),
9.80 (s, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.7 Hz,
2170479
X-9712 -114-
1H), 7.29 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 8.7 Hz, 2H),
6.87-6.81 (m, 5H), 4.21 (bt, 2H), 3.53-3.41 (m, 4H), 3.01 (m,
2H), 1.95-1.82 (m, 4H). FD mass spec: 464. Anal. Calcd. for
C26H25N03S2=1.0HC1: C, 62.45; H, 5.24; N, 2.80. Found: C,
62.36; H, 5.37; N, 2.61.
Examflle 57
Prepared from the product of Example 45 by the
hydrogenolysis of the triflate as described below in
Example 58 was 6-methoxy-3-[4-[2-(1-piperidinyl)
ethoxy] phenoxy]-2-(phenyl)]benzo[b]thiophene
hydrochloride
=ac1
Qo
Q
O
~
ji
g,co
mp 187-195 C. 1H NMR (DMSO-d6) d 7.66 (d, J = 2.8 Hz,
2H), 7.58 (d, J = 2.0 Hz, 1H), 7.39 (t, J= 7.5 Hz, 2H), 7.28
(m, 1H), 7.17 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 8.8, 2.0 Hz,
1H), 6.89 (s, 4H), 4.23 (bt, J = 5.7 Hz, 2H), 3.79 (s, 3H),
3.45-3.38 (m, 4H), 2.98 (m, 2H), 1.77-1.61 (m, 5H), 1.31 (m,
1H). FD mass spec: 460. Anal. Calcd. for C28H29N03S=1.OHC1:
C, 67.80; H, 6.10; N, 2.84. Found: C, 67.62; H, 5.89; N,
2.67.
X-9712 -115-
Examnle 58
6-Hydroxy-3-(4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(phenyl)]benzo[b]thiophene hydrochloride
=HC1
N-%, O
~ /
O
HO
To a solution of 6-hydroxy-3-[4-[2-(1-piperidinyl)
ethoxy]phenoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene
hydrochloride (5.00 g, 10.0 mmol) in 100 mL of anhydrous
methylene chloride at 00 C under N2 was added triethylamine
(8.38 mL, 60.0 mmol) followed by triflouromethanesulfonic
anhydride (1.69 mL, 10.0 mmol). The resulting mixture was
allowed to gradually warm to room temperature and stirred for
1.5 hours. The reaction was then quenched by pouring into
200 mL of saturated sodium bicarbonate solution. The aqueous
phase was then extracted with ethyl acetate (3 x 100 mL).
The organic layer was dried (sodium sulfate) and concentrated
in vacuo to an oil. Chromatography (0-3 %
methanol/chloroform) provided 2.82 g (39%) of 6-
triflouromethanesulfonate-3-[4-[2-(1-piperidinyl)ethoxy]
phenoxy]-2-(4-triflouromethane-sulfonatephenyl)]benzo[b]
thiophene, 1.82 g (31%) of a 1:1 mixture of 6-triflouro-
methanesulfonate-3-[4-[2-(1-piperidinyl)ethoxy]phenoxyl-2-(4-
phenyl)]benzo[b]thiophene and 3-[4-[2-(1-piperidinyl)ethoxy]
phenoxy]-2-(4-triflouromethanesulfonatephenyl)]benzo[b]
thiophene, and 1.48 g (36%) of recovered staring material as
the free base.
To a solution of a 1:1 mixture of monotriflate
derivatives from the last reaction (0.50 g, 0.84 mmol) in 60
mL of ethanol-ethyl acetate (5:1) was added triethylamine
(2.0 mL) and 5% palladium-on-carbon (0.50 g). The resulting
2170479
X-9712 -116-
mixture was hydrogenated at 40 psi for 2 hours. The mixture
was then filtered through Celite to remove the catalyst.
The filtrate was concentrated to an oil. The resulting
mixture of monohydroxy derivatives was dissolved in ethyl
acetate from which 3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-hydroxyphenyl)]benzo[b]-thiophene precipitated. The
filtrate consisted of a 4:1 mixture of monohydroxy
derivatives where 6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]
phenoxy]-2-(phenyl)]benzo[b]thiophene was the major
component. The filtrate was concentrated in vacuo, and the
resulting solid dissolved in minimal ethyl acetate and
treated with ethyl ether=hydrochloric acid. The resulting
solid was recrystallized from ethanol to give 69 mg (18%) of
isomerically pure 6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]
phenoxy]-2-(phenyl)]benzo[b]thiophene hydrochloride. mp 217-
219 C. 1H NMR (DMSO-d6) d 9.87 (s, 1H), 7.64 (d, J = 7.5 Hz,
2H), 7.39-7.26 (m, 4H), 7.10 (d, J = 8.6 Hz, 1H), 6.89 (s,
4H), 6.78 (dd, J= 8.6, 2.0 Hz, 1H), 4.22 (bt, 2H), 3.39-3.37
(m, 4H), 2.97-2.90 (m, 2H), 1.74-1.60 (m, 5H), 1.39 (m, 1H).
