U.S. patent application number 09/564966 was filed with the patent office on 2002-01-31 for treatment of central nervous system disorders with selective estrogen receptor modulators.
Invention is credited to Bales, Kelly Renee, Bryant, Henry Uhlman, Knadler, Mary Patricia, Paul, Steven Marc.
Application Number | 20020013342 09/564966 |
Document ID | / |
Family ID | 21925589 |
Filed Date | 2002-01-31 |
United States Patent
Application |
20020013342 |
Kind Code |
A1 |
Bales, Kelly Renee ; et
al. |
January 31, 2002 |
Treatment of central nervous system disorders with selective
estrogen receptor modulators
Abstract
The present invention provides a method of treating depression,
mood swings, or Alzheimer's disease in a patient in need of such
treatment by administering a selective estrogen receptor modulating
compound of the formula 1 in which R.sup.1 and R.sup.2 are
independently hydroxy and alkoxy of one to four carbon atoms; and
R.sup.3 and R.sup.4 are independently methyl or ethyl, or R.sup.3
and R.sup.4, taken together with the nitrogen atom to which they
are attached, form a pyrrolidino, methyl-pyrrolidino,
dimethylpyrrolidino, piperidino, morpholino, or hexamethyleneimino
ring.
Inventors: |
Bales, Kelly Renee;
(Cloverdale, IN) ; Bryant, Henry Uhlman;
(Indianapolis, IN) ; Paul, Steven Marc; (Carmel,
IN) ; Knadler, Mary Patricia; (Indianapolis,
IN) |
Correspondence
Address: |
William R. Boudreaux
ELI LILLY and COMPANY
Lilly Corporate Center
Patent Division DC:1104
Indianapolis
IN
46285
US
|
Family ID: |
21925589 |
Appl. No.: |
09/564966 |
Filed: |
May 4, 2000 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09564966 |
May 4, 2000 |
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09057723 |
Apr 9, 1998 |
|
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6077852 |
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60043117 |
Apr 9, 1997 |
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Current U.S.
Class: |
514/319 |
Current CPC
Class: |
A61K 31/381 20130101;
A61K 31/5377 20130101; A61K 31/55 20130101; A61P 25/24 20180101;
Y10S 514/879 20130101; A61K 31/4025 20130101; A61P 25/18 20180101;
Y10S 514/878 20130101; A61K 31/4535 20130101; A61P 25/28
20180101 |
Class at
Publication: |
514/319 |
International
Class: |
A61K 031/445; A01N
043/40 |
Claims
We claim:
1. The use of a compound having the structure 45or a
pharmaceutically acceptable salt or pro-drug thereof, wherein
R.sup.1 and R.sup.2 are independently selected from the group
consisting of hydroxy and alkoxy of one to four carbon atoms; and
R.sup.3 and R.sup.4 are independently selected from methyl or
ethyl, or R.sup.3 and R.sup.4, taken together with the nitrogen
atom to which they are attached, form a pyrrolidino,
methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or
hexamethyleneimino ring; in the preparation of a medicament useful
for treating a central nervous system disorder selected from
depression, mood swings, and Alzheimer's disease in a patient.
2. The use of claim 1 wherein said medicament is useful for
treating depression or mood swings.
3. The use of claim 1 wherein said medicament is useful for
treating Alzheimer's disease.
4. The use of claim 1 wherein R.sup.1 and R.sup.2 are both
hydroxy.
5. The use of claim 2 wherein R.sup.1 and R.sup.2 are both
hydroxy.
6. The use of claim 3 wherein R.sup.1 and R.sup.2 are both
hydroxy.
7. The use of claim 1 wherein R.sup.1 is hydroxy and R.sup.2 is
alkoxy of one to four carbon atoms.
8. The use of claim 2 wherein R.sup.1 is hydroxy and R.sup.2 is
alkoxy of one to four carbon atoms.
9. The use of claim 3 wherein R.sup.1 is hydroxy and R.sup.2 is
alkoxy of one to four carbon atoms.
10. The use of claim 1 wherein R.sup.3 and R.sup.4 combine with the
nitrogen atom to which they are attached to form a piperidino
ring.
11. The use of claim 2 wherein R.sup.3 and R.sup.4 combine with the
nitrogen atom to which they are attached to form a piperidino
ring.
12. The use of claim 3 wherein R.sup.3 and R.sup.4 combine with the
nitrogen atom to which they are attached to form a piperidino
ring.
13. The use of a compound having the structure 46or a
pharmaceutically acceptable salt or pro-drug thereof, wherein
R.sup.2 is hydroxy or methoxy; in the preparation of a medicament
useful for treating depression or mood swings in a patient.
14. The use of claim 13 wherein said compound is
6-hydroxy-2-(4-methoxyphe-
nyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiophene or a
pharmaceutically acceptable salt thereof.
15. The use of claim 13 wherein said compound is
6-hydroxy-2-(4-hydroxyphe-
nyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiophene or a
pharmaceutically acceptable salt thereof.
16. The use of a compound having the structure 47or a
pharmaceutically acceptable salt or pro-drug thereof, wherein
R.sup.2 is hydroxy or methoxy; in the preparation of a medicament
useful for treating Alzheimer's disease in a patient.
17. The use of claim 16 wherein said compound is
6-hydroxy-2-(4-methoxyphe-
nyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]thiophene or a
pharmaceutically acceptable salt thereof.
18. The method of claim 16 wherein said compound is
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]th-
iophene or a pharmaceutically acceptable salt thereof.
19. The use of claim 13 wherein said salt is the hydrochloride
salt.
20. The use of claim 16 wherein said salt is the hydrochloride
salt.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/043,117, filed Apr. 9, 1997.
TECHNICAL FIELD
[0002] The present application relates to medical methods of
treatment. More particularly, the present invention concerns the
use of a class of substituted benzo[b]thiophene compounds for the
treatment of depression, mood swings, and Alzheimer's disease in
patients in need thereof.
BACKGROUND OF THE INVENTION
[0003] In addition to the well documented effects of estrogen on
reproductive tissue, bone and cholesterol metabolism in
post-menopausal women, it is known that estrogen has a number of
actions in the central nervous system with both somatic and
behavioral consequences.
[0004] In climacteric women, anxiety, depression, tension and
irritability begin during the perimenopause and can be correlated
to reduced estrogen levels. Estrogen replacement therapy has been
recommended for the treatment of these symptoms (cf. J. Malleson,
Lancet, 2: 158 (1953) and R. Wilson, et al., J. Am. Geriatric Soc.,
11:347 (1963)).
[0005] The mechanism for the protective effects of estrogen against
depression and mood swings is not well understood, but may be
related to the potential effects of estrogen on biogenic amines
such as serotonin (cf. M. Aylward, Int. Res. Communications System
Med. Sci., 1: 30 (1973).
[0006] In the area of memory and cognition enhancement, S.
Phillips, et al., Psychoneuroendocrinology, 17: 485-495 (1992) have
reported that in surgically menopausal women given estrogen, scores
in immediate and delayed recall tests are greater than in similar
women not given estrogen. In a prospective cohort study in
post-menopausal women, A. H. Paganini-Hill, et al., Am. J.
Epidemiol., 140(3): 256-261 (1994) demonstrated that the risk of
Alzheimer's disease was less in estrogen users as compared with
women who did not use estrogen. Furthermore, the risk of
Alzheimer's disease decreased significantly with increasing doses
of estrogen and increased duration of estrogen use.
[0007] All of the these studies have lead to the growing perception
in the literature that estrogen replacement therapy is a promising
treatment for central nervous system disorders such as depression
and mood swings and of Alzheimer's disease in post-menopausal
women. These promising uses of estrogen replacement therapy are
off-set, however, by the disadvantages of long-term estrogen
therapy associated with the risks of developing reproductive tissue
cancers.
