Structure-activity relationships of selective estrogen receptor modulators: Modifications to the 2-arylbenzothiophene core of raloxifene

146

J . Med. Chem. 1997, 40, 146-167

Articles

Str u ctu r e-Activity Rela tion sh ip s of Selective Estr ogen Recep tor Mod u la tor s:

Mod ifica tion s to th e 2-Ar ylben zoth iop h en e Cor e of Ra loxifen e

Timothy A. Grese,* Stephen Cho, Don R. Finley, Alexander G. Godfrey, Charles D. J ones, Charles W. Lugar III,

Michael J . Martin, Ken Matsumoto, Lewis D. Pennington, Mark A. Winter, M. Dee Adrian, Harlan W. Cole,

David E. Magee, D. Lynn Phillips, Ellen R. Rowley, Lorri L. Short, Andrew L. Glasebrook, and Henry U. Bryant

Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285

Received September 6, 1996^X

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is

currently under clinical evaluation for the prevention and treatment of postmenopausal

osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylben-

zothiophene core have been prepared and evaluated for the ability to bind to the estrogen

receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function

as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized

(OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine

eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and,

to a lesser extent, the 4′-hydroxy substituents of raloxifene are important for receptor binding

and in vitro activity, (2) small, highly electronegative 4′-substituents such as hydroxy, fluoro,

and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4′-position

leads to increased uterine stimulation in vivo, and (4) additional substitution of the 2-aryl

moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene

results in reduced biological activity. In addition, compounds in which the 2-aryl group is

replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in

vivo biological activity qualitatively similar to that of raloxifene. Several novel structural

variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated

efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at

doses of 0.1-10 mg/kg.

In tr od u ction

The central role of endogenous estrogens, such as 17â-

estradiol and estrone, in the development and mainte-

nance of the female reproductive organs, mammary

glands, and other sexual characteristics has long been

appreciated. More recently estrogens’ involvement in

the growth and/or function of a number of other tissues,

such as the skeleton, the cardiovascular system, and the

central nervous system, in both males and females has

also been recognized.^1,2The decreased production of

ovarian steroids which occurs after the climacteric has

been linked to a number of postmenopausal pathologies,

particularly osteoporosis and coronary artery disease.^3,4

Estrogen replacement therapy is effective in reducing

the risks associated with these pathologies; however,

concerns relating to the increased risk of endometrial

cancer have necessitated the development of therapeutic

regimens in which the uterine effects of estrogen are

opposed by progestin treatment.⁵Side effects of proges-

tin treatment, such as resumption of menses, central

nervous system disturbances, and the possibility of

attenuated cardiovascular benefits, have significantly

reduced patient compliance.⁶Furthermore, recent stud-

ies which confirm the increased risk of breast cancer

associated with estrogen replacement therapy have

stimulated the search for treatment alternatives.⁷

Over the years a variety of steroidal and nonsteroidal

compounds which interact with the estrogen receptor

(ER) have been developed as contraceptives and for the

treatment of breast cancer, uterine dysfunction, and

other disorders of the female reproductive system.⁸

Tamoxifen, originally developed as an anti-estrogen and

widely utilized for the treatment of breast cancer, has

paradoxically been found to act as a partial estrogen

agonist in the uterus and to display estrogen agonist

effects in bone and the cardiovascular system.⁹Re-

cently, several groups have described molecules which

fully antagonize the effects of estrogen on uterine and

mammary tissue, while mimicking the effects of estro-

^XAbstract published in Advance ACS Abstracts, December 15, 1996.

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 147

Sch em e 1^a

explore an alternative route involving the addition of a

Grignard reagent to a 2-amino-3-aroylbenzothiophene.

This strategy had previously been reported to result in

exclusive 1,4-addition to the enone, even in the presence

of excess Grignard reagent.¹⁵

As described in Scheme 2, we have prepared a variety

of substituted 2-aminobenzothiophenes 6 following the

general method of Hopkinson and Lee-Ruff.¹⁶Conden-

sation of 6 with the substituted benzoyl chloride 3 then

provided the requisite 2-amino-3-aroylbenzothiophenes

7 in acceptable yields.^15,17Treatment of 7 with 4-ani-

sylmagnesium bromide gave a series of raloxifene

analogs 8 which exhibit alternative substitution pat-

terns on the benzothiophene ring. These could then be

demethylated (AlCl₃/EtSH or BX₃)¹⁸to provide their

phenolic counterparts 9 if so desired. Alternatively, we

have treated 7a with a variety of substituted phenyl

Grignard reagents (Scheme 3) or alkyl, naphthyl, and

heteroaryl Grignard reagents (Scheme 4) to provide

additional raloxifene analogs 10 and 12 in which the

2-substituent has been altered. Once again, demethy-

lation generally provided the phenolic analogs 11 and

13. In a few cases (e.g., 8f, 10k /11l, 10t), however,

standard demethylation protocols were ineffective or led

to products with additional modifications.

In order to incorporate functionality in the 2-sub-

stituent which was incompatible with the Grignard

reaction, an umpolung of the reaction partners was

desired. Toward that end, 7a was treated with tri-

methylstannyllithium¹⁹to provide, after rapid aqueous

workup, the modestly stable 2-stannyl-3-aroylben-

zothiophene 14 (Scheme 5). Stille coupling with a

variety of aryl bromides followed by demethylation then

provided the raloxifene analogs 15 and 16, respec-

tively.²⁰

A more efficient synthesis of selectively 6- or 4′-

functionalized raloxifene analogs was accomplished via

the preparation and separation of the raloxifene silyl

ethers 17-19 (Scheme 6). After conversion to the aryl

triflates 20 and 21, the triflate moieties were readily

transformed into a variety of functional groups via

palladium-catalyzed reactions.²¹Methyl esters 22a and

23a were further transformed into the carboxylic acid-

containing analogs via hydrolysis or the amide-contain-

ing analogs via the Weinreb protocol (Scheme 6).²²In

all cases, the silyl ether was readily removed with acid

or fluoride to provide the functionalized raloxifene

analogs 22 and 23.

a

Reagents: (a) AlCl₃, CH₂Cl₂, 27-84%; (b) AlCl₃, EtSH, CH₂Cl₂,

36-83%, or NaOH, 84%; (c) 3, AlCl₃, EtSH, CH₂Cl₂, 12-50%.

^bProtected as methyl ether in compounds 2 and 4. Protected as

c

mesylate in compounds 2 and 4. ^dProtected as 4-fluorobenzoate

in compounds 2 and 4.

gen on bone and the cardiovascular system.¹⁰The term

selective estrogen receptor modulator (SERM)^10bhas

been coined to describe these agents, and one such

compound, raloxifene (LY139481 HCl; 1), is in advanced

clinical trials for the prevention and treatment of

osteoporosis.^11,12As part of a program to further explore

structure-activity relationships in the raloxifene series,

we have examined a series of analogs in which the

2-arylbenzothiophene substructure has been modified.

Herein, we describe the synthesis of these analogs, their

in vitro effects in receptor binding and cell proliferation

assays, and their effects on bone, uterus, and serum

lipids in an ovariectomized (OVX) rat model.¹³

Ch em istr y

Several methods for the synthesis of 2-aryl-3-aroyl-

benzothiophenes have previously been described.^11,14

The Friedel-Crafts acylation of a 2-arylbenzothiophene

2 with 4-[2-(1-piperidino)ethoxy]benzoyl chloride, 3, has

been utilized for the preparation of a variety of ralox-

ifene analogs 4 and 5 as outlined in Scheme 1. In this

sequence, phenolic protecting groups (usually methyl

ethers) may be removed in a separate reaction or in situ

as part of the acylation protocol. Optimal yields are

obtained for substrates in which the 3-position of the

benzothiophene is further activated by electron-donating

substituents on the 2-aryl moiety.

During the course of these investigations, it rapidly

became clear that a more general method for the

synthesis of 2-aryl-3-aroylbenzothiophenes was re-

quired. Difficulties in the preparation of more highly

substituted 2-arylbenzothiophenes and inconsistent re-

gioselectivity in the acylation step were problematic.

Our desire to prepare analogs which would define a

more diverse structure-activity relationship led us to

Biologica l Testin g

In Vitr o. ER binding affinities were determined by

displacement of bound [³H]-17â-estradiol from MCF-7

cell lysate for compounds 4, 5, 8-13, 15, 16, 22, and 23

and are reported in Table 1.²³Antagonism of estrogen

action in a mammary tumor cell line was assayed via

inhibition of MCF-7 cell proliferation stimulated by

10^-11M 17â-estradiol, and IC₅₀values are also included

in Table 1.²⁴

In Vivo. Tissue-specific estrogen agonist effects were

examined in OVX rats,²⁵utilizing uterine weight,

uterine eosinophil peroxidase (EPO) activity,²⁶and

serum cholesterol levels as end points (Tables 2 and 3).

Specifically, 75-day old OVX Sprague-Dawley rats were

dosed daily by oral gavage, for 4 consecutive days,

commencing 2 weeks after ovariectomy. A vehicle (20%

148 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

Sch em e 2^a

a

Reagents: (a) i. CH(S)NMe₂, LDA, -78 °C, 28-62%, ii. MsOH, CH₂Cl₂, 9-99%; (b) 3, PhCl, 38-77%; (c) 4-anisylMgBr, THF, 15-

77%; (d) AlCl₃, EtSH, CH₂Cl₂, or BX₃, dichloroethane, 31-97%. ^bProtected as methyl ether in compounds 6-8. Protected as 5-methyl

c

ether, 6-benzyl ether in compounds 6 and 7. Grignard reaction was carried out using 4-TBSO-phenylMgBr, and the benzyl and silyl

protecting groups were removed via TBAF and catalytic transfer hydrogenation following Grignard addition; therefore, in 8e the 6- and

4′-substituents are hydroxy.

Sch em e 3^a

Reagents: (a) THF, 34-90%; (b) AlCl₃, EtSH, CH₂Cl₂, or BX₃, dichloroethane, 15-95%. ^bProtected as methyl ether in compound 10.

a

^cProtected as TBS ether during Grignard reaction. In some cases, the TBS group was removed during workup.

Sch em e 4^a

Sch em e 5^a

a

Reagents: (a) R′MgBr, THF, 29-81%; (b) AlCl₃, EtSH, CH₂Cl₂,

or BX₃, dichloroethane, 68-86%. ^bProtected as methyl ether in

compound 12. Protected as TBS ether in compound 12.

c

â-hydroxycyclodextrin)-treated OVX control group was

included in each experiment, as well as OVX rats given

either ethynylestradiol (0.1 mg/kg) or raloxifene (0.1 mg/

kg) as internal standards. Each new compound was

tested at a minimum of three doses. All control groups

and experimental groups included five animals at each

dose. Selected compounds were further evaluated in a

5-week, OVX rat model in which effects on bone mineral

density (BMD) were also examined.²⁷In this model,

daily oral dosing of Sprague-Dawley rats was initiated

4 days postovariectomy. Bone mineral density was

assessed at the distal metaphysis of the femur by X-ray

a

Reagents: (a) Me₃SnLi, THF, 99%; (b) R′Br, Pd(PPh₃)₄, DMF,

32-87%; (c) AlCl₃, EtSH, CH₂Cl₂, or BX₃, dichloroethane, 56-97%.

image analysis and is reported as percent protection

relative to sham-operated and OVX controls (Table 4).

Resu lts

In Vitr o. The in vitro results in Table 1 clearly

indicate the relative importance of the 6- and 4′-hydroxy

groups of raloxifene with respect to receptor binding and

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 149

Sch em e 6^a

a

Reagents: (a) TBSCl, Et₃N, THF; (b) PhN(Tf)₂, Et₃N, THF, 75-85%; (c) R′OH, CO, Pd(OAc)₂, dppp, Et₃N, DMF, 70-80 °C; (d) butyl

vinyl ether, Pd(OAc)₂, dppp, Et₃N, DMF, 75 °C; (e) HP(O)(OEt)₂, Pd(PPh₃)₄, Et₃N, CH₃CN, 75 °C; (f) HCtC-TMS, PdCl₂(PPh₃)₂(or

Pd(OAc)₂, dppp), Et₃N, DMF, 90 °C; (g) vinyl acetate, Pd(OAc)₂, dppp, Et₃N, DMF, 100 °C; (h) TBAF, THF; (i) aq HCl (THF); (j) R₁R₂NH₂Cl,

AlMe₃, toluene, 50 °C; (k) aq NaOH or LiOH, THF, reflux.

cell proliferation activity. Comparison of the binding

activities of 11a , 5c, and 4a with that of raloxifene

reveals 5-, 100-, and >100-fold decreases in relative

binding affinity (RBA) when the 4′-, 6-, or both hydroxy

groups, respectively, are replaced with a proton. Activ-

ity in the MCF-7 proliferation assay parallels binding

activity in this series. A similar trend exists for the

mono- and dimethoxy derivatives 5b,b′ and 4b. It has

previously been demonstrated that the 3-hydroxy of 17â-

estradiol has a greater influence on receptor binding

than does the 17-hydroxy.²⁸Our results, therefore,

imply that the 6-hydroxy group of raloxifene may be

imitating the phenolic 3-hydroxy of 17â-estradiol. Simi-

lar observations have been made in a series of hydroxy-

lated diarylindenes.²⁹The increased importance of the

6-hydroxy moiety relative to the 4′-hydroxy is further

evidenced by the relative activities of analogs bearing

additional 5- or 7-substituents (i.e., 9e,h -j) in compari-

son to those bearing analogous 3′-substituents (i.e.,

11p -s). Steric effects on binding have similarly been

reported for 2-substituted estradiols.³⁰Alternate place-

ment of the hydroxy at the 5-position (9c) resulted in a

3-fold reduction in binding but a 500-fold reduction in

MCF-7 growth inhibition. Placement at the 7-position

(5j) or 4-position (9b) produced even more dramatic

reductions. Notably, no 6-substituent included within

this study functioned as an effective replacement for

hydroxy with respect to ER binding or MCF-7 growth

inhibition.

4′-hydroxyl substituent in terms of receptor binding or

inhibition of MCF-7 proliferation can be identified from

Table 1. A 4′-fluoro substituent (5i) reduced ER binding

affinity by 2-fold or less relative to raloxifene. Further-

more, the 4′-chloro analog 5e inhibited MCF-7 prolifera-

tion with an IC₅₀of 1 nM, approximately 1000-fold

greater potency than the corresponding 6-chloro analog

5f. Movement of the 4′-hydroxyl to the 3′- and 2′-

positions (11b,c) reduced binding affinity by 2- and

6-fold and MCF-7 growth inhibition by factors of 15 and

50, respectively. Surprisingly, significant binding activ-

ity was observed for a number of derivatives in which

the entire 2-phenyl ring had been replaced. Naphthyl

(13a ,c), thienyl (13d ,e), alkyl (13f-h ), benzyl (13l), and,

to a lesser extent, cycloalkyl (13i-k ) all function as

effective replacements for the 2-phenyl ring with respect

to receptor binding. With the exception of 1-naphthyl,

however, these substitutions all reduced MCF-7 growth

inhibition by at least 10-fold. The only substitution

which was found to enhance ER binding affinity relative

to raloxifene was the incorporation of a 2′-alkyl sub-

stituent (11d ,n ). A similar, although more pronounced,

effect has been observed in the 2,3-diarylindene series,

and a torsional effect about the double bond between

the pendant aryl rings has been implicated.³¹Presum-

ably, the imposition of the carbonyl group reduces this

effect in the raloxifene series.

In Vivo. The in vivo data from the 4-day OVX rat

assay (Tables 2 and 3) provide a number of additional

insights into the effects of subtle structural modifica-

Conversely, a number of effective alternatives to the

150 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

Ta ble 1. ER Binding and Inhibition of MCF-7 Cell Proliferation by Raloxifene Analogs

ER

MCF-7 inhibtn

IC₅₀(nM)^c

ER

MCF-7 inhibtn

IC₅₀(nM)^c

no.

R

R′

RBA^a,b

no.

R

R′

RBA^a,b

estradiol

4-OH-tam^e

raloxifene

4a ^f

1.00

0.36

0.34

NA^d

0.5

0.2

300

1000

250

100

35

11m 6-OH

11n 6-OH

11o 6-OH

11p 6-OH

11q 6-OH

4′-CF₃

0.008

0.41

0.16

0.13

0.12

0.20

0.12

<0.01

0.05

1000

2

2′-Me, 4′-OH

2′-OMe, 4′-OH

3′-Me, 4′-OH

3′-Cl, 4′-OH

3′-F, 4′-OH

3′,5′-di(Me), 4′-OH

3′,4′-OCH₂O_-

4′-NO₂

2

1

none

6-OMe

6-OH

6-OMe

none

6-OH

6-Cl

6-OH

6-Me

6-OH

7-OH

4-OH

5-OH

4,6-di(OH)

5,6-di(OH)

5,6,7-tri(OMe)

6-NMe₂

5-F, 6-OH

5-Me, 6-OH

5,7-di(Me), 6-OH 4′-OH

4,7-di(Me), 6-OH 4′-OH

4,5-benzo, 6-OH 4′-OH

6-OMe

6-OH

6-OMe

6-OH

none

<0.002

0.073

0.008

0.006

0.003

<0.002

0.046

0.006

0.07

4b^f

5b

4′-OMe

4′-OH

4′-OMe

4′-OH

4′-Cl

2.3

0.3

100

500

30

11r

11s 6-OH

10t 6-OMe

16a 6-OH

6-OH

5b′

4c^g

5c^f

4d ^f

5e^f

NA^d

1

1000

50

300

2.3

300

190

100

350

400

350

ND^h

3

22a ^f6-CO₂Me 4′-OH

22c 6-CO₂H 4′-OH

22d 6-CONH₂4′-OH

22g 6-COMe 4′-OH

22h 6-PO₃Et₂4′-OH

22i 6-CtCH 4′-OH

<0.01

NA^d

4′-Cl

NA^d

1000

60

200

20

50

325

200

40

5f^f

4′-OH

4′-Me

4′-OH

4′-F

4′-OH

4′-OMe

4′-OH

<0.01

0.008

<0.01

0.029

0.07

5g^f

5h ^f

NA^d

0.19

0.02

<0.002

0.10

0.05

5i^f

5j

9b

9c

9d

23a 6-OH

23b 6-OH

23c 6-OH

23d 6-OH

23eⁱ6-OH

4′-CO₂Me

4′-CO₂Et

4′-CO₂H

4′-CONH₂

4′-CON(H)Me

4′-CONMe₂

4′-COMe

4′-PO₃Et₂

4′-CtCH

4′-CHdCH₂

1′-naphthyl

2′-naphthyl

4′-OH-1′-naphthyl

2′-thienyl

3′-thienyl

methyl

ethyl

isopropyl

0.06

0.012

0.039

0.016

0.040

0.075

0.010

0.12

0.10

0.20

0.067

0.16

0.30

0.20

0.15

0.13

0.15

0.08

0.09

0.19

9e

<0.01

0.05

8f^f

23f

6-OH

20

32

9g

9h

9i

9j

9k

9l

10a

11a ^f

11b

11c

11d

11e

11f

11g

11h

11i

11j

10k

11l

0.004

0.098

0.07

0.005

0.002

0.009

<0.002

0.062

0.057

0.16

0.40

0.29

0.012

0.03

0.01

23g 6-OH

23h 6-OH

210

0.8

7

0.8

80

2

20

10

35

20

3

5

2.5

2

5

100

ND^h

500

100

500

>1000

2.5

23i

23j

6-OH

13a 6-OH

13b 6-OH

13c 6-OH

13d 6-OH

13e 6-OH

none

2′-OH

3′-OH

2′-Me

3′-F

10

3.2

0.7

2.5

5

30

10

100

ND^h

600

100

13f

6-OH

13g 6-OH

13h 6-OH

4′-Et

13i

13j

6-OH

cyclopentyl

cyclohexyl

trans-4′-OH-cyclohexyl

4′-hydroxybenzyl

4′-pyridyl

4′-i-Pr

4′-n-Bu

4′-Ph

4′-SMe

13k 6-OH

13l 6-OH

16b 6-OH

16c 6-OH

0.011

0.04

4′-CH₂OH <0.01

4′-CH₂SEt 0.07

0.056

0.005

4′-pyridyl N-oxide

a

b

RBA ) relative binding affinity by competition with [³H]-17â-estradiol. Average of at least two determinations. Values are (10%.

^cDose required to give 50% inhibition of a maximally effective (10^-11) dose of 17â-estradiol. Average of at least three determinations.

Values are (10%. NA ) not active at the doses tested. ^e4-Hydroxytamoxifen, the primary biologically active metabolite of tamoxifen.

d

^fTested as the hydrochloride salt. Tested as the citrate salt. ND ) not determined. Tested as the trifluoroacetate salt.

g

h

i

tions on the complex biological activities of SERMs. The

inconsistent correlation between elevation of uterine

weight and stimulation of other uterine parameters in

this series led to reliance on uterine EPO activity as

the primary indicator of estrogenic effects on the

uterus.^26,32,33While both ethynylestradiol and tamox-

ifen potently reduce serum cholesterol, they also induce

significant increases in uterine EPO while raloxifene

does not. We have used this parameter, therefore, to

discriminate compounds which demonstrate a tamox-

ifen-like profile from those whose activity parallels that

of raloxifene.^32,34

Compounds in which the 6- and/or 4′-hydroxyls are

absent (4a , 5c, 11a ) or are capped as methyl ethers (4b,

5b,b′) exhibited potent effects on serum cholesterol

reduction and mild to moderate increases in uterine

weight without increases in EPO, similar to raloxifene

itself. When considered with the receptor binding data

for these compounds, these data imply potential meta-

bolic activation either by hydroxylation (as is observed

with tamoxifen) or by demethylation. The improved

potency and relatively flat dose-response curves ob-

tained for these analogs may be indicative of improved

bioavailability. Presence of the hydroxyls at other

positions about the 2-arylbenzothiophene (9b,c, 5j,

11b,c) impaired their ability to lower serum cholesterol.

Only the 6,3′-dihydroxy analog 11c maintained a sig-

nificant level of activity, with potency decreased ap-

proximately 10-fold from that of raloxifene.

As was observed in the in vitro assays, the placement

of an additional 4-, 5-, or 7-substituent on the ben-

zothiophene (9h ,i) resulted in reduced in vivo activity.

Conversely, additional substituents on the pendant

phenyl ring had a more modest effect on biological

activity. The 2′-methyl (11n ), 3′-fluoro (11r ), and 2′-

methoxy (11o) analogs were particularly potent with

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 151

Ta ble 2. Serum Cholesterol-Lowering and Uterine Effects of 2-Aryl Raloxifene Analogs in the OVX Rat

serum cholesterol (% decr OVX)^c

d

uterine weight

uterine EPO

ED₅₀

b

no.

