U.S. patent application number 11/652766 was filed with the patent office on 2007-06-14 for 2-phenyl-1-[4-(2-aminoethoxy)-benzyl]-indole and estrogen formulations.
This patent application is currently assigned to Wyeth. Invention is credited to Barry Samuel Komm, James Harrison Pickar.
Application Number | 20070135397 11/652766 |
Document ID | / |
Family ID | 26807395 |
Filed Date | 2007-06-14 |
United States Patent
Application |
20070135397 |
Kind Code |
A1 |
Pickar; James Harrison ; et
al. |
June 14, 2007 |
2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole and estrogen
formulations
Abstract
The present invention relates to new formulations containing one
or more estrogens and 2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole
compounds which are useful as estrogenic agents, as well as
pharmaceutical compositions and methods of treatment utilizing
these compounds, which have the general structures below:
##STR1##
Inventors: |
Pickar; James Harrison;
(Springfield, PA) ; Komm; Barry Samuel;
(Havertown, PA) |
Correspondence
Address: |
Pepper Hamilton LLP
500 Grant Street
One Mellon Bank Center, 50th Floor
Pittsburgh
PA
15219-2502
US
|
Assignee: |
Wyeth
Madison
NJ
|
Family ID: |
26807395 |
Appl. No.: |
11/652766 |
Filed: |
January 12, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11430295 |
May 8, 2006 |
|
|
|
11652766 |
Jan 12, 2007 |
|
|
|
10264187 |
Oct 3, 2002 |
|
|
|
11430295 |
May 8, 2006 |
|
|
|
09306073 |
May 6, 1999 |
6479535 |
|
|
10264187 |
Oct 3, 2002 |
|
|
|
60109809 |
May 15, 1998 |
|
|
|
Current U.S.
Class: |
514/171 ;
514/217.08 |
Current CPC
Class: |
A61K 31/155 20130101;
A61K 31/55 20130101; A61P 5/30 20180101; A61K 31/566 20130101; A61K
31/565 20130101; A61K 31/56 20130101; A61K 31/405 20130101; A61K
31/155 20130101; A61K 2300/00 20130101; A61K 31/405 20130101; A61K
2300/00 20130101; A61K 31/565 20130101; A61K 2300/00 20130101; A61K
31/55 20130101; A61K 2300/00 20130101; A61K 31/56 20130101; A61K
2300/00 20130101 |
Class at
Publication: |
514/171 ;
514/217.08 |
International
Class: |
A61K 31/56 20060101
A61K031/56; A61K 31/55 20060101 A61K031/55 |
Claims
1. A pharmaceutical composition comprising a pharmaceutically
effective amount of
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-meth-
yl-1H-indol-5-ol acetate and a pharmaceutically effective amount of
conjugated estrogens.
2. A pharmaceutical composition comprising a pharmaceutically
effective amount of
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-meth-
yl-1H-indol-5-ol hydrochloride and a pharmaceutically effective
amount of conjugated estrogens.
3. A method of treating vasomotor symptoms in a postmenopausal or
estrogen deficient woman in need thereof, which comprises
administering to said woman an effective amount of a combination of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol or a pharmaceutically acceptable salt thereof and conjugated
estrogens.
4. The method according to claim 3, wherein the vasomotor symptom
is hot flushes.
5. The method according to claim 3, wherein said pharmaceutically
acceptable salt is the acetate salt of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol.
6. The method according to claim 3, wherein said pharmaceutically
acceptable salt is the hydrochloride salt of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol.
7. A method of inhibiting or retarding bone demineralization or
treating or inhibiting osteoporosis in a postmenopausal or estrogen
deficient woman in need thereof, which comprises administering to
said woman an effective amount of a combination of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol or a pharmaceutically acceptable salt thereof and conjugated
estrogens.
8. The method according to claim 7, wherein said pharmaceutically
acceptable salt is the acetate salt of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol.
9. The method according to claim 7, wherein said pharmaceutically
acceptable salt is the hydrochloride salt of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol.
10. A method of treating or inhibiting menopausal or postmenopausal
disorders in a postmenopausal or estrogen deficient woman in need
thereof, which comprises administering to said woman an effective
amount of a combination of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol or a pharmaceutically acceptable salt thereof and conjugated
estrogens.
11. The method according to claim 10, wherein said pharmaceutically
acceptable salt is the acetate salt of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol.
12. The method according to claim 10, wherein said pharmaceutically
acceptable salt is the hydrochloride salt of
1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-
-5-ol.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/109,809, which was converted from U.S. patent
application Ser. No. 09/079,561, filed May 15, 1998, pursuant to a
petition filed under 37 C.F.R. 1.53(c)(2)(i).
[0002] The present invention relates to the use of new
2-Phenyl-1-[4-(2-Aminoethoxy)-Benzyl]-Indole compounds which are
useful as estrogenic agents, in conjunction with estrogens, as well
as pharmaceutical compositions and methods of treatment utilizing
these compounds.
BACKGROUND OF THE INVENTION
[0003] The use of hormone replacement therapy for bone loss
prevention in post-menopausal women is well precedented. The normal
protocol calls for estrogen supplementation using such formulations
containing estrone, estriol, ethynyl estradiol, 17.beta.-estradiol,
esterified estrogens, or conjugated estrogens isolated from natural
sources (i.e. Premarin.RTM. conjugated estrogens from Wyeth-Ayerst)
or synthetic estrogens. In some patients, therapy may be
contraindicated due to the proliferative effects of unopposed
estrogens (estrogens not given in combination with progestins) have
on uterine tissue. This proliferation is associated with increased
risk for endometriosis and/or endometrial cancer. The effects of
unopposed estrogens on breast tissue are less clear, but are of
some concern. The need for estrogens which can maintain the bone
sparing effect while minimizing the proliferative effects in the
uterus and breast is evident. Certain nonsteroidal antiestrogens
have been shown to maintain bone mass in the ovariectomized rat
model as well as in human clinical trials. Tamoxifen (sold as
Novadex.RTM. brand tamoxifen citrate by Zeneca Pharmaceuticals,
Wilmington, Del.), for example, is a useful palliative for the
treatment of breast cancer and has been demonstrated to exert an
estrogen agonist-like effect on the bone, in humans. However, it is
also a partial agonist in the uterus and this is cause for some
concern. Raloxifene, a benzothiophene antiestrogen, has been shown
to stimulate uterine growth in the ovariectomized rat to a lesser
extent than Tamoxifen while maintaining the ability to spare bone.
A suitable review of tissue selective estrogens is seen in the
article "Tissue-Selective Actions Of Estrogen Analogs", Bone Vol.
17, No. 4, October 1995, 181S-190S.
[0004] The use of indoles as estrogen antagonists has been reported
by Von Angerer, Chemical Abstracts, Vol. 99, No. 7 (1983), Abstract
No. 53886u. Also, see, J. Med. Chem. 1990, 33, 2635-2640; J. Med.
Chem. 1987, 30, 131-136. Also see Ger. Offen., DE 3821148 A1 891228
and WO 96/03375. These prior art compounds share structural
similarities with the present compounds, but are functionally
different. For compounds containing a basic amine, there is no
phenyl group to rigidify the side chain.
[0005] WO A 95 17383 (Karo Bio AB) describes indole antiestrogens
with long straight chains. Another related patent WO A 93 10741
describes 5-Hydroxyindoles with a broad range of side chains. WO
93/23374 (Otsuka Pharmaceuticals, Japan) describes compounds
sharing structural similarities with those of the present
invention, except with the structure referred to as R.sub.3 in the
present formulas I and II, below, is defined as thioalkyl and the
reference discloses no such compounds having chains from the indole
nitrogen having the same structure as the ones provided by the
present invention.
[0006] In their article Postmenopausal Hormone replacement therapy
with estrogen periodically supplemented with antiestrogen, Am. J.
Obstet. Gynecol., Vol. 140, No. 7, 1981, pp. 787-792, Kauppila et
al. describe their study of postmenopausal estrogen therapy of
seven-week estrogen regimens followed by 10-day treatments with the
antiestrogen clomiphene citrate.
[0007] Also, in their article Comparison of Megestrol Acetate and
Clomiphene Citrate as Supplemental Medication in Postmenopausal
Oestrogen Replacement Therapy, Arch. Gynecol. (1983) 234:49-58,
Kauppila et al. describe combination therapies in postmenopausal
women of estrogen with random supplementation of megestrol acetate
or clomiphene citrate.
[0008] U.S. Pat. No. 4,894,373 (Young) teaches the use of
antiestrogens, including clomiphene and its isomers, citrates and
derivatives, in the absence of estrogen for treating menopausal
symptoms and treating or preventing osteoporosis. U.S. Pat. No.
5,552,401 (Cullinan et al.) describes benzothiophene compounds as
useful for the treatment of various medical indications associated
with post-menopausal syndrome, and uterine fibroid disease,
endometriosis, and aortal smooth muscle cell proliferation, the
compounds being used in pharmaceutical formulations optionally
containing estrogen or progestin. U.S. Pat. Nos. 5,646,137 and
5,591,753 (both issued to Black et al.) discloses methods of
treating osteoporosis with formulations of raloxefine-type
arylbenzothiophene compounds in conjunction with a progestin
selected from medroxyprogesterone, norethindrone or norethynodrel,
or pharmaceutically acceptable salts thereof. U.S. Pat. No.
5,550,107 (Labrie) claims an invention comprising the treatment of
breast or endometrial cancer with an antiestrogen together with at
least one compound selected from the group of an androgen, a
progestin, at least one inhibitor of sex steroid formation,
expecially 17.beta.-hydroxysteroid dehydrogenase and aromatase
activity, at least one inhibitor of prolactin secretion, one
inhibitor of growth hormone secretion and one inhibitor of ACTH
secretion. U.S. Pat. No. 5,672,609 (Bryant et al.) discloses
pyridine compounds useful in treating post menopausal syndrome and
formulations therefore containing estrogen or progestin. U.S. Pat.
No. 5,534,527 (Black et al.) teaches the use of
aroylbenzothiophenes and estrogens in the inhibition of bone
loss.
DESCRIPTION OF THE INVENTION
[0009] The present invention provides pharmaceutical formulations,
and methods for using them, comprising compounds of formulas (I)
and (II), below, in conjunction with estrogens, preferably in
conjunction with one or more pharmaceutically acceptable carriers
or excipients. Among the uses of the present formulations is
alleviating the symptoms of post-menopausal syndrome in women,
including peri-menopausal and post-menopausal symptoms. The present
formulations and methods of treatment can be used to minimize
undesirable side effects of estrogen treatment or therapy and may
be used to minimize the amounts of estrogen(s) necessary for a
particular regimen.
[0010] Compounds of the general structure type shown in formulas
(I) and (II) are estrogen agonists/antagonists useful for the
treatment of diseases associated with estrogen deficiency. The
compounds are capable of antagonizing the effects of
17.beta.-estradiol while showing little uterine stimulation when
dosed alone.
[0011] The present invention includes, in conjunction with one or
more estrogens, the use of compounds of formulas (I) or (II),
below: ##STR2## wherein:
[0012] R.sub.1 is selected from H, OH or the C.sub.1-C.sub.12
esters (straight chain or branched) or C.sub.1-C.sub.12 (straight
chain or branched or cyclic) alkyl ethers thereof, or halogens; or
C.sub.1-C.sub.4 halogenated ethers including triflouromethyl ether
and trichloromethyl ether.
[0013] R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
independently selected from H, OH or the C.sub.1-C.sub.12 esters
(straight chain or branched) or C.sub.1-C.sub.12 allyl ethers
(straight chain or branched or cyclic) thereof, halogens, or
C-C.sub.4 halogenated ethers including triflouromethyl ether and
trichloromethyl ether, cyano, C.sub.1-C.sub.6 alkyl (straight chain
or branched), or trifluoromethyl, with the proviso that, when
R.sub.1 is H, R.sub.2 is not OH.
[0014] X is selected from H, C.sub.1-C.sub.6 alkyl, cyano, nitro,
triflouromethyl, halogen;
[0015] n is 2 or 3;
[0016] Y is selected from: [0017] a) the moiety: ##STR3## [0018]
wherein R.sub.7 and R.sub.8 are independently selected from the
group of H, C.sub.1-C.sub.6 alkyl, or phenyl optionally substituted
by CN, C.sub.1-C.sub.6 alkyl (straight chain or branched),
C.sub.1-C.sub.6 alkoxy (straight chain or branched), halogen, --OH,
--CF.sub.3, or --OCF.sub.3; [0019] b) a five-membered saturated,
unsaturated or partially unsaturated heterocycle containing up to
two heteroatoms selected from the group consisting of --O--,
--NH--, --N(C.sub.1C.sub.4 alkyl)-, --N.dbd., and --S(O).sub.m--,
wherein m is an integer of from 0-2, optionally substituted with
1-3 substituents independently selected from the group consisting
of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl, trihalomethyl,
C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 acyloxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl,
C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl,
--CO.sub.2H--, --CN--, --CONHR.sub.1--, --NH.sub.2--,
C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino,
--NHSO.sub.2R.sub.1--, --NHCOR.sub.1--, --NO.sub.2, and phenyl
optionally substituted with 1-3 (C.sub.1-C.sub.4)alkyl; [0020] c) a
six-membered saturated, unsaturated or partially unsaturated
heterocycle containing up to two heteroatoms selected from the
group consisting of --O--, --NH--, --N(C.sub.1-C.sub.4 alkyl)-,
--N.dbd., and --S(O).sub.m--, wherein m is an integer of from 0-2,
optionally substituted with 1-3 substituents independently selected
from the group consisting of hydrogen, hydroxyl, halo,
C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, C.sub.1-C.sub.4 acyloxy, C.sub.1-C.sub.4 alkylthio,
C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl,
hydroxy (C.sub.1-C.sub.4)alkyl, --CO.sub.2H--, --CN--,
--CONHR.sub.1--, --NH.sub.2--, C.sub.1-C.sub.4 alkylamino,
di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2R.sub.1--,
--NHCOR.sub.1--, --NO.sub.2, and phenyl optionally substituted with
1-3 (C.sub.1-C.sub.4)alkyl; [0021] d) a seven-membered saturated,
unsaturated or partially unsaturated heterocycle containing up to
two heteroatoms selected from the group consisting of --O--,
--NH--, --N(C.sub.1C.sub.4 alkyl)-, --N.dbd., and --S(O).sub.m--,
wherein m is an integer of from 0-2, optionally substituted with
1-3 substituents independently selected from the group consisting
of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl, trihalomethyl,
C.sub.1-C.sub.4 alkoxy, trihalomethoxy, C.sub.1-C.sub.4 acyloxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl,
C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl,
--CO.sub.2H--, --CN--, --CONHR.sub.1--, --NH.sub.2--,
C.sub.1-C.sub.4 alkylamino, di(C.sub.1-C.sub.4)alkylamino,
--NHSO.sub.2R.sub.1--, --NHCOR.sub.1--, --NO.sub.2, and phenyl
optionally substituted with 1-3 (C.sub.1-C.sub.4)alkyl; or [0022]
e) a bicyclic heterocycle containing from 6-12 carbon atoms either
bridged or fused and containing up to two heteroatoms selected from
the group consisting of --O--; --NH--, --N(C.sub.1-C.sub.4 alkyl)-,
and --S(O).sub.m--, wherein m is an integer of from 0-2, optionally
substituted with 1-3 substituents independently selected from the
group consisting of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4
alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
C.sub.1-C.sub.4 acyloxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4
alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy
(C.sub.1-C.sub.4)alkyl, --CO.sub.2H--, --CN--, --CONHR.sub.1--,
--NH.sub.2--, C.sub.1-C.sub.4 alkylamino,
di(C.sub.1-C.sub.4)alkylamino, --NHSO.sub.2R.sub.1--,
--NHCOR.sub.1--, --NO.sub.2, and phenyl optionally substituted with
1-3 (C.sub.1-C.sub.4) alkyl; and the pharmaceutically acceptable
salts thereof.
[0023] The more preferred formulations of this invention are those
having, along with one or more pharmaceutical carriers or
excipients:
[0024] a) one or more estrogens; and
[0025] b) one or more compounds selected from the general
structures I or II, above, wherein:
[0026] R.sub.1 is selected from H, OH or the C.sub.1-C.sub.12
esters or alkyl ethers thereof, halogen;
[0027] R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are
independently selected from H, OH or the C.sub.1-C.sub.12 esters or
alkyl ethers thereof, halogen, cyano, C.sub.1-C.sub.6 alkyl, or
trihalomethyl, preferably trifluoromethyl, with the proviso that,
when R.sub.1 is H, R.sub.2 is not OH;
[0028] X is selected from H, C.sub.1-C.sub.6 alkyl, cyano, nitro,
triflouromethyl, halogen;
[0029] Y is the moiety ##STR4##
[0030] R.sub.7 and R.sub.8 are selected independently from H,
C.sub.1-C.sub.6 alkyl, or combined by --(CH.sub.2)p-, wherein p is
an integer of from 2 to 6, so as to form a ring, the ring being
optionally substituted by up to three substituents selected from
the group of hydrogen, hydroxyl, halo, C.sub.1-C.sub.4 alkyl,
trihalomethyl, C.sub.1-C.sub.4 alkoxy, trihalomethoxy,
C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl,
C.sub.1-C.sub.4 alkylsulfonyl, hydroxy (C.sub.1-C.sub.4)alkyl,
--CO.sub.2H, --CN, --CONH(C.sub.1-C.sub.4), --NH.sub.3,
C.sub.1-C.sub.4 alkylamino, C.sub.1-C.sub.4 dialkylamino,
--NHSO.sub.2(C.sub.1-C.sub.4), --NHCO(C.sub.1-C.sub.4), and
--NO.sub.3;
and the pharmaceutically acceptable salts thereof.