[0008] Women on estrogen replacement therapy develop endometrial
cancer at rates three to six times higher than nonusers after three
to six years of use; after ten years on estrogen replacement
therapy, the risk ratio increases to tenfold. A growing body of
literature suggests that long-term (i.e. 10-15 years) causes a
thirty to fifty percent increase in the risk of breast cancer.
[0009] Thus, there is a need for the development of compounds which
are alternatives to estrogen possessing the same beneficial effects
on depression and mood swings and on the treatment of Alzheimer's
disease, but which lack the detrimental effects on reproductive
tissue.
BRIEF SUMMARY OF THE INVENTION
[0010] In accordance with the present invention, there is provided
a method of treating in a patient in need of such treatment, a
central nervous system disorder selected from depression, mood
swings, and Alzheimer's disease comprising administering a
therapeutically effective amount of a compound having the structure
2
[0011] or a pharmaceutically acceptable salt or pro-drug
thereof.
[0012] In the structure shown above, R.sup.1 and R.sup.2 are
independently selected from the group consisting of hydroxy and
alkoxy of one to four carbon atoms.
[0013] R.sup.3 and R.sup.4 are independently selected from methyl
or ethyl, or R.sup.3 and R.sup.4, taken together with the nitrogen
atom to which they are attached, form a pyrrolidino,
methylpyrrolidino, dimethylpyrrolidino, piperidino, morpholino, or
hexamethyleneimino ring.
[0014] The compounds of the present invention are selective
estrogen receptor modulators (SERM's), that is, compounds which
produce estrogen agonism in one or more desired target tissues
while producing estrogen antagonism and/or minimal (i.e. clinically
insignificant) agonism in reproductive tissue such as the breast or
uterus.
DETAILED DESCRIPTION
[0015] Throughout this specification and the appended claims,
general terms bear their usual meanings.
[0016] The term "alkyl" denotes a monovalent radical derived by
removal of one hydrogen atom from methane, ethane, or a straight or
branched hydrocarbon and includes such groups as methyl, ethyl,
propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl and
the like.
[0017] "Alkoxy" means an alkyl group, as defined above, attached to
the parent molecular moiety through an oxygen atom and includes
such groups as methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy,
sec-butoxy, iso-butoxy, tert-butoxy and the like. In the present
invention, methoxy is the preferred alkoxy group.
[0018] The term "pro-drug," as used herein means a compound of the
present invention bearing a group which is metabolically cleaved in
a human to produce a therapeutically active compound of the present
invention. In particular, such pro-drug compounds include those in
which either or both of the substituent groups R.sup.1 and R.sup.2
of the structure shown above are hydroxy groups which have been
protected by a pharmaceutically acceptable hydroxy protecting group
which is metabolically cleaved in the body to yield a corresponding
monohydroxy or dihydroxy compound of the present invention. Hydroxy
protecting groups are described in Chapter 2 of T. W. Greene, et
al., "Protective Groups in Organic Synthesis," Second Edition, John
Wiley & Sons, Inc., New York, 1991. Simple ether and ester
groups are preferred as pro-drug hydroxy protecting groups.
[0019] The term "patient" refers to a mammal which is in need of
treatment for mood swings, depression or Alzheimer's disease. It is
understood that guinea pigs, dogs, cats, rats, mice, hamsters,
rabbits and primates, including humans, both male and female, are
examples of patients within the scope of the meaning of the
term.
[0020] Preferred compounds of the present invention include
[0021]
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidino-ethoxy)phenoxy]ben-
zo[b]thiophene or a pharmaceutically acceptable salt or pro-drug
thereof; and
[0022]
6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidino-ethoxy)phenoxy]ben-
zo[b]thiophene or a pharmaceutically acceptable salt or pro-drug
thereof.
[0023] Preparation of Compounds of the Invention
[0024] The starting material for one route for preparing compounds
of the present invention is prepared essentially as described by C.
D. Jones in U.S. Pat. Nos. 4,418,068, and 4,133,814. The starting
materials have the formula 1: 3
[0025] wherein R.sup.5 and R.sup.6 are independently --H or a
hydroxy protecting group.
[0026] The R.sup.5 and R.sup.6 hydroxy protecting groups are
moieties 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 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); Greene, 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).
[0027] Representative hydroxy protecting groups include, for
example, -C.sub.1-C.sub.4 alkyl, -C.sub.1-C.sub.4 alkoxy,
--CO--(C.sub.1-C.sub.6 alkyl), --SO.sub.2--(C.sub.4-C.sub.6 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 C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, hydroxy, nitro,
halo, and tri(chloro or fluoro) methyl. The term "halo" refers to
bromo, chloro, fluoro, and iodo.
[0028] For compounds of formula 1, preferred R.sup.5 and R.sup.6
substituents are methyl, isopropyl, benzyl, and methoxymethyl.
Compounds in which R.sup.5 and R.sup.6 each are methyl are prepared
via the procedure described in the above-referenced Jones
patent.
[0029] Compounds of formula 1 are also prepared in which the
R.sup.5 hydroxy protecting group is selectively removed, leaving
R.sup.6 as a hydroxy protecting group as part of the final product.
The same is true in the case in which the R.sup.6 hydroxy
protecting group is selectively removed, leaving the R.sup.5
hydroxy protecting group in place. For example, R.sup.5 can be
isopropyl or benzyl and R.sup.6 methyl. The isopropyl or benzyl
moiety is selectively removed via standard procedures, and the
R.sup.6 methyl protecting group is left as part of the final
product.
[0030] As shown in Reaction Scheme I, the first steps of the
present process for preparing certain compounds of the present
invention include selectively placing a leaving group, R.sup.7 at
the 3 position of a compound of formula 1, to form a compound of
formula 2, coupling the product of that reaction with a
4-(protected-hydroxy)phenol, 3, to form a compound of formula 4,
and selectively removing the R.sup.8 hydroxy protecting group to
form a compound of formula 5. In the sequence of steps shown in
Reaction Scheme I, the hydroxy protecting groups R.sup.5, R.sup.6
and R.sup.8 are chosen in such a manner that, in the final step,
the hydroxy protecting group R.sup.8 can be selectively removed in
the presence of hydroxy protecting groups R.sup.5 and R.sup.6.
4
[0031] In the first step of Reaction Scheme I, an appropriate
leaving group is selectively placed at the 3-position of the
formula 1 starting material via standard procedures. Appropriate
R.sup.7 leaving groups include the sulfonates such as
methanesulfonate, 4-bromobenzenesulfonate, toluenesulfonate,
ethanesulfonate, isopropanesulfonate, 4-methoxybenzenesulfonate,
4-nitrobenzenesulfonate, 2-chlorobenzenesulfonate, triflate, and
the like, halogens such as bromo, chloro, and 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.
[0032] 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 1 substrate,
in a suitable solvent such as, for example, chloroform or acetic
acid. The reaction is typically run at a temperature from about
40.degree. C. to about 80.degree. C.
[0033] The reaction product from the above process step, a compound
of formula 2, is then reacted with a 4-(protected-hydroxy)phenol,
3, to form compounds of formula 4 in which R.sup.8 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 R.sup.5 and, when present, R.sup.6 moieties of a
formula 3 compound. Preferred R.sup.8 protecting groups include
methoxymethyl, when R.sup.5 and/or R.sup.6 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.
[0034] The coupling reaction between compounds of formula 2 and
those of formula 3 is known in the art as an Ullman reaction and is
generally 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)].
[0035] 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 2 compound
in which R.sup.7 is bromo is reacted with an equivalent amount of
4-benzyloxyphenol in the presence of an equivalent of cuprous
oxide.
[0036] 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.
[0037] The temperature employed in this step is generally
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 is usually from about 20 to about
60 hours.
[0038] Following coupling of a compound of formula 2 with one of
formula 3, to form a formula 4 compound, formula 5 compounds are
prepared by selectively removing the R.sup.8 hydroxy protecting
group of a formula 4 compound via well known reduction procedures.
It is imperative that the selected procedure will not affect the
R.sup.5 and, when present, R.sup.6 hydroxy protecting groups.
