Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
ESTROGEN RECEPTOR MODULATORS
BACKGROUND OF THE INVENTION
Naturally occurring and synthetic estrogens have broad therapeutic
utility, including: relief of menopausal symptoms, treatment of acne,
treatment of
dysmenorrhea and dysfunctional uterine bleeding, treatment of osteoporosis,
treatment
of hirsutism, treatment of prostatic cancer, treatment of hot flashes and
prevention of
cardiovascular disease. Because estrogen is very therapeutically valuable,
there has
been great interest in discovering compounds that mimic estrogen-like behavior
in
estrogen responsive tissues.
For example, estrogen-like compounds would be beneficial in the
treatment and prevention of bone loss. Bone loss occurs in a wide range of
subjects,
including women that are post-menopausal or have had a hysterectomy, patients
who
were or are currently being treated with carticosteroids, and patient's having
gonadal
dysgenesis. The cuwent major bone diseases of public concern are osteoporosis,
hyperealcemia of malignancy, osteopenia due to bone metastases, periodontal
disease,
hypetparathyroidism, periarticular erosions in rheumatoid arthritis, Pager's
disease,
immobilization-induced osteopenia, and glucocorticoid-induced osteoporosis.
All of
these conditions are characterized by bane loss, resulting From an imbalance
between
bone resorption, i.e. breakdawn, and bone formation, which cantinues
throughout life
at the rate of abaut 1~1%a per year on the average. However, the rate of bane
turnover
differs from site to site, for example, it is higher in the trabecular bone of
the
vertebrae and the alveolar bane in the jaws than in the cortices of the long
bones. The
potential For bone loss is directly related to turnover and can amount to over
5%a per
year in vertebrae immediately Following menopause, a condition which leads to
increased Fracture risk.
In the I~.S., there Ire cut~rently about 20 million people with detectable
Fractures of the vertebrae due to osteoporosis. In addition, there are about
X50,000 hip
Fractures per year attributed ro osteoporosis. This clinical situation is
associated with
a 12°l~ mortality rare within the first two years, while 30~/~ of the
patients require
nursing home care after the fracture.
Osteoporosis affects approximately 20 to 25 million past-menopausal
women in the C.S. alone. It has been theorized than the rapid loss of bone
mass in
these women is due to the cessation of estragen production of the avaries.
Since
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studies have shown that estrogen slows the reduction of bone mass due to
osteoporosis, estrogen replacement therapy is a recognized treatment t'or past-
menopausal osteoporosis,
In addition to bane mass, estrogen appears to have an eFfect on the
biosynthesis ol~ cholesterol and cardiovascular health. Statistically, the
rate of
occurrence of cardiovascular disease is roughly equal in pos~tmenapausal women
and
men; however, premenapausal women have a much lower incidence of
cardiovascular
disease than men. Because pastmenopausal women are estrogen deficient, it is
believed that estrogen plays a beneficial role in preventing cardiovascular
disease.
The mechanism is not well understood, but evidence indicates that estrogen can
upregulate the low density lipid (LDL) cholesterol receptors in the liver to
remove
excess cholesterol.
Postmenopausal women given estrogen replacement therapy
experience a return of lipid levels to concentrations comparable to levels
associated
with the premenapausal state. Thus, estrogen replacement therapy could be an
effective treatment for such disease. However, the side effects associated
with long
term estrogen use limit the use of this alternative.
Other disease states that affect postmenopausal women include
estrogen-dependent breast cancer and uterine cancer. Anti-estrogen compounds,
such
as tamoxifen, have commonly been used as chemotherapy to treat breast cancer
patients. Tamoxifen, a dual antagonist and agonist of estrogen receptors, is
beneficial
in treating estrogen-dependent breast cancer. However, treatment with
tamoxifen is
less than ideal because tamoxifen's agonist behavior enhances its unwanted
estrogenic
side effects. For example, tamoxifen and other compounds that agonize estrogen
receptors tend to increase cancer cell production in the uterus. A better
therapy for
such cancers would be an anti-estrogen compound that has negligible or
nonexistent
agonist properties.
Although estrogen can be beneficial for treating pathologies such as
bone loss, increased lipid levels, and cancer, lonb term estrogen therapy has
been
implicated 3n a variety of disorders, including an increase in the risk of
uterine and
endametrial cancers. These and other side effects of estrogen replacement
therapy are
not acceptable to many women, thus limiting its use.
Alternative regimens, such as a combined progestagen and estrogen
dose, have been suggested in an attempt to lessen the rislt of cancer.
However, such
regimens cause the patient to experience withdrawal bleeding, which is
unacceptable
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to many older women. Furthermore, combining estrogen with progestogen reduces
the beneficial cholesterol-lowering effect of estrogen therapy. In addition,
the long
term effects of progestogen treatment are unknown.
In addition to post-menopausal women, men suffering from prostatic
cancer can also benefit from anti-estrogen compounds. Prostatic cancer is
often
endocrine-sensitive; androgen stimulation Fosters tumor growth, while androgen
suppression retards tumor growth. The administration of estrogen is helpful in
the
treatment and control of prostatie cancer because estrogen administration
lowers the
level of ganadotropin and, consequently, androgen levels.
The estrogen receptor has been found to have two forms: ERcc and
ER(3. Ligands bind differently to these two forms, and each form has a
different
tissue specificity to binding ligands. Thus, it Is possible to have compounds
that are
selective for ERa or ER~3, and therefare confer a degree of tissue specificity
to a
particular ligand.
What is needed in the art are compounds that can praduce the same
positive responses as estrogen replacement therapy without the negative side
effects.
Also need are estrogen-like compaunds that exert selective effects on
different tissues
of the body.
The compounds of the instant invention are ligands for estrogen
receptors and as such may be useful for treatment or prevention of a variety
of
conditions related to estrogen functioning including: bone loss, bone
fractures,
osteoporosis, cartilage degeneration, endometriosis, uterine fibroid disease,
hot
flashes, increased levels of LDL cholesterol, cardiovascular disease,
impairment of
cognitive functioning, cerebral degenerative disorders, restinosis,
gynacomastia,
vascular smooth muscle cell proliferation, obesity, incontinence, and cancer,
in
particular of the breast, uterus and prostate.
-3 _
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SUMMARY OF THE INVENTION
The present invention relates to compounds of the following chemical
formula:
R1
R2 \ Y R5
R3 / X
R~ / ~i(CH2)nNtz)z
wherein R~, R2, R3, and R'~ are each independently selected from the group
consisting of hydrogen, C f_S alkyl, C3_g cycloallcyl, C?_5 alkenyl, C?_
5 alkynyl, C3_g cycloalkenyl, phenyl, heteroaryl, heterocyclical, CF3, -
OR6, halogen, C f-5 alkylthio, thiocyanato, cyano, -CO?H, -COOC f_S
alkyl, -COC f_5 alkyl, -CONZ?, -S02NZ?, and -SO~C~..S alkyl,
wherein said alkyl, allcenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl,
heteraaryl, heterocyelical groups can be optionally substituted with C1_
5 alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -OR6,
halogen, amino, C f_~ alkylthio, thiocyanato, cyano, -COSH> -COOL f_
5 alkyl, -COC~_5 alkyl, -CONZ~, -SO?NZ~, and -SO?C I_~ alkyl;
RS is selected from the group consisting of C ~_5 alkyl, C3-g cycloalkyl, C~_5
alkenyl,
C~_5 alkynyl, C3_g cycloalkenyl, phenyl, heteroaryl, heterocyclical
groups wherein said groups can be optionally substituted with C1_S
alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -ORS,
halogen, amino, C~_5 allcylthio, thiocyanato, cyano, -CO?H, -COOC1_
~ alkyl, -COC1_5 alkyl, -CONZ?, -SO?NZ?, and -SO?C I_5 alkyl;
~ and Y are each independently selected from the group consisting of oxygen,
sulfur,
sulfoxide and sulfone;
?5 R~ is selected from the group consisting of hydrogen, Cf_5 alkyl, ben~yl,
methoxymethyl, triorganosilyl, C~_5 alkylcarbonyl, alkoxycarbonyl
and CONZ?;
Each Z is independently selected From the group consisting of hydrogen, C f_~
alkyl,
trifluoromethyl, wherein said alkyl group can be optionally substituted
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with C1_5 alkyl, CF,, -ORS, halogen, amino, C1_5 allcylthio,
thiocyanato, cyano, -CO?H, -COOC 1_5 alkyl, -COC 1_5 alkyl, -
CONV?, -SO?NV~, and-SO?Cl_5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken
together to form a 3-8 membered ring, said ring may optionally contain
atoms selected from the group consisting of carbon, oxygen, sulfur,
and nitrogen, wherein said ring may either be saturated or unsaturated,
and the carbon atoms of said ring maybe optionally substituted with
one to three substituents selected from the group consisting of C1-5
alkyl, CF3, -ORS, halogen, amino, C 1-~ alkylthio, thiocyanato, cyano,
-CO?>'I, -COOC~_5 alkyl, -COC f_5 alkyl, -CONV?, -SO?NV~, and -
SO?C l_$ alkyl;
Each V is independently selected from the group consisting of C~_~ alkyl, CF3,
-ORS,
halogen, amino, C~_~ alkylthio, thiocyanato, cyano, -COSH> -COOC~-
5 alkyl, -COC1-5 alkyl, and -SO~Cf_5 alkyl;
Each n is independently an integer from one to five;
and the pharmaceutically acceptable salts thereof.
The present invention also relates to pharmaceutical compasitions
comprising the compounds of the present invention and a pharmaceutically
acceptable
carrier.
The present invention also relates to methods for making the
pharmaceutical compositions of the present invention.
The present invention also related to pracesses and intermediates
useful for making the compounds and pharmaceutical compositions of the present
invention.
The present invention also relates to methods far eliciting an estrogen
receptor modulating effect in a mammal in need thereof by administering the
compounds and pharmaceutical compositions of the present invention.
The present invention also relates to methods for eliciting an estrogen
receptor antagonizing effect in a mammal in need thereof by administering the
compounds and pharmaceutical compositions of the present invention. The
estrogen
receptor antagonizing efFect can be either an ERcx, antagonizing effect, and
ER(3
antagonizing effect or a mixed ERcc and ER(3 antagonizing effect.
_5_
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The present invention also relates to methods For eliciting an estrogen
receptor agonizing effect in a mammal in need thereoF by administering the
compounds and pharmaceutical compositions of the present invention. The
estragen
receptor agonizing effect can be either an ERCC agonizing effect, and ER~3
agonizing
eFFect or a mixed ERcx and ER(3 agonizing effect.
The present invention also relates to methods for treating or preventing
disorders related to estrogen functioning, bone lass, bone Fractures,
osteoporosis,
cartilage degeneration, endometriosis, uterine fibroid disease, cancer of the
breast,
uterus or prostate, hot flashes, cardiovascular disease, impairment of
cognitive
function, cerebral degenerative disorders, restenosis, gynacomastia, vascular
smaoth
muscle cell proliferation, obesity and incontinence in a mammal in need
thereoF by
administering the compounds and pharmaceutical compositions of the present
invention.
The present invention also relates to methods for reducing bone loss,
lowering LDL cholesterol levels and eliciting a vasodilatory effect, in a
mammal in
need thereof by administering the compounds and pharmaceutical compositions of
the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
?0 The present inventian relates to compounds useful as estragen receptor
modulators. Compounds of the present invention era described by the following
chemical formula:
R1
R2 \ Y R5
R3 / X
R'~ / ~i(C1-12)nN~Z)2
wherein R F, R~, R3, and R'F are each independently selected from the group
consisting of hydrogen, C f-5 alkyl, C3-g cycloall<yl, C~_5 alkenyl, C?_
$ alkynyl, C3-g cycloalkenyl, phenyl, heteroaryl, heterocyclical, CF3, -
OR~, halogen, C1_~ alkylthio> thiocyanato, cyano, -CO?H, -GOOC1-5
alkyl, -COCI_~ alkyl, -CONZ?, -SO?NZ?, and -SO?CF_5 alkyl,
wherein said alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, phenyl,
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heteroaryl, heterocyclical groups can be optionally substituted with C 1-
alkyl, C~_g cyeloallcyl, CI~3, phenyl, heteroaryl, heterocyclical, -ORb,
halogen, amino, Cl_5 alkylthio, thiocyanato, cyano, -CO?fI, -COOCI_
5 alkyl, -COC1-5 alkyl, -CONZ?, -SO?NZ?, and -SO?C1_5 alkyl;
5 R~ is selected from the group consisting of C1_5 alkyl, C3-g cycloalkyl,
C~_5 all<enyl,
C?_5 alkynyl, C3_g cycloalkenyl, phenyl, heteroaryl, heterocyclical
groups wherein said groups can be optionally substituted with C~_~
alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl, heterocyclical, -ORS,
halogen, amino, C t-S alkylthio, thiocyanato, cyano, -CO?H, -COOC f-
5 alkyl, -COC l-5 alkyl, -CONZ?, -SO?NZ~, and -SO~C 1_5 alkyl;
X and Y are each independently selected from the group consisting of oxygen,
sulFur,
sulfoxide and sulFone;
R6 is selected from the group consisting of hydrogen, C f_S alkyl, benzyl,
methoxymethyl, triorganosilyl, C~-~ alkylcarbonyl, alkoxycarbonyl
and CONZ?;
Each Z is independently selected from the group consisting of hydrogen, C f-5
alkyl,
trifluoromethyl, wherein said alkyl group can be optionally substituted
with CL_5 alkyl, CF3, -ORS, halogen, amino, C~_~ allcylthio,
thiocyanato, cyano, -CO?H, -COOC~_5 alkyl, -COC1_5 alkyl,
CONV?, -SO?NV~, and -SO?C~_5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken
together to form a 3-8 membered ring, said ring may optionally contain
atoms selected from the group consisting of carbon, oxygen, sulFur,
and nitrogen, wherein said ring may either be saturated or unsaturated,
and the carbon atoms of said ring maybe optionally substituted with
ane to three substituents selected from the group consisting of C f_~
alkyl, CF3, -ORS, halogen, amino, Cl_5 alkylthio, thiocyanato, cyano,
-CO?H, -COOC~_~ alkyl, -COC f_S alkyl, -CONVL, -SO?NV~, and
SO?C~_5 alkyl;
Each V is independently selected From the group consisting of C 1-s alkyl,
CF3, -OR6,
halogen, amino, C f-$ alkylthio, thiocyanato, cyano, -CO?H, -COOC~_
~ alkyl, -COC f-5 alkyl, and -SO?C 1_~ alkyl;
Each n is independently an integer from one to five;
and the pharmaceutically acceptable salts thereoF.
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In one class of compounds of the present invention, X is Oxygen, and
Y is Sulfur.
In one class of compounds of the present invention, Rl ,R~ ,R'~ and R'F
are selected from the group consisting of hydrogen, C ~_5 alkyl, C3_g
cycloalkyl, C l_5
s alkcnyl, Cl_~ allcynyl,-ORS and halogen.
In one class of compounds of the present invention RS is selected From
the group cansisting of C3_g cycloalleyl, phenyl, heteroaryl and
heterocyclical groups
wherein said groups can be optionally substituted with -ORS and halogen.
In one class of compounds of the present invention, R~ is preferably
selected from the group consisting of hydrogen, C~_$ alkyl, benzyl,
methoxymethyl
and triisopropylsilyl.
The present invention also relates to a process for preparing a
compound of formula I
R1
2 Y R5
Rs / X ~ \
R4 / ~~(CH2)nN~z)2
>,s
wherein R~ is H, F, or CI;
R? is H or OR6;
R3 is H or ORS;
Rd is H or CH3;
R5 is C 1_5 alkyl, C3_g cycloalkyl, C3_g cycloalkenyl, phenyl, heteroaryl, or
heterocyclical groups wherein said groups can be optionally substituted with C
t_~
alkyl, C3_g cycloall<yl, CF3, phenyl, heteroaryl, heterocyclical, -OR6,
halogen,
amino, Cl_S alkylthio, thiocyanato, cyano, carboxyl (-CO?H), carboalkoxyl (-
2s COOCI_5 alkyl), carbonyl (-COCI_5 alkyl, carboxamido (-CON~~), sulfonamido
(-
S02NZ?), and sulfonyl {-SO?C1_5 alkyl);
Rb is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso
that
when ORS exists elsewhere, it is chemically differentiable;
_g_
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X and Y are each independently selected from the group consisting of oxygen,
sulfur,
sulfoxide and sulfone;
Each Z is independently selected From the group consisting of hydrogen, C I_5
alkyl,
trifluoromethyl, wherein said alkyl group can be optionally substituted with
CI_5
alkyl, CF3, -ORG, halogen, amino, C f-5 alkylthio, thiocyanato, cyano, -CO?>-
I,
COOC f-~ alkyl, -COCA-S alkyl, -CONV?, -SO?NV~, and -S02C I-~ alkyl;
Or both Zs and the nitrogen to which they are attached may be taken together
to form
a 3-8 membered ring, said ring may optionally contain atoms selected from the
group
consisting of carbon, oxygen, sulfur, and nitrogen, wherein said ring may
either be
L0 saturated or unsaturated, and the carbon atoms of said ring maybe
optionally
substituted with C~_5 alkyl, CF3, -ORS, halogen, amino, C f-~ alkylthio,
thiocyanato,
cyano, -COSH, -COOL f-~ alkyl, -COC f_$ alkyl, -CONV2, -SO~NV~, and -SO~C~-5
alkyl;
Each V is independently selected from the group consisting of C1_5 alkyl, CF3,
-ORS,
halogen, amino, C~-5 alkylthio, thiocyanato, cyano, -COSH, -COOC f-5 alkyl, -
COC1_~ alkyl, and-SO?Cf-5 alkyl;
n is an integer from one to five;
and the stereoisomer is cis;
or a pharmaceutically acceptable salt thereof,
comprising the steps of
a) reacting a compound of formula II with a campound of formula III
under basic conditions
R1
5
Rz \ YH Br R
Rs / XH O~ \
Ra / ORs
II III
?5
to form a compound of formula IV
_c~_
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R~ XH
R3 ~ ~ Y R5
R2 R1 O \
IV / OR6
b) cyclizing IV, of step a, under acidic conditions in the presence of a
reducing agent,
to provide the cis compound of formula V
R1
R2 Y R5
R3 / X \
R4 /
V OR6
c) removing the protecting group R6 to yield the substituted phenol of formula
VI
R1
R2 Y Rs
R3 / X \
R4 /
VI OH
d) alkylating the substituted phenol of farmula VI, from step c, with a
reagent,
HO(CH?)nN(Z)?, to give a compound of formula I
-10~
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R1
Y R~
R3 / X \
R'~ / Oi(CH2)nN~z)2
e) removing either protecting group From I, from step d, to afFord either a
compound
of formula VIII or a compound of Formula IX
R1
HO \ Y R5--(OR6)
R3 / X \
R~ vm / o~t~H2)nN(z)2
R1
R60 \ Y R~-(OH)
R3 / X \
R4 / O~(CH2)nN~z)2
IX
F~ removing the remaining protecting group From either VIII or IX, From step
e, to
give a compound of formula 1.
The present invention also relates to a process for preparing a
compound of Formula ID
-11-
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/ OH
R
HO \ S
Ra / O .,,>> \
R~ / O
(+) - I D
wherein Rl is H, F, or Cl;
R~ is H;
R'~isHorCH3;
and the stereoisomer is ci,~~;
and the optical isomer is dextrorotatory {+), having the absolute
configuration: {?S,
3R);
or a pharmaceutically acceptable salt thereof,
camprising the steps of
a) reacting a compound of formula lID with a compound of Formula
ll~D under basic conditions
'~TI PS
Bn0 ~ SH Br
OH C
IID
IIID
to Form a compaund of l:ormula IVD
- 1? -
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OH TIPS
S
Bn0 O
H
IVD
b) cyclizing IVD, of step a, under acidic conditions in the presence of a
reducing
agent to provide the racemic, cis compound of formula VD
TIPS
B
VD
c) performing a chiral chromatography with VD, From step b, to resolve the
en antiomeric Forms to provide the dextrorotatory (+) isomer VID;
OTI PS
Bn0 ~ S
~...
O ,,
OH
(+)-V I D
d) alkylating the dextrorotatory (+) isomer VID, from step c, with 1-
piperidineethanol
to give a compound of formula VILD
-13-
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/ OTI PS
B n O ~ S ,,,v \
/ O .,,u \
/ O~ N
VIID
e) removing either protecting group from VIID, foam step d, to aFFord either a
compound aF Formula VIIID or a compound of Formula LYD
/ OTIPS
H O \ S ,,~~ \
/ O .,..i \
/ O~ N
VIIID
/ OH
B n0 ~ S ,,,~ \
O ,, \
O~ N
IXD
f) removing the remaining protecting group From either VI LID or LXD, from
step e, to
give a compound of Formula I.
LO
The present invention also comprises a process according for preparing
a compound of formula IE
- 14 --
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/ R~
R
H O \ S ,,,v
m
R3 p ~''u \
Ra / O~ N
(+)-IE
wherein
R~ is selected From the group consisting oFH, F, or Cl;
R3 and R~ are each H;
R~ is selected From the group consisting of H or OH;
the stereoisamer is cis, antl the optical isomer is dextroratatory (+), having
the
absolute canfiguration (2S, 3R);
or a pharmaceutically acceptable salt thereoF
comprising the steps of
a) reacting a compound of Formula IIE with a compound of Formula
IIIE under basic conditions
R1 R~
Bn0 ~ SH E
OH
IIE ORS
IIIE
to Form a compound of formula IVE
1 _5
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OH
Bn0 R1
R6
IVE
b) cyclizing IVE, of step a, under acidic conditions in the presence of a
reducing
agent to provide the racemic, cis compound of Formula VE
Bn
Rs
VE
c) selectively removing the protecting group of VE, from step b, to yield the
substituted phenol of formula VIE
Bn
H
VIE
l0
d) alkylating the subsfiituted phenol of formula VIE, From step c, with l~
piperidineethanol to give a compound of formula VIIE
- 16-
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7
Bn0
R1 / R
S
/ O
~O~ N
VIIE
e) removing either protecting group from VIIE to afford either a compound of
formula VIIIE or a compound of formula IXE
R~ TI PS
HO ~ S
/ O
V~ N
VIIIE
R1 / OH
Bn0 ~ S
/
O
/ O~ N
S IXE
f) removing the remaining protecting group from either VIII or I~, from step
e, to
provide racemic I.
g) performing a resolution of the enantiomeric forms of I to provide the
dextrorotatory
(+) isomer I, having the (2S, 3R) absolute configuration.
The present invention also relates to novel intermediates useful for
preparing compounds and compositions described heroin, i.e compounds of
formula I,
IA, IB, IC, ID and I:E.
An emobidment of the invention is an intermediate of the formula:
- 17-
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R1
R2 \ S Rs
R3 ~ O \
R~
OR6
wherein R1 is H, F, or CI;
R? is H or ORS;
R3 is H or ORS;
R'~ is H or CH3;
R$ is Cl-~ alkyl, C3_8 cycloalkyl, C3_g cycloalkenyl, phenyl, heteroaryl, or
heterocyelical groups wherein said groups can be optionally substituted
with C~-5 alkyl, C3-g cycloalkyl, CF3, phenyl, heteroaryl,
heterocyclical, -OR6, halogen, amino, C1_~ all<ylthio, thiocyanato,
cyano, carboxyl (-CO?H), carboallcoxyl (-COOC1_5 alkyl), carbonyl (-
COCl-~ alkyl, carboxamido (-CO ~ 'Z?), sulfonamido (-SO~NZ~), and
sulfonyl (-SO?C1-~ alkyl);
R~ is H, benzyl, methyl, methoxymethyl, or trisopropylsilyl, with the proviso
that when OR6 exists elsewhere, it is chemically differentiable;
J 5 Each Z is independently selected From the group consisting of hydrogen,
C1_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally
substituted with C~-S alkyl, CF3, -ORS, halogen, amino, C1_~
alkylthio, thiocyanato, cyano, -CO?H, -COOC1_5 alkyl, -COC 1-5
alkyl, -CONV~, -SO?NV~, and -SO~C1-5 alkyl;
Or both Zs and the nitrogen to which they are attached may be taken
together to form a 3-8 membered ring, said ring may optionally cantain
atoms selected from the group consisting of carbon, oxygen, sulFur,
and nitrogen, wherein said ring may either be saturated or unsaturated,
and the carbon atoms of said ring maybe optionally substituted with
C1_S alkyl, CF3, -ORS, halogen, amino, C1_5 alkylthio, thiocyanato,
cyano, -CO?H, -COOCI-5 alkyl, -COCI_~ alkyl, -CONV?, -SO?NV?,
and-SO?Cl_s alkyl;
- 18-
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Mach V is independently selected from the group consisting of C I_5 alkyl,
CF3, -ORb,
halogen, amino, C I_5 alkylthio, thiocyanato, cyano, -CO?I-I, -COOL I_
alkyl, -coCl_5 alkyl, and ~so~cl_5 alkyl.
Another embodiment of the invention is an intermediate of the
Formula:
R1
R2 \ S R5
R3 O \
R~ / O~ N
wherein Rf is H, F> or Cl;
R~ is H or ORS;
R3 is H or OR6;
LO R't is H or CH3;
RS is C1_S alkyl, C3-g cycloalkyl, C3_g cycloalkenyl, phenyl, heteroaryl, or
heterocyclical groups wherein said groups can be optionally substituted
with C~_5 alkyl, C3_g cycloalkyl, CF3, phenyl, heteroaryl,
heterocyclical, -ORd, halogen, amino, C~_5 alkylthio, thiocyanato,
cyano, carboxyl (-CO?H), carboalkoxyl (-COOC1_5 alkyl), carbonyl ~-
COCA-S alkyl, carboxamido (-CONZ?), sulFonamido (-SO~NZ?), and
sulFonyl ~-SO?C1_~ alkyl);
R~ is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso
that when ORS exists elsewhere, it is chemically diFferentiable;
Each Z is independently selected From the group consisting of hydrogen, C~_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally
substituted with C~_~ alkyl, CF3, -OR~> halogen, amino, CL_~
all<ylthio, thiocyanato, cyano, -CO?H, -COOC1-5 alkyl, -COC1_~
alkyl, -CONV?, -SO?NV~, and -SO?C~_5 alkyl;
Or both Zs may be taken together Form a 3-8 membered ring, said ring
may optionally contain atoms selected from the group consisting of
carbon, oxygen, sulfur, and nitrogen, wherein said rind may either be
saturated or unsaturated, rind the carbon atoms of said ring maybe
optionally substituted with CI_5 alkyl, CF3>-ORS, halogen, amino,
I 9 .-
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C 1 _5 allcylthio, thiocyanato, cyano, -CO? H, -COOC 1 _5 alkyl, -COC 1 _
alkyl, -CONV~, -SO?NV?, and -SO?C f_5 alkyl.
Each V is independently selected from the group consisting of Cl_5 alkyl,
CF's, -ORS,
halogen, amino, C 1_5 rLlkylthio, thiocyanato, cyano, -C02H, -COOC 1_
5 S alkyl, -COC 1_~ alkyl, and -SO~C 1 _5 alkyl.
Another embodiment of the invention is an intermediate of the
formula:
R~ / ORs
R60 ~ S
~~-) _ ~ /
O
OR6
wherein R1 is H, F, or Cl;
~0 R~ is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, wifh the
proviso
that all existing R~ groups are chemically differentiable.
Another embodiment of the invention is an intermediate of the
formula:
R1
R60 ~ S
t.~-> _ ~ /
0
N
wherein R1 is H, F, or Cl;
R~ is H, ben~yl, methyl, methoxymethyl, or tnisopropylsilyl, with the proviso
that all existing R~ groups are chemically differentiable.
Another embodiment of the invention is an intermediate of the
formula:
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R1
R2 \ S ,,~~ R~
(+) -
Rs ~ O ,.>>i \
R~
OR6
wherein R t is H, F, or Cl;
R~ is H or ORG;
R3 is H or ORS;
R~ is H or CH3;
R5 is Cl_s alkyl, C3_g cycloalkyl, C3_g cycloallcenyl, phenyl, heteroaryl, or
heterocyclical groups wherein said groups can be optionally substituted
with C~_5 alkyl, C3_g cycloall<yl, CF3> phenyl, heteroaryl,
heterocyclical, -ORS, halogen, amino, C1_S alkylthio, thiocyanato,
cyano, carboxyl (-CO?H), carboalkoxyl {.-COOCI_~ alkyl), carbonyl {-
COC~_~ alkyl, carboxamido (-CONZ?), sulfonamido {-SO?NZ?), and
sulfonyl {-SO~C~_~ alkyl);
R~ is H, ben~yl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso
that when O.R6 exists elsewhere, it is chemically differentiable;
Each Z is independently selected from the group consisting of hydrogen, C~_~
alkyl, trifluoromethyl, wherein said alkyl group can be optionally
substituted with C~_S alkyl, CF3, -ORS, halogen, amino, C~_5
alkylthio, thiocyanato, cyano, -CO?H, -COOCf_5 alkyl, -COC~_~
alkyl, -CONV~, -SO~NV~, and -SO?C f-5 alkyl;
Or both ~s and the nitrogen to which they are attached may be taken to
together form a 3-8 membered ring, said ring may optionally contain
atoms selected from the group consisting of carbon, oxygen, sulfur,
and nitrogen, wherein said ring may either be saturated or unsaturated,
?5 and the carbon atoms of said ring maybe optionally substituted with
Cl_s alkyl, CF3, -OR6, halogen, amino, Cl_5 alkylthio, thiocyanato,
cyano, -CO?H, -COOC1_~ alkyl, -COCI_~ alkyl, -CONV~, -SO~NV~,
and -SO?Cf_~ alkyl;
-21-
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Each V is independently selected from the group consisting of C 1 _5 alleyl,
CF3, -ORS,
halogen, amino, C1_5 alkylthio, thiocyanato, cyano,-CO?I-I,-COOCI_
alkyl, -COC I-5 alkyl, and -SO?C I_~ alkyl.