[0031] The rings formed by a concatenated R.sub.7 and R.sub.8,
mentioned above, may include, but are not limited to, aziridine,
azetidine, pyrrolidine, piperidine, hexamethyleneamine or
heptamethyleneamine rings.
[0032] The most preferred compounds of the present formulations are
those having the structural formulas I or II, above, wherein
R.sub.1 is OH; R.sub.2-R.sub.6 are as defined above; X is selected
from the group of Cl, NO.sub.2, CN, CF.sub.3, or CH.sub.3; and Y is
the moiety ##STR5## and R.sub.7 and R.sub.8 are concatenated
together as --(CH.sub.2).sub.r--, wherein r is an integer of from 4
to 6, to form a ring optionally substituted by up to three
subsituents selected from the group of hydrogen, hydroxyl, halo,
C.sub.1-C.sub.4 alkyl, trihalomethyl, C.sub.1-C.sub.4 alkoxy,
trihalomethoxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4
alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, hydroxy
(C.sub.1-C.sub.4)alkyl, --CO.sub.2H, --CN,
--CONH(C.sub.1-C.sub.4)alkyl, --NH.sub.2, C.sub.1-C.sub.4
alkylamino, di(C.sub.1-C.sub.4)alkylamino,
--NHSO.sub.2(C.sub.1-C.sub.4)alkyl, --NHCO(C.sub.1-C.sub.4)alkyl,
and --NO.sub.2; and the pharmaceutically acceptable salts
thereof.
[0033] In another embodiment of this invention, when R.sub.7 and
R.sub.8 are concatenated together as --(CH.sub.2)p-, wherein p is
an integer of from 2 to 6, preferably 4 to 6, the ring so formed is
optionally substituted with 1-3 substituents selected from a group
containing C.sub.1-C.sub.3 alkyl, trifluoromethyl, halogen,
hydrogen, phenyl, nitro, --CN.
[0034] The invention includes sulfate, sulfamates and sulfate
esters of phenolic groups. Sulfates can be readily prepared by the
reaction of the free phenolic compounds with sulfur trioxide
complexed with an amine such as pyridine, trimethylamine,
triethylamine, etc. Sulfamates can be prepared by treating the free
phenolic compound with the desired amino or alkylamino or
dialkylamino sulfamyl chloride in the presence of a suitable base
such as pyridine. Sulfate esters can be prepared by reaction of the
free phenol with the desired alkanesulfonyl chloride in the
presence of a suitable base such as pyridine. Additionally, this
invention includes compounds containing phosphates at the phenol as
well as dialkyl phoshates. Phosphates can be prepared by reaction
of the phenol with the appropriate chlorophosphate. The
dialkylphosphates can be hydrolyzed to yield the free phosphates.
Phosphinates are also claimed where the phenol is reacted with the
desired dialkylphosphinic chloride to yield the desired
dialkylphosphinate of the phenol.
[0035] The invention includes acceptable salt forms formed from the
addition reaction with either inorganic or organic acids. Inorganic
acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sufuric acid, phoshoric acid, nitric acid useful as well as organic
acids such as acetic acid, propionic acid, citric acid, maleic
acid, malic acid, tartaric acid, phthalic acid, succinic acid,
methanesulfonic acid, toluenesulfonic acid, napthalenesulfonic
acid, camphorsulfonic acid, benzenesulfonic acid are useful. It is
known that compounds possessing a basic nitrogen can be complexed
with many different acids (both protic and non-protic) and usually
it is preferred to administer a compound of this invention in the
form of an acid addition salt. Additionally, this invention
includes quaternary ammonium salts of the compounds herein. These
can be prepared by reacting the nucleophilic amines of the side
chain with a suitably reactive alkylating agent such as an alkyl
halide or benzyl halide.
Methods
[0036] Compounds of this invention can be synthesized in a general
sense according to Scheme 1, below. ##STR6##
[0037] The initial indole synthesis is accomplished by heating an
appropriately substituted alpha-bromo ketone (1) with the desired
anile (a) in DMF to form the indole (c). The product is then
alkylated with a benzyl chloride (e) to give the substituted indole
(f). The benzyl chloride (e) can be readily prepared from the
aldehyde (d) in 2 steps as given. Product (g) can be prepared from
(f) by reduction of the ester, conversion of the alcohol to a
bromide, displacement of the bromide with the desired amine in a
suitable solvent such as THF or DMF, and finally, deprotection if
necessary. Deprotection is necessary when either R.sub.1 or R.sub.2
or both is a protected phenol. The preferred protecting group is a
benzyl group which can be conveniently removed by several
conventional methods, especially hydrogenolysis.
[0038] For the synthesis of compounds with X.dbd.H, halogen,
trifluoromethyl, cyano, nitro, an alternative synthesis shown in
scheme 2 may be preferable. The formation of halogens at the
3-position can be easily performed with such reagents as
N-chlorosuccinamide, N-bromosuccinamide, or N-iodosuccinamide. A
3-Iodoindole compound obtained can be used as a precursor to the
3-trifluoromethyl compound by a coupling reaction utilizing a
palladium catalyst and bistrifluoromethyl mercury (II). A compound
with a cyano group in the 3-position can be prepared by
electrophilic cyanation or alternatively the 3-position can be
formylated (with a formyl iminium salt, for example) then the
formyl group converted to an oxime and subsequently dehydrated to a
nitrile. Alternatively, the 3-cyano compound can be synthesized by
reaction of the 3-unsubstituted indole with
chlorosulfonylisocyanate followed by triethylamine. A compound with
the nitro group in the 3-position can be prepared by treating the
indole with sodium nitrite and acetic acid. One skilled in the art
recognizes these routes are not limiting and other routes are also
available. ##STR7##
[0039] Synthesis of selected representative examples are given in
the following schemes: ##STR8## ##STR9## The synthesis of analogues
with a 3-carbon chain (example No. 166) between the oxygen and the
basic amine can be accomplished as shown in scheme 4. ##STR10## The
synthetic procedure shown in scheme 4 may be used for compounds
with two carbon chains analogous to example No. 97 in scheme 3.
This is shown in scheme 4a for the synthesis of example No. 127.
##STR11## The synthesis of indoles with alternative substituents
(CN, Cl) at the 3-position of the indole both utilize the
3-unsubstituted indole No. 141 for a precursor. The indole
issynthesized by the Fisher method utilizing the hydrazone derived
from the condensation of 4-benzyloxyacetophenone CAS No.
[54696-05-8] and 4-benzyloxyphenylhydrazine CAS No. [51145-58-5].
The hydrazone No. 140 is then cyclized in acetic acid using zinc
chloride to afford the desired indole No. 141. This synthesis can
be seen in scheme 5. ##STR12##
[0040] The synthesis of 3Chloroindole compounds is demonstrated for
example No.134 and shown, infra, in scheme 6. The indole No. 141
from scheme 5 is chlorinated with N-chlorosuccinamide. The
3-Chloroindole No. 142, thus obtained, is taken to the final
product in analogous fashion to that shown in scheme 3.
##STR13##
[0041] 3-Cyano analogues are synthesized from the precursor indole
No. 141 as shown in Scheme 7. Reaction of the precursor indole No.
141 with chlorosulfonylisocyanate followed by addition of
triethylamine yields the 3-Cyanoindole No. 155. The side chain is
made by conversion of the benzylic alcohol of CAS No. [111728-87-1]
to the benzylic bromide No. 156 using thionyl bromide in THF. The
indole is alkylated by the side chain in DMF using sodium hydride
to give the intermediate No. 157. This can then be taken to the
final product No. 138 in an analogous fashion to that shown in
scheme 4. ##STR14##
[0042] The compounds of Formulas (I) and (II) are partial estrogen
agonists and display high affinity for the estrogen receptor.
Unlike many estrogens, however, these compounds do not cause
increases in uterine wet weight. These compounds areantiestrogenic
in the uterus and can completely antagonize the trophic effects of
estrogen agonists in uterine tissue. These compounds are useful in
treating or preventing mammal disease states or syndromes which are
caused or associated with an estrogen deficiency. This tissue
selectivity allows their use for desirable estrogenic activity in
certain tissues, such as bone, while limiting that activity in
others, such as uterine tissue.
[0043] Estrogens useful in the formulations of this invention
include estrone, estriol, equilin, estradiene, equilenin, ethinyl
estradiol, 17.beta.-estradiol, 17.alpha.-dihydroequilenin,
17.beta.-dihydroequilenin (U.S. Pat. No. 2,834,712),
17.alpha.-dihydroequilin, 17.beta.-dihydroequilin, menstranol and
conjugated estrogenic hormones, such as those in Wyeth-Ayerst
Laboratories' Premarin.RTM. products. Phytoestrogens, such as equol
or enterolactone, may also be used in the present formulations and
methods. A preferred embodiment of this invention comprises
pharmaceutical compositions and methods of treatment utilizing
conjugated estrogenic hormones, such as those in Wyeth-Ayerst
Laboratories' Premarin.RTM. products, with one or more compounds of
Formulas (I) or (III) listed herein. Esterified estrogens, such as
those sold by Solvay Pharmaceuticals, Inc. under the Estratab.RTM.
tradename, may also be used with the present formulations. Also
preferred for use with the present invention are the salts of the
applicable estrogens, most preferably the sodium salts. Examples of
these preferred salts are Sodium estrone sulfate, Sodium equilin
sulfate, Sodium 17alpha-dihydroequilin sulfate, Sodium
17alpha-estradiol sulfate, Sodium Delta8,9-dehydroestrone sulfate,
Sodium equilenin sulfate, Sodium 17beta-dihydroequilin sulfate,
Sodium 17alpha-dihydroequilenin sulfate, Sodium 17beta-estradiol
sulfate, Sodium 17beta-dihydroequilenin sulfate, Estrone 3-sodium
sulfate, Equilin 3-sodium sulfate, 17alpha-Dihydroequilin 3-sodium
sulfate, 3beta-Hydroxy-estra-5(10),7-dien-17-one 3-sodium sulfate,
5alpha-Pregnan-3beta-20R-diol 20-sodium sulfate,
5alpha-Pregnan-3beta,16alpha-diol-20-one 3-sodium sulfate,
delta(8,9)-Dehydroestrone 3-sodium sulfate, Estra-3beta,
17alpha-diol 3-sodium sulfate, 3beta-Hydroxy-estr-5(10)-en-17-one
3-sodium sulfate or 5alpha-Pregnan-3beta,16alpha,20R-triol 3-sodium
sulfate. Preferred salts of estrone include, but are not limited
to, the sodium and piperate salts.
[0044] The present compounds of Formulas (I) and (II) are tissue
selective compounds having the ability to behave like estrogen
agonists, such as by lowering cholesterol and preventing bone loss,
or like estrogen antagonists. Therefore, these compounds in the
present formulations are useful for treating many maladies
including osteoporosis, prostatic hypertrophy, infertility, breast
cancer, endometrial hyperplasia, endometrial cancer, endometriosis,
cystic glandular hyperplasia, uterine hyperplasia, cervical
hyperplasia, benign prostatic hyperplasia, cardiovascular disease,
contraception, Alzheimer's disease and melanoma. The formulations
of this invention may also be used to treat bone loss resulting
from secondary osteoporosis, including that categorized as
endocrine in nature, including that resulting from glucocorticoid
excess, hyperparathyroidism, hyperthyroidism, hypogonadism,
hyperprolactinemia, and diabetes mellitus. The bone loss may also
be the drug-induced, such as that resulting from heparin
treatments, alcohol consumption, or the use of tobacco,
barbiturates or corticosteroids. The drug-induced loss of bone may
also stem from treatment with gonadotropin releasing hormone (GnRH
or LHRH) or synthetic GnRH antagonists or agonists, such as the
leuprolide acetate injectable sold by TAP Pharmaceuticals Inc.
under the tradename LUPRON.RTM. or the goserelin acetate implant
sold by Zeneca Pharmaceuticals under the Zoladex.RTM. tradename.
Such bone loss may also result from immobilization of the
individual, chronic renal failure, malabsorption syndrome, hepatic
disease, chronic obstructive lung disease, rheumatoid arthritis, or
sarcoidosis.
[0045] Additionally, these formulations can be used for hormone
replacement therapy in post-menopausal women or in other estrogen
deficiency states where estrogen supplementation would be
beneficial. The symbiotic activity of the compounds and estrogen(s)
of the present methods of treatment are particularly of interest in
overcoming the unwanted consequences of estrogen therapy, such as
breakthrough bleeding and/or excessive endometrial stimulation,
which may lead to endometrial hyperplasia or endometriosis. These
formulations, therefore, may be used in methods of treating or
preventing excessive estrogenic uterine stimulation in a
mammal.
[0046] The formulations of this invention may also be used in
methods of treatment for bone loss, which may result from an
imbalance in an individual's formation of new bone tissues and the
resorption of older tissues, leading to a net loss of bone. Such
bone depletion results in a range of individuals, particularly in
post-menopausal women, women who have undergone
hysterectomy/oophorectomy, those receiving or who have received
extended corticosteroid therapies, those experiencing gonadal
dysgenesis, and those suffering from Cushing's syndrome. Special
needs for bone replacement can also be addressed using these
formulations in individuals with bone fractures, defective bone
structures, and those receiving bone-related surgeries and/or the
implantation of prosthesis. In addition to those problems described
above, these formulations can be used in treatments for
osteoarthritis, Paget's disease, osteomalacia, osteohalisteresis,
endometrial cancer, multiple myeloma and other forms of cancer
having deleterious effects on bone tissues. Methods of treating the
maladies listed herein are understood to comprise administering to
an individual in need of such treatment a pharmaceutically
effective amount of one or more of the compounds of Formulas (I)
and (II), or a pharmaceutically acceptable salt thereof, in
conjunction with a therapeutically desirable amount of an estrogen.
This invention also includes pharmaceutical compositions utilizing
one or more of the present compounds, and/or the pharmaceutically
acceptable salts thereof, along with one or more pharmaceutically
acceptable carriers, excipients, etc.
[0047] Estrogens regulate a number of physiological processes. The
primary target tissues for estrogens include the reproductive tract
(ovary; uterus; vagina), mammary tissue, skeleton, cardiovascular
system and the central nervous system (CNS). The reduction in
circulating estrogens results in a number of changes. There is a
cessation in reproductive function with an associated amenorrhea,
uterine atrophy, and increase in vaginal dryness (lack of
keratinization). Mammary tissue becomes relatively quiescent. There
is an increase in the rate of loss of bone mass (2-7%) compared to
the normal 0.5-1.0%/year that is seen in all individuals over the
age of 35. A change in lipid profile occurs with increases in Low
Density Lipoprotein (LDL) and decreases in High Density Lipoprotein
(HDL) commonly measured and an associated increased risk of a
cardiovascular event (heart attack, stroke). Changes in the central
nervous system include an increase in vasomotor symptoms (hot
flush) and potentially changes in cognition and memory.
[0048] Estrogen replacement therapy (ERT) normalizes some of these
changes, particularly those associated with the cardiovascular
system (reduced LDL, increased HDL, reduced risk of heart attack),
the skeleton (maintenance of bone mass, reduced fracture risk), and
central nervous system (reduction in frequency and severity of the
hot flush). While the reproductive tract responds, it is not all
positive. On the positive side, vaginal dryness is alleviated.
However, negative uterine responses include hypertrophy and
hyperplasia, along with some menstrual-like bleeding. The breast is
also affected and there are data correlating exogenous estrogen
therapy with an increased risk of breast cancer.
[0049] Currently, women with intact uteri are generally not
prescribed estrogens alone, but estrogens in combination with a
progestin to reduce uterine stimulation. While the risks of
endometrial cancer are reduced to non-hormone treated levels, the
other side effects of progestins reduce compliance in women on
hormone replacement
[0050] The tissue selective estrogen (TSE) compounds of this
invention provide positive skeletal and cardiovascular affects
similar to estrogens, without the negative effects associated with
the uterus and breast. The combinations of TSEs and estrogens
derive the positive effects of estrogens on the CNS, bone and
cardiovascular, with the combination providing complimentary or
additive effects on the bone and cardiovascular systems. The major
variable is the TSEs ability to block estrogenic influence on the
uterus and breast, which are the two major negative effects of
unopposed estrogens.