[0039] When R.sup.8 is the preferred benzyl moiety, and R.sup.5
and, when present, R.sup.6 each are methyl, the present process
step is carried out via standard hydrogenolysis procedures.
Typically, the formula 4 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.
[0040] 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
C.sub.1-C.sub.4 aliphatic alcohols, particularly ethanol, is
preferred. For the present reaction, hydrochloric acid serves as an
adequate and preferred proton donor.
[0041] When run at ambient temperature and a pressure ranging form
about 30 psi (206.8 kilopascals) to about 50 psi 344.7
kilopascals), the present reaction runs quite rapidly. Progress of
this reaction may be monitored by standard chromatographic
techniques such as thin layer chromatography.
[0042] As shown in Reaction Scheme II, upon preparation of a
formula 5 compound, it is reacted with a compound of formula
R.sup.4R.sup.5N--(CH.sub.2).sub.2--Q 6
[0043] wherein R.sup.4 and R.sup.5 are as defined above, and Q is a
bromo or, preferably, chloro, to form a compound of formula 7. The
formula 7 compound is then deprotected to form a compound of
formula I. 5
[0044] In the first step of the process shown in Reaction Scheme
II, the reaction is carried out via standard procedures. Compounds
of formula 6 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 6 compound is used. In a
particularly preferred case of the compounds of the present
invention, 2-chloroethylpiperidine hydrochloride, is used.
[0045] Generally, at least about 1 equivalent of a formula 5
substrate is reacted with 2 equivalents of a formula 6 compound in
the presence of at least about 4 equivalents of an alkali metal
carbonate, preferably cesium carbonate, and an appropriate
solvent.
[0046] Suitable solvents for this reaction are those solvents or
mixture of solvents which remain inert throughout the 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.
[0047] Under the preferred reaction conditions, this reaction will
run to completion in about 16 to about 20 hours. The progress of
the reaction can be monitored via standard chromatographic
techniques.
[0048] In an alternative process for preparing compounds of the
present invention, shown in Reaction Scheme III below, a formula 5
compound is reacted in an alkali solution with an excess of an
alkylating agent of formula 8:
Q--(CH.sub.2).sub.n--Q' 8
[0049] in which Q and Q' are the same or different leaving groups.
Appropriate leaving groups are those mentioned above. 6
[0050] 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
unprotected hydroxy group of the formula 5 compound is converted to
a phenoxide ion which displaces one of the leaving groups of the
alkylating agent.
[0051] This reaction proceeds 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 range from about 6 hours to about 20
hours.
[0052] The reaction product from this step, a compound of formula
9is then reacted with a compound of formula 10selected from
1-piperidine, 1-pyrrolidine, methyl-1-pyrrolidine,
dimethyl-1-pyrrolidine, 4-morpholine, dimethylamine, diethylamine,
diisopropylamine, or 1-hexamethyleneimine, via standard techniques,
to form compounds of formula 7. Preferably, the hydrochloride salt
of a compound of formula 10 is employed, with piperidine
hydrochloride being particularly preferred. The reaction is
typically carried out with the alkylated compound of formula 9in an
inert solvent, such as anhydrous DMF, and heated to a temperature
in the range from about 60.degree. C. to about 110.degree. C. When
the mixture is heated to a preferred temperature of about
90.degree. 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.
The progress of this reaction step can be monitored via standard
chromatographic techniques.
[0053] Certain preferred compounds of formula I are obtained by
cleaving the R.sup.5 and, when present, R.sup.6 hydroxy protecting
groups of formula I 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); Greene, 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 R.sup.7 and/or R.sup.8 hydroxy
protecting groups, particularly methyl and methoxymethyl, are
essentially as described in the Examples, infra.
[0054] An alternative, and preferred, method for the preparation of
compounds of the present invention is shown in Reaction Scheme IV.
In the process shown there, the sulfur atom of a formula 2 compound
is oxidized to form a sulfoxide, 11, which is then reacted with a
nucleophilic group to introduce the oxygen atom linker of formula I
compounds. The sulfoxide moiety of formula 12 compounds is then
reduced to provide certain compounds of the present invention.
7
[0055] In the first step of this process, a compound of formula 2
is selectively oxidized to the sulfoxide, 12. A number of known
methods are available for the process step [see, e.g., Madesclaire,
M., Tetrahedron, 42 (20); 5459-5495 (1986); Trost, B. M., et al.,
Tetrahedron Letters, 22 (14); 1287-1290 (1981); Drabowicz, J., et
al., Synthetic Communications, 11 (12); 1025-1030 (1981); Kramer,
J. B., et al., 34th National Organic Symposium, Williamsburg, Va.,
Jun. 11-15, 1995]. However, many oxidants provide only poor
conversion to the desired product as well as significant
over-oxidation to the sulfone. The preferred process, however,
converts a formula 2 compound to a sulfoxide of formula 12 in high
yield with little or no formation of sulfones. This process
involves the reaction of a formula 2 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.degree. C. to about
50.degree. C., and usually required from about 1 to about 2 hours
to run to completion.
[0056] Next, the 3-position leaving group, R.sup.7, is displaced by
the desired nucleophilic derivative of formula 13. Such
nucleophilic derivatives are prepared via standard methods.
[0057] 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.degree. C. and about 30.degree.
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.degree. C. and about 50.degree. C., and is usually run in
about 1 to about 2 hours. The product is isolated by standard
procedures.
[0058] In the next step of the present process, the sulfoxide of
formula 14 is reduced to a benzothiophene compound of formula
I.
[0059] When desired, the hydroxy protecting group or groups of the
products of the process shown in Reaction Scheme IV can be removed,
and a salt of the product of any step of the process.
[0060] Pro-drug ester compounds of formula I are prepared by
replacing the 6- and/or 4'-position hydroxy moieties, when present,
with a moiety of the formula --OCO(C.sub.1-C.sub.6 alkyl), or
--OSO.sub.2(C.sub.2-C.sub.6 alkyl) via well known procedures. See,
e.g., U.S. Pat. No. 4,358,593.
[0061] For example, when an --OCO(C.sub.1-C.sub.6 alkyl) group is
desired, a mono- or dihydroxy compound of formula I is 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. See, e.g., Haslam, et al.,
Tetrahedron, 36:2409-2433 (1980).
[0062] These reactions are carried out at moderate temperatures, in
the range from about -25.degree. C. to about 100.degree. C.,
frequently under an inert atmosphere such as nitrogen gas. However,
ambient temperature is usually adequate for the reaction to
run.
[0063] 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.
[0064] The aforementioned ester pro-drug 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, 38:1979
(1965), and Chem. Ber., 788 and 2024 (1970).
[0065] Each of the above techniques which provide
--OCO(C.sub.1-C.sub.6 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 call for
the use of an acid scavenger in the reaction mixture.
[0066] When a 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 --OSO.sub.2(C.sub.2-C.sub.6 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.
[0067] Preparation of Pharmaceutically Acceptable Salts of
Compounds of the Present Invention
[0068] Although the free-base form of formula I compounds can be
used in the medical methods of treatment of the present invention,
it is preferred to prepare and use a pharmaceutically acceptable
salt form. 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. Such salts are also
contemplated as falling within the scope of the present
invention.
[0069] The term "pharmaceutically acceptable salts" as used
throughout this specification and the appended claims denotes salts
of the types disclosed in the article by Berge, et al., J.
Pharmaceutical Sciences, 66(1): 1-19 (1977). Suitable
pharmaceutically acceptable salts include salts formed by typical
inorganic acids such as hydrochloric, hydrobromic, hydroiodic,
nitric, sulfuric, phosphoric, hypophosphoric, and the like as well
as 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. Such pharmaceutically
acceptable organic acid addition salts include acetate,
phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate,
chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate,
methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide,
isobutyrate, phenylbutyrate, b-hydroxybutyrate, butyne-1,4-dioate,
hexyne-1,4-dioate, caprate, caprylate, chloride, cinnamate,
citrate, formate, fumarate, glycollate, 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-hydroxyethanesulfonate,
methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,
p-toluene-sulfonate, xylenesulfonate, tartarate, and the like.