Another embodiment of the invention is an intermediate of the
5 Formula:
wherein R~ is H, F, or Cl;
R1 / ORs
Rs0 \ S ,,,~ \
(+) _ ~ /
/ ORS
R6 is H, benzyl, methyl, methoxymethyl, or triisoprapylsilyl, with the proviso
that all existing R~ groups are chemically differentiable.
Anather embodiment of the present invention is an intermediate of of
the Formula:
OR6
R1 /
Rs0 \ S .,,v \
+) _
/ O ''~, \
/ O~ N
wherein R~ is H, F, or Cl;
R~ is H, benzyl, methyl, methoxymethyl, or triisopropylsilyl, with the proviso
that all existing R6 groups are chemically differentiable.
Non-limiting examples of the present invention include:
CA 02424729 2003-04-03
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/ OH
HO \ S ,~~I\
/ O ,,,, \ ~i
/' ~ N
O
/ OH
HO \ S ,,,~I\
t+) -
/ O ''lf \
~ 'NCHs
O
/ OH
HO \ S ~~'\ Pil
+ ~ / ~.,1/
/ O~ N
/ OH
HO .~ S ,,,v\
~+) _ ti
/ ~I 'n~ \
O ~~~ ~'~CHs
O~ N CH3
OH
HO
t+) _ n
O ~~, \~ ~.~~CH3
~ N
O
/ OH
H O .~ S
~+> - ~~ ~ CH3
/ p ''~~ \
f~~ /i ~N CHa
O
-23--
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HO \ S ~~' \ I OH
p 1'~~ i \
~ N
O
I
HO \ S .~~'I\ I OH
/ O ~'~, \
~CH3
/ O~ N
/
HO I \ S .,~''w I OH
(+) ~ /'
O
/ O~ N
/
HO \ S .,~'~~ ~I OH
(+) _
p ~II / ~ N
O
HO \ S .,~' \ ~ OH
-) _
o .,,> ~ \
/ N~CH3
O~
I/
HO \ S ~~' \ l OH
t~) _ , / ~A, C H3
O ',~~ \
CH3
/ O~ N
?~ _
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F / OH
i
HO ~ S ,
+) - ~ ~,.
N
O~
OH
F
y
HO ~ S
O ~~ / NCH
O ------~~~
F / OH
i
HO ~ S
~+) _
o .,,,
,~n~CH3
N
O~
F
HO ~, S ,,,vv
~,' OH
O '~
N
O~
F /
HO ~ S
t+) - I~~ i~~\ ~ off
/
0
/ N~~° C H3
O~
F /
HO ~ S ~~' ~ OH
~+) _ 16 / i ~L,y
O
i ~v'~i'CH3
/ N
O~
?5
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OH
~I I
HO ~ S ,''~~ H C
(+) - ~ ~ ~~', 3 CH3
O ,''y ~ 'w
i O~ N
HO ~, S I,,,v w
~ ~ OH H3C CH
JfJ,, ~
O
~ , o~ N
HO ~ S ~''~~ l OH
t+> -
~>>,,
O ~Ii , N~~ ~ ~CH3
O~
OH
HO ~ S ,,'v~\
(+) _ ,
/ ~ ~.~ HaC
O ~~y \
.r~CH3
/ O~ ~~''N
i
HO ~ S '~'' ~ OH
) H C,,
/ ~,'i
!) I
~'CH3
/ O~N
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/ OH
HO \ S
,,~~ \
\CHs
''l~ \ ~ ~
~_CH3
O ~ .~N
OH
HO \ S
,,v \
I ~~. CH3
O .,,1, \
~~,~ fiCHs
/ ~N~
O
/ OH
H O \ S I' I
,,~~ \
~+) _ I .,
/ O ill i
II ~ CHs
/, O~N
CHs
/ OH
HO \ S , ~~I\ II
I O.
O .,,1~ .~ HsC
I ~~~C H s
/ O~N
OH
HO \ S \ I
/ O ,,l/ I \
~1CH3
/' O~N
CHs
a_~ _
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HO ~ S
(+) _ I, ~I,,.'' \
OH CH3
/ O '''j \
/' N~CHa
O~
HO \ S ,,
(+) _ ~1 OH CH3
/ O '''~ \
~. nCH3
O~N
HO \ S
(+) _ I ~ '~'~~\ OH
/ ~~'r
p 1I \
CH3
O
CH3
HO \, S ,~''I\ I OH
(+) _
y~~, H C
p
/ ~I NCHa
O~
HO \ S
OH
(+) -
/ p ''>> \
~~C H 3
/, O~N
CH3
m?S-
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OH
HO ~ S
~+~ _
y't~
~l,~nCH
/ O~ N s
CH3
HO ~ S .~'' ~ I OH
~ O ,,,,
~ nCH3
N
O~
CH3
OH
HO ~ S
O .,,j I ~ H3Cu,,
~~'"CH3
/ O~ N
HO ~ S
OH
H C~,
O~.r
O ,, ~ 3 ,.
~~nCH3
/' O~N
/ OH
HO ~ S
~+~
n'CH
/ O~ N a
CH3
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I
HO \ S .,~~~OH
~+)
O 1'''
,~~iCH3
/' O~N
CHs
OH
HO \ S
+) -
o ~I
/ o~N
OH CHs
HO \ S ,,,~'\ III
(+) _ ~I~ ~ .,
/ O t~r I \
/ ~ O~ N
~CH3
/ I I OH
HO \ S
(+) - I
O:~j
O ,, P \
CH2CHs
/' O~N
CHs
OH
,,v ~ \
H O .~ S
+) -
O '~~~ \
N~CH2CH3
O
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H O ~ I S ,,,' ~ I
II ~; OH
yIl ~ I
~N
O
CHI
HO ~ S ,,'~ ~ OH
/ N
O~
~~CH3
HO ~ S ~~'' ~ OH
(+) I
/ O '''f
CHzCH3
/ O~ N
CH3
HO ~ S
) _ ~ OH
/ O
~'CH~CH3
O~N
HO ~ S ,,~'' ~ OH
)_
O j~~~~~i ~ ,~N~CH2CH3
N~,
/ O~
-31
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/ OH
HO \ S ' '~'~\ ~ i
~I~>, CH CH
O ~, ~ \
~~~sCH3
~ O~ N
HO \ S I' I
OH
(+) -
~'>, CH CH
p ~i \ I ~ i'2 3
~nCH3
O~N
/ OH
HO \ S '
(+) _ i
/ O '''l, \
~~~nCH2CH3
/ ~N
0
/
Ho \ s
.,,,, \
OH
I ~,~nCH2CH3
/ O~ ~,~N
/ OH
HO \ S ',~~ \
~,'.
/ O ~,~~ \
'I .~~iCH3
j O~N
CH3
- 3?
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/ OH
HO \ S , ~''\ i
' ,
/ O '''j~ \
~h ~.~hGCH~CH3
/ O~ N
/ OH
HO \
O.
~ ~ O ~ ,,,~ \
f ~CH3
/ I O~N ~CH~CH3
~+) -HO I \ I S .~'' \ OH
/ ~~'i
p '' I \ ~'CH3
/ O~N ~~CH2CH3
HO I \I S ,,~'~\ OH
~+) _ ~ '.
/ O '''i \
"nCH3
/~ O~N
CH3
An embodiment of the invention is a method of eliciting an estrogen
receptor modulating cFFect in a mammal in need thereof: comprising
administering to
the mammal a therapeutically effective amaunt of any of the compounds or any
of the
above pharmaceutical compositions described above.
A class of the embodiment is the method wherein the estrogen receptor
modulating effect is an antagonizing effect.
A subclass of the embodiment is the method wherein the estrogen
receptor is an ERcc receptor.
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A second subclass of the embodiment is the method wherein the
estrogen receptor is an ER~3 receptor.
A third subclass of the embodiment is the method wherein the estrogen
receptor modulating effect is a mixed ERcc and ER(3 receptor antagonizing
eFfect.
A second class of the embodiment is the method wherein the estrogen
receptor modulating eFFect is an agonizing eFFect.
A subclass of the embodiment is the method wherein the estrogen
receptor is an ERc~, receptor.
A second subclass of the embodiment is the method wherein the
estrogen receptor is an ER(3 receptor.
A third subclass of the embodiment is the method wherein the estrogen
receptor modulating efFect is a mixed ERce and ER(3 receptor agonizing efFect.
Another embodiment of the invention is a method of treating or
preventing post-menopausal osteoporosis in a mammal in need thereof by
administering to the mammal a therapeutically effective amount of any of the
compounds or pharmaceutical compositions described above.
Another embodiment of the invention is a method of treating or
preventing uterine fibroids in a mammal in need thereof by administering to
the
mammal a therapeutically effective amount of any of the compounds or
pharmaceutical compositions described above.
Another embodiment of the invention is a method of treating or
preventing restenosis in a mammal in need thereoF by administering to the
mammal a
therapeutically effective amount of any of the compounds or pharmaceutical
compositions described above.
?5 Another embodiment of the invention is a method of treating or
preventing endometriosis in a mammal in need thereof by administering to the
mammal a therapeutically effective amount of any of the compounds or
pharmaceutical campos3tlons described above.
Another embodiment of the invention is a method of treating or
preventing hyperlipidemia in a mammal in need thereof by administering to the
mammal a therapeutically effective amount of any of the compounds or
pharmaceutical Compositions described above.
ExempliFying the invention is a pharmaceutical compasition
comprising any ol~ the compounds described above and a pharmaceutically
acceptable
cawier, Also exernpliFying the invention is a pharmaceutical composition made
by
3~ -
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combining any of the compounds described above and a pharmaceutically
acceptable
carrier. An illustration oC the invention is a process Cor making a
pharmaceutical
composition comprising combining any of the compounds described above and a
pharmaceutical 1y acceptable ca o-ier.
Further exemplifying the invention is the use of any of the compounds
described above in the preparation of a medicament for the treatment and/or
prevention of osteoporosis in a mammal in need thereof. Still further'
exemplifying
the invention is the use of any of the compounds described above in the
preparation of
a medicament for the treatment andlar prevention of: bone loss, bone
reso~ption, bone
Fractures, cacti loge degeneration, endometriosis, uterine fibroid disease,
breast cancer,
uterine cancer, prostate cancer, hot flashes, cardiovascular disease,
impairment of
cognitive functioning, cerebral degenerative disorder, restenosis, vascular
smooth
muscle cell proliferation, incontinence, and/or disorders related to estrogen
functioning.
The present invention is also directed to combinations of any of the
compounds or any of the pharmaceutical compositions described above with one
or
more agents useful in the prevention or treatment of osteoporosis. For
example, the
compounds of the instant invention may be effectively administered in
combination
with effective amounts of other agents such as an organic bisphosphonate or a
cathepsin K inhibitor. Nonlimiting examples of said organic bisphosphonates
include
alendronate, cladronate, etidronate, ibandronate, incadronate, minodronate,
neridranate, risedranate, piridronate, pamidronate, tiludronate, zoledronate,
pharmaceutically acceptable salts or esters thereof, and mixtures thereof.
Preferred
organic bisphosphonates include alendronate and pharmaceutically acceptable
salts
and mixtures thereof. Most preferred is alendronate monosodium trihydrate.
The precise dosage of the bisphosphonate will vary with the dosing
schedule, the oral potency of the particular bisphosphonate chosen, the age,
size, sex
and condition of the mammal or human, the nature and severity of the disorder
to be
treated, and other relevant medical and physical factors. Thus, a precise
pharmaceutically effective amount cannot be specified in advance and can be
readily
determined by the caregiver or clinician. Appropriate amounts can be
determined by
routine experimentation From animal models and human clinical studies.
Generally,
an appropriate amount of bisphosphonate is chosen to obtain a bone resarption
inhibiting effect, i.e. a bone reso~ption inhibiting amount of the
bisphosphonate is
administered. Far humans, an effective oral dose of bisphasphonate is
typically from
_3_5-
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about l ,_5 to about 6000 ~.~/k~ body weight and preferably about 10 to about
2000
~,g/Icg of body weight.
For human oral compositions comprising alendronate,
pharmaceutically acceptable salts thereof, or pharmaceutically acceptable
derivatives
thereof, a unit dosage typically comprises From about $.75 mg to about 140 mg
of the
alendronate compound, on an alendronic acid active weight basis, i.e. on the
basis of
the con-esponding acid.
For use in medicine, the salts of the compounds of this invention refer
to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be
useful
in the preparation of the compounds according to the invention or of their
pharmaceutically acceptable salts. When the compounds of the present invention
contain a basic group, salts encompassed within the term "pharmaceutically
acceptable salts" refer to non-toxic salts which are generally prepared by
reacting the
free base with a suitable organic or inorganic acid. Representative salts
include but
are not limited to the following: acetate, benzenesulfonate, benzoate,
bicarbonate,
bisulfate, bitartrate, borate, bromide, calcium, camsylate, carbonate,
chloride,
clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate,
fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine,
hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate,
lact0bionate, laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, oleate, oxalate, pamoate (embonate), palmitate, pantothenate,
phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate,
subacetate,
succinate, tannate, tartrate, teoclate, tosylate, triethiodide and valerate.
Furthermore,
where the compounds of the invention carry an acidic moiety, suitable
pharmaceutically acceptable salts thereof may include alkali metal salts,
e.g., sodium
or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium
salts; and
salts formed with suitable organic ligands, e.g., quaternary ammonium salts.
The compounds of the present invention can have chiral centers and
occur as racemates, racemic mixtures, diastereomerlc mixtures, and as
individual
diastereomers, or enantiomers with all isameric Forms being included in the
present
invention. Therefore, where a compound is chiral, the separate enantiomers,
substantially free of the other, are included within the scope of the
invention; further
included are all mixtures of the two enantiomers. Also included within the
scope of
-3G-
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the invention are polymorphs, hydrates unci solvates of the compounds of the
instant
mventian.
The present invention includes wifhin its scope prodrugs of the
compounds of this invention. In general, such pradrugs will be functional
derivatives
of the compounds of this invention which are readily convertible in vine into
the
required compound, Thus, in the methods of treatment of the present invention,
the
term "administering" shall encompass the treatment of the various conditions
described with the compound specifically disclosed or with a compound which
may
not be specifically disclosed, but which converts to the specified compound in
vivo
after administration to the patient. Conventional procedures for the selection
and
preparation of suitable prodrug derivatives are described, far example, in
''Design of
Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by
reference
herein in its entirety. Metabolites of these compounds include active species
produced upon introduction of compounds of this invention into the biological
milieu.
The term "therapeutically effective amount" shall mean that amount of
a drug or pharmaceutical agent that will elicit the biological or medical
response of a
tissue, system, animal an human that is being sought by a researcher or
clinician.
The term "bone resarption," as used herein, refers to the process by
which asteoclasts degrade bone.
The term "basic conditions,°' as used herein, refers to the
incorporation
or use of a base in the reaction medium. According to the Lowry-Bronsted
definition,
a base is a substance that accepts a proton; or according to the Lewis
definition, a base
is a substance that can furnish an electron pair to form a covalent hoed.
Examples of
bases used herein, but are not limited to, are tertiary amine bases such as
triethylamine, diisoprapylethylamine, or the like.
The term "acidic conditions," as used herein, refers to the
incorporation or use of an acid in the reaction medium. According to the Lawry-
Bronsted definition, an acid is a substance That gives up a proton; or
according to the
Lewis definition, an acid is a substance that can take up an electron pair to
form a
~0 covalent bond. Examples of acids used herein, but are not limited to, are
strong
carboxylic acids such as trifluaroacetic acid, or the like, strong sulfonic
acids, such as
trifluoromethane sulfonic acid, or the like, and Lewis acids, such as boron
tritluoride
etherate, or stannous chloride, or the like.
The term " reducing agent," as used herein, refers to a reagent capable
of performing a reduction. A reduction is the conversion of a functional group
or an
-37--
CA 02424729 2003-04-03
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intermediate From one category to a lower one. Examples of reducing agents
used
herein, but are not limited to, are triorganosilanes or stannanes, such as
triethylsilane,
triphenylsilane, and tri-n-butyl tin hydride, or the like.
The term °°ehemically diFFerentiable" reFers to two or more
non-
identical Rb substituents whose unique structures are such that one of
ordinary skill in
the art could choose reaction conditions which would convert one of the nan-
identical
R~ substituents to H> without affecting the other R~ substituent.
The term ''alkyl" shall mean a substituting univalent group derived by
conceptual removal of one hydrogen atom from a straight or branched-chain
acyelie
IO saturated hydrocarbon (i.e., -CH3, -CH?CH3, -CH~CH~CH3, -CH(CH3)~,
-CH~CH?CH2CH3, -CH~CH(CH3)?, -C(CH3)3, etc.).
The term "alkenyl" shall mean a substituting univalent group derived
by conceptual removal of one hydrogen atom From a straight or branched-chain
acyclic unsaturated hydrocarbon containing at least one double bond (i.e., -
CH=CH2,
15 -CH~CH=CH?> -CH=CHCH~, -GH~CH=C(CH~)~, etc.).
The term '°alkynyl" shall mean a substituting univalent group
derived
by conceptual removal of one hydrogen atom from a straight or branched-chain
acyclic unsaturated hydrocarbon containing at least one triple bond (i.e., -CH-
--CH,
-CHaC=CH, -C---CCH3, -CH~CH2C=CCH~, etc.).
20 The term °'cycloalkyl" shall mean a substituting univalent group
derived by
conceptual removal of one hydrogen atom From a saturated monocyclie
hydrocarbon
(i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl).
The term "cycloalkenyl" shall mean a substituting univalent group
derived by conceptual removal of one hydrogen atom from an unsaturated
monoeyclic
25 hydrocarbon containing a double bond (i.e., cyclopentenyl or cyelohexenyl).
The term "heterocyclical" shall mean a substituting univalent group
derived by conceptual removal of one hydragen atom from a heteracycloalkane
wherein said heterocyeloalkane is derived From the corresponding saturated
monocyclic hydrocarbon by replacing one or two carbon atoms with atoms
selected
30 from N, O or S. Examples of heterocyclical graups include, but are not
limited to,
oxiranyl, azetidinyl, pyn-olidinyl, piperidinyl, pipera zinyl, and
morpholinyl.
Heterocyclical substituents can be attached at a carbon atom. If the
substituent is a
nitrogen containing heterocyclical substituent, it can be attached at the
nitrogen atom.
The term "heteroaryl" as used herein reFers to a substituting univalent
3S group derived by the conceptual removal of one hydrogen atom from a
monocyclic or
- 38
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WO 02/32377 PCT/USO1/42735
bicyclic aromatic ring system containing I , 2, 3, or ~- heteroatoms selected
From N', O,
or S. Examples of heteroaryl groups include, but are not limited to, pyrrolyl,
furyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thia~olyl, py~~~dyl,
py~~~lnldlnyl,
pyrazinyl, ben7imida~olyl, indolyl, and purinyl. Heteraryl substituents can be
S attached at a carbon atam or through the heteroatom.
The term "triorganosilyl" means those silyl groups trisubstituted by
lower alkyl groups or aryl groups or combinations thereof and wherein one
substituent
may be a lower alkoxy group. Examples of triorganosilyl groups include
trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, triisopropylsilyl,
triphenylsilyl,
dimethylphenylsilyl, t-butyldiphenylsilyl, phenyl-t-butylmethoxysilyl and the
like.
Tn the compounds of the present invention, alkyl, alkenyl, alkynyl,
cycloalkyl, cyclaalkenyl, heterocyclical and heteroaryl groups can be further
substituted by replacing one or more hydrogen atoms be alternative non-
hydrogen
groups. These include, but are not limited to, halo, hydroxy, mereapto, amino,
carboxy, cyano and carbamoyl.
Whenever the term "alkyl" or "aryl" or either of their prefix roots
appear in a name of a substituent (e.g., aryl Cp-g alkyl) it shall be
interpreted as
including those limitations given above for "alkyl" and "aryl." Designated
numbers of
carbon atoms (e.g., C~-gyp) shall refer independently to the number of carbon
atoms in
an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger
substituent in which
alkyl appears as its prefix root.
The terms "arylall<yl" and "alkylaryl" include an alkyl portion where
alkyl is as defined above and to include an aryl portion where aryl is as
defined above.
Examples of arylalkyl include, but are not limited to, benzyl, fluoroben~yl,
chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl,
thienylmethyl, thienylethyl, and thienylpropyl, examples of alkylaryl include,
but are
not limited to, toluyl, ethylphenyl, and propylphenyl.
The term "heteroarylalkyl," as used herein, shall refer to a system that
includes a heteroaryl portion, where heteroaryl is as defined above, and
contains an
alkyl poution. Examples of heteroarylalkyl include, but are limited to,
pyridylmethyl,
pyridylethyl and imidazoylmethyl.
The term "halo" shall include iodo, bromo, chloro and fluoro.
The term "oxy'' means an oxygen (O) atom. The term "thio" means a
sulfur (S) atom. The term "oxo" means =O. The term '~oximino" means the =N-O
3S group.
_39_
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The term "substituted" shall be deemed to include multiple degrees of
substitution by a named substitutent. Where multiple substituent moieties are
disclosed or claimed, the substituted compound can be independently
substituted by
one or more of the disclosed or claimed substituent moieties, singly or
plurally. By
independently substituted, it is meant that the (two or more) substituents can
be the
same or difFerent.
Under standard nonmenclature used throughout this disclosure, the
terminal pouion of the designated side chain is described first, followed by
the
adjacent functionality toward the point of attachment. For example, a Cl-S
allcylcarbonylamino Cl_~ alkyl substituent Is equivalent to
O
I I
-C ~-~allcyl-~1H-C-C ~-salkyl
In choosing compounds of the present invention, one of ordinary skill
in the art will recognize that the various substituents, i.e. R1, R~, R3, R~,
R5, R~'> R~,
R~, V, X, Y, Z, n, m and p are to be chosen in conformity with well-known
principles
l5 of chemical structure connectivity.
Representative compounds of the present invention typically display
submicromolar affinity for alpha and/or beta estrogen receptors. Compounds of
this
invention are therefore useful in ti°eating mammals suffering from
disorders related to
estrogen functioning. Pharmacologically effective amounts of the compound,
2Q including the pharmaceutically effective salts thereof, are administered to
the
mammal, to treat disorders related to estrogen functioning, such as bone loss,
hot
flashes and cardiovascular disease.
The campounds of the present invention are available in racemic form
or as individual enantiomers. For convenience, some structures are graphically
2S represented as a single enantiomer but, unless otherwise indicated, is
meant to include
both racemic and enantiomeric forms. Where cia~ and lr-cans sterochemistry is
indicated for a compound of the present invention, it should be noted that the
stereochemistry can be construed as relative, unless indicated otherwise,
_~p_
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R1
R~ ~ Y R~
R3 / X \
R~ / ~~(CH2)nN~Z)2
Tt is generally preferable to administer compounds of structure {I) as
enantiamerically puce formulations since most or all of the desired
bioactivity resides
with a single enant3omer. Racemic mixtures can be separated into their
individual
enantiomers by any of a number of conventional methods. These include chiral
chromatography, derivatizatian with a chiral auxiliary followed by separation
by
chromatography or crystallization, and fractional crystallization of
diastereomeric
salts.
The compounds of the present invention can be used in combination
with other agents useful for treating estrogen-mediated conditions. The
individual
components of such combinations can be administered separately at different
times
during the course of therapy or concurrently in divided or single combination
farms.
The instant invention is therefore to be understood as embracing all such
regimes of
simultaneous or alternating treatment and the teen "administering" is to be
interpreted
accordingly. It will be understood that the scope of combinations of the
compounds
of this invention with other agents useful for treating estrogen-mediated
conditions
includes in principle any combination with any pharmaceutical composition
useful for
treating disorders related to estrogen functioning.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well
as any
product which results, directly or indirectly, from combination of the
specified
ingredients in the specified amounts,
The compounds of the present invention can be administered in such
oral dosage forms as tablets, capsules {each of which includes sustained
release or
timed release formulations), pills, powders, granules, elixers, tinctures,
suspensions,
syrups and emulsions. Likewise, they may also be administered in intravenous
{bolus
or infusion), intraperitoneal, topical {e.g., ocular eyedrap), subcutaneous,
~~1 -
CA 02424729 2003-04-03
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intramuscular or transdermal (e.g., patch) form, all using Forts well known to
those
oFordinary skill in the pharmaceutical arts.
The dosage regimen utilising the compounds of the present invention
is selected in accordance with a variety aF Factors including type, species,
age, weight,
sex and medical condition of the patient; the severity of the condition to be
treated;
the route of administration; the renal and hepatic Function of the patient;
and the
particular compound or salt thereof employed. An ordinarily skilled physician,
veterinarian or clinician can readily determine and prescribe the effective
amount of
the drug required to prevent, counter or arrest the progress of the condition.
Oral dosages of the present invention, when used far the indicated
effects, will range between about 0.01 mg per kg of body weight per day
(mglleg/day)
to about 100 mg/kglday, preferably 0.01 to 10 mg/kg/day, and most preferably
0.1 to
5.0 mglkg/day. For oral administration, the compositions are preferably
provided in
the form of tablets containing 0.01, 0.05, 0.1, 0._5, 1.0, 2.5, 5.0, 10.0,
15.0, 25.0, 50.0,
I00 and 500 milligrams of the active ingredient For the symptomatic adjustment
of the
dosage to the patient to be treated. A medicament typically contains from
about 0.01
mg to about 500 mg of the active ingredient, preferably, from about 1 mg to
about 100
mg of active ingredient. Intravenously, the most preferred doses will range
from
about 0.1 to about 10 mg/lcg/minute during a constant rate infusion.
Advantageously,
compounds of the present invention may be administered in a single daily dose,
or the
total daily dosage may be administered in divided doses of two, three or four
times
daily, Furthermore, preferred compounds for the present invention can be
administered in intranasal form via topical use of suitable intranasal
vehicles, or via
transdermal routes, using those forms of transdermal skin patches well known
to those
of ordinary skill in the art. To be administered in the form of a transdermal
delivery
system, the dosage administration will, of course, be continuous rather than
intermittent throughout the dosage regimen.
In the methods of the present invention, the compounds herein
described in detail can Form the active ingredient, and are typically
administered in
admixture with suitable pharmaceutical diluents, excipients or carriers
(collectively
refewed to herein as 'carrier' materials) suitably selected with respect to
the intended
Farm of administration, that is, oral tablets, capsules, elixirs, syrups and
the like, and
consistent with conventional pharmaceutical practices.
For instance, for oral administration in the form of a tablet or capsule,
the active drug component can be combined with an oral, non-toxic,
pharmaceutically
_ ~2
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acceptable, inert carrier such a s lactose, starch, sucrase, glucose, methyl
cellulose,
magnesium siearafe, dicalcium phosphate, calcium sulfate, mannitol, sorbifal
and the
like; For aril administration in liquid Dorm, the oral drub components can be
combined
with any oral, non-toxic, pharmaceutically acceptable inert carrier such as
ethanol,
S glycerol, water and the like. Moreover, when desired or necessary, suitable
binders,
lubricants, disintegrating agents and coloring agents can also be incorporated
into the
mixture. Suitable binders include starch, gelatin, natural sugars such as
glucose or
beta-lactose, com sweeteners, natural and synthetic gums such as acacia,
tragacanth or
sodium alginate, carboxymethyleellulose, polyethylene glycal, wages and the
like.
Lubricants used in these dosage forms include sodium oleate, sodium stearate,
magnesium stearate, sodium benzoate, radium acetate, sodium chloride and the
like.
Disintegrators include, without limitation, starch, methyl cellulose, agar,
bentonite,
xanthan gum and the like.
The compounds of fhe present invention can also be administered in
the form of liposome delivery systems, such as small unilamellar vesicles,
large
unilamellar vesicles and multilamellar vesicles. Lipasomes can be formed from
a
variety of phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
Compounds of the present invention may also be delivered by the use
of monoclonal antibodies as individual can-iers to which the compound
molecules are
coupled. The compounds of the present invention may also be coupled with
soluble
polymers as targetable drug carriers. Such polymers can include
polyvinylpywolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxy-ethylaspartamide-phenal, or polyethyleneoxide-polylysine
substituted
with palmitoyl residues. Furthermore, the compounds of the present invention
may be
coupled to a class of biodegradable polymers useful in achieving controlled
release of
a drug, for example, polylactic acid, polyglycolie acid, copolymers of
polyactic and
polyglycolic acid, polyepsilon caprolaetone, polyhydroxy butyric acid,
palyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and
crosslinked
or amphipa Chic block copolymers of hydrogels.