FD mass spec: 446. Anal. Calcd. for C27H27N03S=1.OHC1: C,
67.28; H, 5.86; N, 2.91. Found: C, 67.00; H, 5.59; N, 2.87.
Alternatively, Example 58 is prepared by demethylation of the
product of Example 57 as described in Example 18.
2170479
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Example 59
[6-Isoprpoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene-(S-oxide) was
prepared as described for [6-methoxy-3-[4-[2-(1-
piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene-(S-oxide)
(Example 30).
oo0'o
~~( ~
~ / OCH3
O II
O
Yellow oil. 1H NMR (DMSO-d6) d 7.69 (d, J = 2.0 Hz, 1H),
7.67(d, J= 8.6 Hz, 2H), 7.09-6.99 (m, 5H), 6.96-6.87 (m,
3H), 4.76 (septet, J= 6.0 Hz, 1H), 3.99 (bt, J= 6.0 Hz,
2H), 3.78 (s, 3H), 2.61 (bt, J= 6.0 Hz, 2H), 2.44-2.37 (m,
4H), 1.53-1.43 (m, 4H), 1.40-1.32 (m, 2H), 1.29 (d, J= 6.0
Hz, 6H). FD mass spec 533. Anal. Calcd. for C31H35N05S=0.67
H20: C, 68.23; H, 6.71; N, 2.57. Found: C, 67.90; H, 6.31; N,
2.53.
[6-Isoprpoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-
(4-methoxyphenyl)]benzo[b]thiophene hydrochloride was
prepared as described for [6-methoxy-=3-[4-[2-(1-
piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene (Example 32).
=CI
N~~O
a O
S~ OCH3
217 0479
...
X-9712 -118-
mp 168-170 C. 1H NMR (DMSO-d6) d 10.37 (s, 1H), 7.58
(d, J = 8.6 Hz, 2H), 7.52 (d, J = 1.3 Hz, 1H), 7.12 (d, J
8.8 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.92-6.85 (m, 5H),
4.64 (septet, J= 6.0 Hz, 1H), 4.28 (bt, J= 6.0 Hz, 2H),
3.72 (s, 3H), 3.44-3.37 (m, 4H), 2.95-2.89 (m, 2H), 1.73-1.60
(m, 5H), 1.36-1.28 (m, 1H), 1.25 (d, J= 6.0 Hz, 6H). FD
mass spec 517. Anal. Calcd. for C31H35N04S=HC1: C, 67.19; H,
6.55; N, 2.53. Found: C, 67.15; H, 6.29; N, 2.62.
[6-Isoprpoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene hydrochloride was converted
to [6-hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-
methoxyphenyl)]benzo[b]thiophene by treatment with 2.0
equivalents of BC13 at 0-10 C in anhydrous dichloromethane
(the methyl ether is not cleaved under these conditions).
Test Procedure
General Prevaration Procedure
In the examples illustrating the methods, a post-
menopausal model was used in which effects of different
treatments upon circulating lipids were determined.
Seventy-five day old female Sprague Dawley rats
(weight range of 200 to 225g) were obtained from Charles
River Laboratories (Portage, MI). The animals were either
bilaterally ovariectomized (OVX) or exposed to a Sham
surgical procedure at Charles River Laboratories, and then
shipped after one week. Upon arrival, they were housed in
metal hanging cages in groups of 3 or 4 per cage and had ad
libitum access to food (calcium content approximately 0.5%)
and water for one week. Room temperature was maintained at
22.2 1.7 C with a minimum relative humidity of 40%. The
photoperiod in the room was 12 hours light and 12 hours dark.
CA 02170479 2007-02-14
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DosinQ Reaimen Tissue Collection. After a one week
acclimation period (therefore, two weeks post-OVX) daily
dosing with test compound was initiated. 17a-ethynyl
estradiol or the test compound were given orally, unless
otherwise stated, as a suspension in 1%
carboxymethylcellulose or dissolved in 20% cyclodextrin.
Animals were dosed daily for 4 days. Following the dosing
regimen, animals were weighed and anesthetized with a
ketamine: Xylazine (2:1, V:V) mixture and a blood sample was
collected by cardiac puncture. The animals were then
sacrificed by asphyxiation with C02, the uterus was removed
through a midline incision, and a wet uterine weight was
determined.