[0051] It is understood that the dosage, regimen and mode of
administration of these compounds of Formulas (I) and (II) will
vary according to the malady and the individual being treated and
will be subjected to the judgment of the medical practitioner
involved. It is preferred that the administration of one or more of
the compounds herein begins at a low dose and be increased until
the desired effects are achieved. Similarly, it will be understood
that the dosage(s) of the estrogen(s) utilized in the present
formulations will be selected according to conventional methods. It
is most preferred that the dosage will be monitored to achieve the
desired result with the minimum of estrogen(s) necessary.
[0052] Effective administration of these compounds of Formulas (I)
and (II) may be given at a dose of from about 0.01 mg/day to about
1,000 mg/day. Preferably, administration will be from about 1
mg/day to about 600 mg/day in a single dose or in two or more
divided doses. Most preferably a daily dose of between about 1
mg/day and about 150 mg/day will be administered. Such doses may be
administered in any manner useful in directing the active compounds
herein to the recipient, including orally, parenterally (including
intravenous, intraperitoneal and subcutaneous injections, implants,
etc.), intravaginally and transdermally. For the purposes of this
disclosure, transdermal administrations are understood to include
all administrations across the surface of the body and the inner
linings of bodily passages including epithelial and mucosal
tissues. Such administrations may be carried out using the present
compounds, or pharmaceutically acceptable salts thereof, in
lotions, creams, foams, patches, suspensions, solutions, and
suppositories (rectal and vaginal).
[0053] Oral formulations containing the active compounds of
Formulas (I) and (II) may comprise any conventionally used oral
forms, including tablets, capsules, buccal forms, troches, lozenges
and oral liquids, suspensions or solutions. Capsules may contain
mixtures of the active compound(s) with inert fillers and/or
diluents such as the pharmaceutically acceptable starches (e.g.
corn, potato or tapioca starch), sugars, artificial sweetening
agents, powdered celluloses, such as crystalline and
microcrystalline celluloses, flours, gelatins, gums, etc. Useful
tablet formulations may be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically
acceptable diluents, binding agents, lubricants, disintegrants,
suspending or stabilizing agents, including, but not limited to,
magnesium stearate, stearic acid, talc, sodium lauryl sulfate,
microcrystalline cellulose, carboxymethylcellulose calcium,
polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan
gum, sodium citrate, complex silicates, calcium carbonate, glycine,
dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate,
lactose, kaolin, mannitol, sodium chloride, talc, dry starches and
powdered sugar. Oral formulations herein may utilize standard delay
or time release formulations to alter the absorption of the active
compound(s). Suppository formulations may be made from traditional
materials, including cocoa butter, with or without the addition of
waxes to alter the suppository's melting point, and glycerin. Water
soluble suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0054] It will be understood that the estrogen of this invention
will be administered in the dosages of conventional regimens,
according to the recipient's tolerance and the particular treatment
or maintenance schedule intended. The compounds of Formulas (I) and
(II) herein will be administered in an amount necessary to agonize
or antagonize the estrogen(s) of the formulation's activity to the
level desired. When conjugated estrogens, USP, are used, it is
preferred that the daily doseage is from 0.1 mg to 5.0 mg, more
preferably between about 0.3 mg and about 2.5 mg, most preferably
between about 0.3 and about 1.25 mg/day. For mestranol or ethynyl
estradiol a daily dosage may be from about 1 .mu.g to about 0.15
mg/day and a dosage of from about 1 .mu.g to about 0.3 mg/day may
be used for ethynyl estradiol, preferably between about 2 .mu.g to
about 0.15 mg/day of ethynyl estradiol.
[0055] The compounds of this invention can be formulated neat or
with a pharmaceutical carrier for administration, the proportion of
which is determined by the solubility and chemical nature of the
compound, chosen route of administration and standard
pharmacological practice. The pharmaceutical carrier may be solid
or liquid.
[0056] A solid carrier can include one or more substances which may
also act as flavoring agents, lubricants, solubilizers, suspending
agents, fillers, glidants, compression aids, binders or
tablet-disintegrating agents; it can also be an encapsulating
material. In powders, the carrier is a finely divided solid which
is in admixture with the finely divided active ingredient. In
tablets, the active ingredient is mixed with a carrier having the
necessary compression properties in suitable proportions and
compacted in the shape and size desired. The powders and tablets
preferably contain up to 99% of the active ingredient. Suitable
solid carriers include, for example, calcium phosphate, magnesium
stearate, talc, sugars, lactose, dextrin, starch, gelatin,
cellulose, methyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidine, low melting waxes and ion exchange
resins.
[0057] Liquid carriers are used in preparing solutions,
suspensions, emulsions, syrups, elixirs and pressurized
compositions. The active ingredient can be dissolved or suspended
in a pharmaceutically acceptable liquid carrier such as water, an
organic solvent, a mixture of both or pharmaceutically acceptable
oils or fats. The liquid carrier can contain other suitable
phamaceutical additives such as solubilizers, emulsifiers, buffers,
preservatives, sweeteners, flavoring agents, suspending agents,
thickening agents, colors, viscosity regulators, stabilizers or
osmo-regulators. Suitable examples of liquid carriers for oral and
parenteral administration include water (partially containing
additives as above, e.g. cellulose derivatives, preferably sodium
carboxymethyl cellulose solution), alcohols (including monohydric
alcohols and polyhydric alcohols, e.g. glycols) and their
derivatives, lethicins, and oils (e.g. fractionated coconut oil and
arachis oil). For parenteral administration, the carrier can also
be an oily ester such as ethyl oleate and isopropyl myristate.
Sterile liquid carriers are useful in sterile liquid form
compositions for parenteral administration. The liquid carrier for
pressurized compositions can be halogenated hydrocarbon or other
pharmaceutically acceptable propellant.
[0058] Liquid pharmaceutical compositions which are sterile
solutions or suspensions can be utilized by, for example,
intramuscular, intraperitoneal or subcutaneous injection. Sterile
solutions can also be administered intravenously. The compounds of
this invention can also be administered orally either in liquid or
solid composition form.
[0059] The compounds of this invention may be administered rectally
or vaginally in the form of a conventional suppository, creams,
gels, etc. For administration by intranasal or intrabronchial
inhalation or insufflation, the compounds of this invention may be
formulated into an aqueous or partially aqueous solution, which can
then be utilized in the form of an aerosol. The compounds of this
invention may also be administered transdermally through the use of
a transdermal patch containing the active compound and a carrier
that is inert to the active compound, is non toxic to the skin, and
allows delivery of the agent for systemic absorption into the blood
stream via the skin. The carrier may take any number of forms such
as creams and ointments, pastes, gels, and occlusive devices. The
creams and ointments may be viscous liquid or semisolid emulsions
of either the oil-in-water or water-in-oil type. Pastes comprised
of absorptive powders dispersed in petroleum or hydrophilic
petroleum containing the active ingredient may also be suitable. A
variety of occlusive devices may be used to release the active
ingredient into the blood stream such as a semipermeable membrane
covering a reservoir containing the active ingredient with or
without a carrier, or a matrix containing the active ingredient.
Other occlusive devices are known in the literature.
[0060] The dosage requirements vary with the particular
compositions employed, the route of administration, the severity of
the symptoms presented and the particular subject being treated.
Treatment will generally be initiated with small dosages less than
the optimum dose of the compound. Thereafter the dosage is
increased until the optimum effect under the circumstances is
reached; precise dosages for oral, parenteral, transdermal, rectal
or vaginal suppositories, nasal, or intrabronchial and other
administrations will be determined by the administering physician
based on experience with the individual subject treated.
Preferably, the pharmaceutical composition is in unit dosage form,
e.g. as tablets or capsules. In such form, the composition is
sub-divided in unit dose containing appropriate quantities of the
active ingredient; the unit dosage forms can be packaged
compositions, for example, packeted powders, vials, ampoules,
prefilled syringes or sachets containing liquids. The unit dosage
form can be, for example, a capsule or tablet itself, or it can be
the appropriate number of any such compositions in package
form.
[0061] The compound(s) of Formulas (I) and (II) and the estrogen(s)
of the present formulations may be administered in separate dosage
units, such as separate pills, tablets, powders, etc., or combined
into one formulation. When optimum dosages for the compounds of
Formulas (I) and (II) and the estrogens of these formulations have
been determined, it may preferable to incorporate both into a
single formulation for ease of administration. It is also
understood that the formulations herein may or may not include
other pharmaceutically active components.
[0062] Solvents used for the reactions described herein were
anhydrous Aldrich Sure Seal.TM. without further purification.
Reagents were typically Aldrich and used without further
purification. All reactions were carried out under a nitrogen
atmosphere. Chromatography was performed using 230-400 mesh silica
gel (Merck Grade 60, Aldrich Chemical Company). Thin layer
chromatography was performed with Silica Gel 60 F.sub.254 plates
from EM Science. .sup.1H NMR spectra were obtained on a Bruker
AM-400 instrument in DMSO and chemical shifts reported in ppm.
Melting points were determined on a Thomas-Hoover apparatus and are
uncorrected. IR spectra were recorded on a Perkin-Elmer diffraction
grating or Perkin-Elmer 784 spectrophotometers. Mass spectra were
recorded on a Kratos MS 50 or Finnigan 8230 mass spectrometers.
Elemental analyses were obtained with a Perkin-Elmer 2400 elemental
analyzer. Analysis values for compounds with CHN analysis reported
were within 0.4% of theoretical values.
Synthesis of .alpha.-Bromo Ketones
Method a
[0063] The synthesis of the alpha bromo ketones is conveniantly
accomplished by simply dissolving the starting phenyl ketone in
ethyl ether (0.05-0. 10 M) and at room temperature, 1.1 equivalents
of bromine is added in dropwise. The reaction can be monitored by
TLC for consumption of starting materials. The reaction is worked
up by washing with an aqueous sodium bicarbonate solution followed
by a 10% aqueous sodium sulfite solution. The ether layer is washed
with brine and dried over magnesium sulfate. Concentration of the
reaction mixture typically yields the bromoketones in good yield
and purity. The bromoketones were taken "as is" (without
purification or characterization) to the next step.
3-Methyl Indoles
[0064] ##STR15## TABLE-US-00001 TABLE 1 Example No. X O No. 1 H H
No. 1a F OBn No. 2 H 4'-Obn No. 6 OBn 4'-OEt No. 7 OBn 4'-OBn No. 8
OBn 4'-F No. 9 OBn 3'-OMe, 4'-OBn No. 10 OBn 3',4'-OCH.sub.2O-- No.
11 OBn 4'-O-iPr No. 12 OBn 4'-O-Cp No. 13 OBn 4'-CF.sub.3 No. 14
OBn 4'-CH.sub.3 No. 15 OBn 4'-Cl No. 16 OBn 2'-OMe, 4'-OMe No. 17
OBn 3'-OBn No. 18 OBn 4'-OBn,3'-F No. 19 OBn 3'-OMe No. 20 OBn
4'-OCF.sub.3
Method 1
Illustrated for Example No. 7
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole
[0065] A flask was charged with 4-benzyloxyaniline hydrochloride
CAS No. [51145-58-5]. (45 g, 0.23 mol),
4'-benzyloxy-2-bromophenylpropiophenone CAS No. [66414-19-5] (21 g,
0.066 mol), and 50 mL DMF. The reaction was heated at reflux for 30
minutes and then cooled to rt and then partitioned between 250 mL
EtOAc and 100 mL 1N HCl (aq). The EtOAc was washed with NaHCO.sub.3
(aq) and brine, then dried over MgSO.sub.4. The solution was
concentrated and the residue taken up in CH2Cl.sub.2 and hexanes
added to precipitate out 25 g of a crude solid. The solid was
dissolved in CH.sub.2Cl.sub.2 and evaporated onto silica gel and
chromatographed using CH.sub.2Cl.sub.2/Hexane (1:5) to yield 9.2 g
of a tan solid (33%): Mp=150-152.degree. C.; .sup.1H NMR (DMSO),
10.88 (s, 1H), 7.56 (d, 2H, J=8.8 Hz), 7.48 (d, 4H, J=7.9 Hz),
7.42-7.29 (m, 6H), 7.21 (d, 1H, J=7.0 Hz), 7.13 (d, 2H, J=8.8 Hz),
7.08 (d, 1H, J=2.2 Hz), 6.94 (dd, 1H, J=8.8, 2.4 Hz), 5.16 (s, 2H),
5.11 (s, 2H), 2.33 (s, 3H); IR (KBr), 3470, 2880, 2820, 1620
cm.sup.-1; MS eI m/z 419.
Method 2 (Shown in Scheme 8)
Also Illustrated for Example No. 7
[0066] Reagents used were same as in method 1 except the additional
use of triethylamine in this method. The bromoketone CAS No.
[66414-19-5] (50.0 g, 0.16 mol) in 200 mL DMF was treated with the
aniline hydrochloride CAS No. [51145-58-5] (44 g, 0.22 mol) and the
reaction purged with nitrogen for about 10 minutes. The
triethylamine (54.6 mL) was added and the reaction was heated at
120.degree. C. for 2 hours. TLC analysis (EtOAc/hexanes) shows the
starting material has dissappeared forming a more polar spot. The
reaction mixture is allowed to cool down and an additional 48 g of
the aniline hydrochloride was added. The reaction was heated to
150.degree. C. for 2 hours. An additional 5 grams of the aniline
hydrochloride was added and the reaction was heated at 150.degree.
C. for an additional 30 minutes. The reaction mixture is allowed to
cool to room temperature and then poured into approximately 1.5
liters of water and extracted with 2 liters of ethyl acetate.
Solids are dissolved with additional ethyl acetate as neccessary.
The ethyl acetate layer is washed with 1 liter of 1 N NaOH solution
aq., 1 liter of water, brine, then dried over magnesium sulfate and
filtered. The organic layers were concentrated down to yield a
crude solid which is stirred with 500 mL of methanol and filtered.
This solid is then stirred with 500 mL of ethyl ether and filtered.
The solid is stirred alternatively with methanol and ether until it
is of whitish color and has a melting point similar to that
described for No. 7 in method 1. Reaction yields 36 grams of
product.
Physical Data for Indoles
[0067] The following 3-methyl indoles (No. 1-No. 20) were
synthesized according to the procedure outlined in scheme 2 using
method 2 using the appropriately substituted bromoketones (prepared
as given above) and anilines (commercially available; Aldrich) as
starting materials.
EXAMPLE NO. 1
2-Phenyl-3-methyl-1H-indole
[0068] Mp=90-94.degree. C.; .sup.1H NMR (DMSO), 11.13 (s, 1H),
7.68-7.64 (m, 2H), 7.54-7.46 (m, 3H), 7.37-7.32 (m, 2H), 7.12-7.06
(m, 1H), 7.03-6.97 (m, 1H), 2.40 (s, 3H); MS eI m/z 207 (M+).
EXAMPLE NO. 1a
5-Flouro-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole
[0069] Mp=143-146.degree. C.
EXAMPLE NO. 2
2-(4-Benzyloxy-phenyl)-3-methyl-1H-indole
[0070] Mp=118-120.degree. C.; .sup.1H NMR (DMSO), 11.03 (s, 1H),
7.57 (dd, 2H, J=2.0 Hz, 6.6 Hz), 7.48-7.46 (m, 3H), 7.44-7.28 (m,
4H), 7.18-7.11 (m, 2H), 7.08-7.03 (m, 1H), 7.0-6.95 (m, 1H), 5.16
(s, 2H), 2.36 (s, 3H); MS eI m/z 313 (M+).
EXAMPLE NO. 3
5-Benzyloxy-2-phenyl-3-methyl-1H-indole
[0071] Mp=141-144.degree. C.; .sup.1H NMR (DMSO), 10.98 (s, 1H),
7.65-7.61 (m, 2H), 7.51-7.44 (m, 4H), 7.42-7.28 (m, 4H), 7.23 (d,
1H, J=8.8 Hz), 7.10 (d, 1H, J=2.5 Hz), 6.80 (d, 1H , J=6.0 Hz),
5.10 (s, 2H), 2.36 (s, 3H); MS eI m/z 313 (M+).
EXAMPLE NO. 4
5-Benzyloxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole
[0072] Mp=158.degree. C.; .sup.1H NMR 10.85 (brs, 1H), 7.56 (d, 2H,
J=8.8 Hz), 7.48 (d, 2H, J=8.3 Hz), 7.45-7.36 (m, 2H), 7.34-7.28 (m,
1H), 7.21 (d, 1H, J=8.6 Hz), 7.09-7.04 (m, 3H), 6.79 (dd, 1H, J=8.8
Hz), 5.11 (s, 2H), 3.80 (s, 3H), 2.33 (s, 3H); IR (KBr), 3400,
2900, 1610 cm.sup.-1; MS eI m/z 343 (M+); CHN calcd for
C.sub.23H.sub.21NO.sub.2+0.25 H.sub.2O.