The novel compounds of the present Invention can be prepared
according to the procedure of the following schemes and examples, using
appropriate
materials and are further exemplified by the following specific examples. The
compounds illustrated in the examples are not, however, to be construed as
forming
the only genus that is considered as the invention. The following examples
further
3S illustrate details for the preparation of the compounds of the present
invention. Those
- X13
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skilled in the art will readily understand that Known variations oFthe
conditions and
processes of the Following preparative procedures can be used to prepare these
compounds. All temperatures are degrees Celsius unless otherwise nated.
The compounds of the present invention are prepared according to the Following
generic Scheme 1:
~d4-
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SCHEME I. GENERAL SYNTHESIS FOR
CIS-DIHYDROBENZOXATHIINS AND BENZODIOXANES
R1
R2 ~ YH Br R Base
R3 / XH O~ ~ \
Ra / ORs
R~ XH R1
R5
R3 ~ ~ Y R5 R2 ~ Y
Reductive
R2 R1 ~ Cyclization R3 / X
p 4
s R / ORs
IV OR V
R'
R5
Deprotection R2 ~ Y
Mitsunobu Reaction
R3 ~ ~( \ HO(CH2)nNtz)2
R~ / OH
VI
R1
2 5
R ~ Y R Deprotection of OR6
R3 / X ~ (if necessary)
R~ / Oi(CH2)nNtz)2
_ ~5 _
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In words relative to the scheme, an appropriately Functionalized bis-
phenol II (X=O, Y=O), which are readily available, or a mereapto-phenol II
(X=O,
Y=S), which are prepared according to literature procedures, was reacted with
a
bromo-ketone derivative III, which was readily prepared From the corresponding
1<etone by bromination with phenyltrimethylammonium tribromide (PTAB), in the
presence of a teutiary amine base, such as triethylamine,
diisopropylethylamine, or the
like, in a solvent such as dimethylformamide (DMF), formamide, acetonitrile,
dimethylsulFoxide (DMSO), tetrahydrofuran (T1~F), dichloromethane, or the
like, at a
temperature of from -20oC to 80oC for as long as it takes For the reaction to
complete
to provide the displacement product IV. When X--Y=O, only R3 maybe -ORS.
Alternatively, when X--Y=O and R~ is -ORS, the requisite cyclization
intermediate is
obtained by interchangement of the ketone and bromide Functianalities. These
stipulations are required to allow For the preparation of these compounds of
the
invention where the presence of certain substituents will alter the reactivity
of the
t5 phenolic oxygen atoms.
Intermediate IV was reductively cyclized in the presence of an organic
acid such as triFluoraacetic acid, triFlie acid, or the like, or aLewis acid
such as boron
trifluoride etherate, stannous chloride, or the like, and a reducing agent
such as a
trisubstituted silane, such triethylsilane, or the like, in a solvent such as
dichloromethane, chloroform, Tt~F, toluene, or the like at a temperature of
from --
40oC to 100oC For as long as it takes for the reaction to complete to provide
the
cyclized product V, in which the stereochemistry of the aryl substituent and
R$ in the
newly created ring is exclusively cia~. The Formation of the intermediates
with
analogous traps stereochemistry is depicted in the next general Scheme II.
In product V, when Rd is a protecting group it is then removed in a
manner consistent with its nature. Such methods are well documented in the
literature
which are incorporated in standard textbooks, such as Greene, T.W. and Wuts,
P.G.M., Protective Groups in O~ aanic S nty h~sis, Third Ed.,Wiley, New York
(1999).
Further, it is understood that it is possible to have any number of the
substitutents Rl-
Rd be or contain-ORS, or RS may contain-ORS, where Rd is a protecting group,
and
it is Further understood that in these instances the protecting groups are
chemically
diFFerentiable, re., they maybe selectively removed when necessary. Far
example in
product V, RG is a methoxymethyl (MOM) group, R~ is -OR6, wherein R6 is a
benzyl (Bp) group, R~ is a phenyl ring substituted by R~ where R~ is ORb,
wherein
Rd is a triisopropylsilyl (TIPS) group, and all unspecified substitutents are
hydrogen.
-~4G-
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As indicated, as part of the synthetic seduence it is necessary to selectively
remove the
MOM group in preference to either the TIPS or B~, groups. Utilizing methods
found in
Green and Wuts, it is possible to generate the preferred intermediate V,
wherein R~ is
H, R2 is-OBn, R~ ispcrr~cr-OTIPS-phenyl, and all unspecified substitutents are
hydrogen. ~t is also noted that in product V, that when either R? or R3 is
ORS, R~
must be a protecting group, and that prior to its removal, the existing -ORS
group
must be covered by a differentiable protecting group.
The alcohol intermediate VI was then reacted with a reagent
HO(CH2)nNZ~ in a Mitsunobu reaction protocol, in which they are combined with
a
trisubstituted phosphine, such as triphenylphosphine and a diazodicarboxylate,
such as
diisopropylazodicarboxylate, in a suitable solvent such as THF at from 0oC to
80oC
for as long as it takes For the reaction to complete to provide the coupled
product I.
The variables for the Mitsunobu reaction have been well documented and are
incorporated herein by reference: Mitsunobu, O. Syntlre,~i,~, 1981, 1; Castro,
B.R. Org.
Rr?crct. 1983, 29, 1; Hughes, D.L. Org. React. 1992, 42, 335.
Finally, after the Mitsunobu reaction, it is understood that in I if any R
group is or
contains -ORS, wherein R~ is a protecting group, it was removed utilizing the
appropriate method found in Green and Wuts to give the final praduct where R~
is H.
_47--
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SCHEME II. GENERAL SYNTHESIS FOR
TRANS-DIHYDROBENZOXATHIINS AND BENZODIOXANES
R~ XH R4 XH
R3 ~ ~ Y R5 R3 ~ ~ Y R5
Reduction Cyclization
R2 R1 O \ R2 R~ O \
i
s H /
IV OR VII ORS
_5
R1 R1
R2 \ Y R5 R~ \ Y R5
Deprotection
R3 ~ X ~'''~ \ ~ R3 / X ~''~~ \
4 4
R / OR6 R ~ OH
VIII
IX
R1
2 5
Mitsunobu Reaction R \ Y R Deprotection of OR6
HO(CH2)nN(Z)2 Ra / X w.~, \ (if necessary)
R~ / Oi~CH2)nN~z)2
IO In words relative to the above scheme for the general preparation of the
trons isomers of I, the ketone intermediate IV from Scheme I was reduced with
sodium borohydrlde, super hydride, or the like, in a mixture of methanol and
dichlaromethane, or THF or the like at From OoC to ambient temperature For
from a
Few minutes to a few hours to provide the analogous hydroxyl intermediate VII,
_ dg _
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Cycli7ation of intermediate VII was accomplished in the presence of
an acid catalyst such as amberlyst 15, or triflic acid or the like, in a
solvent such
toluene, or dichloromethane or the like, at a temperature of (from ambient to
reflex to
afford the trczn,~ campound VIII as the major isomer.
The remainder of the synthetic sequence to produce tr-~nt,~ I is identical
to that outlined in Scheme I and detailed above.
The compounds of the invention where X=O and Y=SO or SO? are
prepared as outlined in the specific schemes that follow.
SCHEME III. GENERAL SYNTHESIS FOR
fp DIHYDROBENZOXATHIIN DIOXIDES
R~
Rz \ S Rs
R3 / p \
R~ / O~ (CHz)nNtZ)z
R1
R2 O\SO R5
Peroxidation I \
R3 / O \
R4 ~ / i ~CHz)nN~z)2
O
X OCR
R1
Rz O Sl0 Rs
Selective Deoxygenation
R ~ ,O
R'~ / Oi ~CHz)nN~Z)2
-~9-
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In words relative to Scheme III, the compounds I of the invention are
peroxidi~ed with an oxidant such as m-chlaroperben7aic acid, or per-
triFluoroacetic
acid, or the like, in a solvent such diehloromethane or the like, at a
temperature of
From OoC to reflex to produce the trioxide intermediate X. In tru~n X was
selectively
deoxygenated at the nitrogen atom by treatment with a reducing agent such as
sodium
bisulfate or the like in a biphasic medium such as ethyl acetate and water, or
the like,
to provide I.
In the compounds of the present invention, X is preferably O, and Y is
l~l preFerably S.
In the compounds of the present invention, RI ,R~ ,R3 and R'I are
preferably selected from the group consisting of hydrogen, C~_5 alkyl, C3_g
cycloallcyl, CI-5 all<enyl, C,I_5 alkynyl, -ORS and halogen.
In the compounds of the present invention, R~ is preferably selected
IS From the group consisting of C3-g cyeloalkyl, phenyl, and substituted
phenyl.
In the compounds of the present invention, R~ is preferably selected
from the group consisting of hydrogen, CI_5 alkyl, benzyl, methoxymethyl and
trisopropylsilyl.
In the compounds of the present invention, a preFer-r-ed subset is found
20 where RI and R'I are hydrogen, R? and R3 are independently -OH, and RS is
independently selected from the group consisting of phenyl and substituted
phenyl.
In the compounds of the present invention, another preferred subset is
found where R~ is independently selected fluorine and chlorine, R4 is
hydrogen, R~
and R3 are independently -OH, and R~ is independently selected from the group
25 consisting of phenyl and substituted phenyl.
In the compounds of the present invention, the most preferred subset is
Found where RI and R'~ are hydrogen and, R~ is -OH, and R~ is independently
selected from the group consisting of phenyl and par-cr-hydroxy-phenyl.
-50-
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SCHEME IV. GENERAL SYNTHESIS FOR DIHYDROBENZOXATHIIN
OXIDES
R~ R1 O
R5
R2 S R5 R2 S
\ Mono-oxidation
R3 / p \ R3 / O \
R~ / 6 R~ ~ ~ s
OR OR
V XI
R1 O
R2 S Rs
R3 / p \
R~ / pi~CH2)nN~Z)2
S
In words relevant to Scheme IV, the intermediate V of Scheme I was
mono-oxidized by careful treatment with one equivalent or a slight excess of
an
oxidant such as nr-chloroperbenzoic acid, ar dimethyldioxirane, or the like,
in a
1Q solvent such as dichloromethane, ether, acetone, or the like, at a
temperature of from -
78oC to ambient temperature for from a few minutes to a few hours to give the
con'esponding sulfoxide intermediate .YI. The remainder of the synthetic
sequence to
produce I is identical to that outlined in Scheme 1 and detailed above.
In the compounds of the present invention, X is preferably O, and Y is
I S preferably S.
In the compounds of the present invention, Rl ,R~ ,R3 and R~ are
preferably selected From the group consisting of hydrogen, C1-5 alkyl, C3_g
cycloalkyl. C1_5 alkenyl, CI-~ alkynyl, -ORG and halogen.
-51 -
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In the compounc(s of the present invention, R~ is preFerably selected
From the group consisting of C3_g cycloalkyl, phenyl, and substituted phenyl
In the compounds of the present invention, R~' is preferably selected
From the group consisting of hydrogen, C 1_5 alkyl, ben~yl, methoxymethyl and
trisopropylsilyl.
In the compounds of the present invention, a preferred subset is Found
where R~ and R~ are hydrogen, R2 and R~ are independently-OH, and RS is
independently selected from the group consisting of phenyl and substituted
phenyl.
In the compounds of the present invention, another' prefewed subset is
found where Rl is independently selected fluarine and chlorine, R't is
hydrogen, R
and R3 are independently-OH, and RS is independently selected from the group
consisting of phenyl and substituted phenyl.
In the compounds of the present invention, the most prefen -ed subset is
found where R~ and R~ are hydrogen and, R? is -OH, and R~ is independently
selected from the group consisting of phenyl, t~leta-hydroxy-phenyl, and
przrcz-
hydro~y-phenyl.
_ 5~
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EXAMPLE 1
GENERAL PREPARATION OF THIOPHENOLS
R1 R
CuSO~, NH~SGN
/ / S
~O
HO \ OH HO \ O
R2 R
2
R1 R1
Protection / S 1. NaOH / SH
O
\ ~ ~ 2. H~ \
PO ~ PO ~ ~OH
2 2
The Functionali~ed thiophenals were prepared by the known procedure, with
minor
modification, which is depicted in above scheme: Wermer, G.; Biebrich, W. US
Patent 2,276,553 and 2,332,4 18.
O OH
Thiourea / S NH2C1~ / O
Heat ~ O
HCl \ NH2 HO \ S
O OH
PhCH2Br / ~ O OH
1. NaOH
Base \
Bn0 2. H+ Bn0 \ SH
_53_
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The thiophenol depicted above was prepared according to the following
references:
Maxwell, S. J. flat. Cltr.~nt. Suc. 197, G9, 712; Hanzlik, R. P. et. al. J,
pry. CJtcllt.
1990, s5, 2736.
EXAMPLE 2
PREPARATION OF 2-THIOPI-IENE-4-METHOXY-BENZOPHENONE
O s
Me0
To a stirred solution of anisole (1.49 g, 13.8 mmol) in anhydrous
dichloromethane (5
mL) was added AICI~ (1.2320 g, 9.2 mmol) followed by dropwise addition of 2-
thiophene acetyl chloride (0.57 mL, 4.6 mmol) at 0 °C Lender I~F~. The
reaction was
stirred for 1.5 h, then poured into a separatory funnel containing
icelbrinelElOAc.
The organic layer was washed further with brine, dried over Na~SO~, and
concentrated
112 lltlCllp. The resulting residue was purified by silica gel chromatography
with 30°lo
EtOAclhexane as the eluant to afford the desired product as a yellow oil. ~H
500MHz
NMR(CDCl3) ppm(b): 3.89 (s, 3H), 4.46 (s, 2H), 6.98 (m, 4H), 7.24 (d, 1H), and
8.05 (d, 2H).
EXAMPLE 3
PREPARAT10N OF 2-TH10PHENE-4-HYDROXY-BENZOPHENONE
O s
w
HO
A mixture of the 2-thophene-4-methoxy-benzaphenone (p.8294 g, 3.5 mmol),
generated in Example 2, and pyridine-HCl (4.0627 g, 35.2 mmol) was heated to
190
_5d_
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C'C under N~ for 6 h. The reaction was monitored by examining worked-up
aliquots of
the reaction by TLC {30~'If EtOAclhexane). The reaction was cooled in an ice
bath
and icelH~O was added. The resulting mixture was extracted with EtOAc. The
organic extract was washed with 2 N HCI and brine, dried over Na~SO;~, and
concentrated r'n vcrcuo. The resulting brown residue was purified by silica
gel
chromatography with 30%a EtOAclhexane as the eluant to afford the desired
product
as a yellow/orange solid. ~H 500MHz NMR(CDCI~) ppm{S): ~..~.3 (s, 2H), 5.60
(bs,
1H), G,90 {d, 2H), 6.92 {m, 1 H), 6.97 {m, 1H), 7.22 (d, 1 H) and 8.00 {d,
2H).
LO
EXAMPLE ~
GENERAL PREPARATION OF CYCLOALKYL-4-HYDROXY-
BENZOPHENONES
O
a U
HO
To a stirred solution of the 2-cycloalkyl-1-(4-methoxy-phenyl)-ethanone
[prepared
according to the method of Bawio, ~tcrl, J. Med. Ch~n~.,1971, 1~, 898] in dry
methylene chloride at 0°C was added 3.6 equivalents of aluminum
chloride and 3.0
equivalents of isopropyl mercaptan. The ice-water bath was removed and the
reaction
mixture was stiu-ed further overnight under an inert atmosphere of nitrogen.
The
reaction mixture was poured onto a mixture of 2N HCI/ice and extracted with
ethyl
acefiate. The ethyl acetate extract was washed with brine, dried over
anhydrous sodium
sulfate, filfered, and evaporated. Purification by silica gel chromatography
afforded
the con-esponding 2-cycloalkyl-I-(4-hydroxy-phenyl)-ethanone.
ZS Utilizing the foregoing experimental procedure the following campounds were
prepared:
2-cyclohexyl-1-(~-hydroxy-phenyl)-ethanone: 70~'~c~ yield using methylene
chloride-
ethyl acetate(50:1) as the chromatography eluant. jH 500MHz NMR{CDCI~)
ppm{b): l-2.0 {m, 1 IH), 2.96 {d, 1H), 5.6 (bs, 1 H), 6.92 (d, 2H), and 7.9_5
(d, 2H).
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2-cyclopentyl-1-(~l-hydroxy-phenyl)-ethanone: 7~°lc~ yield using
methylene chloride-
ethyi acetate(50:1) a s the chromatography eluant. ~H 500MHz NMR(CDCI~)
ppm(b):1,2-1.92 (m, l OH), 2.~ (m, 1 H), 2.96 (d, 1 H), 5.6 (bs, 1 H), 6.91
(d, 2H), and
7,95 (d, ?H).
s
EXAMPLE 5
PREPARAT10N OF ISOPROPYL-4-HYDROXY-BENZOPHENONE
O
v ~
HO
To a mixture of isovaleric acid (1.4 mL,13.0 mmol) and phenol (1.0253 g, 10.9
mmol)
was added BF~OEt2 (15 mL) under nitrogen. The resulting mixture was heated to
80
°C for approximately 3.5 h. The reaction was poured into ice/2 N HCl
and extracted
with EtOAc. The organic extract was washed with brine, dried over Na2S0,~, and
concentrated isi vaGaao to give a yellow residue. The final product was
isolated as a
pale yellow oil aFter silica gel chromatography with 30~7o EtOAc/hexane as the
eluant.
Upon standing at ambient temperature, the oil solidified to give a white
solid. 'H
500MHz N'MR(CDCI~) ppm(~):1.01 (d, 6H)> 2.2'7 (m, 1H), 2.81 (d, 2H), 6.99 (d,
2H),
7.93 (d, 2H).
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EXAMPLE G
PREPARATION OF 4-PYRIDYL-~l-HYDROXY-BENZOP1-IENONE
O ~ ~N
HO
A dried flask equipped with a stin-er bar was charged with a 2.5 M solution of
nBuLi
in hexane (18 mL, X5.0 mmol) and cooled to 0°C under NZ. A solution of
diisopropylamine (6.~ mL, d5.7 mmol) in distilled THF (20 mL) was added
slowly.
After stirring for 25 min., a solution of 4-picoline (2.0 mL, Zl.d mmol) in
distilled
THF (8 mL) was added to the reaction. The resulting red solution was stirc~ed
for 25
min. before removing the ice bath. A solution of cyanophenol 0.5670 g, 21.d.
mmol)
in distilled THF (?0 mL) was added vin a dropping funnel over 30 min. Upon
addition of the phenol, the reaction became a thick slurry with oiling out of
a
redlbrown tar. Further addition of THF did not alleviate the difficulty in
stio-ing. The
reaction stood at ambient temperature for 1~ h, and was poured into a mixture
of
ice/sat. NH~CI/EtOAc. The intermediate enamine precipitated from the mixture
as an
insoluble yellow solid and was collected by vacuum filtration. The solid was
redissolved in 2 N HC1. The EtOAc layer from the filtrate was also collected
and
extracted with 2 N HCl/ice. The acidic aqueous extract was combined with the
enamine solution in 2 N HCl and stirred at ambient temperature for 16 h. The
acidic
solution was washed with EtOAc, cooled to 0°C, and neutralized to pH7
with sat.
NaHCO~. The desired product precipitated from the solution as a yellow solid
and
was collected, washed with cold water, and dried in vacuo. 1H 500MHz NMR(d-
acetone) ppm{~): x.37 (s, 2H), 6.97 (d, 2H), 7.31 {d, ?H), 8.01 {d, 2H), 8.5?
{bs, 2H).
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EXAMPLE 7
PREPARATION OF 3-PYRIDYL-4-HYDROXY-BENZOPHENONE
O
\ N
HO
Following the procedure outlined in Example 6 with the exception that 1
equivalent of
HMPA in THF was added to the reaction following addition of diisopropylamine,
the
3-pyridyl-4-hydroxy-benzophenone was prepared from 3-picoline, The work-up
differed slightly in that hydrolysis with 2 N HCI was unnecessary. Instead,
the
reaction was simply partitioned between icelsat. NH~CI and EtOAc. The organic
layer was washed with brine, dried over ~ 'a~S04, and concentrated icT
nrcceto. The
residue was triturated with CH~CI~ and EtOAc to give the desired product as an
orange solid. 'H 500MHz NMR{d-acetone) ppm{8): 4.39 (s, 2H), 6.97 ~d, 2H),
7.31
{m, LH), 7.68 {m, 1 H), 8.01 {d, 2H), 8.~3 (m, 1H), 8.52 (m, 1H).
EXAMPLE $
GENERAL PREPARATION OF CYCLOALKYL-4-TRIISOPROPYLSILYLOXY-
BENZOPHENONES
O
~ ~/
TIPSO
To a stirred solution of the ?-cycloalkyl-1-{4-hydroxy-phenyl)-ethanone,
prepared in
Example 4, in dry DMF at 0~'C was added 1.3 equivalents of
diisopropylethylamine
and 1,2 equivalents of triisopropylchlorosilane{T>PSCI). The ice-water bath
was
removed and the reaction mixture was stirred further until tlc showed the
reaction to
be complete ( I-3 hours) under an inert atmosphere of nitrogen. The reaction
mixture
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was partitioned between ether/2N HCI/ice and the organic phase was separated,
washed twice with water, washed with brine, dried over anhydrous sodium
sulfate,
filtered, and evaporated. Purification by silica gel chromatography afforded
the
corresponding '?-cycloal l<yl-1-(~I-triisopropyloxy-phenyl)-ethanone.
Utilizing the foregoing experimental procedure the following compounds were
prepared:
2-cyclohexyl-1-(~-triisopropylsilyloxy-phenyl)-ethanone: use methylene
chloride-
hexanes(1:1) as the chromatography eluant. 'H 500MHz NMR(CDCI~) ppm(~);1.13
(d, 18H), 1-1.99 (m, l~IH), 2.78 (d, 1H), 6.91 (d, 2H), and 7.89 (d, 2H).
2-cyclopentyl-1-(4-triisopropylsilyloxy-phenyl)-ethanone: use methylene
chlorlde-
hexanes(1:1) as the chromatography eluant. 'H 500MHz NMR(CDC1~) ppm(~):1.12
(d, 18H), 1.2-1.91 (m, 13H), 2.4 (m, 1H), 2.95 (d, 1H), 6.92 (d, 2H), and 7.9
(d, 2H).
1~ EXAMPLE 9
GENERAL PREPARAT10N OF ALKYL-4-TR1ISOPROPYLSILYLOXY
BENZOPHENONES
O
R
TI PSO
To a solution of the 2-alkyl-1-(4-hydroxy-phenyl)-ethanane, prepared in
Examples 3,
6, and 7, in distilled THF was added 1.3 equivalents of 60% NaH in mineral oil
at 0
°C under N~. After the gas evolution ceased, 1.1 equivalents of was
added dropwise
and the resulting solution stirred for 30 min. The reaction was partitioned
between
ice/water and EtOAc. The organic layer was washed with brine, dried over ~
~aaSO~,
and concentrated in vczc~to. Purification by silica gel chromatography
afforded the
coiTesponding 2-alkyl-1-(4-triisopropylsilyloxy-phenyl)-ethanones.
Utilizing the foregoing experimental procedure the following compounds were
prepared:
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2-(2-thiophene)-1-(~l-triisopropylsilyloxy-phenyl)-ethanone: isolated as an
orange/yellow solid using 15~'l~ EtOAc/hexane as the chromatography cluant. ~t-
1
500MHz NMR(CDCI;) ppm(c~): l,1~ (d, l8H), 1.30 (m, 3H ), tl..~? (s, 2H), and
6.93-
7.98 (m, 7 H).
2-(~-pyridyl)-1-(4-triisopropylsilyloxy-phenyl)-ethanone: isolated as a yellow
solid
using ~0'~o EtOAc/hexane as the chromatography eluant. ~H 500MHz NMR(CDCI~)
ppm(b):1.1~. (d, 18H), 1,30 (m, 3H), 4.28 (s, 2H), 6.97 (d, 2H), 7.35 (m, 1H),
7.69 (m,
1H), 7.97 (d, 2H), and 8,56 (bs> 2H).
2-(3-pyridyl)~l-(~-triisopropylsilyloxy-phenyl)-ethanone: isolated as a yellow
solid
using ~0°lp EtOAclhexane as the chromatography eluant. ~H 500MHz
NMR{CDC13)
ppm(~):1.1~ (d, 18H), 1.20 (m, 3H), x.18 (s, 2H), 6.82 (d, 2H), 7.10 (d, 2H),
7.82 (d,
2H), and 8.43 (d, 2H).
EXAMPLE 10
GENERAL BROMINAT10N PROCEDURE OF ALKYL AND CYCLOALKYL-~-
TR1ISOPROPYLS1LYLOXY-BENZOPHENONES
O
R
Br
TIPSO
To a stiu~ed solution of the 2-alkyl- and 2-cycloall<yl-1-(4-
triisopropylsilyloxy-
phenyl)-ethanones> prepared in Examples 8 and 9, in dry THF at OpC was added
1.0
equivalent of trimethylammoniumphenyl perbromide. The ice-water bath was
removed and the reaction mixture was stilted further for 1 hour under an inert
atmosphere of nitrogen. The reaction mixture was partitioned between ethyl
acetate/brine/ice/5°~osodium thiosulFate/sodium bicarbonate and the
organic phase was
separated, washed with brine, dried over anhydrous sodium sulFate, Filtered,
and
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evaporated. Purificafian by silica gel chromatography afforded the
corresponding 2-
cycloall<yl-2-bromo-1-(4-triisopropylsilyloxy-phenyl)-ethanone.
Utilizing the foregoing experimental procedure the following compounds were
prepared:
_5 2-cyclohexyl-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-cthanone: use
methylene
chloride-hexanes{1:1) as the chromatography eluant. ~H 500MHz NMR(CDCI~)
ppm{8): 1.14 {d, 18H), 0.98-2.27 (m> 1~H), 4.91 {d, 1H), 6.94 (d, 2H), and
7.94 (d>
2H).
LO 2-cyclopentyl-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-ethanone: use
methylene
chloride-hexanes{1:1) as the chromatography eluant. ~H 500MHz NMR(CDCIs)
ppm{8):1.13 {d, 18H), 1.1-2.2 {m, 11H), 2.8 {m, 1H), 4.98 (d, 1H), 6.94 (d,
2H), and
7.96 {d, 2H).
15 2-(2-thiophene)-2-bromo-1-(4-triisopropylsilyloxy-phenyl)-ethanone: stirred
at 0 °C
for 40 min.; isolated as a dark brown oil and used in the next reaction
without
purification.
~H SOOMHz ~1MR(CDCI;) ppm{0:1.13 {d, 18H), 1.30 (m, 3H), 6.73 {s, 1H), 6.97
(d,
2H), 7.00 {m, 1H ), 7.30 (m, 1H), 7.49 {d, 1H), and 8.00 (d, 2H).
2-(4-pyridyl)-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-ethanone: added 2
equivalents of trimethylammoniumphenyl perbromide and stirred at 0 °C
for 1 h;
isolated as an orangelyellow oil and used in the next reaction without
purification. ~H
500MHz NMR{CDCI;) ppm(8):1.03 {d, 18H), 1.21 {m, 3H), 6.21 (s, 1H), 6.98 (d,
2H), 7.40 {d, 2H), 7.90 {d, 2H), and 8.57 {d, 2H).
2-{3-pyridyl)-2-bromo-1-{4-triisopropylsilyloxy-phenyl)-ethanone: added 2
equivalents of trimethylammoniumphenyl perbromide and stirred at 0 °C
for 3 h;
isolated as an orangelyellow oil and used in the next reaction without
purification, IH
SOOMHz NMR(CDCI~) ppm{8):1.13 {d, 18H), 1.30 {m, 3H), 6.30 (s, ll~, 6.98 (d,
2H), and 7.39-8.75 {m, 6H).
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EXAMPLE 11
PREPARATION OF' 2-ISOPROPYL-2-BROMO-1-(~.-HYDROXYPHENYL)
ETHA NO NE
O
~w
HO \ ~ IBr
Following the procedure outlined in Example 10 and using the product obtained
from
Example 5, 2-isopropyl-2-bromo-1-(~.-hydroxyphenyl)-ethanone was isolated as a
yellow oil and used in the next reaction without purification. ~H SOOMHz
NMR(CDC13) ppm(8): 1.01 (d, 3H), 1.2I. (d, 3H)> 2.46 (m, 1H}, 4.93 (d, 1H},
G.96 ~d,
2H), and 7.9G (d, 2H}.