Preferred salts are the hydrochloride and oxalate salts.
[0070] The pharmaceutically acceptable acid addition salts are
typically formed by reacting a compound of formula I with an
equimolar or slight molar excess 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.
[0071] 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.
[0072] Pharmaceutical Formulations
[0073] The compounds of this invention are 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
containing an effective amount of estrogen or progestin, and a
pharmaceutically acceptable carrier, diluent, or excipient.
[0074] 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.
[0075] Pharmaceutical formulations of the present invention are
prepared by procedures known in the art using well known and
readily available ingredients. For example, the compounds of
Formula I, either alone, or in combination with an estrogen or
progestin compound, are formulated with common excipients,
diluents, or carriers, and formed into tablets, capsules,
suspensions, solutions, injectables, aerosols, powders, and the
like.
[0076] 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.
[0077] The formulations may be specially formulated for oral
administration, in solid or liquid form, for parenteral injection,
topical or aerosol administration, or for rectal or vaginal
administration by means of a suppository.
[0078] The pharmaceutical compositions of this invention can be
administered to humans and other mammals orally, rectally,
intravaginally, parenterally, topically (by means of powders,
ointments, creams, or drops), bucally or sublingually, or as an
oral or nasal spray. The term "parenteral administration" refers
herein to modes of administration which include intravenous,
intramuscular, intraperitoneal, instrasternal, subcutaneous, or
intraarticular injection or infusion.
[0079] Pharmaceutical compositions of this invention for parenteral
administration comprise sterile aqueous or non-aqueous solutions,
dispersions, suspensions, or emulsions, as well as sterile powders
which are reconstituted immediately prior to use into sterile
solutions or suspensions. Examples of suitable sterile aqueous and
non-aqueous carriers, diluents, solvents or vehicles include water,
physiological saline solution, ethanol, polyols (such as glycerol,
propylene glycol, poly(ethylene glycol), and the like), and
suitable mixtures thereof, vegetable oils (such as olive oil), and
injectable organic esters such as ethyl oleate. Proper fluidity is
maintained, for example, by the use of coating materials such as
lecithin, by the maintenance of proper particle size in the case of
dispersions and suspensions, and by the use of surfactants.
[0080] Parenteral compositions may also contain adjuvants such as
preservatives, wetting agents, emulsifying agents, and dispersing
agents. Prevention of the action of microorganisms is ensured by
the inclusion of antibacterial and antifungal agents, for example,
paraben, chlorobutanol, phenol sorbic acid, and the like. It may
also be desirable to include isotonic agents such as sugars, sodium
chloride, and the like. Prolonged absorption of injectable
formulations may be brought about by the inclusion of agents which
delay absorption such as aluminum monostearate and gelatin.
[0081] In some cases, in order to prolong the effect of the drug,
it is desirable to slow the absorption of the drug following
subcutaneous or intramuscular injection. This may be accomplished
by the use of a liquid suspension or crystalline or amorphous
material of low water solubility or by dissolving or suspending the
drug in an oil vehicle. In the case of the subcutaneous or
intramuscular injection of a suspension containing a form of the
drug with low water solubility, the rate of absorption of the drug
depends upon its rate of dissolution.
[0082] Injectable "depot" formulations of the compounds of this
invention are made by forming microencapsulated matrices of the
drug in biodegradable polymers such as poly(lactic acid),
poly(glycolic acid), copolymers of lactic and glycolic acid, poly
(orthoesters), and poly (anhydrides) these materials which are
described in the art. Depending upon the ratio of drug to polymer
and the characteristics of the particular polymer employed, the
rate of drug release can be controlled.
[0083] Injectable formulations are sterilized, for example, by
filtration through bacterial-retaining filters, or by
presterilization of the components of the mixture prior to their
admixture, either at the time of manufacture or just prior to
administration (as in the example of a dual chamber syringe
package).
[0084] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active component is mixed with at least one inert,
pharmaceutically acceptable carrier such as sodium citrate, or
dicalcium phosphate, and/or (a) fillers or extenders such as
starches, lactose, glucose, mannitol, and silicic acid, (b) binding
agents such as carboxymethyl-cellulose, alginates, gelatin,
poly(vinylpyrrolidine), sucrose and acacia, (c) humectants such as
glycerol, (d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, silicates and
sodium carbonate, (e) solution retarding agents such as paraffin,
(f) absorption accelerating agents such as quaternary ammonium
compounds, (g) wetting agents such as cetyl alcohol and glycerin
monostearate, (h) absorbents such as kaolin and bentonite clay, and
(i) lubricants such as talc, calcium stearate, magnesium stearate,
solid poly(ethylene glycols), sodium lauryl sulfate, and mixtures
thereof. In the case of capsules, tablets and pills, the dosage
form may also contain buffering agents.
[0085] Solid compositions of a similar type may also comprise the
fill in soft or hard gelatin capsules using excipients such as
lactose as well as high molecular weight poly(ethylene glycols) and
the like.
[0086] Solid dosage forms such as tablets, dragees, capsules, pills
and granules can also be prepared with coatings or shells such as
enteric coatings or other coatings well known in the pharmaceutical
formulating art. The coatings may contain opacifying agents or
agents which release the active ingredient(s) in a particular part
of the digestive tract, as for example, acid soluble coatings for
release of the active ingredient(s) in the stomach, or base soluble
coatings for release of the active ingredient(s) in the intestinal
tract.
[0087] The active ingredient(s) may also be microencapsulated in a
sustained-release coating, with the microcapsules being made part
of a pill of capsule formulation.
[0088] Liquid dosage forms for oral administration of the compounds
of this invention include solution, emulsions, suspensions, syrups
and elixirs. In addition to the active components, liquid
formulations may include inert diluents commonly used in the art
such as water or other pharmaceutically acceptable solvents,
solubilizing agents and emulsifiers such as ethanol, isopropanol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in
particular, cottonseed, ground nut, corn, germ, olive, castor, and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, poly(ethylene
glycols), fatty acid esters of sorbitol, and mixtures thereof.
[0089] Besides inert diluents, the liquid oral formulations may
also include adjuvants such as wetting agents, emulsifying and
suspending agents, and sweetening, flavoring, and perfuming
agents.
[0090] Liquid suspension, in addition to the active ingredient(s)
may contain suspending agents such as ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide, bentonite clay,
agar-agar, and tragacanth, and mixtures thereof.
[0091] Compositions for rectal or intravaginal administration are
prepared by mixing one or more compounds of the present invention
with suitable non-irritating excipients such as cocoa butter,
polyethylene glycol or any suppository wax which is a solid at room
temperature, but liquid at body temperature and therefore melt in
the rectum or vaginal cavity to release the active component(s).
The compounds are dissolved in the melted wax, formed into the
desired shape, and allowed to harden into the finished suppository
formulation.
[0092] Compounds of the present invention may also be administered
in the form of liposomes. As is know in the art, liposomes are
generally derived from phospholipids or other lipid substances.
Lipososome formulations are formed by mono- or multilamellar
hydrated liquid crystals which are dispersed in an aqueous medium.
Any non-toxic, pharmaceutically acceptable, and metabolizable lipid
capable of forming liposomes can be used. The present compositions
in liposome form can contain, in addition to one or more active
compounds of the present invention, stabilizers, excipients,
preservatives, and the like. The preferred lipids are phospholipids
and the phosphatidyl cholines (lecithins), both natural and
synthetic.
[0093] Methods for forming liposomes are know in the art as
described, for example, in Prescott, Ed., Methods in Cell Biology,
Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et
seq.