Cholesterol Analysis. Blood samples were allowed to clot at
room temperature for 2 hours, and serum was obtained
following centrifugation for 10 minutes at 3000 rpm. Serum
cholesterol was determined using a Boehringer Mannheim
Diagnostics high performance cholesterol assay. Briefly the
cholesterol was oxidized to cholest-4-en-3-one and hydrogen
peroxide. The hydrogen peroxide was then reacted with phenol
and 4-aminophenazone in the presence of peroxidase to produce
a p-quinone imine dye, which was read spectrophotemetrically
at 500 nm. Cholesterol concentration was then calculated
against a standard curve. The entire assay was automated
using a Biomek*Automated Workstation.
Uterine Fosinophil Peroxidase (EPO) Assay. Uteri were kept
at 4 C until time of enzymatic analysis. The uteri were
then homogenized in 50 volumes of 50 mM Tris buffer (pH -
8.0) containing 0.005% Triton*X-100. Upon addition of 0.01%
hydrogen peroxide and 10 mM 0-phenylenediamine (final
concentrations) in Tris buffer, increase in absorbance was
monitored for one minute at 450 nm. The presence of
eosonophils in the uterus is an indication of estrogenic
activity of a compound. The maximal velocity of a 15 second
*Trademark
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interval was determined over the initial, linear portion of
the reaction curve.
Source of Comnound: 17a-ethynyl estradiol was obtained from
Sigma Chemical Co., St. Louis, MO.
Influence of Formula I Comnounds on Serum Cholesterol and
Determination of Aaonist/Non-Aaonist Activity
Data presented in Table 1 below show comparative
results among ovariectomized rats, rats treated with 17a-
ethynyl estradiol (EE2; an orally available form of estrogen),
and rats treated with certain compounds of the present
invention. Although EE2 caused a decrease in serum
cholesterol when orally administered at 0.1 mg/kg/day, it
also exerted a stimulatory action on the uterus so that EE2
uterine weight was substantially greater than the uterine
weight of ovariectomized test animals. This uterine response
to estrogen is well recognized in the art.
Not only did the compounds of the present invention
generally reduce serum cholesterol compared to the
ovariectomized control animals, but uterine weight was only
minimally increased to slightly decreased with the majority
of the formula compounds tested. Compared to estrogenic
compounds known in the art, the benefit of serum cholesterol
reduction without adversely affecting uterine weight is quite
rare and desirable.
As is expressed in the below data, estrogenicity
also was assessed by evaluating the adverse response of
eosinophil infiltration into the uterus. The compounds of
the present invention did not cause any increase in the
number of eosinophils observed in the stromal layer of
ovariectomized rats, while estradiol cause a substantial,
expected increase in eosinophil infiltration.
The data presented in the Tables 1 below reflects
the response of 5 to 6 rats per treatment.
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Table 1
Dose Uterine Weight Uterine EPO Serum Cholesterol
Comoound ma/ka A increase vs. OVX) (V. max) A decrease vs. OVX)
EE2 0.1 229.2 308.1 94.8
Example 3 0.01 29.1 1.8 50.6
0.1 55.4 4.8 47.8
1.0 61.9 5.4 49.2
Example 4 0.1 33.2 3.9 53.7
1.0 35.6 4.8 62.1
10.0 34.7 3.0 65.3
Example 5 0.1 66.7 7.2 67.2
1.0 106.9 54.6 67.7
10.0 109.8 59.4 60.2
Example 7 0.1 32.0 4.8 56.2
1.0 44.3 4.5 42.6
5.0 41.6 4.8 29.5
Example 10 0.1 19.7 12.0 50.2
1.0 18.4 17.7 59.0
10.0 13.3 4.8 38.9
Example 19 0.01 11.4 2.1 25.1
0.1 24.9 2.4 45.3
1.0 24.7 3.6 53.6
Example 20 0.01 16.9 0.9 29.4
0.05 40.9 3.0 35.9
0.1 30.6 3.0 58.7
Example 21 0.01 21.0 1.2 26.8
0.1 24.8 4.8 47.5
1.0 51.4 9.3 54.4
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Table 1 (Cont.)