EXAMPLE NO. 5
5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole
[0073] Mp=139-142.degree. C.; .sup.1H NMR (DMSO), 10.85 (s, 1H),
7.57 (d, 2H, J=8.8 Hz), 7.19 (d, 1H, J=8.6 Hz), 7.04 (d, 2 H, J=6.8
Hz), 6.95 (d, 1H , J=2.2 Hz), 6.71 (dd, 1H , J=8.5 Hz, J=2.4 Hz),
3.80 (s, 3H), 3.76 (s, 3H), 2.33 (s, 3H); MS eI m/z 267 (M+); CHN
calc for C.sub.17H.sub.17NO.sub.2.
EXAMPLE NO. 6
5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1H-indole
[0074] Mp=143-145.degree. C.; .sup.1H NMR (DMSO), 10.86 (s, 1H),
7.54 (d, 2H, J=8.5 Hz), 7.46 (d, 2H , J=7.3 Hz), 7.41-7.37 (m, 2H),
7.32-7.30 (m, 1H), 7.20 (d, 1H, J=8.6 Hz), 7.05 (d, 1H), 7.03 (d,
2H, J=8.8 Hz), 6.79 (dd, 1H, J=8.6 Hz, J=2.4 Hz), 5.10 (s, 2H),
4.07 (q , 2H, J=6.8 Hz), 2.32 (s, 3H), 1.34 (t, 3H, J=7.0 Hz); MS
eI m/z 357 (M+).
EXAMPLE NO. 8
5-Benzyloxy-2-(4-fluoro-phenyl)-3-methyl)-1H-indole
[0075] Mp=132.degree. C.; .sup.1H NMR (DMSO), 11.0 (s, 1H),
7.68-7.64 (m, 2H), 7.49-7.47 (m, 2H), 7.41-7.31 (m, 5H), 7.23 (d,
1H, J=8.8 Hz), 7.10 (d, 1H, J=2.4 Hz), 6.82 (dd, 1H, J=8.8, 2.4
Hz), 5.11 (s, 2H), 2.34 (s, 3H); MS EI m/z 331; CHN calcd for
C.sub.22H.sub.18FNO.
EXAMPLE NO. 9
5-Benzyloxy-2-(4-benzyloxy-3-methoxy-phenyl)-3-methyl-1H-indole
[0076] Mp=155-158.degree. C.; .sup.1H NMR (DMSO), 10.88 (s, 1H),
7.50-7.45 (m, 4H), 7.41-7.35 (m, 6H), 7.22-7.20 (m, 2H), 7.14 (s,
2H), 7.08 (d, 1H, J=2.2 Hz), 6.78 (dd, 1H, J=8.5 Hz, J=2.4 Hz),
5.13 (s, 2H), 5.11 (s, 2H), 3.85 (s, 3H), 2.35 (s, 3H); MS eI m/z
449 (M+).
EXAMPLE NO. 10
2-Benzo[1,3]dioxol-5-yl-5-benzyloxy-3-methyl-1H-indole
[0077] Mp=142-145.degree. C.; .sup.1H NMR (DMSO), 10.86 (s, 1H),
7.48 (d, 2H, J=7.0 Hz), 7.40-7.30 (m, 3H), 7.20 (m, 2H), 7.10-7.05
(m, 3H), 6.78 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.06 (s, 2H), 5.10 (s,
2H), 2.31 (s, 3H); MS eI m/z 357 (M+); CHN calc for
C.sub.23H.sub.19NO.sub.3.
EXAMPLE NO. 11
5-Benzyloxy-2-(4-isopropoxy-phenyl)-3-methyl)-1H-indole
[0078] Mp=136-138.degree. C.; .sup.1H NMR (DMSO), 10.86 (s, 1H),
7.55-7.51 (m, 2H), 7.50-7.47 (d, 2H, J=7.3 Hz), 7.40-7.34 (m, 2H),
7.39-7.28 (m, 1H), 7.20 (d, 1H, J=8.7 Hz), 7.06 (d, 1H, J=2.2 Hz),
7.02 (d, 2H, J=8.8 Hz), 6.77 (dd, 1H, J=2.4 Hz, 8.8 Hz), 5.10 (s,
2H), 4.68-4.62 (m, 1H), 2.32 (s, 3H), 1.28 (d, 6H, J=6.0 Hz); MS eI
m/z 371 (M+).
EXAMPLE NO. 12
5-Benzyloxy-2-(4-cyclopenyloxy-phenyl)-3-methyl-1H-indole
[0079] Mp=161-167.degree. C.; .sup.1H NMR (DMSO), 10.85 (s, 1H),
7.53 (d, 2H, J=8.8 Hz), 7.47 (d, 2H, J=8.4 Hz), 7.40-7.36 (m, 2H),
7.33-7.28 (m, 1H), 7.20 (d, 1H, J=8.6 Hz), 7.07 (d, 1H, J=2.4 Hz),
7.01 (d, 2H, J=8.8 Hz), 6.78 (dd, 1H, J=8.6 Hz, 2.2 Hz), 5.10 (s,
2H), 4.88-4.84 (m, 1H), 2.32 (s, 3H), 1.99-1.88 (m, 2H), 1.78-1.69
(m, 4H), 1.64-1.52 (m, 2H); IR (KBr), 3400, 2920, 1600 cm.sup.-1;
MS eI m/z 397 (M+); CHN calcd for C.sub.27H.sub.27NO.sub.2+0.25
H.sub.2O.
EXAMPLE NO. 13
5-Benzyloxy-2-(4-triflouromethyl-phenyl)-3-methyl-1H-indole
[0080] .sup.1H NMR (DMSO), 11.0 (br s, 1H), 7.87-7.82 (m, 4H), 7.48
(d, 2H, J=8.8 Hz), 7.44-7.35 (m, 2H), 7.34-7.26 (m, 2H), 7.15 (d,
1H, J=2.2 Hz), 6.87 (dd, 1H, J=8.6 Hz, 2.4 Hz), 5.12 (s, 2H), 2.41
(s, 3H); CHN calcd for C.sub.23H.sub.18F.sub.3NO.
EXAMPLE NO. 14
5-Benzyloxy-2-(4-methyl-phenyl)-3-methyl-1H-indole
[0081] Mp=144-146.degree. C.; .sup.1H NMR (DMSO), 10.91 (s, 1H),
7.56-7.20 (m, 10H), 7.08 (d, 1H, J=2.4 Hz), 6.80 (dd, 1H, J=2.4 Hz,
8.6 Hz), 5.11 (s, 2H), 2.34 (s, 3H), 2.34 (s, 3H); MS eI m/z 327
(M+).
EXAMPLE NO. 15
5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1H-indole
[0082] Mp=134-136.degree. C.; .sup.1H NMR (DMSO), 11.04 (s, 1H),
7.65 (d, 2H, J=8.3 Hz), 7.53 (d, 2H, J=8.5 Hz), 7.47 (d, 2H, J=6.8
Hz), 7.41-7.37 (m, 2H), 7.31-7.28 (m, 1H), 7.25 (d, 1H, J=8.5 Hz),
7.11 (d, 1H, J=2.4 Hz), 6.82 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.11 (s,
2H), 2.35 (s, 3H); IR (KBr), 3380, 1210 cm.sup.-1, Ms eI m/z 347
(M+); CHN calc for C.sub.22H.sub.18ClNO.sub.2.
EXAMPLE NO. 16
5-Benzyloxy-2-(2,4-dimethoxy-phenyl)-3-methyl-1H-indole
[0083] Oil; .sup.1H NMR (DMSO), 10.58 (s, 1H), 7.50-7.18 (m, 7H),
7.04 (d, 1H, J=2.4 Hz), 6.76 (dd, 1H, J=2.3 Hz, 8.6 Hz), 6.69-6.62
(m, 2H), 5.11 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H), 2.12 (s,
3H).
EXAMPLE NO. 17
5-Benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1H-indole
[0084] Mp=83-86.degree. C.
EXAMPLE NO. 18
5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1H-indole
[0085] Mp=135-137.degree. C.; .sup.1H NMR (DMSO), 10.94 (s, 1H),
7.50-7.31 (m, 13H), 7.22 (d, 1H, J=8.6 Hz), 7.10 (d, 1H, J=2.2 Hz),
6.81 (dd, 1H, J=8.6 Hz, 2.2 Hz), 5.23 (s, 2H), 5.11 (s, 2H), 2.34
(s, 3H); MS eI m/Z 437 (M+); CHN calcd for
C.sub.29H.sub.24FNO.sub.2.
EXAMPLE NO. 19
5-Benzyloxy-2-(3-methoxy-phenyl)-3-methyl-1H-indole
[0086] Mp=107-109.degree. C.; .sup.1H NMR (DMSO), 11.00 (s, 1H),
7.51-7.48 (m, 2H), 7.43-7.20 (m, 7H), 7.13-7.12 (d, 1H, J=2.1 Hz),
6.93-6.90 (dd, 1H, J=2.3 Hz, J=5.7 Hz), 6.86-6.82 (dd, 1H, J=2.3
Hz, J=6.3 Hz), 5.12 (s, 2H), 3.83 (s, 3H), 2.38 (s, 3H); IR (KBr),
3400, 2900, 1600 cm.sup.-1; MS eI m/z 343 (M+); CHN calcd for
C.sub.23H.sub.21NO.sub.2.
EXAMPLE NO. 20
5-Benzyloxy-3-methyl-2-(4-trifluoromethoxy-phenyl)-1H-indole
[0087] Mp=127-128.degree. C.; .sup.1H NMR (DMSO), 11.07 (s, 1H),
7.77-7.74 (dd, 2H, J=1.8 Hz, J=5.0 Hz), 7.50-7.48 (d, 4H, J=8.3
Hz), 7.42-7.25 (m, 4H), 7.14-7.13 (d, 1H, J=2.2 Hz), 6.87-6.83 (dd,
1H, J2.3 Hz, J=6.3 Hz), 5.13 (s, 2H), 2.37 (s, 3H); IR (KBr), 3360,
1600 cm.sup.-1; MS eI m/z 396 (M+); CHN calcd for
C.sub.23H.sub.18F.sub.3NO.sub.2.
3-Methylindole acetic acid ethyl esters
[0088] ##STR16## TABLE-US-00002 TABLE 2 Example No. X O No. 21 H H
No. 22 OBn H No. 23 OBn 4'-OMe No. 24 OMe 4'-OMe No. 25 OBn 4'-OEt
No. 26 OBn 4'-OBn No. 27 OBn 4'-F No. 28 OBn 3'-OMe, 4'-OBn No. 29
OBn 4'-O-iPr No. 30 OBn 3',4'-OCH.sub.2O-- No. 31 OBn 4'-OCp No. 32
OBn 4'-CF.sub.3 No. 33 OBn 4'-Cl No. 34 OBn 2'-OMe, 4'-OMe
Experimental Procedure For 3-Methylindole Acetic Acid Ethyl
Esters
Synthesis Method 3
Illustrated for Example No. 26
{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-
-acetic acid ethyl ester
[0089] A solution of
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (indole
example No. 7) (32 g, 77 mmol) in DMF (0.15 L) was cooled to
0.degree. C. and treated with sodium hydride (2.2 g, 89 mmol). The
reaction was stirred for 20 minutes and then the benzyl chloride
CAS No. [80494-75-3] (29 g, 127 mmol) was added and the reaction
stirred for 18 hours at room temperature. The reaction mixture was
poured into water and extracted with ethyl acetate. The ethyl
acetate was washed with brine and dried over magnesium sulfate. The
ethyl acetate was concentrated and triturated with ether to obtain
21 g of a white solid. The filtrate was concentrated and triturated
with ether to give an additional 7 g of white solid for a total
yield of 28 g: Mp=129-131.degree. C.; .sup.1H NMR (DMSO), 7.47 (d,
4H, J=7.2 Hz), 7.39 (q, 4H, J=7.9 Hz), 7.36-7.32 (m, 1H), 7.29 (d,
2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz), 7.13-7.09 (m, 4H), 6.80 (dd,
1H, J=8.8, 24 Hz), 6.73 (s, 4H), 5.16 (s, 2H), 5.13 (s, 2H), 5.11
(s, 2H), 4.66 (s, 2H), 4.11 (q, 2H, J=7.2 Hz), 2.15 (s, 3H), 1.16
(t, 3H, J=7.2 Hz); MS eI m/z 612.
Physical Data For Indole Ethyl Esters
[0090] The following indole alkylation products were prepared
according to scheme 9 using method 3 with the appropriately
substituted 3-methyl indole selected from (No. 1-No. 16) as the
starting material.
EXAMPLE NO. 21
{4-2-Phenyl-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acid ethyl
ester
[0091] Oil; .sup.1H NMR (DMSO), 7.57-7.30 (m, 7H), 7.13-7.02 (m,
2H), 6.77-6.70 (m, 4H), 5.22 (s, 2H), 4.65 (s, 2H), 4.09 (q, 2H,
J=7.2 Hz), 2.20 (s, 3H), 1.15 (t, 3H, J=7.0 Hz); MS eI m/z 399
(M+).
EXAMPLE NO. 22
{4-[5-Benzyloxy-2-phenyl-3-methyl-indol-1-ylmethyl}-phenoxy-acetic
acid ethyl ester
[0092] Oil; .sup.1H NMR (DMSO), 7.50-7.40 (m, 10H), 7.22 (d, 1H,
J=8.4 Hz), 7.14 (d, 1H, J=2.5 Hz), 6.83 (d, 1H, J=2.5 Hz), 6.72 (s,
4H), 5.18 (s, 2H), 5.11 (s, 2H), 4.65 (s, 2H), 4.10 (q, 2H, J=7.2
Hz), 2.16 (s, 3H), 1.14 (t, 3H, J=7.0 Hz); MS eI m/z 505 (M+).
EXAMPLE NO. 23
{4-[5-Benzyloxy-2-(4-methoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-a-
cetic acid ethyl ester
[0093] Mp=90-96.degree. C.; .sup.1H NMR (DMSO), 7.47 (d, 2H, J=6.8
Hz), 7.41-7.37 (m, 2H), 7.33-7.27 (m, 3H), 7.19 (d, 1H, J=8.8 Hz),
7.12 (d, 1H, J=2.4 Hz), 7.03 (d, 2H, J=8.8 Hz), 6.80 (dd, 1H, J=8.8
Hz, 2.4 Hz), 6.74 (s, 4H), 5.16 (s, 2H), 5.11 (s, 2H), 4.65 (s,
2H), 4.11 (q, 2H, J=7.0 Hz), 3.79 (s, 3H), 2.15 (s, 3H), 1.16 (t,
3H, J=7.0 Hz); IR (KBr), 2990, 2900, 1760, 1610 cm-1; MS FAB m/z
536 (M+H+).
EXAMPLE NO. 24
{4-[5-Methoxy-2-(4-methoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ace-
tic acid ethyl ester
[0094] Mp=109-113.degree. C.; .sup.1H NMR (DMSO), 7.27 (d, 2H,
J=8.8 Hz), 7.17 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.6 Hz), 6.99 (d,
1H, J=2.5 Hz), 6.78-6.70 (m, 5H), 5.15 (s, 2H), 4.65 (s, 2H), 4.11
(q, 2H, J=7.0 Hz), 3.78 (s, 3H), 3.76 (s, 3H), 2.15 (s, 3H), 1.15
(t, 3H, J=7.1 Hz); MS eI m/z 459 (M+).
EXAMPLE NO. 25
{4-[5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ac-
etic acid ethyl ester
[0095] Mp=113-115.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 2H,
J=7.3 Hz), 7.40-7.25 (m, 5H), 7.17 (d, 1H , J=8.8 Hz), 7.11 (d, 1H,
J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz), 6.78 (dd, 1H, J=8.8 Hz, J=2.4
Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.65 (s, 2H),
4.15-4.01 (m, 4H), 2.14 (s, 3H), 1.33 (t, 3H, J=5.7 Hz), 1.16 (t,
3H, J=7.1 Hz); MS eI m/z 549 (M+).
EXAMPLE NO. 27
{4-[5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ac-
etic acid ethyl ester
[0096] .sup.1H NMR (DMSO), 7.50-7.15 (m, 16H), 5.20 (s, 2H), 5.12
(s, 2H), 4.62 (s, 2H), 4.13 (q, 2H, J=7.1 Hz), 2.18 (s, 3H), 1.20
(t, 3H, J=7.1 Hz).
EXAMPLE NO. 28
{4-[5-Benzyloxy-2-(3-methoxy-4-benzyloxy)-3-methyl-indol-1-ylmethyl]-pheno-
xy}-acetic acid ethyl ester
[0097] Foam; .sup.1H NMR DMSO), 7.50-7.30 (m, 10H), 7.22(d, 2H,
J=9.1 Hz), 7.13 (d, 2H, J=8.6 Hz), 6.85-6.70 (m, 6H), 5.17 (s, 2H),
5.13 (s, 2H), 5.11 (s, 2H), 4.66 (s, 2H), 4.14 (m, 2H), 3.61 (s,
3H), 2.17 (s, 3H), 1.16 (t, 3H, J=7.0 Hz).