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EXAMPLE 12
GENERAL PREPARATfON OF BROMOKETONES
PS
R=H or MOM
Step A
To a stirred solution of 3.0g {13.2mmole) of dry desoxybenzoin {freshly
azeotroped
with toluene) in 25mL of DMF at 0°C was added 5.7mL {5.7mmale) of neat
diisopropylethylamine. To this stirred solution was added slowly 1.25mL (19.73
mmole) of chloromethylmethylether (MOMCI). The ice-water bath was removed and
the mixture was stirred further under an atmosphere of nitrogen for 18 hours.
The
mixture was then poured into a saturated NaHC03 solution, extracted with
EtOAc,
and the extract washed with water, and dried over anhydrous MgSO~. After
evaporation of the solvent, the residue was purified by silica gel
chromatography
(EtOAc/Hexane =1:1) to provide the product, as a solid. 'H NMR (400 MHz,
CDC13)
8 (ppm): 8.0 (d, 2H), 7.19(d, 2H), 7.10 (d, 2H), 6.8 (d, 2H), 5.23 (s, 2H),
~1.8 (s, 1H),
4.2 {s, 2H), 3.S (s, 3H}.
St-ep B
To a stirred solution of the product obtained from Step A (~?3mg, 1.55mmole)
and
imidazole (21 1 mg, 3.lmmole) in 20mL of dry DMF at 0°C was added
triisopropylsilyl chloride (3.lmmole) and the reaction mixture was allowed to
warm
to room temperature and stirred further for ?-3 hours. The reaction was
quenched by
the addition of aqueous NaHCO~ solution and extracted with EtOAc. The organic
layer was washed with brine and dried with MgSO;~. Chromatography (10%
EtOAc/hexane) yielded the desired product. 'H NMR (~00 MHz, CDCI.,) b (ppm):
8.0 (d, 2H), 7.12 (d, ?H), 7.08 (d, 2H). 6.82 (d, ~H>, _5.21 (s, 2H), x.18 (s,
2H), 3.5 (s,
3H), 1.21 (m, 3H), I.I (d, 18H).
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Step C
To a mixture of the compound from Step B (0.5g, 1. l6mmole) in LOOmL of
anhydrous TI-IF was added 0.398 {1.16mmole) of trimethylphenylammonium
perbromide (PTAB) at 0°C. The ice-water bath was removed, and the
mixture was
stirred further for one hour, The solution was then filtered and washed with
water and
brine and dried over MgSO~. Removal of the solvent afforded the mixture of
bromo-
ketones (MOM group was partially removed), which was used without further
purification due to their instability toward chromatography.
Bromolcetone with MOM group: 'H NMR (400 MHz, CDCI;) ~ (ppm): 8.0 (d, ZH),
'7.4 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H), 6.36 {s, 1H), I.24 (m, 3H}, 1.I (d,
I8H};
Bromolcetone without MOM group: 'H NMR (400 MHz, CDCI;} 8 (ppm): 7.94 {d,
2H), 7.4 (d, 2H), 6.88 {d, 2H), 6.86 (d, 2H), 6.36 (s, IH), 1.2~ (m, 3H), 1.1
(d, I8H).
EXAMPLE 13
PREPARATION OF
i
Br
O I \
OTIPS
The required bromoketone was prepared using the procedure in Example I2 (Step
C).
'H NMR (400 MHz, CDCI~,) b (ppm) 7.94 {d, 2H), 7.56 (m, 2H), 7.38 (m, 3H}, 6.9
{d,
2H), 6.36 {s, 2H), 1.28 (m, 3H), 1.1 (d, I8H).
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EXAMPLE I==1
PREPARATION OF
OMe
Br
O' ~~
~ OTIPS
The required bromoketone was prepared using the procedure in Example 12 (Step
C).
IH NMR 0100 MHO, CDCI~) b {ppm) 7.9 (d, 2H), 7.5 {d, 2H), 6.9 (d & d, 4~-I),
6.~ {s,
1H), 3.8 (s, 3H), 1.28 (m, 3H), 1.1 (d, 18H).
EXAMPLE 1_5
PREPARAT10N OF
OMOM
Br
O
OMOM
St._ ep A
To a sowed solution of a mixture of the 0.1g (0.37mmale) mano phenolie
compound
from Step A in Example 12 and diisopropylethylamine (0.13mL, 2eq) in SmL of
DMF
at room temperature was added slowly neat MOMCI (O.OSmL, 2eq), and the mixture
was heated at 85°C under N~ for three hours. The mixture was then
poured into a
saturated NaHCO~ solution, extracted with EtOAc, washed with water, and dried
over MgSO..~. After evaporation of the solvent, the residue was purified by
silica gel
chromatography (EtOAclHexane =1:1) to provide the pure bis-protected MOM
product, as a solid. ~H NMR (400 MHO, CDCI=) ~ (ppm): 8.0 {d, 2H), 7.19(d,
2H~,
7.10 (d, 2H), 7.02 (d, 2H), 5.23 {s, 2H), 5.2 (s, 2H), ~1.? (s, 2H), 3.5 (two
s, 6H).
2S
-- 65 n
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S t_ e.p B
The product ol~ Step A was treated with bromine to give the bromolcetone. 1H
NMR
(400 MHz, CDCI;) b (ppm); 8.0 (d, 2H), 7.45(d, ?1-1), 7.10 (two d, 4H), 6.~
(s, 1H),
5.23 (two s, 4H), 3.5 (two s, 6H).
EXAMPLE 16
GENERAL PREPARATION OF
O / OTIPS
MOMO ~ I S
Ho
I0
To a stirred, freshly prepared solution of 2-thiophenol (0.2g, l.6mmole) and
Et3N
(0.34mL, 2eq) in ISmL DMF at 0°C was slowly added a solution of 0.6278
(I.232mmole) of bromoketone (prepared from Step C in Example 12) in I3mL of
DMF. The reaction mixture was stirred for three hours at room temperature and
was
then pautitioned between saturated I~aHCO~ and EtOAc, the layers were
separated,
and the aqueous layer was extracted again with EtOAc. The combined organic
layers
were dried (Na~SO~), Filtered, and evaporated in uczcato. The resulting ail
was purified
by flash chromatography (EtOAc/Hex=Ll4) to provide the desired product as an
oil.
~H NMR (400 MHz, acetone-d~) b (ppm): 8.0 (d, 2H). 7.2-6.6 (m, 8H), 6.8 (d,
2H),
?0 6.2 (s, 1H), 5.21 (s, 2H), 3.4 (s, 3H), .1.22 (m, 3H), 1. l (d, I8H); MS
mlz 575
(M~'~+23).
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EXAMPLE 17
CYCLIZATION OF COUPLED PRODUCT
O / OMOM MOM
\ ~ O
MOMO
HO ~ ~ MOM
Follawing the procedure outlined in Example 16, 1,2-dihydroxybenzene and the
bromide oFExample 15 was converted to the product which was puriFied by silica
gel
chromatography using EtOAc/hexane (1/4) as eluant. MS ml~ 448 (M~+2~).
EXAMPLE 18
PREPARAT10N OF
OTIPS OT(PS
O
/ \
HO \ S MO
HO
OBn
A
L5 Following the procedure outlined in Example 16 and using 0.838 (3.6mmole)
of 4-
benzyloxy-thiophenol, prepared from Example 1, product A and produ cfi I3 were
obtained aFter silica gel chromatography using EtOAclhexane (1/5) as eluant.
A: ~H NMR {400 MHz, acetone-d~) ~ (ppm): 8.15 (s, 1H), 7.8 (d, 2H), 7.4 (m,
SH),
6.98 (d, 2H), 6.98 (d, 1H), 6.7_5 (d & d, 4H), G.0 ( s, 1H), 5.62 (s, 1H), 5.0
(s, 2H),
1.22 (m, 3H), 1.15 ~d, 18H).
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B; ~H NMR 0100 MHL, acetone-d~,) S (ppm): 8.0 (d, 2H), 7.5 (m, 5H), 7.18 (d,
2H),
7.0~ (d, 2I-I), G.9G (d, 1I-I), G.8 (d, 2H), G.SG (d, 1 H), G.32 (dd, 1 H), G.
l (s, I I-I), 5.35
(s, 2H), 5.09 (s, II-I), 3.~. (s, 3H), 1.22 (m, 3HI}, I.I (d, 18I-I).
EXAMPLE 19
PREPARATION OF
O / OMe
I
TIPSO \ ~ S
No
OBn
Following the procedure outlined in Example 1G and using 1.1g (2.3mmole} of
the
bromoketone from Example 14, the desired product was obtained after silica gel
chramatography using EtOAc/hexane (1/5) as eluant. ~HNMR (~00 MHz, acetone-
d~} ~ (ppm): 8.4G (br s, 1H), 7.98 (d, 2H), 7.~8-7.3 (m, 5H), 7.24 (d, 2H),
7.~ (d, 1H),
6.92 (d, 2H), 6.82 (d, 2H), 6.56 (d, 1H), 6.38 (dd, IH), 6.1 (s, 1H), 5.0~ (s,
2H), 3.72
(s, 3H), 1.25 (m, 3H), 1.1 (d, 18H).
EXAMPLE 20
PREPARATION OF
PS
H
2p OBn
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Following the procedure outlined in Example 1G and using 0,748 (I._Smmole) of
the
bromol<etone from l;xample 12 (Step C), the desired product was obtained after
silica
gel chromatography using EtOAc/hexane (1/5) as eluant. ~k(NMR (400 MHz,
acetone-d~) ~ (ppm): 7.92 (d, 2I-I), 7.46-7.1 (m, 5H), 7,18 (d, 2H), 6.84 (d>
2I-I), 6.78
{d, 2I-I), 6.~2 (d, 1 H)> 6.36 (d, IH), 5.98 (s, 1H), 5.02 (s, 2H), 2.2 {s,
3H), 1.22 (m,
3H), l, l (d> 18H).
EXAMPLE 21
PREPARATION OF
OTIPS
H
Me Utin
Following the procedure outlined in Example 16 and using 0.8g (1.57mmole) of
the
bromoketone fram Example 12 (Step C) with the thiophenol derivative prepared
from
Example 1, the desired product was obfiained after silica gel chromatography
using
EtOAc/hexane (ll5) as eluant. 'H NMR (400 Ml-lz, acetone-d~) 8 {ppm): 7.9 (d,
2H),
7.5-7.3 (m, 5H), 7.12 (d, 2H), 6,9 (d, 1H)> 6.84 (d, 2H), 6.79 (d, 2H), 6.4
(d, 1H), 6.0
(s, 1H), 5.1 (s, 2H), 2,1 (s, 3H), 1.?5 (m, 3H), 1.1 (d, 18H).
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EXAMPL.sE 22
PREPARATION OF
O / OTIPS
\ ~ S Et
NO
HO
OBn
Following the procedure outlined in Example 16 and using 0.568 (l.lmmole) of
the
bromoketone from Example 12 (Step C) with 0.198 (0.73mmole) of thiophenol
derivative prepared from Example 1, the desired product was obtained after
silica gel
~0 chromatography using EtOAe/hexane (1/5) as eluant. 1H NMR (400 MHz, acetone-
d~) ~ (ppm); 7.9 (d, 2H), 7.~8-7.3 (m, SH), 7,16 (d, 2H), 6.8~ (d, 2H), 6.78
(d, 2H),
6.12 (d, 1H), 6.38 (d, 1H), 5.96 (s, 1H), 5.1 (s, 2H), 2.6 (q, 2H), J .22 (m,
3H), 1.1 (d,
18H), 1.1 (t, 3H).
15 EXAMPLE 23
PREPARATION OF
O / OTIPS
\
I
HO \ ~ S
HO
Et OBn
20 Following the procedure outlined in Example 16 and using ?.04g (~.33mmole)
of the
bromoketone from Example 12 (Step C) with the thiophenol derivative prepared
from
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Example 1, the desired product was obtained alter silica gel chromatography
using
EtOAclhexanc ( 1/5) as eluant. ~H NMR (400 MI-Iz, acetone-dc,) ~ (ppm); 7.9
(d, 2H),
7.5-7.3 (m, SH), 7.12 (d, 2H), 6.92 (rl, LH), 6.84 (d, 2H), 6,78 (d, 2I-I),
6.42 (d, 11~),
6.0 (s, lI-I), 5.1 (s, ?H), 2.7 (q, 2H), 1.24 (m, 3H), 1,1 (d & t, 21H).
EXAMPLE 24
PREPARATION OF
O / OTIPS
\
\ ~ S OBn
NO
Ho
OBn
Following the procedure outlined in Example 16 and using 2.0g (4.33mmole) of
the
bromoketone from Example 12 (Step C) with the thiophenol derivative prepared
from
Example 1, the desired product was obtained after silica gel chromatography
using
EtOAc/hexane (1l5) as eluant. ~H NMR (400 MHz, acetone-d~) 8 (ppm): 7.8 (d,
2H),
7.62 (d, 2H), 7.48-7.3 (m, 8H), 7.12 (d, 2H), 6.8 (d, 2H), 6.76 (2H, d), 6.28
(d, 1H),
6.18 (d, LH), 6.0 (s, 1H), 5.24 (s, 2H), 5.05 (s, 2H), 1.22 (m, 3H), 1.1 (d,
18H).
EXAMPLE 25
PREPARAT10N OF
0
TIPSO \ I s
Ho
OBn
-71-
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Following the procedure outlined in Example l6 and using l.Gg (3.S lmmole) of
the
bromoi<etone From Example 13 with the thiophenol derivative prepared From
Example
l, the desired product was obtained otter silica gel chromatography using
EtOAc/hexane (1/S) as eluant. ~H NMR (400 MHz, acetone-ci~,) ~ (ppm): 8.0 (d,
2H),
7.5-7.2 (m, 10H), 7.0 (d, 1H), 6.92 (d, 2H), 6.54 (d, 1H), G.35 (dd, 1 H),
6.12 (s, 1H),
S.OG (s, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
EXAMPLE 2G
PREPARAT10N OF
TI
~Bn
Following the procedure outlined in Example 1G and using 2,6g (5.82mmole) of
the
bromoketone from Example 13 with the thiophenol derivative prepared from
Example
1, the desired product was obtained after silica gel chromatography using
EtOAc/hexane (1l5) as eluant. ~H NMR (400 MHz, acetone-d~) b (ppm): 8.0 (d,
2H),
7.4-7.2 (m, 10H), 6.94 (d, 2H), 6.84-6.74 (m, 3H), G.24 (s, 1H), 4.85 (s, 2H),
1.23 (m,
3H), 1.1 (d, 18H).
EXAMPLE 27
PREPARAT10N OF
F
TIPS
OBn
72
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Following the procedure outlined in Example 16 and using the bromoketone From
Example 12 (Stop G) with the thiophenol derivative prepared From Example l,
the
desired product wus obtained aFter silica gel chromatography using
EtOAc/hexane
(I/5) as the eluant. 'H NMR (~00 MHz, acetone-dr,) ~ (ppm): 8.0 (d, 2H), 7,4-
7.2 (m,
7H), 7.0 (m, SI-I), 6.5~ (d, LH), 6.28 (dd, 1H), 6.1~ (s, IH), 5.08 (s, 2H),
1.23 (m, 3H),
I.l (d, 18H).
EXAMPLE 28
PREPARATION OF
O
I
TIPSO \ I S F
HO
OBn
Following the procedure outlined in Example 16 and using the bromoketone from
Example 13 with the appropriate thiophenol derivative prepared from Example 1,
the
desired product was obtained after silica gel chromatography using
EtOAc/hexane
(1l5) as the eluant. IHNMR (500 MHz> CDC13) ~ (ppm) 8.28 (s, lH), 7.82 (d,
2H),
7.40 (m, SH), 7.22 (m, SH), 6.80 (d, 2H), 6.d0 (d, 1H), 6.21 (dd, 1H), 5.80
(s, LH),
5.00 (s, 2H), 1.24. (m, 3H), 1. LO (d, 18H).
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EXAMPLE 29
PREPARATION OF
O
TIPSO \ S CI
HO
OBn
Following the procedure outlined in Example 16 and using the bromoketone from
Example 13 with the appropriate thiophenol deuivative prepared from Example 1,
the
desired product was obtained alter SiOZ using EtOAc/hexane (1/5) as eluant. 'H
NMR (500 MHz, CDCI;} 8 (ppm) 8.19(s, 1H), 7.82(d, 2H), 7.~0{m, 5H), 7.24(m,
5H), 6.80(d, 2H), 6.64(d, 1H), 6.~.~{d, 11~~, 5.84{s, 1H), 5.00(s, 2H),
1.?3(m, 3H),
1.10(m, 18H).
EXAMPLE 30
PREPARATION OF
IPS
OBn
Following the procedure outlined in Example 16 and using the bromoketone from
Example I2 with the thiophenol derivative prepared from Example l, the desired
product was obtained after silica gel chromatography using EtOAclhexane (1/5}
as
eluant. ' H NMR (500 MHz, CDC13) 8 (ppm): 8.?0 (s, I I-I), 7.81 (d, 2H), 7.40
(m,
_ 7
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5I-I), 7.0? (d, 2H), 6.75 (ri, 4H), 6.36 (d, 1 H), 6.20 (dd. 1 H), 5.78 (s, 1~-
I), x.95 (s, 2H),
1.23 (m, 3H), 1.10 (m, 18I-I).
EXAMPLE 31
S PREPARATION OF
OTIPS
OBn
Following the procedure outlined in Example 16 and using the bromoketone from
Example 12 with the thiophenol derivative prepared from Example 1, the desired
product was obtained after silica gel chromatography using EIOAc/hexane (1/5)
as
eluant. 'H NMR (500 MHz, CDC13) ~ (ppm): 8,24 (s, IH), 7.80 (d, 2H), 7.40 (m,
5H), '7.10 (d, 2H), 6.'78 (d, 4H), 6.62 (d, 1H), 6.42 (d, 1H), 5.84 (s, ~H),
4.98 (s, 2H),
1.23 (m, 3H), 1.10 (m, 18H); MS m/z 650 (M~+1).
EXAMPLE 32
PREPARATION OF
IPS
Following the procedure outlined in Example 16 and using the bramoketone from
Example 12 with the thiophenol derivative prepared from Example 1, the desired
product was obtained after silica gel chromnto~raphy using EtOAc/hexane (1/5)
as
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eluant. ~H NMR {500 MHz, acetone-d~,) 8 {ppm): 7.95 {d, 2H), 7.~0 {m, SH),
7.20 {d,
2I-I), G.80 {m, 7I-I), G.?0 {s, 1H), x.85 {s, 2H), 1.23 {m, 3H), 1.10 {m,
18H); MS mlz
G 1 G {M~+1 ),
EXAMPLE 33
PREPARATIO~F OF
O / OTIPS
I
HO ~ ~ S
HO ~ ~ Me
OBn
Following the procedure outlined in Example 1G9 and using the bromoketone from
Example 12 with the thiophenol derivative prepared from Example 1, the desired
product was obtained after silica gel chromatography using EtOAclhexane {1/5)
as
eluant. 'H NMR {500 MHz, CDCI3) 8 (ppm): 7.82 {d, 2H~, 7.~0 (m, 5H), 7.05 (d,
2H), 6.95 {s, 1H), G.80 {d, 4H), G.52 {s, 1H), S.G~ {s, 1H), 5.00 {s, 2H),
1.23 {m, 3H),
1 S 1.10 {m, I 8H); MS mlz 629 {M~+1).
EXAMPLE 34
PREPARAT10~1 OF
OTI PS
H
OBn
-7G-
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Following the procedure outlined in Example IG and using the bromoleetone From
Example 12 with the thiophenol derivative prepared from Example 1, the desired
product was abtained aFter silica gel chromatography using EtOAc/hexane (1/5)
as
eluant. 'H NMR (500 MHz, CDCI~) cS (ppm: 8.24 (s, IH), 7.80 (d, 2H), 7.40 (m,
5I-I),
_5 7.10 (d, 2H), G.78 (d, 2H), G.7G (d, 2H), G.64 (d, 2H), G.~._5 (d, 2H},
S.BG (s, IH), 4.98
(s, 2H), 1,23 (m, 3H)> 1.10 (m, 18H); MS m/z G50 (M~+1).
EXAMPLE 35
PREPARAT10N OF
TI
Bn
Following the procedure outlined in Example 1G and using the bromoketone Pram
Example 12 with the thiophenol derivative prepared from Example 1, the desired
product was obtained after silica gel chromatography using EtOAc/hexane (1/5)
as
eluant. 'H NMR (500 MHz, CDCI~} 8 {ppm): 7.82 (d, 2H), 7.40 (m, 5H), 7.24 (m,
3H), 7.20 (d, 2H), 6.82 (d, 2H), G.80 {d, 2H), G.58 {d, 2H), S.GS {s, 1H),
4.80 (d, 2H),
2.22 {s, 3H}, 1.23 (m, 3H), 1.10 {m, 18H).
EXAMPLE 36
PREPARATIO ~ ~ OF
TIPS
Bn
CI
-77-
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Following the procedure outlined in Example 16 and the bromol<etone from
Example
13 with the thiophenol derivative prepared from Example I, the desired product
was
obtained after silica gel chromatography using EtOAc/hexane (1l5) as eluant.
~H
N'MR (500 MHz, CDCI~) b (ppm): 7.98 (s, 1 H), 7.82 (d, 2H), 7.~0 (m, 5H), 7.25
(m,
S 3I-I), 7.20 (d, 2H), 7.00 (d, 1H), 6.80 (d, 2H), 6.60 (d, 1H), 5.78 (s, 1H),
x.78 (d, 2H),
1.23 (m, 3H), 1.10 (m, 18H).
EXAMPLE 37
PREPARATION OF
O
O
TIPSO \ S TIPSO ~ I S CI
HO ~ ~ OBn HO ~ ~ OBn
CI
IL
Following the procedure outlined in Example 16 and using the bromoketone from
Example 13 with the mixture of the two thiophenol derivatives prepared from
Example 1, the two desired products 71 and II were obtained after silica gel
chromatography using EtOAc/hexane (1l5) as eluant.
I: ~H NMR (500 MHz, CDC13) 8 (ppm): 7.80 (d, 2H), 7.40 (m, 5H), 7.25 r;m, 3H),
7.16 (d, 2H), 7.04 (s, 1H), 6.80 (d, 2H), 6.60 (s, 1H), 5.78 (s, 1H), 4.80 (d,
2H), 1.23
(m, 3H), 1.10 (m, 18H).
II: ~H NMR (500 MHz, CDC13) ~ (ppm): 7.80 (d, 2H), 7.65 (s, 1H), 7.~1~. (d,
1H),
7.40 (m, 5H), 7.25 (m, 5H), 6.96 (d, 1H), 6.80 (m, 3H), 6.00 (s, 1H), 5.15 (s,
2H),
1.23 (m, 3H), 1.10 (m, 18H).
,78-
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EXAMPLE 38
PREPARATION OF'
o ~ F
I
TiPSO ~ I s
Ho ~ ~ oBn
Following the procedm°e outlined in Example 16 and using the
bromoketone from
Example 12 with the thiophenol derivative prepared from Example 1, the desired
product was obtained after silica gel chromatography using EtOAclhexane {1/5)
as
eluant. iH NMR (500 MHz, CDC1~) ~ (ppm): 7.80 {d, 2H), 7.~I0 (m, 5H), '7.14
{m,
2H), 6.96 {m, 2H), 6.8~. {m, 2H), 6.82 {d, 2H), 6.70 {d, 1H), 5.68 {s, 1H),
4.86 d, 2H),
1.23 {m, 3H), 1.10 {m, 18H).
EXAMPLE 39
GENERAL PREPARAT10N OF
OTIPS
S
O
Ph~O \ OH
Utilizing the bromides prepared in the Example 10 and the appropriate
mercaptan
prepared in Example 1 and employing the procedure outlined in Example 16 the
following compaunds were prepared:
Cyclohexyl derivative: use methylene chloride/hexanes{3:1) as the
chromatography
eluant. ~H 500MHz NMR{CDC13) ppm(~): 1.12 {d, 18H), 1.11-2.34 {m, 15H), x.19
(d, 1H), 5,0 (s, 2I-I), 6.4~ {dd, 1H), 6.5~ (d, 1H), 6.86 Vim, 3H), 7.25-7.72
(m, 7H).
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Cyclopentyl derivative: use methylene chloride/hexanes(2: I ) as the
chromatography
eluant. ~ H 500MHz NMR(CDCI;~) ppm(~): I .12 (d, 181-1), 1.28-2.49 {m, 12H),
x.18
{d, 1I-I), 5.0 {s, 2H), 6.45-7.77 {m, I2H).
EXAMPLE 40
PREPARATION OF
OH
S ~ v
O
Ph~O \ OH
Utilizing the bromide prepared in Example 11 and the appropriate mercaptan
prepared in Example I and employing the procedure outlined in Example 9, the
desired product was obtained as a yellow oil in 77°~o yield after
silica gel
chromatography with 30°~° EtOAc/hexane as the eluant. ~H 500MHz
NMR{CDCI~)
IS ppm{8): 1.00 {d, 3H), L21 {d, 3 H), 2.30 (m, 1H), X1.13 (d, 1H), X1.99 {s,
2H), 6.~1.1-
7.72 {m, 12H), 8.02 {bs, 1H), 8.80 (bs, 1H); MS m/z X09 (M+)
EXAMPLE ~I I
GENERAL PREPARATION OF
OTIPS
Ph.~O / S
O
OH
-80-
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Lltiliring the bromides prepared in Example 10 and the appropriate mercaptan
prepared in Example 1 and employing the procedure outlined in Example 16 the
Following compounds were prepared:
Cyclohexyl dcrivafiive: use methylene chloride/hexanes(3:1) as the
chromatography
eluant. ~H 500MHz NMR(CDCI~) ppm(c~): 1.12 {d, 18H), 1.11-2.3 (m, 15H), 4.2~.
(d,
11-I), ~-.89 (m, 2H), 6.8-7.6 {m, 12H).
Cyclopenfiyl derivative: use methylene chloride/hexanes~2:1) as the
chromatography
eluant. ~H 500MHz NMR(CDC13) ppm(~):1.12 (d, 18H), 1.26-2.12 (m, 11H}, 2.5 {m,
1H), x..24 (d, 1H), 4.9 (m, 2H), 6.8-7.69 {m, 12H).
4-Pyridyl derivative: isolated as a yellow oil using 30% EtOAc/hexane as the
chromatography eluant. ~H 500MHz NMR(CDCIs) ppm(~):1.12 (d, 18H), 1.28 (m,
3H), 4.8~ (q, 2 H), x.88 {s, 1H), 5.63 (s, 1H), and 6.69-8.50 {m, 16H).
3-Pyridyl derivative: isolated as a yellow oil using 30% EtOAclhexane as the
chromatography eluant. 'H 500MH2 NMR{CDC13) ppm(~):1.12 (d, 18H), 1.28- (m,
3H), 4.81 (q, 2H), 4.90 (s, 1H), 5.79 (s, 1H), and 6.70-8.50 (m, 16H).
EXAMPLE ~.2
PREPARAT10N OF
OH
Ph~O , S
O
OH
Utilizing the bromide prepared in Example 11 and the appropriate mercaptan
prepared
in Example l and employing the procedure autlined in Example 16, the desired
product was obtained as a yellow oil aFter silica gel chroma tography with
30%a
EtOAc/hexane a s the eluant. ~ H 500MHz NMR(CDC13) ppm{8): 1.02 (d, 3H), 1.21
(d, 3 H), 2.31 (m, I H), x.13 (d, 1 H), x.90 (q, 2H), 6.25 (bs, 1H), 6.79-7.70
(m, 12H).
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EXAMPLE 43
PREPARATION OF
S / , OTIPS
HO , S
O
\ OH
Utilizing the appropriate bromide prepared in Example 10 and the
mercaptoquinol
[prepared according to the method of Burton, elcrl, J. Chejn. Soc., 1952,
2193] and
employing the procedure outlined in Example 16, the desired product was
obtained as
an orange/red oil after silica gel chromatography with 30Q1o EtOAclhexane as
the
eluant. ~H S00MHz NMR(CDCI~) ppm(8): 1.10 (d, 18H), 1.27 (m, 3H), 6.00 {s,
1H),
and 6.76-7.89 {m, 10H)> MS m/z S1S (M~).
EXAMPLE 4~1
PREPARATION OF
PS
Bn
vn
To a flask charged with O.lg {0. l6mmole) of thio-1<etone generated in Example
22 in
dichloromethane {ca 0.04M) was slowly added trifluoroacetic acid(TFA) (2 X
0.062mL, l0eq) under an N~ atmosphere at room temperature. To the sowed
reaction
mixture was slowly added triethylsilane (2 X 0.05mL, 4eq) and the resulting
mixture
until starting material was consumed (approximately 5-6 hours, as monitored by
TLC). The reaction mixture was poured into saturated NaHCO~lice water, stin-ed
l0
minutes, and extracted with dichloromethane. The organic extract was washed
with
brine {2 X SOmL), dried with Na~SO,~, and concentrated in vac~co to afford a
light
yellow oil. Purification via flash chromatography (EtOAc/Hex=1:5) provided the
desired compound as an oil. ~H NMR {100 MHz> CDCI;) cS (ppm): 7.44 (m, 5H),
6.98
_g~_
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(d, I I-I), 6.90 (d, 2H), 6.7_5 (d, 21-I), 6.68 (d, 2H), 6.65 (d, IH), 6.63
(d, 2H), 5_51 (d,
J=2.3Hz, 1 H), 5.10 (s, 2H), 4.74 (brs, 1 H), 4_32 (d, J=2.31-lz, 1 H), 2.77
(dd, 2H), l .?2
(m, 3H), 1.08 (d, 18H), 1.1 (m, 31-I); MS mlz 6?8.5 (M~+1).