[0094] Method of the Present Invention
[0095] As discussed above, estrogen has a beneficial effect on mood
swings and depression in post-menopausal women and has been
credited with also having a beneficial effect in memory and
cognition in elederly patients. To be used as a therapeutic agent
for such conditions, it may be necessary to administer a drug to a
patient over an extended period of time. However, the drawbacks
associated with the long-term use of estrogen and the risk of
attendant reproductive tissue cancers mitigate against such
long-term use of estrogen. A substitute for estrogen must have the
beneficial effects of estrogen in the brain without the associated
detrimental effects in the breast and uterus. Moreover, such a
substitute must be capable of crossing the blood-brain barrier in
order to exert the desired effect.
[0096] The compounds of the present invention possess the desired
profile, being selective estrogen receptor modulators (SERM's) with
estrogen-like effects in certain tissues while lacking (or having
minimal agonistic effect) in the breast and uterus. Moreover, as
demonstrated by the following data, certain compounds of the
present invention have been found to cross the blood-brain barrier
and to have effective levels in brain following oral administration
in laboratory animals.
[0097] Distribution of Compounds of the Invention Among Various
Tissues in the Female F344 Rat
[0098] Female Fischer 344 rats (approximately twelve weeks old)
were given a single oral gavage dose of 5 mg/kg (30 mCi/kg) of
.sup.14C-labeled
6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thio-
phene hydrochloride in 50% PEG 300/50% water. Blood and tissues
were collected from three rats at each time point: just prior to
dosing and at 2, 4, 8, and 24 hours after dosing. At each time
point, the animals were sacrificed, blood samples were collected
and the heparinized blood was centrifuged and the plasma obtained.
Following collection of the bloood sample in each case, the animals
were perfused with 0.9% saline solution and the brain, pituitary,
femurs, ovaries, uterus and liver were surgically removed and
placed in separate containers. The brain was further divided into
the hypothalamus, hippocampus, cerebellum, and cerebral cortex. All
samples were stored at -70.degree. C.
[0099] The radioactivity of each sample was determined by liquid
scintillation spectrometry. Plasma was counted directly, while the
other tissues were either homogenized, digested, or oxidized prior
to liquid scintillation counting. All tissues were weighed prior to
treatment. The liver and cerebrum were homogenized in 0.9% saline
solution and an aliquot of the homgenate was oxidized. The
pituitary, hippocampus, hypothalamus, ovaries, uterus and
cerebellum were oxidized directly after drying. The femur was
digested with a mixture of 30% hydrogen peroxide, and concentrated
perchloric acid (2/1 v/v) prior to liquid scintillation
counting.
[0100] Samples were oxidized on a Packard Model307 Oxidizer and the
resulting .sup.14CO.sub.2 trapped for liquid scintillation
counting. The radioactivity in each tissue sample was converted to
nanogram equivalents per gram of tissue (specific activity=16.3
dpm/ng). The 0-24 hour area under the curve (AUC.sub.0-24 hr) was
calculated for each sample.
[0101] A liver and cerebral cortex homogenate were analyzed by HPLC
and UV detection at 315 nm to determine if the radioactivity in
these tissues was actually due to the drug initially dosed, to the
primary metabolite,
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]-benzo[b]thi-
ophene, or there glucuronide conjugates. The cerebral cortex sample
was obtained eight hours after dosing and the liver samples were
collected at four and eight hours after dosing. The proteins in the
homogenate were precipitated with acetonitrile and the supernate
was evaporated to dryness. The residue was reconstituted in mobile
phase and injected onto a SynChropak SCD-100 column with the
initial mobile phase composed of 60% 0.05 M KH.sub.2PO.sub.4, pH
7/17% methanol/17% acetonitrile. (v/v/v). The retention times of
the peaks from the homogenate were compared with those obtained
from authentic samples of 6-hydroxy-2-(4-methoxyphenyl)-3-[4-(pi-
peridinoethoxy)phenoxy]benzo[b]thiophene and its metabolite,
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo
[b]-thiophene.
[0102] Radioactivity was found in all tissues as shown by the data
presented in Table 1.
1TABLE 1 Mean Pharmakokinetic Parameters for Radioactivity after a
Single Oral Dose of .sup.14C-6-hydroxy-2-(4-methoxyphenyl)-3-[4-
(piperidinoethoxy)phenoxy]benzo[b]-thiophene to Female F344 Rats
C.sub.max* T.sub.max AUC* TISSUE (ng/ml) (hr) (ng hr/mL) Plasma 53
.+-. 6 7 653 .+-. 28 Cerebellum 425 .+-. 25 8 5442 .+-. 456
Cerebrum 488 .+-. 37 8 6259 .+-. 560 Femur 523 .+-. 193 8 6458 .+-.
1666 Hippocampus 517 .+-. 37 8 7024 .+-. 660 Uterus 609 .+-. 31 7
8093 .+-. 311 Hypothalamus 689 .+-. 112 8 8310 .+-. 1295 Ovaries
1321 .+-. 187 7 16761 .+-. 1785 Pituitary 3203 .+-. 608 8 37666
.+-. 8829 Liver 3839 .+-. 669 7 51913 .+-. 3126
[0103] Examination of the data appearing in Table 1 indicate that
radioactive material was found in all tissues, with peak levels
being reached at 8 hours after dosing, with the exception of the
liver where peak levels were reached at 4 hours after dosing. The
lowest concentrations were found in plasma and the highest in the
liver. Both the C.sub.max and AUC.sub.0-24 hr of radioactivity for
the cerebellum, cerebrum, hippocampus, and hypothalamus were
greater than those observed in the plasma, indicating that
radioactivity distributed into the brain areas after administration
of the parent compound,
.sup.14C-6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]ben-
zo[b]thiophene. Analysis of the cerebral cortex homogenate
(described above) showed that the radioactivity was due both to the
parent compound,
.sup.14C-6-hydroxy-2-(4-methoxyphenyl)-3-[4-(piperidinoethoxy)phenoxy]ben-
zo[b]thiophene and its dihydroxy metabolite,
.sup.14C-6-hydroxy-2-(4-hydro-
xyphenyl)-3-[4-(piperidinoethoxy)phenoxy]benzo[b]thiophene, in a
ratio of approximately 4:1. Peaks corresponding to the glucuronide
conjugates of either the parent compound or its dihydroxy
metabolite were not observed in the HPLC chromatogram of the
cerebral cortex homogenate. The HPLC chromatogram of the liver
homogenates did, however, show peaks whose retention times
corresponded to the parent compound and its glucuronide
conjugate.
[0104] Similarity of
6-hydroxy-2-(4-methoxyphenyl)-3-[2-(piperidino-ethoxy-
)phenoxy]benzo [b]thiophene to Estrogen in the Hippo-campus
[0105] Estrogens, such as 17b-estradiol, regulate gene
transcription by binding to estrogen receptors (ER) which reside in
the cytoplasm of certain cell populations. Ligand activation of the
ER is a prerequisite for nuclear transport of the complex where
binding to a 13 base-pair palindromic DNA consensus sequence
(estrogen response element, or ERE) begins assembly of a
transcriptional apparatus which culminates in the activation of
appropriate target genes. A variety of genes have been identified
which are regulated by estrogen. These include cytoskeletal
proteins, neurotransmitter biosynthetic and metabolic enzymes and
receptors, as well as other hormones and neuropeptides. ERE's have
been identified in many estrogen-responsive genes including
vitellogenin, c-fos, prolactin, and luteinizing hormone.
[0106] Of significance in the central nervous system, ERE-like
sequences have been identified in p75.sup.ngr and trkA, both of
which serve as signaling molecules for the neurotrophins: nerve
growth factor (NGF), brain derived nerve growth factor (BDNGF), and
neurotrophin-3.
[0107] BDNF as well as NGF have been shown to promote the survival
of cholinergic neurons in culture. It is postulated that if the
interactions between neurotrophins and estrogens are important for
the development and survival of basal forebrain neurons (which
degenerate in Alzheimer's disease) then clinical conditions in
which an estrogen deficiency exists (as after menopause) may
contribute to a loss of thses neurons.