EXAMPLE NO. 29
{4-[5-Benzyloxy-2-(4-isopropoxy-phenyl)-3-methyl-indol-ylmethyl]-phenoxy}--
acetic acid ethyl ester
[0098] Oil; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28
(m, 3H), 7.25 (d, 2H, J=8.7 Hz), 7.17 (d, 1, J=8.7 Hz), 7.11 (d,
1H, J=2.4 Hz), 6.99 (d, 2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8
Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.70-4.60 (m, 3H),
4.10 (q, 2H, J=7.0 Hz), 2.15 (s, 3H), 1.27 (d, 6H, J=5.9 Hz), 1.16
(t, 3H, J=7.1 Hz); MS eI m/z 563 (M+).
EXAMPLE NO. 30
{4-[5-Benzyloxy-2-(3,4-methlyenedioxy-benzyloxy)-3-methyl-indol-1-ylmethyl-
]-phenoxy}-acetic acid ethyl ester
[0099] Oil; .sup.1H NMR (DMSO), 7.45 (d, 2H, J=7.0 Hz), 7.37 (m,
2H), 7.32 (m, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz),
7.00 (d, 1H, J=7.9 Hz), 6.90 (d, 1H, 5.0 Hz), 6.82-6.75 (m, 6H),
6.07 (s, 2H), 5.16 (s, 2H), 5.10 (s, 2H), 4.65 (s, 2H), 4.10 (m,
2H), 2.15 (s, 3H), 1.15 (t, 3H, J=7.0 Hz); MS eI m/z 549 (M+).
EXAMPLE NO. 31
{4-[5-Benzyloxy-2-(4-cyclopentyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phe-
noxy}-acetic acid ethyl ester
[0100] Mp=96-98.degree. C.; .sup.1H NMR (DMSO), 7.47 (d, 1H, J=7.2
Hz), 7.40-7.36 (m, 2H), 7.33-7.30 (m, 1H), 7.26 (m, 2H), 7.18 (d,
1H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.98 (d, 2H, J=8.8 Hz), 6.79
(dd, 1H, J=8.8 Hz, 2.4 Hz), 6.74 (s, 5H), 5.15 (s, 2H), 5.11 (s,
2H), 4.86-4.80 (m, 1H), 4.66 (s, 2H), 4.13 (q, 2H, J=7.2 Hz), 2.15
(s, 3H), 1.98-1.85 (m, 2H), 1.79-1.65 (m, 4H), 1.62-1.55 (m, 2H),
1.16 (t, 3H, J=7.0 Hz); IR (KBr), 2950, 2910, 2890, 1760, 1610
cm.sup.-1; MS eI m/z 589 (M+); CHN calcd for C:77.39, H:6.67,
N:2.38, Found: C:76.76, H:6.63, N:2.27.
EXAMPLE NO. 32
{[5-Benzyloxy-3-methyl-2-(4-trifluoromethyl-phenyl)-indol-1-ylmethyl]-phen-
oxy}-acetic acid ethyl ester
[0101] Mp=221.degree. C.; .sup.1H NMR (DMSO), 7.83 (d, 2H, J=8.1
Hz), 7.60 (d, 2H, J=7.9 Hz), 7.48 (d, 2H, J=8.4 Hz), 7.40-7.36 (m,
4H), 7.18 (d, 1H, J=2.4 Hz), 6.86 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.72
(s, 4H), 5.21 (s, 2H), 5.12 (s, 2H), 4.65 (s, 2H), 4.11 (q, 2H,
J=7.2 Hz), 2.20 (s, 3H), 1.16 (t, 3H, J=7.0 Hz); IR (KBr), 2920,
1730 cm-1; MS eI m/z 573 (M+); CHN calcd for
C.sub.34H.sub.30F.sub.3NO.sub.4+0.25 H.sub.2O.
EXAMPLE NO. 33
{4-[5-Benzyloxy-2-(4-chlorophenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ace-
tic acid ethyl ester
[0102] Mp=99-101.degree. C.; .sup.1H NMR (DMSO), 7.52 (d, 2H, J=8.6
Hz), 7.46 (d, 2H, J=6.8 Hz), 7.42-7.38 (m, 4H), 7.36 (m, 1H), 7.25
(d, 1H, J=9.0 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.83 (dd, 1H, J=8.8 Hz,
J=2.5 Hz), 6.72 (s, 4H), 5.18 (s, 2H), 5.11 (s, 2H), 4.65 (s, 2H),
4.11 (q, 2H, J=7.2 Hz), 2.16 (s, 3H), 1.15 (t, 3H, J=7.2 Hz); MS eI
m/z 539 (M+); CHN calc for C.sub.33H.sub.30ClNO.sub.4.
EXAMPLE NO. 34
{4-[5-Benzyloxy-2-(2.4-dimethoxy)-3-methyl-indol-1-ylmethyl]-phenoxy}-acet-
ic acid ethyl ester
[0103] Oil; .sup.1H NMR (DMSO), 7.30-6.45 (m, 15H), 4.95 (s, 2H),
4.75-4.65 (m, 2H), 4.50 (s, 2H), 3.97 (q, 2H, J=7.1 Hz), 3.65 (s,
3H), 3.51 (s, 3H), 1.87 (3H), 1.01 (t, 3H, J=7.1 Hz).
3-Methylindole phenylethanols
[0104] ##STR17## TABLE-US-00003 TABLE 3 Example No. X O No. 35 H H
No. 36 OMe 4'-OMe No. 37 OBn 4'-OEt No. 38 OBn 4'-OBn No. 39 OBn
4'-F No. 40 OBn 3',4'-OCH.sub.2O-- No. 41 OBn 4'-O-iPr No. 42 OBn
4'-OCp No. 43 OBn 4'-CF.sub.3 No. 44 OBn 4'-CH.sub.3 No. 45 OBn
4'-Cl No. 46 OBn 2'-OMe, 4'-OMe
Experimental Procedure For 3-Methylindole Phenethanols
Synthesis
Method 4
Illustrated for Example No. 38
2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenox-
y}-ethanol
[0105] A solution of No. 26 from previous step (5.5 g, 8.8 mmol) in
THF (50 mL) was cooled to 0.degree. C. and a solution of LiAlH (10
mL, 1 M) in THF was added dropwise. After 30 minutes at 0.degree.
C. the reaction was carefully quenched with water, and partitioned
between EtOAc and 1 N HCl. The EtOAc was dried with MgSO.sub.4,
concentrated, and chromatographed on silica gel EtOAc/hexane (2:3)
to yield 4.0 g of No. 38 as a white foam: .sup.1H NMR (DMSO),
7.48-7.46 (m, 4H), 7.42-7.27 (m, 8H), 7.20 (d, 1H, J=8.8 Hz),
7.12-7.10 (m, 3H), 6.80 (dd, 1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.15
(s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 4.80 (t, 1H, J=5.5 Hz), 3.86
(t, 2H, J=4.8 Hz), 3.63 (q, 2H, J=5.3 Hz), 2.15 (s, 3H).
Physical Data For Indole Phenethanols
[0106] Following compounds were made according to scheme 10 and
method 4 using the appropriately substituted indole ethyl ester
selected from No. 21-No. 34.
EXAMPLE NO. 35
2-{4-[2-phenyl-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol
[0107] Oil; .sup.1H NMR (DMSO), 7.57-7.32 (m, 7H), 7.13-7.02 (m,
2H), 6.74 (s, 4H), 5.21 (s, 2H), 4.80 (s, 1H), 3.86-3.83 (m, 2H),
3.62 (s, 2H), 2.20 (s, 3H); MS eI m/z 357 (M+).
EXAMPLE NO. 36
2-{4-[5-methoxy-2-(4-methoxy-phenyl)
-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol
[0108] Oil; .sup.1H NMR (DMSO), 7.27 (d, 2H, J=8.8 Hz), 7.17 (d,
1H, J=8.8 Hz ), 7.03 (d, 2H, J=8.6 Hz, 6.99 (d, 1H, J=2.5 Hz),
6.78-6.70 (m, 5H), 5.14 (s, 2H), 4.80 (brs, 1H), 3.85 (t, 2H, J=5.0
Hz), 3.78 (s, 3H), 3.76 (s, 3H), 3.63 (t, 2H, J=5.0 Hz), 2.16 (s,
3H); MS eI m/z 417 (M+).
EXAMPLE NO. 37
2-{4-[5-benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}--
ethanol
[0109] Foam; .sup.1H NMR (DMSO), 7.45 (d, 2H, J=7.3 Hz), 7.40-7.25
(m, 5H), 7.17 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz), 7.01 (d,
2H , J=6.8 Hz), 6.78 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 6.73 (s, 4H),
5.15 (s, 2H), 5.10 (s, 2H), 4.80 (brs, 1H), 4.06 (q, 2H, J=6.8 Hz),
3.85 (t, 2H, J=5.0 Hz), 3.63 (t, 2H, J=4.8 Hz), 2.14 (s, 3H), 1.33
(t, 3H, J=6.9 Hz); MS eI m/z 507 (M+).
EXAMPLE NO. 39
2-{4-[5-benzyloxy-2-(4-flouro-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}--
ethanol
[0110] .sup.1H NMR (DMSO), 7.40-6.60 (m, 16H), 5.10 (s, 1H), 5.07
(s, 2H), 5.02 (s, 2H), 3.76 (t, 2H, J=4.9 Hz), 3.53 (t, 2H, J=5.0
Hz), 2.06 (s, 3H).
EXAMPLE NO. 40
2-{4-[5-benzyloxy-2-(3,4-methylenedioxy-phenyl)-3-methyl-indol-1-ylmethyl]-
-phenoxy}-ethanol
[0111] Oil; .sup.1H NMR (DMSO), 7.45 (d, 2H, J=7.0 Hz), 7.37 (m,
2H), 7.32 (m, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.2 Hz),
7.00 (d, 1H, J=7.9 Hz), 6.90 (d, 1H , 5.0 Hz), 6.82-6.75 (m, 6H),
6.07 (s, 2H), 5.16 (s, 2H), 5.10 (s, 2H), 3.86 (t, 2H, J=5.0 Hz),
3.63 (t, 2H, J=5.0 Hz), 2.15 (s, 3H); MS eI m/z 507 (M+).
EXAMPLE NO. 41
2-{4-[5-Benzyloxy-2-(4-isopropoxy-phenyl)-3-methyl-indol-1-ylmethyl]-pheno-
xy}-ethanol
[0112] Foam; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28
(m, 3H), 7.25 (d, 2H, J=8.7 Hz), 7.17 (d, 1H, J=8.7 Hz), 7.11 (d,
1H, J=2.4 Hz), 6.99 (d, 2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8
Hz), 6.73 (s, 4H), 5.14 (s, 2H), 5.10 (s, 2H), 4.80 (bs, 1H),
4.70-4.60 (m, 1H), 3.85 (t, 2H, J=4.8 Hz), 3.63 (t, 2H, J=5.1 Hz),
2.13 (s, 3H), 1.30 (d, 6H, J=5.9 Hz); MS eI m/z 521 (M+).
EXAMPLE NO. 42
2-{4-[5-Benzyloxy-2-(4-cyclopentyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-p-
henoxy}-ethanol
[0113] Mp=129-131.degree. C.; .sup.1H NMR (DMSO), 7.7 (d, 2H, J=7.2
Hz), 7.38 (t, 2H, J=7.2 Hz), 7.33-7.28 (m, 1H), 7.25 (d, 2H, J=8.8
Hz), 7.18 (d, 1H, J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.98 (d, 2H,
J=8.8 Hz), 6.79 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.74 (s, 4H), 5.15 (s,
2H), 5.11 (s, 2H), 4.84-4.80 (m, 1H), 4.79 (t, 1H, J=5.7 Hz), 3.86
(t, 2H, J=4.8 Hz), 3.63 (q, 2H, J=5.1 Hz), 2.15 (s, 3H), 1.96-1.87
(m, 2H), 1.77-1.65 (m, 4H), 1.62-1.53 (m, 2H); IR (KBr), 3490 br,
2920, 1620 cm-1; MS eI m/Z 547 (M+).
EXAMPLE NO. 43
2-{4-[5-Benzyloxy-2-(4-triflouromethyl-phenyl)-3-methyl-indol-1-ylmethyl]--
phenoxy}-ethanol
[0114] Foam; .sup.1H NMR (DMSO), 7.83 (d, 2H, J=8.1 Hz), 7.59 (d,
2H, J=7.9 Hz), 7.47 (d, 2H, J=8.3 Hz), 7.42-7.36 (m, 2H), 7.35-7.29
(m, 2H), 7.18 (d, 1H, J=2.4 Hz), 6.87 (dd, 1H, J=8.1 Hz, 2.4 Hz),
6.77-6.68 (m, 4H), 5.21 (s, 2H), 5.12 (s, 2H), 4.81 (br s, 1H),
3.85 (t, 2H, J=5.1 Hz), 3.63 (t, 2H, J=5.1 Hz), 2.19 (s, 3H); MS eI
m/z 531.
EXAMPLE NO. 44
2-{4-[5-Benzyloxy-2-(4-methyl-phenyl)-3-methyl-indol-1-methyl]-phenoxy}-et-
hanol
[0115] Oil; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.2 Hz), 7.45-7.18
(m, 8H), 7.12 (d, 1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4 Hz, 8.6 Hz),
6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.80 (bs, 1H), 3.85 (t,
2H, J=4.8 Hz), 3.63 (t, 2H, J=4.9 Hz), 2.34 (s, 3H), 2.15 (s, 3H);
MS eI m/z 477 (M+).
EXAMPLE NO. 45
2-{4-[5-Benzyloxy-2-(4-choro-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-e-
thanol
[0116] Mp=110-113.degree. C.; .sup.1H NMR (DMSO), 7.52 (d, 2H,
J=8.6 Hz), 7.46 (d, 2H, J=6.8 Hz), 7.38 (m, 4H), 7.42-7.37 (m, 1H),
7.25 (d, 1H, J=9.0 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.83 (dd, 1H, J=8.8
Hz, J=2.5 Hz), 6.76-6.70 (m, 4H), 5.17 (s, 2H), 5.11 (s, 2H), 3.85
(t, 2H, J=5.2 Hz), 3.63 (t, 2H, J=5.0 Hz), 2.16 (s, 3H); MS eI m/z
497 (M+).
EXAMPLE NO. 46
2-{4-[5-Benzyloxy-2-(2,4-dimethoxy-phenyl)-3-methyl-indol-1-ylmethyl]-phen-
oxy}-ethanol
[0117] Oil; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.5 Hz), 7.39-7.35
(m, 2H), 7.31-7.28 (m, 1H), 7.16-7.06 (m, 3H), 6.82-6.72 (m, 5H),
6.68 (d, 1H, J=2.2 Hz), 6.61 (dd, 1H, J=2.4 Hz, 8.3 Hz), 5.0 (s,
1H), 4.88 (s, 2H), 4.85 (d, 1H, J=6.3 Hz), 4.69 (d, 1H, J=6.3 Hz),
3.63 (t, 2H, J=6.9 Hz), 3.58 (s, 3H), 3.46 (s, 3H), 3.40 (t, 2H,
J=6.9 Hz), 1.80 (s, 3H).
Data for 3-methylindole phenylethyl bromides
[0118] ##STR18## TABLE-US-00004 TABLE 4 Example No. X O No. 47 H H
No. 48 OMe 4'-OMe No. 49 OBn 4'-OEt No. 50 OBn 4'-OBn No. 51 OBn
4'-F No. 52 OBn 3',4'-OCH.sub.2O-- No. 52a OBn 3'-OMe, 4'-OBn No.
53 OBn 4'-O-iPr No. 54 OBn 4'-OCp No. 55 OBn 4'-CF.sub.3 No. 56 OBn
4'-CH.sub.3 No. 57 OBn 4'-Cl
Experimental Procedure For 3-Methylindole Phenethyl bromide
Synthesis
Method 5
Illustrated for Example No. 50
EXAMPLE NO. 50
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-f[4-(2-bromo-ethoxy)-benzyl]-3-methyl-
-1H-indole
[0119] To a solution of example No. 38 (3.3 g, 5.8 mmol) in THF (50
mL) was added CBr.sub.4 (2.9 g, 8.7 mmol) and PPH.sub.3 (2.3 g, 8.7
mmol). The reaction was stirred at rt for 3 h and then concentrated
and chromatographed on silica gel using a gradient elution from
EtOAc/hexane (1:4) to EtoAc to give 3.2 g of a white solid:
Mp=131-134.degree. C.; .sup.1H NMR (DMSO), 7.64-7.30 (m, 10H), 7.29
(d, 2H, J=8.8 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.12-7.09 (m, 3H), 6.80
(dd, 1H, J=8.8, 2.4 Hz), 6.77-6.73 (m, 4H), 5.16 (s, 2H), 5.13 (s,
2H), 5.11 (s, 2H), 4.20 (t, 2H, J=5.3 Hz), 3.73 (t, 2H, J=5.5 Hz),
2.15 (s, 3H); MS FAB 631/633 (M+H.sup.+, Br present).