Dose Uterine Weight Uterine EPO Serum Cholesterol
Comnound ma/ka increase vs. OVXI (V. max) decrease vs. OVX)
Example 23 0.01 21.6 3.3 36.2
0.1 33.4 84.3 47.2
1.0 148.9 150.6 66.1
Example 24 0.01 9.2 3.6 23.7
0.1 18.2 0.9 46.4
1.0 81.0 29.4 79.3
Example 25 0.01 5.4 3.0 13.1
0.1 16.7 3.3 67.6
1.0 96.6 36.0 73.9
Example 26 0.01 14.0 4.8 29.0
0.1 81.0 29.1 45.2
1.0 117.1 175.1 62.7
Example 27 0.01 2.2 3.3 12.2
0.1 49.2 4.8 50.8
1.0 86.4 52.5 76.5
Example 43 0.01 0.0 3.3 9.2
0.1 17.2 4.8 43.8
1.0 31.0 6.0 39.4
Example 44 0.01 43.8 3.6 12.6
0.1 80.5 88.5 43.8
1.0 74.8 94.5 67.4
Example 53 0.1 40.6 0.9 62.7
1.0 24.1 1.3 57.5
10.0 32.0 4.8 58.7
X-9712 -123- 2170479
In addition to the demonstrated benefits of the
compounds of the present invention, especially when compared
to estradiol, the above data clearly demonstrate that
compounds of Formula I are not estrogen mimetics.
Furthermore, no deleterious toxicological effects (survival)
were observed with any treatment.
Osteonorosis Test Procedure
Following the General Preparation Procedure, infra,
the rats were treated daily for 35 days (6 rats per treatment
group) and sacrificed by carbon dioxide asphyxiation on the
36th day. The 35 day time period was sufficient to allow
maximal reduction in bone density, measured as described
herein. At the time of sacrifice, the uteri were removed,
dissected free of extraneous tissue, and the fluid contents
were expelled before determination of wet weight in order to
confirm estrogen deficiency associated with complete
ovariectomy. Uterine weight was routinely reduced about 75%
in response to ovariectomy. The uteri were then placed in
10% neutral buffered formalin to allow for subsequent
histological analysis.
The right femurs were excised and digitilized x-
rays generated and analyzed by an image analysis program (NIH
image) at the distal metaphysis. The proximal aspect of the
tibiae from these animals were also scanned by quantitative
computed tomography.
In accordance with the above procedures, compounds
of the present invention and ethynyl estradiol (EE2) in 20%
hydroxypropyl b-cyclodextrin were orally administered to test
animals. Distal femur metaphysis data presented in Tables 2
and 3 below are the results of formula I compound treatments
compared to intact and ovariectomized test animals. Results
are reported as the mean the standard error of the mean.
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Table 2
Distal Femur Metaphysis
(X-ray Image Analysis-
Compound/Treatment Dose /kg Gray Score
Sham (20% cyclodextrin) - 27.2 6.0
Overiectomy control - 8.1 1.8
(20% cyclodextrin)
EE2 0.1 mg 11.5 2.9*
Example 19 0.1 mg 14.7 1.9
1.0 mg 15.0 3.5*
10.0 mg 15.3 4.0*
*P <= 0.5 two tailed Student's T Test on raw data.
Table 3
Distal Femur
Metaphysis (X-ray
Compound/Treatment Dose /kg Image Analysis-Gray
Score
Sham (20% cyclodextrin) - 31.1 6.3
Overiectomy control - 6.2 1.4
(20% cyclodextrin)
EE2 0.1 mg 17.8 3.5
Example 10 0.1 mg 15.3 3.0
1.0 mg 15.2 3.7
3.0 mg 18.5 3.2*
Example 24 0.1 mg 18.3 2.6*
1.0 mg 19.6 2.3*
3.0 mg 17.1 5.5
*P <= 0.05 two tailed Student's T Test on raw data.
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In summary, ovariectomy of the test animals caused
a significant reduction in femur density compared to intact,
vehicle treated controls. Orally administered ethynyl
estradiol (EE2) prevented this loss, but the risk of uterine
stimulation with this treatment is ever-present.
The compounds of the present invention also
prevented bone loss in a general, dose-dependent manner.
Accordingly, the compounds of the present invention are
useful for the treatment of post-menopausal syndrome,
particularly osteoporosis.
MCF-7 Proliferation Assav
MCF-7 breast adenocarcinoma cells (ATCC HTB 22)
were maintained in MEM (minimal essential medium, phenol red-
free, Sigma, St. Louis, MO) supplimented with 10% fetal
bovine serum (FBS) (V/V), L-glutamine (2 mM), sodium pyruvate
(1 mM), HEPES {(N-[2-hydroxyethyl]piperazine-N'-[2-
ethanesulfonic acid]10 mM), non-essential amino acids and
bovine insulin (1 ug/mL) (maintenance medium). Ten days
prior to assay, MCF-7 cells were switched to maintenance
medium supplemented with 10% dextran coated charcoal stripped
fetal bovine serum (DCC-FBS) assay medium) in place of 10%
FBS to deplete internal stores of steroids. MCF-7 cells were
removed from maintenance flasks using cell dissociation
medium (Ca++/Mg++ free HBSS (phenol red-free) supplemented
with 10 mM HEPES and 2 mM EDTA). Cells were washed twice
with assay medium and adjusted to 80,000 cells/mL.