[0108] A commonly employed model of estrogen depletion is the
ovariectomized adult rat. An experiment was conducted in
ovariectomized rats using differential mRNA display to determine
the similarities and/or differences between a representative
compound of the present invention,
6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]-benzo[b]t-
hiophene, and estrogen at affecting gene expression in various
brain regions. Specifically, female Sprague-Dawley rats, 6 weeks of
age, were ovariectomized by the vendor. Following one week of
acclimation to the laboratory facility, daily subcutaneous
injections of estradiol benzoate (0.03 mg/kg) or
6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)ph-
enoxy]-benzo[b]thiophene (1 mg/kg), or vehicle (control) were
initiated.
[0109] After five weeks of daily treatment, animals were sacrificed
and their brains removed and hippocampi collected by
microdissection. The hippocampi were fast frozen in liquid nitrogen
and stored at -70_C. Total RNA was prepared from pooled tissue from
the appropriate treatment and control groups and reverse
transcribed using a 3' oligonucleotide primer which selected for
specific mRNA (poly-A+) populations. Polymerase chain reactions
(PCR) were carried out in a cocktail consisting of: random 5'
oligonucleotides (10 base-pairs in length; total of 150), reaction
buffer, Taq polymerase, and a .sup.32PdTCP.
[0110] After 40 rounds of amplification, the reaction products were
size fractionated on a 6% TBE-urea gel, dried and exposed to x-ray
film. The resulting mRNA display patterns were compared between
treatment groups.
6-Hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo
[b]-thiophene produced a parallel pattern of gene activation or
inactivation in the rat himmpocampus as that observed for estrogen.
These data indicate that
6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy-
)phenoxy]benzo [b]-thiophene produced an estrogen-like effect in
the hippocampus, a key brain region associated with Alzheimer's
disease in humans.
[0111] Thus, administration of an effective amount of a compound of
the present invention, especially
6-hydroxy-2-(4-methoxyphenyl)-3-[4-(2-piper-
idinoethoxy)phenoxy]benzo[b]-thiophene and its primary metabolite,
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)phenoxy]benzo[b]-t-
hiophene would be useful in the treatment of Alzheimer's disease in
a human patient.
[0112] 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 conditions herein described. The
specific dose of a compound administered according to this
invention is determined by the particular circumstances surrounding
the case including, for example, the potency of 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.
[0113] The exact dose is determined, in accordance with the
standard practice in the medical arts of dose titrating the
patient; that is, initially administering a low dose of the
compound, and gradually increasing the does until the desired
therapeutic effect is observed.
[0114] The following examples are presented to further illustrate
the preparation of compounds of the present invention. The Examples
are not to be read as limiting the scope of the invention as it is
defined by the appended claims.
[0115] NMR data for the following Examples were generated on a GE
300 MHz NMR instrument, and anhydrous hexadeutero-dimethylsulfoxide
was used as the solvent unless otherwise indicated.
EXAMPLE 1
[0116] Preparation of
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-methoxyphenyl)]benzo[b]thiophene Oxalate Salt 8
[0117] Step a: Preparation of
[6-methoxy-2-(4-methoxy-phenyl)-3-bromo]benz- o[b]thiophene 9
[0118] 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.degree. 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 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.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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
C.sub.16H.sub.13O.sub.2SBr: C, 55.03; H, 3.75. Found: C, 54.79; H,
3.76.
[0119] Step b): Preparation of
[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzylo-
xy)phenoxy]benzo[b]thiophene 10
[0120] 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
N.sub.2 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 3N hydrochloric acid
(3.times.300 mL), followed by 1N sodium hydroxide (3.times.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 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]-thiop-
hene 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.degree. C.
.sup.1H NMR (CDCl.sub.3): 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 C.sub.29H.sub.24O.sub.4S: C,
74.34; H, 5.16. Found: C, 74.64; H, 5.29.
[0121] Step c): Preparation of
[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy-
)phenoxy]benzo[b]thiophene 11
[0122] To a solution of
[6-methoxy-2-(4-methoxyphenyl)-3-(4-benzyloxy)phen-
oxy]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 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-methoxyph-
enyl)-3-(4-hydroxy)phenoxy]benzo[b]-thiophene as a white solid. mp
123-126.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.22H.sub.18O.sub.4S: C,
69.82; H, 4.79. Found: C, 70.06; H, 4.98.
[0123] Step d): Preparation of
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]ph-
enoxy]-2-(4-methoxyphenyl)]benzo[b]-thiophene Oxalate Salt
[0124] To a solution of
[6-methoxy-2-(4-methoxyphenyl)-3-(4-hydroxy)phenox-
y]benzo[b]thiophene (1.12 g, 2.97 mmol) in 7 mL of anhydrous
N,N-dimethylformamide under N.sub.2 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.times.50 mL). The organic was
combined and washed with water (2.times.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)]be-
nzo[b] thiophene as the oxalate salt. mp 197-200.degree. C. (dec).
.sup.1H NMR (DMSO-d.sub.6) 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
C.sub.29H.sub.31NO.sub.4S.0.88HO.sub.2CCO.sub- .2H: C, 64.95; H,
5.80; N, 2.46. Found: C, 64.92; H, 5.77; N, 2.54.
EXAMPLE 2
[0125] Preparation
of[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2--
(4-methoxyphenyl)]benzo[b]thiophene hydrochloride salt 12
[0126] Treatment of the oxalate salt from Example 1 with aqueous
base to produce the free base, followed by reaction with diethyl
ether saturated with HCl yielded the title salt, mp 216-220.degree.
C. .sup.1H NMR (DMSO-d.sub.6) 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, J.sub.AB=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), 1.37 (m, 1H). FD mass spec: 489. Anal.
Calcd. for C.sub.29H.sub.31NO.sub.4S.1.0HCl: C, 66.21; H, 6.13; N,
2.66. Found: C, 66.,46; H, 6.16; N, 2.74.
EXAMPLE 3
[0127] Preparation of
[6-Methoxy-3-[4-[2-(1-pyrolodinyl)ethoxy]-phenoxy]-2-
-(4-methoxyphenyl)]benzo[b]thiophene 13
[0128] The title compound was prepared in the same manner as the
compound of Example 1, mp 95-98.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 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 C.sub.28H.sub.29NO.sub.4S: C,
70.71; H, 6.15; N, 2.99. Found: C, 70.59; H, 6.15; N, 3.01.
EXAMPLE 4
[0129] Preparation of
[6-Methoxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phen-
oxy]-2-(4-methoxyphenyl)]benzo[b]thiophene Hydrochloride 14
[0130] The title compound was prepared in the same manner as the
compound of Example 1, mp 189-192.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 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 C.sub.30H.sub.33NO.sub.4S.1.0HCl: C,
66.71; H, 6.35; N, 2.59. Found: C, 66.43; H, 6.46; N, 2.84.
EXAMPLE 5
[0131] Preparation of
[6-Methoxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenox-
y]-2-(4-methoxyphenyl)]benzo[b]thiophene Hydrochloride 15
[0132] The title compound was prepared in the same manner as the
compound of Example 1, mp 196-198.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 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, J.sub.AB=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
C.sub.28H.sub.31NO.sub.4S.1.5HCl: C, 63.18; H, 6.15; N, 2.63.
Found: C, 63.46; H, 5.79; N, 2.85.
EXAMPLE 6
[0133] Preparation of
[6-Methoxy-3-[4-[2-(morpholino)ethoxy]-phenoxy]-2-(4-
-methoxyphenyl)]benzo[b]thiophene Hydrochloride 16
[0134] The title compound was prepared in the same manner as the
compound of Example 1, mp 208-211.degree. C. .sup.1H NMR
(DMSO-d.sub.6) 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, J.sub.AB=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
C.sub.28H.sub.29NO.sub.5S.1.0HCl: C, 63.09; H, 5.73; N, 2.65.
Found: C, 63.39; H, 5.80; N, 2.40.