EXAMPLE 45
PREPARATION OF
PS IPS
OM
Utilizing the procedure from Example 44, the desired dihydrobenzoxathiin
without
MOM protection was isolated after purification by silica gel chromatography
with
10% EtOAclhexane. 1H NMR (400 MHz, CDC13) b (ppm): 7.2-G.98 (m, 4H), 6.85 (d,
2H), 6.78 (d, 2H), 6.66 (two d, 4H), 5.5 (d, J=2.2Hz, 1H}, 4.8 (s, 1H), 4.33
(d,
J=2.lHz, IH), 1.22 (m, 3H), 1.1 (d, 18H); MS mlz 515 (M~+23).
The other dihydrobenzooxathiin with MOM protection was also isolated. 1H NMR
(400 MHz, CDCI~) ~ (ppm): 7.2-6.6 (m, 8H), 6.78 (d, 2H), G.66 (d, 2H), 5.5 (d,
J=2.4Hz, 1H), 5.14 (s, 2H), 4.35 (d, J=2.lHz, 11-1), 3.48 (s, 3H), 1.22 (m,
3H), 1.1 (d,
18H).
EXAMPLE 4G
PREPARATION OF
OH
OMOM
_g3_
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Utilizing the procedure from Example 71 (Step C), the dihydrobenzoxafhiin
generated
From Example ~.5, was desilylated to give the product- ~H NMR 0100 MI-Iz,
CDCI~) ~
(ppm): 7.2-G.9G (m, ~1H), G.92 two d, ~1.H), G.82 (d, 2H), G.G (d, 2H}, 5,52
(d, J=2.2Hz,
1H), S.1G (s, 2H), ~..GB tbr s, 1H}, x,38 (d, J=2.2Hz, 1H}, 3.x.8 (s, 3H).
EXAMPLE 47
PREPARATION OF
'~" "~M OH
M OH
The ketone generated in Example 17 was conveated to the desired product
Following
the procedure described in Example X14 with the exception that 5 equivalents
of TFA
and 2 equivalents of EtsSiH was necessary to drive the reaction to completion.
The
MOM group was removed with mild acid treatment (2N-HCI, 75°C) to
give the
desired product. 'H NMR 0100 MHz, CDCl3) ~ (ppm): 7.0 (m, ~.H), G.85 (d, 2H),
6.G5 (d, 2H), 5.38 (s, 2H); MS mfz 313 (M++23}.
EXAMPLE 48
PREPARATION OF
~TIPS
Bn
H
The l:etone generated in Example 18 was converted to the dihydrobenzoxathiin
utilizing the procedure From Example ~1~I with the exception that 20
equivalents of
_$~_
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TI=~A and 15 equivalents of Et~SiH were necessary to drive the reaction to
completion.
The desired product was isolated aFter puriOication by silica gel
chromatography using
10%~ EIOAc/hexane as eluant. ~H NMR (~00 MHz, CDCI~} ~ (ppm): 7.5-7.34 {m,
5H), 7.08 (d, LH), 6.84 (d, 21-1), 6.76 (d, 21-I), 6.7 (dd, 1H), 6.67 (d, 1
H), 6.68 (two d,
4H), 5.5 (d, J=2.2Hz, 1H), 5.04 (br q, 2H), 4.68 (s, 1H), ~.3 (d, J=2.2I-lz,
1H), 1.22
(m, 3H), 1.1 (d, 18H); MS mlz 515 {M~+23).
EXAMPLE 49
PREPARATION OF
OMe
B
IO OTIPS
The ketone generated in Example 19 was converted to the dihydrobenzoxathiin
utilizing the procedure from Example 4~1 with the exception that the reaction
was run
at -10°C for A~8 hours in the presence of 20 equivalents of TFA and 2
equivalents of
Et~SiH. The desired product [with 20% recovered starting material] was
isolated after
purification by silica gel chromatography using 10% EtOAc/hexane as eluant. ~H
NMR (400 MHz, CDCl3) & (ppm): 7.5-7.3 (m, 5H), 7.1-6.6 (m, 11H), 5.54 (d,
T=l.9Hz, 1H), 5.06 (dd, 2H)> 4.32 (d, 1H), 3.74 (s, 3H), 1.22 (m, 3H), 1.1 (d,
18H).
EXAMPLE 50
PREPARATION OF
Me / OTIPS
/ S \
Bn0 \ O ~ \
OH
_85_
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Following the procedure outlined in Example 44 and using the 1<etone
derivative in
Example 20, the desired product was obtained after purification by silica gel
chromatography using S~l~ EtOAc/hexane as eluant. ~H NMR (400 MHz, CDCI~,) b
(ppm): 7.46-7.32 (m, 5H), 6.84 (d, 2H), 6.78 (d, 2H), 6.66 (two d, ~-H), 6.62
(d, LH),
6._57 (d, 1 H}, 5.3 (d, J=2,2Hz, 1 H), 4,35 (d, 1H), 2.28 (s, 3H), 1.22 (m,
3H), 1. L (d,
L8H).
EXAMPLE 51
PREPARATION OF
OTIPS
Bn
LO OH
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 21, the desired product was obtained after purification by silica gel
chromatography using 5°~c~ EtOAclhexane as eluant. 'H NMR (400 MHz,
CDC13) 8
(ppm): 7.5-7.3 (m, 5H), 6.98 (d, 1H), 6.9 (d, 1H), 6.76 (d, 2H}, 6.6 {m, 5H),
5.5~ (d,
J=2.2Hz, 1H), 5. J~ (s, 2H), 4.8 (s, LH), 4.32 (d, 1T~, 2.4 (s, 3H), 1.22 (m,
3H), 1.1 (d,
18H).
EXAMPLE 52
PREPARATION OF
Et IPS
Bn0 \
Following the procedure outlined in Example ~~ and using the ketone derivative
from
Example 22, the desired product was obtained after purification by silica pel
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chromatography using 5°l~ EtOAc/hexane as eluant. ~H NMR (400 MHz,
CDCI~) ~
(ppm): 7.5-7.3 (m> 5I-I), G.85 (d, 2H), G.78 (d> ?H), G.GG (m, 5H), G.SG (d,
1H). 5,x-8
(d, J=2.OHz> 1H), 5.0~- (br q, 2H), 4.74 (br s, 1 H), 4.34 (d, J-2.OHZ, 1 H),
2.G4 (q, 2H),
I .3 (t, 3H), I.2~ (m> 3H), t. l (d, 18f-I).
EXAMPLE 53
PREPARATION OF
OTIPS
Bn0
OH
Following the procedure outlined in Example ~~ and using the ketone derivative
From
Example 23, the desired product was obtained after purification by silica gel
chromatography using 5%a EtOAc/hexane as eluant. 1HNMR (400 MHz, CDCI~) 8
(ppm: 7.5-7.3 (m, 5H), G.98 (d, 1H), G.9 (d, 2H), G.74 (d, 2H), 6.7-G.6 {three
d, 5H),
5.5 (d, J=2.3Hz, 1H), 5.1 (s, 2H), 4.74 (br s, 1H), 4..32 (d, J-2.4Hz, 1H),
2.79 (m, 2H),
1.~? (m, 3H), 1.1 (d & t, 21H); MS m/z 628.5 (M++I).
EXAMPLE 54
PREPARATION OF
PS
Bn
?0
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 24, the desired product was obtained alter purification by silica gel
chromatography using 5% EtOAc/hexane as eluant. ~H NMR (400 MHz, CDCI~) 8
(ppm): 7.5r7,3 Vim, l OH), G.84 {d, ?H)> 6.78 (d, 2H), G.GG (two d, 4H), 6.38
(s> 2H),
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5.48 (d, J=2.1 H7a, 1 H), 5.14 (s, 2H), 5.0 (d, 2H), 4.76 (br s, l I-I), 4.32
(d, J=2.1 Hz,
1 H), I.?? (m, 3I-I), L1 (d, 18H).
EXAMPLE 55
PREPARATION OF'
Bn
IPS
Following the procedure outlined in Example 44 and using the ketone derivative
obtained from Example 25, the desired product was obtained after purification
by
silica gel chromatography using 5~/c. EtOAclhexane as eluant. ~H NMR {400 MHO,
CDCI,;) ~ (ppm): 7.5-7.32 (m, 5H), 7.2-7.1 (m, 4H), G.9-6.82 (m, ~-H), 6.76-
6.7 (m,
4H), 5.56 (d, 1H), 5.06 (br q, 2H), 4.36 {d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).
EXAMPLE 56
PREPARATION OF
Bn0 / S \
O
OTIPS
Following the procedure autlined in Example 44, with the exception that the
reaction
was run at 0'~C for three hours, and using 1.7g{2.83mmole) of the ketane
derivative
?0 obtained from Example 26, the desired product was obtained after
purification by
silica gel chromatography using 5~7o EtOAclhexane as eluant. ~H NMR (400 MHO,
CDC1;) S (ppm): 7.5-7.34 (m, 5H), 7.2-7.1 (m, 3H), 6.94 (d, 1H), 6.9-6.82 (m,
5H),
6.4 (m, 3H), 5.48 (d, J=1.9H~, 1H), 5.05 (s, 2H), 4.36 (d, J=l.9Hz, 1H), 1.22
(m, 3H),
1.1 (d, 18H).
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EXAMPLE 57
PREPARATION OF
F
S
Bn0 O
OH
Following fihe procedure outlined in Example ~~ and using the ketone
derivative
obtained from Example 27, the desired product was obfiained, which was
subseduenfily
desilylated using the procedure described in Example 71 (Step C). The desired
product was obtained as an oil after purification by silica gel chromatography
using
15ala EtOAc/hexane as eluant. 1H NMR (400 MHz, CDCl3) ~ (ppm): 7.5-7.32 (m,
5H), 7.09 (d, 1H), 6.9-6.8 (m, 6H), 6.73-6.7 (m, 4H), 5.52 (d, 1H), 5.04 (br
d, 2H),
4.34 (d, 1H), 1.22 (m, 3H), 1.1 (d, 18H).
EXAMPLE 58
PREPARATION OF
Bn0
OTIPS
Following fihe procedure oufilined in Example 44 and using the ketone
derivative from
Example 28, the desired product was obtained after purification by silica gel
chromatography using 5°l~ EfOAelhexane as eluanfi. ~H NMR (500 MHz,
CDCI,,) ~
(ppm): 7.5-7.3 (m, 5H), 7.22-7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.75 (d, 2H),
6.55 (d,
2H)> 5.55 (d, J=2.lPlz> LH), 5.05 (d, 2H), 4.40 (d, J=2. LHz> 1H), 1.22 (m>
3H), 1.1 (d,
18H).
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EXAMPLE 59
PREPARATION OI~
Bn
TIPS
Following the procedure outlined in Example ~~ and using the ketone derivative
from
Example 29, the desired product was obtained after purification by silica gel
chromatography using 5% EtOAclhexane as eluant. 'H NMR (500 MHz, CDC13} ~
{ppm): 7.S-7.3 (m, 5H), 7.22_7.10 (m, 3H), 6.90-6.80 (2d, 4H), 6.73 (d, 2H),
6.64 ~d,
2H), 5.50 {d, J=2.lHz, 1H), 5.05 (d, 2H), 4.43 (d, J=2.2Hz, 1H}, 1.23 (m, 31-
1), 1.10
(d, 18H).
EXAMPLE 60
PREPARATION OF
IPS
Bn0
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 30, the desired product was obtained after purification by silica gel
chromatography using S~lo EtOAc/hexane as eluant. ~H NMR {500 MHz, CDCI~} b
(ppm): 7.5-7.3 {m, 5H}, 6.82 {d, 2H), 6.G8 {d, 2H), 6.64 (d, 2H), 6.62 (d,
2H), 6,46 {d,
2H), 5.44 {d, J~l.9Hz, 1H), 5.02 ~d, 2H), 4.30 {d, J=2.0Hz, 1H}, 1.22 (m, 3H),
1.10
(d, 18H); MS m/z 618 (M++1).
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EXAMPLE 61
PREPARATION OF
"TIPS
Bn
H
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 31, the desired product was obtained after purification by silica gel
chromatography using 5% EtOAc/hexane as eluant. 1H NMR (400 MHz, CDC13) b
(ppm: 7.5-7.3 {m, 5H), 6.86 (d, 1H~, 6.82 {d, 2H), 6.76 {d, 2H), 6.70 {d, IH),
6.67(d,
2H), 6.65(d, 2H), 5.41 {d, J=2.OHz, 1H), 5.04 {s, 2H), 4.38 {d, J=l.9Hz, 1H),
1.23 {m,
31-I), 1.10 (d, 18H); MS m/z 634 (M~+I).
EXAMPLE 62
PREPARATION OF
PS
Bn0
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 32, the desired product was obtained after purification by silica gel
chromatography using 5~/n EtOAc/hexane as eluant. 'H NMR {500 MHz, CDCI;~) b
{ppm): 7.5-7.3 {m, 5H), 6.94 {d, LH), 6.85 {d, 2H), 6.80 {d, 2H), 6.74 (dd,
2H),
6.65{m, 4H), 5.43 (d, J=2. LHz, 1H), 5.05 (d, 2H), 4.30 (d, J=2.lHz, LH), I.23
{m,
3H), 1.10 (d, 18H).
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EXAMPLE 63
PREPARATION OF
IPS
M
Bn
Following the pracedure outlined in Exttmple 44 and using the ketone
derivative from
Example 33, the desired product was obtained after purification by silica gel
chromatography using 5°7o EtOAclhexane as eluant. ~H NMR (500 MHz,
CDC13) b
(ppm): 7.5-7.3 (m, 5H), 6.88 (s, 1H), 6.84 (d, 2H), 6.82 (d, 2H), 6.70 (d,
2H), 6.68 (d,
2H), 6.66 (s, 1H), 5.50 (d, 1H), 5.05 (s, 2H), 4.43 (d, 1H}, 2.35 (s, 3H),
1.23 (m, 3H),
1.10 (d, 18H).
EXAMPLE 64
PREPARATION OF
IPS
C
Bn
LS
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 34, the desired product was obtained after puriFication by silica gel
chromatography using 5°~o EtOAc/hexane as eluant. ~H NMR (500 MHz,
CDCI~) ~
(ppm): 7.5-7.3 (m, 5H), 7.24 (s, LH), 7.20 (s, lH), 6.82 (d, 2H), 6.68 (d,
2H), 6.64 (m,
4H), 5,44 (d, J=2.OHz, 1H), 5.05 (d, 2H), 4.28 (d, J=2.3Hz, IH), 1.23 (m, 3H),
1.10
(d, I8H).
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EXAMPLE 65
PREPARATION OF
Bn0 / S
~O
-0T1 PS
S
Following the procedure outlined in Example 44 and using the ketone deoivative
from
Example 35, the desired product was obtained after purification silica gel
chromatography using S% EtOAe/hexane as eluant. 'H NMR {500 MHz, CDCI~) 8
(ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, ~1H), 6.90 (d, 2H), 6.88 (d, 2H), 6,78
(d, 2H),
6.70 (d, 1H), 6.65 (d, 1H), 5.30 (d, J=l.BHz, 1H), 5.05 (d, 2H), 4.20 (d,
J=2.3Hz, 1H),
1.23 (m, 3H), 1.10 (d, 18H).
EXAMPLE 66
PREPARATION OF
B
OTIPS
Following the procedure outlined in Example 44 and using the ketane derivative
from
Example 36, the desired product was abtained after purification by silica gel
chromatography using 5% EtOAclhexane as eluant. 1H NMR X500 MHz, CDCI;~) ~
(ppm): 7.5-7.3 (m, 5H), 7.05-7.20 (m, 2H), 7.10 (m, 2H), 6.98 (d, 2H), 6.88
(m, 2H),
6.80 {m, 1H), 6.60 {d, LH), 5.56 (d, J=l.BHz, 1H), 5.05 (d, 2H), 4.~4. (d,
J=2.3Hz,
1H), 1.23 (m, 3H), 1.10 (d, 18H).
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EXAMPLE 67
PREPARATION OF
B
TIPS
Following the procedure outlined in Example 44 and using the ketone derivative
From
Example 37(1), the desired product was obtained after purification by silica
gel
chromatography using 5°la EtOAc/hexane as eluant. 1H NMR (500 MHz,
CDCI~) b
(ppm)_ 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.20 (d, LH), 7.15 {m, 3H),
6.88 (d,
2H), 6.84 (d, 3H), 6.78 (d, 2H), 5.46 (d, J=2.lHz, 1H), 5.15 (s, 2H), x.39 (d,
J=2.lHz,
1H), 1.23 {m, 3H), 1.10 (d, 18H).
EXAMPLE 68
PREPARATTO.N OF
Bn
TIPS
Following the procedure outlined in 44 and using the ketone derivative from
Example
37(TI), the desired product was obtained after purification by silica gel
chromatography using 5 to EtOAc/hexane as eluant. 'H NMR (500 MHz, CDCI~) 8
(ppm): 7.55 (d, 2H), 7.45 (t, 2H), 7.35 (t, 1H), 7.20 (d, 1H), 7.15 (t, 2H),
6.80-6.90
(m, 4H), 6.78 (d, 2H), 6.76 (d, 2H), 5.42 (d, J=2.~Hz, 1H), 5.18 (s, 2H),
~.~I2 (d,
J=2. lHz, 1 H), 1.23 (m, 3H), 1.10 (d, 18H).
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EXAMPLE G9
PREPARATION OF
Bn0
IPS
Following the procedure outlined in Example 44 and using the ketone derivative
from
Example 38, the desired product was obtained aFter purification by silica gel
chromatography using 5°Ic~ EtOAc/hexane as eluant. 'H NMR (500 MHz,
CDC1~) ~
(ppm}: 7.36-7.50 (m, 5H), 6.96 (d, 2H), 6.80-6.90 (m, 4H), 6.70-6.78 (m, 5H),
5.42
(d, J=2.lHz, 1H), 5.18 (s, 2H), 4.38 (d, J=2. LHz, 1H}, 1.23 (m, 3H}, 1.10 (d,
18H}.
EXAMPLE 70
CHIRAL SEPARAT10N OF
OTIPS
Bn0 / S
O
OH
Each enantiomer of the racemic dihydrobenzoxathiin, obtained from Example 62,
was
obtained via chiral chromatography using a Chiralpak AD column, with
30°lp
isopropanol in hexane as the eluant.
The fast moving isomer: [cc]o= +18.44°(c=0.725, MeOH).
The slow moving isomer: [ecJ~= -18.85°(c=0.74, MeOH}.
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EXAMPLE 71
GENERAL PREPARATION Oh TWINS
PREPARATION' OF
OH
S
Ho 0
i ~ N
0
sty
To a stirred solution of a mixture of dihydrobenzoxathiin (60mg, 0.1 mmole),
obtained from Example 48 (which was dried by the azeotropic method prior to
use),
triphenylphosphine {157mg, 0.6mmole), and 1-piperidlneethanol (0.08mL,
0.6mmole)
in 4mL of anhydrous THF at 0°C was added dropwise 0.118mL {0.6mmale)of
diisapropyl azodicarboxylate {DIAD) over 0.2 hours. The resulting pale yellow
solution was stin-ed at room temperature for 2-3 hours. The volatile
components were
remaved in vacuo and the residue puriFied by flash chromatagraphy
{EtOAclhexane=1:5, followed by 2-3% MeOH/dichloromethane) to give desired
product. jH NMR (400 MHO, CDC13) ~ (ppm): 7.5-7.34 (m, SH), 7.08 (d, LH), 6.86
{d, 2H), 6.78=6.64 (m, 8H), 5.5 (d> 1H), 5.01 {br q> 2H)> 4.3 (d> 1H)> 4.2 (t,
2H), 2.75
{t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1.48 (m, 2H), 1.22 {m, 3H), 1.1 (d,
18H); MS mlz~
712.4 {Nl~+1).
S te~B
To a stirred solution of the adduct {7lmg, 0.09$mmole), generated in Step A,
in 2mL
or' EtOH/EtOAcIH~O (7:2:1) was added l3mg ( 1.2eq) of palladium black and
ammonium formate (62mg, l0eq).The resulting mixture was heated at 80°C
and
monitored by TLC. After 3hours, the reaction mixture was cooled to room
temperature, Filtered thraugh a pad of Celite to remove the catalyst, and the
filtrate
was partitioned between water and EtOAc. The organic phase was separated,
dried
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over MgSO.~ and concentrated in vacuo to give desired product. ~H NMR (400 MI-
Iz,
CDCI~) c~ (ppm): 7.01 (d, I H), 6.8 (d, 2H), 6.75 (d, 2I-I), 6.66 (two d, 4I-
I), 6.54 (dd,
II-1), 6.5 (d, I I-I}, 5.45 (d, J=2.3Hz, LH), x.28 (d, J=2.3Hz, IH), d.08 (t,
2I-I), 2.8 (t,
2H), 2.6 (br s, 4H), 1.68 (m, 4H), 1.5 (m, ?I-I), 1.22 (m, 31-I), 1.1 (d,
18H).
_5
Step C
To a stin-ed solution of a mixture of the debenzylated product generated in
Step B and
HOAc (l0eq) in mL of THF was added a solution of tetrabutylammonium fluoride
(3eq) in Tl-IF at room temperature. The resulting solution was allowed to stir
for two
hours at room temperature and then poured into saturated aqueous NaHC03 and
extracted with EtOAc. The organic layer was washed with brine, dried over
MgSO~,
filtered, and evaporated. Purification by silica gel chromatography using 5-
7%p MeOH
in methylene chloride as eluant afforded the desired product. ~H NMR (400 MHz,
CD~OD) ~ (ppm): 6.95 (d, 2H), 6.92 (d, 1H), 6.78 (d, ZH), 6.71 (d, 2H), 6.48
(d, 2H),
6.47 (d, 1H), 6.44 (dd, 1H), 5.47 (d, J=2.lHz, 1H}, 4.37 (d, J=2.lHz, 1H), 4.1
(t, 2H),
2.85 (t, 2H), 2.65 (br s, 4H), 1.66 (m, 4H), 1.5 (m, 2H).
EXAMPLE 72
PREPARATION OF
H
N
Step A
Using the procedure described in Example 71 (Step A), the dihydrobenzoxathiin
?5 obtained from Example 53 was coupled with 1-piperidineethanol. After
purification
by silica gel chromatography, using 3% MeOHICH~CI~ as eluant, the desired
adduct
was obtained. ~H NMR (400 MHz, CDCI~) ~ (ppm): 6.98 (d, 1H), 6.92 (d, 2H),
6.74
(two d, 4H), 6.65 (d, IH), 6.62 (d, 2H), 5.5 (d, 1H), 5.1 (s, 2H), 4.31 (d, 1
H), 4.09 (m,
2H), 2.75 (t, 2H), 2.5_5 (m, 2H), 2.5 (m, 4H), 1.6 (m, 4H), 1.4_5 (m, 2H),
1.22 (m, 3H),
1.1 (m, 21H).
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PREPARATION OF
St_ en B
The adduct generated in Step A was debeW ylated using the procedure described
in
Example 71 (Step B) to give the desired product. ~H N'MR (x.00 MHz, CDCI~) c~
(ppm): 6.92 (d, 1 H), 6.89 (d, 21-1), 6.72 (d & d, 4H), 6.62 (d, 21-1), 6.5
(d, I H), 5.5 (d,
J=2.2 Hz, IH), ~..3 (d, J=?.2Hz, 1H), ~.1 (m, 2H), 2.8 {t, 2H), 2.68 (m, 2H),
2.58 (br s,
~H), 1.61 (m, ~1H), 1.18 (m, 2H), 1.2 (m, 3H), 1.09 {d & m, 21H).
Step C
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid. 'H
NMR
(d00 MHz, CD30D) ~ {ppm): 7.0 (d, 2H), 6.79 {d, 2H), 6.76 (d, 1H), 6.71 (d,
2H),
6.~7 (d, 3H), 5.~6 {d, J=2.2Hz, 1H), d.38 (d, 1H), X1.08 (t, 2H), 2.8 (t, 2H),
2.5 (m,
2H), 2.6 (m, 4H), 1.62 (m, ~H), 1.5 {m, 2H), 1.1 (t, 3H); MS m/z ~-93.2
(M~+I).
EXAMPLE 73
OH
S \
\ O \
O
Step A
The dihydrobenzoxathiin obtained from Example 45 was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chromatography using 3% MeOHICH~CI~ as eluant, the
desired adduct was obtained. jH NMR (400 MHz, CDC13) 8 {ppm): 7.14-6.92 (m,
4H}, 6.8 {d, ZH), 6.76 {d, 2H}, 6.72 (d, 2H), 6.64 (d, 2H), 5.48 (d, J-2.2Hz,
1H), ~.3A
{d, J=2.1 Hz, IH), 4.1 (m, 2H), 2.85 (m, 2H), 2.6 (m, ~H), 1.65 {m, ~.H), 1.5
(m, 2H),
1.22 (m, 3H), 1.1 (d, 18H).
S tee
The adduct from Step A was desilylated using the procedure described in
Example 71
{Step C}. The desired product was obtained as a white solid. 'H NMR 0400 MHz,
CD;OD) ~ (ppm): 7.1~-a6.92 (m,~-H), 6.06 (d, 2H), 6.78 (d, 21-1), 6,72 (d,
2H), 6.~fi8 (d,
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2H), 5.48 (d, J=2.1 Hz, 1 H), 4.44 (d, 1 I-I), 4. I (t. 2H), 2.78 (t, 2I-I),
2.58 (br s, 4H),
I.64 (m, 4I-I), 1.5 (m, 2H); MS m/z 450.2 (M~+1).
EXAMPLE 74
PREPARATIOL~I' OF
ON
~ N
O
Step A
The dihydrobenzoxathiin obtained from Example 46 was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chromatography with 3% MeOH/CHzCl2, the desired
adduct
was obtained as an oil. 'H NMR (400 MHz, CDCI~) ~ (ppm): 7.14-6.94 (m, 4H),
6.96
(d, 2H), 6.84 (two d, 4H), 6.66 (d, 2H), 5.5 (d, J=2.lHz, 1H), 5.12 (s, 2H),
4,5 (d,
J=2.lHz, 1H), 4.04 (t, 2H), 3.42 (s, 3H), 2.75 (t, 2H), 2.55 (br s, 4H), 1.6
Vim, 4H),
1.48 (m, 2H); MS mlz 495.2 (M'~+1).
Step B
The adduct (lOmg, 0.02 mmole) from Step A was deprotected with TFA (l0eq) and
MeOH (6eq) in CH~C12 at room temperature to afford the desired product. 'H NMR
(400 MHz, CD;OD) ~ (ppm): 7.14-6.92 (m, 4H), 6.84 (two d, 4H), 6.66 (d, 2H),
G.6
(d, 2H), 5.45 (d, J=2.2Hz, 1H), 4.45 (d, J=2.2Hz, 1H), 4.05 (t, 2H), 2.8 (i,
2H), 2.6 (br
s, 4H), 1.6 (m, 4H), 1.5 (m, 2H) ; MS m/z 450.2 (M'~+1).
EXAMPLE 75
PREPARATION OF
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OH
O \
O I \
~ N
O
The dioxane derivative obtained from Example 47 was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A) to give
the
product. ~HNMR (400 MHz, CD~OD) ~ (ppm): 7.04 (d, 2H), 6.98-G.84 (m, ~-H),
G.82 (d, 2I~, G,74 (d, 1H), G.G3 (d, 2I~, G.SG (d, ?H), 5.3G (d, 1H), 5.33 (d,
J=3,0Hz,
1H), 4.02 (m, ?H), 2.8 (m, 2H), 2.G (br s, 4H), 1.G2 (m, 4H), 1.5 (m, 2H); MS
mlz 43~?
(M+).
EXAMPLE 7G
PREPARAT10N OF
OMe
S
HO ~ O ~ \
~ N
O
Step A
The dihydrobenzoxathiin generated from Example d.9 was desilylated using the
procedure described in Example 7l (Step C). The desired product was obtained
as a
white solid. 'H NMR (400 MHz, CDCI~) ~ (ppm): 7.5-7.3 (m, 5H), 7.2 (d, 1H),
6.9
(d, 2H), 6.88 (d, 2H), 6.G8 (m, GH), 5.53 (d, J='?.2PIz, 1H), 4.33 (d,
J=?.3Hz, lH),
3.75 (s, 3H).