Approximately 100 mL (8,000 cells) were added to flat-bottom
microculture wells (Costar 3596) and incubated at 37 C in a
5% C02 humidified incubator for 48 hours to allow for cell
adherence and equilibration after transfer. Serial dilutions
of drugs or DMSO as a diluent control were prepared in assay
medium and 50 mL transferred to triplicate microcultures
followed by 50 mL assay medium for a final volume of 200 mL.
After an additional 48 hours at 37 C in a 5% CO2 humidified
incubator, microcultures were pulsed with tritiated thymidine
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(1 uCi/well) for 4 hours. Cultures were terminated by
freezing at -70 C for 24 hours followed by thawing and
harvesting of microcultures using a Skatron Semiautomatic
Cell Harvester. Samples were counted by liquid scintillation
using a Wallac BetaPlace b counter. Results in Table 4 below
show the IC50 for certain compounds of the present invention.
Table 4
Compound IC50nM
Example 3 4.0
Example 10 2.00
Example 19 0.028
Example 21 0.05
Example 23 0.08
Example 53 0.28
DMBA-Induced Mammary Tumor Inhibition
Estrogen-dependent mammary tumors are produced in
female Sprague-Dawley rats which are purchased from Harlan
Industries, Indianapolis, Indiana. At about 55 days of age,
the rats receive a single oral feeding of 20 mg of 7,12-
dimethylbenz[a]anthracene (DMBA). About 6 weeks after DMBA
administration, the mammary glands are palpated at weekly
intervals for the appearance of tumors. Whenever one or more
tumors appear, the longest and shortest diameters of each
tumor are measured with a metric caliper, the measurements
are recorded, and that animal is selected for
experimentation. An attempt is made to uniformly distribute
the various sizes of tumors in the treated and control groups
such that average-sized tumors are equivalently distributed
between test groups. Control groups and test groups for each
experiment contain 5 to 9 animals.
Compounds of Formula I are administered either
through intraperitoneal injections in 2% acacia, or orally.
2170479
X-9712 -127-
Orally administered compounds are either dissolved or
suspended in 0.2 mL corn oil. Each treatment, including
acacia and corn oil control treatments, is administered once
daily to each test animal. Following the initial tumor
measurement and selection of test animals, tumors are
measured each week by the above-mentioned method. The
treatment and measurements of animals continue for 3 to 5
weeks at which time the final areas of the tumors are
determined. For each compound and control treatment, the
change in the mean tumor area is determined.
Uterine Fibrosis Test Procedures
Test 1
Between 3 and 20 women having uterine fibrosis are
administered a compound of the present invention. The amount
of compound administered is from 0.1 to 1000 mg/day, and the
period of administration is 3 months.
The women are observed during the period of
administration, and up to 3 months after discontinuance of
administration, for effects on uterine fibrosis.
Test 2
The same procedure is used as in Test 1, except the
period of administration is 6 months.
Test 3
The same procedure is used as in Test 1, except the
period of administration is 1 year.
Test 4
A. Induction of fibroid tumors in guinea pig.
Prolonged estrogen stimulation is used to induce
leiomyomata in sexually mature female guinea pigs. Animals
are dosed with estradiol 3-5 times per week by injection for
2-4 months or until tumors arise. Treatments consisting of a
compound of the invention or vehicle is administered daily
2170479
X-9712 -128-
for 3-16 weeks and then animals are sacrificed and the uteri
harvested and analyzed for tumor regression.
B. Implantation of human uterine fibroid tissue in nude
mice.
Tissue from human leiomyomas are implanted into the
peritoneal cavity and or uterine myometrium of sexually
mature, castrated, female, nude mice. Exogenous estrogen are
supplied to induce growth of the explanted tissue. In some
cases, the harvested tumor cells are cultured in vitro prior
to implantation. Treatment consisting of a compound of the
present invention or vehicle is supplied by gastric lavage on
a daily basis for 3-16 weeks and implants are removed and
measured for growth or regression. At the time of sacrifice,
the uteri is harvested to assess the status of the organ.
Test 5
A. Tissue from human uterine fibroid tumors is harvested
and maintained, in vitro, as primary nontransformed cultures.
Surgical specimens are pushed through a sterile mesh or
sieve, or alternately teased apart from surrounding tissue to
produce a single cell suspension. Cells are maintained in
media containing 10% serum and antibiotic. Rates of growth
in the presence and absence of estrogen are determined.