Physical Data for Indole Phenethyl Bromides
[0120] The following compounds were made according to scheme 11 as
described in Method 5 using the appropriately substituted indole
selected from No. 35-No. 45.
EXAMPLE NO. 47
1-[4-(2-bromo-ethoxy)-benzyl]-2-phenyl-3-methyl-1H-indole
[0121] Oil; .sup.1H NMR (DMSO), 7.57-7.32 (m, 7H), 7.13-7.02 (m,
2H), 6.74 (s, 4H), 5.21 (s, 2H), 4.19(t, 2H, J=5.2 Hz), 3.71 (t,
2H, J=5.5 Hz), 2.20 (s, 3H); MS eI m/z 419 (M+).
EXAMPLE NO. 48
5-Methoxy-2-(4-methoxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-i-
ndole
[0122] Oil; .sup.1H NMR (DMSO), 7.27 (d, 2H, J=8.8 Hz), 7.17 (d,
1H, J=8.8 Hz), 7.03 (d, 2H, J=8.6 Hz), 6.99 (d, 1H, J=2.5 Hz),
6.80-6.69 (m, 5H), 5.14 (s, 2H), 4.19 (t, 2H, J=5.4 Hz), 3.78 (s,
3H), 3.76 (s, 3H), 3.72 (t, 2H, J=5.5 Hz), 2.16 (s, 3H); MS eI m/z
479 (M+).
EXAMPLE NO. 49
5-Benzyloxy-2-(4-ethoxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H--
indole
[0123] Mp=118-120.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 2H,
J=7.3 Hz), 7.41-7.26 (m, 5H), 7.17 (d, 1H, J=8.8 Hz), 7.11 (d, 1H,
J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz), 6.78 (dd, 1H, J=8.8 Hz, J=2.4
Hz), 6.78-6.74 (m, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.22-4.18 (m,
2H), 4.04 (q, 2H, J=6.8 Hz), 3.72 (t, 2H, J=5.5 Hz), 2.14 (s, 3H),
1.33 (t, 3H, J=7.0 Hz); MS eI m/z 569 (M+).
EXAMPLE NO. 51
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H--
indole
[0124] Mp=114-116.degree. C.; .sup.1H NMR (DMSO), 7.47 (m, 2H),
7.45-7.20 (m, 8H), 7.14 (d, 1H, J=2.4 Hz), 6.83 (dd, 1H, J=2.7 Hz,
9.0 Hz), 6.80-6.70 (m, 4H), 5.16 (s, 2H), 5.11 (s, 2H), 4.19 (t,
2H, J=5.27 Hz), 3.72 (t, 2H, J=6.4 Hz), 2.15 (s, 3H); MS eI m/z 543
(M+); CHN calc for C.sub.31H.sub.27BrFNO.sub.2.
EXAMPLE NO. 52
2-Benzo[1,3]dioxyl-5-yl-5-benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-
-1H-indole
[0125] Mp=133-136.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 2H,
J=7.0 Hz), 7.41-7.38 (m, 2H), 7.35-7.30 (m, 1H), 7.19 (d, 1H, J=8.8
Hz), 7.11 (d, 1H, J=2.2 Hz), 7.00 (d, 1H, J=7.9 Hz), 6.90 (d, 1H,
1.4 Hz), 6.82-6.78 (m, 2H), 6.77 (s, 4H), 6.07 (s, 2H), 5.16 (s,
2H), 5.10 (s, 2H), 4.20 (t, 2H, J=5.5 Hz), 3.73 (t, 2H, J=5.2 Hz),
2.15 (s, 3H); MS eI m/z 569 (M+).
EXAMPLE NO. 52a
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(3-methoxy-4-benzyloxy-phenyl)-
-3-methyl-1H-indole
[0126] Foam; .sup.1H NMR (DMSO), 7.47-7.42 (m, 4H), 7.40-7.30 (m,
6H), 7.20 (d, 1H, J=8.8 Hz), 7.12-7.10 (m, 2H), 6.86-6.84 (m, 2H),
6.81 (dd, 1H, J=8.8 Hz, 2.4 Hz), 6.78 (s, 4H), 5.17 (s, 2H), 5.11
(s, 2H), 5.10 (s, 2H), 4.20 (t, 2H, J=5.0 Hz), 3.72 (t, 2H, J=5.4
Hz), 3.63 (s, 3H), 2.17 (s, 3H); MS FAB m/z 662 (M+H+).
EXAMPLE NO. 53
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-
-1H-indole
[0127] Mp=125-128.degree. C.; .sup.1H NMR (DMSO), 7.46 (d, 2H,
J=7.7 Hz), 7.42-7.28 (m, 3H), 7.25 (d, 2H, J=8.7 Hz), 7.17 (d, 1H,
J=8.7 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.99 (d, 2H, J=8.6 Hz), 6.79
(dd, 1H, J=2.4 Hz, 8.8 Hz), 6.73 (s, 4H), 5.14 (s, 2H), 5.10 (s,
2H), 4.70-4.60 (m, 1H), 4.19 (t, 2H, J=5.3 Hz), 3.72 (t, 2H, J=4.4
Hz), 2.13 (s, 3H), 1.30 (d, 6H, J=5.9 Hz); MS eI m/z 583 (M+).
EXAMPLE NO. 54
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-2-(4-cyclopentyloxy-phenyl)-3-me-
thyl-1H-indole
[0128] Mp=110-112.degree. C.; 7.47 (d, 2H, J=7.0 Hz), 7.38 (t, 2H,
J=7.0 Hz), 7.35-7.28 (m, 1H), 7.25 (d, 2H, J=8.8 Hz), 7.18 (d, 1H,
J=8.8 Hz), 7.11 (d, 1H, J=2.4 Hz), 6.98 (d, 2H, J=8.6 Hz), 6.79
(dd, 1H, J=8.6 Hz, 2.4 Hz), 6.78-6.74 (m, 4H), 5.16 (s, 2H), 5.11
(s, 2H), 4.86-4.83 (m, 1H), 4.20 (t, 2H, J=5.3 Hz), 3.73 (t, 2H,
J=5.5 Hz), 2.15 (s, 3H), 2.00-1.87 (m, 2H), 1.79-1.65 (m, 4H),
1.63-1.56 (m, 2H); IR (KBr), 2950, 2910, 1610 cm-1; MS eI m/z 609,
611 (M+, Br present).
EXAMPLE NO. 55
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-2-(4-trifluoromethyl-ph-
enyl)-1H-indole
[0129] Mp=106-109.degree. C.; .sup.1H NMR (DMSO), 7.83 (d, 2H,
J=8.1 Hz), 7.60 (d, 2H, J=7.9 Hz), 7.35-7.29 (m, 2H), 7.48 (d, 2H,
J=8.6 Hz), 7.39 (t, 2H, J=7.0 Hz), 7.18 (d, 1H, J=2.2 Hz), 6.87
(dd, 1H, J=9.0 Hz, 2.6 Hz), 6.77-6.71 (m, 4H), 5.22 (s, 2H), 5.12
(s, 2H), 4.20 (t, 2H, J=5.3 Hz), 3.72 (t, 2H, J=5.3 Hz), 2.20 (s,
3H); IR (KBr), 2910, 2850, 1620 cm-1; MS eI m/z 595, 593 (M+)
EXAMPLE NO. 56
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-2-(4-methyl-phenyl)-1H--
indole
[0130] Mp=82-95.degree. C.; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.2
Hz), 7.45-7.18 (m, 8H), 7.12 (d, 1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4
Hz, 8.6 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.19 (t, 2H,
J=5.3 Hz), 3.72 (t, 2H, J=4.4 Hz), 2.34 (s, 3H), 2.15 (s, 3H); MS
eI m/z 539 (M+).
EXAMPLE NO. 57
5-Benzyloxy-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-2-(4-chloro-phenyl)-1H--
indole
[0131] .sup.1H NMR (DMSO), 7.52 (d, 2H, J=8.6 Hz), 7.46 (d, 2H,
J=6.8 Hz), 7.38 (m, 4H), 7.36 (m, 1H), 7.25 (d, 1H, J=9.0 Hz), 7.14
(d, 1H , J=2.4 Hz), 6.83 (dd, 1H, J=8.8 Hz, J=2.5 Hz), 6.72 (m, 4H,
5.17 (s, 2H), 5.11 (s, 2H), 4.19 (t, 2H, J=5.5 Hz), 3.72 (t, 2H,
J=5.5 Hz), 2.16 (s, 3H); MS eI m/z 559 (M+).
Data for some 3-methylindole phenylethyl chlorides used as
intermediates
[0132] ##STR19## TABLE-US-00005 TABLE 5 Example No. X O No. 58 OBn
3'-OBn No. 59 OBn 3'-F, 4'-OBn No. 60 OBn 4'-OCF.sub.3
Experimental Procedure For 3-Methylindole Phenethylchloride
Synthesis
Method 5a
Illustrated for Example No. 58
5-Benzyloxy-2-(3-benzyloxy-phenyl)-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-
-1H-indole
[0133] To a solution of 9.7 g (0.0231 mol) of
5-benzyloxy-3-methyl-2-3-benzyloxy-phenyl)-1H-indole (indole
example No. 17) in 80 mL of dry DMF was added 0.85 g of sodium
hydride (60% in mineral oil). After allowing this mixture to stir
for 30 minutes (until no more bubbling was indicated), 4.8 g of
1-chloromethyl-4-(2-chloro-ethoxy)benzene CAS No. [99847-87-7] was
added. The reaction mixture was allowed to react at room
temperature overnight. 200 mL of ethyl acetate were added to the
reaction mixture and then washed with water (3.times.100 mL). The
organic solution was collected, washed with saturated brine,
removed, dried over magnesium sulfate, filtered and evaporated to
dryness in a rotary evaporator. The product was recrystallized in
ethyl acetate.
[0134] Mp=125-127.degree. C.; .sup.1H NMR (DMSO), 7.48-7.46 (d, 2H,
J=6.8 Hz), 7.40-7.35 (m, 7H), 7.33-7.28 (m, 2H), 7.23-7.21 (d, 1H,
J=8.8 Hz), 7.13-7.12 (d, 1H, J=2.2 Hz), 7.07-7.04 (m, 1H),
6.94-6.92 (d, 2H, J=6.1 Hz), 6.83-6.80 (dd, 1H, J=2.5 Hz, J=6.3
Hz), 6.78-6.72 (m, 4H), 5.14 (s, 2H), 5.11 (s, 2H), 5.04 (s, 2H),
4.13-4.10 (t, 2H, J=5.1 Hz), 3.86-3.84 (t, 2H, J=5.1 Hz), 2.14 (s,
3H); IR 3420, 2900 cm.sup.-1; MS eI m/z 587 (M+); CHN calcd for
C.sub.38H.sub.34ClNO.sub.3.
Physical Data for Indole Phenethyl Chlorides
[0135] The following compounds were made according to scheme 12 as
described in Method 5a using the appropriately substituted indoles
No. 18, No. 20.
EXAMPLE NO. 59
5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-1-[4-(2-chloro-ethoxy)-benzyl]-
-3-methyl-1H-indole
[0136] Mp=88-91.degree. C.; .sup.1H NMR (DMSO), 7.49-7.43 (m, 4H),
7.43-7.28 (m, 7H), 7.26-7.21 (m, 2H), 7.13-7.09 (m, 2H), 6.88-6.72
(m, 5H), 5.21 (s, 2H), 5.18 (s, 2H), 5.11 (s, 2H), 4.13 (t, 2H,
J=5.2 Hz), 3.87 (t, 2H, J=5.2 Hz), 2.16 (s, 3H); MS eI m/Z 605
(M+); CHN calcd for C.sub.38H.sub.33ClFNO.sub.3.
EXAMPLE NO. 60
5-Benzyloxy-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-2-(4-trifluoromethoxy--
phenyl)-1H-indole
[0137] Mp=108-110.degree. C.; .sup.1H NMR (DMSO), 7.49-7.48 (m,
6H), 7.40-7.25 (m, 4H), 7.17-7.16 (d, 1H, J=2.9 Hz), 6.88-6.84 (m,
1H), 6.77-6.72 (m, 4H), 5.20 (s, 2H), 5.14-5.14-5.13 (d, 2H, J=2.3
Hz), 4.16-4.11 (m, 2H), 3.89-3.84 (m, 2H), 2.19-2.17 (m, 3H); IR
3400, 2900, 1600 cm.sup.-1; MS eI m/z 566 (M+); CHN calcd for
C.sub.32H.sub.27ClF.sub.3NO.sub.3+0.25 H.sub.2O.
Aminoethoxy indoles
[0138] ##STR20## TABLE-US-00006 TABLE 6 Example No. X O Z No. 61
OBn 4'-OEt ##STR21## No. 62 OBn H ##STR22## No. 63 OBn 4'-OBn
##STR23## No. 64 OBn 4'-OBn ##STR24## No. 65 OBn 4'-OBn ##STR25##
No. 66 OBn 4'-OBn ##STR26## No. 66a OBn 4'-OBn ##STR27## No. 67 OBn
4'-OBn ##STR28## No. 68 OBn 4'-OBn ##STR29## No. 69 OBn 4'-OBn
##STR30## No. 70 OBn 4'-OBn ##STR31## No. 71 OBn 4'-OBn ##STR32##
No. 71a OBn 4'-OBn ##STR33## No. 72 OBn 4'-F ##STR34## No. 72a OBn
4'-F ##STR35## No. 72b OBn 4'-Cl ##STR36## No. 73 OBn
3',4'-OCH.sub.2O-- ##STR37## No. 74 OBn 4'-O--iPr ##STR38## No. 75
OBn 4'-CH.sub.3 ##STR39## No. 76 OBn 3'-OBn ##STR40## No. 77 OBn
3'-OBn ##STR41## No. 78 OBn 4'-OBn,3'-F ##STR42## No. 79 OBn
4'-OBn,3'-F ##STR43## No. 80 OBn 3'-OMe ##STR44## No. 81 OBn
4'-OCF.sub.3 ##STR45## No. 82 OBn 4'-OBn ##STR46## No. 83 OBn
4'-OBn ##STR47## No. 84 OBn 3'-OMe ##STR48##
Experimental Procedure For 3-Methyl aminoethoxyindole Synthesis
Method 6
Illustrated for Example No. 63
Substitution of the Bromide
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-
-benzyl]-1H-indole
[0139] A solution of example No. 50 (3.2 g, 5.0 mmol) in THF (50
mL) was treated with piperidine (5.0 mL, 50 mmol) and heated to
reflux. After 5 hours, the reactionmixture was concentrated and
taken up in EtOAc, washed with saturated NaHCO.sub.3, dried over
MgSO.sub.4 and column chromatographed on silica gel using a
gradient elution of EtOAc/Hexane to EtOAc. The product (2.7 g) was
a white solid with a Mp=93-95.degree. C.; .sup.1H NMR (DMSO),
7.48-7.46 (m, 4H), 7.42-7.38 (m, 4H), 7.38-7.32 (m, 2H), 7.29 (d,
2H, J=8.8 Hz), 7.19 (d, 1H, J=9.0 Hz), 7.12-7.10 (m, 3H), 6.80 (dd,
1H, J=8.8, 2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.13 (s, 2H), 5.11
(s, 2H), 3.93 (t, 2H, J=5.7 Hz), 2.60-2.50 (m, 2H), 2.41-2.30 (m,
4H), 2.15 (s, 3H), 1.47-1.42 (m, 4H), 1.36-1.32 (m, 2H); MS FAB 637
(M+H.sup.+).
Alternative Procedure
Method 6a
Substitution of chlorides
Synthesis Illustrated for Product No. 76
EXAMPLE NO. 76
5-Benzyloxy-2-(3-benzyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-
-benzyl]-1H-indole
[0140] To a solution of 1.1 g (0.00953 mol) of
5-benzyloxy-2-(3-benzyloxy-phenyl-1-[4-(2-chloro-ethoxy)-benzyl]-3-methyl-
-1H-indole (example No. 58) in 10 mL of DMF was added 1.1 mL
(0.0112 mol) of piperidine, and 0.93 g (00561 mol) of potassium
iodide. The reaction mixture was heated to .about.40-50.degree. C.
for 4 hours. Aftercooling the reaction mixture to room temperature,
150 mL of ethyl acetate were added and the mixture was washed with
water (3.times.100 mL). The organic solution was collected, washed
with saturated brine, removed, dried over magnesium sulfate,
filtered and evaporated to yield 1.0 g of product of the product
after purification.