EXAMPLE 7
[0135] Preparation of
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-hydroxyphenyl)]benzo[b]thiophene 17
[0136]
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-methoxypheny-
l)]benzo[b]thiophene hydrochloride (10.00 g, 19.05 mmol) was
dissolved in 500 mL of anhydrous methylene chloride and cooled to
8.degree. C. To this solution was added boron tribromide (7.20 mL,
76.20 mmol). The resultant mixture was stirred at 8.degree. C. for
2.5 hours. The reaction was quenched by pouring into a stirring
solution of saturated sodium bicarbonate (1 L), cooled to 0.degree.
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.times.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-piperidinyl)
ethoxy]phenoxy]-2-(4-hydroxyphenyl)]be- nzo[b]-thiophene as a white
solid. mp 93.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.27H.sub.27NO.sub.4S: C, 70.20; H, 5.90;
N, 3.03. Found: C, 69.96; H, 5.90; N, 3.14.
EXAMPLE 8
[0137] Preparation of
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-hydroxyphenyl)]benzo[b]thiophene Oxalate Salt 18
[0138] The title compound was prepared in 80% yield from the free
base, mp 246-249.degree. C. (dec). .sup.1H NMR (DMSO-d.sub.6) 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
C.sub.27H.sub.27NO.sub.4S.0.75HO.sub.2CCO.sub.2H: C, 64.63; H,
5.42; N, 2.64. Found: C, 64.61; H, 5.55; N, 2.62.
EXAMPLE 9
[0139] Preparation of
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-hydroxyphenyl)]benzo[b]thiophene hydrochloride 19
[0140] The title compound was prepared in 91% yield by treatment of
the corresponding free base with HCl saturated diethyl ether, mp
158-165.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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, J.sub.AB=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 C.sub.27H.sub.27NO.sub.4- S.1.0HCl: C, 65.11; H, 5.67;
N, 2.81. Found: C, 64.84; H, 5.64; N, 2.91.
EXAMPLE 10
[0141] Preparation of
[6-Hydroxy-3-[4-[2-(1-pyrolidinyl)ethoxy]-phenoxy]-2-
-(4-hydroxyphenyl)]benzo[b]thiophene 20
[0142] The title compound was prepared from the product of Example
3 in a manner similar to that employed in Example 7 above; mp
99-113.degree. C. .sup.1H NMR (DMSO-d.sub.6) d 9.75 (s, 1H), 9.71
(s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.25 (d, J=2.0 Hz, 1H), 7.09 (d,
J=9.0 Hz, 1H), 6.85 (s, 1H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d,
J=9.0 Hz, 2H), 3.93 (m, 2H), 2.73 (m, 2H), 2.53 (m, 4H), 0.96 (t,
J=7.0 Hz, 4H). Anal. Calcd. for
C.sub.26H.sub.25NO.sub.4S.0.5H.sub.2O: C, 68.40; H, 5.74; N, 3.07.
Found: C, 68.52; H, 6.00; N, 3.34.
EXAMPLE 11
[0143] Preparation of
[6-Hydroxy-3-[4-[2-(1-hexamethyleneimino)ethoxy]phen-
oxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene 21
[0144] The title compound was prepared from the product of Example
4 in a manner similar to that employed in Example 7 above; mp
125-130.degree. C. .sup.1H NMR (DMSO-d.sub.6) d 9.75 (s, 1H), 9.71
(s, 1H), 7.50 (d, J=9.0 Hz, 2H), 7.26 (d, J=2.0 Hz, 1H), 7.09 (d,
J=9.0 Hz, 1H), 6.85 (s, 3H), 6.80 (dd, J=9.0, 2.0 Hz, 1H), 6.79 (d,
J=9.0 Hz), 3.94 (t, J=6.0 Hz, 2H), 2.80 (t, J=6.0 Hz, 2H), 2.66 (m,
4H), 1.53 (m, 8H). Anal. Calcd. for C.sub.28H.sub.29NO.sub.4S: C,
70.71; H, 6.15; N, 2.94. Found: C, 70.67; H, 6.31; N, 2.93.
EXAMPLE 12
[0145] Preparation of
[6-Hydroxy-3-[4-[2-(1-N,N-diethylamino)ethoxy]phenox-
y]-2-(4-hydroxyphenyl)]benzo[b]thiophene 22
[0146] The title compound was prepared from the product of Example
5 in a manner similar to that employed in Example 7 above; mp
137-141.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.26H.sub.27NO.sub.4S:
C, 69.46; H, 6.05; N, 3.12. Found: C, 69.76; H, 5.85; N, 3.40.
EXAMPLE 13
[0147] Preparation of
[6-Hydroxy-3-[4-[2-(morpholino)ethoxy]-phenoxy]-2-(4-
-hydroxyphenyl)]benzo[b]thiophene Hydrochloride 23
[0148] The title compound was prepared from the product of Example
6 in a manner similar to that employed in Example 7 above; mp
157-162.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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=2.0
Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 6.92 (q, J.sub.AB=9.0 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 C.sub.26H.sub.25NO.sub.5S-HCl: C, 62.46; H, 5.24; N,
2.80. Found: C, 69.69; H, 5.43; N, 2.92.
EXAMPLE 14
[0149] Preparation of
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-methoxyphenyl)]benzo[b]thiophene 24
[0150] Step a): Preparation of 6-Methoxybenzo[b]thiophene-2-boronic
Acid 25
[0151] To a solution of 6-methoxybenzo[b]thiophene (18.13 g, 0.111
mol) in 150 mL of anhydrous tetrahydrofuran (THF) at -60.degree. C.
was added n-butyllithium (76.2 mL, 0.122 mol, 1.6 M solution in
hexanes), dropwise via syringe. After stirring for 30 minutes,
triisopropyl borate (28.2 mL, 0.122 mol) was introduced via
syringe. The resulting mixture was allowed to gradually warm to
0.degree. C. and then distributed between 1N 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.degree. C. (dec).
.sup.1H NMR (DMSO-d.sub.6) 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.
[0152] Step b): Preparation of
[6-Methoxy-2-(4-methanesulfonyloxyphenyl)]b- enzo[b]thiophene
26
[0153] 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)phenylbro- mide (3.98 g, 15.8 mmol) followed
by 16 mL of 2.0 N sodium carbonate solution. After stirring for 10
minutes, tetrakistriphenylphosphinepallad- ium (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 (77%) of
[6-methoxy-2-(4-methanesulfonyloxy-phenyl)]benzo[b]thiophene as a
tan solid. mp 197-201.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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, 3H),
3.39 (s, 3H). FD mass spec 334. Anal. Calcd. for
C.sub.16H.sub.14O.sub.4S.sub.2: C, 57.46; H, 4.21. Found: C, 57.76;
H, 4.21.
[0154] Step c): Preparation of
[6-Hydroxy-2-(4-methanesulfonyloxyphenyl)]b- enzo[b]thiophene
27
[0155] To a solution of
[6-methoxy-2-(4-methanesulfonyloxyphenyl)]benzo[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-methanesulfonyl- oxyphenyl)]
benzo[b]thiophene as a white solid. mp 239-243.degree. C. .sup.1H
NMR (DMSO-d.sub.6) 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 C.sub.15H.sub.12O.sub.4S.sub.2: C, 56.23; H,
3.77. Found: C, 56.49; H, 3.68.
[0156] Step d): Preparation of
[6-Benzyloxy-2-(4-methanesulfonyloxyphenyl)- ]benzo[b]thiophene
28
[0157] To a solution of
[6-hydroxy-2-(4-methanesulfonyloxyphenyl)]benzo[b]- thiophene (3.20
g, 10.0 mmol) in 75 mL of anhydrous DMF was added Cs.sub.2CO.sub.3
(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-methanesulfonyloxyphenyl)]benzo- [b]thiophene as
a white solid. mp 198-202.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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.
[0158] Step e): Preparation of
[6-Benzyloxy-2-(4-hydroxyphenyl)]-benzo[b]t- hiophene 29
[0159] To a solution of
[6-benzyloxy-2-(4-methanesulfonyloxyphenyl)]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.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.21H.sub.16O.sub.2S:
C, 75.88; H, 4.85. Found: C, 75.64; H, 4.85.