R

R′

MED (% incr OVX)^a

MED (V_max

)

0.001 mg/kg

0.01 mg/kg

0.1 mg/kg

(mg/kg)

17R-ethinyl estradiol

0.01 (41.5 ( 13.7)

0.1 (281.7 ( 6)

32.0* ( 10.4

57.1* ( 4.9

84.5* ( 1.7

0.005

0.1 mg/kg

39.2* ( 4.5

44.9* ( 8.0

59.4* ( 2.0

62.2* ( 4.2

65.2* ( 7.2

54.8* ( 3.5

70.7* ( 5.6

55.6* ( 4.5

29.6* ( 6.7

10.4 ( 7.7

1.0 mg/kg

71.1* ( 4.3

66.7* ( 4.1

72.6* ( 6.1

78.0* ( 3.4

75.6* ( 2.8

64.5* ( 5.3

69.9* ( 5.5

10.0 mg/kg

67.0* ( 2.2

74.0* ( 2.1

45.6* ( 5.8

68.5* ( 2.6

72.6* ( 4.0

50.0* ( 9.9

67.4* ( 4.2

tamoxifen

0.1 (62.4 ( 3.0)

0.1 (57.1 ( 3.3)

0.2

raloxifene

none

0.1 (23.5 ( 10.0) >10

4a ^e

none

4′-OMe

4′-OH

none

4′-OH

0.1 (59.2 ( 9.2)

0.1 (57.3 ( 9.5)

>10

<0.1

>10

4b^e6-OMe

5b

6-OH

6-OMe

none

>10

5b′

1.0 (33.5 ( 10.1) >10

0.1 (39.2 ( 15.7) >10

5c^e

11a ^e6-OH

0.1 (38.7 ( 3.9)

>10

10 (43.5 ( 18.2)

>10

10 (25.2 ( 10.8)

>10

0.1 (53.2 ( 3.2)

>10

53.4* ( 12.5 66.0* ( 4.1

9b

9c^e

5j

4-OH

5-OH

7-OH

18.0* ( 5.2

3.7 ( 13.6

-6.1 ( 18.6 -11.7 ( 16.7 -3.4 ( 12.0

31.8* ( 6.3

22.6 ( 3.9

11b 6-OH

11c 6-OH

2′-OH

3′-OH

4′-OH

7.8 ( 10.3

24.3 ( 4.9

4.6 ( 5.0

19.5 ( 5.7

52.3* ( 5.5

4.1 ( 5.6

33.2* ( 11.8 >10

49.1* ( 6.3

31.6* ( 6.4

43.7*

0.8

>10

5.4

9h

9i

5-F, 6-OH

5-Me, 6-OH 4′-OH

-4.3

42.2*

11d 6-OH

11e 6-OH

11n 6-OH

11o 6-OH

11p 6-OH

11q 6-OH

2′-Me

3′-F

31.7 ( 8.5

18.6 ( 18.9

39.2* ( 18.5

58.8* ( 12.6

28.4 ( 10.8

18.6 ( 12.5

45.9* ( 6.9

23.1 ( 11.2

-5.1 ( 18.7

16.9 ( 11.6

13.8 ( 11.3

-16.4 ( 12.5

38.6* ( 3.2

62.0* ( 9.3

62.6* ( 2.6

79.0* ( 6.0

73.9* ( 3.9

52.7* ( 6.2

59.2* ( 5.3

29.3 ( 14.5 >10

67.3* ( 4.8

68.5* ( 3.9

71.6* ( 9.6

49.7* ( 9.6

71.5* ( 2.8

55.3* ( 6.0

1.0

2′-Me, 4′-OH

2′-OMe, 4′-OH

3′-Me, 4′-OH

3′-Cl, 4′-OH

3′-F, 4′-OH

3′,5′-Me, 4′-OH

4′-OH

4′-Cl

4′-Me

4′-F

4′-Et

4′-i-Pr

4′-n-Bu

4′-Ph

4′-SMe

4′-CH₂SMe

4′-CF₃

4′-CO₂Me

4′-CO₂H

4′-CONH₂

4′-CtCH

4′-CHdCH₂

0.1 (54.5 ( 8.2)

0.1 (64.1( 17.8)

>10

0.4

<0.1

1.0

1.2

0.4

1.8

>10

1.0 (34.2 ( 1.0)

>10

10 (30.3 ( 9.3)

0.1 (34.3 ( 7.5)

1.0 (33.8 ( 8.4)

10 (49.6 ( 11.1)

1.0 (23.9 ( 7.2)

0.1 (37.5 ( 3.2)

1.0 (40.8 ( 8.8)

10 (30.7 ( 11.5)

1.0 (27.8 ( 7.7)

11r

6-OH

11s 6-OH

1.0 (40.8 ( 20.7)

40.2* ( 11.3 69.1* ( 3.6

5f^e

6-Cl

>10

-6.8 ( 13.8

33.9* ( 6.0

42.8* ( 7.5

12.5 ( 8.7

37.6* ( 7.0

21.6 ( 10.8 >10

61.0* ( 4.6

53.3* ( 3.2

10.5 ( 6.3

65.8* ( 2.4

65.0* ( 7.7

5h ^e6-Me

22a ^e6-CO₂Me

22c 6-CO₂H

22d 6-CONH₂

2.8

9.0

-33.9 ( 17.4 -14.9 ( 18.9

22i

5e^e

5g^e

5i^e

6-CtCH

6-OH

39.4* ( 7.9

32.3* ( 9.5

12.2 ( 5.5

20.6 ( 23.5

3.3 ( 18.8

58.7* ( 3.3

69.9* ( 6.9

0.5

0.3

2.9

1.4

4.3

3.6

2.3

2.4

0.9

2.5

0.4

3.8

0.1 (56.5 ( 12.2) >10

1.0 (34.6 ( 5.8)

1.0 (50.2 ( 5.2)

10 (29.7 ( 15.6)

0.1 (24.9 ( 7.4)

>10

26.5* ( 15.8 69.1* ( 6.0

46.0* ( 3.2

71.9* ( 6.7

11f

1.0 (39.9 ( 15.3)

37.2* ( 11.8 57.4* ( 8.3

47.1* ( 10.9 48.5* ( 11.3

11g 6-OH

11h 6-OH

1.0 (33.3 ( 0.9) -24.1 ( 10.2

>10

10 (20.8 ( 3.8)

1.0 (25.4 ( 0.9)

1.0 (37.5 ( 0.9)

1.0 (36.9 ( 0.9)

5.0 (16.4 ( 2.1)

10 (13.2 ( 1.2)

21.3 ( 5.8

12.9 ( 9.4

27.7 ( 9.7

21.7 ( 8.8

45.5* ( 7.8

23.8 ( 11.7

3.1 ( 7.1

-3.2 ( 9.3

9.1 ( 25.4

-7.0 ( 12.1

14.5 ( 12.3

37.0* ( 9.1

72.0* ( 6.2

68.5* ( 10.6

11i

11j

11l

6-OH

0.1 (50.3 ( 10.1)

1.0 (50.2 ( 7.2)

1.0 (30.5 ( 6.5)

5.0 (37.4 ( 5.8)

1.0 (37.2 ( 6.4)

51.5* ( 10.1 75.3* ( 5.7

40.1* ( 8.4

63.0* ( 4.9

11m 6-OH

23a 6-OH

23c^g6-OH

23d 6-OH

47.9* (10.4 71.5* ( 5.6^f

42.1* ( 5.1

-8.8 ( 9.5

-21.3* ( 8.6

56.1* ( 2.2

24.6 ( 3.1

10.0 ( 3.5

>10

23i

23j

6-OH

32.7* ( 12.4 35.8* ( 11.5 >10

41.5* ( 7.5

0.1 (26.9 ( 2.3)

1.0 (48.0 ( 0.0)

49.7* ( 9.6

10

a

MED ) minimally effective dose (mg/kg of body weight) at which a statistically significant (p e 0.05) increase in uterine weight/body

b

weight was observed. Activity at the MED is expressed as percent increase relative to OVX controls ( standard error. MED at which

a significant (>5-fold increase relative to OVX control and value of V_maxg 10) increase in EPO activity was observed. Activity at the

MED is expressed as V_max( standard error. ^cPercent decrease in serum cholesterol relative to OVX controls ( standard error. Statistically

d

significant (p e 0.05) differences are denoted with an asterisk. Dose required to reduce serum cholesterol by 50% relative to OVX controls.

^eTested as the hydrochloride salt. ^fMaximum dose tested ) 5.0 mg/kg. Tested as the trifluoroacetate salt.

g

respect to cholesterol reduction, although the latter

compound showed some evidence of uterine stimulation.

In general, replacement of the 6-hydroxy substituent

with various functional groups (5f,h , 22a -i) led to a

dramatic reduction in in vivo activity. Notable excep-

tions include the 6-carbomethoxy and 6-alkynyl analogs

22a ,i which effectively lowered serum cholesterol with-

out stimulation of uterine EPO. In 22i, the acetylenic

hydrogen may serve to mimic the hydrogen bond-

donating capability of the phenolic hydroxy. The in vivo

activity of 22a is surprising, in light of its low binding

affinity. Metabolic conversion to the corresponding acid

22c may occur; however, 22c is less potent in vivo and

also shows very low receptor affinity. Furthermore, 22c

is inactive in the MCF-7 proliferation assay, while 22a

has an IC₅₀of approximately 30 nM. The corresponding

amide 22d is also essentially inactive.

In contrast, replacement of the 4′-hydroxy moiety with

small electronegative groups (5e,i) led to analogs which

demonstrate an in vivo profile similar to that of ralox-

ifene, albeit with slightly lower potency. Larger sub-

stituents at this position (11f-m , 23a ,j) tended to

provoke increased uterine stimulation. Of particular

interest is the trifluoromethyl analog 11m which had

152 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

Ta ble 3. Serum Cholesterol-Lowering and Uterine Effects of 2-Alkyl, 2-Naphthyl, and 2-Heteroaryl Raloxifene Analogs in the OVX

Rat

serum cholesterol (% decr OVX)^c

uterine weight

uterine EPO

b

d

no.

R

MED (% incr OVX)^a

MED (V_max

)

0.001 mg/kg

0.01 mg/kg

0.1 mg/kg

ED₅₀(mg/kg)

17R-ethynylestradiol

0.01 (41.5 ( 13.7)

0.1 (281.7 ( 6)

32.0* ( 10.4 57.1* ( 4.9 84.5* ( 1.7

0.005

0.1 mg/kg

39.2* ( 4.5

44.9* ( 8.0

40.1* ( 14.9 53.9* ( 5.1 67.8* ( 4.1

48.1* ( 6.8 54.5* ( 6.9 63.6* ( 3.6

31.6* ( 15.2 54.7* ( 7.4 59.9* ( 4.8

-18.6 ( 12.4

0.6 ( 18.9

7.2 ( 6.6

-16.6 ( 11.8

8.3 ( 13.3

4.4 ( 17.3

12.4 ( 9.9

18.4 ( 16.0

-0.1 ( 9.2

48.7* ( 4.0

-17.6 ( 12.8

1.0 mg/kg 10.0 mg/kg

71.1* ( 4.3 67.0* ( 2.2

66.7* ( 4.1 74.0* ( 2.1

tamoxifen

raloxifene

13a 1-naphthyl

13b 2-naphthyl

13c 4-hydroxy-1-naphthyl

13d 2-thienyl

13e 3-thienyl

16b 4-pyridyl

16c 4-pyridyl N-oxide

13f Me

13g Et

0.1 (62.4 ( 3.0)

0.1 (23.5 ( 10.0)

>10

0.1 (57.1 ( 3.3)

0.2

0.5

0.2

1.2

>10

0.1 (12.3 ( 0.3)

0.1 (29.4 ( 0.6)

>10

0.1 (72.7 ( 5.3)

0.1 (59.6 ( 19.7)

1.0 (32.4 ( 18.3)

10 (54.3 ( 10.8)

1.0 (33.3 ( 10.2)

>10

-0.9 ( 8.0

29.8* ( 6.0 31.8* ( 5.9

24.0 ( 4.4 47.6* ( 9.9

51.4* ( 10.8

11

>10

14.6

>10

1.8

1.8 ( 10.1 42.6* ( 6.2

53.8* ( 9.5 62.9* ( 7.3

26.5 ( 26.4 31.1 ( 6.9

30.5* ( 6.5 35.0* ( 16.1

55.6* ( 5.0 69.6* ( 7.1

52.9* ( 9.9 61.7* ( 2.3

41.1* ( 4.6 60.4* ( 3.1

41.7* ( 8.8 54.0* ( 5.5^e

>10

10 (55.03 ( 12.2)

>10

13h i-Pr

>10

1.2

2.1

1.0

4.0

13i cyclopentyl

13j cyclohexyl

13k trans-4-hydroxycyclohexyl

13l 4-hydroxybenzyl

>10

1.0 (30.2 ( 5.9)

0.1 (46.7 ( 4.9)

5.0 (36.9 ( 5.6)

a

MED ) minimally effective dose (mg/kg of body weight) at which a statistically significant (p e 0.05) increase in uterine weight/body

b

weight was observed. Activity at the MED is expressed as percent increase relative to OVX controls ( standard error. MED at which

a significant (>5-fold increase relative to OVX control and value of V_maxg 10) increase in EPO activity was observed. Activity at the

MED is expressed as V_max( standard error. ^cPercent decrease in serum cholesterol relative to OVX controls ( standard error. Statistically

d

significant (p e 0.05) differences are denoted with an asterisk. Dose required to reduce serum cholesterol by 50% relative to OVX controls.

^eMaximum dose tested ) 5.0 mg/kg.

Ta ble 4. Bone Protective Effects of Raloxifene Analogs in the

OVX Rat

potent in vivo activity but was nearly inactive in the in

vitro assays. Although the carbomethoxy replacement

bone mineral density, distal femur

(23a ) is similar in activity to the 6-carbomethoxy analog

22a , the corresponding acetylenic compound 23i is

substantially less potent than its 6-substituted coun-

terpart 22i. Conversely, replacement of the 6-hydroxy

with chloro (5f) resulted in a substantial reduction of

in vivo activity, while the 4′-substituted analog 5e

maintained activity similar to that of raloxifene. Clearly

the structural requirements associated with the two

phenol moieties differ, and changes at these positions

affect in vivo biological activity in different ways. These

differences are not surprising since the natures of the

hydroxy substituents in the natural ligand are dis-

similar, one being phenolic and the other an alkyl

hydroxy. Indeed, a similar divergence of biological

activity for 3- and 17-modified estradiol analogs has

been observed.³⁵

(% protection vs OVX)^a

0.01

mg/kg/day

0.1

mg/kg/day

1.0

mg/kg/day

10.0

mg/kg/day

no.

17R-ethynyl-

69.2* ( 7.7

estradiol^b

raloxifene^b

5c^c,d

11c

11r

13c

9.6 ( 5.8

50.0* ( 5.8 57.7* ( 5.8 53.8* ( 5.8

-1.3 ( 12.7

-4.0 ( 9.6

41.8* ( 19.0 26.7* ( 14.7

-30.9 ( 20.7^e79.7* ( 17.1^e44.2* ( 22.9^e

34.1 ( 17.2 68.0* ( 15.1 69.8* ( 20.5

34.5 ( 36.5

35.9* ( 14.0 42.3* ( 13.7 82.5* ( 14.0

13k

22a

17.0 ( 8.4

-10.0 ( 8.4

61.3* ( 30.0 67.4* ( 15.0

17.0 ( 8.3 43.9* ( 23.1

a

Measured by X-ray image analysis. Values are given as

percent protection relative to OVX controls ( standard error, with

sham control values defined as 100% and OVX controls defined

as 0. ^bValues taken from ref 25. ^cTested as the hydrochloride salt.

d

Tested in 75-day old rats. ^eBMD determined by quantitative

computed tomography at the proximal tibia.

A number of the analogs in which the 2-phenyl ring

was replaced by alkyl, cycloalkyl, naphthyl, heteroaryl,

or benzyl substituents also demonstrated potent in vivo

biological activity (Table 3). In particular, naphthyl

(13a -c), methyl (13f), and cycloalkyl (13i-k ) analogs

potently reduced serum cholesterol with minimal uter-

ine stimulation. The surprising finding that substitu-

ents as small as methyl and as large as naphthyl give

relatively similar biological profiles is intriguing. It may

indicate that the positive interactions afforded by the

2-phenyl substituent are of relatively minor importance

with respect to their influence on biological activity. The

undesirable interactions introduced by larger substit-

uents, particularly at the 4′-position, appear to play a

greater role in determining the biological profile of these

compounds.

Some of the analogs in this study were further

evaluated in an OVX rat model of estrogen deficiency-

induced osteopenia, and Table 4 contains a representa-

tive sampling of these results. All of the analogs tested

prevented bone loss to some degree; however, due to the

nature and variability of the assay, quantitative com-

parisons are somewhat speculative. Nevertheless, a

number of the compounds showed efficacy similar to

that observed for raloxifene and estrogen.

Discu ssion

In this study, we have employed a battery of assays

which reflects by design the unique pattern of tissue-

selective estrogen agonist/antagonist activities that have

been previously described for the SERM raloxifene.^23-25

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 153

the pure anti-estrogen ICI-164384, a feature which may

be reflected by raloxifene’s unique profile of estrogen

agonist/antagonist effects.^39a,41To the extent that struc-

tural modification of the raloxifene core disrupts or

alters this receptor-ligand conformation, different sets

of estrogen responsive genes may be influenced posi-

tively or negatively, resulting in an altered biological

profile. For that reason, a compound which potently

inhibits MCF-7 proliferation may not effectively induce

the genes responsible for the reduction of serum cho-

lesterol or for the maintenance of bone density.⁴²The

recent identification of a novel ER expressed in prostate

and ovary adds a further layer of complexity.⁴³Clearly,

the agonist/antagonist profile for any ER modulator

must be determined for each target tissue in question.

As additional target tissues are explored and new

estrogen-regulated genes are discovered, we anticipate

the further development of SERMs with unique selec-

tivity profiles.

In conclusion, we have explored a number of the

structural features associated with the 2-arylben-

zothiophene core of raloxifene and have demonstrated

that some of those features are critical for maintenance

of the raloxifene profile while others are more flexible.

In particular, the 6-hydroxy and, to a lesser extent, the

4′-hydroxy substituents are important for receptor bind-

ing and in vitro activity and appear to mimic the

corresponding 3- and 17â-hydroxy substituents of es-

tradiol. Modified or additional substitution of the

benzothiophene generally results in reduced biological

activity; however, some variance in the substitution

pattern of the 2-aryl ring is tolerated. Indeed, the entire

2-aryl ring can be replaced by alkyl, cycloalkyl, or

naphthyl substituents without disrupting the SERM

profile of in vitro and in vivo biological activity, although

increased steric bulk at the 4′-position leads to increased

uterine stimulation. Several novel structural variants

including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy

analogs maintain activity similar to that of raloxifene.

Nevertheless, the 6-hydroxy-2-(4′-hydroxyphenyl) sub-

stitution pattern of raloxifene appears to be nearly

optimal for both in vitro and in vivo activity, especially

with respect to serum cholesterol reduction and protec-

tion against ovariectomy-induced bone loss without

significant stimulation of the uterus.³³Studies associ-

ated with modification of other portions of the raloxifene

structure will be reported in due course.

F igu r e 1. Correlation of ER binding with inhibition of MCF-7

proliferation (r ) -0.586).

Thus, ER binding activity is requisite for SERM activ-

ity.³⁶Inhibition of MCF-7 cell proliferation and the lack

of in vivo increases in uterine weight and uterine EPO

are predictive of estrogen antagonist or neutral activi-

ties in sexually dimorphic tissues. Finally, reduction

in serum cholesterol and preservation of bone mineral

density in the OVX rat are indicative of the desirable

estrogen agonist effects demonstrated by SERMs.

The overall correlation of inhibition of MCF-7 prolif-

eration with receptor binding for this series was rela-

tively poor (Figure 1, r ) -0.586). In several cases,

compounds with similar RBA′s exhibited up to 100-fold

differences in MCF-7 activity (i.e., 13d vs raloxifene).

For some analogs, this discrepancy may arise from

partial agonist activity, or it may reflect the complex

nature of the interactions which determine biological

activity. Clearly, receptor binding is only the first step

in the pathway which leads to inhibition of tumor cell

proliferation.

The correlation of in vivo biological activity (as

measured by ED₅₀for cholesterol lowering) with binding

(RBA) or inhibition of MCF-7 proliferation (IC₅₀) is

disappointing (r ) 0.057 and 0.096, respectively), even

when the importance of hydroxy substituents for in vitro

activity (vide supra) is accounted for by limiting the set

to those compounds which contain at least one hydroxy

moiety. Reasons for this anomoly presumably include

differences in absorption, metabolism, and distribution.

Indeed, a strong correlation (r ) 0.93) between choles-

terol lowering and ER binding has recently been dem-

onstrated for a smaller set of analogs, in which the

position of hydroxylation and substitution pattern of the

2-arylbenzothiophene was less variable.³⁷The flat

dose-reponse and substantial reduction in maximum

efficacy observed with some analogs (e.g., 9b, 11d , 5h )

may imply that alternative mechanisms of action which

do not involve the ER, such as those recently proposed

to explain some of the biological activities of tamoxifen,

are operable in these cases.³⁸Nevertheless, additional

factors associated with the mechanisms by which the

ER controls gene transcription may also be involved. It

has recently been proposed that the conformation of the

ER-ligand complex is dependent upon the nature of the

interacting ligand and that the distinct conformation

induced by a particular ligand differentially affects

which genes are transcriptionally activated.^39,40Fur-

thermore, it has been demonstrated that the conforma-

tion of the ER-raloxifene complex is distinct from those

of the ER complexed with 17â-estradiol, tamoxifen, or

Exp er im en ta l Section

Ch em istr y. All reactions were carried out under a nitrogen

atmosphere. All solvents and reagents were used as obtained

from commercial sources unless otherwise indicated. Flash

chromatography was carried out on E. Merck Kieselgel 60

(230-400 mesh). Radial chromatography was carried out on

a Harrison Research Chromatotron, using Analtech precoated

rotors (1-6 mm) under an atmosphere of nitrogen or ammonia.

Preparative HPLC was carried out on Waters PrepPak silica

gel cartridges using a Waters Prep LC 2000 or Prep 500

system. Benzothiophenes 2a -h were prepared by literature

methods.^11,14Preparations of benzothiophenes 2i,j are in-

cluded in the Supporting Information. Aminobenzothiophenes

6a -l were prepared in two steps from the corresponding

benzaldehydes and the lithium anion of dimethylthioforma-

mide by the method of Hopkinson and Lee-Ruff.¹⁶The

preparation of compounds 3 and 4b has been previously

described.¹¹Grignard reagents were obtained from com-

mercial sources or were prepared from the alkyl or aryl halides

by literature methods.⁴⁴Silylated bromo alcohols and bro-

154 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

mophenols, utilized for the synthesis of Grignard reagents,

were prepared by the method of Corey.⁴⁵The abbreviations

THF, DMF, DCE, DMSO, TBS, TBAF, and DMAP refer to

tetrahydrofuran, dimethylformamide, 1,2-dichloroethane, dim-

ethyl sulfoxide, tert-butyldimethylsilyl, tetra-N-butylammo-

nium fluoride, and (N,N-dimethylamino)pyridine, respectively.

Fast atom bombardment mass spectra (FAB) were obtained

on a VG ZAB-3 instrument; field desorption mass specta (FD)

were obtained on a VG 70SE instrument; high-resolution mass

specta (HRMS) were obtained on a VG Analytical ZAB2-SE

instrument. NMR spectra were recorded on a GE QE300

specrometer at 300 MHz for proton and 75 MHz for carbon-

13. All spectra were recorded in deuteriochloroform unless

otherwise indicated. Elemental analyses were carried out by

the Physical Chemistry Department of Lilly Research Labo-

ratories and are within (0.4% of theory unless otherwise

noted.

[2-(4-Ch lor op h en yl)b en zo[b]t h ien -3-yl][4-[2-(1-p ip e-

r id in yl)eth oxy]p h en yl]m eth a n on e (4d ). A solution of 2d

(1.0 g, 4.1 mmol) and 3 (3.0 g, 9.8 mmol) in DCE was treated

with AlCl₃(1.5 g, 11.2 mmol) and heated at reflux for 2 days.

After cooling to room temperature, the solvent was removed

in vacuo and the residue was suspended in 1:1 ethanol:1 M

NaOH and heated for 1 h to hydrolyze residual acid chloride.

The resulting mixture was filtered hot and concentrated in

vacuo to a dark, aqueous solution. This mixture was extracted

with CHCl₃(3 × 300 mL), and the combined organic extracts

were dried (Na₂SO₄) and concentrated to provide, after flash

chromatography (acetone), the title compound as a yellow oil.

This material was treated with concentrated HCl (1 mL) in

acetone (25 mL) to give 1.1 g (52%) of the corresponding HCl

salt as a yellow solid, mp 95-98 °C: ¹H NMR δ 1.3-1.6 (m,

1H), 1.8-2.1 (m, 5H), 2.79 (dd, J ) 9.0, 7.0 Hz, 2H), 3.40 (m,

2H), 3.53 (d, J ) 12 Hz, 2H), 4.81 (m, 2H), 6.80 (d, J ) 9.0 Hz,

2H), 7.25 (d, J ) 9.0 Hz, 2H), 7.3-7.5 (m, 4H), 7.66 (d, J ) 6.0

Hz, 1H), 7.77 (d, J ) 9.0 Hz, 2H), 7.90 (d, J ) 6 Hz, 1H); MS

(FD) m/e 475 (M⁺). Anal. (C₂₈H₂₆ClNO₂S‚HCl‚H₂O) C,H,N.

(2-P h enylbenzo[b]th ien -3-yl)[4-[2-(1-piper idinyl)eth oxy]-

p h en yl]m eth a n on e (4a ). The title compound was prepared

in 36% yield from 2a and 3 by a method similar to that

described for 4d ; analyzed as the corresponding HCl salt: ¹H

NMR (DMSO-d₆) δ 1.34 (m, 1H), 1.63 (m, 1H), 1.74 (m, 4H),

2.91 (m, 2H), 3.41 (m, 4H), 4.42 (m, 2H), 6.96 (d, J ) 8.5 Hz,

2H), 7.38 (m, 8H), 7.70 (d, J ) 8.5 Hz, 2H), 8.06 (m, 1H); MS

(EI) m/e 440 (M - H)⁺. Anal. (C₂₈H₂₇NO₂S‚HCl) C,H,N.

[2-(4-Met h ylp h en yl)-6-m et h oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (4g). The

title compound was prepared from 2g and 3 by a method

similar to that described for 4d . The free base was converted

to the HCl salt using acetone/concentrated HCl to afford 62%

of a beige solid, mp 185 °C: ¹H NMR (free base) δ 1.4-1.6 (m,

2H), 1.6-1.8 (m, 4H), 2.35 (s, 3H), 2.5-2.8 (m, 4H), 3.90 (m,

2H), 3.95 (s, 3H), 4.1-4.3 (m, 2H), 6.80 (d, J ) 8 Hz, 2H), 7.00

(d, J ) 10 Hz, 1H), 7.10 (d, J ) 8 Hz, 2H), 7.3-7.4 (m, 3H),

7.55 (d, J ) 10 Hz, 1H), 7.80 (d, J ) 8 Hz, 2H); MS (FD) m/e

485 (M⁺). Anal. (C₃₀H₃₁NO₃S‚HCl‚H₂O) C,H,N.

[2-[4-[(4-F lu or ob en zoyl)oxy]p h en yl]-7-[(4-flu or ob en -

zoyl)oxy]ben zo[b]th ien -3-yl][4-[2-(1-p ip er id in yl)eth oxy]-

p h en yl]m eth a n on e (4j). The title compound was prepared

in 84% yield from 2j and 3 by a method similar to that

described for 4d : ¹H NMR δ 1.4-1.7 (m, 6H), 2.50 (br s, 4H),

2.73 (m, 2H), 4.13 (m, 2H), 6.83 (m, 2H), 7.1-7.6 (m, 11H),

7.78 (m, 2H), 8.18 (m, 2H), 8.33 (m, 2H); MS (FD) m/e 717

(M⁺). Anal. (C₄₂H₃₃F₂NO₆S) C,H,N.