[0141] Mp=125-126.degree. C.; .sup.1H NMR (DMSO), 7.48-7.45 (d, 2H,
J=7.2 Hz), 7.41-7.35 (m, 7H), 7.33-7.28 (m, 2H), 7.23-7.21 (d, 1H,
J=9.0 Hz), 7.13-7.12 (d, 1H, J=2.4 Hz), 7.06-7.03 (m, 1H),
6.95-6.91 (m, 2H), 6.83-6.80 (dd, 1H, J=2.4 Hz, J=6.3 Hz),
6.75-6.70 (m, 4H), 5.13 (s, 2H), 5.11 (s, 2H), 5.02 (s, 2H),
3.93-3.90 (t, 2H, J=6.0 Hz), 2.56-2.53 (t, 2H, J=5.9 Hz), 2.49-2.48
(m, 4H), 2.14 (s, 3H), 1.46-1.40 (m, 4H), 1.35-1.31 (m, 2H); IR
(KBr), 3400, 2900 cm.sup.-1; MS eI m/z 636 (M+); CHN calcd for
C.sub.43H.sub.44N.sub.2O.sub.3+0.25 H.sub.2O.
Physical Data for the Amine Substituted Compounds
[0142] The following compounds were prepared by scheme 13 using
method 6. Except for examples No. 76-No. 84 which were prepared
using method 6a.
EXAMPLE NO. 61
5-Benzyloxy-2-(4-ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-1-yl-ethoxy)--
benzyl]-1H-indole
[0143] Mp=188-191.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 2H,
J=7.3 Hz), 7.40-7.25 (m, 5H), 7.17 (d, 1H, J=8.8 Hz), 7.11 (d, 1H,
J=2.2 Hz), 7.01 (d, 2H, J=6.8 Hz), 6.78 (dd, 1H, J=8.8 Hz, J=2.4
Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 4.05 (q, 2H, J=6.8
Hz), 3.93 (t, 2H, J=6.0 Hz), 2.55 (t, 2H, J=5.7 Hz), 2.41-2.35 (m,
4H), 2.14 (s, 3H), 1.46-1.40 (m, 4H), 1.38-1.30 (m, 5H); MS eI m/z
574 (M+).
EXAMPLE NO. 62
5-Benzyloxy-2-phenyl-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indol-
e
[0144] Oil; .sup.1H NMR (DMSO), 7.50-7.43 (m, 4H), 7.42-7.37 (m,
5H), 7.33-7.30 (m, 1H), 7.22 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=2.4
Hz), 6.81 (d, 1H, J=6.6 Hz), 6.72 (s, 4H), 5.18 (s, 2H), 5.11 (s,
2H), 3.90 (t, 2H, J=6.1 Hz), 2.81-2.75 (m, 2H), 2.68-2.59 (m, 4H),
2.16 (s, 3H), 1.58-1.43 (m, 8H); MS eI m/z 544 (M+).
EXAMPLE NO. 64
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-be-
nzyl]-1H-indole
[0145] Mp=106-107.degree. C.; .sup.1H NMR (DMSO), 7.47 (d, 4H,
J=8.3 Hz), 7.41-7.36 (m, 4H), 7.36-7.30 (m, 2H), 7.29 (d, 2H, J=8.8
Hz), 7.19 (d, 1H, J=8.8 Hz), 7.14-7.10 (m, 3H), 6.80 (dd, 1H, J=8.8
Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H), 3.90
(t, 2H, J=5.9 Hz), 2.76 (t, 2H, J=5.9 Hz), 2.64-2.56 (m, 4H), 2.15
(s, 3H), 1.58-1.44 (m, 8H); MS FAB m/z 651 (M+H+).
EXAMPLE NO. 65
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-diisopropylamino-1-yl--
ethoxy)-benzyl]-1H-indole
[0146] Mp=148-150.degree. C.; .sup.1H NMR (DMSO), 7.47 (d, 4H,
J=8.3 Hz), 7.41-7.36 (m, 4H), 7.36-7.32 (m, 2H), 7.28 (d, 2H, J=8.8
Hz), 7.19 (d, 1H, J=9.0 Hz), 7.13-7.08 (m, 3H), 6.80 (dd, 1H, J=8.8
Hz, 2.4 Hz), 6.76-6.68 (m, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11
(s, 2H), 3.75 (t, 2H, J=7.0 Hz), 2.95 (m, 2H), 2.67 (t, 2H, J=7.0
Hz), 2.15 (s, 3H), 0.93 (d, 12H, J=6.4 Hz); MS FAB m/z 653
(M+H+).
EXAMPLE NO. 66
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-butyl-methylamino-1-yl-
ethoxy)-benzyl]-1H-indole
[0147] Mp=101-104.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 4H,
J=7.5 Hz), 7.40-7.25 (m, 8H), 7.19 (d, 1H, J=8.8 Hz), 7.12-7.08 (m,
3H), 6.80 (dd, 1H, J=6.5 Hz, J=2.4 Hz), 6.72 (s, 4H), 5.14 (s, 2H),
5.13 (s, 2H), 5.10 (s, 2H), 3.91 (t, 2H, J=5.9 Hz), 2.64-2.59 (m,
2H), 2.35-2.29 (m, 2H), 2.17 (s, 3H), 2.14 (s, 3H), 1.40-1.31 (m,
2H), 1.25-1.19 (m, 2H), 0.83 (t, 3H, 7.2 Hz); MS eI m/z 638
(M+).
EXAMPLE NO. 66a
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-dimethylamino)-ethoxy]-be-
nzyl}-1H-indole
[0148] Mp=123-124.degree. C.
EXAMPLE NO. 67
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1--
yl)-ethoxy]-benzyl}-1H-indole
[0149] Mp=121.degree. C.
EXAMPLE NO. 68
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperidin-1--
yl)-ethoxy]-benzyl}-1H-indole
[0150] Mp=90.degree. C.
EXAMPLE NO. 69
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin--1-
-yl)-ethoxy]-benzyl}-1H-indole
[0151] Mp=98.degree. C.; .sup.1H NMR (DMSO), 7.46 (d, 4H, J=7.2
Hz), 7.42-7.36 (m, 4H), 7.36-7.31 (m, 2H), 7.28 (d, 2H, J=8.6 Hz),
7.19 (d, 1H, J=9.0 Hz), 7.12-7.10 (m, 3H), 6.80 (dd, 1H, J=8.8 Hz,
2.4 Hz), 6.73 (s, 4H), 5.15 (s, 2H), 5.13 (s, 2H), 5.11 (s, 2H),
3.93 (t, 2H, J=5.9 Hz), 2.85-2.78 (m, 2H), 2.62-2.56 (m, 2H), 2.15
(s, 3H), 1.97-1.87 (m, 2H), 1.55-1.47 (m, 2H), 1.30-1.20 (m, 1H),
1.15-1.02 (m, 2H), 0.85 (d, 3H, J=6.6 Hz); MS esI m/z 651
(M+1)+.
EXAMPLE NO. 70
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1{4-[2-((cis)-2,6-Dimethyl-pip-
eridin-1-yl)-ethoxy]-benzyl}-1H-indole
[0152] Mp=106-107.degree. C.; .sup.1H NMR (DMSO), 7.46 (d, 4H,
J=8.1 Hz), 7.42-7.36 (m, 4H), 7.37-7.31 (m, 2H), 7.29 (d, 2H, J=8.8
Hz), 7.18 (d, 1H, J=8.8 Hz), 7.14-7.09 (m, 3H), 6.80 (dd, 1H, J=8.8
Hz, 2.4 Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11 (s,
2H), 3.84 (t, 2H, J=7.0 Hz), 2.84 (t, 2H, J=6.6 Hz), 2.44-2.37 (m,
2H), 2.15 (s, 3H), 1.60-1.43 (m, 3H), 1.32-1.18 (m, 1H), 1.16-1.06
(m, 2H), 1.01 (d, 6H, J=6.2 Hz).
EXAMPLE NO. 71
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-{4-[2-(1,3,3-trimethyl-6-aza-b-
icyclo[3.2.1]oct-6-yl)-ethoxy]-benzyl}-1H-indole
[0153] Mp=107.degree. C.; MS ESI m/z 705 (M+1)+
EXAMPLE NO. 71a
(1S,4R)-5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl{4-[2-(2-Aza-bicyclo[2.-
2.1]hept-2-yl)-ethoxy]-benzyl}-1H-indole
[0154] The (1S,2R)-2-aza-bicyclo[2.2.1]heptane used to substitute
the bromide was prepared according to the procedure outlined in
Syn. Comm. 26(3), 577-584 (1996).
[0155] Mp=95-100.degree. C.; .sup.1H NMR (DMSO), 7.32-6.55 (m,
21H), 5.10-4.90 (m, 6H), 3.69 (t, 2H, J=5.9 Hz), 2.65-2.5 (m, 3H),
2.10 (s, 2H), 2.0 (s, 3H), 1.50-1.0 (m, 7H).
EXAMPLE NO. 72
5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzy-
l]-1H-indole
[0156] Oil; .sup.1H NMR (DMSO), 7.50-7.43 (m, 2H), 7.42-7.33 (m,
4H), 7.32-7.20 (m, 4H), 7.13 (d, 1H, J=2.4 Hz), 6.83 (dd, 1H, J=2.4
Hz, 6.7 Hz), 6.71 (s, 4H), 5.14 (s, 2H), 5.11 (s, 2H), 3.89 (t, 2H,
J=5.9 Hz), 3.20 (m, 4H), 2.74 (t, 2H, J=6.0 Hz), 2.15 (s, 3H),
1.60-1.40 (m, 8H); MS eI m/z 562 (M+).
EXAMPLE NO. 72a
5-Benzyloxy-2-(4-flouro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be-
nzyl]-1H-indole
[0157] Oil; .sup.1H NMR (DMSO), 7.32-6.53 (m, 16H), 5.00 (s, 2H),
4.96 (s, 2H), 3.77 (t, 2H, J=5.8 Hz), 3.22-3.14 (m, 4H), 2.40 (t,
2H, J=5.8 Hz), 2.0 (s, 3H), 1.29-1.17 (m, 6H).
EXAMPLE NO. 72b
5-Benzyloxy-2-(4-chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be-
nzyl]-1H-indole
[0158] Oil; .sup.1H NMR (DMSO), 7.52 (d, 2H, J=8.6 Hz), 7.46 (d,
2H, J=6.8 Hz), 7.41-7.37 (m, 4H), 7.35-7.29 (m, 1H), 7.25 (d, 1H,
J=9.0 Hz), 7.14 (d, 1H, J=2.4 Hz), 6.83 (dd, 1H, J=8.8 Hz, 2.5 Hz),
6.72-6.65 (m, 4H), 5.16 (s, 2H), 5.11 (s, 2H), 3.90 (t, 2H, J=5.9
Hz), 2.55 (t, 2H, J=6.0 Hz), 2.41-2.26 (m, 4H), 2.16 (s, 3H),
1.44-1.39 (m, 4H), 1.38-1.29 (m, 2H); MS eI m/z 564 (M+).
EXAMPLE NO. 73
5-Benzyloxy-2-[3,4-methylenedioxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-eth-
oxy)-benzyl]-1H-indole
[0159] Foam; .sup.1H NMR (DMSO), 7.45 (d, 2H, J=7.0 Hz), 7.41-7.37
(m, 2H), 7.33-7.29 (m, 1H), 7.19 (d, 1H, J=8.8 Hz), 7.11 (d, 1H,
J=2.2 Hz), 7.00 (d, 1H, J=7.9 Hz), 6.90 (d, 1H, 1.4 Hz), 6.82-6.78
(m, 2H), 6.74 (s, 4H), 6.07 (s, 2H), 5.16 (s, 2H), 5.10 (s, 2H),
3.93 (t, 2H, J=6.0 Hz), 2.56 (t, 2H, J=6.0 Hz), 2.41-2.35 (m, 4H),
2.15 (s, 3H), 1.48-1.41 (m, 4H), 1.38-1.28 (m, 2H); MS eI m/z 574
(M+).
EXAMPLE NO. 74
5-Benzyloxy-2-[4-isopropoxy-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy-
)-benzyl]-1H-indole
[0160] Foam; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.7 Hz), 7.42-7.28
(m, 3H), 7.25 (d, 2H, J=8.7 Hz), 7.17 (d, 1H, J=8.7 Hz), 7.11 (d,
1H, J=2.4 Hz), 6.99 (d, 2H, J=8.6 Hz), 6.79 (dd, 1H, J=2.4 Hz, 8.8
Hz), 6.73 (s, 4H), 5.14 (s, 2H), 5.10 (s, 2H), 4.70-4.60 (m, 1H),
3.92 (t, 2H, J=5.7 Hz), 2.55 (t, 2H, 5.7 Hz), 2.40-2.30 (bs, 4H),
2.15 (s, 3H), 1.50-1.40 (m, 4H), 1.40-1.30 (m, 2H), 1.28 (d, 6H,
J=6.2 Hz); MS eI m/z 588 (M+).
EXAMPLE NO. 75
5-Benzyloxy-2-[4-methyl-phenyl]-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-be-
nzyl]-1H-indole
[0161] Oil; .sup.1H NMR (DMSO), 7.46 (d, 2H, J=7.2 Hz), 7.45-7.18
(m, 8H), 7.12 (d, 1H, J=2.4 Hz), 6.81 (dd, 1H, J=2.4 Hz, 8.6 Hz),
6.73 (s, 4H), 5.15 (s, 2H), 5.10 (s, 2H), 3.92 (t, 2H, J=5.9 Hz),
2.55 (t, 2H, J=5.9 Hz), 2.45-2.30 (m, 7H), 2.10 (s, 3H), 1.50-1.40
(m, 4H), 1.48-1.35 (m, 2H); MS eI m/z 544 (M+).
EXAMPLE NO. 77
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-benzyloxy-phenyl)-3-m-
ethyl-1H-indole
[0162] Mp=103-105.degree. C.; .sup.1H NMR (DMSO), 7.47-7.45 (d, 2H,
J=8.1 Hz), 7.41-7.35 (m, 7H), 7.32-7.29 (t, 2H, 7.0 Hz), 7.23-7.21
(d, 1H, J=8.7 Hz), 7.13-7.12 (d, 1H, J=2.1 Hz), 7.06-7.03 (m, 1H),
6.95-6.91 (m, 2H), 6.83-6.80 (m, 1H), 6.75-6.73 (m, 4H), 5.13 (s,
2H), 5.11 (s, 2H), 5.02 (s, 2H), 3.90-3.87 (t, 2H, J=6.0 Hz),
2.76-2.73 (t, 2H, J=6.0 Hz), 2.49-2.48 (m, 4H), 2.13 (s, 3H), 1.51
(s, 8H); IR 3400, 2900 cm.sup.-1; MS eI m/z 650 (M+); CHN calcd for
C.sub.44H.sub.46N.sub.2O.sub.3.
EXAMPLE NO. 78
5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-piperidin-1-y-
l-ethoxy)-benzyl]-1H-indole
[0163] Mp=125-128.degree. C.; .sup.1H NMR (DMSO), 7.50-7.45 (m,
4H), 7.43-7.28 (m, 7H), 7.26-7.20 (m, 2H), 7.14-7.09 (m, 2H), 6.82
(dd, 1H, J=2.4 Hz, 8.8 Hz), 6.72 (s, 4H), 5.21 (s, 2H), 5.16 (s,
2H), 5.11 (s, 2H), 3.94 (t, 2H, J=5.8 Hz), 2.62-2.56 (m, 2H),
2.41-2.36 (m, 4H), 2.15 (s, 3H), 1.45-1.40 (m, 4H), 1.40-1.31 (m,
2H); MS eI m/Z 654 (M+); CHN calcd for
C.sub.43H.sub.43FN.sub.2O.sub.3.
EXAMPLE NO. 79
5-Benzyloxy-2-(4-benzyloxy-3-fluoro-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-e-
thoxy)-benzyl]-1H-indole
[0164] Mp=122-124.degree. C.; .sup.1H NMR (DMSO), 7.50-7.28 (m,
10H), 7.26-7.20 (m, 2H),7.15-7.10 (m, 2H), 6.88-6.76 (m, 2H), 6.70
(s, 4H), 5.22 (s, 2H), 5.16 (s, 2H), 5.11 (s, 2H), 3.92-3.86 (m,
2H), 2.82-2.65 (m, 2H), 2.65-2.55 (m, 4H), 2.15 (s, 3H), 1.60-1.4
(m, 8H); MS eI m/Z 668 (M+); CHN calcd for
C.sub.44H.sub.45FN.sub.2O.sub.3.