Cells are assayed for their ability to produce complement
component C3 and their response to growth factors and growth
hormone. In vitro cultures are assessed for their
proliferative response following treatment with progestins,
GnRH, a compound of the present invention and vehicle.
Levels of steroid hormone receptors are assessed weekly to
determine whether important cell characteristics are
maintained in vitro. Tissue from 5-25 patients are utilized.
Activity in at least one of the above tests
indicates the compounds of the present invention are of
potential in the treatment of uterine fibrosis.
2170479
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Endometriosis Test Procedure
In Tests 1 and 2, effects of 14-day and 21-day
administration of compounds of the present invention on the
growth of explanted endometrial tissue can be examined.
Test 1
Twelve to thirty adult CD strain female rats are
used as test animals. They are divided into three groups of
equal numbers. The estrous cycle of all animals is
monitored. On the day of proestrus, surgery is performed on
each female. Females in each group have the left uterine
horn removed, sectioned into small squares, and the squares
are loosely sutured at various sites adjacent to the
mesenteric blood flow. In addition, females in Group 2 have
the ovaries removed.
On the day following surgery, animals in Groups 1
and 2 receive intraperitoneal injections of water for 14 days
whereas animals in Group 3 receive intraperitoneal injections
of 1.0 mg of a compound of the present invention per kilogram
of body weight for the same duration. Following 14 days of
treatment, each female is sacrificed and the endometrial
explants, adrenals, remaining uterus, and ovaries, where
applicable, are removed and prepared for histological
examination. The ovaries and adrenals are weighed.
Test 2
Twelve to thirty adult CD strain female rats are
used as test animals. They are divided into two equal
groups. The estrous cycle of all animals is monitored. On
the day of proestrus, surgery is performed on each female.
Females in each group have the left uterine horn removed,
sectioned into small squares, and the squares are loosely
sutured at various sites adjacent to the mesenteric blood
flow.
Approximately 50 days following surgery, animals
assigned to Group 1 receive intraperitoneal injections of
water for 21 days whereas animals in Group 2 receive
2170479
X-9712 -130-
intraperitoneal injections of 1.0 mg of a compound of the
present invention per kilogram of body weight for the same
duration. Following 21 days of treatment, each female is
sacrificed and the endometrial explants and adrenals are
removed and weighed. The explants are measured as an
indication of growth. Estrous cycles are monitored.
Test 3
A. Surgical induction of endometriosis
Autographs of endometrial tissue are used to induce
endometriosis in rats and/or rabbits. Female animals at
reproductive maturity undergo bilateral oophorectomy, and
estrogen is supplied exogenously thus providing a specific
and constant level of hormone. Autologous endometrial tissue
is implanted in the peritoneum of 5-150 animals and estrogen
supplied to induce growth of the explanted tissue. Treatment
consisting of a compound of the present invention is supplied
by gastric lavage on a daily basis for 3-16 weeks, and
implants are removed and measured for growth or regression.
At the time of sacrifice, the intact horn of the uterus is
harvested to assess status of endometrium.
B. Implantation of human endometrial tissue in nude mice.
Tissue from human endometrial lesions is implanted
into the peritoneum of sexually mature, castrated, female,
nude mice. Exogenous estrogen is supplied to induce growth
of the explanted tissue. In some cases, the harvested
endometrial cells are cultured in vitro prior to
implantation. Treatment consisting of a compound of the
present invention supplied by gastric lavage on a daily basis
for 3-16 weeks, and implants are removed and measured for
growth or regression. At the time of sacrifice, the uteri
is harvested to assess the status of the intact endometrium.
Test 4
A. Tissue from human endometrial lesions is harvested and
maintained in vitro as primary nontransformed cultures.
2i7~479
X-9712 -131-
Surgical specimens are pushed through a sterile mesh or
sieve, or alternately teased apart from surrounding tissue to
produce a single cell suspension. Cells are maintained in
media containing 10% serum and antibiotic. Rates of growth
in the presence and absence of estrogen are determined.
Cells are assayed for their ability to produce complement
component C3 and their response to growth factors and growth
hormone. In vitro cultures are assessed for their
proliferative response following treatment with progestins,
GnRH, a compound of the invention, and vehicle. Levels of
steroid hormone receptors are assessed weekly to determine
whether important cell characteristics are maintained in
vitro. Tissue from 5-25 patients is utilized.
Activity in any of the above assays indicates that
the compounds of the present invention are useful in the
treatment of endometriosis.