[2-(4-Meth oxyp h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (5b) an d [2-(4-

H yd r oxyp h en yl)-6-m et h oxyb en zo[b]t h ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5b′). A solution

of 4b (32.3 g, 60 mmol) in CH₂Cl₂(360 mL) was treated with

AlCl₃(48.0 g, 360 mmol), stirred until dissolution was com-

plete, and treated with n-propanethiol (4.57 g, 5.43 mL, 60

mmol). The mixture was heated at 33-35 °C for 1.5 h, cooled

to 0 °C, and treated with THF (180 mL), 2.5 M HCl (60 mL),

and water (180 mL). The mixture was diluted with CH₂Cl₂

(200 mL) and water (200 mL), the layers were separated, and

the aqueous layer was brought to pH 10 with aqueous NaOH.

The aqueous layer was extracted with CH₂Cl₂(200 mL), and

the organic layer was concentrated to give 28.7 g of a yellow

solid. The residue was partitioned between ether (200 mL)

and water (200 mL) at reflux (3×), and the aqueous layer was

acidified with 2.5 M HCl and washed with CH₂Cl₂(200 mL).

The organic layer was neutralized with saturated NaHCO₃and

concentrated to provide 7.7 g (26%) of a mixture of monomethyl

ethers 5b,b′. The mixture was combined with samples from

other runs and purified via gravity chromatography (silica gel,

10:1 CHCl₃:MeOH). 5b was obtained as a yellow foam:^{46,47 1}

H

NMR (DMSO-d₆) δ 1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.38 (m,

4H), 2.61 (t, J ) 5.8 Hz, 2H), 3.71 (s, 3H), 4.08 (t, J ) 5.8 Hz,

2H), 6.8-7.0 (m, 5H), 7.2-7.4 (m, 4H), 7.67 (d, J ) 8.8 Hz,

2H) 9.83 (s, 1H). Anal. (C₂₉H₂₉NO₄S) C,H,N.

5b′ was further purified by recrystallization from Et₂O:

MeOH, to give a yellow powder: ¹H NMR (DMSO-d₆) δ 1.3-

1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.39 (m, 4H), 2.62 (t, J ) 5.8 Hz,

2H), 3.84 (s, 3H), 4.08 (t, J ) 5.8 Hz, 2H), 6.69 (d, J ) 8.6 Hz,

2H), 6.92 (d, J ) 8.8 Hz, 2H), 6.99 (dd, J ) 8.8, 2.3 Hz, 1H),

7.22 (m, 1H), 7.33 (d, J ) 8.9 Hz, 1H), 7.65 (m, 4H), 9.76 (s,

1H). Anal. (C₂₉H₂₉NO₄S) C,H,N.

[2-(4-Hyd r oxyp h en yl)ben zo[b]th ien -3-yl][4-[2-(1-p ip e-

r id in yl)eth oxy]p h en yl]m eth a n on e (5c). A slurry of 2c (3.8

g, 16 mmol) and 3 (5.5 g, 18 mmol) in DCE (250 mL) was cooled

to 0 °C and treated with AlCl₃(6.4 g, 48 mmol). After 1.5 h,

ethanethiol (5.0 g, 6.0 mL, 80 mmol) was added followed by

additional AlCl₃(4.0 g, 30 mmol) and the mixture stirred at 0

°C for 1 h. The reaction was quenched with THF (50 mL)

followed by concentrated HCl (100 mL), and the layers were

separated. The organic layer was dried (MgSO₄) and concen-

trated, and the residue was purified via flash chromatography

(CH₂Cl₂, 0-10% MeOH) to provide 2.45 g (29%) of a yellow

foam which crystallized upon trituration with MeOH: ¹H NMR

(270 MHz, DMF-d₇) δ 1.4-1.6 (m, 1H), 1.7-1.9 (m, 3H), 1.9-

2.2 (m, 2H), 3.0-3.2 (m, 2H), 3.5-3.7 (m, 4H), 4.65 (t, J ) 4.3

Hz, 2H), 6.86 (d, J ) 7.9 Hz, 2H), 7.03 (d, J ) 7.9 Hz, 2H),

7.35 (d, J ) 7.9 Hz, 2H), 7.45 (m, 2H), 7.59 (m, 1H), 7.79 (d, J

) 7.9 Hz, 2H), 8.13 (m, 1H), 10.22 (s, 1H), 11.98 (br s, 1H).

Anal. (C₂₈H₂₇NO₃S‚HCl) C,H,N.

[2-(4-Met h oxyp h en yl)-6-m et h ylb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (4h ). The

title compound was prepared from 2h and 3 by a method

similar to that described for 4d . The free base was converted

to the HCl salt using acetone/concentrated HCl to afford 89%

of a beige solid, mp 225-228 °C: ¹H NMR (DMSO-d₆) δ 1.3-

1.5 (m, 1H), 1.7-2.0 (m, 5H), 2.55 (s, 3H), 2.9-3.2 (m, 2H),

3.4-3.6 (m, 4H), 3.80 (s, 3H), 4.5-4.6 (m, 2H), 7.00 (d, J ) 10

Hz, 2H), 7.10 (d, J ) 10 Hz, 2H), 7.30 (d, J ) 8 Hz, 1H), 7.3-

7.5 (m, 3H), 7.80 (d, J ) 10 Hz, 2H), 7.95 (s, 1H); MS (FD) m/e

485 (M⁺). Anal. (C₃₀H₃₁NO₃S‚HCl) C,H,N.

[2-(4-F lu or op h en yl)-6-[(m eth ylsu lfon yl)oxy]ben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (4i). The title compound was prepared in 64% yield from

2i and 3 by a method similar to that described for 4d : ¹H NMR

(270 MHz) δ 1.44 (m, 2H), 1.59 (m, 4H), 2.48 (m, 4H), 2.73 (t,

J ) 6 Hz, 2H), 3.21 (s, 3H), 4.19 (t, J ) 6 Hz, 2H), 6.83 (d, J

) 9 Hz, 2H), 6.99 (t, J ) 9 Hz, 2H), 7.37 (m, 1H), 7.46 (m,

2H), 7.71 (m, 3H), 7.86 (d, J ) 2 Hz, 1H); MS (EI) m/e 553

(M⁺).

[2-(4-Ch lor op h en yl)-6-h yd r oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5e). The

title compound was prepared in 12% yield from 2e and 3 by a

method similar to that described for 5c; analyzed as the

corresponding HCl salt: ¹H NMR (270 MHz, DMSO-d₆) δ 1.38

(m, 1H), 1.75 (m, 5H), 2.97 (m, 2H), 3.45 (m, 4H), 4.46 (m,

2H), 6.92 (dd, J ) 9, 2.5 Hz, 1H), 7.02 (d, J ) 9 Hz, 2H), 7.29

(d, J ) 9 Hz, 1H), 7.41 (m, 5H), 7.73 (d, J ) 9 Hz, 2H), 10.02

(s, 1H), 10.58 (br s, 1H); MS (FD) m/e 492 (M⁺). Anal. (C₂₈H₂₆

ClNO₃S‚HCl) C,H,N.

-

[2-(4-Hyd r oxyp h en yl)-6-ch lor oben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5f). The title

compound was prepared in 15% yield from 2f and 3 by a

method similar to that described for 5c; analyzed as the

corresponding HCl salt: ¹H NMR (270 MHz, DMSO-d₆) δ 1.38

(m, 1H), 1.75 (m, 5H), 2.95 (m, 2H), 3.44 (m, 4H), 4.45 (m,

2H), 6.75 (d, J ) 9 Hz, 2H), 6.99 (d, J ) 9 Hz, 2H), 7.25 (d, J

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 155

) 9 Hz, 2H), 7.46 (m, 2H), 7.72 (d, J ) 9 Hz, 2H), 8.26 (d, J )

2.5 Hz, 1H), 10.02 (s, 1H), 10.52 (br s, 1H); MS (EI) m/e 491

(M⁺). Anal. (C₂₈H₂₆ClNO₃S‚HCl) C,H,N.

separated, and the organic layer was washed with 50%

saturated Na₂CO₃(40 mL). The organic layer was dried over

solid sodium chloride, decanted, and concentrated under

reduced pressure to yield a thick dark oil. Purification via

chromatography (CH₂Cl₂, 0-5% MeOH) provided 19.8 g (64%,

corrected for trapped CH₂Cl₂) of the title compound as a thick

dark oil: ¹H NMR δ 1.3-1.4 (m, 2H), 1.5-1.6 (m, 4H), 3.43

(m, 4H), 2.70 (t, J ) 5.9 Hz, 2H), 2.76 (s, 6H), 3.70 (s, 3H),

4.07 (t, J ) 5.9 Hz, 2H), 6.73 (dd, J ) 8.9, 2.4 Hz, 1H), 6.84 (d,

J ) 8.8 Hz, 2H), 7.03 (d, J ) 2.4 Hz, 1H), 7.29 (d, J ) 8.9 Hz,

1H), 7.76 (d, J ) 8.8 Hz, 2H); ¹³C NMR δ 190.8, 162.1, 160.8,

155.3, 133.2, 132.0, 131.5, 131.4, 121.8, 113.9, 113.1, 111.2,

104.9, 65.8, 57.4, 55.2, 54.7, 44.6, 25.5, 23.8. Anal.

(C₂₅H₃₀N₂O₃S) C,H,N.

[2-(Dim et h yla m in o)-4-m et h oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (7b). The

title compound was prepared in 44% yield from 6b and 3 by a

method similar to that described for 7a : ¹H NMR δ 1.4-1.7

(m, 6H), 2.51 (m, 4H), 2.79 (m, 2H), 2.88 (s, 6H), 3.41 (s, 3H),

4.14 (m, 2H), 6.62 (d, J ) 8 Hz, 1H), 6.89 (m, 2H), 7.09 (m,

1H), 7.26 (d, J ) 8 Hz, 1H), 7.84 (m, 2H).

[2-(Dim et h yla m in o)-5-m et h oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a n on e (7c). The

title compound was prepared in 44% yield from 6c and 3 by a

method similar to that described for 7a : ¹H NMR δ 1.4-1.7

(m, 6H), 2.51 (m, 4H), 2.83 (m, 2H), 2.88 (s, 6H), 3.71 (s, 3H),

4.14 (m, 2H), 6.62 (d, J ) 8 Hz, 1H), 6.88 (m, 2H), 7.09 (m,

1H), 7.26 (d, J ) 8 Hz, 1H), 7.84 (m, 2H).

[2-(Dim eth yla m in o)-4,6-d im eth oxyben zo[b]th ien -3-yl]-

[4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (7d ). The

title compound was prepared in 47% yield from 6d and 3 by a

method similar to that described for 7a : ¹H NMR δ 1.4-1.7

(m, 6H), 2.50 (m, 4H), 2.77 (m, 2H), 2.81 (s, 6H), 3.41 (s, 3H),

3.82 (s, 3H), 4.14 (m, 2H), 6.27 (m, 1H), 6.78 (s, 1H), 6.88 (m,

2H), 7.81 (m, 2H); MS (FD) m/e 468 (M⁺).

[2-(Dim eth yla m in o)-5-m eth oxy-6-(ben zyloxy)ben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (7e). The title compound was prepared in 38% yield

from 6e and 3 by a method similar to that described for 7a :

¹H NMR δ 1.4-1.7 (m, 6H), 2.50 (m, 4H), 2.83 (m, 8H), 3.80

(s, 3H), 4.18 (m, 2H), 5.18 (s, 2H), 6.91 (m, 2H), 7.10 (s, 1H),

7.21 (s, 1H), 7.3-7.5 (m, 5H), 7.84 (m, 2H); MS (FD) m/e 544

(M⁺).

[2-(Dim eth yla m in o)-5,6,7-tr im eth oxyben zo[b]th ien -3-

yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (7f). The

title compound was prepared in 51% yield from 6f and 3 by a

method similar to that described for 7a : ¹H NMR δ 1.4-1.7

(m, 6H), 2.51 (m, 4H), 2.80 (m, 2H), 2.88 (s, 6H), 3.75 (s, 3H),

3.89 (s, 3H), 4.05 (s, 3H), 4.18 (m, 2H), 6.9-7.0 (m, 3H), 7.84

(d, J ) 8 Hz, 2H).

[2,6-Bis(d im eth yla m in o)ben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (7g). The title com-

pound was prepared in 6% yield from 6g and 3 by a method

similar to that described for 7a . This material was carried

forward without complete purification: MS (FD) m/e 451 (M⁺).

[2-(Dim eth yla m in o)-5-flu or o-6-m eth oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (7h ).

The title compound was prepared in 24% yield from 6h and 3

by a method similar to that described for 7a : ¹H NMR δ 1.21

(m, 2H), 1.55 (m, 4H), 2.50 (m, 4H), 2.82 (t, J ) 5.4 Hz, 2H),

2.88 (s, 3H), 3.89 (s, 6H), 4.16 (t, J ) 5.4 Hz, 2H), 6.92 (m,

3H), 7.15 (m, 1H), 7.84 (d, J ) 8.7 Hz, 1H), 7.98 (d, J ) 8.8

Hz, 1H); MS (FD) m/e 456 (M⁺).

[2-(Dim eth ylam in o)-5-m eth yl-6-m eth oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (7i).

The title compound was prepared in 30% yield from 6i and 3

by a method similar to that described for 7a : ¹H NMR δ 1.48

(m, 2H), 1.60 (m, 4H), 2.18 (s, 3H), 2.52 (m, 4H), 2.80 (t, J )

6.0 Hz, 2H), 2.84 (s, 6H), 3.85 (s, 3H), 4.18 (t, J ) 6.0 Hz, 2H),

6.93 (d, J ) 8.6 Hz, 2H), 7.05 (s, 1H), 7.30 (s, 1H), 7.85 (d, J

) 8.7 Hz, 2H); MS (FD) m/e 452 (M⁺).

[2-(4-Met h ylp h en yl)-6-h yd r oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5g). A sus-

pension of 4g (6.0 g, 11.4 mmol, ca. 50% purity) and ethaneth-

iol (9.45 g, 7.0 mL, 153 mmol) in DCE (300 mL) was cooled to

5 °C and treated with AlCl₃(10.0 g, 11.3 mmol). The resultant

mixture was allowed to stir at 5 °C for 3 h and warmed to

room temperature for an additional 2 h, and the reaction was

quenched by the addition of THF (100 mL). The solvents were

removed in vacuo, and the residue was partitioned between

EtOAc (300 mL) and 10% aqueous NaHCO₃(300 mL). The

aqueous layer was extracted with EtOAc (2 × 300 mL) and

CH₂Cl₂(2 × 300 mL), and the combined organic layers were

dried (Na₂SO₄) and concentrated in vacuo to afford a dark oil.

Purification via flash chromatography (acetone) and conversion

to the HCl salt using acetone/concentrated HCl afforded 1.6 g

(54%) of the title compound as a tan solid, mp 100-105 °C:

¹H NMR (free base) δ 1.4-1.6 (m, 2H), 1.6-1.8 (m, 4H), 2.30

(s, 3H), 2.5-2.8 (m, 4H), 2.8-3.0 (m, 2H), 4.1-4.3 (m, 2H),

6.75 (d, J ) 10 Hz, 2H), 6.95 (d, J ) 10 Hz, 2H), 7.05 (d, J )

8 Hz, 1H), 7.30 (s, 1H), 7.45 (d, J ) 10 Hz, 1H), 7.85 (d, J )

10 Hz, 2H), 8.00 (d, J ) 10 Hz, 2H); MS (FD) m/e 471 (M⁺).

Anal. (C₂₉H₂₉NO₃S‚HCl‚2H₂O) C,H,N.

[2-(4-H yd r oxyp h en yl)-6-m et h ylb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5h ). The

title compound was prepared in 62% yield from 4h by a method

similar to that described for 5g; analyzed as the corresponding

HCl salt, a tan solid, mp 220-223 °C: ¹H NMR (DMSO-d₆) δ

1.3-1.5 (m, 1H), 1.7-2.0 (m, 5H), 2.55 (s, 3H), 3.0 (m, 2H),

3.4-3.6 (m, 4H), 4.4-4.6 (m, 2H), 6.80 (d, J ) 10 Hz, 2H),

7.05 (d, J ) 10 Hz, 2H), 7.2-7.4 (m, 3H), 7.40 (d, J ) 8 Hz,

1H), 7.75 (d, J ) 10 Hz, 2H), 7.90 (s, 1H), 10.00 (s, 1H); MS

(FD) m/e 471 (M⁺). Anal. (C₂₉H₂₉NO₃S‚HCl‚H₂O) C,H,N.

[2-(4-Flu or op h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5i). A solution

of 4i (2.5 g, 4.5 mmol) in THF:MeOH (2:1, 120 mL) at room

temperature was treated with 5 N NaOH (10.0 mL, 50 mmol)

for 18 h. After acidification to pH 8 with 1 N HCl, the mixture

was extracted with EtOAc (3 × 200 mL) and the combined

organic extracts were washed sequentially with water (200

mL) and brine (200 mL), dried (Na₂SO₄), and concentrated.

The residue was purified via chromatography (CHCl₃, 3%

MeOH), and the resulting solid was dissolved in ether, treated

with excess HCl gas, and concentrated. The crude residue was

recrystallized from ethanol to give 0.73 g (35%) of the title

compound as the corresponding HCl salt: ¹H NMR (270 MHz,

DMSO-d₆) δ 1.38 (m, 2H), 1.78 (m, 4H), 2.98 (m, 2H), 3.45 (m,

4H), 4.45 (m, 2H), 6.93 (dd, J ) 9, 3 Hz, 1H), 7.01 (d, J ) 7.5

Hz, 2H), 7.19 (m, 2H), 7.31 (d, J ) 9 Hz, 1H), 7.42 (m, 3H),

7.74 (d, J ) 7.5 Hz, 2H). Anal. (C₂₈H₂₆FNO₃S‚HCl) C,H,N.

[2-(4-Hyd r oxyp h en yl)-7-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (5j). Aque-

ous 5 N NaOH (0.6 mL, 3 mmol) was added to 4j (0.42 g, 0.6

mmol) in EtOH:THF (5:1, 30 mL) and the mixture stirred for

30 min at room temeperature. The reaction mixture was

poured into saturated NaHCO₃/ice (200 mL), stirred 15 min,

and extracted with EtOAc (3 × 200 mL). The combined

organic extracts were washed with brine (200 mL), dried (Na₂-

SO₄), concentrated, and triturated with petroleum ether to give

0.23 g (84%) of the title product as a yellow solid, mp 135-

145 °C: ¹H NMR (DMSO-d₆) δ 1.3-1.5 (m, 6H), 2.48 (m, 4H),

2.6-2.7 (m, 2H), 4.10 (m, 2H), 6.7-6.8 (m, 4H), 6.91 (m, 4H),

7.18 (m, 1H), 7.28 (m, 1H), 7.67 (m, 1H), 9.81 (br s, 1H), 10.55

(br s, 1H); MS (FD) m/e 474 (M⁺) Anal. (C₂₈H₂₇NO₄S) C,H,N.

[2-(Dim et h yla m in o)-6-m et h oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (7a ). A solu-

tion of 6a (10.3 g, 49.8 mmol) in chlorobenzene (100 mL) was

treated with 3 (15.9 g, 52.3 mmol) and warmed to 100-105

°C for 9 h. The mixture was then allowed to cool to room

temperature resulting in complete solidification. The solid was

broken up and treated with saturated Na₂CO₃(60 mL), water

(30 mL), CH₂Cl₂(200 mL), and 50% aqueous NaOH (10 mL).

After stirring for a short period, the mixture was diluted with

CH₂Cl₂(300 mL) and water (100 mL), the layers were

[2-(Dim eth yla m in o)-5,7-d im eth yl-6-m eth oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (7j). The title compound was prepared in 88% yield from

6j and 3 by a method similar to that described for 7a : ¹H NMR

δ 1.45 (m, 2H), 1.63 (m, 4H), 2.26 (s, 3H), 2.42 (s, 3H), 2.58

156 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

(m, 4H), 2.81 (t, J ) 5.9 Hz, 2H), 2.87 (s, 6H), 3.74 (s, 3H),

4.18 (t, J ) 5.9 Hz, 2H), 6.92 (d, J ) 7.6 Hz, 2H), 7.18 (s, 1H),

7.85 (d, J ) 7.0 Hz, 2H); MS (FD) m/e 466 (M⁺). Anal.

(C₂₇H₃₄N₂O₃S) C,H,N.

[2-(Dim eth yla m in o)-4,7-d im eth yl-6-m eth oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (7k ). The title compound was prepared in 29% yield

from 6k and 3 by a method similar to that described for 7a :

¹H NMR δ 1.45 (m, 2H), 1.62 (m, 4H), 2.15 (s, 3H), 2.38 (s,

3H), 2.65 (m, 4H), 2.75 (s, 6H), 2.80 (t, J ) 5.9 Hz, 2H), 3.83

(s, 3H), 4.17 (t, J ) 6.0 Hz, 2H), 6.68 (s, 1H), 6.90 (d, J ) 8.6

Hz, 2H), 7.75 (d, J ) 8.5 Hz, 2H); MS (FD) m/e 466 (M⁺). Anal.

(C₂₇H₃₄N₂O₃S) C,H,N.

[2-(Dim eth yla m in o)-7-m eth oxyn a p h th o[1,2-b]th ien -3-

yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (7l). The

title compound was prepared in 20% yield from 6l and 3 by a

method similar to that described for 7a : ¹H NMR δ 1.50 (m,

2H), 1.59 (m, 4H), 2.49 (m, 4H), 2.77 (m, 8H), 4.06 (s, 3H),

4.12 (t, J ) 6.0 Hz, 2H), 6.88 (d, J ) 8.9 Hz, 2H), 7.15 (s, 1H),

7.29 (m, 2H), 7.80 (d, J ) 8.8 Hz, 1H), 7.91 (d, J ) 8.7 Hz,

2H), 8.28 (d, J ) 8.8 Hz, 1H).

[2-(4-Meth oxyp h en yl)-4-m eth oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (8b). A solu-

tion of 7b (1.5 g, 3.4 mmol) in THF (20 mL) at 0 °C was treated

with a 1 M THF solution of 4-methoxyphenylmagnesium

bromide (prepared from magnesium turnings and 4-bromoani-

sole) (25 mL, 25 mmol) portionwise. After warming to room

temperature, the reaction mixture was stirred for 1.5 h and

then recooled and the reaction quenched with ice water. The

mixture was extracted with CH₂Cl₂(3 × 100 mL), and the

combined organic layers were washed with brine (100 mL),

dried (Na₂SO₄), concentrated, and purified by preparative

HPLC (CH₂Cl₂/0-10% EtOH gradient) to give 1.0 g (60%) of

the title compound as a foam: ¹H NMR δ 1.4-1.7 (m, 6H),

2.50 (m, 4H), 2.77 (m, 2H), 3.60 (s, 3H), 3.80 (s, 3H), 4.12 (m,

2H), 6.70 (d, J ) 8 Hz, 1H), 6.83 (m, 4H), 7.29 (m, 2H), 7.46

(m, 2H), 7.77 (m, 2H); MS (FD) m/e 501 (M⁺).

[2-(4-Meth oxyp h en yl)-5-m eth oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a n on e (8c). The

title compound was prepared in 44% yield from 7c by a method

similar to that described for 8b: ¹H NMR δ 1.4-1.7 (m, 6H),

2.50 (m, 4H), 2.77 (m, 2H), 3.73 (s, 3H), 3.79 (s, 3H), 4.13 (m,

2H), 6.7-6.8 (m, 4H), 7.03 (m, 1H), 7.18 (m, 1H), 7.38 (m, 2H),

7.7-7.8 (m, 3H); MS (FD) m/e 501 (M⁺).

[2-(4-Meth oxyp h en yl)-4,6-d im eth oxyben zo[b]th ien -3-

yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a n on e (8d ).

The title compound was prepared in 88% yield from 7d by a

method similar to that described for 8b. The product was

obtained as a white solid, mp 108-110 °C: ¹H NMR δ 1.4-

1.7 (m, 6H), 2.49 (m, 4H), 2.75 (m, 2H), 3.52 (s, 3H), 3.75 (s,

3H), 3.87 (s, 3H), 4.10 (m, 2H), 6.33 (s, 1H), 6.7-6.9 (m, 4H),

6.91 (s, 1H), 7.2 (m, 2H), 7.77 (m, 2H); MS (FD) m/e 531 (M⁺).

Anal. (C₃₁H₃₃NO₅S) C,H,N.

[2-(4-Hyd r oxyp h en yl)-5-m eth oxy-6-h yd r oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (8e). By the method described for the preparation of

8b, 7e (8 mmol) was condensed with 4-(TBSoxy)phenylmag-

nesium bromide (55 mmol). The crude product was treated

with a 1.0 M solution of TBAF (12 mL, 12 mmol) in THF at 0

°C, and after 1 h the resultant mixture was poured into

saturated NaHCO₃/ice (200 mL) and extracted with EtOAc (4

× 200 mL). The combined organic extracts were washed with

brine, dried (Na₂SO₄), and concentrated to give 4.9 g (100%)

of crude material as a brown foam.

A solution of the crude product obtained above (1.1 g, ∼1.8

mmol) and ammonium formate (0.23 g, 3.7 mmol) in EtOH

(100 mL) was treated with 10% Pd/C (0.16 g, 0.15 mmol) and

the mixture stirred at 60 °C for 1 h. Additional ammonium

formate (0.75 g, 12 mmol) and 10% Pd/C (0.1 g, 0.1 mmol) were

then added, and the reaction mixture was stirred at 60 °C until

the starting material was consumed. After cooling to room

temperature, the mixture was filtered and concentrated, and

the residue was dissolved in EtOAc (200 mL), washed with

brine (200 mL), dried (Na₂SO₄), and concentrated. Purification

by radial chromatography (CH₂Cl₂/0-20% EtOH gradient) and

trituration of the product with CH₂Cl₂/Et₂O provided 0.5 g

(55%) of the title product as a yellow solid, mp 153-155 °C:

¹H NMR δ 1.4-1.8 (m, 6H), 2.65 (m, 4H), 2.85 (m, 2H), 3.88

(s, 3H), 4.14 (m, 2H), 6.5-6.6 (m, 4H), 7.10 (m, 2H), 7.36 (m,

2H), 7.63 (m, 2H); MS (FD) m/e 503 (M⁺). Anal. (C₂₉H₂₉NO₅S)

C,H,N.