[0160] Step f): Preparation of
[6-Benzyloxy-2-(4-methoxyphenyl)]-benzo[b]t- hiophene 30
[0161] 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)]
benzo[b]thiophene as a white solid. mp 180-185.degree. C. .sup.1H
NMR (DMSO-d.sub.6) 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
C.sub.22H.sub.18O.sub.2S: C, 76.27; H, 5.24. Found: C, 76.54; H,
5.43.
[0162] Step g): Preparation of
[6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]be- nzo[b]thiophene 31
[0163] [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.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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
C.sub.22H.sub.17O.sub.2SBr: C, 62.13; H, 4.03. Found: C, 61.87; H,
4.00.
[0164] Step h): Preparation of
[6-Benzyloxy-2-(4-methoxyphenyl)-3-bromo]be-
nzo[b]thiophene-(S-oxide) 32
[0165] The title compound was prepared by oxidation of the product
from step g) with 1.5 equivalents of hydrogen peroxide in a mixture
of trifluoroacetic acid in methylene chloride. The product was
isolated as a yellow solid by crystallization from ethyl acetate.
mp 202-205.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.22H.sub.17O.sub.3SBr: C,
59.87; H, 3.88. Found: C, 59.59; H, 3.78.
[0166] Step i): Preparation of
[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]-
phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene-(S-oxide) 33
[0167] Reaction of the product of step i) above with
4-(2-piperidinoethoxy)phenol in base yielded the title compound as
a yellow oil. .sup.1H NMR (DMSO-d.sub.6) 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, 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 C.sub.35H.sub.35NO.sub.5S: C, 72.26; H, 6.06; N, 2.41.
Found: C, 72.19; H, 5.99; N, 2.11.
[0168] Step j): Preparation of
[6-Benzyloxy-3-[4-[2-(1-piperidinyl)ethoxy]-
phenoxy]-2-(4-methoxyphenyl)]-benzo[b]thiophene 34
[0169] Reduction of the product of step i) above yielded the title
compound, isolated in 95% overall yield. Purification by
chromatography (SiO.sub.2, 1-5% methanol/chloroform) provided an
off-white solid, mp 105-108.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.35H.sub.35NO.sub.4S: C, 74.31; H, 6.24; N, 2.48.
Found: C, 74.35; H, 6.07; N, 2.76.
[0170] Step k): Preparation of
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]ph-
enoxy]-2-(4-methoxyphenyl)]benzo[b]-thiophene 35
[0171] 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)]be- nzo[b]thiophene as foam
that converted to solid upon trituration with hexanes. mp
174-176.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.28H.sub.29NO.sub.4S: C, 70.71; H, 6.15; N, 2.94.
Found: C, 70.46; H, 5.93; N, 2.71.
EXAMPLE 15
[0172] Preparation of
[6-Hydroxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-methoxyphenyl)]benzo[b]thiophene Hydrochloride Salt 36
[0173] The product of Example 14 was converted to the corresponding
hydrochloride salt in 85% yield by treatment with a mixture of HCl
saturated diethyl ether in ethyl acetate followed by
crystallization from ethanol/ethyl acetate; mp 156-160.degree. C.
.sup.1H NMR (DMSO-d.sub.6) 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, J.sub.AB=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 C.sub.28H.sub.29NO.sub.4S.1.0HCl: C, 65.68; H, 5.90; N, 2.73.
Found: C, 65.98; H, 6.11; N, 2.64.
EXAMPLE 16
[0174] Preparation of
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2--
(4-hydroxyphenyl)]benzo[b]thiophene 37
[0175] Step a): Preparation of
[6-methoxy-2-(4-benzyloxyphenyl)]-benzo[b]t- hiophene 38
[0176] Following the general procedures of steps a) through g) of
Example 14, the title compound was obtained in 73% yield, mp
217-221.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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
C.sub.22H.sub.18O.sub.2S: C, 76.27; H, 5.24. Found: C, 76.00; H,
5.25.
[0177] Step b):
[6-methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo-[b]thiophen- e
39
[0178] The title compound was obtained in 91% yield, mp
125-127.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.22H.sub.17O.sub.2SBr: C,
62.13; H, 4.03. Found: C, 62.33; H, 3.93.
[0179] Step c):
[6-Methoxy-2-(4-benzyloxyphenyl)-3-bromo]benzo[b]-thiophen-
e-(S-oxide) 40
[0180] The title compound was isolated as a yellow solid by
chromatography (SiO.sub.2, CHCl.sub.3). mp 119-123.degree. C.
.sup.1H NMR (DMSO-d.sub.6) 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 C.sub.22H.sub.17O.sub.3SBr: C,
59.87; H, 3.88. Found: C, 60.13; H, 4.10.
[0181] Step d):
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-ben-
zyloxyphenyl)]benzo[b]thiophene-(S-oxide) 41
[0182] The title compound was obtained as a yellow solid, mp
89-93.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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
C.sub.35H.sub.35NO.sub.5S.0.25EtOAc: C, 71.62; H, 6.18; N, 2.32.
Found: C, 71.32; H, 5.96; N, 2.71.
[0183] Step e):
[6-Methoxy-3-[4-[2-(1-piperidinyl)ethoxy]phenoxy]-2-(4-ben-
zyloxyphenyl)]benzo[b]thiophene 42
[0184] The title compound was obtained in 91% yield, mp
106-110.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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
C.sub.35H.sub.35NO.sub.4S: C, 74.31; H, 6.24; N, 2.48. Found: C,
74.26; H, 6.17; N, 2.73.
[0185] Step f): Preparation of
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]ph-
enoxy]-2-(4-hydroxyphenyl)]benzo[b]thiophene 43
[0186] The title compound was obtained in 88% yield, mp
147-150.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.28H.sub.29NO.sub.4S: C, 70.71; H, 6.15; N, 2.94.
Found: C, 71.00; H, 6.17; N, 2.94.
EXAMPLE 17
[0187] Preparation of
[6-methoxy-3-[4-[2-(1-piperidinyl)ethoxy]-phenoxy]-2-
-(4-hydroxyphenyl)]benzo[b]thiophene Hydrochloride 44
[0188] The title compound was prepared in a manner analogous to
that employed in Example 15 to yield the title compound, mp
215-217.degree. C. .sup.1H NMR (DMSO-d.sub.6) 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 C.sub.28H.sub.29NO.sub.4S.1.0HCl: C, 65.68; H, 5.90; N,
2.73. Found: C, 65.87; H, 5.79; N, 2.99.
FORMULATION EXAMPLES
[0189] In the formulations which follow, "active ingredient" means
a compound of formula I, or a salt or solvate thereof.
2 Formulation Example 1 Gelatin Capsules Ingredient Quantity
(mg/capsule) Active ingredient 0.1-1000 Starch, NF 0-650 Starch
flowable powder 0-650 Silicone fluid 350 centistokes 0-15
Formulation Example 2 Tablets Ingredient Quantity (mg/tablet)
Active ingredient 2.5-1000 Cellulose, microcrystalline 200-650
Silicon dioxide, fumed 10-650 Stearate acid 5-15 Formulation
Example 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
[0190] 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.degree.-60.degree. 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.
3 Formulation Example 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
[0191] 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.
4 Formulation Example 5 Aerosol Quantity (% by Ingredient weight)
Active ingredient 0.25 Ethanol 25.75 Propellant 22
(Chlorodifluoromethane) 70.00
[0192] 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.
5 Formulation Example 6 Suppositories Ingredient Quantity
(mg/suppository) Active ingredient 250 Saturated fatty acid
glycerides 2,000
[0193]
6 Formulation Example 7 Injectable Formulations Ingredient Quantity
Active ingredient 50 mg Isotonic saline 1,000 mL
[0194] The solution of the above ingredients is intravenously
administered to a patient at a rate of about 1 mL per minute.
* * * * *