The present invention also provides a method of
alleviating post-menopausal syndrome in women which comprises
the aforementioned method using compounds of Formula I and
further comprises administering to a woman an effective
amount of estrogen or progestin. These treatments are
particularly useful for treating osteoporosis and lowering
serum cholesterol because the patient will receive the
benefits of each pharmaceutical agent while the compounds of
the present invention would inhibit undesirable side-effects
of estrogen and progestin. Activity of these combination
treatments in any of the post-menopausal tests, infra,
indicates that the combination treatments are useful for
alleviating the symptoms of post-menopausal symptoms in
women.
Various forms of estrogen and progestin are
commercially available. Estrogen-based agents include, for
example, ethynyl estrogen (0.01 - 0.03 mg/day), mestranol
(0.05 - 0.15 mg/day), and conjugated estrogenic hormones such
as Premarin (Wyeth-Ayerst; 0.3 - 2.5 mg/day). Progestin-
based agents include, for example, medroxyprogesterone such
as ProveraO (Upjohn; 2.5 -10 mg/day), norethylnodrel (1.0 -
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X-9712 -132-
10.0 mg/day), and nonethindrone (0.5 - 2.0 mg/day). A
preferred estrogen-based compound is Premarin, and
norethylnodrel and norethindrone are preferred progestin-
based agents.
The method of administration of each estrogen- and
progestin-based agent is consistent with that which is known
in the art. For the majority of the methods of the present
invention, compounds of Formula I are administered
continuously, from 1 to 3 times daily. However, cyclical
therapy may especially be useful in the treatment of
endometriosis or may be used acutely during painful attacks
of the disease. In the case of restenosis, therapy may be
limited to short (1-6 months) intervals following medical
procedures such as angioplasty.
As used herein, the term "effective amount" means
an amount of compound of the present invention which is
capable of alleviating the symptoms of the various
pathological conditions herein described. The specific dose
of a compound administered according to this invention will,
of course, be determined by the particular circumstances
surrounding the case including, for example, the compound
administered, the route of administration, the state of being
of the patient, and the pathological condition being treated.
A typical daily dose will contain a nontoxic dosage level of
from about 5 mg to about 600 mg/day of a compound of the
present invention. Preferred daily doses generally will be
from about 15 mg to about 80 mg/day.
The compounds of this invention can be administered
by a variety of routes including oral, rectal, transdermal,
subucutaneus, intravenous, intramuscular, and intranasal.
These compounds preferably are formulated prior to
administration, the selection of which will be decided by the
attending physician. Thus, another aspect of the present
invention is a pharmaceutical composition comprising an
effective amount of a compound of Formula I, or a
pharmaceutically acceptable salt thereof, optionally
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containing an effective amount of estrogen or progestin, and
a pharmaceutically acceptable carrier, diluent, or excipient.
The total active ingredients in such formulations
comprises from 0.1% to 99.9% by weight of the formulation.
By "pharmaceutically acceptable" it is meant the carrier,
diluent, excipients and salt must be compatible with the
other ingredients of the formulation, and not deleterious to
the recipient thereof.
Pharmaceutical formulations of the present
invention can be prepared by procedures known in the art
using well known and readily available ingredients. For
example, the compounds of formula I, with or without an
estrogen or progestin compound, can be formulated with common
excipients, diluents, or carriers, and formed into tablets,
capsules, suspensions, powders, and the like. Examples of
excipients, diluents, and carriers that are suitable for such
formulations include the following: fillers and extenders
such as starch, sugars, mannitol, and silicic derivatives;
binding agents such as carboxymethyl cellulose and other
cellulose derivatives, alginates, gelatin, and polyvinyl-
pyrrolidone; moisturizing agents such as glycerol;
disintegrating agents such as calcium carbonate and sodium
bicarbonate; agents for retarding dissolution such as
paraffin; resorption accelerators such as quaternary ammonium
compounds; surface active agents such as cetyl alcohol,
glycerol monostearate; adsorptive carriers such as kaolin and
bentonite; and lubricants such as talc, calcium and magnesium
stearate, and solid polyethyl glycols.
The compounds also can be formulated as elixirs or
solutions for convenient oral administration or as solutions
appropriate for parenteral administration, for example, by
intramuscular, subcutaneous or intravenous routes.
Additionally, the compounds are well suited to formulation as
sustained release dosage forms and the like. The
formulations can be so constituted that they release the
active ingredient only or preferably in a particular
physiological location, possibly over a period of time. The
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coatings, envelopes, and protective matrices may be made, for
example, from polymeric substances or waxes.
Compounds of formula I, alone or in combination
with a pharmaceutical agent of the present invention,
generally will be administered in a convenient formulation.