[2-(4-Meth oxyp h en yl)-5,6,7-tr im eth oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (8f).

The title compound was prepared in 71% yield from 7f by a

method similar to that described for 8b. The product was

analyzed as the corresponding HCl salt, obtained by treatment

with HCl/MeOH, concentration, and trituration with Et₂O, mp

188-190 °C: ¹H NMR (DMSO-d₆) δ 1.4-1.7 (m, 6H), 2.51 (m,

4H), 2.78 (m, 2H), 3.78 (s, 3H), 3.85 (s, 3H), 3.94 (s, 3H), 4.08

(m, 2H), 4.15 (s, 3H), 6.74 (m, 4H), 6.98 (s, 1H), 7.33 (m, 2H),

7.77 (m, 2H); MS (FD) m/e 561 (M⁺). Anal. (C₃₂H₃₅NO₆S‚-

HCl) C,H,N.

[2-(4-Meth oxyph en yl)-6-(dim eth ylam in o)ben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (8g).

The title compound was prepared in 21% yield from 7g by a

method similar to that described for 8b: ¹H NMR δ 1.45 (m,

2H), 1.60 (m, 4H), 2.45 (m, 4H), 2.75 (t, J ) 6.0 Hz, 2H), 3.03

(s, 6H), 3.76 (s, 3H), 4.09 (t, J ) 6.0 Hz, 2H), 6.76 (m, 4H),

6.86 (dd, J ) 9.0, 2.1 Hz, 1H), 7.10 (d, J ) 2.1 Hz, 1H), 7.34

(d, J ) 8.7 Hz, 2H), 7.46 (d, J ) 8.9 Hz, 1H), 7.78 (d, J ) 8.7

Hz, 2H); MS (FD) m/e 515 (M⁺).

[2-(4-Meth oxyph en yl)-5-flu or o-6-m eth oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (8h ).

The title compound was prepared in 24% yield from 7h by a

method similar to that described for 8b: ¹H NMR δ 1.48 (m,

2H), 1.58 (m, 4H), 2.48 (m, 4H), 2.74 (t, J ) 6.0 Hz, 2H), 3.77

(s, 3H), 3.98 (s, 3H), 4.10 (t, J ) 6.0 Hz, 2H), 6.76 (d, J ) 7.8

Hz, 4H), 7.34 (m, 4H), 7.74 (d, J ) 8.8 Hz, 2H); MS (FD) m/e

519 (M⁺). Anal. (C₃₀H₃₀FNO₄S) C,H,N.

[2-(4-Met h oxyp h en yl)-5-m et h yl-6-m et h oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (8i). The title compound was prepared in 43% yield from

7i by a method similar to that described for 8b: ¹H NMR δ

1.46 (m, 2H), 1.60 (m, 4H), 2.25 (s, 3H), 2.50 (m, 4H), 2.77 (t,

J ) 5.9 Hz, 2H), 3.76 (s, 3H), 3.92 (s, 3H), 4.10 (t, J ) 6.0 Hz,

2H), 6.76 (d, J ) 8.9 Hz, 4H), 7.25 (s, 1H), 7.34 (d, J ) 8.7 Hz,

2H), 7.41 (s, 1H), 7.76 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 515

(M⁺).

[2-(4-Meth oxyph en yl)-5,7-dim eth yl-6-m eth oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (8j). The title compound was prepared in 37% yield from

7j by a method similar to that described for 8b: ¹H NMR δ

1.45 (m, 2H), 1.63 (m, 4H), 2.34 (s, 3H), 2.50 (m, 4H), 2.54 (s,

3H), 2.74 (t, J ) 5.9 Hz, 2H), 3.76 (s, 3H), 3.79 (s, 3H), 4.09 (t,

J ) 5.9 Hz, 2H), 6.76 (d, J ) 8.5 Hz, 4H), 7.33 (s, 1H), 7.36 (d,

J ) 6.7 Hz, 2H), 7.76 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 529

(M⁺). Anal. (C₃₂H₃₅NO₄S‚2.0H₂O) C,H,N.

[2-(4-Meth oxyph en yl)-4,7-dim eth yl-6-m eth oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (8k ). The title compound was prepared in 35% yield

from 7k by a method similar to that described for 8b: ¹H NMR

δ 1.44 (m, 2H), 1.58 (m, 4H), 2.24 (s, 3H), 2.44 (s, 3H), 2.48

(m, 4H), 2.74 (t, J ) 6.0 Hz, 2H), 3.76 (s, 3H), 3.89 (s, 3H),

4.10 (t, J ) 6.0 Hz, 2H), 6.76 (m, 5H), 7.40 (d, J ) 6.9 Hz,

2H), 7.76 (d, J ) 8.3 Hz, 2H); MS (FD) m/e 529 (M⁺). Anal.

(C₃₂H₃₅NO₄S) C,H,N.

[2-(4-Meth oxyp h en yl)-7-m eth oxyn a p h th o[1,2-b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (8l).

The title compound was prepared in 15% yield from 7l by a

method similar to that described for 8b: ¹H NMR δ 1.44 (m,

2H), 1.56 (m, 4H), 2.46 (m, 4H), 2.72 (t, J ) 6.0 Hz, 2H), 3.76

(s, 3H), 4.02 (t, J ) 5.9 Hz, 2H), 4.08 (s, 3H), 6.79 (m, 4H),

7.24 (s, 1H), 7.36 (m, 2H), 7.44 (d, J ) 8.7 Hz, 2H), 7.85 (d, J

) 8.6 Hz, 2H), 7.93 (d, J ) 8.3 Hz, 1H), 8.35 (d, J ) 8.3 Hz,

1H); MS (FD) m/e 551 (M⁺). Anal. (C₃₄H₃₃NO₄S) C,H,N.

[2-(4-Hyd r oxyp h en yl)-4-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (9b). The

title compound was prepared in 77% yield from 8b by a method

similar to that described for 5g. The product was obtained as

a yellow solid, mp 205-210 °C: ¹H NMR δ 1.1-1.4 (m, 6H),

2.22 (m, 4H), 2.48 (m, 2H), 3.84 (m, 2H), 6.4-6.6 (m, 5H), 6.8-

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 157

7.1 (m, 4H), 7.47 (d, J ) 8 Hz, 2H), 8.90 (br s, 2H); MS (FD)

m/e 473 (M⁺). Anal. (C₂₈H₂₇NO₄S) C,H,N.

2.65 (m, 2H), 4.06 (m, 2H), 6.64 (d, J ) 8.6 Hz, 2H), 6.88 (d, J

) 8.8 Hz, 2H), 7.00 (s, 1H), 7.15 (d, J ) 8.5 Hz, 2H), 7.62 (d,

J ) 8.7 Hz, 2H), 8.70 (s, 1H), 9.70 (s, 1H); MS (FD) m/e 502

(M⁺). Anal. (C₃₀H₃₁NO₄S‚0.5H₂O) C,H,N.

[2-(4-Hydr oxyph en yl)-4,7-dim eth yl-6-h ydr oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (9k ). The title compound was prepared in 49% yield

from 8k by a method similar to that described for 5g. The

product was obtained as a yellow solid: ¹H NMR (DMSO-d₆)

δ 1.35 (m, 2H), 1.44 (m, 4H), 1.98 (s, 3H), 2.28 (s, 3H), 2.38

(m, 4H), 2.59 (m, 2H), 4.06 (m, 2H), 6.65 (m, 3H), 6.93 (d, J )

7.9 Hz, 2H), 7.19 (d, J ) 8.2 Hz, 2H), 7.60 (d, J ) 8.0 Hz, 2H),

9.50 (s, 1H), 9.67 (s, 1H); MS (FD) m/e 501 (M⁺). Anal.

(C₃₀H₃₁NO₄S‚0.5H₂O) C,H,N.

[2-(4-Hyd r oxyp h en yl)-5-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a n on e (9c). The

title compound was prepared in 97% yield from 8c by a method

similar to that described for 5g. The product was obtained as

a yellow solid, mp 125 °C dec: ¹H NMR (DMSO-d₆) δ 1.2-1.7

(m, 6H), 2.36 (m, 4H), 2.59 (m, 2H), 4.06 (m, 2H), 6.6-7.0 (m,

6H), 7.18 (m, 2H), 7.65 (m, 2H), 7.79 (m, 1H), 9.47 (br s, 1H),

9.77 (br s, 2H). Anal. (C₂₈H₂₇NO₄S) C,H,N.

[2-(4-H yd r oxyp h en yl)-4,6-d ih yd r oxyb en zo[b]t h ien -3-

yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (9d ). A

solution of 8d (4.8 g, 9.0 mmol) in MeOH (20 mL) at 0 °C was

treated with saturated HCl/MeOH (10 mL). After 15 min, the

mixture was concentrated, slurried with Et₂O, and concen-

trated to give the hydrochloride salt as a foam. This residue

was diluted with DCE (50 mL), cooled to 0 °C, treated with

5.5 M BCl₃in DCE (7 mL, 38 mmol), and allowed to warm to

room temperature over 20 h. The reaction was quenched at 0

°C with MeOH (10 mL), and the mixture was poured into

saturated aqueous NaHCO₃/ice (200 mL) and extracted with

CH₂Cl₂(2 × 200 mL). The combined organic extracts were

washed with brine (200 mL), dried (Na₂SO₄), concentrated, and

purified by preparative HPLC (CH₂Cl₂/0-30% EtOH gradient).

Trituration with EtOH/Et₂O provided 2.9 g (63%) of the title

compound as the dihydrate, mp 151-155 °C: ¹H NMR δ 1.3-

1.6 (m, 6H), 2.21 (m, 4H), 2.58 (m, 2H), 3.30 (br s, 4H, H₂O),

4.08 (m, 2H), 6.20 (s, 1H), 6.6-6.8 (m, 3H), 6.91 (m, 2H), 7.18

(m, 2H), 7.58 (m, 2H), 9.55 (br s, 1H), 9.70 (br s, 2H); MS (FD)

m/e 489 (M⁺). Anal. (C₂₈H₂₇NO₅S‚2.25H₂O) C,H,N.

[2-(4-H yd r oxyp h en yl)-5,6-d ih yd r oxyb en zo[b]t h ien -3-

yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (9e). The

title compound was prepared in 59% yield from 8e by a method

similar to that described for 9d . The product was obtained

as the monohydrate, mp 190-200 °C: ¹H NMR (DMSO-d₆) δ

1.3-1.5 (m, 6H), 2.35 (m, 4H), 2.42 (m, 2H), 4.08 (m, 2H), 6.63

(s, 2H), 6.78 (s, 1H), 6.93 (m, 2H), 7.14 (m, 2H), 7.30 (s, 1H),

7.63 (m, 2H), 9.25 (br s, 1H), 9.35 (br s, 1H), 9.70 (br s, 2H);

MS (FD) m/e 490 (MH)⁺. Anal. (C₂₈H₂₇NO₅S‚H₂O) C; H:

calcd, 5.76; found, 5.28. N: calcd, 2.76; found, 2.25.

[2-(4-Hyd r oxyp h en yl)-6-h yd r oxyn a p h th o[1,2-b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (9l).

The title compound was prepared in 50% yield from 8l by a

method similar to that described for 5g. The product was

obtained as a yellow solid: ¹H NMR (DMSO-d₆) δ 1.32 (m, 2H),

1.43 (m, 4H), 2.35 (m, 4H), 2.60 (m, 2H), 4.03 (m, 2H), 6.68 (d,

J ) 8.7 Hz, 2H), 6.93 (d, J ) 8.3 Hz, 2H), 7.23 (d, J ) 7.5 Hz,

2H), 7.40 (m, 4H), 7.70 (m, 2H), 8.22 (d, J ) 8.3 Hz, 1H), 8.30

(s, 1H), 9.70 (s, 1H); MS (FD) m/e 524 (M⁺). Anal. (C₃₂H₂₉

NO₄S‚0.75H₂O) C,H,N.

-

(2-P h en yl-6-m et h oxyb en zo[b]t h ien -3-yl)[4-[2-(1-p ip e-

r id in yl)eth oxy]p h en yl]m eth a n on e (10a ). The title com-

pound was prepared in 87% yield from 7a and phenylmagne-

sium bromide by a method similar to that described for 8b:

¹H NMR (90 MHz) δ 1.51 (m, 6H), 2.48 (m, 4H), 2.76 (t, J )

6.4 Hz, 2H), 3.85 (s, 3H), 4.08 (t, J ) 6.4 Hz, 2H), 6.75 (d, J )

9 Hz, 2H), 6.90 (dd, J ) 9, 2 Hz, 1H), 7.30 (m, 7H), 7.76 (d, J

) 9 Hz, 2H); MS (EI) m/e 471 (M⁺). Anal. (C₂₉H₂₉NO₃S)

C,H,N.

[2-(2-Meth oxyp h en yl)-6-m eth oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10b). The

title compound was prepared in 62% yield from 7a and

2-methoxyphenylmagnesium bromide by a method similar to

that described for 8b: ¹H NMR δ 1.44 (m, 2H), 1.60 (m, 4H),

2.48 (m, 4H), 2.72 (t, J ) 5.9 Hz, 2H), 3.51 (s, 3H), 3.87 (s,

3H), 4.06 (t, J ) 5.9 Hz, 2H), 6.65 (d, J ) 8.2 Hz, 1H), 6.73 (d,

J ) 8.6 Hz, 2H), 6.89 (t, J ) 7.4 Hz, 1H), 6.98 (d, J ) 8.9 Hz,

1H), 7.17 (t, J ) 7.7 Hz, 1H), 7.33 (s, 1H), 7.41 (d, J ) 7.4 Hz,

1H), 7.68 (d, J ) 8.9 Hz, 1H), 7.75 (d, J ) 8.6 Hz, 1H); MS

(FD) m/e 501 (M⁺).

[2-[3-[(ter t-Bu tyld im eth ylsilyl)oxy]p h en yl]-6-m eth oxy-

b en zo[b]t h ien -3-yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]-

m eth a n on e (10c). The title compound was prepared in 73%

yield from 7a and 3-[(tert-butyldimethylsilyl)oxy]phenyl-

magnesium bromide by a method similar to that described for

8b: ¹H NMR δ 0.11 (s, 6H), 0.95 (s, 9H), 1.45 (m, 2H), 1.61

(m, 4H), 2.50 (m, 4H), 2.76 (t, J ) 5.9 Hz, 2H), 3.89 (s, 3H),

4.09 (t, J ) 5.9 Hz, 2H), 6.69 (d, J ) 8.5 Hz, 1H), 6.77 (d, J )

8.5 Hz, 2H), 6.90 (s, 1H), 6.9-7.1 (m, 3H), 7.34 (m, 1H), 7.55

(d, J ) 8.8 Hz, 1H), 7.78 (d, J ) 8.2 Hz, 2H); MS (FD) m/e 601

(M⁺). Anal. (C₃₅H₄₃NO₄SSi) C,H,N.

[2-(2-Met h ylp h en yl)-6-m et h oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10d ). The

title compound was prepared in 49% yield from 7a and

2-methylphenylmagnesium bromide by a method similar to

that described for 8b. The product could not be fully purified

at this stage and was carried on to 11d without complete

characterization: ¹H NMR δ 1.5 (m, 2H), 1.7 (m, 4H), 2.4 (s,

3H), 2.6 (m, 4H), 2.8 (t, 2H), 4.0 (s, 3H), 4.2 (t, 2H), 6.8 (d,

2H), 7.0 (dd, 1H), 7.1-7.2 (m, 3H), 7.3-7.4 (m, 1H), 7.5 (d,

1H), 7.7 (d, 1H), 7.8 (d, 2H).

[2-(4-Hydr oxyph en yl)-6-(dim eth ylam in o)ben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (9g).

The title compound was prepared in 41% yield from 8g by a

method similar to that described for 5g. The product was

obtained as a yellow solid: ¹H NMR δ 1.48 (m, 2H), 1.62 (m,

4H), 2.54 (m, 4H), 2.76 (t, J ) 6.0 Hz, 2H), 3.03 (s, 6H), 4.10

(t, J ) 4.1 Hz, 2H), 6.60 (d, J ) 8.5 Hz, 2H), 6.68 (d, J ) 8.6

Hz, 2H), 6.89 (d, J ) 8.9 Hz, 1H), 7.10 (s, 1H), 7.19 (d, J ) 8.8

Hz, 2H), 7.61 (d, J ) 8.9 Hz, 2H), 7.69 (d, J ) 8.6 Hz, 2H); MS

(FD) m/e 501 (M⁺). Anal. (C₃₀H₃₂N₂O₃S) C,H,N.

[2-(4-Hydr oxyph en yl)-5-flu or o-6-h ydr oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (9h ).

The title compound was prepared in 43% yield from 8h by a

method similar to that described for 5g. The product was

obtained as a yellow solid: ¹H NMR (DMSO-d₆) δ 1.35 (m, 2H),

1.48 (m, 4H), 2.39 (m, 4H), 2.65 (t, J ) 6.0 Hz, 2H), 4.10 (t, J

) 6.0 Hz, 2H), 6.65 (d, J ) 9.0 Hz, 2H), 6.96 (d, J ) 7.8 Hz,

2H), 7.18 (m, 3H), 7.54 (d, J ) 7.8 Hz, 1H), 7.63 (d, J ) 9.0

Hz, 2H), 9.98 (br s, 2H); MS (FD) m/e 492 (M⁺). Anal. (C₂₈H₂₆

-

FNO₄S) C,H,N.

[2-(4-H yd r oxyp h en yl)-5-m et h yl-6-h yd r oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (9i). The title compound was prepared in 40% yield from

8i by a method similar to that described for 5g. The product

was obtained as a yellow solid: ¹H NMR (DMSO-d₆) δ 1.27

(m, 2H), 1.49 (m, 4H), 2.06 (s, 3H), 2.45 (m, 4H), 2.50 (t, J )

5.9 Hz, 2H), 3.90 (t, J ) 5.8 Hz, 2H), 6.49 (d, J ) 8.5 Hz, 2H),

6.57 (d, J ) 8.5 Hz, 2H), 7.02 (d, J ) 8.3 Hz, 2H), 7.09 (s, 1H),

7.14 (s, 1H), 7.56 (d, J ) 8.5 Hz, 2H), 8.80 (br s, 2H); MS (FD)

m/e 488 (M⁺). Anal. (C₂₉H₂₉NO₄S) C,H,N.

[2-(4-Hydr oxyph en yl)-5,7-dim eth yl-6-h ydr oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (9j). The title compound was prepared in 69% yield from

8j by a method similar to that described for 5g. The product

was obtained as a yellow solid: ¹H NMR (DMSO-d₆) δ 1.34

(m, 2H), 1.45 (m, 4H), 2.17 (s, 3H), 2.37 (s, 3H), 2.42 (m, 4H),

[2-(3-F lu or op h en yl)-6-m et h oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10e). The

title compound was prepared in 68% yield from 7a and

3-fluorophenylmagnesium bromide by a method similar to that

described for 8b: ¹H NMR δ 1.44 (m, 2H), 1.58 (m, 4H), 2.47

(m, 4H), 2.73 (t, J ) 6.0 Hz, 2H), 3.89 (s, 3H), 4.08 (t, J ) 6.0

Hz, 2H), 6.78 (d, J ) 8.8 Hz, 2H), 6.90 (m, 1H), 6.97 (dd, J )

8.9, 2.3 Hz, 1H), 7.1-7.2 (m, 3H), 7.33 (d, J ) 2.3 Hz, 1H),

7.53 (d, J ) 8.9 Hz, 1H), 7.75 (d, J ) 8.8 Hz, 2H); MS (FD)

m/e 489 (M⁺). Anal. (C₂₉H₂₈FNO₃S) C,H,N.

158 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

[2-(4-Eth ylp h en yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10f). The title

compound was prepared in 68% yield from 7a and 4-ethylphe-

nylmagnesium bromide by a method similar to that described

for 8b: ¹H NMR δ 1.18 (t, J ) 7.6 Hz, 3H), 1.45 (m, 2H), 1.60

(m, 4H), 2.48 (m, 4H), 2.58 (q, J ) 7.6 Hz, 2H), 2.74 (t, J ) 5.9

Hz, 2H), 3.89 (s, 3H), 4.09 (t, J ) 5.9 Hz, 2H), 6.77 (d, J ) 8.8

Hz, 2H), 6.97 (dd, J ) 8.8, 2.2 Hz, 1H), 7.06 (d, J ) 8.0 Hz,

2H), 7.35 (m, 3H), 7.52 (d, J ) 8.8 Hz, 1H), 7.77 (d, J ) 8.7

Hz, 2H); MS (FD) m/e 499 (M⁺). Anal. (C₃₁H₃₃NO₃S) C,H,N.

[2-[4-(2-P r op yl)p h en yl]-6-m eth oxyben zo[b]th ien -3-yl]-

[4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10g). The

title compound was prepared in 65% yield from 7a and 4-(2-

propyl)phenylmagnesium bromide by a method similar to that

described for 8b: ¹H NMR δ 1.17 (d, J ) 7.0 Hz, 6H), 1.43 (m,

2H), 1.59 (m, 4H), 2.45 (m, 4H), 2.73 (t, J ) 6.0 Hz, 2H), 2.82

(m, 1H), 3.88 (s, 3H), 4.07 (t, J ) 6.0 Hz, 2H), 6.76 (d, J ) 8.8

Hz, 2H), 6.95 (dd, J ) 8.8, 2.1 Hz, 1H), 7.07 (d, J ) 8.1 Hz,

2H), 7.34 (m, 3H), 7.52 (d, J ) 8.9 Hz, 1H), 7.75 (d, J ) 8.8

Hz, 2H); MS (FD) m/e 513 (M⁺). Anal. (C₃₂H₃₅NO₃S) C,H,N.

[2-[4-(1-Bu tyl)p h en yl]-6-m eth oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10h ). The

title compound was prepared in 65% yield from 7a and 4-(1-

butyl)phenylmagnesium bromide by a method similar to that

described for 8b: ¹H NMR δ 0.90 (t, J ) 7.3 Hz, 3H), 1.2-1.4

(m, 2H), 1.4-1.7 (m, 8H), 2.4-2.6 (m, 6H), 2.75 (t, J ) 6.0 Hz,

2H), 3.90 (s, 3H), 4.09 (t, J ) 6.0 Hz, 2H), 6.76 (d, J ) 8.9 Hz,

2H), 6.97 (dd, J ) 8.9, 2.4 Hz, 1H), 7.03 (d, J ) 8.1 Hz, 2H),

7.34 (m, 3H), 7.54 (d, J ) 8.9 Hz, 1H), 7.76 (d, J ) 8.7 Hz,

2H); MS (FD) m/e 527 (M⁺). Anal. (C₃₃H₃₇NO₃S) C,H,N.

[2-(4-Bip h en ylyl)-6-m et h oxyb en zo[b]t h ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10i). The title

compound was prepared in 49% yield from 7a and 4-biphenyl-

ylmagnesium bromide by a method similar to that described

for 8b: ¹H NMR δ 1.42 (m, 2H), 1.57 (m, 4H), 2.46 (m, 4H),

2.71 (t, J ) 5.9 Hz, 2H), 3.88 (s, 3H), 4.07 (t, J ) 5.9 Hz, 2H),

6.77 (d, J ) 8.8 Hz, 2H), 6.97 (dd, J ) 8.8, 2.6 Hz, 1H), 7.2-

7.6 (m, 11H), 7.80 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 547 (M⁺).

Anal. (C₃₅H₃₃NO₃S) C,H,N.

a method similar to that described for 8b: ¹H NMR δ 1.45

(m, 2H), 1.63 (m, 4H), 2.54 (m, 4H), 2.79 (t, J ) 5.8 Hz, 2H),

3.89 (s, 3H), 4.13 (t, J ) 5.8 Hz, 2H), 6.78 (d, J ) 8.8 Hz, 2H),

6.98 (dd, J ) 8.9, 2.3 Hz, 1H), 7.34 (d, J ) 2.2 Hz, 1H), 7.48

(d, J ) 8.4 Hz, 2H), 7.54 (d, J ) 8.4 Hz, 2H), 7.75 (d, J ) 8.8

Hz, 2H); MS (FD) m/e 539 (M⁺). Anal. (C₃₀H₂₈F₃NO₃S) C,H,N.

[2-(2-Met h yl-4-m et h oxyp h en yl)-6-m et h oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (10n ). The title compound was prepared in 55% yield

from 7a and 2-methyl-4-methoxyphenylmagnesium bromide

by a method similar to that described for 8b: ¹H NMR δ 1.46

(m, 2H), 1.63 (m, 4H), 2.26 (s, 3H), 2.54 (m, 4H), 2.79 (t, J )

5.8 Hz, 2H), 3.47 (s, 3H), 3.89 (s, 3H), 4.12 (t, J ) 5.8 Hz, 2H),

6.60 (m, 2H), 6.74 (d, J ) 8.8 Hz, 2H), 6.98 (dd, J ) 8.9, 2.4

Hz, 1H), 7.19 (d, J ) 9.3 Hz, 1H), 7.32 (d, J ) 2.4 Hz, 1H),

7.60 (d, J ) 8.9 Hz, 1H), 7.69 (d, J ) 8.8 Hz, 2H); MS (FD)

m/e 515 (M⁺). Anal. (C₃₁H₃₃NO₄S) C,H,N.