Std
The desilylated product abtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
chromatography with 3~Q MeOH/CH~CI~, the desired adduct was obtained. 'H NMR
(400 MHz, CDCI~) ~ (ppm): 7.57.3 (m, 5H), 7.08 td, LH), G,9 (d, 2H), 6.84 (d,
2H),
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6.76 (d, 2I-I), 6.66 (m, 4H), 5.52 (d, 1H), 5.03 (s, 2H), 4.32 (d, II-I), 4.06
(t, 2H), 3.75
(s, 3I-1), 2.75 (t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1_45 {m, 2I-I).
Step C,
The adduct generated in Step B was debenzylated using the procedure described
in
Example 71 (Step B) to give the product. ~H NMR {400 MHz, CD~OD) ~ {ppm):
6.96 (d, 2H), 6.92 (d, 1H), 6.82 {d, 2H), 6.78 {d, 2H), 6.63 (d, 2H), 6.48
(dd, 1H), 6.44
(d, 1H)> 5.S {d, J=2.2Hz, 1H), 4.42 (d, J=2.2Hz, 1H)> 4.08 (t, 2H), 3.68 (s,
3I~), 2.78
{t, 2H)> 2.59 (br s, 4H), 1.6 {m, 4H), 1.48 {m, 21~; MS mlz 479.4 {M~+1).
EXAMPLE 77
PREPARATION OF
Me
HO
N
Step A,
The dihydrobenzoxathiln obtained from Example 50 was coupled with 1-
piperidineethanol using the procedure described in Example 71 {Step A). After
purification by silica gel chromatography with 3% MeOHICH~CI~, the desired
adduct
was obtained. 'H NMR {400 MHz, CDCI;) ~ {ppm): 6.83 (d, 2H), 6.75 {d, 2H),
6.69
(d, 2H), 6.62 (d, 2H), 6.5 (d, 1H), 6.48 {d, 1H), 5.42 {br s, 1H), 4.3 (br s,
1H), 4,06 (t,
2H), 2.78 (t, 2H), 2.5 {br s, 4H), 1.6 {m, 4H), 1.44 (m, 2H), 1.22 {m, 3H),
1.1 (d,
l8H).
St_ ep B,
The adduct generated in Step A was debenzylated using the procedure described
in
Example 71 {Step B).
Step G
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid. ~H
NMR
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(400 MHz, CDw,OD) ~ (ppm): 6.94 (d, 2I-I), 6,76 {d, 2H), 6.7 (d, 2H), 6.49 (d,
2H), 6.4
(d, 1I-I), 6.32 (d, 1H), 5.43 (d, J=2.3I-I7, 11-I), ~..4 {d, J=2,3Hz, 1I-I),
4,08 (t, 2H}, 2.8 (t,
2H), 2.6 (br s, 4H), 2.18 (s, 3H), 1.64 (m, 4I-I), 1.5 (m, 2I-I); MS m/z 479,2
{M~+1).
_5 EXAMPLE 78
PREPARATION OF
H
N
St-ep A
The dihydrobenzoxathiin obtained from Example 51 was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A}. After
purification by silica gel chromatography with 3°~o MeOH/CH~C12, the
desired adduct
was obtained.
Step B
The adduct generated in Step A was debenzylated using the procedure described
in
Example 71 {Step B). After purification by silica gel chromatography using 5%
MeOHICH~CI~ as the eluant, the desired product was obtained as an oil. ~H NMR
(400 MHz, CDCI,;) 8 {ppm): 6.9 {d, ZH), 6.89 {d, 1H), 6.73 {m, 4H), 6.62 {d,
2H),
6.52 {d, 1H), 5.5 {d, 1H), 4.3 (d, LH), 4.1 {br s, 2H), 2.8 {br t, 2H), 2.6
{br s, 4H), 2.2
(s, 3H), 1.6 (m, 4H), L.5 {m, 2H), 1.22 {m, 3H), 1. L (d, 18H).
St_ePC,
The debenzylated product from Step B was desilylated using the procedure
described
in Example 7l (Step C). The desired product was obtained as a white solid. ~H
NMR
(400 MHz, CD~OD) ~ {ppm): 7.02 (d, 2H), 6.76 (d, 2H}, 6.7 {d, 2H), 6.47 {two
d,
3H), 5.48 {d, J=2.3Hz, I H), 4.38 (d, J=2.3Hz, 1H), ~. L (t, 2I-I), 2.8 {t,
2H), 2.6 {br s,
4H), 2.1 (s, 3H), 1.6 {m, 4H), L.5 {m, 2H); MS m/z 479.2 ~M*+I}.
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EXAMPLE 79
PREPARATION OF
S
HO ~ O
Et N
Step A
The dihydrobenzoxathiin obtained from Example 53 was coupled with 1-
piperidineethanol using the procedure described in Example 7I (Step A). After
purification by silica gel chromatography with 3%a MeOH/CH~CI~, the desired
adduct
LO was obtained.
Step B
The adduct generated in Step A was debenzylated using the procedure described
in
Example 71 (Step B).
Step G
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid
after
silical gel chromatagraphy with 5~/o MeOH/CH~C1~ as eluant. 'H NMR (400 MHz,
CD~OD) b (ppm): 6.94 (d> 2H)> 6.76 (d, 2H), 6.7 (2H, d)> 6.48 (d> 2H), 6.41
(d, 1H),
6.3 (d, 1H), 5.44 (d, J=2.2Hz> IH), 4.4 (d, J=2.2Hz, ~H)> 4.08 (t, 2H)> 2.8
(t, 2H), 2.62
(br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t, 3H); MS mlz 493.2
(M~+1).
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EXAMPLE 80
PREPARATION OF
OH
H
O~ N
St! ep A
The dihydrobenzoxathiin obtained from Example 54 was coupled with 1-
piperidineethanol using the pracedure described in Example 71 (Step A). After
purification by silica gel chromatagraphy with 3% MeOH/CH~CI~, the desired
adduct
was obtained. 1H NMR (400 MHz, CDC1~) b (ppm): 7.5-7.3 (m, 10H), 6.86 (d, 2h),
6.78 (d, 2H), 6.74 (d, 2H), 6.64 (d, 2H), 6.38 (s, 2H), 5.48 (d, 1H), 5.14 (s,
2H), 5.02
(q, 2H), 4.32 (d, 1H), ~-.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4I-
~, 1.5 (m,
2H), 1.22 (m, 3H), 1.1 (d, l8H).
Step B
The adduct generated in Step A was debenzylated using the procedure described
in
Example 71 (Step B). After purification by silica gel chromatography using 5%
MeOH/CHfCl2 as eluant, the desired product was obtained as an oil.
St_ ep C
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid.
~HNMR
(400 MHz, CD~OD) ~ (ppm): 6.94 (d, 2H), 6.78 (d, 2H), 6.72 (d, 2H), 6.5 (d,
2H),
6,06 (d, 1 H), 6.02 (d, 1H), 5.42 (d, J-2.?Hz, 1H), 4.33 (d, J=2.2Hz, IH),
4.09 (t, 2H),
2.8 (t, 2H), 2.6 (br s, 4H), 1.64 (m, 4H), 1.5 (m, 2H); MS m/z 48?.? (M'~+1).
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PREPARATION OF
EXAMPLE 81
S w
HO O
~ N
O
St-ep A
The dihydrobenzoxathiin generated from Example 55 was desilylated using the
procedure described in Example 71 {Step C). The desired product was obtained
as a
white solid. ~HNMR (400 MHz, CDCI~) ~ {ppm: 7.48-7.32 (m, 5H), 7.2-7.1 (m,
4H),
6.94-6.84 (two d, 4H), G.7 {m, 4H), 5.56 (d, J=2.lHz, 1H), 5.04 (br q, 2H),
4.74 (s,
1H), 4.37 (d, J=2.lHz, 1H).
Ste~B
The desilylated product obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
ehromatogl°aphy with 3%~ MeOH/CHZC12, the desired adduct was obtained.
~HNMR
(400 MHz, CDCI~) 8 (ppm): 7.5-7.32 (m, 5H), 7.2-7.04 (m, 4H), 6.94-6.86 (m,
4H),
6.76-6.66 (m, 4H), 5.54 {br s, 1H), 5.04 (br s, 2H), 4.38 {br s, 1H), 4.06 (t,
2H)> 2.76
(t, 2H), 2.5 (br s, 4H), 1.6 (m, 4H), 1..42 (m, 2H).
Step C
The adduct generated in Step B was debenzylated using the procedure described
in
Example 71 (Step B) to afford the desired product. 'H NMR (400 MHz, CD30D) 8
(ppm): 7.2-7.14 (m, 3H), 6.94 (m, 3H), 6.9 (d, 2H), 6.74 (d, 2H), 6.48 add,
1H), 6.45
{d, 1H), 5.53 (d, J=2,3Hz, 1H), 4.46 (d, 1H), 4.06 {t, 2H), 2.78 (t, ZH~, 2.58
(br s, 4H),
1.62 (m, 4H), 1.5 (m, 2H); MS m/z 449.2 (M~+1 ).
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E~CAMPLE 82
PREPARATION OF
H
Step A
i
O , S
O ~ ~ ~ N
O
The dihydrobenzoxathiin generated from Example SG was desilylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
white solid. ~H NMR {400 MHz, CDC13) 8 (ppm): 7.5-7.3 {m, SH), 7.2-7.1 {m,
3H),
G.9G {m, 2H), G.92 (d, 1H), G.88 {d, 2H), G.84 (d, 1H), 6.74 (dd, 1H), 6.66
(d, 2H),
5.48 (d, J=2.lHz, 1H~, 5.04 (s, 2H), 4.37 {d, J=2. LHz, 1H); MS m/z 428,2
{M++1).
Step B
The desilylated product obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
l5 chromatography with 3% MeOH/CH~C12, the desired adduct was obtained.
Step C
The adduct generated in Step B was debenzylated using the procedure described
in
Example 71 {Step B) to afford the desired product, 'H NMR {400 MHz, CD30D) 8
(ppm): 7.14-7.02 (m, 3H), 6.92 (m, 4H), G.8 {d, 1H), G.74 (d, 2H), G.58 (d,
1H), 6.51
{dd, 1H), 5.42 {br s, 1H), 4.45 {br s, 1H), 4.0G (t, 2H), 2.78 {t, 2H), 2.55
(br s, 4H), 1.6
{m, 4H), 1.5 {m, 2H); MS mlz 449.2 {M~+1).
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EXAMPLE 83
PREPARATION OF
/ OH
O \
\ \
O SAO
/ O~ N
Step A
To a well stilled solution of the dihydrobenzoxathiin (30mg, 0.061mmole)
prepared
from Example 74 (Step A) was added Sequivalents of meta-chloroperbenzoic acid
{m-
CPBA) in methylene chloride at 0°C. The ice bath was removed and the
reaction
mixture was stirred at room temperature for three hours. The reaction mixture
was
quenched with a saturated solution of NaHS03 and stic7-ed for additional 30
minutes.
The aqueous layer was extracted with EtOAe and the organic layer was washed
with
brine, dried with MgSO~, and evaporated to give a residue which was used for
next
step without further purification. 'H NMR {400 MHz, CD~OD) 8 (ppm): 7.82 (dd,
1H), 7.67 {dt, 1H), 7.28 {m, 2H), 7.2 {d, 2H), 7.03 {d, 2H), 6.92 (d, 2H),
6.82 (d, 2H),
6.32 (d, 1H), 5.12 (s, 2H), 4.84 (d, 1H), 4.2 (br t, 2H), 3.40 {s, 3H), 3.2
(m, 2H), 3.0
(m, 4H), 1.75 (m, 4H), 1.6 (m, 2H).
Ste ep B
The MOM protecting group was removed following the procedure outlined in
Example 74 (Step B). The desired product was isolated after purification by
silica gel
chromatography using 5°lo MeOH/CH-~Cl~ as the eluant. ~H NMR (400 MHz,
CD~OD) b {ppm): 7.82 {dd, 1H), 7.64 (dt, 1H), 7.'26 (m, 2H), 7.04 (d, 2H),
6.06 (d,
2H), 6.76 (d, 2H), 6.65 (d, 2H), 6.24 (d, J=l,9Hz, 1H), 4.71 (d, 1H), 4.1 (t,
2H), 2,72
(t, 2H), 2.5 (br s, 4H), I,G {m, ~H), 1.45 (m, 2H); MS mlz 481.1 (M~+1).
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EXAMPLE 8~
PREPARATION OF
OH
~ OAc
~N
°J
H
Step A
To a well stirred solution of the dihydrobenzoxathiin (60mg) prepared from
Example
73 (Step A) was added 5 equivalents of m-CPBA in CH~C12 at OQC. The ice bath
was
removed and the reaction mixture was stitTed at room temperature for 3 hours.
The
reaction mixture was quenched with a saturated solution of NaHS03 and
saturated
NaHCO~, and stirred for additional 30 minutes. The aqueous layer was extracted
with
EtOAc and the combined organic layer was washed with brine and dried with
MgSO~.
The solvent was removed by evaporation to give an oily residue, which was
purified
by silica gel chromatography with 3% MeOH/CH~CI~ as the eluant to give the
pure
product. ~H NMR 0100 MHz, CD~OD) 8 (ppm): 7.85 (dd, 1H), 7.66 (m, 1H), 7.28
(m, 2H), 7.12 (d, 2H), 6.86 (d, 2I~, 6.8 (d, 2H), 6.7 (d, 2H), 6.22 (d,
J=2.lHz, 1H),
4.72 (d, J=2.3Hz, IH), 4.08 (m, 2H), 2.8 (t, 2F~, 2.6 (br s, 4H), 1.6 (m, 4H),
1.5 (m,
2H), 1.22 (m, 3H), 1.J (d, 18H); MS mlz 637 (M~+23).
Step B
The silyl protecting group was removed following the procedure outlined in
Example
71 (Step C). The desired product was isolated after purification by silica gel
chromatography using 5% MeOH/CH~CI~ as the eluant. ~H NMR (400 MHz,
CD~OD) ~ (ppm): 7.81 (dd, IH), 7.64 (m, 1H), 7.35 (m, 2H), 7.2 (d, 2H), 6.82
(two d,
4H), 6.6 (d, 2H), 6.28 (d, J=2.2Hz, 1H), X1.69 (d, J=2.2Hz, IH), 4.2 (t, 2H),
3.08 (t,
2H), 2.85 (br s, ~H), 1.7 (m, ~IH), I.55 (m, 2H).
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EXAMPLE 85
PREPARATION' OF
OH
HO~O
/ n~ N
Step A
Utilizing the procedure from Example 83 (Step A), the dihydrobenzoxathiin
(20mg,
0.028 mmole) obtained from Example 71 (Step A), was oxidized by m-GPBA at roam
temperature. The crude material was used for next step without further
purification.
jH NMR (400 MHz, GDG1~} ~ tppm): 7.84 (d, 1H), 7.7-7.4 (m, 5H), 7,02 (d, 2H},
6.88 (dd, 1H), 6.82 (d, 2H), 6.76 (two d, 4H), 6.72 (d, 1H), 6.22 (d, J=2.2Hz,
1H),
5.18 (q, 2H), 4.28 (d, J=2.lHz, tH}, 4.09 (t, 2H), 2.8 (t, 2H), 2.55 (br s,
4H), 1.63 (m,
4H), 1.48 (m, 2H), 1.22 (m, 3H), 1.1 (d, 18H).
Step B
The product from Step A was deblocked using the standard procedure described
in
Example 71 (Step B) to afford the debenzylated product, which was used without
fuuther purification.
S t
The silyl protecting group was removed following the procedure outlined in
Example
71 (Step C). The final product was isolated after purification by silica gel
chromatography using 5% MeOH/GH~CI~ as the eluant. 1H NMR (400 MHz,
GD~OD} 8 (ppm): 7.62 (d, 1H), 7.14 (d, 2H), 6.84 (two d, 4H), 6.68 (dd, I H),
6.6 (d,
2H), 6.55 (d, 1H), 6.22 (d, tH), 4.55 (d, J=2,IHz, 1H), 4.1 (t, 2H), 2.8 (t,
2H), 2.6 (br
s, 4H), 1.64 (M, 4H), 1.5 (M, 2H); MS mlz 496. I (M++I).
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EXAMPLE 86
PREPARATION OF
~ N
H
Step A
To a solution of dihydrobenzoxathiin (100mg, 0. I67 mmole) generated from
Example
48 in CHZCI~ was added triethylamine (0.07mL), a catalytic amount of N,N-
dimethylaminopyridine (DMAP) and acetic anhydride (0.034mL, 2eq) at room
temper°ature. The ~°esultant mixture was stirred For 30 minutes
and then poured into
saturated NaHC03. The aqueous layer was extracted with CHZCIZ and then dried
over
anhydrous Na~SO~. The solvent was evaporated to give an oil, which was
subjected
to silica gel chromatography with 10% EtOAclhexane as eluant to give the
product.
IH NMR {400 MHz, CDC13) b (ppm): 7.48-7.34 (m, 5H), 7.08 (d, 1H), 6.99 {d,
2H),
6.94 (d, 2H), 6.76 (d, 2H), 6.72-6.67 (m, 4H), 5.56 (d, 1H), 5.06 (br q, 2H),
4.34 (d,
1H), 2.3 (d, 3H), 1.22 (m, 3H), ~.l (d, 18 H).
Step B
The silyl protecting group was removed following the procedure outlined in
Example
71 (Step C). The desired product was isolated after purification by silica gel
chromatography using 5~1o MeOH/CH~CI~ as the eluant. ~H NMR (400 MHz, CDC1;)
8 (ppm): 7.48-7.34 (m, 5H), 7.09 (d, 1H), 7.04 ~d, 2H), 6.98 (d, 2H), 6.78 (d,
2H), 6.7
{m, 2H), 6.59 (d, 2~, 5.56 (d, 1H), 5.06 (br q, 2H), 4.74 (s, LH), 4.36 (d, 1
H), 2.2 (s,
3H).
Sto ~~C
The desilylated product (80mg, 0.165mmole) obtained from Step B was coupled
with
1-piperidineethanal using the procedure described in Example 71 (Step A).
After
purification by silica gel chromatography with 3°la MeOH/CH~C1~, the
desired adduct
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was obtained. ~ H NMR (400 MHz, CDCI~) b (ppm): 7.48-7.34 {m, 5H), 7.08 {d, 1
H),
7.04 {d, 2H), G,98 (d, 2I-I), G.82 (ci, 2I-I), G.7 (dd, 11-1), 6.G8 (d, l I-
I), G.GB (d, 2H), 5.58
{d, J=2.2Hz, I H), 5.05 {br d, 2H), 4.3G (d, J=2.2Hz, 1 H), 4.05 (t, 2H), 2.G8
(t, 2H), 2.5
(br s, 4H), 2.25 (s, 3H), I.G (m, 4H), 1.45 (m, 2H); MS m/z 597,3 (M~+l.
Step D
To a solution of IOmg (O.Ol7mmole) of the adduct, generated from Step, in
anhydrous
TELF was added Four equivalents of a I.OM Super hydride solution in THF. The
resulting mixture was stirred For 2 hours at 0°C and then allowed to
room temperature
(30 minutes). The reaction mixture was hydi°olyzed with H~OINaHCO;. The
aqueous
layer was extracted with EtOAc, the organic layer separated, dried, and
evaporated to
give an oil, which was used for next step withaut further purification.
Step E
IS The crude product From Step D was deblocked using the standard procedure
described
in Example 71 (Step B) to aFford the final product, alter puriFication by
silica gel
chromatography using 5% MeOHICH~CI~ as the eluant. 1H NMR (400 MHz,
CD~OD) 8 (ppm): G.92 {d, IH), G.83 (d, 2H), G.82 (d, 2H), 6.G5 (d, 2H), 6.58
(d, 2H),
G.4G (dd, IH), 6.42 (d, 1H), 5.44 {d, J=2.IHz, IH), 4.38 (d, IH, J=2.3Hz, 1H),
4.04 {t,
2H), 2.78 (t, 2H), 2.G (br s, 4H), I.G (m, 4H), 1.5 {m, 2H); MS m/z 4G5
(M~+1).
EXAMPLE 87
PREPARATION OF
r
S
O O I / ~ N
I JO
St_ ep A
The desilylated product obtained from Example 57 was coupled with l~
pieridineethanol using the procedure described in Example 7I (Step A). AFter
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puriFication by silica gel chromatography with 3% MeOH/CH~CI~, the desired
adduct
was obtained.
St. ep B
The adduct generated in Step A was debenzylated using the procedure described
in
Example 7 L (Step B) to aFFord the desired product. ~ H NMR 0100 MHz, CD~OD) ~
(ppm): 6.98-G.7G (m, 9H)> G.5 (dd, IH), 6.4G (d, 1H), 5.52 (d, J=2.3Hz, 1H),
d..5 (d,
LH), 1,05 {t, 2H), 2.80 (t, 2H), 2.G2 (br s, ~H), L.G2 (m, ~.H), 1.5 (m, 2H)>
MS m/z
4GG.2 (M'~).
EXAMPLE 8 8
CHIRAL SEPARATION OF
The racemic dihydrobenzoxathiin obtained From Example 81 (Step C) was resolved
via chiral chromatography on a Chiralpak AD column, using 20% EtOH in hexane
as
the eluant. The Fast moving isomer: [cx]D=+33.43°(c=L.205, MeOH).
The slow moving isomer: [a]D=-3~.2°(c=1.09, MeOH).
EXAMPLE 89
CHTRAL SEPARATION OF
HO
N
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The racemie dihydrobenzoxathiin obtained from Example 82 (Step C} was resolved
via chiral chromatography on a Chiralpalc AD column, using ?0"/~ EtOH in
hexane as
the eluant. The fast moving isomer: [cxJ,~=+32.4"(c=1.36, MeOH).
The slow moving isomer: [ccJ,~= -31.3°(c=1.37, MeOH).
EXAMPLE 90
PREPARATION OF
H
~~ N
The dihydrobenzoxathiin generated from Example 58 was desilylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
white solid. 'H NMR (500 MHz, CDC13) b (ppm): 7.5-7.3 (m, SH), 7.2-7.1 (m,
3H),
6.85 (2d, 4H), 6.68 (d, 2H), 6.55 (d, 2H), 5.55 (d, 1H), 5.04 (s, 2H), 4.40(d,
1H}.
Step B
The desilylated product obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
chromatography with 3%a MeOH/CH~C1~, the desired adduct was obtained.
Step C
A mixture of the adduct {80mg, O.l44mmole), generated in Step B, 20 mg of
palladium black and 5 drops of AcOH in 4 mL of ethanol, was stirred under a
balloon
of hydrogen gas and monitored by TLC. After 18 hours, the reaction mixture was
filtered through a pad of Celite to remove the catalyst, and the filtrate was
neutralized
by the addition of saturated, aqueous NaHCO~ solution and extracted by EtOAc.
The
organic layer was separated, dried over MgSO~ and concentrated in vacuo to
give the
desired product. ~H NMR (500 MHz, CD~OD) ~ (ppm): 7.20-7.02 (m, 3H), 6.92 (m,
4H), 6.78 (d, 2H), 6.30 (d, 2H), 5.55 (d, J=2.lHz, 1H}, 4.50(d, J=2.3Hz, IH},
4.06 (t,
2H), 2.78 (t, ?H), 2.55 (br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H}; MS mlz 467
(M~+1).
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EXAMPLE 91
PREPARATION OF
H
~N
St_ ep A
The dihydrobenzoxathiin generated from Example 59 was desllylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
white solid. 'H NMR (500 MHz, CDC13} 8 (ppm): 7.5-7.3 (m, SH), 7.2-7.1 (m,
3H),
6.95 (d, 2H), 6.90 (d, 1H), 6.85 (d, 2H)> 6.70 (d, 2H}, 6.65 (d, LH), 5.50 (d,
1H), 5.04
(s, 2~I~, 4.4? (d, 1H).
St_ ep B
The desilylated praduct obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
chromatography with 3% MeOHICH~CIz, the desired adduct was obtained.
St_ eP C
The adduct, generated in Step B, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD_;OD) b
(ppm): 7.1~1~7.02 (m, 3H}, 6.92 (d, 2H}, 6.85 (d, 2H), 6.74 (d, 2H}, 6.58 (d,
1~, 6.41
(d, LH), S.S2 (d, J-2.3Hz, 1H), 4.55 (d, J=2.3Hz, 1H), 4.06 (t, 2H}, 2.78 (t,
2H), ?.55
~br s, 4H), 1.6 (m, 4H), 1.5 (m, 2H); MS mlz 483 (M~+1}.
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EXAMPLE 92
PREPARATION OF
/ ~ r-i
/ S \
O \ O I \
/ ~ N
O
Step A
The dihydrobenzoxathiin, obtained from Example 60, was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chramatography with 3% MeOH/CHaCl2 the desired
adduct
was obtained. ~H NMR (500 MHz, CDCI~) ~ (ppm): 7.5-7.3 (m, 5H), 6.80 {d, 2H),
6.70 {2d, 4H), 6.60 (d, 2H), 6.40 (2d, 2H), 5.40 {s, 1H), 4.90 (d, 2H), 4.20
(s, 1H),
4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 (m, 4H), 1.5 (m, ZH), 1.22 {m,
3H), 1.1
(d, 18H).
Step B
The adduct, generated in Step A, was debenzylated using the procedure
described in
Example 71 (Step B).
Step G
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid. 'H
NMR
{500 MHz, CD,,OD) 8 (ppm): 6.93 (d, 3H), 6.78 (d, 2H), 6.69 (d, 2H), 6.50 {d,
2H),
6.28 {m, 1H), _5.46 (d, J=l.BHz, 1H), 4.39 (d, J=2.2Hz, 1H), 4.05 (t, 2H), 2.8
{t, 2H),
2.6 {br s, 4H), 1.64 (m, 4H), 1.5 {m, 2H); MS m/z 482.2 (M++1).
1 1 S --
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EXAMPLE 93
PREPARATLON O F
CI / vh
s
o ~ o
i
0
St_ ep A
The dihydrobenzoxathiin, obtained from Example 61, was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chromatography with 3°/a MeOH/CHzCl2 the
desired adduct
was obtained. ~H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, 5H), 6.85 (m, 3H),
6.70 (d, 4H), 6.63 (d, 2H), 6.60 (d, 1H), 5.42 (s, llTj, 5.02 {d, 2H), 4.40
(s, 1H), 4.08
(t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.62 {m, 4H), 1.5 (m, 2H), 1.22 (m, 3H),
1.1 {d,
18H).
Ste~B
The adduct, generated in Step A, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. 'H ~NMR (500 MHz, CD30D) 8
(ppm): 6.82 (d, 2H), 6.78 (d, H), 6.70 {2d, 4H), 6.62 {d, 2H), 6.58 {d, 1H),
5.40 (d,
1H), 4.30 (d, 1H), 4.06 (t, 2H), 2.78 (t, 2H), 2.55 (br s, 4H), 1.6 (m, 4H),
1.5 (m, 2H);
MS mlz 655 (M++1).
Step C
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid. jH
NMR
(500 MHz, CD~OD) 8 (ppm): 6.92 (d, 2H), 6.75 (d, 2H), 6.68(d, 2H), 6.60 (d, 1
H),
6.50 (d, 2H), 6.42(d, 1 H), 5.42 {d, J-2.2Hz, 1H), 4.42 (d, J-2.3Hz, LH), 4.07
{t, 2H),
2.78 {t, 2H), 2.55 (brs, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS mlz 499 {M++1).
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EXAMPLE 94
PREPARATION OF"
OH
H
~ N
O
s
step A
The dihydrobenzoxathiin, obtained from Example 62, was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chromatagraphy with 3~1o MeOH/CHzCI~ the desired
adduct
was obtained.
Ste ~~B
The adduct, generated in Step A, was debenzylated using the procedure
described in
Example 71 (Step B).
Step C
The debenzylated product from Step B was desilylated using the pracedure
described
in Example 71 (Step C). The desired product was obtained as a white solid
after
purification by silica gel chromatography with S% MeOH/CH~C1~ as eluant. 'H
NMR
(500 MHz, acetone-d~) ~ {ppm): 7.04 (d, 2H), 6.90 (dd, 3H), 6.72 (d, 2H), 6.64
{d,
1H), 6.59 (d, 2H), 6.57(dd, 1H), 5.44 (d, J=2.3Hz, 1H), 4.52 (d, J-2.lHz, 1H),
4.08 (t,
2H), 2.8 {t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2
{t, 2H);
MS mlz 465 (M~+1).
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EXAMPLE 95
PREPARATLON OI~
Me /
NO
N
St_ ep A
The dihydrobenzoxathiin, obtained from Example 63, was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chromatography with 3%n MeOH/CH~C1~ the desired
adduct
was obtained.
Step B
The adduct, generated in Step A, was debenzylated using the procedure
described in
Example 71 {Step B).
Step C:
The debenzylated product from Step B was desilylated using the procedure
described
3n Example 71 (Step C). The desired product was obtained as a white solid
after
purification by silica gel chromatography with 5% MeOH/CH~CI~ as eluant. ~H
NMR
(500 MHz, acetone-dG) ~ (ppm): 7.00 (d, 2H), 6.85 (s, LH), 6.80 (d, 2H), 6.78
(d, 2H),
6.59 (d, 2H), 6.52 (s, LH), 5.49 (d, J=2.3Hz, LH), 4.65(d, J=2.2Hz, LH), 4.08
(t, 2H),
2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, 4H), 1.45 (m, 2H), 1.2 (t,
2H); MS
m/z 479 (M~+1).