The following formulation examples only are illustrative and
are not intended to limit the scope of the present invention.
Formulations
In the formulations which follow, "active
ingredient" means a compound of formula I, or a salt or
solvate thereof.
Formulation 1: Gelatin Capsules
Hard gelatin capsules are Quantity (mg/capsule)
prepared using the
Ingredient
Active ingredient 0.1 - 1000
Starch, NF 0 - 650
Starch flowable powder 0 - 650
Silicone fluid 350 centistokes 0 - 15
The formulation above may be changed in compliance
with the reasonable variations provided.
A tablet formulation is prepared using the
ingredients below:
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Formulation 2: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 2.5 - 1000
Cellulose, microcrystalline 200 - 650
Silicon dioxide, fumed 10 - 650
Stearate acid 5 - 15
The components are blended and compressed to form tablets.
Alternatively, tablets each containing 2.5 - 1000
mg of active ingredient are made up as follows:
Formulation 3: Tablets
Ingredient Quantity (mg/tablet)
Active ingredient 25 - 1000
Starch 45
Cellulose, microcrystalline 35
Polyvinylpyrrolidone 4
(as 10% solution in water)
Sodium carboxymethyl cellulose 4.5
Magnesium stearate 0.5
Talc 1
The active ingredient, starch, and cellulose are
passed through a No. 45 mesh U.S. sieve and mixed thoroughly.
The solution of polyvinylpyrrolidone is mixed with the
resultant powders which are then passed through a No. 14 mesh
U.S. sieve. The granules so produced are dried at 50 -60 C
and passed through a No. 18 mesh U.S. sieve. The sodium
carboxymethyl starch, magnesium stearate, and talc,
previously passed through a No. 60 U.S. sieve, are then added
to the granules which, after mixing, are compressed on a
tablet machine to yield tablets.
Suspensions each containing 0.1 - 1000 mg of
medicament per 5 ml dose are made as follows:
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Formulation 4: Suspensions
Ingredient Quantity (mg/5 ml)
Active ingredient 0.1 - 1000 mg
Sodium carboxymethyl cellulose 50 mg
Syrup 1.25 mg
Benzoic acid solution 0.10 mL
Flavor q.v.
Color Q.V.
Purified water to 5 mL
The medicament is passed through a No. 45 mesh U.S. sieve and
mixed with the sodium carboxymethyl cellulose and syrup to
form a smooth paste. The benzoic acid solution, flavor, and
color are diluted with some of the water and added, with
stirring. Sufficient water is then added to produce the
required volume.
An aerosol solution is prepared containing the following
ingredients:
Formulation 5: Aerosol
Ingredient Quantity (% by weight)
Active ingredient 0.25
Ethanol 25.75
Propellant 22 (Chlorodifluoromethane) 70.00
The active ingredient is mixed with ethanol and the
mixture added to a portion of the propellant 22, cooled to
30 C, and transferred to a filling device. The required
amount is then fed to a stainless steel container and diluted
with the remaining propellant. The valve units are then
fitted to the container.
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Suppositories are prepared as follows:
Formulation 6: Suppositories
inqredient Quantity (mg/suppository)
Active ingredient 250
Saturated fattv acid glvicerides 2,000
The active ingredient is passed through a No. 60
mesh U.S. sieve and suspended in the saturated fatty acid
glycerides previously melted using the minimal necessary
heat. The mixture is then poured into a suppository mold of
nominal 2 g capacity and allowed to cool.
An intravenous formulation is prepared as follows:
Formulation 7: Intravenous Solution
Ingredient Quantity
Active ingredient 50 mg
Isotonic saline____ 1,000 mL
The solution of the above ingredients is
intravenously administered to a patient at a rate of about 1
mL per minute.
Formulation 8: Combination Capsule I
Ingredient Quantity (mg/capsule)
Active ingredient 50
Premarin* 1
Avicel*pH 101 50
Starch 1500 117.50
Silicon oil 2
Tween*80 0.50
Cab-o-Sil* 0.25
*Trademark
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Formulation 9: Combination Capsule II
Ingredient Quantity (mg/capsule)
Active ingredient 50
Norethylnodrel 5
Avicel*pH 101 82.50
Starch 1500 90
Silicon Oil 2
Tween*80 0.50
Formulation 10: Combination Tablet
Inaredient Quantity (mg/capsule)
Active ingredient 50
Premarin* 1
Corn Starch NF 50
Povidone, K29-32 6
Avicel*pH 101 41.50
Avicel*pH 102 136.50
Crospovidone XL10 2.50
Magnesium Stearate 0.50
Cab-O-Sil* 0.50
*Trademark