[2-(2,4-Dim eth oxyp h en yl)-6-m eth oxyben zo[b]th ien -3-

yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (10o).

The title compound was prepared in 58% yield from 7a and

2,4-dimethoxyphenylmagnesium bromide by a method similar

to that described for 8b: ¹H NMR δ 1.44 (m, 2H), 1.60 (m,

4H), 2.49 (m, 4H), 2.74 (t, J ) 6.0 Hz, 2H), 3.49 (s, 3H), 3.75

(s, 3H), 3.87 (s, 3H), 4.07 (t, J ) 6.0 Hz, 2H), 6.21 (d, J ) 2.2

Hz, 1H), 6.42 (dd, J ) 8.5, 2.3 Hz, 1H), 6.74 (d, J ) 8.8 Hz,

2H), 6.95 (dd, J ) 8.9, 2.3 Hz, 1H), 7.32 (m, 2H), 7.63 (d, J )

8.9 Hz, 1H), 7.74 (d, J ) 8.7 Hz, 2H); MS (FD) m/e 531 (M⁺).

Anal. (C₃₁H₃₃NO₅S) C,H,N.

[2-(3-Met h yl-4-m et h oxyp h en yl)-6-m et h oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (10p ). The title compound was prepared in 69% yield

from 7a and 3-methyl-4-methoxyphenylmagnesium bromide

by a method similar to that described for 8b: ¹H NMR δ 1.43

(m, 2H), 1.58 (m, 4H), 2.11 (s, 3H), 2.46 (m, 4H), 2.71 (t, J )

5.8 Hz, 2H), 3.75 (s, 3H), 3.86 (s, 3H), 4.06 (t, J ) 5.8 Hz, 2H),

6.64 (d, J ) 8.9 Hz, 1H), 6.75 (d, J ) 8.6 Hz, 2H), 6.95 (d, J )

8.9 Hz, 1H), 7.20 (s, 2H), 7.31 (s, 1H), 7.54 (d, J ) 8.9 Hz,

1H), 7.77 (d, J ) 8.6 Hz, 2H); MS (FD) m/e 515 (M⁺). Anal.

(C₃₁H₃₃NO₄S) C,H,N.

[2-(3-Ch lor o-4-m et h oxyp h en yl)-6-m et h oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (10q). The title compound was prepared in 62% yield

from 7a and 3-chloro-4-methoxyphenylmagnesium bromide by

a method similar to that described for 8b: ¹H NMR δ 1.43

(m, 2H), 1.58 (m, 4H), 2.73 (t, J ) 5.9 Hz, 2H), 3.82 (s, 3H),

3.87 (s, 3H), 4.08 (t, J ) 5.9 Hz, 2H), 6.74 (d, J ) 9.2 Hz, 1H),

6.78 (d, J ) 9.2 Hz, 2H), 6.96 (dd, J ) 8.9, 2.2 Hz, 1H), 7.26

(dd, J ) 8.7, 2.2 Hz, 1H), 7.31 (d, J ) 2.1 Hz, 1H), 7.46 (d, J

) 2.1 Hz, 1H), 7.53 (d, J ) 8.9 Hz, 1H), 7.75 (d, J ) 8.7 Hz,

2H); MS (FD) m/e 535 (M⁺). Anal. (C₃₀H₃₀ClNO₄S) C,H,N.

[2-[3-F lu or o-4-[(ter t-bu tyld im eth ylsilyl)oxy]p h en yl]-6-

m eth oxyben zo[b]th ien -3-yl][4-[2-(1-p ip er id in yl)eth oxy]-

p h en yl]m eth a n on e (10r ). The title compound was prepared

in 75% yield from 7a and 3-fluoro-4-(TBSoxy)phenylmagne-

sium bromide by a method similar to that described for 8b:

¹H NMR δ 0.12 (s, 6H), 0.96 (s, 9H), 1.43 (m, 2H), 1.59 (m,

4H), 2.48 (m, 4H), 2.74 (t, J ) 6.0 Hz, 2H), 3.87 (s, 3H), 4.07

(t, J ) 6.0 Hz, 2H), 6.7-6.8 (m, 3H), 6.9-7.2 (m, 3H), 7.32 (d,

J ) 2.4 Hz, 1H), 7.59 (d, J ) 8.9 Hz, 1H), 7.73 (d, J ) 8.8 Hz,

2H); MS (FD) m/e 619 (M⁺). Anal. (C₃₅H₄₂FNO₄SSi) C,H,N.

[2-(3,5-Dim eth yl-4-m eth oxyp h en yl)-6-m eth oxyben zo-

[b]th ien -3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a -

n on e (10s). The title compound was prepared in 57% yield

from 7a and 3,5-dimethyl-4-methoxyphenylmagnesium bro-

mide by a method similar to that described for 8b: ¹H NMR

δ 1.45 (m, 2H), 1.60 (m, 4H), 2.17 (s, 6H), 2.49 (m, 4H), 2.75

(t, J ) 5.9 Hz, 2H), 3.65 (s, 3H), 3.90 (s, 3H), 4.09 (t, J ) 5.9

Hz, 2H), 6.76 (d, J ) 8.7 Hz, 2H), 7.16 (m, 2H), 7.25 (s, 2H),

7.33 (d, J ) 2.1 Hz, 1H), 7.58 (d, J ) 8.9 Hz, 1H), 7.74 (d, J )

8.7 Hz, 1H); MS (FD) m/e 529 (M⁺).

[2-[4-(Th iom eth yl)p h en yl]-6-m eth oxyben zo[b]th ien -3-

yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a n on e (10j).

The title compound was prepared in 90% yield from 7a and

4-thioanisylmagnesium bromide by a method similar to that

described for 8b: ¹H NMR δ 1.46 (m, 2H), 1.62 (m, 4H), 2.43

(s, 3H), 2.51 (m, 4H), 2.77 (t, J ) 6.0 Hz, 2H), 3.89 (s, 3H),

4.12 (t, J ) 6.0 Hz, 2H), 6.78 (d, J ) 8.7 Hz, 2H), 6.97 (dd, J

) 8.9, 2.6 Hz, 1H), 7.09 (d, J ) 8.5 Hz, 2H), 7.35 (m, 3H), 7.51

(d, J ) 8.8 Hz, 1H), 7.77 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 517

(M⁺). Anal. (C₃₀H₃₁NO₃S₂‚0.5H₂O) C,H,N.

[2-[4-(Hydr oxym eth yl)ph en yl]-6-m eth oxyben zo[b]th ien -

3-yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (10k).

The title compound was prepared from 7a and 4-[(TBSoxy)-

methyl]phenylmagnesium bromide by a method similar to that

described for 8b. After the reaction was complete, the mixture

was concentrated in vacuo and the residue was dissolved in

CH₂Cl₂(20 mL) and treated with 1.0 M TBAF in THF (5.1

mL, 5.1 mmol). After 1 h, the mixture was partitioned between

CH₂Cl₂(100 mL) and saturated NaHCO₃(100 mL), and the

organic layer was washed with brine (100 mL), dried (MgSO₄),

and concentrated. The residue was purified by flash chroma-

tography (1:1 hexane:EtOAc, 0-5% MeOH) to provide 0.46 g

(20%) of the title compound as an off-white solid: ¹H NMR δ

1.46 (m, 2H), 1.63 (m, 4H), 2.54 (m, 4H), 2.75 (t, J ) 4.9 Hz,

2H), 3.90 (s, 3H), 4.11 (t, J ) 5.4 Hz, 2H), 4.60 (s, 2H), 6.72 (d,

J ) 8.8 Hz, 2H), 6.98 (dd, J ) 8.9, 2.4 Hz, 1H), 7.20 (d, J )

8.1 Hz, 2H), 7.33 (d, J ) 2.4 Hz, 1H), 7.36 (d, J ) 8.1 Hz, 2H),

7.61 (d, J ) 8.9 Hz, 1H), 7.73 (d, J ) 8.8 Hz, 2H); ¹³C NMR δ

24.9, 26.6, 55.9, 56.6, 58.4, 65.3, 67.0, 105.4, 115.2, 115.9, 125.2,

127.9, 130.0, 131.3, 132.3, 133.2, 133.5, 134.8, 141.2, 142.5,

143.4, 158.8, 163.8, 192.9; HRMS (FD) m/e calcd for C₃₀H₃₂

NO₄S (MH⁺) 502.2043, found 502.2052. Anal. (C₃₀H₃₁

NO₄S‚0.5H₂O) C,H; N: calcd, 2.74; found, 2.24.

-

[2-[3,4-(Met h ylen ed ioxy)p h en yl]-6-m et h oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (10t). The title compound was prepared in 65% yield

from 7a and 3,4-(methylenedioxy)phenylmagnesium bromide

by a method similar to that described for 8b: ¹H NMR δ 1.36

(m, 2H), 1.53 (m, 4H), 2.41 (m, 4H), 2.66 (t, J ) 5.8 Hz, 2H),

[2-[4-(Tr iflu or om et h yl)p h en yl]-6-m et h oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (10m ). The title compound was prepared in 81% yield

from 7a and 4-(trifluoromethyl)phenylmagnesium bromide by

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 159

3.78 (s, 3H), 4.02 (t, J ) 5.8 Hz, 2H), 5.82 (s, 2H), 6.60 (d, J )

8.5 Hz, 1H), 6.73 (d, J ) 8.8 Hz, 2H), 6.8-7.0 (m, 3H) 7.24 (d,

J ) 2.2 Hz, 1H), 7.48 (d, J ) 8.9 Hz, 1H), 7.72 (d, J ) 8.8 Hz,

2H); MS (FD) m/e 516 (MH⁺). Anal. (C₃₀H₂₉NO₅S) C,H,N.

7.66 (d, J ) 8.8, 2H); HRMS (FD) m/e calcd for C₃₁H₃₄NO₃S

(MH⁺) 500.2259, found 500.2269. Anal. (C₃₁H₃₃NO₃S‚0.3H₂O)

C,H,N.

[2-[4-(1-Bu tyl)p h en yl]-6-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11h ). The

title compound was prepared in 56% yield from 10h by a

method similar to that described for 5g: ¹H NMR δ 0.89 (t, J

) 7.3 Hz, 3H), 1.27 (m, 2H), 1.4-1.6 (m, 4H), 1.67 (m, 4H),

2.5-2.6 (m, 6H), 2.81 (t, J ) 5.5 Hz, 2H), 4.09 (t, J ) 5.5 Hz,

2H), 6.59 (d, J ) 8.7 Hz, 2H), 6.77 (dd, J ) 8.7, 2.0 Hz, 1H),

7.02 (d, J ) 8.0 Hz, 2H), 7.19 (d, J ) 1.7 Hz, 1H), 7.27 (d, J )

7.8 Hz, 2H), 7.39 (d, J ) 8.8 Hz, 1H), 7.67 (d, J ) 8.6 Hz, 2H);

HRMS (FD) m/e calcd for C₃₂H₃₆NO₃S (MH⁺) 514.2420, found

514.2416. Anal. (C₃₂H₃₅NO₃S‚1.25H₂O) C,H,N.

[2-(4-Bip h en ylyl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11i). The title

compound was prepared in 56% yield from 10i by a method

similar to that described for 5g: ¹H NMR δ 1.47 (m, 2H), 1.65

(m, 4H), 2.56 (m, 4H), 2.80 (t, J ) 5.3 Hz, 2H), 4.10 (t, J ) 5.5

Hz, 2H), 6.67 (d, J ) 8.8 Hz, 2H), 6.83 (dd, J ) 8.8, 2.2 Hz,

1H), 7.25 (d, J ) 2.2 Hz, 1H), 7.2-7.6 (m, 10H), 7.74 (d, J )

8.8 Hz, 2H); MS (FD) m/e 533 (M⁺). Anal. (C₃₄H₃₁NO₃S)

C,H,N.

(2-P h en yl-6-h yd r oxyb en zo[b]t h ien -3-yl)[4-[2-(1-p ip e-

r id in yl)eth oxy]p h en yl]m eth a n on e (11a ). The title com-

pound was prepared in 69% yield from 10a by a method similar

to that described for 5g. The product was converted to its HCl

salt for evaluation: ¹H NMR (DMSO-d₆) δ 1.40 (m, 1H), 1.79

(m, 5H), 2.98 (m, 2H), 3.45 (m, 4H), 4.45 (m, 2H), 6.91 (d, J )

9 Hz, 1H), 6.98 (d, J ) 9 Hz, 2H), 7.35 (m, 7H), 7.78 (d, J ) 9

Hz, 2H), 9.96 (s, 1H), 10.35 (br s, 1H); MS (FD) m/e 457 (M⁺).

Anal. (C₂₈H₂₇NO₃S‚HCl) C,H,N.

[2-(2-Hyd r oxyp h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11b). The

title compound was prepared in 49% yield from 10b by a

method similar to that described for 5g: ¹H NMR δ 1.47 (m,

2H), 1.62 (m, 4H), 2.54 (m, 4H), 2.75 (t, J ) 5.4 Hz, 2H), 4.10

(t, J ) 5.4 Hz, 2H), 4.87 (br s, 2H), 6.64 (d, J ) 8.1 Hz, 1H),

6.7-6.9 (m, 4H), 7.02 (m, 1H), 7.25 (m, 2H), 7.47 (d, J ) 8.9

Hz, 1H), 7.67 (d, J ) 8.6 Hz, 2H); MS (FD) m/e 473 (M⁺). Anal.

(C₂₈H₂₇NO₄S) C,H,N.

[2-(3-Hyd r oxyp h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11c). The

title compound was prepared in 95% yield from 10c by a

method similar to that described for 5g: ¹H NMR (CD₃OD) δ

1.45 (m, 2H), 1.59 (m, 4H), 2.50 (m, 4H), 2.72 (t, J ) 5.5 Hz,

2H), 4.11 (t, J ) 5.5 Hz, 2H), 4.88 (br s, 2H), 6.61 (m, 1H),

6.8-6.9 (m, 5H), 7.01 (t, J ) 8.1 Hz, 1H), 7.27 (d, J ) 2.1 Hz,

1H), 7.39 (d, J ) 8.8 Hz, 1H), 7.70 (d, J ) 8.7 Hz, 2H); HRMS

[2-[4-(Th iom eth yl)p h en yl]-6-h yd r oxyben zo[b]th ien -3-

yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a n on e (11j).

The title compound was prepared in 23% yield from 10j by a

method similar to that described for 5g: ¹H NMR δ 1.49 (m,

2H), 1.68 (m, 4H), 2.42 (s, 3H), 2.62 (m, 4H), 2.83 (t, J ) 5.4

Hz, 2H), 4.12 (t, J ) 5.4 Hz, 2H), 6.59 (d, J ) 8.8 Hz, 2H),

6.76 (dd, J ) 8.8, 2.1 Hz, 1H), 7.07 (d, J ) 8.3 Hz, 2H), 7.17

(d, J ) 2.0 Hz, 1H), 7.28 (d, J ) 8.3 Hz, 2H), 7.35 (d, J ) 8.7

Hz, 1H), 7.68 (d, J ) 8.7 Hz, 2H); ¹³C NMR δ 14.4, 22.9, 24.2,

54.1, 56.8, 64.2, 106.6, 113.3, 114.7, 123.2, 125.2, 128.2, 129.2,

129.5, 130.2, 131.4, 132.2, 138.2, 139.3, 140.2, 154.1, 161.9,

192.7; HRMS (FD) m/e calcd for C₂₉H₃₀NO₃S₂(MH⁺) 504.1647,

found 504.1667. Anal. (C₂₉H₂₉NO₃S₂‚1.5H₂O) C,N; H: calcd,

6.08; found, 5.63.

(FAB) m/e calcd for

C

₂₈H₂₈NO₄S (MH⁺) 474.1739, found

474.1741. Anal. (C₂₈H₂₇NO₄S‚0.75H₂O) C,H,N.

[2-(2-Met h ylp h en yl)-6-h yd r oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11d ). The

title compound was prepared in 36% yield from 10d by a

method similar to that described for 5g: ¹H NMR δ 1.48 (m,

2H), 1.66 (m, 4H), 2.23 (s, 3H), 2.58 (m, 4H), 2.80 (t, J ) 5.6

Hz, 2H), 4.09 (t, J ) 5.6 Hz, 2H), 6.57 (d, J ) 8.8 Hz, 2H),

6.82 (dd, J ) 8.8, 2.1 Hz, 1H), 7.0-7.1 (m, 3H), 7.1-7.3 (m,

2H), 7.48 (d, J ) 8.8 Hz, 1H), 7.61 (d, J ) 8.7 Hz, 2H); HRMS

[2-[4-[(E t h ylt h io)m et h yl]p h en yl]-6-h yd r oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (11l). By the method described for 8b, a solution of 7a

(2.6 g, 6.0 mmol) in THF (23 mL) was treated with a 0.6 M

THF solution of 4-[(TBSoxy)methyl]phenylmagnesium bromide

as described for 10k . Chromatography of the intermediate

product (1:1 hexane:EtOAc, 0-10% MeOH) provided 2.2 g

(60%) of the silylated intermediate as an unstable brown oil.

Treatment of this material by the method described for 5g

followed by treatment with TBAF as described for 10k

provided 0.54 g (14% overall) of the title product as a yellow

solid: ¹H NMR δ 1.14 (t, J ) 7.3 Hz, 3H), 1.47 (m, 2H), 1.66

(m, 4H), 2.29 (q, J ) 7.3 Hz, 2H), 2.59 (m, 4H), 2.80 (t, J ) 5.4

Hz, 2H), 3.60 (s, 2H), 4.10 (t, J ) 5.5 Hz, 2H), 6.58 (d, J ) 8.8

Hz, 2H), 6.76 (dd, J ) 8.8, 2.2 Hz, 1H), 7.1-7.2 (m, 3H), 7.29

(d, J ) 8.2 Hz, 2H), 7.39 (d, J ) 8.7 Hz, 1H), 7.65 (d, J ) 8.7

Hz, 2H); MS (FD) m/e 532 (MH⁺). Anal. (C₃₁H₃₃NO₃S₂) C,H,N.

[2-[4-(Tr iflu or om eth yl)ph en yl]-6-h ydr oxyben zo[b]th ien -

3-yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (11m ).

A solution of 10m (480 mg, 0.89 mmol) in anhydrous CH₂Cl₂

(15 mL) was cooled to -78 °C and treated with a 1.0 M CH₂-

Cl₂solution of boron tribromide (0.8 mL, 0.8 mmol). The

mixture was allowed to warm to room temperature, stirred

overnight, and treated with additional boron tribromide (1.75

mL, 1.75 mmol) in two portions. After 72 h, the mixture was

diluted with 75 mL of water and extracted with CH₂Cl₂(2 ×

75 mL). The organic layers were washed with 2 N NaOH, and

the resultant aqueous layer was acidified and extracted with

CH₂Cl₂(75 mL). The combined organic layers were dried (Na₂-

SO₄), concentrated, and purified via radial chromatography

(2:1:0.1 hexane:EtOAc:MeOH, under an ammonia atmosphere)

to provide 110 mg (24%) of the title product as an amorphous

green solid: ¹H NMR δ 1.45 (m, 2H), 1.63 (m, 4H), 2.57 (m,

4H), 2.79 (t, J ) 4.9 Hz, 2H), 4.08 (t, J ) 4.9 Hz, 2H), 6.59 (d,

J ) 8.6 Hz, 2H), 6.77 (d, J ) 8.7 Hz, 1H), 7.15 (s, 1H), 7.33 (d,

J ) 8.7 Hz, 1H), 7.42 (s, 4H), 7.64 (d, J ) 8.6 Hz, 2H), 8.18 (br

s, 1H); HRMS (FD) m/e calcd for C₂₉H₂₇F₃NO₃S (MH⁺) 526.1664,

found 526.1669. Anal. (C₂₉H₂₆F₃NO₃S‚H₂O) C,H,N.

(FAB) m/e calcd for

C

₂₉H₃₀NO₃S (MH⁺) 472.1946, found

472.1942. Anal. (C₂₉H₂₉NO₃S‚0.5H₂O) C,H,N.

[2-(3-Flu or op h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11e). The title

compound was prepared in 53% yield from 10e by a method

similar to that described for 5g: ¹H NMR δ 1.47 (m, 2H), 1.67

(m, 4H), 2.60 (m, 4H), 2.82 (t, J ) 5.4 Hz, 2H), 4.11 (t, J ) 5.4

Hz, 2H), 6.56 (d, J ) 8.9 Hz, 2H), 6.76 (dd, J ) 8.8, 2.1 Hz,

1H), 6.87 (m, 1H), 7.0-7.2 (m, 4H), 7.34 (d, J ) 8.8 Hz, 1H),

7.64 (d, J ) 8.8 Hz, 2H); HRMS (FD) m/e calcd for C₂₈H₂₇

FNO₃S (MH⁺) 476.1705, found 476.1696. Anal. (C₂₈H₂₆

FNO₃S) C,H,N.

-

[2-(4-Eth ylp h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11f). The title

compound was prepared in 65% yield from 10f by a method

similar to that described for 5g: ¹H NMR δ 1.17 (t, J ) 7.5

Hz, 3H), 1.48 (m, 2H), 1.66 (m, 4H), 2.5-2.6 (m, 6H), 2.80 (t,

J ) 5.7 Hz, 2H), 4.10 (t, J ) 5.5 Hz, 2H), 6.63 (d, J ) 8.9 Hz,

2H), 6.78 (dd, J ) 8.8, 2.2 Hz, 1H), 7.05 (d, J ) 8.1 Hz, 2H),

7.20 (d, J ) 2.2 Hz, 1H), 7.30 (m, 2H), 7.39 (d, J ) 8.8 Hz,

1H), 7.69 (d, J ) 8.8 Hz, 2H); ¹³C NMR δ 15.3, 23.9, 25.2, 28.5,

55.0, 57.7, 65.2, 107.5, 114.1, 115.4, 124.1, 128.1, 128.9, 130.5,

130.8, 131.0, 132.3, 133.3, 140.3, 142.1, 144.6, 154.8, 162.8,

193.7; HRMS (FD) m/e calcd for C₃₀H₃₂NO₃S (MH⁺) 486.2088,

found 486.2103. Anal. (C₃₀H₃₁NO₃S‚1.5H₂O) C,N; H: calcd,

6.69; found, 6.11.

[2-[4-(2-P r op yl)p h en yl]-6-h yd r oxyben zo[b]th ien -3-yl]-

[4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11g). The

title compound was prepared in 33% yield from 10g by a

method similar to that described for 9d : ¹H NMR δ 1.16 (d, J

) 6.9 Hz, 6H), 1.47 (m, 2H), 1.65 (m, 4H), 2.58 (m, 4H), 2.79

(m, 3H), 4.07 (t, J ) 5.3 Hz, 2H), 6.56 (d, J ) 8.8 Hz, 2H),

6.74 (dd, J ) 8.8, 2.1 Hz, 1H), 7.05 (d, J ) 8.2 Hz, 2H), 7.15

(d, J ) 2.1 Hz, 1H), 7.2-7.3 (m, 2H), 7.35 (d, J ) 8.7 Hz, 1H),

[2-(2-Meth yl-4-h ydr oxyph en yl)-6-h ydr oxyben zo[b]th ien -

160 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

3-yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (11n ).

The title compound was prepared in 27% yield from 10n by a

method similar to that described for 5g: ¹H NMR δ 1.47 (m,

2H), 1.61 (m, 4H), 2.13 (s, 3H), 2.55 (m, 4H), 2.77 (t, J ) 5.5

Hz, 2H), 4.09 (t, J ) 5.5 Hz, 2H), 4.87 (s, 2H), 6.45 (m, 2H),

6.77 (d, J ) 8.7 Hz, 2H), 6.87 (dd, J ) 8.8, 2.2 Hz, 1H), 7.01

(d, J ) 9.1 Hz, 1H), 7.23 (d, J ) 2.2 Hz, 1H), 7.51 (d, J ) 8.8

Hz, 1H), 7.60 (d, J ) 8.7 Hz, 2H); HRMS (FAB) m/e calcd for

ylmagnesium bromide by a method similar to that described

for 8b: ¹H NMR δ 1.43 (m, 2H), 1.59 (m, 4H), 2.45 (m, 4H),

2.70 (t, J ) 6.0 Hz, 2H), 3.91 (s, 3H), 4.02 (t, J ) 6.0 Hz, 2H),

6.72 (d, J ) 8.7 Hz, 2H), 7.01 (dd, J ) 8.8, 2.1 Hz, 1H), 7.38

(d, J ) 2.3 Hz, 1H), 7.45 (m, 2H), 7.53 (d, J ) 8.4 Hz, 1H),

7.60 (d, J ) 9.3 Hz, 1H), 7.6-7.8 (m, 4H), 7.82 (d, J ) 8.7 Hz,

2H), 7.94 (d, J ) 1.6 Hz, 1H); MS (FD) m/e 521 (M⁺). Anal.

(C₃₃H₃₁NO₃S) C,H,N.

[2-(4-Meth oxy-1-n a p h th yl)-6-m eth oxyben zo[b]th ien -3-

yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (12c).

The title compound was prepared in 47% yield from 7a and

4-methoxy-1-naphthylmagnesium bromide (prepared from

4-methoxy-1-bromonaphthalene⁴⁸) by a method similar to that

described for 8b: ¹H NMR (acetone-d₆) δ 1.3-1.5 (m, 2H), 1.5-

1.7 (m, 4H), 2.41 (m, 4H), 2.59 (t, J ) 6.0 Hz, 2H), 3.94 (s,

3H), 3.98 (s, 3H), 4.00 (t, J ) 6.0 Hz, 2H), 6.65 (d, J ) 8.8 Hz,

2H), 6.87 (d, J ) 8.0 Hz, 1H), 7.09 (dd, J ) 8.8, 2.2 Hz, 1H),

7.4-7.6 (m, 5H), 7.69 (d, J ) 8.8 Hz, 2H), 8.04 (dd, J ) 7.9,

1.6 Hz, 1H), 8.17 (dd, J ) 7.7, 1.9 Hz, 1H); MS (FD) m/e 551

(M⁺). Anal. (C₃₄H₃₃NO₄S) C,H,N.