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EXAMPLE 9G
PR1JPARATION OF
CI
HO
N
Ste~A
The dihydrobenzoxathiin, obtained from Example G4, was coupled with 1-
piperidineethanol using the procedure described in Example 71 (Step A). After
purification by silica gel chromatography with 3~1o MeOH/CH~CI~ the desired
adduct
was obtained. 'H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, 5H), 7.20 (s, 1H),
G.85 {d, 2H), 6.70 (2d, 4H}, G.G3 (d, 2H), G.GO (s, IH), 5.42 {s, 1H), 5.02
{q, 2H}, 4.30
(s, 1H), 4.08 (t, 2H), 2.8 (t, 2H), 2.5 (br s, 4H), 1.G2 (m, d-H), 1.5 (m,
2H), 1.22 {m,
3H), 1.1 (d, 18H).
Step B
The adduct, generated in Step A, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. IH NMR (500 MHz, acetone-
d~) ~
(ppm): 7.10 (s, LH), 6.98 (d, 2H), 6.82 {d, 2H), G.78 (d, 2H), G.70 {d, 2H),
6.G8 (s,
1H), 5.50 (d, 1H), 4.50 (d, 1H}, 4.0G (t, 2H}, 2.78 (t, 2H}, 2.55 (br s, 4H),
1.6 {m, 4H),
1.5 (m, 2H).
Step_C
The debenzylated product fram Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid. 'H
NMR
(500 MHz, acetone-d~} 8 (ppm): 7.12 (s, 1H), 7.02 (d, 2H}, G.80 (dd, 4H), 6.69
{s,
1H), 6.G0 {d, 2H}, G.42 (d, 1H), 5.55 (d, J=2.3Hz, 1H), d.54 (d, J=2. I Hz,
1H}, 4.07 (t,
2H}, 2.78 (t, 2H), 2.55 (brs, 4H), 1.62 (m, 4H), 1.48 (m, 2H); MS m/z 499
(M~+I ).
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EXAMPLE 97
PREPARATION O1~
H
St- ep A
O , S
O ~ ~ ~ N
O
The dihydrobenzoxathiin generated from Example 65 was desilylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
white salid. 'H NMR (500 MHz, CDC13) 8 (ppm): 7.5-7.3 (m, SH), 7.2-7.1 (m,
5H),
6.95 (m, 3H), 6.64-6.7D (m, 2H), 5.46 (d, 3=l.8Hz, 1H), 5.04 (s, 2H), 4.42 (d,
J=2.OHz, 1H).
Step $
The desilylated pi°oduct obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 7l (Step A). After purification by
silica gel
chromatography with 3% MeOHlCH2C12, the desired adduct was obtained.
St_ ep C
The adduct, generated in Step B, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. 'H NMR (SOD MHz, CD~OD) b
(ppm: 7.00-7.12 (m, 6H), 6.90 (d, 2H), 6.75 (d, 2H), 6.42 (s, 1H), 5.42 (d,
J=2.lHz,
IH), 4.48 (d, J=2.3Hz, 1H), 4.06 (t, 2H), 2.7$ (t, 2H), 2.55 (br s, 4H), 1.6
(m, 4H), 1.5
(m, 2H); MS m/z 463 (M~+1).
12D _
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EXAMPLE 98
PREPARAT10N OF
HO , S
O
C I I / ~ N
O
Step A
The dihydrobenzoxathiin generated from Example 66 was desilylated using the
procedure described in Example 71 {Step C). The desired product was obtained
as a
white solid. 'H NMR {500 MHz, CDC13) ~ {ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m,
3H),
6.95 {d, 2H), 6.92 {d, 2H), 6.90 {d, 1H), 6.78 {d, 1H), 6.70 {d, 2H), 5.52 (d,
J-2.lHz,
1H), 5.04 {s, 2H), 4.46 {d, J=2.2Hz, 1H).
Step B
The desilylated product obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). At'ter purification by
silica gel
chromatography with 3% MeOH/CH?C1~, the desired adduct was obtained.
S t~e~C
The adduct, generated in Step B, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. 'H NMR (S00 MHz, CD~OD) 8
{ppm): 7.05-7.15 {m, 5H), 6.90 {d, 2H), 6.79 (d, 2H), 6.65 {d, 1H}, 6.55 ~d,
1H), 5.50
(d, J=2.lHz, 1 H), 4.62 {d, J=2.3Hz, 1 H}, 4.10 (t, 2H), 2.80 (t, 2H}, 2.60
{br s, 4H), 1.6
{m, 4H), 1.5 {m, 2H); MS m/z 483 {M++1 ).
_1~1_
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EXAMP>fE 99
PREPARATION OF
H
C
~~ N
Ste~A
The dihydrobenzoxathiin generated from Example G7 was desilylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
LO white solid. 'H NMR (500 MHz, CDCI~) c~ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m,
3H)>
7.08 (s, 1H~, 6.95 (d, ZH), 6.8G (m, 3H), 6.70 (d, ZH), 5.42 (d, J=Z.IHz, 1H),
5.14 (s,
2H), d.40 (d, J=2.OHz, 1H).
Step B
The desilylated product obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
chromatography with 3~1o MeOHlCH2C12, the desired adduct was obtained.
Std
The adduct, generated in Step B, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD~OD) 8
(ppm): 7.05-7.15 (m, 3H), 6.95 (m, 3H), 6.90 (d, ZH), 6.75 (d, ZH), 6.72 {s,
LH), 5.45
(d, J=Z.OHz, 1H), 4.52 (d, J=2.3Hz, 1H), x.10 (t, ZH), 2.80 (fi, 2H), 2.60 (br
s, 4H), 1.6
(m, ~LH), 1.5 (m, ZH); MS mlz 483 (M++1).
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EXAMPLE 100
PREPARATION OF
CI
HO
N
St__ ep A
The dihydrobenzoxathiin generated from Example G8 was desilylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
white solid. ~HNMR (500 MHz, CDC13) ~ (ppm): 7.5-7.3 (m, 5H), 7.2-7.1 (m, 3H),
G.92-6.80 (m, SIB, G.78 (d, 2H), 6.70 (d, 2H), 5.40 (d, J=2.lHz, 1H), 5.20 (s,
ZH),
4.4G (d, J=2.0Hz, 1H).
Step B
The desilylated product obtained from Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
chromatography with 3% MeOH/CHzCl2, the desired adduct was obtained.
St. ep C
The adduct, generated in Step B, was debenzylated using the procedure
described in
71 (Step B) to afford the desired product. 'H NMR (500 MHz, CD30D) 8 (ppm):
7.05-7.15 (m, 3H), G.95 (d, 2H), 6.90 (d, 2H), G.80 (d, 1H), 6.75 (d, 2H),
G.70 (d, 1H),
5.38 (d, J=l.BHz, lH), 4.5G (d, J=2. LHz, 1H), 4,06 (t, 2H), 2.78 (t, 2H),
2.G0 (br s,
4H), 1.6 (m, 4H), 1.5 (m, 2H); MS mlz 483 (M~+1).
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EXAMPLE 101
Cl-IIRAL SEPARATION OF
CI
HO
O~ N
The racemic dihydrobenzoxathiin obtained from Example 100 (Step C) was
resalved
via chiral chromatography on a Chiralpak AD calumn, using 20~/o EtOH in hexane
as
the eluant. The fast moving isomer: [ec]D= +26.09°(e=1.025, MeOH).
The slaw moving isomer: [oc]p= -25.44°(c=0.95, MeOH).
EXAMPLE IO?
PREPARATION OF
H
r
O / S
O
O
Step A
The dihydrobenzoxathiin generated from Example 69 was desilylated using the
procedure described in Example 71 (Step C). The desired product was obtained
as a
white solid. ~H NMR (500 MHz, CDCI~) ~ (ppm): 7.5-7.3 (m, 5H), 6.95 (d, 2H),
6.90(m, 3H), 6.85 (m, 3H), 6.74 (dd, 1H), 6.70 (d, 2H), 5.45 (d, J=l.9Hz, LH),
5.05 {s,
2H), 4.35 (d, J-?.lHz, III.
I2~
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St_ ep B
The desilylated product obtained From Step A was coupled with 1-
piperidineethanol
using the procedure described in Example 71 (Step A). After purification by
silica gel
chromatography with 3~1a MeOH/CH~C1~, the desired adduct was obtained, which
was
used without Fuuher puriFication.
Step C
The adduct, generated in Step B, was debenzylated using the procedure
described in
Example 71 (Step B) to afford the desired product. ~H NMR {500 MHz, CD;OD) 8
(ppm): 6.98 {d, ZH), 6,94 (m, ZH), 6.80 (m, 5H), 6.60 (d, 1H), 6.75 (dd, 1H),
5.40 (d,
J=l.BHz, 1H), 4.50 {d, J=Z.lHz, 1H), 4.08 (t, ZH), 2.78 (t, ZH), 2.60 (br s,
~H), 1,6
{m, 4.H), 1.5 (m, ZH); MS mlz 466 (M~+1).
EXAMPLE 103
CHIRAL PREPARAT10N OF
/ OH
HO / S
\ O ,,,.~ \
/ O~ N
(+) isomer
St_ e~A
The Fast moving {+)-dihydrobenzoxathiin obtained From Example 70 was coupled
with 1-piperidlneethanol using the procedure described in Example 71 {Step A).
After
purification by silica gel chromatography with 3~1~ MeOHICH~CIz, the desired
adduct
was obtained.
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St~P B
The adduct, generated in Step A, was deben~ylnted using the procedure
described in
Example 71 (Step B).
Step C
The debenzylated product From Step B was desilylated using the procedure
described
in Example 71 (Step C). The desired product was obtained as a white solid
aFter
purification by silica gel chromatography with 5%p MeOH/CH~CI~ as eluant. 'H
NMR
(500 MHz, acetone-d~) 8 (ppm): 6.90 (d, 2H), 6.78 (d, 1H), 6.72 (d, 2H), 6.70
(d, 2H),
6.60 (d, 1H), 6.50 (d, 1H), 6.x.8 (d, 2H), 5.38 (d, J=2.OHz, 1H), 4.38 (d,
J=2.3Hz, 1H),
4-.08 (t, 2H), 2.8 (t, 2H), 2.62 (br s, 4H), 2.6 (q, 2H), 1.6 (m, ~.H), 1.45
(m, 2H), 1.2 (t,
2H); MS mlz X65 (M++1); [cc]p= +27.68°(c=0.~9, MeOH).
EXAMPLE 10~
CHTRAL PREPARATION OF
H
HO / S
O
~N
(-) isom~x
St-- ep A
The slow moving (-)-dihydrobenzoxathiin obtained From Example 70 was coupled
with 1-piperidineethanol using the procedure described in Example 71 (Step A).
AFter
purification by silica gel chromatography with 3~/o MeOHICH~CIZ, the desired
adduct
was obtained.
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St-ep B
The adduct, generated in Step A, was debenzylated using the procedure
described in
Example 71 {Step B).
_5
Step C
The debenzylated product from Step B was desilylated using the procedure
described
in Example 71 {Step C). The desfired product was obtained as a white solid
after
purification by silica gel chromatography with 5% MeOH/CH~CI~ as eluant. 1H
NMR
{500 MHz, acetone-d~} ~ {ppm}: 6.90 {d, 2H), 6.78 {d, 1H}, 6.72 {d, 2H), 6.70
(d, 2H),
6.60 {d, 1H), 6.50 {d, 1H), 6.48 {d, 2H}, 5.38 {d, J=2.OHz, IH), 4.38 {d,
J=2.3Hz, IH),
4.08 (t, 2H), 2.8 {t, 2H), 2.62 {br s, 4H}, 2.6 {q, 2H), 1.6 {m, 4H), 1.45 {m,
2H), 1.2 {t,
2H); MS mlz 4G5 {M~+I); [cx)D= -26.33°{c=0.515, MeOH).
EXAMPLE 105
GENERAL PREPARATION OF
HO ~ S
O
-~. NJ
O
Step A: Reductive Cyelization
To a stirred solution of I02.2mg (0.17mmole) of the cyclopentyl-thio-ketone
generated in Example 41 in 1mL of dichloromethane at ~-23°C under an N
atmosphere was added 681,~L {0.087mmole) of neat trifluoroaeetic acid{TFA). To
the
stirred reaction mixture at-23°C was slowly added 41.4~,L {0.259mmale)
of neat
triethylsilane and the resulting mixture was stirred further far three hours.
The
reaction mixture was partitioned between ethyl acetate/saturated NaHCO~/ice/
brine,
and the organic phase was separated, washed with brine, dried over anhydrous
sadium
sulfate, filtered, and evaporated. The residue was purified by silica gel
chromatography using methylene chloride/hexanes{ 1:1) as eluant to provide the
ci,s-
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cyclopentyl-dihydrobenzoaxathiin derivative. ~F-I 500MHz NMR(CDCI~)
ppm{b):1.12 (d, I 8H), 1.26-2.12 {m, 12H). 2.5 (m, 1 H), 4.24 {d, 1 H), 4.9
(m, 2H),
6.8-7.69 (m, 12I-I).
Starting with the cyclohexyl derivative prepared in Example 41 and utilizing
the
above procedure the con-esponding cis-cyclohexyl-benzooxathiin was prepared
after
purification by silica gel chromatography using methylene chloride-
hexanes(1:1). 'H
500MHz NMR(CDCI~) ppm{~): 1.14 (d, 18H), 1.11-1.9 (m, 14H), 3.2 (t, 1H), 5.03
(s,
2H), 5.44 (d, J=2.5Hz, 1H), 6.66-7.47 (m, 12H).
Step B: Desilylation
To a stirred solution of 89.6mg (0.156mmole) of the cis-cyclopentyl derivative
prepared in Step A above in 1mL of THF at 0 °C was added sequentially
13.31.~L
(0.234mmole) of acetic acid and then 1711uL (0.171mmole) of a 1M solution of
tetrabutylammonium Fluoride in THF. The mixture was sowed at 0 °C For
0.5 hour and
then partitioned between ethyl acetatel2N HC1/lce/brine, and the organic phase
was
separated, washed with brine, dried over anhydrous sodium sulFate, filtered,
and
evaporated. The residue was puriFied by silica gel chromatography using
methylene
chloride-ethyl acetate (50:1) as eluant to provide the phenolic derivative. ~H
500MHz
NMR(CDGI~) ppm(b):1.32-1.94 (m, 9H), 3.51 (dd, J=5.5, 2.5Hz, 11~, 5.03 (s,
2H),
5.42 (d, J-2.3Hz, 1H), 6.67-7.~7 (m, 12H).
Starting with the cyclahexyl derivative prepared in the previous example and
utilizing
the above procedure the cou-esponding cis-cyclohexyl-benzooxathiin phenol was
prepared. ~H 500MHz NMR~CDC13) ppm(~):1.11-1.93 (m, 11H), 3.23 (t, J=3Hz,
1H), 5.03 (s, 2H), 5.44 (d, J=2.3Hz, 1H), 6.66-7.47 (m, 12H).
Ste~G: Mitsunobu reaction
To a stirred solution of a mixture of 56.3mg (0.135mmole) of the cis-
cyclopentyl
derivative prepared in Step B above, 53.6~L (O.~lO~mmole) of 1-
piperidineethanol,
and 123.5mg {0.47mmole) of triphenylphosphine in 1mL of anhydrous THF at
0°C
was added 87.41~L {0.444mmole) of neat diisopropylazodicarbaxylate {D1AD). The
ice-water bath was removed and the mixture was stit~t~ed Further for six
hours. The
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mixture was partitioned between ethyl acetate/2N HCl/icel brine, and the
organic
phase was separated, washed with brine, dried over anhydrous sodium sulfate,
Filtered, and evaporated. The residue was purified by silica gel
chromatography using
ethyl acetate-methanol(9:1) as eluant to provide the adduct. 'H 500MHz
NMR(CDCI~) ppm(8):1.33-2.0 (m, 15H), 2.56 (m, 4H)> 2.82 (t, J=6Hz, 2H), 3.51
(dd,
J=5.4, 2.4Hz, 1H), 4.16 (t, J=6Hz, 2H), 5.02 (s, 2H), 5.42 (d> J=2.3Hz, 1H),
6.66-7.46
(m, 12H).
Starting with the cyelohexyl derivative prepared in the previous example and
utilizing
the above procedure the corresponding cis-cyclohexyl-benzooxathiin adduct was
prepared. 'H 500MHz NMR(CDCI~) ppm(8):l.ll-1.93 (m, 17H), 2.6 (m, 4H), 2.87
(m, 2H), 3.2 (d, J=2.5Hz, 1H), 4.2 (m, 2H), 5.02 (s, 2H), 5.44 (d, J=2.lHz,
1H), 6.65-
7.46 (m, 12H).
Step D: Debenzylation:
A stirred mixture of 36.6mg (0.0069mmole) of the cis-cyclopentyl derivative
prepared
in Step C above, 14.7mg (0.014mmole) of palladium black, and 87.1mg
(0.138mmole) of ammonium formate in 2mL of ethanol-ethyl acetate-water(7:2:1)
was heated at 80°C for two hours. The mixture was filtered through
celite, washed
well with ethyl acetate and the filtrate was partitioned between ethyl
acetate/saturated
sodium bicarbonate/brine, and the organic phase was separated, washed with
brine,
dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was
purified by silica gel chromatography using ethyl acetate-methanol(9:1) as
eluant to
provide the final product. ~H 500MHz NMR(CDC13) ppm(8):1.33-2.0 (m, 15H), 2.6
(m, 4H), 2.88 (m, 2H), 3.48 (t, J=2.3Hz, 1H), 4.18 (m, 2H), 5.38 (d, J=2.3Hz,
1H), 6.5
(m, 1H), 6.63 (d, 2.9Hz, 1H) 6.74 (d, J=8.7Hz, 1H), 6.89 (d, J=8.7Hz, 2H), and
7.34
(d, J=8.7 Hz, 2H).
Starting with the cyclohexyl derivative prepared in the previous example and
utilizing
the above procedure the corresponding cis-cyclohexyl-benzooxathiin adduct was
prepared. 'H 500MHz NMR(CDC13) ppm(8):1.00-1.90 (m, 18H), 2.6 (m, 4H), 2.81
(t, 2H), 3.19 (t, J=3.0 Hz,lH), 4.18 (m, 2H), 5.38 (d, J=2.3Hz, LH), 6.43 (m,
1H), 6.62
(d> J=3.0 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.87 (d, J=8.7 Hz, 2 H), and 7.34
(d, J=8.7
Hz, ?H); MS m/z 454 (M~).
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EXAMPLE IOG
PREPARATION OF
H
N
Step A: Reductive C clization
Starting with the isopropyl adduct (0.0208 g, 0.049 mmol) prepared in Example
42
and utilizing the procedure outlined in Example 105 (Step A), the crude
product was
isolated after stirring at -23 °C for 6 h 20 min. Purification by
silica gel
chromatography with 30~/a EtOAc/hexane as the eluant afforded the desired
product
as a yellow oil. ~H 500MHz NMR(CDC13) ppm(8): 0.95 (d, 3H), 0.98 (d, 3H), 1.95
(m, LH), 3.30 (t, J=3 Hz, 1H), 5.03 (s, ZH), 5.42 (d, J=2.6 Hz, 1H), 6.66-7.47
(m,
12H).
Step B: Mitsunobu reaction
The dihydrobenzoxathiin prepared in Step A above was coupled with 1-
piperidineethanol using the procedure described in Example 105 (Step C) with
the
exception that the reaction was allowed to slowly warm from 0 °C to
ambient
temperature over 3.5 h. Purification by silica gel chromatography with
10°70
MeOH/CH~C12 as the eluant afforded the desired product as a pale yellow oil.
~H
500MHz NMR(CDC13) ppm(8): 0.95 (d, 3H), 0.98 (d, 3H), 1.50-1.68 (m, 6H), 1.95
(m, 1H), 2.60 (m, 4H), 2.86 (t, 2H), 3.30 (t, J=3 Hz, 1H), 4.20 (t, ZH), 5.03
(s, ZH),
5.42 (d, J=2.6 Hz, 1H), 6.66-7.49 (m, 12H).
Step C: Debenz, lation
Starting with the compound prepared in Step B above, and utilizing the
procedure
outlined in Example 105 (Step D), the cowesponding ci,~-isopropyl-benzoxathiin
adduct was prepared after silica gel chromatography with IOIa MeOH/CHZC1~ as
the
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eluant. ~H 500M1-Iz NMR(CDCI~) ppm(c~): 0.95 (d, 3H), 0.98 (d, 31-1), 1.50-
1.68 (m,
6f-I), 1.95 (m, 1H), 2.60 (m, ~H), 2.86 (t, 2H), 3.26 (t, J=3.0 Hz, 1H),
~l.'~0 (t, 21-I),
5.37 (d, J=2.5 Hz, 1H), 6.47 (dd, 11-1), 6.65 (d, J=3 Hz, 1H), 6.72 (d, J=8.6
Hz, 2H),
and 7.35 (d, J=8.7 Hz, 2I-1); MS m/z 414 (M~).
EXAMPLE 107
PREPARATION OF
H
S
O ~ S w
0
~NJ
0
Step A: Reductive Cyclization
Starting with the 2-thiophene adduct (0.0208 g, .049 mmol) prepared in Example
43
and slightly modiFying the procedure outlined in Example 105 (Step A), the
crude
product was isolated after sowing at 0 °C to ambient temperature For 1
h 40 min.
Purification by silica gel chromatography with 30%a EtOAclhexane as the eluant
afforded the desired product as a red oil. 'H 500MHz NMR(CDCI_;) ppm(8):1.11
(d,
18H), 1.24 (m, 3H), 4.67 (d, J=2.0 Hz, 1H), 5.50 (d, J=1.8 Hz, 1H), 6.60-7.12
(m,
10H}.
Step B: Protection with MOM
To a solution of the didhydrabenzoxathiin (0.0629 g, 0.13 mmol) prepared in
Step A
above in distilled THF {1 mL) was added 60% NaH in mineral oil (0.0090 g, 0.19
mmol) at 0 °C under N~. AFter the gas evolution had ceased, MOMCI
(0.013 mL,
0.16 mmol) was added dropwise to the reaction. After 30 min., another 1.3
equivalents of MOMC1 was added to the reaction. Within 5 min., the reaction
was
complete by TLC. The resulting dark red solution was partitioned between EtOAc
and ice/HzO. The organic layer was washed with brine, dried over Na~SO~, and
concentrated in vacrto. The desired product was used in the next reaction
without
purification. tH 500MH~ NMR(CDCI~) ppm(8):1.11 (d, 1$H}, 1.24 (m, 3H), 3.52
(s,
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3H), 4,G7 (d, J=2.1 Hz, IH), 5.14 (m, 2H), 5.50 (d, J=1.8 Hz, 1H), G.GO-7.12
(m,
101-1 ).
Step C: Desilyla Lion
The dihydrobenzoxathiin prepared in Step B above was desilylated using the
procedure described in Example 105 (Step B) to afford the desired product as a
colorless oil after silica gel chromatography with 30% EtOAc/hexane as the
eluant.
jH 500MHz NMR{CDCI~) ppm{~): 3.52 (s, 3H), 4.G9 {d, J=1.8 Hz, 1H), 5.15 (m,
2H), 5.51 (d, J=1.8 Hz, 1H), G.60-7.15 (m, lOH).
Step D: Mitsunobu reaction
Following the procedure detailed in Example 105 (Step C) with the exception
that the
reaction was allowed to warm from 0 °C to ambient temperature over 4 h,
the material
prepared in the previous step was converted to the desired product after
silica gel
chromatography (one elution with 30%n EtOAclhexane followed by a second
elution
with 10% MeOHlCH2Clz). 1H 500MHz NMR~CDC13) ppm{8): 1.40-2.G0 (m, lOH),
2.79 {t, 2H), 3.52 (s, 3H), 4-.10 (t, 2H), 4.69 (d, J=1.8 Hz, 1H), 5.15 {m,
2H), 5.51 {d,
J=1.8 Hz, 1H), 6.60-7.15 (m, lOH).
Step E: Deprotection of MOM
A mixture of the material {0.0401 g, 0.080 mmol) prepared in Step D above and
2 N
HCl (0.20 mL, 0.40 mmol) in MeOH ( 1.0 mL) was heated to GO °C under N~
for 2.5 h.
The reaction was partitioned between EfOAc and ice/sat. NaHCO~. The organic
layer
was washed with brine, dried over Na~SO~, and concentrated in uacuo. The
residue
was triturated with Et~O and desired product was obtained as a white solid. 'H
500MHz NMR(d~-acetone + CD30D) ppm(~): 1.50-3.19 {m, lOH), 3.23 (t, 2H), 4.30
(t, ?H), 5.00 (d, J=1.8 Hz, 1H), 5._51 (d, J=1.8 Hz, 11~, G.57-7.25 {m, 10H);
MS m/z
454 (M'~)
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EXAMPLE 108
PREPARATION OF
H
O~ N
Step A: Reductive Cyclization
Following the procedure outlined in Example ~1~., 0.0792 g of the 3-pyridyl
derivative
prepared in Example ~.1 was converted to its corresponding benzoxathiin after
stirring
at ambient temperature For 5 h. The desired product was isolated from the
reaction
mixture after silica gel chramatography using 30% EtOAclhexane as the eluant.
'H
500MHz NMR(CDCI~) ppm{8):l.l 1 {d, 18H), 1.2~I (m, 3H), ~.3G {d, J=2.1 Hz,
1H),
5.05 (s> 2H), 5.50 {d, J=1.G Hz, 1H), 6.77-8.~3 (m, 1GH).
Step B: Desilylation
Following the procedure outlined in Example 105 (Step B), the
dihydrobenzoxathiin
generated in Step A above was desilylated to afford the desired product after
silica gel
chromatography (one elution with 50%a EtOAc/hexane followed by a second
elution
with 30% EtOAc/hexane}. 'H 500MHz NMR{CDCI,,) ppm{8): 4.~2 (d, J=2.1 Hz,
1H), 5.07 (s, ~H), 5.50 {d, J=1.6 Hz, 1H), 6.77-8.x.3 {m, 1GH).
Step C: Mitsunobu reaction
Following the procedure detailed in Example 105 {Step C) with the exception
that the
reaction was allowed to warm from 0 °C to ambient temperature over ~1
h, the material
prepared in the previous step was converted to the desired product after
silica gel
chromatography using 10% MeOH/CH~CI~ as the eluant. ' H 500MHz NMR(CDCI_;)
ppm(~):1.~10-2.G0 (m, 10H), 2.80 (t, 2H), x..10 (t, ZH), 4.38 (d, J=1.8 Hz,
1H), 5.07 {s,
2H), 5.50 {d, J=1.8 Hz, 1H), G.77-8.43 {m, 1GH).
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Stop D: Deben7yla tion
Starting with the material prepared in Step C above, and utilizing the
procedure
outlined in Example 105 (Stop D), the corresponding cr's-3-pyridyl-
dihydrobenzoxa thiin adduct was prepared aFter silica gel chromatography with
10%
MeOHICH~CI~ as the oluant. ~H500MHz NMR(CDCI,,) ppm(cS):1.40-2.60 (m, 10H),
2.80 {t, 2H), 4.10 (t, 2H), 4.36 (d, J=2.1 Hz, 1H), 5.45 (d, J=1.9 Hz, 1H),
6.59-8.43
{m, I1H); MS mlz 449 (M+)
EXAMPLE 109
PREPARATION OF
~ ~N
HO ~ S
O \
~NJ
O
Stop A: Reductive G clization
Following the procedure outlined in Example 44, 0.1871 g of the 4-pyridyl
derivative
prepared in Example 41 was converted to its corresponding dihydrobenzoxathiin
after
sowing at ambient temperature for 30 h. The desired product was isolated from
the
reaction mixture after silica gel chromatography using 30% EtOAclhexane as the
eluant. 'H 500MHz NMR{CDCI~) ppm(~):1.11 (d, 18H), 1.24 {m, 3H), 4.32 (d, 1H),
5.08 (s, 2H), 5.50 (d, IH), 6.60-8.39 (m, 16H).
Stop B: Desilylation
Following the procedure outlined in Example 105 {Stop B), the
dihydrabenzoxathiin
generated in Stop A above was desilylated to afFord the desired product after
silica gel
chromatography (ono elution with 50°lp EtOAclhexane followed by a
second elution
with 30% EtOAclhexane). ~H 500MHz NMR(CDCI~) ppm(~): 4.33 (d, 1 H), 5.07 {s,
2H), 5.46 (d, 1H), 6.63-8.37 (m, 16H).
Step C: Mitsunobu reaction
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Following the procedure detailed in Example 105 (Step C) with the exception
that the
reaction was allowed to warm From 0"C to ambient temperature over 5 h, the
material
prepared in the previous step was converted to the desired product aFter
silica gel
chromatography {one elution with 10°~a MeOH/CH4C1~ Followed by a second
elution
with 20alo EtOAc/CH~C14). ~H 500MHz NMR(CDCI~) ppm(S):1.40-2.G0 (m, 10H),
2.80 (t, 2H), 4.14 (t, 2H), 4.32 {d, J=3.0 Hz, 1H), 5.0G (s, 2H), 5.49 (d,
J=2.I Hz, l H),
6.79-8.38 (m, 1GH).