C₂₉H₃₀NO₄S (MH⁺) 488.1896, found 488.1911. Anal. (C₂₉H₂₉

-

NO₄S‚0.5H₂O) C,H,N.

[2-(2-Met h oxy-4-h yd r oxyp h en yl)-6-h yd r oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (11o). The title compound was prepared in 15% yield

from 10o by a method similar to that described for 5g: ¹H

NMR (1:1 CDCl₃/CD₃OD) δ 1.44 (m, 2H), 1.59 (m, 4H), 2.49

(m, 4H), 2.73 (t, J ) 5.7 Hz, 2H), 3.43 (s, 3H), 4.07 (t, J ) 5.7

Hz, 2H), 6.11 (d, J ) 2.1 Hz, 1H), 6.31 (dd, J ) 8.5, 2.2 Hz,

1H), 6.72 (d, J ) 8.8 Hz, 2H), 6.84 (dd, J ) 8.8, 2.3 Hz, 1H),

7.16 (d, J ) 8.3 Hz, 1H), 7.21 (d, J ) 2.1 Hz, 1H), 7.53 (d, J )

8.9 Hz, 1H), 7.68 (d, J ) 8.7 Hz, 2H); HRMS (FAB) m/e calcd

for C₂₉H₃₀NO₅S (MH⁺) 504.1845, found 504.1875. Anal.

(C₂₉H₂₉NO₅S‚0.5H₂O) C,H,N.

[2-(2-Th ien yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (12d ). The title com-

pound was prepared in 72% yield from 7a and 2-thienylmag-

nesium bromide by a method similar to that described for 8b:

¹H NMR (acetone-d₆) δ 1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.42

(m, 4H), 2.66 (t, J ) 5.8 Hz, 2H), 3.88 (s, 3H), 4.12 (t, J ) 5.9

Hz, 2H), 6.96 (m, 4H), 7.16 (d, J ) 2.5 Hz, 1H), 7.35 (d, J )

8.9 Hz, 1H), 7.43 (d, J ) 5.0 Hz, 1H), 7.55 (d, J ) 2.2 Hz, 1H),

[2-(3-Meth yl-4-h ydr oxyph en yl)-6-h ydr oxyben zo[b]th ien -

3-yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth an on e (11p).

The title compound was prepared in 64% yield from 10p by a

method similar to that described for 5g: ¹H NMR (DMSO-d₆)

δ 1.34 (m, 2H), 1.44 (m, 4H), 2.37 (m, 4H), 2.60 (t, J ) 5.7 Hz,

2H), 4.05 (t, J ) 5.7 Hz, 2H), 6.64 (d, J ) 8.3 Hz, 1H), 6.82

(dd, J ) 8.8, 2.1 Hz, 1H), 6.89 (d, J ) 8.8 Hz, 2H), 6.96 (dd, J

) 8.3, 2.1 Hz, 1H), 7.05 (d, J ) 1.8 Hz, 1H), 7.22 (d, J ) 8.8

Hz, 1H), 7.30 (d, J ) 1.8 Hz, 1H), 7.61 (d, J ) 8.8 Hz, 2H),

9.62 (br s, 1H), 9.75 (br s, 1 H); MS (FD) m/e 487 (M⁺). Anal.

(C₂₉H₂₉NO₄S) C,H,N.

7.77 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 477 (M⁺). Anal. (C₂₇H₂₇

NO₃S₂) C,H,N.

-

[2-(3-Th ien yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (12e). The title com-

pound was prepared in 81% yield from 7a and 3-thienylmag-

nesium bromide by a method similar to that described for 8b:

¹H NMR (acetone-d₆) δ 1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.43

(m, 4H), 2.66 (t, J ) 5.8 Hz, 2H), 3.88 (s, 3H), 4.12 (t, J ) 5.9

Hz, 2H), 6.92 (d, J ) 8.8 Hz, 2H), 6.97 (dd, J ) 8.9, 2.3 Hz,

1H), 7.12 (dd, J ) 5.1, 1.0 Hz, 1H), 7.40 (m, 2H), 7.53 (m, 2H),

[2-(3-Ch lor o-4-h ydr oxyph en yl)-6-h ydr oxyben zo[b]th ien -

3-yl][4-[2-(1-p iper id in yl)eth oxy]p h en yl]m eth a n on e (11q).

The title compound was prepared in 59% yield from 10q by a

method similar to that described for 5g: ¹H NMR δ 1.33 (m,

2H), 1.44 (m, 4H), 2.37 (m, 4H), 2.48 (s, 1H), 2.60 (t, J ) 5.7

Hz, 2H), 4.06 (t, J ) 5.7 Hz, 2H), 6.8-7.0 (m, 4H), 7.12 (dd, J

) 8.5, 2.0 Hz, 1H), 7.25 (m, 2H), 7.33 (d, J ) 2.0 Hz, 1H), 7.63

(d, J ) 8.7 Hz, 2H), 9.82 (br s, 1H); HRMS (FAB) m/e calcd for

7.75 (d, J ) 8.8 Hz, 2H); HRMS (FAB) m/e calcd for C₂₇H₂₈

-

NO₃S₂(MH⁺) 478.1511, found 478.1521.

(2-Met h yl-6-m et h oxyb en zo[b]t h ien -3-yl)[4-[2-(1-p ip e-

r id in yl)eth oxy]p h en yl]m eth a n on e (12f). The title com-

pound was prepared in 52% yield from 7a and methylmagne-

sium bromide by a method similar to that described for 8b:

¹H NMR δ 1.46 (m, 2H), 1.62 (m, 4H), 2.47 (s, 3H), 2.52 (m,

4H), 2.81 (t, J ) 6.0 Hz, 2H), 3.87 (s, 3H), 4.18 (t, J ) 6.0 Hz,

2H), 6.90 (dd, J ) 8.9, 2.3 Hz, 1H), 6.94 (d, J ) 8.8 Hz, 2H),

7.26 (d, J ) 2.3 Hz, 1H), 7.39 (d, J ) 8.9 Hz, 1H), 7.82 (d, J )

8.8 Hz, 2H); MS (FD) m/e 409 (M⁺). Anal. (C₂₄H₂₇NO₃S)

C,H,N.

(2-Eth yl-6-m eth oxyben zo[b]th ien -3-yl)[4-[2-(1-p ip er id -

in yl)eth oxy]p h en yl]m eth a n on e (12g). The title compound

was prepared in 58% yield from 7a and ethylmagnesium

bromide by a method similar to that described for 8b: ¹H NMR

δ 1.27 (t, J ) 7.5 Hz, 3H), 1.44 (m, 2H), 1.60 (m, 4H), 2.50 (m,

4H), 2.78 (t, J ) 5.9 Hz, 2H), 2.83 (q, J ) 7.5 Hz, 2H), 3.83 (s,

3H), 4.16 (t, J ) 5.9 Hz, 2H), 6.87 (dd, J ) 8.9, 2.2 Hz, 1H),

6.92 (d, J ) 8.8 Hz, 2H), 7.26 (d, J ) 2.2 Hz, 1H), 7.33 (d, J )

8.9 Hz, 1H), 7.81 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 424 (M⁺).

Anal. (C₂₅H₂₉NO₃S) C,H,N.

[2-(2-P r op yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (12h ). The title com-

pound was prepared in 57% yield from 7a and 2-propylmag-

nesium bromide by a method similar to that described for 8b:

¹H NMR δ 1.32 (d, J ) 6.8 Hz, 6H), 1.52 (m, 2H), 1.75 (m,

4H), 2.72 (m, 4H), 2.97 (m, 2H), 3.35 (m, 1H), 3.87 (s, 3H),

4.32 (m, 2H), 6.88 (dd, J ) 8.9, 2.3 Hz, 1H), 6.94 (d, J ) 8.8

Hz, 2H), 7.28 (s, 1H), 7.29 (d, J ) 2.3 Hz, 1H), 7.84 (d, J ) 8.8

Hz, 2H); MS (FD) m/e 437 (M⁺).

(2-Cyclop en t yl-6-m et h oxyb en zo[b]t h ien -3-yl)[4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (12i). The title

compound was prepared in 60% yield from 7a and cyclopen-

tylmagnesium bromide by a method similar to that described

for 8b: ¹H NMR δ 1.4-1.8 (m, 12H), 2.04 (m, 2H), 2.53 (m,

4H), 2.80 (t, J ) 5.9 Hz, 2H), 3.35 (quintet, J ) 8.3 Hz, 1H),

3.85 (s, 3H), 4.18 (t, J ) 5.9 Hz, 2H), 6.87 (dd, J ) 8.8, 2.2 Hz,

C₂₈H₂₇ClNO₄S (MH⁺) 508.1349, found 508.1344. Anal. (C₂₈H₂₇

ClNO₄S) C,H,N.

-

[2-(3-Flu or o-4-h ydr oxyph en yl)-6-h ydr oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (11r ).

The title compound was prepared in 60% yield from 10r by a

method similar to that described for 5g: ¹H NMR (MeOD-d₄)

δ 1.62 (m, 2H), 1.80 (m, 4H), 3.11 (m, 4H), 3.34 (t, J ) 6.0 Hz,

2H), 4.32 (t, J ) 6.0 Hz, 2H), 4.86 (br s, 2H), 6.75 (t, J ) 8.6

Hz, 1H), 6.88 (dd, J ) 8.8, 2.2 Hz, 1H), 6.92 (d, J ) 8.8 Hz,

2H), 6.9-7.1 (m, 3H), 7.27 (d, J ) 2.2 Hz, 1H), 7.43 (d, J ) 8.8

Hz, 1H), 7.73 (d, J ) 8.8 Hz, 2H); HRMS (FAB) m/e calcd for

C₂₈H₂₇FNO₄S (MH⁺) 492.1645, found 492.1642. Anal. (C₂₈H₂₆

-

FNO₄S‚0.75H₂O) C,H,N.

[2-(3,5-Dim eth yl-4-h ydr oxyph en yl)-6-h ydr oxyben zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (11s). The title compound was prepared in 49% yield

from 10s by a method similar to that described for 5g: ¹H

NMR δ 1.48 (m, 2H), 1.66 (m, 4H), 2.11 (s, 6H), 2.58 (m, 4H),

2.80 (t, J ) 5.4 Hz, 2H), 4.09 (t, J ) 5.4 Hz, 2H), 6.60 (d, J )

8.7 Hz, 2H), 6.79 (dd, J ) 8.7, 2.0 Hz, 1H), 6.96 (s, 2H), 7.19

(d, J ) 2.0 Hz, 1H), 7.46 (d, J ) 8.7 Hz, 1H), 7.66 (d, J ) 8.7

Hz, 1H); HRMS (FAB) m/e calcd for C₃₀H₃₂NO₄S (MH⁺)

502.2052, found 502.2054. Anal. (C₃₀H₃₁NO₄S‚1.75H₂O) C,H,N.

[2-(1-Na p h th yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (12a ). The title

compound was prepared in 58% yield from 7a and 1-naphth-

ylmagnesium bromide by a method similar to that described

for 8b: ¹H NMR δ 1.46 (m, 2H), 1.60 (m, 4H), 2.47 (m, 4H),

2.68 (t, J ) 5.9 Hz, 2H), 3.92 (s, 3H), 3.96 (t, J ) 5.9 Hz, 2H),

6.47 (d, J ) 8.8 Hz, 2H), 7.06 (dd, J ) 8.9, 2.3 Hz, 1H), 7.2-

7.5 (m, 5H), 7.54 (d, J ) 8.8 Hz, 2H), 7.6-7.8 (m, 2H), 7.79 (d,

J ) 8.9 Hz, 1H), 8.08 (m, 1H); MS (FD) m/e 521 (M⁺).

[2-(2-Na p h th yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (12b). The title

compound was prepared in 75% yield from 7a and 2-naphth-

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 161

1H), 6.93 (d, J ) 8.7 Hz, 2H), 7.27 (d, J ) 8.8 Hz, 1H), 7.27 (d,

J ) 2.2 Hz, 1H), 7.84 (d, J ) 8.7 Hz, 2H); MS (FD) m/e 463

(M⁺).

ethyl acetate provided a 68% yield of the title compound as

yellow crystals, mp 121-123 °C: ¹H NMR (CD₃OD) δ 1.4-1.5

(m, 2H), 1.5-1.7 (m, 4H), 2.49 (m, 4H), 2.72 (t, J ) 5.5 Hz,

2H), 4.10 (t, J ) 5.5 Hz, 2H), 6.86 (m, 3H), 7.05 (dd, J ) 5.1,

1.1 Hz, 1H), 7.2-7.4 (m, 4H), 7.73 (d, J ) 8.8 Hz, 2H); HRMS

(FAB) m/e calcd for C₂₆H₂₆NO₃S₂(MH⁺) 464.1354, found

464.1368. Anal. (C₂₆H₂₅NO₃S₂‚0.5H₂O) C,H,N.

(2-Met h yl-6-h yd r oxyb en zo[b]t h ien -3-yl)[4-[2-(1-p ip e-

r id in yl)eth oxy]p h en yl]m eth a n on e (13f). The title com-

pound was prepared in 72% yield from 12f by a method similar

to that described for 5g: ¹H NMR δ 1.54 (m, 2H), 1.77 (m,

4H), 2.42 (s, 3H), 2.50 (s, 1H), 2.77 (m, 4H), 3.00 (t, J ) 5.2

Hz, 2H), 3.99 (t, J ) 5.2 Hz, 2H), 6.82 (m, 3H), 7.2-7.3 (m,

2H), 7.75 (d, J ) 8.7 Hz, 2H); MS (FD) m/e 396 (MH⁺). Anal.

(C₂₃H₂₅NO₃S) C,H,N.

(2-Cycloh exyl-6-m eth oxyben zo[b]th ien -3-yl)[4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (12j). The title com-

pound was prepared in 65% yield from 7a and cyclohexylmag-

nesium chloride by a method similar to that described for 8b:

¹H NMR δ 1.23 (m, 3H), 1.44 (m, 5H), 1.59 (m, 4H), 1.74 (m,

2H), 1.99 (d, J ) 12.3 Hz, 2H), 2.51 (m, 4H), 2.79 (t, J ) 6.0

Hz, 2H), 2.99 (m, 1H), 3.83 (s, 3H), 4.17 (t, J ) 6.0 Hz, 2H),

6.85 (dd, J ) 8.9, 2.3 Hz, 1H), 6.92 (d, J ) 8.8 Hz, 2H), 7.23

(d, J ) 8.9 Hz, 1H), 7.27 (d, J ) 2.3 Hz, 1H), 7.81 (d, J ) 8.8

Hz, 2H); MS (FD) 478 (MH⁺). Anal. (C₂₉H₃₅NO₃S) C,H,N.

[2-tr a n s-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]cycloh exyl]-

6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-piper idin yl)eth oxy]-

p h en yl]m eth a n on e (12k ). The title compound was prepared

in 53% yield from 7a and trans-4-(TBSoxy)cyclohexylmagne-

sium bromide¹³by a method similar to that described for 8b:

¹H NMR δ 0.54 (s, 6H), 0.88 (s, 9H), 1.2-1.8 (m, 10H), 1.8-

2.1 (m, 4H), 2.53 (m, 4H), 2.81 (m, 2H), 2.92 (m, 1H), 3.61 (m,

1H), 3.84 (s, 3H), 4.18 (m, 2H), 6.87 (m, 1H), 6.93 (d, J ) 8.8

Hz, 2H), 7.2-7.3 (m, 2H), 7.81 (d, J ) 8.8 Hz, 2H); MS (FD)

m/e 607 (M⁺). Anal. (C₃₅H₄₉NO₄SSi) C,H,N.

(2-Eth yl-6-h yd r oxyben zo[b]th ien -3-yl)[4-[2-(1-p ip er id i-

n yl)eth oxy]p h en yl]m eth a n on e (13g). The title compound

was prepared in 81% yield from 12g by a method similar to

that described for 5g: ¹H NMR δ 1.23 (t, J ) 7.5 Hz, 3H),

1.46 (m, 2H), 1.66 (m, 4H), 2.60 (m, 4H), 2.79 (q, J ) 7.5 Hz,

2H), 2.84 (t, J ) 5.7 Hz, 2H), 4.17 (t, J ) 5.7 Hz, 2H), 6.73

(dd, J ) 8.8, 2.2 Hz, 1H), 6.78 (d, J ) 8.8 Hz, 2H), 7.15 (d, J

) 2.2 Hz, 1H), 7.19 (d, J ) 8.8 Hz, 1H), 7.74 (d, J ) 8.8 Hz,

[2-[(4-Meth oxyph en yl)m eth yl]-6-m eth oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (12l).

The title compound was prepared in 29% yield from 7a and

4-methoxybenzylmagnesium chloride by a method similar to

that described for 8b as a tan crystalline solid, mp 126 °C:

¹H NMR (acetone-d₆) δ 1.3-1.5 (m, 2H), 1.5-1.7 (m, 4H), 2.4-

2.6 (m, 4H), 2.77 (m, 2H), 3.73 (s, 3H), 3.83 (s, 3H), 4.08 (s,

2H), 4.23 (m, 2H), 6.82 (d, J ) 8.5 Hz, 2H), 6.90 (dd, J ) 8.8,

2.5 Hz, 1H), 7.06 (d, J ) 8.7 Hz, 2H), 7.16 (d, J ) 8.6 Hz, 2H),

7.27 (d, J ) 8.9 Hz, 1H), 7.43 (d, J ) 2.3 Hz, 1H), 7.80 (d, J )

8.7 Hz, 2H); HRMS (FAB) m/e calcd for C₃₁H₃₄NO₄S (MH⁺)

516.2208, found 516.2200. Anal. (C₃₁H₃₃NO₄S‚0.5H₂O) C,H,N.

[2-(1-Na p h th yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (13a ). The title

compound was prepared in 53% yield from 12a by a method

similar to that described for 5g: ¹H NMR δ 1.46 (m, 2H), 1.65

(m, 4H), 2.54 (m, 4H), 2.73 (t, J ) 5.4 Hz, 2H), 3.96 (t, J ) 5.4

Hz, 2H), 6.37 (d, J ) 8.7 Hz, 2H), 6.88 (dd, J ) 8.8, 1.9 Hz,

1H), 7.2-7.3 (m, 2H), 7.3-7.5 (m, 5H), 7.6-7.7 (m, 3H), 8.04

(m, 1H), 8.28 (br s, 1H); MS (FD) m/e 508 (MH⁺). Anal.

(C₃₂H₂₉NO₃S) C,H,N.

[2-(2-Na p h th yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (13b). The title

compound was prepared in 98% yield from 12b by a method

similar to that described for 5g: ¹H NMR δ 1.46 (m, 2H), 1.66

(m, 4H), 2.58 (m, 4H), 2.77 (t, J ) 5.5 Hz, 2H), 4.04 (t, J ) 5.5

Hz, 2H), 6.54 (d, J ) 8.9 Hz, 2H), 6.75 (dd, J ) 8.8, 2.2 Hz,

1H), 7.20 (d, J ) 2.2 Hz, 1H), 7.4-7.5 (m, 4H), 7.64 (d, J ) 8.6

Hz, 1H), 7.7-7.8 (m, 4H), 7.86 (d, J ) 1.5 Hz, 1H); MS (FD)

m/e 507 (M⁺). Anal. (C₃₂H₂₉NO₃S) C,H,N.

[2-(4-Hyd r oxy-1-n a p h th yl)-6-h yd r oxyben zo[b]th ien -3-

yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (13c).

The title compound was prepared in 71% yield from 12c by a

method similar to that described for 5g: ¹H NMR (DMF-d₇) δ

1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.38 (m, 4H), 2.59 (t, J )

5.8 Hz, 2H), 4.01 (t, J ) 5.8 Hz, 2H), 6.74 (d, J ) 8.7 Hz, 2H),

6.88 (d, J ) 7.8 Hz, 1H), 7.04 (dd, J ) 8.7, 2.2 Hz, 1H), 7.39

(d, J ) 7.9 Hz, 1H), 7.4-7.6 (m, 4H), 7.66 (d, J ) 8.7 Hz, 2H),

8.04 (m, 1H), 8.18 (d, J ) 7.9 Hz, 1H), 10.1 (br s, 2H); HRMS

(FAB) m/e calcd for C₃₂H₃₀NO₄S (MH⁺) 524.1896, found

524.1907. Anal. (C₃₂H₂₉NO₄S‚0.5H₂O) C,H,N.

[2-(2-Th ien yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (13d ). The title com-

pound was prepared in 95% yield from 12d by a method

similar to that described for 5g: ¹H NMR (acetone-d₆) δ 1.3-

1.4 (m, 2H), 1.5-1.6 (m, 4H), 2.43 (m, 4H), 2.66 (t, J ) 5.9 Hz,

2H), 4.12 (t, J ) 5.9 Hz, 2H), 6.9-7.0 (m, 4H), 7.13 (m, 1H),

7.28 (d, J ) 8.7 Hz, 1H), 7.38 (m, 2H), 7.77 (m, 2H); MS (FD)

m/e 463 (M⁺). Anal. (C₂₆H₂₅NO₃S₂) C,H,N.

2H); MS (FD) m/e 410 (MH

⁺). Anal. (C₂₄H₂₇NO₃S) C,H,N.

[2-(2-P r op yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (13h ). The title com-

pound was prepared in 84% yield from 12h by a method

similar to that described for 5g: ¹H NMR δ 1.29 (d, J ) 6.8

Hz, 6H), 1.51 (m, 2H), 1.72 (m, 4H), 2.68 (m, 4H), 2.93 (t, J )

5.4 Hz, 2H), 3.32 (septet, J ) 6.8 Hz, 1H), 4.24 (t, J ) 5.4 Hz,

2H), 6.75 (dd, J ) 8.7, 2.2 Hz, 1H), 6.82 (d, J ) 8.7 Hz, 2H),

7.14 (d, J ) 8.7 Hz, 1H), 7.23 (d, J ) 2.2 Hz, 1H), 7.77 (d, J )

8.7 Hz, 2H); MS (FD) m/e 424 (MH⁺). Anal. (C₂₅H₂₉NO₃S)

C,H,N.

(2-Cyclop en t yl-6-h yd r oxyb en zo[b]t h ien -3-yl)[4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (13i). The title

compound was prepared in 86% yield from 12i by a method

similar to that described for 5g: ¹H NMR δ 1.4-1.8 (m, 12H),

2.03 (m, 2H), 2.60 (m, 4H), 2.85 (t, J ) 5.7 Hz, 2H), 3.30

(quintet, J ) 8.2 Hz, 1H), 4.17 (t, J ) 5.7 Hz, 2H), 6.70 (dd, J

) 8.8, 2.2 Hz, 1H), 6.78 (d, J ) 8.8 Hz, 2H), 7.12 (d, J ) 8.8

Hz, 1H), 7.16 (d, J ) 2.2 Hz, 1H), 7.76 (d, J ) 8.8 Hz, 2H); MS

(FD) m/e 449 (M⁺). Anal. (C₂₇H₃₁NO₃S) C,H,N.

(2-Cycloh exyl-6-h yd r oxyben zo[b]th ien -3-yl)[4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (13j). The title com-

pound was prepared in 76% yield from 12j by a method similar

to that described for 5g: ¹H NMR δ 1.22 (m, 4H), 1.47 (m,

4H), 1.68 (m, 7H), 1.96 (m, 2H), 2.63 (m, 4H), 2.88 (t, J ) 5.4

Hz, 2H), 2.96 (m, 1H), 4.20 (t, J ) 5.4 Hz, 2H), 6.71 (dd, J )

8.7, 1.9 Hz, 1H), 6.78 (d, J ) 8.7 Hz, 2H), 7.07 (d, J ) 8.7 Hz,

1H), 7.18 (d, J ) 1.9 Hz, 1H), 7.74 (d, J ) 8.7 Hz, 2H); MS

(FD) m/e 463 (M⁺). Anal. (C₂₈H₃₃NO₃S) C,H,N.

[2-tr a n s-(4-H yd r oxycycloh exyl)-6-h yd r oxyb en zo[b]-

t h ie n -3-yl][4-[2-(1-p ip e r id in yl)e t h oxy]p h e n yl]m e t h a -

n on e (13k ). The title compound was prepared in 84% yield

from 12k by a method similar to that described for 5g: ¹H

NMR (DMSO-d₆) δ 1.0-1.2 (m, 2H), 1.3-1.6 (m, 8H), 1.85 (m,

4H), 2.46 (m, 4H), 2.70 (t, J ) 5.7 Hz, 2H), 2.77 (m, 1H), 3.42

(m, 1H), 4.17 (t, J ) 5.7 Hz, 2H), 4.57 (d, J ) 4.0 Hz, 1H),

6.79 (dd, J ) 8.8, 2.2 Hz, 1H), 7.06 (d, J ) 8.8 Hz, 2H), 7.07

(d, J ) 8.8 Hz, 1H), 7.29 (d, J ) 2.2 Hz, 1H), 7.71 (d, J ) 8.8

Hz, 2H), 9.68 (br s, 1H); MS (FD) m/e 480 (MH⁺). Anal.

(C₂₈N₃₃NO₄S) C,H,N.

[2-[(4-Hydr oxyph en yl)m eth yl]-6-h ydr oxyben zo[b]th ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (13l).

The title compound was prepared in 86% yield from 10g by a

method similar to that described for 9d . Residual EtOAc was

removed via azeotropic distillation with CCl₄: ¹H NMR

(acetone-d₆) δ 1.3-1.5 (m, 2H), 1.5-1.7 (m, 4H), 2.4-2.6 (m,

4H), 2.73 (t, J ) 5.8 Hz, 2H), 4.01 (s, 2H), 4.18 (t, J ) 5.8 Hz,

2H), 6.72 (d, J ) 8.5 Hz, 2H), 6.84 (dd, J ) 8.8, 2.1 Hz, 1H),

7.01 (d, J ) 8.8 Hz, 2H), 7.06 (d, J ) 8.5 Hz, 2H), 7.21 (d, J )

8.7 Hz, 1H), 7.27 (d, J ) 2.2 Hz, 1H), 7.79 (d, J ) 8.7 Hz, 2H);

¹³C NMR (acetone-d₆) δ 24.8, 26.4, 35.1, 55.5, 58.3, 66.9, 107.9,

115.2, 115.4, 116.0, 116.1, 124.6, 130.5, 131.2, 132.0, 132.6,

132.8, 140.7, 146.2, 155.8, 156.9, 164.0, 192.3; IR (CHCl₃) 3599,

[2-(3-Th ien yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (13e). The title com-

pound was prepared from 12e by a method similar to that

described for 5g. Crystallization from methylene chloride/

162 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

3309, 1644, 1599 cm^-1; HRMS (FAB) m/e calcd for C₂₉H₃₀NO₄S

(MH⁺) 488.1896, found 488.1857. Anal. (C₂₉H₂₉NO₄S‚0.5CCl₄)

C,H,N.

[2-(Tr im et h ylst a n n yl)-6-(m et h oxyoxy)ben zo[b]t h ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (14).

Lithium metal (7.1 g, 1.02 mol) was suspended in THF (100

mL) and treated with trimethylstannyl chloride (1.0 M in THF,

103 mL, 103 mmol) dropwise at 0 °C. After warming to room

temperature, the mixture was allowed to stir overnight.

An aliquot of the Me₃SnLi solution prepared above (0.507

M in THF, 19.4 mL, 9.85 mmol) was added dropwise to a

solution of 7a (2.4 g, 5.47 mmol) in THF (48 mL) at -78 °C.

The mixture was allowed to slowly warm to room temperature

over 5 h and the reaction quenched rapidly by pouring into a

mixture of ice-cold saturated NH₄Cl (100 mL) and CH₂Cl₂(100

mL). The layers were separated, the aqueous layer was

extracted with CH₂Cl₂(100 mL), and the combined organic

layers were washed with saturated NaHCO₃(100 mL), dried

(Na ₂SO₄), and concentrated to provide 3.1 g of the crude title

compound as a brown oil: ¹H NMR δ 0.34 (s, 9H), 1.4-1.6 (m,

2H), 1.6-1.8 (m, 4H), 2.6-2.8 (m, 4H), 2.86 (m, 2H), 3.86 (s,

3H), 4.27 (m, 2H), 6.84 (dd, J ) 8.9, 2.3 Hz, 1H), 6.92 (d, J )

8.7 Hz, 2H), 7.25 (m, 1H), 7.34 (d, J ) 2.4 Hz, 1H), 7.77 (d, J

) 8.6 Hz, 2H).

2H); HRMS (FD) m/e calcd for C₂₈H₂₇N₂O₅S (MH⁺) 503.1642,

found 503.1641. Anal. (C₂₈H₂₆N₂O₅S‚0.25H₂O) C,H,N.

[2-(4-P yr id yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (16b). The title com-

pound was prepared in 92% yield from 15b by a method

similar to that described for 5g: ¹H NMR (acetone-d₇) δ 1.3-

1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.45 (m, 4H), 2.68 (t, J ) 5.9 Hz,

2H), 4.12 (t, J ) 5.9 Hz, 2H), 6.91 (d, J ) 8.8 Hz, 2H), 6.97

(dd, J ) 8.8, 2.3 Hz, 1H), 7.35 (m, 2H), 7.41 (d, J ) 8.8 Hz,

1H), 7.46 (d, J ) 2.2 Hz, 1H), 7.74 (d, J ) 8.7 Hz, 2H), 8.47

(dd, J ) 4.5, 1.5 Hz, 2H); ¹³C NMR δ 23.74, 25.18, 54.91, 57.51,

65.39, 107.42, 114.42, 116.18, 122.97, 124.71, 130.09, 132.25,

132.75, 134.19, 136.53, 140.89, 141.54, 149.52, 156.21, 163.22,

192.84; HRMS (FD) m/e calcd for C₂₇H₂₇N₂O₃S (MH)⁺459.1742,

found 459.1746. Anal. (C₂₇H₂₆N₂O₃S‚2.25H₂O) C,N; H: calcd,

6.16; found, 5.39.

[2-(N-Oxo-4-p yr id yl)-6-h yd r oxyb en zo[b]t h ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (16c). The

title compound was prepared in 97% yield from 15c by a

method similar to that described for 5g: ¹H NMR (acetone-

d₇) δ 1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.43 (m, 4H), 2.66 (t,

J ) 6.0 Hz, 2H), 4.12 (t, J ) 6.0 Hz, 2H), 6.95 (m, 3H), 7.36

(d, J ) 7.1 Hz, 2H), 7.44 (m, 2H), 7.75 (d, J ) 8.8 Hz, 2H),

8.02 (d, J ) 7.1 Hz, 2H); MS (FD) m/e 475 (MH)⁺. Anal.

(C₂₇H₂₆N₂O₄S) C,H,N.

[2-(4-Nitr op h en yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (15a ). A solu-

tion of 14 (2.5 g, 4.5 mmol), 1-bromo-4-nitrobenzene (2.9 g, 15.0

mmol), and Pd(PPh₃)₄(0.41 g, 0.4 mmol) in DMF (20 mL) was

heated at 100 °C overnight. After cooling to room temperature,

the mixture was concentrated and the residue was purified

via flash chromatography (1:1 hexane:EtOAc, 0-1% MeOH)

to provide 0.35 g (15%) of the title compound as a bright yellow

solid: ¹H NMR δ 1.43 (m, 2H), 1.57 (m, 4H), 2.46 (m, 4H),

2.72 (t, J ) 6.0 Hz, 2H), 3.89 (s, 3H), 4.08 (t, J ) 6.0 Hz, 2H),

6.79 (d, J ) 8.8 Hz, 2H), 6.98 (dd, J ) 9.0, 2.3 Hz, 1H), 7.34

(d, J ) 2.3 Hz, 1H), 7.52 (d, J ) 9.0 Hz, 1H), 7.58 (d, J ) 8.7

Hz, 2H), 7.75 (d, J ) 8.8 Hz, 2H), 8.09 (d, J ) 8.8 Hz, 2H); MS

(FD) m/e 516 (M⁺). Anal. (C₂₉H₂₈N₂O₅S) C,H,N.

[2-(4-P yr id yl)-6-m eth oxyben zo[b]th ien -3-yl][4-[2-(1-p i-

p er id in yl)eth oxy]p h en yl]m eth a n on e (15b). The title com-

pound was prepared in 54% yield from 14 and 4-bromopyridine

by a method similar to that described for 15a : ¹H NMR

(acetone-d₆) δ 1.3-1.4 (m, 2H), 1.4-1.6 (m, 4H), 2.04 (m, 2H),

2.65 (t, J ) 6.0 Hz, 2H), 3.90 (s, 3H), 4.10 (t, J ) 6.0 Hz, 2H),

6.92 (d, J ) 8.8 Hz, 2H), 7.04 (m, 1H), 7.36 (dd, J ) 4.5, 1.5

Hz, 2H), 7.4-7.8 (m, 4H), 8.48 (m, 2H); MS (FD) m/e 472 (M⁺).

[2-(N-Oxo-4-p yr id yl)-6-m eth oxyben zo[b]th ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (15c). The

title compound was prepared in 41% yield from 14 and

4-bromopyridine N-oxide by a method similar to that described

for 15a : ¹H NMR (acetone-d₆) δ 1.3-1.5 (m, 2H), 1.4-1.6 (m,

4H), 2.04 (m, 4H), 2.67 (t, J ) 5.9 Hz, 2H), 3.91 (s, 3H), 4.13

(t, J ) 5.9 Hz, 2H), 6.95 (d, J ) 8.8 Hz, 2H), 7.04 (dd, J ) 8.9,

2.2 Hz, 1H), 7.38 (d, J ) 7.1 Hz, 2H), 7.48 (d, J ) 9.2 Hz, 1H),

7.62 (d, J ) 2.4 Hz, 1H), 7.76 (d, J ) 8.8 Hz, 2H), 8.03 (d, J )

7.0 Hz, 2H); HRMS (FAB) m/e calcd for C₂₈H₂₉N₂O₄S (MH)⁺

489.1848, found 489.1849.

[2-(4-Ca r b et h oxyp h en yl)-6-m et h oxyb en zo[b]t h ien -3-

yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (15d ).

The title compound was prepared in 87% yield from 14 and

ethyl 4-bromobenzoate by a method similar to that described

for 15a : ¹H NMR (acetone-d₇) δ 1.34 (t, J ) 7.7 Hz, 3H), 1.4-

1.6 (m, 2H), 1.6-1.8 (m, 4H), 2.52 (m, 4H), 2.77 (t, J ) 5.8 Hz,

2H), 3.88 (s, 3H), 4.11 (t, J ) 5.8 Hz, 2H), 4.32 (q, J ) 7.1 Hz,

2H), 6.76 (d, J ) 9.7 Hz, 2H), 6.99 (dd, J ) 9.7, 2.9 Hz, 1H),

7.34 (d, J ) 2.9 Hz, 1H), 7.5-7.7 (m, 3H), 7.75 (d, J ) 9.7 Hz,

2H), 7.90 (d, J ) 9.7 Hz, 2H).

[2-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]p h en yl]-6-h yd r oxy-

ben zoth ien -3-yl][4-[2-(1-piper idin yl)eth oxy]ph en yl]m eth -

a n on e (17) a n d [2-(4-Hyd r oxyp h en yl)-6-[(ter t-bu tyld im -

e t h ylsilyl)oxy]b e n zot h ie n -3-yl][4-[2-(1-p ip e r id in yl)-

eth oxy]p h en yl]m eth a n on e (18). A solution of raloxifene

(10.0 g, 21.1 mmol) and DMAP (6.0 g, 49.1 mmol) in 6:1 THF:

DMF (700 mL) was stirred at room temperature for 1 h. After

cooling to 0 °C, TBSCl (2.9 g, 19.3 mmol) was added slowly

and the mixture was allowed to warm to room temperature.

After 72 h, the mixture was washed with saturated NH₄Cl (500

mL), water (500 mL), and brine (500 mL), and the organic

extract was filtered and concentrated. The crude product was

triturated with CH₂Cl₂and the resulting mixture allowed to

stand at room temperature for 3 h and then filtered to remove

unreacted starting material. To the filtrate was added silica

gel (500 g), and the slurry was carefully concentrated. Puri-

fication by flash chromatography (silica gel, CHCl₃/0-10%

MeOH gradient) provided 5.1 g of 17 (41%) and 4.8 g of 18

(38%), both as yellow crystalline solids. 17: ¹H NMR δ 0.12

(s, 6H), 0.92 (s, 9H), 1.46 (m, 2H), 1.67 (m, 4H), 2.56 (m, 5H),

2.79 (t, J ) 5.6 Hz, 2H), 4.07 (t, J ) 5.7 Hz, 2H), 6.55 (d, J )

8.9 Hz, 2H), 6.66 (d, J ) 8.5 Hz, 2H), 6.77 (dd, J ) 8.7, 2.2 Hz,

1H), 7.17 (d, J ) 2.2 Hz, 1H), 7.20 (d, J ) 8.6 Hz, 3H), 7.44 (d,

J ) 8.8 Hz, 1H), 7.63 (d, J ) 8.9 Hz, 2H); MS (FD) m/e 587

(M⁺). Anal. (C₃₄H₄₁NO₄SSi) C,H,N.

18: ¹H NMR δ 0.23 (s, 6H), 1.00 (s, 9H), 1.47 (m, 2H), 1.64

(m, 4H), 2.56 (m, 4H), 2.77 (t, J ) 5.6 Hz, 2H), 4.08 (t, J ) 5.6

Hz, 2H), 6.58 (d, J ) 6.9 Hz, 2H), 6.64 (d, J ) 7.0 Hz, 2H),

6.89 (dd, J ) 8.7, 2.2 Hz, 1H), 7.15 (d, J ) 8.4 Hz, 2H), 7.27

(d, J ) 2.3 Hz, 1H), 7.42 (s, 1H), 7.60 (d, J ) 8.9 Hz, 2H); MS

(FD) m/e 587 (M⁺). Anal. (C₃₄H₄₁NO₄SSi) C,H,N.

[2-[4-[(ter t-Bu tyld im eth ylsilyl)oxy]p h en yl]-6-[[(tr iflu o-

r om eth yl)su lfon yl]oxy]ben zoth ien -3-yl][4-[2-(1-p ip er id i-

n yl)eth oxy]p h en yl]m eth a n on e (20). A solution of 17 (10

g, 17.5 mmol) in DCE (100 mL) was cooled to 5 °C and treated

with Et₃N (5 mL, 3.6 g, 35.9 mmol, 2.0 equiv) followed by

N-phenyltrifluoromethanesulfonimide (7 g, 19.5 mmol, 1.1

equiv). The resultant solution was allowed to warm to room

temperature overnight, filtered to remove insolubles, and

concentrated. Purification via chromatography (CH₂Cl₂) af-

forded 11 g (88%) of the title compound as an off-white foam:

¹H NMR δ 0.05 (s, 6H), 0.85 (s, 9H), 1.35 (m, 2H), 1.55 (m,

4H), 2.40 (m, 4H), 2.65 (t, J ) 7 Hz, 2H), 4.00 (t, J ) 7 Hz,

2H), 6.65 (m, 4H), 7.20 (m, 3H), 7.65 (d, J ) 10 Hz, 2H), 7.75

(m, 2H); MS (FD) m/e 720 (MH⁺).

[2-(4-Nitr op h en yl)-6-h yd r oxyben zo[b]th ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (16a ). The title

compound was prepared in 56% yield from 15a by a method

similar to that described for 9d : ¹H NMR δ 1.49 (m, 2H), 1.67

(m, 4H), 2.61 (m, 4H), 2.84 (t, J ) 5.4 Hz, 2H), 4.13 (t, J ) 5.4

Hz, 2H), 6.61 (d, J ) 8.8 Hz, 2H), 6.80 (dd, J ) 8.8, 2.1 Hz,

1H), 7.20 (d, J ) 2.1 Hz, 1H), 7.37 (d, J ) 8.8 Hz, 1H), 7.51 (d,

J ) 8.7 Hz, 2H), 7.66 (d, J ) 8.8 Hz, 2H), 8.06 (d, J ) 8.7 Hz,

[2-[4-[[(Tr iflu or om eth yl)su lfon yl]oxy]p h en yl]-6-[(ter t-

bu tyld im eth ylsilyl)oxy]ben zoth ien -3-yl][4-[2-(1-p ip er id i-

n yl)eth oxy]p h en yl]m eth a n on e (21). The title compound

was prepared in 88% yield from 18 by a method similar to

that described for 20: ¹H NMR δ 0.24 (s, 6H), 1.02 (s, 9H),

1.44 (m, 2H), 1.58 (m, 4H), 2.48 (m, 4H), 2.73 (t, J ) 6.0 Hz,

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 163

2H), 4.08 (t, J ) 6.0 Hz, 2H), 6.77 (d, J ) 8.8 Hz, 2H), 6.92

(dd, J ) 8.8, 2.2 Hz, 1H), 7.13 (d, J ) 8.8 Hz, 2H), 7.33 (d, J

) 2.1 Hz, 1H), 7.48 (d, J ) 8.6 Hz, 2H), 7.57 (d, J ) 8.8 Hz,

1H), 7.72 (d, J ) 8.8 Hz, 2H); MS (FD) m/e 719 (M⁺). Anal.

(C₃₅H₄₀F₃NO₆S₂Si) C,H,N.

of 20 (1.0 g, 1.4 mmol), butyl vinyl ether (1.1 mL, 7.7 mmol),

Et₃N (1 mL), 1,3-bis(diphenylphosphino)propane (58 mg, 0.14

mmol), and Pd(OAc)₂(31 mg, 0.14 mmol) in DMF (15 mL) was

heated at 75 °C for 5 h. After cooling to room temperature, 5

N HCl (15 mL) was added and the solution which resulted

was stirred overnight. Workup similar to that described for

22a afforded 430 mg (62%) of the title compound as an orange

solid, mp 97-100 °C: ¹H NMR (DMSO-d₆) δ 1.40 (m, 2H), 1.80

(m, 4H), 2.70 (s, 3H), 3.35 (m, 4H), 3.45 (m, 2H), 4.40 (m, 2H),

6.75 (d, J ) 8 Hz, 2H), 7.00 (d, J ) 8 Hz, 2H), 7.30 (d, J ) 8

Hz, 2H), 7.55 (d, J ) 8 Hz, 1H), 7.75 (d, J ) 8 Hz, 2H), 7.90

(d, J ) 8 Hz, 1H), 8.80 (s, 1H), 10.00 (s, 1H); MS (FD) m/e 499

(M⁺). Anal. (C₃₀H₂₉NO₄S‚H₂O) C,H,N.

[2-(4-H y d r o x y p h e n y l)-6-(d ie t h y lp h o s p h o n y l)b e n -

zot h ien -3-yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a -

n on e (22h ). A solution of 20 (2.0 g, 2.8 mmol), diethyl

phosphite (0.58 g, 0.54 mL, 4.2 mmol), and Et₃N (5 mL) in

CH₃CN (15 mL) was degassed via N₂stream for 15 min,

treated with Pd(PPh₃)₄, and heated at 75 °C for 36 h. Workup

similar to that described for 22a afforded 800 mg (49%) of the

title compound as a yellow solid, mp 75-78 °C: ¹H NMR

(DMSO-d₆) δ 1.25 (t, J ) 7 Hz, 6H), 1.40 (m, 2H), 1.50 (m,

4H), 2.45 (m, 4H), 2.70 (t, J ) 5 Hz, 2H), 4.0-4.3 (m, 6H),

6.80 (d, J ) 8 Hz, 2H), 7.00 (d, J ) 8 Hz, 2H), 7.35 (d, J ) 8

Hz, 2H), 7.6-7.7 (m, 2H), 7.75 (d, J ) 8 Hz, 2H), 8.55 (d, J )

15 Hz, 1H), 10.05 (br s, 1H); MS (FD) m/e 594 (MH⁺). Anal.

(C₃₂H₃₆NO₆PS‚1.5H₂O) C,H,N.

[2-(4-Hydr oxyph en yl)-6-(m eth oxycar bon yl)ben zoth ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (22a ).

A solution of 20 (1 g, 1.4 mmol), Et₃N (5 mL), MeOH (5 mL),

and 1,3-bis(diphenylphosphino)propane (58 mg, 0.14 mmol) in

anhydrous DMF (15 mL) was purged with electronic grade CO

at room temperature for 15 min. Palladium(II) acetate (31

mg, 0.14 mmol) was then added, and the mixture was heated

to 75 °C for 6 h under a CO atmosphere. After cooling to room

temperature, the mixture was concentrated in vacuo and the

residue was dissolved in THF (25 mL), filtered, and reconcen-

trated. The crude product was then partitioned between

EtOAc (100 mL) and 1 N HCl (100 mL) and stirred at room

temperature for 2 h. The solution was then brought to pH

4-5 with HOAc/OAc^-buffer, the layers were separated, and

the aqueous layer was extracted with EtOAc (3 × 100 mL).

The combined organic layers were dried (Na₂SO₄), concen-

trated, and purified via chromatography (CH₂Cl₂, 0-15%

MeOH) to provide 555 mg (77%) of the title compound, which

was converted to its HCl salt (mp 128 °C) using MeOH/

anhydrous HCl: ¹H NMR (DMSO-d₆) δ 1.3-1.9 (m, 6H), 2.9-

3.1 (m, 4H), 3.45 (m, 2H), 3.95 (s, 3H), 4.35 (m, 2H), 6.80 (d,

J ) 8 Hz, 2H), 7.05 (d, J ) 8 Hz, 2H), 7.35 (d, J ) 8 Hz, 2H),

7.65 (d, J ) 8 Hz, 1H), 7.80 (d, J ) 8 Hz, 2H), 8.00 (d, J ) 8

Hz, 1H), 8.80 (s, 1H), 10.00 (s, 1H); MS (FD) m/e 515 (M⁺).

Anal. (C₃₀H₂₉NO₅S‚HCl‚1.5H₂O) C,H,N.

[2-(4-Hyd r oxyp h en yl)-6-ca r boxyben zoth ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (22c). A solu-

tion of 22a (2 g, 4.0 mmol) and LiOH (0.2 g, 8.0 mmol) in a

mixture of THF (100 mL) and H₂O (10 mL) was heated at

reflux for 18 h. After the solution was allowed to cool to room

temperature, the solvents were removed in vacuo, and the

residue was partitioned between EtOAc (300 mL) and 1 N HCl

(300 mL). The precipitate was filtered, washed with acetone,

and dried to afford 0.7 g (37%) of the HCl salt of the title

compound as a yellow solid: ¹H NMR (DMSO-d₆) δ 1.3-1.5

(m, 2H), 1.5-1.6 (m, 4H), 2.4-2.6 (m, 4H), 2.7-2.8 (m, 2H),

4.1-4.2 (m, 2H), 6.75 (d, J ) 8 Hz, 2H), 6.95 (d, J ) 8 Hz,

2H), 7.30 (d, J ) 8 Hz, 2H), 7.55 (d, J ) 8 Hz, 1H), 7.75 (d, J

) 8 Hz, 2H), 7.95 (d, J ) 8 Hz, 1H), 8.65 (s, 1H); MS (FD) m/e

501 (M⁺). Anal. (C₂₉H₂₇NO₅S‚HCl‚1.5H₂O) C,H,N.

[2-(4-Hyd r oxyp h en yl)-6-ca r ba m oylben zoth ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (22d ). A so-

lution of 22a (500 mg, 0.97 mmol) and Et₃N (1 mL) in THF

(50 mL) was treated with TBSCl (300 mg, 1.99 mmol), and

the resultant mixture was stirred overnight at room temper-

ature. The solvents were removed in vacuo, and the remnant

was suspended in toluene (25 mL) and filtered to remove

unreacted TBSCl. The filtrate was concentrated in vacuo, and

the toluene extraction was repeated twice to afford ap-

proximately 700 mg of crude silyl ether which was used

without purification.

The crude silyl ether generated above was dissolved in

toluene (10 mL), treated with a 0.32 M solution of MeAl(Cl)-

NH₂in toluene (15 mL, 4.8 mmol), and stirred overnight at

room temperature.²²The solvent was removed in vacuo, and

the residue was suspended in THF:1 N HCl (9:1, 50 mL) and

heated at reflux for 5 h. After concentration, the residue was

purified via chromatography (CHCl₃, 0-15% MeOH) to afford

150 mg (31%) of the title compound as a yellow oil. The

hydrochloride salt was subsequently prepared by treatment

with THF/concentrated HCl and trituration of the resultant

material with Et₂O: ¹H NMR (free base, CD₃OD) δ 1.5-1.7

(m, 2H), 1.7-1.8 (m, 4H), 2.80-3.0 (m, 4H), 3.10 (t, J ) 5 Hz,

2H), 4.25 (t, J ) 5 Hz, 2H), 6.70 (d, J ) 8 Hz, 2H), 6.90 (d, J

) 10 Hz, 2H), 7.30 (d, J ) 8 Hz, 2H), 7.6-7.8 (m, 3H), 7.90 (d,

[2-(4-Hyd r oxyp h en yl)-6-eth yn ylben zoth ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (22i). A solu-

tion of 20 (2.0 g, 2.8 mmol), (trimethylsilyl)acetylene (0.68 g,

1.0 mL, 6.9 mmol), 1,3-bis(diphenylphosphino)propane (116

mg, 0.28 mmol), and Et₃N (5 mL) in DMF (20 mL) was

degassed via N₂stream for 15 min, treated with Pd(OAc)₂(62

mg, 0.24 mmol), and heated at 75 °C for 10 h. Workup similar

to that described for 22a afforded 1.5 g of a dark yellow foam.

The crude product was then dissolved in THF (100 mL) and

treated with TBAF (0.5 g, 2.7 mmol) and the mixture stirred

overnight. The reaction mixture was concentrated in vacuo,

and the residue was purified via chromatography (CHCl₃,

0-20% EtOH) to afford 300 mg (22%) of the title compound

as a beige solid, mp 97-100 °C: ¹H NMR δ 1.60 (m, 2H), 1.80

(m, 4H), 2.80 (m, 4H), 3.00 (t, J ) 5 Hz, 2H), 3.25 (s, 1H), 4.25

(t, J ) 5 Hz, 2H), 6.7-6.8 (m, 4H), 7.25 (d, J ) 8 Hz, 2H), 7.60

(d, J ) 10 Hz, 1H), 7.75 (d, J ) 10 Hz, 2H), 7.85 (d, J ) 10 Hz,

1H), 8.10 (s, 1H); MS (FD) m/e 481 (M⁺). Anal. (C₃₀H₂₇

NO₃S‚H₂O) C,H,N.

-

[2-[4-(Meth oxycar bon yl)ph en yl]-6-h ydr oxyben zoth ien -

3-yl][4-[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (23a ).