Stop D: Debenzylation
Starting with the material prepared in Step C above, and utilizing the
procedure
outlined in Example 105 {Step D), the desired product was obtained as a 4:1
cis/trans
mixture after silica gel chromatography (1X elution with 30°Io
EtOAc/hexane
Followed by a second elution with 10% MeOH/CHZCI~).
Cis isomer: ~H 500MHz NMR{CDC1~) ppm(~):1.40-2.70 (m, 1 OH), 2.80 (t, 2H),
4.10
(t, 2H), 4.30 (d, J=2.0 Hz, 1H), 5.44 (d, J=1.8 Hz, 1H), G.59-8.40 (m, I1H).
Traps isomer: 1H 500MHz NMR(CDC1~) ppm{0:1.40-2.70 (m, 10H), 2.80 {t, 2H),
4.15 (t, 2H), 4.38 (d, T=8.7 Hz, 1H), 4.92 (d, J=8.7 Hz, 1H), 6.59-8.46 (m,
11H);
MS m/z 449 (M+).
EXAMPLE 110
PREPARATION OF
HO \ S
O ~''e \
Step A: Reduction
To a stin-ed solution of 2G5.lmg (0.449mmole) of the cyclopentyl-thio-ketone
generated in Example 41 In 3mL of methanol-dlchloromethane(1: L) at 0
°C to room
temperature was added portion-wise suFficient sodium borohydride to complete
the
reduction. The reaction mixture was partitioned between ethyl acetate/2N
HC1/ice/
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brine, and the organic phase was separated, washed with brine, dried over
anhydrous
sodium sulfate, filtered, and evaporated to provide crude cyclopentyl-thio-
carbinols,
which was used without Further purification in the next step.
Step B: Cyelization
A mixture of 2GGmg (0.449mmole) of the crude product, prepared in Step A
above,
and 89mg of amberlyst 15 in 3mL of toluene was stin-ed at ambient temperature
for
iwo hours. The resin was removed by filtration and washed well with ethyl
acetate.
The filtrate was evaporated and the residue obtained was purified by silica
gel
chromatography using dichlot°omethane-hexanes(1:1) as eluant to provide
the trans-
dihydro-benzoxathiin derivative. tH 500MHz NMR(CDCI~) ppm(8):1.13 (d, 18H),
1.26-1.94 (m, 12H), 3.G4 (dd, J=7.8Hz, 5.5Hz, 1H), x.78 (d, J=7.8Hz, 1H), 5.02
(s,
2H)> 6.6-7.45 (m, 12H).
Step C: Desil lation
Follawing the procedure outlined in Step B of Example 105, 228.5mg
(0.397mmole)
of material prepared in the previous step was desilylated to give the
correspanding
phenol.
Stea D: Mitsunobu reach
Following the procedure detailed in Step C of Example 105, the material
prepared in
the previous step was converted to the coa-esponding tram-cyclopentyl-
dihydrobenzoxathiin adduct. tH 500MHz NMR(CDC13) ppm(c~):1.39-2.0 (m, lSITj,
2.6 (m, 4H), 2.88 (m, 2H), 3.66 (dd, J=7.8Hz, 5.5Hz, 1H~, x.21 (m, 2H), 4.81
(t,
J=7.8Hz, 2H), 5.01 (s, 2H), 6.G4-7.~9 (m, 12H).
Step E: Debenz lation
Following the procedure detailed in Step D of Example 105, the material
prepared in
the previous step was converted to the corresponding trcrns-cyclopentyl-
dihydrobenzoxathiin product. tH 500MHz NMR(CDCI~) ppm(8):1.29-2.0 (m, 15H),
2.6 (m, 4H), 2.88 (m, 2H), 3.67 (dd, J=8Hz, SHz, 1H), 4.18 (m, 2H), 4.77 (t,
J=8Hz,
2H), 6.5 (dd. J= 2.7Hz, 8.7Hz, 1H), 6.65 (d, 2.7Hz, lH) 6.77 (d, J=8.7Hz, 1H),
6.88
(d, J=7.5Hz, 2H), and 7.27 (d, J=7.5Hz, 2H).
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EXAMPLE 111
GENERAL PREPARATION Oh
S
HO ~ O
~ , O~ NJ
Steps A and B: Reduction and Cyclizatian
Utilizing the thio-ketanes prepared in Example 39 and employing the procedures
outlined above in Step A and B of Example 110, the Following compounds were
prepared:
Traps-cyclohexyl derivative: 'H 500MHz NMR(CDCI~) ppm(~): 1.14 (d, 18H), 0.98-
1.8 (m, 14H), 3.37 (dd, J=2.5Hz, 8.lHz, 1H), 5.01 (s, 2H), 5.05 (d, J=8.lHz,
1H), 6.6-
7.44 (m, 12H).
Traps-cyclopentyl derivative: 'H 500MHz NMR(CDCI~) ppm(~):1.1~1 (d, 18H), 1.28-
1.9 (m, 12H), 4.53 (m, 1H), 4.93 (d,lH), 5.01 (s, 2H), 6.6-7.43 (m, 12H).
Ste~C: Desil, lation
Utilizing the traps-dihydrobenzoxathiiins prepared in the previous step and
employing
the procedure outlined above in Step B oFExample 105, the Following compounds
were prepared:
Traps-cyclohexyl phenol: ~H 500MHz NMR(CDCI~) ppm(~):1.0-1.8 (m, 11H), 3.3
(m, LH), 5.05 (s, 2H), 5.1 (d, 1H), 6.6-7.44 (m, 12H).
Trcrvs-cyclopentyl phenol: 1H 500MHz NMR(CDC1;) ppm(~): l.?9-2.0 (m, 9H), 3.55
(dd, J=5.7Hz, 7.6Hz, 1H)> 4.95 (d, J=7.6Hz, 1H)> 5.0? (s, 2H), G.6-7.45 (m,
12H).
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Step D: Mitsunobu reaction:
Utilizing the trcrn,l~-dihydrobonzoxathiiin phenols prepared In the previous
stop and
employing the pracedure outlined above in Step C of Example 105, the following
compounds were prepared:
Turns-cyclohoxyl adduct: ~H 500MHz NMR(CDC1~) ppmC~):1.0-1.8 {m, 17H), 2.58
(m, 4H}, 2.84 (m, 2H), 3.37 (m, 1H), 4.17 (t, J=6Hz, 2H), 5.0 (s, 2H}, 5.08
(d,
J=7.8Hz, 1 H), 6.6-7.43 (m, 12H).
Traps-cyclopontyl adduct: 'H 500MHz NMR(CDC1~) ppm(8}:1.29-2.0 (m, 15H), 2.58
(m, 4H), 2.84 (m, 2H), 3.55 (m, 1H), 4.17 (m, 2H}, 4.94 {d, J=7.3Hz, 1H), 5.0
(s, 2H),
6.6-7.72 (m, 12H).
Stop E: Debenz la~tion:
Utilizing the tr-a~2s-dihydrobenzoxathiiin adducts prepared in the previous
stop and
employing the procedure outlined above in Stop D of Example 105, the following
compounds wore prepared:
Tr-nf2s-cyclohexyl adduct: ~H 500MHz NMR(CDCI~) ppm(b}:1.0-1.8 (m, 17H), 2.58
(m, 4H)> 2.86 (m, 2H), 3.33 (m, 1H), 4.16 (m, 2H), 5.08 (d, J=7.8Hz, 1H), 6.4-
7.23
(m, 7H).
Traps-cyclopontyl adduct: 'H 500MHz NMR(CDC13) ppm(b):1.29-2.0 (m, 15H), 2.68
(m, 4H), 2.94 (m, 2H), 3.51 (m, 1H), 4.2 {m, 2H}, 4.95 (d, J=7.4Hz, 1H), 6.45-
7.31
(m, 7H).
EXAMPLE 112
PREPARATION OF
HO \ S
/ ~ ~''e \
/ O~N
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Step A. Silylation
To a stirred solution oFthe isopropyl-thio-1<etone {0.0395 g, 0.097 mmol)
generated in
Example 42 in distilled THF (1 mL) at 0°C was added 60% NaH in
mineral oil
(0.0183 g, 0.20 mmol) Followed by T1PSC1 (0.048 mL, 0.22 mmol). After 35 min.,
another equivalent of TIPSCI was added to di°ive the reaction to
completion. The
reaction was partitioned between EtOAc and ice/HZO, and the organic layer was
washed with brine, dried over Na2S0~, and concentrated in vacito to afFord the
desired
product. The crude material was used in the next step without Further
purification.
15
Stet B: Reduction
To a solution of the crude product (0.097 mmol) prepared in Step A above in
distilled
THF (1 mL) was added a 1 M solution of super-hydride in THF {0.15 mL, 0.15
mmol)
at 0 °C under NZ. The reaction mixture was stirred For 20 min. before
partitioning
between EtOAc and icelHzO. The organic layer was Further washed with brine,
dried
over Na~SOa, and concentrated izz vacico to give the desired praduet. The
crude
material was used in the next step without further purification. IH 500MHz
NMR(CDC1~) ppm(8): 0.90-1.40 (m, 49H), 1.69 (m, 1H), 3.10 (dd, 1H), 4.60 (d,
1H),
5.05 (s, 2 H), 6.70-7.50 (m, 12H).
Step C: Desil lation
To a solution of the material (0.097 mmol) prepared in the previous step in
distilled
THF (1 mL) was added AcOH {0.018 mL, 0.32 mmol) at 0 °C under NZ
Followed by
the addition of a 1 M solution of TBAF in THF (0.29 mL, 0.29 mmol). After 15
min.,
the reaction was partitioned between EtOAc and icelsat. NaHCO~. The organic
layer
was washed with brine, dried over Na~SO~, and concentrated llz vrrcaco.
PuriFicatian
by silica gel chromatography using 40%a EtOAc/hexane as the eluant afforded
the
desired product as a yellow Foam. ~H SOOMHz NMR(CDC1.,) ppm{~): 0.92 (d, 3H),
0.98 (d, 3H), 1.59 (m, lH), 2.86 (dd, 1H), 4.62 (d, 1H), 5.02 (q, 2 H), 6.77-
7.45 (m,
12H).
Step D: C clization
Following the procedure outlined in Example l 10 (Step B), the material
(0.0366 g,
0.089 mmol) generated in the previous step was converted to its corresponding
irafZs-
dihydrobenzoxathiin aFter stirring for 5 h 15 min. at ambient temperature.
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Purification by silica gel chromatography using 30%a EtOAclhexane as the
eluant
afforded the desired product as a white solid. ~ H 500MHz NMR(CDC1~) ppm(~):
0.98 (d, 3I-1), 1.03 (d, 3H), 1.78 {m, 1H), 3.57 (dd, J=3.7 Hz, J=8,5 Hz,
lII), 4.82 (d,
J=8.4 Hz, 1H), 5.02 (s, 2 H), 6.63-7.46 {m, 12I-1).
Step E: Mitsunobu reaction
Following the procedure detailed in Example 105 (Step C), the material (0.0266
g,
0.068 mmol) generated in the previous step was convec-ted to its carresponding
trans-
isopropyl-dihydrobenzoxathiin adduct after warming from 0 °C to ambient
temperature over 4 h 20 min. Purificatian by silica gel chromatography (one
elution
with 10% MoOH/CH~CIZ followed by a second elution with 30%~ EtOAc/hexane)
afforded the desired product as a white solid. 'H 500MHz NMR{CDC1~) ppm(8):
0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 (m, GH), 1.78 (m, 1H), 2.58 (m, 4H),
2.85 {t,
2H), 3.57 {dd, J=3.7 Hz, J=8.5 Hz, 1H), 4.18 {t, 2H), x.83 (d, J=8.4. Hz, 1H),
5.02 (s,
2 H), 6.63-7.46 {m, 12H).
Step F: Debenzylation
Following the procedure detailed in Example 105 (Step D), the material (0.0395
g,
0.068 mmol) generated in the previous step was converted to its corresponding
trans-
isoprapyl-dihydrobenzoxathiin product. Purification was accomplished by silica
gel
chromatography using 10%a MeOH/CH2Clz as the eluant. 'H 500MHz NMR{CDCI;)
ppm(~): 0.98 (d, 3H), 1.02 (d, 3H), 1.29-1.67 {m, 6H), 1.78 (m, 1H), 2.58 {m,
4H),
2.85 (t, 2H), 3.57 {dd, J=3.7 Hz, J=8.5 Hz, 1H), 4.18 fit, 2H), X1.83 {d,
J=8.4 Hz, LH~,
6.48-7.29 {m, 7H); MS mlz 414 (M+).
EXAMPLE 113
PREPARATION OF
S
HO ~ O
' - o-~-NJ
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Step A: Silyla tion
Following the procedure outlined in Example 1 12 (Step A), the isopropyl-thio-
1<etone
~0.631~- g, 1.5 mmol) generated in Example 40 was silylated. Purification by
silica
gel chromatography using 30% EtOAc/hexane as the eluant afforded the desired
praduct as a yellow oil. ~H 500MHz 1~1MR(CDC1~) ppm(b): 0.98-1.30 (m, 49H),
2.35
(m, LH), 4.38 (d, lH), 4.99 (q, 2H), 6.33-7.79 (m, 12H).
Step B: Reduction
Following the procedure outlined in Example 112 (Step B), the material (0.8009
g,
1.1 mmol) isolated in Step A above was reduced to its corresponding alcohol
and
used without Further purification in the next step. 'H 500MHz NMR(CDC1~)
ppm(8):
0.98-1.30 (m, 49H), 1.90 (m, 1H), 2.92 (dd, 1H), 4.59 (d, 1H), 5.05 (q, 2 H),
6.47-
7.43 (m, t2H).
Step C: Desil l~n
Following the procedure outlined in Example 112 (Step C), the material (0,022
mmol)
isalated in Step B above was deprotected to afford the desired product which
was
used in the next step without purification.
Step D: Cyclization
Following the procedure outlined in Example 110 (Step B), the material
generated in
the previous step was converted to its corresponding trczns-
dihydrobenzoxathiin after
stirring for 22 h at ambient temperature. Purification by silica gel
chromatography
using 30% ECOAc/hexane as the eluant afForded the desired product as a
colorless oil.
'H 500MHz NMR(CDCI~) ppm(8): 0.98 (d, 3H), 1.03 (d, 3H), 1.79 (m, 1H), 3.45
(dd,
1H), 4.98 (d, 1I-1), 5.02 (s, 2 H), G.~9-7.46 (m, 12H); MS m/z 393 (M~).
Step E: Mitsunobu reaction
Fallowing the procedure detailed in Example 105 (Step C), the material (0.008
g,
0.020 mmol) generated in the previous step was converted to its corresponding
rr-ans-
isopropyl-dihydrobenzoxathiin adduct aFter warming From 0 °C to ambient
temperature over 6 h. Purification by silica gel chromatography using 10~'~p
MeOH/CH~CI~ as the eluant aFForded the desired product as a pale yellow oil.
'H
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500MHz NMR(CDCI~) ppm(c~): 0.98 (d, 3H), 1_0? (d, 3H), 1.29-1.67 (m, 6H), 1.79
(m, I H), ?.58 (m, 4H), 2.81 (t, 2H), 3.50 (dd, J=3.8 Hz, J=8.3 Hz, 1 H), ~. I
8 (t, 2I-1),
4.97 (d, J=8.2 Hz, 1H), 5.01 (s, 2 1-1), 6.59-7.d6 (m, 12H).
Step F: Debenz, lation
Following the procedure detailed in Example 105 (Step D), the material (0.0085
g,
0.017 mmol} generated in the previous step was converted to its corresponding
trccrZS-
isopropyl-dihydrobenzoxathiin product. Purification was accomplished by silica
gel
chromatography using 10~/o MeOH/CHZC12 as the eluant. 'H SOOMHz NMR(CDC1;)
ppm(8}: 0.98 (d, 3H), 1.02 (d, 31T), 1.49-1.70 (m, GH}, 1.75 (m, 1H), 2.61 (m,
4H),
2.85 (t, 2H}, 3.41 (dd, J=3.8 Hz, J=8.3 Hz, 1H), 4.18 (t, 2H), 4.96 (d, J=8.2
Hz, LH),
6.43-7.26 (m, 7H}; MS m/z 414 (M+}.
EXAMPLE 114
PREPARAT10N OF
O / OTIPS
/ \
NO \ S
HS
Following the procedure outlined in Example 16 and using 0.36g (2.Smmole) of
1,2-
benzenedithiol, purchased from Aldrich, 221mg (ca 20%, impure} of desired
product
was obtained after silica gel chromatography using EtOAc/hexane (1/5) as
eluant.
EXAMPLE 115
PREPARAT10N OF
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/ OTIPS / OTIPS OTIPS
/ S ~ I / S ~ ( S
.,,i
S ~ S
/ I / S
OH OH / OH
A g C
Utilizing the procedure from Example d~, I2lmg (80%p) of a mixture of three
products (A : B : C = 1 : O.I : 0.25) was isolated after purification by
silica gel
chromatography with 10%~ EtOAe/hexane.
EXAMPLE 1I6
PREPARATION OF
/ S
S
TFA B TFA
St_ ep A
The thiin obtained from Example xx was coupled with 1-piperidineethanol using
the
procedure described in Example 71 (Step A). After purification by silica gel
chromatography using 3%a MeOHICH~CI~ as eluant, the desired adducts were
obtained as a mixture.
St_ eP B,
The adducts from Step A were desilylated using the procedure described in
Example
71 (Step C). The desired product A was separated by HPLC (Meta Chem Polaris C
184.6x50, 5 micron; gradient 5 to 75%~ of acetanitrile on Reverse Phase
Column) as a
while solid. A: ~H NMR (400 MHz, CD~OD) b (ppm):7.2 (m, 2H), 7.1 (m, 2H), 6.9
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(m, 2H), 6.8 (m, 4H), 6,55 (d, 2I-I), 4.75 (m, 2H), ~-.3 (m, 2H), 3,6 (br d,
2H), 3.5 (m,
2I-I), 3.0 (br t, 2H), 1.95 (m, 2H}, 1.8 (m, 4I-I); ( MS m/z 464 (M~}. B: ~ H
I~tMR
(400 MI-Iz, CD~OD) ~ (ppm): 7.d (m, 2H), 7,3 (m, 2H), 7.1 (d, 2H), 6.9_5 (d,
2H), 6.8
(d, 2H), 6,6 (d, 2H), ~-.3 (br t, 2H}, 3.6 (br d, 2H), 3.5 (br t, 2H), 3.05
(br t, 2H), 2.0
(br d, 2H), 1,8 (m, 4H}; }; MS m/z 462 (M~)
Assay Methods
The utility of the compounds of the instant invention can be readily
determined by
methods well known to one of ordinary skill in the art. These methods may
include,
but are not limited to, the methods described in detail below.
Estrogen Receptor Binding Assay
The estrogen receptor ligand binding assays are designed as
scintillation proximity assays employing the use of tritiated estradiol and
recombinant
expressed estrogen receptors. The full length recombinant human ER-cx and ER-
(3
proteins are produced in a bacculoviral expression system. ER-oc or ER-(3
extracts are
diluted 1:400 in phosphate buffered saline containing 6 mM cc-
monothiolglycerol.
200 ~,L aliquots of the diluted receptor preparation are added to each well of
a 96-well
Flashplate. Plates are covered with Saran Wrap and incubated at 4 ° C
overnight.
The Following morning, a 20 u1 aliquot of phosphate buffered saline
containing 10°70 bovine serum albumin is added to each well of the 96
well plate and
allowed to incubate at 4° C for 2 hours. Then the plates are washed
with 200 u1 of
buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA, 10% Glycerol, 50 mM KCI,
and 6 mM a-monathiolglycerol. To set up the assay in these receptor coated
plates,
add 178 u1 of the same buffer to each well of the 96 well plate. Then add 20
u1 of a
10 nM solution of ~H-estradiol to each well of the plate.
Test compounds are evaluated over a range of concentrations from
0.01 nM to 1000 nM. The test compound stock solutions should be made in 100/0
DMSO at 100X the final concentration desired far testing in the assay. The
amount of
DMSO in the test wells of the 96 well plate should not exceed l~/o. The final
addition
to the assay plate is a 2 u1 aliquot of the test compound which has been made
up in
J.00°~Q DMSO. Seal the plates and allow them to equilibrate at room
temperature Far 3
hours. Count the plates in a scintillation counter equipped for counting 96
well plates.
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Ovariectomit~ed Rat Assay
In the ovariectomiaed (OVX) Rat Assay, estrogen-deficiency is used to
induce cancellous osteopenia (e.g. low bone mineral density [BMD; mg/cm?]),
associated with accelerated bone resotption and formation. Both the BMD and
bone
resolptionlformation outcomes are used to model the changes in bone that occur
as
women pass through menopause. The OVX Rat Assay is the principal in uivo assay
used by all major academic and industrial laboratories studying the efficacy
of new
chemical entities in preventing estrogen-deficiency bone loss.
Spl°ague-Dawley female rats aged 6-$ months are OVXd and, within
24 hours, started on treatment for 42 days with vehicle or multiple doses of
test
compound. Untreated sham-OVX and alendronate-treated (.003 mg/kg s.c., q.d.)
or
17-13-estradiol-treated (.004 mglkg s.c., q.d.) groups are included as
positive controls.
Test compounds may be administered orally, subcutaneously, or by infusion
through
subcutaneously-implanted minipump. Before necropsy, in vivo dual labeling with
caleein ($ mg/kg by subcutaneous injection), a bone seeking fluoroehrome, is
completed. At necropsy, blood, femurs, a vertebral body segment, and the
uterus, are
obtained.
The routine endpoints for the OVX Rat Assay include assessments of
bone mass, bone resorption, and bone formation. For bone mass, the endpoint is
BMD of the distal femoral metaphysic, a region that contains about 20~/o
cancellous
bone. The vertebral segment, a region with ~25%~ cancellous bone may also be
used
for BMD determination. The BMD measurement is made by dual energy x-ray
absoiptiometry (DXA, Hologic 4500A; Waltham, MA). For bone resoiption, the
endpoint is urinary deoxypyr 3dinoline crosslinks, a bone collagen breakdown
product
(uDPD; expressed as nM DPD/ nM creatinine). This measurement is made with a
commercially available kit (Pyrilinks; Metra Biosystems, Mountain View, CA).
For
bone formation, the endpoints are mineralising surface and mineral apposition
rate,
histomorphometric measures of osteoblast number and activity. This measurement
is
done on S~,m sections of the non-decalcified proximal tibial metaphysic, using
a semi-
automated system (Bioquant; R&M Biometrics; Nashville, TN). Similar endpoints
and measuring techniques for each endpoint are commonly used in postmenopausal
women.
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Rat Cholesterol LowErin~ Assay
Sprague-Da wley rats (5 per group) weighing about 2508 were
subcutancously dosed with compounds of the present invention dissolved in
propylene glycol For ~ days. A group of 5 rats were dosed with vehicle only.
On the
FiFth day, rats were euthanized with carbon dioxide and their blood samples
were
obtained. Plasma levels of cholesterol were assayed From these samples with
commercially available cholesterol determination kits from Sigma.
MCF-7 Estro en Dependent Proliferation Assay
MCF-7 cells (ATCC #HTB-22) are human mammary gland
adenocarcinoma cells that require estrogen for growth. The growth media (GM)
for
the MCF-7 cells is Minimum Essential Media (without phenol red) supplemented
with fetal bovine serum{FBS) to LO%. The FBS serves as the sole source of
estrogen
and this GM supports the full growth of the cells and is used for the routine
growth of
the cell cultures. When MCF-7 cells are placed in a media in which 10%
Charcoal-
Dextran treated fetal bovine serum (CD-FBS) is substituted for FBS, the cells
will
cease to divide but will remain viable. The CD-FBS does not contain detectable
levels
of estrogen and the media containing this sera is refen-ed to as Estrogen
Depleted
Media (EDM). The addition of estradiol to EDM stimulates the growth of the MCF-
7
cells in a dose dependent manner with an EC~~ of 2pM.
Growing MCF-7 cells are washed several times with EDM and the
cultures then maintained in EDM for a minimum of 6 days in order to deplete
the cells
of endogenous estrogen. On day 0 {at the startof the assay), these estrogen
depleted
cells are plated into 96-well cell culture plates at a density of 1000
cells/well in EDM
in a volume of 180ullwell. On day 1 test compounds are diluted in a 10-fold
dilution
series in EDM and 20u1 of these dilutions added to the 180u1 of media In the
appropriate well of the cell plate resulting in a Further 1:10 dilution of the
test
compounds. On days 4 and 7 of the assay, the culture supernatant is aspirated
and
replaced with Fresh EDM and test compound dilutions as above. The assay is
terminated at day 8-10 when the appropriate controls reach 80-90% conFluency.
At
this point, the culture supernatants are aspirated, the cells washed 2~ with
PBS, the
wash solution aspirated and the protein content of each well determined. Each
drug
dilution is evaluated on a minimum of 5 wells and the range of dilution of the
test
compounds in the assay is 0.OOlnM to 1000nM. The assay in the above format is
employed to determine the estradiol agonist potential of a test compound.
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In order to evaluate the antagonist activity of a test compound, the
MCF-7 cells are maintained in EDM for a minimum of 6 days. Then on day 0 (at
the
start of the assay), these estrogen depleted cells are plated into 96-well
cell culture
plates at a density of 1000 cells/well in EDM in a volume of 180u1/well. On
day 1 the
test compounds in fresh media containing 3 pM estradiol are applied to the
cells. On
days 4 and 7 of the assay, the culture supernatant is aspirated and replaced
with fresh
EDM containing 3 pM estradiol and the test compound. The assay is terminated
at
day 8-10 when the apprapriate controls reach 80-90% conFluency and the protein
content of each well is determined as above.
Rat endometriosis model
Animals:
Species: Rattus norvegicus
.15 Strain: Sprague-Dawley CD
Supplier: Charles River Laboratories, Raleigh, NC
Sex: Female Weight : 200 - 240 gram
Rats are single-housed in polycarbonate cages and are provided
Teklad Global Diet 2016 (Madison, WI) and bottled reverse osmosis purified H20
ad
libitum. They are maintained on a12/J2 light/dark cycle.
Rats are anesthetized with TelazolT~' (20 mg/kg, ip) and oxymorphone
(0.2 mg/kg sc) and positioned dorsoventrally on a sterile drape. Body
temperature is
maintained using a underlying circulating water blanket. The surgical sites
are shaved
with clippers and cleaned using three cycles of betadinel isapropyl alcahol or
Duraprep0 (3M). The incisional area is covered with a sterile drape.
Using aseptic technique, a 5 cm midline lower abdominal incision is
made through the skin, subcutaneous and muscle layers. A bilateral ovariectomy
is
performed. The left uterine blood vessels are ligated and a 7 mm segment of
the left
uterine horn is excised. The uterus is closed with 4-0 gut suture. The
myometrium is
aseptically separated from the endometrium and trimmed to 5X5 mm. The trimmed
section of the endometrium is transplanted to the ventral peritoneal wall with
the
epithelial lining of the segment opposed to the peritoneal wall. The explanted
endometrial tissue is sutured at its four corners to the body wall using
sterile 6-0 silk.
The abdominal muscular layer is closed using sterile ~l-0 chramic gut. The
skin
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incision is closed using sterile stainless surgical clips. A sterile 90-day
sustained
release estrogen pellet (Innovative Research of America, 0.72 ng/pellet;
circulating
estrogen equivalent of 200-250 pg/mL) is implanted subcutaneously in the
dorsal
lateral scapular area. A sterile implantable programmable temperature
transponder
(IPTT) (BMDS, Seaford, D>J) is injected subcutaneausly in the dorsoscapular
region.
The rats are observed until Fully ambulatory, and allowed to recover from
surgery
undisturbed for 3 weeks.
Three weeks after ti°ansplantation of the endometr3al tissue, the
animals
undergo a repeat laparotomy using aseptic surgical site preparation and
technique. The
explant is evaluated for graft acceptance, and the area is measured with
calipers and
recorded. The animals with rejected grafts are removed from the study. Animals
are
sorted to create similar average explant volume per group.
Drug or vehicle(control) treatment is initiated one day after the second
laparotomy and continued for 1~ days. Body temperature is recorded every other
day
at 10:00 am using the BMDS scanner.
At the end of the 1~ day treatment period, the animals are euthanized
by COZ overdose. Blood is collected by cardiocentesis far circulating estrogen
levels.
The abdomen is opened, the explant is examined, measured, excised, and wet
weight
is recorded. The right uterine horn is excised, and wet and dry weights are
recorded.
Pharmaceutical Composition
As a specific embodiment of this invention, 25 mg of the compound
from Example 71, is formulated with sufficient finely divided lactose to
provide a
total amound of 580 to 590 mg to fill a size 0, hard-gelatin capsule.
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