Carbon monoxide was bubbled through solutions of 21 (10.2

g, 14 mmol) in DMF (45 mL) and of Pd(OAc)₂(0.10 g, 0.46

mmol), 1,3-bis(diphenylphosphino)propane (0.17 g, 0.41 mmol),

MeOH (22.5 mL, 560 mmol), and Et₃N (4.1 mL, 29 mmol) in

DMF (45 mL) for 15 min. The solutions were then combined

and heated to 70 °C under a CO atmosphere for 4.5 h. The

mixture was then diluted with saturated NaHCO₃(200 mL)

and extracted with CH₂Cl₂(3 × 200 mL). The combined

organic layers were washed with brine (200 mL), dried

(MgSO₄), concentrated, and purified by chromatography (1:1

hexane:EtOAc, 0-10% MeOH) to give 1.9 g (27%) of the title

compound as a bright yellow solid: ¹H NMR (DMSO-d₆) δ 1.36

(m, 2H), 1.45 (m, 4H), 2.37 (m, 4H), 2.59 (t, J ) 5.8 Hz, 2H),

3.82 (s, 3H), 4.07 (t, J ) 5.8 Hz, 2H), 6.92 (m, 3H), 7.34 (d, J

) 8.9 Hz, 1H), 7.43 (s, 1H), 7.51 (d, J ) 7.8 Hz, 2H), 7.68 (d,

J ) 7.8 Hz, 2H), 7.87 (d, J ) 7.8 Hz, 2H); ¹³C NMR (DMSO-

d₆) δ 23.8, 25.4, 52.1, 54.2, 57.0, 65.9, 107.1, 114.6, 115.7, 124.0,

128.4, 129.0, 129.4, 129.6, 131.8, 132.0, 132.6, 137.5, 137.7,

140.1, 156.2, 163.0, 165.5, 192.0; HRMS (FD) m/e calcd for

C₃₀H₃₀NO₅S (MH⁺) 516.1856, found 516.1845. Anal. (C₃₀H₂₉

-

NO₅S‚1.5H₂O) C,H,N.

An additional 4.8 g (54%) of the corresponding TBS ether

was also obtained and used in subsequent reactions: ¹H NMR

δ 0.23 (s, 6H), 1.00 (s, 9H), 1.45 (m, 2H), 1.61 (m, 4H), 2.52

(m, 4H), 2.77 (t, J ) 5.6 Hz, 2H), 3.87 (s, 3H), 4.10 (t, J ) 5.7

Hz, 2H), 6.75 (d, J ) 8.7 Hz, 2H), 6.89 (dd, J ) 8.8, 2.0 Hz,

1H), 7.31 (d, J ) 2.0 Hz, 1H), 7.49 (m, 3H), 7.75 (d, J ) 8.7

Hz, 2H), 7.89 (d, J ) 8.3 Hz, 2H); MS (FD) m/e 629 (M⁺).

J

) 8 Hz, 1H), 8.50 (s, 1H); HRMS (FAB) m/e calcd for

C₂₉H₂₉N₂O₄S (MH⁺) 501.1848, found 501.1855. Anal.

(C₂₉H₂₈N₂O₄S‚HCl‚2.25H₂O) C; H: calcd, 5.85; found, 5.31.

N: calcd, 4.85; found, 4.37.

[2-(4-Hyd r oxyp h en yl)-6-a cetylben zoth ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (22g). A solution

164 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2

Grese et al.

[2-[4-(Eth oxyca r bon yl)p h en yl]-6-h yd r oxyben zoth ien -

3-yl][4-[2-(1-pip er id in yl)eth oxy]ph en yl]m eth a n on e (23b).

Carbon monoxide was bubbled through solutions of 21 (6.2 g,

8.7 mmol) in DMF (30 mL) and of Pd(OAc)₂(70 mg, 0.3 mmol),

1,3-bis(diphenylphosphino)propane (120 mg, 0.3 mmol), EtOH

(22.8 mL, 390 mmol), and Et₃N (2.9 mL, 20 mmol) in DMF

(20 mL) for 10 min. The solutions were then combined and

heated to 70 °C under a CO atmosphere for 4.5 h. The mixture

was then concentrated to dryness, and the residue was

dissolved in CH₂Cl₂(50 mL) and treated with 1.0 M TBAF

(9.5 mL, 9.5 mmol) in THF for 3 h. The reaction mixture was

then partitioned between saturated NH₄Cl (200 mL) and

EtOAc (200 mL), and the organic layer was washed with

saturated NH₄Cl (3 × 200 mL) and brine (200 mL), dried (Na₂-

SO₄), and concentrated. Purification by chromatography (1:1

hexane:EtOAc, 6-10% MeOH) provided 2.1 g (44%) of the title

compound as a bright yellow solid: ¹H NMR δ 1.35 (t, J ) 7.1

Hz, 3H), 1.47 (m, 2H), 1.65 (m, 4H), 2.58 (m, 4H), 2.80 (t, J )

5.5 Hz, 2H), 4.10 (t, J ) 5.5 Hz, 2H), 4.33 (q, J ) 7.1 Hz, 2H),

6.60 (d, J ) 8.8 Hz, 2H), 6.78 (dd, J ) 8.8, 2.1 Hz, 1H), 7.18

(d, J ) 2.1 Hz, 1H), 7.37 (d, J ) 8.8 Hz, 2H), 7.42 (d, J ) 8.3

Hz, 2H), 7.67 (d, J ) 8.7 Hz, 2H), 7.87 (d, J ) 8.3 Hz, 2H); MS

(FD) m/e 530 (MH⁺). Anal. (C₃₁H₃₁NO₅S) C,H,N.

[2-(4-Ca r boxyp h en yl)-6-h yd r oxyben zoth ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (23c). A solu-

tion of 23a (1.0 g, 1.9 mmol) in THF (100 mL) was treated

with 1.0 N NaOH (47.2 mL, 47.2 mmol) and heated to 70 °C

for 22 h. The mixture was then diluted with saturated

NaHCO₃(200 mL) and extracted with EtOAc (3 × 200 mL).

The combined organic layers were washed with brine (200 mL),

dried (Na₂SO₄), concentrated, and purified by chromatography

(1:1 hexane:EtOAc, 10-70% MeOH) to give 0.49 g (51%) of

the title product as a bright yellow solid: ¹H NMR (CD₃OD) δ

1.4-1.9 (m, 6H), 2.98 (m, 2H), 3.48 (m, 4H), 4.36 (m, 2H), 6.93

(dd, J ) 6.4, 2.2 Hz, 1H), 7.00 (d, J ) 8.8 Hz, 2H), 7.33 (d, J

) 7.9 Hz, 1H), 7.44 (d, J ) 2.0 Hz, 1H), 7.49 (d, J ) 8.7 Hz,

2H), 7.74 (d, J ) 9.1 Hz, 2H), 7.86 (d, J ) 7.9 Hz, 2H); HRMS

(FD) m/e calcd for C₂₉H₂₈NO₅S (MH⁺) 502.1694, found 502.1688.

Anal. (C₂₉H₂₇NO₅S‚1.6H₂O) C,N; H: calcd, 5.74; found, 5.11.

[2-(4-Ca r ba m oylp h en yl)-6-h yd r oxyben zoth ien -3-yl][4-

[2-(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (23d ). The

title compound was prepared in 46% yield from the TBS ether

of 23a and MeAl(Cl)NH₂by a method similar to that described

for 22d : ¹H NMR (CD₃OD) δ 1.45 (m, 2H), 1.59 (m, 4H), 2.52

(m, 4H), 2.74 (t, J ) 5.4 Hz, 2H), 4.09 (t, J ) 5.5 Hz, 2H), 6.82

(d, J ) 8.8 Hz, 2H), 6.88 (dd, J ) 8.8, 2.0 Hz, 1H), 7.30 (d, J

) 2.1 Hz, 1H), 7.43 (m, 3H), 7.71 (m, 4H); HRMS (FD) m/e

calcd for C₂₉H₂₉N₂O₄S (MH⁺) 501.1860, found 501.1848. Anal.

(C₂₉H₂₈N₂O₄S‚0.75H₂O) C,H,N.

[2-[4-(N -Me t h ylc a r b a m oyl)p h e n yl]-6-h yd r oxyb e n -

zot h ien -3-yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a -

n on e (23e). A solution of the TBS ether of 23a (1.0 g, 1.6

mmol) in toluene (50 mL) was treated with a 0.32 M solution

of MeAl(Cl)N(H)Me in toluene (30 mL, 9.6 mmol) and stirred

at 50 °C for 21 h.²²After the reaction was quenched with 0.01

N HCl, the mixture was diluted with saturated NaHCO₃(200

mL) and washed with EtOAc (3 × 200 mL). The combined

organic layers were washed with brine (200 mL), dried (Na₂-

SO₄), concentrated, and purified via chromatography to provide

0.67 g (67%) of the TBS ether of 23e as an off-white foam: ¹H

NMR (CD₃OD) δ 0.24 (s, 6H), 1.01 (s, 9H), 1.45 (m, 2H), 1.58

(m, 4H), 2.50 (m, 4H), 2.72 (t, J ) 5.5 Hz, 2H), 2.85 (s, 3H),

4.08 (t, J ) 5.5 Hz, 2H), 6.82 (d, J ) 8.8 Hz, 2H), 6.96 (dd, J

) 8.8, 2.1 Hz, 1H), 7.40 (d, J ) 2.1 Hz, 1H), 7.46 (m, 3H), 7.68

(m, 4H); MS (FD) m/e 628 (M⁺).

The silyl ether obtained above was desilylated by a method

similar to that described for 23b to provide 0.46 g (91%) of

the title compound as a bright yellow solid: ¹H NMR (CD₃-

OD) δ 1.26 (m, 2H), 1.40 (m, 4H), 2.30 (m, 4H), 2.51 (t, J )

5.4 Hz, 2H), 2.68 (s, 3H), 3.87 (t, J ) 5.4 Hz, 2H), 6.61 (d, J )

8.8 Hz, 2H), 6.70 (dd, J ) 8.8, 2.1 Hz, 1H), 7.12 (d, J ) 2.0 Hz,

1H), 7.23 (m, 3H), 7.49 (m, 3H); HRMS (FD) m/e calcd for

C₃₀H₃₁N₂O₄S (MH⁺) 515.2021, found 515.2005. Anal.

(C₃₀H₃₀N₂O₄S‚H₂O) C,H,N.

n on e (23f). The title compound was prepared in two steps

and 72% overall yield from the TBS ether of 23a by a method

similar to that described for 23e: ¹H NMR (CD₃OD) δ 1.29

(m, 2H), 1.44 (m, 4H), 2.34 (m, 4H), 2.56 (t, J ) 5.4 Hz, 2H),

2.64 (s, 3H), 2.87 (s, 3H), 3.89 (t, J ) 5.4 Hz, 2H), 6.61 (d, J )

8.8 Hz, 2H), 6.73 (dd, J ) 8.8, 2.1 Hz, 1H), 7.08 (d, J ) 8.1 Hz,

2H), 7.14 (d, J ) 2.1 Hz, 1H), 7.24 (d, J ) 8.1 Hz, 2H), 7.30 (d,

J ) 8.8 Hz, 1H), 7.49 (d, J ) 8.7 Hz, 2H); HRMS (FD) m/e

calcd for C₃₁H₃₃N₂O₄S (MH⁺) 529.2145, found 529.2161. Anal.

(C₃₁H₃₂N₂O₄S‚0.5H₂O) C,H,N.

[2-(4-Acetylp h en yl)-6-h yd r oxyben zoth ien -3-yl][4-[2-(1-

p ip er id in yl)eth oxy]p h en yl]m eth a n on e (23g). A solution

of 21 (0.88 g, 1.2 mmol), butyl vinyl ether (0.9 mL, 6.9 mmol),

Et₃N (0.39 mL, 2.8 mmol), 1,3-bis(diphenylphosphino)propane

(25 mg, 0.061 mmol), and Pd(OAc)₂(19 mg, 0.086 mmol) in

DMF (4 mL) was heated at 80 °C for 19 h. The mixture was

then diluted with 0.1 M HCl (20 mL) and extracted with CH₂-

Cl₂(3 × 50 mL). The combined organic layers were washed

with saturated NaHCO₃(3 × 50 mL), dried (Na₂SO₄), and

concentrated. The residue was desilylated by a method similar

to that described for 23b to provide 0.25 g (41%) of the title

compound as a bright yellow solid: ¹H NMR δ 1.47 (m, 2H),

1.66 (m, 4H), 2.52 (s, 3H), 2.60 (m, 4H), 2.82 (t, J ) 5.4 Hz,

2H), 4.10 (t, J ) 5.4 Hz, 2H), 6.58 (d, J ) 8.8 Hz, 2H), 6.77

(dd, J ) 8.8, 2.0 Hz, 1H), 7.16 (d, J ) 2.0 Hz, 1H), 7.34 (d, J

) 8.8 Hz, 1H), 7.43 (d, J ) 8.4 Hz, 2H), 7.67 (d, J ) 8.8 Hz,

2H), 7.77 (d, J ) 8.4 Hz, 2H); MS (FD) m/e 500 (MH⁺). Anal.

(C₃₀H₂₉NO₄S) C,H,N.

[2-[4-(D ie t h y lp h o s p h o n y l)p h e n y l]-6-h y d r o x y b e n -

zot h ien -3-yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a -

n on e (23h ). A solution of 21 (1.1 g, 1.5 mmol), 2,6-lutidine

(0.5 mL, 4.3 mmol), diethyl phosphite (0.22 mL, 1.7 mmol),

and Pd(PPh₃)₄(0.078 g, 0.067 mmol) in CH₃CN (10 mL) was

heated at 70 °C for 16 h. The mixture was then diluted with

EtOAc (50 mL), washed with 10% citric acid (3 × 50 mL),

saturated NaHCO₃(3 × 50 mL), and brine (50 mL), dried (Na₂-

SO₄), and concentrated. The residue was desilylated by a

method similar to that described for 23b to provide 0.77 g

(86%) of the title compound as a bright yellow solid: ¹H NMR

δ 1.28 (t, J ) 7.0 Hz, 6H), 1.45 (m, 2H), 1.62 (m, 4H), 2.55 (m,

4H), 2.78 (t, J ) 5.6 Hz, 2H), 4.0-4.2 (m, 6H), 6.66 (d, J ) 8.8

Hz, 2H), 6.85 (dd, J ) 8.8, 2.1 Hz, 1H), 7.18 (d, J ) 2.1 Hz,

1H), 7.38 (d, J ) 8.8 Hz, 1H), 7.47 (m, 2H), 7.6-7.7 (m, 4H);

MS (FD) m/e 594 (MH⁺). Anal. (C₃₂H₃₆NO₆PS) C,H,N.

[2-(4-Eth yn ylp h en yl)-6-h yd r oxyben zoth ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (23i). The title

compound was prepared in 45% yield by a method similar to

that described for 22i: ¹H NMR δ 1.48 (m, 2H), 1.67 (m, 4H),

2.60 (m, 4H), 2.82 (t, J ) 5.4 Hz, 2H), 3.09 (s, 1H), 4.10 (t, J

) 5.4 Hz, 2H), 6.56 (d, J ) 8.8 Hz, 2H), 6.75 (dd, J ) 8.8, 2.1

Hz, 1H), 7.15 (d, J ) 2.1 Hz, 1H), 7.2-7.4 (m, 5H), 7.64 (d, J

) 8.7 Hz, 2H); ¹³C NMR δ 23.9, 25.2, 55.0, 57.7, 60.5, 65.3,

78.5, 83.2, 107.5, 114.2, 115.8, 121.9, 124.4, 128.7, 130.3, 132.0,

132.3, 133.1, 134.0, 140.3, 140.6, 155.3, 163.0, 193.4; HRMS

(FAB) m/e calcd for C₃₀H₂₈NO₃S (MH⁺) 482.1790, found

482.1798. Anal. (C₃₀H₂₇NO₃S‚0.25H₂O) C,H; N: calcd, 2.88;

found, 2.46.

[2-(4-Eth en ylp h en yl)-6-h yd r oxyben zoth ien -3-yl][4-[2-

(1-p ip er id in yl)eth oxy]p h en yl]m eth a n on e (23j). A solu-

tion of 21 (10.1 g, 14 mmol), vinyl acetate (12.8 mL, 140 mmol),

Et₃N (6.0 mL, 43 mmol), 1,3-bis(diphenylphosphino)propane

(0.63 g, 1.5 mmol), and Pd(OAc)₂(0.32 g, 1.4 mmol) in DMF

(20 mL) was heated at 100 °C for 4 h. After cooling to room

temperature, the mixture was diluted with CH₂Cl₂(100 mL),

washed with 5% HCl (2 × 100 mL) and water (2 × 100 mL),

dried (Na₂SO₄), and concentrated. The residue was desilylated

by a method similar to that described for 23b to provide 0.48

g (7%) of the title product as a bright yellow solid: ¹H NMR δ

1.48 (m, 2H), 1.67 (m, 4H), 2.60 (m, 4H), 2.81 (t, J ) 5.4 Hz,

2H), 4.10 (t, J ) 5.4 Hz, 2H), 5.23 (d, J ) 10.9 Hz, 1H), 5.70

(d, J ) 17.6 Hz, 1H), 6.58 (d, J ) 8.7 Hz, 2H), 6.65 (d, J )

10.9 Hz, 1H), 6.75 (dd, J ) 8.7, 2.1 Hz, 1H), 7.1-7.4 (m, 6H),

7.68 (d, J ) 8.7 Hz, 2H); MS (FD) m/e 484 (MH⁺). Anal.

(C₃₀H₂₉NO₃S) C,H,N.

[2-[4-(N,N-Dim eth ylca r ba m oyl)p h en yl]-6-h yd r oxyben -

zot h ien -3-yl][4-[2-(1-p ip er id in yl)et h oxy]p h en yl]m et h a -

Ra d ioliga n d Bin d in g Stu d ies. Serial dilutions of test

3

compounds or standards were mixed with 0.5 nM H-labeled

SARs of Selective Estrogen Receptor Modulators

J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 2 165

17â-estradiol, along with 0.5-1.0 mg/mL total protein content

(MCF-7 cell lysate), in a total volume of 0.14 mL. Binding

took place for 18 h at 4 °C followed by addition of 0.07 mL of

dextran/charcoal and centrifugation to remove nonbound ra-

dioligand. Aliquots of supernatant containing bound radioli-

gand were removed, mixed with scintillant, and counted using

a microbeta scintillation â-counter (Wallac). Relative binding

affinity (RBA) was calculated as (IC₅₀(17â-estradiol)/IC₅₀(test

compound)) × 100.

microtiter plate. The reaction was initiated with the addi-

tion of 200 µL of substrate solution containing 3.5 mM

o-phenylenediamine‚2HCl and 0.0005% H₂O₂in 50 mM Tris

buffer (pH 8.0). The apparent maximal velocity was deter-

mined by continuously monitoring the oxidation of o-phe-

nylenediamine in the presence of H₂O₂at 490 nm at room

temperature using a computer-controlled microplate reader

(EL312 Bio-kinetic microplate reader, Bio-Tek Instruments,

Winooski, VT) utilizing the DeltaSoft software program.

Ser u m Ch olester ol Assa y. Blood samples were allowed

to clot at 4 °C for 2 h and then centrifuged at 2000g for 10

min. Serum samples were collected and stored at -70 °C for

subsequent analytical procedures. Serum cholesterol was

determined using a Boehringer Mannheim Diagnostics high-

performance cholesterol colorimetric assay (Indianapolis, IN)

as originally described by Weibe and Bernet.⁵⁰

F ive-Week Ova r iectom ized Ra t Assa y. Following a

protocol similar to that described above, 6-month old, virgin,

OVX Sprague-Dawley rats (Harlan, IN) were treated daily

for 35 days, beginning on day 4 following ovariectomy. At the

time of sacrifice, the uteri were removed and dissected free of

extraneous tissue, and the fluid contents were expelled before

determination of wet weight in order to confirm estrogen

deficiency associated with complete ovariectomy. Uterine

weight was routinely reduced about 75% in response to

ovariectomy.

Methods of tissue collection and data analysis have been

previously described.^51,52Generally, the right femurs were

excised and digitized X-rays generated and analyzed at the

distal metaphysis.⁵¹In one case, the proximal aspect of the

tibiae from these animals was scanned by quantitative com-

puted tomography.⁵²Percent protection was calculated by the

following formula: % protection ) [(BMD_{test compound}- BMD_OVX

MCF -7 P r olifer a tion Assa y. MCF-7 breast adenocarci-

noma cells (ATCC HTB 22) were maintained in MEM (minimal

essential medium, phenol red-free; Sigma, St. Louis, MO)

supplemented with 10% fetal bovine serum (FBS) (v/v), ^L-

glutamine (2 mM), sodium pyruvate (1 mM), HEPES (N-(2-

hydroxyethyl)piperazine-N ′-2-ethanesulfonic acid; 10 mM),

nonessential amino acids, and bovine insulin (1 µg/mL)

(maintenance medium). Ten days prior to assay, MCF-7 cells

were switched to maintenance medium supplemented with

10% dextran-coated charcoal-stripped fetal bovine serum

(DCC-FBS) (assay medium) in place of 10% FBS to deplete

internal stores of steroids. Cells were removed from mainte-

nance flasks using cell dissociation medium (Ca²⁺/Mg²⁺-free

HBSS) (phenol red-free) supplemented with 10 mM HEPES

and 2 mM EDTA. Cells were washed twice with assay

medium, and 100 µL (8000 cells) was added to flat-bottom

microculture wells (Costar 3596) followed by incubation at 37

°C in a 5% CO₂humidified incubator for 24 h to allow for cell

adherence and equilibration after transfer. Serial dilutions

of drugs, or DMSO as a diluent control, were prepared in assay

medium, and 50 µL was transferred to triplicate microcultures

followed by 50 µL of assay medium containing 17â-estradiol

(10 pM final concentration). After an additional 48 h at 37

°C in a 5% CO₂humidified incubator, microcultures were

pulsed with tritiated thymidine (1 µCi/well) for 4 h. Cultures

were terminated by freezing at -70 °C for 24 h followed by

thawing and harvesting of microcultures using a Skatron

semiautomatic cell harvester. Samples were counted by liquid

scintillation using a Wallac BetaPlate â-counter.

^control)/(BMD_sham

- BMD_{OVX control})] × 100.

control

For both the 4-day and 5-week OVX rat assays, statistical

evaluations were made by one-way analysis of variance

(ANOVA). Significance was ascribed at a p e 0.05.

F ou r -Da y Ova r iectom ized Ra t Assa ys. Virgin, virus-

antibody-free, OVX Sprague-Dawley rats (75-days old) were

obtained from Charles Rivers Laboratories (Portage, MI) and

group housed on a 12 h light:12 h dark cycle (lights on at 0600

h) with room temperature set at 22 °C. The animals had ad

libitum access to both food and tap water. Animals were

randomized into experimental treatment groups, with five to

six animals per treatment group. Compound administration

was initiated 14 days after ovariectomy, in order to insure

clearance of endogenous estrogen and to allow for acclimation

to the home cage. For most studies, compounds were dissolved

in 20% â-hydroxycyclodextrin (CDX) and given by daily oral

gavage in a volume of 1 mL/kg of body weight. In some cases,

1.5% carboxymethylcellulose was used in place of CDX.

Animals were dosed for 4 consecutive days and fasted the

evening following the final dose. On the following morning

the animals were weighed and anesthetized (carbon dioxide),

and a blood sample was collected by cardiac puncture. The

animals were then euthanized by carbon dioxide asphyxiation,

and the uteri were collected and weighed. One horn of the

uterus was removed, weighed, and transferred into a Tris

buffer for analysis of uterine EPO activity. Ethynylestradiol

and tamoxifen were purchased from Sigma Chemical Co. (St.

Louis, MO), and â-hydroxycyclodextrin was purchased from

SAF Bulk Chemicals (Milwaukee, WI).

Uter in e Eosin op h il P er oxid a se Activity. Uterine EPO

activity was determined by a modification of the method of

White.⁴⁹After removal of the uterus and recording of whole

uterine weight, the uterine horns were bisected. One horn

from each animal was weighed and homogenized (Brinkmann

Polytron, Brinkmann Instruments Co., Westbury, NY) on ice

in 50 mM Tris buffer (pH 8.0, 50 µL/mg of tissue) containing

0.05% (v/v) Triton X-100 (Pierce, Rockford, IL). Samples were

centrifuged at 3000 rpm for 10 min at 4 °C in a Beckman GPR

centrifuge (Palo Alto, CA). The resulting supernatant was

filtered in a 3 mL syringe through a 45 µm filter. Duplicate

50 µL aliquots of the filtered supernatant fraction (equivalent

to 1 mg of tissue) were added to a 96-well flat-bottomed

Ack n ow led gm en t. The authors wish to thank Dr.

Masahiko Sato (QCT analysis), Larry Black, Dr. Lee

Ellis, and George Weaver (biological testing of some

compounds), Gilbert Staten and the Lilly Custom Syn-

thesis Laboratory (intermediate and starting material

preparation), and the Physical Chemistry Department

of Lilly Research Laboratories (analytical and spectral

data and support). We also wish to thank Alan Thomp-

son and Pam Pennington for the synthesis and struc-

tural characterization of compounds 5b,b′ and Kollol Pal

for the synthesis of 5c.

Su p p or tin g In for m a tion Ava ila ble: Experimental de-

tails and spectral data for compounds 2i,j (4 pages). Ordering

information is given on any current masthead page.

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J M9606352

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Structure-activity relationships of selective estrogen receptor modulators: Modifications to the 2-arylbenzothiophene core of raloxifene

DOI: 10.1021/jm9606352

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