EXAMPLE NO. 80
5-Benzyloxy-2-(3-methoxy-phenyl-1-[4-(2-piperidin-1yl-ethoxy)-benzyl]-3-me-
thyl-1H-indole
[0165] Mp=86-87.degree. C.; .sup.1H NMR (DMSO), 7.50-7.49 (m, 2H),
7.46-7.31 (m, 4H), 7.24-7.21 (d, 1H, J=8.8 Hz), 7.15-7.14 (d, 1H,
J=2.3 Hz), 7.00-6.93 (m, 2H),6.88-6.81 (m, 2H), 6.75 (s, 4H), 5.18
(s, 2H), 5.12 (s, 2H), 3.96-3.92 (t, 2H, J=5.9 Hz), 3.71 (s, 3H),
2.59-2.55 (t, 2H, J=5.8 Hz), 2.37 (s, 4H), 2.18 (s, 3H), 1.49-1.42
(m, 4H), 1.37-1.34 (m, 2H); MS eI m/z 561 (M+); CHN calcd for
C.sub.37H.sub.40N.sub.2O.sub.3+0.25 H.sub.2O.
EXAMPLE NO. 81
5-Benzyloxy-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoro-
methoxy-phenyl)-1H-indole
[0166] Mp=107-108.degree. C.; .sup.1H NMR (DMSO), 7.52-7.45 (m,
6H), 7.41-7.26 (m, 4H), 7.17-7.16 (d, 1H, J=2.3 Hz), 6.87-6.84 (dd,
1H, J=2.3 Hz, J=6.4 Hz), 6.75-6.68 (m, 4H), 5.18 (s, 2H), 5.13 (s,
2H), 3.95-3.91 (t, 2H, J=5.9 Hz), 2.58-2.54 (t, 2H, J=5.9 Hz),
2.38-2.34 (m, 4H), 2.17-2.15 (s, 3H), 1.49-1.42 (m, 4H), 1.35-1.34
(d, 2H, J=4.9 Hz); IR 3400, 2900, 1600 cm.sup.-1; MS eI m/z 615
(M+); CHN calcd for C.sub.37H.sub.37F.sub.3N.sub.2O.sub.3.
EXAMPLE NO. 82
(2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-pheno-
xy}-ethyl)-cyclohexyl-amine
[0167] Mp=87-90.degree. C.; .sup.1H NMR (DMSO), 7.46 (dd, 4H, J=6.9
Hz, 0.6 Hz), 7.42-7.27 (m, 9H), 7.19 (d, 1H, J=9 Hz), 7.14-7.08 (m,
3H), 6.80 (dd, 1H, J=6.4 Hz, 2.4 Hz), 6.75-6.70 (m, 4H), 5.15 (s,
2H), 5.13 (s, 2H), 5.13 (s, 2H), 3.89 (t, 2H, J=5.6), 2.84 (m, 2H),
2.48 (m, 1H), 2.14 (s, 3H), 1.80 (m, 2H), 1.65 (m, 2H), 1.61 (m,
1H), 0.96-1.19 (m, 5H); MS eI m/Z 650 (M+); CHN calcd for
C.sub.44H.sub.46N.sub.2O.sub.4.
EXAMPLE NO. 83
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-{4-methylpiperazin-1-yl)-eth-
oxy]-benzyl}-1H-indole
[0168] Mp=88-91.degree. C.; .sup.1H NMR (DMSO), 7.47 (m, 4H),
7.26-7.42 (m, 8H), 7.19 (d, 1H, J=8.8), 7.10-1.12 (m, 3H), 6.80 (q,
1H, J=6.3 Hz, 2.4 Hz), 6.73 (m, 4H), 5.15 (s, 2H), 5.13 (s, 2H),
5.11 (s, 2H), 3.94 (t, 2H, J=5.9 Hz), 2.59 (t, 2H), 2.42 (m, 4H),
2.29 (m, 4H), 2.15 (s, 3H), 2.12 (s, 3H); MS eI m/Z 652 (M+); CHN
calcd for C.sub.43H.sub.45N.sub.3O.sub.3.
EXAMPLE NO. 84
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(3-methoxy-phenyl)-3-met-
hyl-1H-indole
[0169] Mp=103-105.degree. C.; .sup.1H NMR (DMSO), 7.47-7.45 (d, 2H,
J=8.1 Hz), 7.41-7.35 (m, 7H), 7.32-7.29 (t, 2H, 7.0 Hz), 7.23-7.21
(d, 1H, J=8.7 Hz), 7.13-7.12 (d, 1H, J=2.1 Hz), 7.06-7.03 (m, 1H),
6.95-6.91 (m, 2H), 6.83-6.80 (m, 1H), 6.75-6.73 (m, 4H), 5.13 (s,
2H), 5.11 (s, 2H), 5.02 (s, 2H), 3.90-3.87 (t, 2H, J=6.0 Hz),
2.76-2.73 (t, 2H, J=6.0 Hz), 2.49-2.48 (m, 4H), 2.13 (s, 3H), 1.51
(s, 8H); IR 3400, 2900 cm.sup.-1; MS eI m/z 650 (M+); CHN calcd for
C.sub.44H.sub.46N.sub.2O.sub.3.
Data and Procedures for Compounds From Table 11 (ER Receptor Data
Table, infra) of Text
[0170] TABLE-US-00007 TABLE 7 ##STR49## Example No. X O Z No. 85 H
H ##STR50## No. 86 H 4'-OH ##STR51## No. 87 OH H ##STR52## No. 88
OMe 4'-OH ##STR53## No. 89 OH 4'-OMe ##STR54## No. 90 OMe 4'-OMe
##STR55## No. 91 OMe 4'-OMe ##STR56## No. 92 OH 4'-OEt ##STR57##
No. 93 OH 4'-OEt ##STR58## No. 94 F 4'-OH ##STR59## No. 95 OH H
##STR60## No. 96 OH 4'-OH ##STR61## No. 97 OH 4'-OH ##STR62## No.
98 OH 4'-OH ##STR63## No. 99 OH 4'-OH ##STR64## No. 100 OH 4'-OH
##STR65## No. 101 OH 4'-OH ##STR66## No. 102 OH 4'-OH ##STR67## No.
103 OH 4'-OH ##STR68## No. 104 OH 4'-OH ##STR69## No. 105 OH 4'-OH
##STR70## No. 106 OH 4'-OH ##STR71## No. 107 OH 4'-OH ##STR72## No.
108 OH 4'-OH ##STR73## No. 109 OH 4'-OH ##STR74## No. 110 OH 4'-OH
##STR75## No. 111 OH 4'-OH ##STR76## No. 112 OH 4'-OH ##STR77## No.
113 OH 4'-OH ##STR78## No. 114 OH 4'-OH ##STR79## No. 115 OH 4'-OH
##STR80## No. 116 OH 4'-F ##STR81## No. 117 OH 4'-F ##STR82## No.
118 OH 3'-OMe,4'-OH ##STR83## No. 119 OH 3',4'-OCH.sub.2O--
##STR84## No. 120 OH 4'-O-iPr ##STR85## No. 121 OH 4'-O-iPr
##STR86## No. 122 OH 4'-O-Cp ##STR87## No. 123 OH 4'-CF.sub.3
##STR88## No. 124 OH 4'-CH.sub.3 ##STR89## No. 125 OH 4'-Cl
##STR90## No. 126 OH 2',4',-Dimethoxy ##STR91## No. 127 OH 3'-OH
##STR92## No. 128 OH 3'-OH ##STR93## No. 129 OH 4'-OH,3'-F
##STR94## No. 130 OH 4'-OH, 3'-F ##STR95## No. 131 OH 3'-OMe
##STR96## No. 132 OH 4'-OCF.sub.3 ##STR97##
Hydrogenation of Indoles Containing Benzyl Ether(s)
Method 7
Illustrated For Example No. 97
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in-
dol-5-ol
[0171] A suspension of 10% Pd/C (1.1 g) in EtOH was treated with a
solution of No. 63 (2.2 g, 3.4 mmol) in THF/EtOH. Cyclohexadiene
(6.0 mL, 63 mmol) was added and the reaction was stirred for 48
hours. The catalyst was filtered through Celite and the reaction
mixture was concentrated and chromatographed on silica gel using a
gradient elution of MeOH/CH.sub.2Cl.sub.2 (1:19 to 1:10) to yield
0.8 g of the product as a white solid. Mp=109-113.degree. C.; CHN
calc'd for C.sub.29H.sub.32N.sub.2O.sub.3+0.5 H.sub.2O; .sup.1H NMR
9.64 (s, 1H), 8.67 (s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.05 (d, 1H,
J=8.6 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.79 (d, 1H, J=2.2 Hz), 6.74 (s,
4H), 6.56 (dd, 1H, J=8.8, 2.4 Hz), 5.09 (s, 2H), 3.95-3.93 (m, 2H),
2.60-2.51 (m, 2H), 2.39-2.38 (m, 4H), 2.09 (s, 3H), 1.46-1.45 (m,
4H), 1.35-1.34 (m, 2H); IR (KBr), 3350 (br), 2920, 1620, 1510
cm.sup.-1; MS (EI) m/z 456.
[0172] Alternatively, the compounds may be dissolved in a THF/EtOH
solution (or other appropriate solvent) and hydrogenated with
H.sub.2 and 10% Pd/C using either a ballon or Parr Hydrogenator.
Either procedure is effective. In many of the examples, the
compounds were made into acid addition salts. The procedure for the
preparation of an HCl salt is given below (Method 8).
Method 8
[0173] 1.0 g of Example No. 97 free base from the hydrogenation
procedure above in a large test tube was dissolved in 20 mL of
MeOH. This was treated with slow addition of 2.6 mL 1.0 N HCl and
then 4.0 mL deionized water. The tube was partially opened to the
atmosphere to encourage slow evaporation of the solvents. After
about ten minutes, crystals began to appear and after 4 hours the
solution was filtered and the solid crystals washed with water. The
product was present as 0.42 g of white crystalline plates with a
melting point of 184-185.degree. C. The mother liquor yielded an
additional crop of 0.30 g of white solid with a melting point of
177-182.degree. C. CHN calc'd for
C.sub.29H.sub.32N.sub.2O.sub.3+HCL+1 H.sub.2O.
Alternatively, the compounds can be made into quaternary ammonium
salts. An example procedure for the synthesis of example No. 107 is
given below (Method 9).
Method 9
EXAMPLE NO. 107
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)benzyl]-1H-ind-
ol-5-ol methiodide
[0174] 0.8 g of example No. 97 was dissolved in 18 mL THF and
treated with 2 mL of methyl iodide. The solution was heated to
reflux for an hour. The reaction was allowed to come to room
temperature and the solids filtered to yield 0.72 kg as a
crystalline solid.
[0175] Mp=214-217.degree. C., CHN calcd for
C.sub.29H.sub.32N.sub.2O.sub.3+CH.sub.3I+0.5 H.sub.2O.
EXAMPLE NO. 106
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-ind-
ol-5-ol methiodide
[0176] was prepared similarly to No. 106 except using No. 100 for
starting material: Mp=245-250.degree. C.; .sup.1H NMR (DMSO), 9.66
(s, 1H), 8.69 (s, 1H), 7.16 (d, 2H, J=8.4 Hz), 7.05 (d, 1H, J=8.8
Hz), 6.84 (d, 1H, J=8.6 Hz), 6.81-6.75 (m, 6H), 6.56 (dd, 1H, J=2.4
Hz, 8.7 Hz), 5.12 (s, 2H), 4.34 (m, 2H), 3.70 (t, 2H, J=4.6 Hz),
3.11 (s, 9H), 2.09 (s, 3H); IR (KBr), 3250, 1500, 1250; MS eI m/z
416 (M+); CHN calcd for C.sub.26H.sub.28N.sub.2O.sub.3+1.09
CH.sub.3I+0.8 H.sub.2O.
Physical Data for Final, Deprotected Compounds
[0177] The following compounds are either free bases, HCl salts or
acetate salts. They were prepared according to the procedure
outlined in method 7 using the appropriate benzyl ether for
precursor. Where a compound from table 1 does not contain a free
phenolic functionality, then it was unnecessary to debenzylate it
and method 7 not applied. The physical data for these compounds
(No. 85, No. 90-No. 91) is still presented below.
EXAMPLE NO. 85
4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indole}
(HCl)
[0178] Mp=134-137.degree. C.; .sup.1H NMR (DMSO), 10.33 (s, 1H),
7.56-7.38 (m, 6H), 7.32 (d, 1H, J=8.1 Hz), 7.14-7.0 (m, 2H), 6.80
(s, 4H), 5.24 (s, 2H), 4.28 (t, 2H, J=5.0 Hz), 3.50-3.40 (m, 4H),
3.0-2.95 (m, 2H), 2.10 (s, 3H), 1.80-1.60 (m, 5H), 1.40-1.35 (m,
1H); IR 3400, 2900, 1510, 1250 cm.sup.-1; MS (+), FAB m/z 425
[M+H].sup.+; CHN calcd for C.sub.29H.sub.32N.sub.2O+1.0 HCl+1.0
H.sub.2O.
EXAMPLE NO. 86
4-{3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-1-phenol
hydrochloride (HCl)
[0179] Mp=192-194.degree. C.; 1H NMR (DMSO), 10.28 (s, 1H), 9.75
(s, 1H), 7.51-7.49 (m, 1H), 7.27 (dd, 1H, J=7.0 Hz, 0.7 Hz), 7.18
(d, 2H, J=7.6 Hz), 7.09-7.02 (m, 2H), 6.86 (d, 2H, J=8.6 Hz), 6.80
(s, 4H), 5.20 (s, 2H), 4.28 (t, 2H, J=4.9 Hz), 3.50-3.35 (m, 4H),
3.0-2.85 (m, 2H), 2.20 (s, 3H), 1.80-1.60 (m, 5H), 1.40-1.30 (m,
1H); IR 3400, 3100, 2600, 1500, 1225 cm.sup.-1; MS eI m/z 440 (M+);
CHN calc for C.sub.29H.sub.32N.sub.2O.sub.2+1 HCl.
EXAMPLE NO. 87
3-Methyl-2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-indol-5-ol
(HCl)
[0180] Mp=228-230.degree. C.; .sup.1H NMR 10.1 (brs, 1H), 8.76 (s,
1H), 7.55-7.45 (m, 5H), 7.10 (d, 1H, J=8.8 Hz), 6.85-6.80 (m, 5H),
6.61 (d, 1H, J=8.8 Hz), 5.15 (s, 2H), 4.25 (t, 2H, J=4.8 Hz),
3.47-3.35 (m, 4H), 2.96-2.87 (m, 2H), 2.12 (s, 3H), 1.75-1.65 (m,
5H), 1.31-1.28 (m, 1H); MS eI m/z 440 (M+); CHN calcd for
C.sub.29H.sub.32N.sub.2O.sub.2+1 HCL+0.33 H.sub.2O; IR (KBr), 3200,
2500, 1450, 1200 cm-1.
EXAMPLE NO. 88
4-{5-Methoxy-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H-indol-2--
yl}-phenol
[0181] Mp=87-90.degree. C.; .sup.1H NMR (DMSO), 9.67 (s, 1H), 7.16
(d, 2H, J=8.6 Hz), 7.16 (1H buried), 6.98 (d, 1H, J=2.4 Hz), 6.85
(d, 2H, J=8.6 Hz), 6.73 (s, 4H), 6.69 (dd, 1H, J=8.8, 2.4 Hz), 5.13
(s, 2H), 3.94 (t, 2H, J=5.7 Hz), 3.76 (s, 3H), 2.63-2.50 (m, 2H),
2.43-2.31 (m, 4H), 2.15 (s, 3H), 1.49-1.40 (m, 4H), 1.39-1.25 (m,
2H); IR (KBr), 3400 (br), 2920, 1610, 1520 cm.sup.-1; MS eI m/z
470; CHN calcd for C.sub.30H.sub.34N.sub.2O.sub.3+0.1 H.sub.2.
EXAMPLE NO. 89
2-(4-methoxy-phenyl)-3-methyl-1-{4-[2-(piperidin-1-yl)-ethoxy]-benzyl}-1H--
indol-5-ol
[0182] Mp=188-189.degree. C.; .sup.1H NMR (DMSO), 8.70 (s, 1H),
7.27 (d, 2H, J=8.6 Hz), 7.06 (d, 1H, J=8.6 Hz), 7.02 (d, 2H, J=8.8
Hz), 6.81 (d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.58 (dd, 1H, J=8.8, 2.4
Hz), 5.10 (s, 2H), 3.93 (t, 2H, J=5.9 Hz), 3.79 (s, 3H), 2.56 (t,
2H, J=5.9 Hz), 2.41-2.32 (m, 4H), 2.10 (s, 3H), 1.47-1.41 (m, 4H),
1.34-1.31 (m, 2H); MS eI m/z 470; CHN calcd for
C.sub.30H.sub.34N.sub.2O.sub.3+0.1 H.sub.2O.
EXAMPLE NO. 90
5-Methoxy-2-(4-methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-ben-
zyl]-1H-indole (HCL)
[0183] Mp=188-191.degree. C.; .sup.1H NMR (DMSO), 10.35 (brs, 1H),
7.27 (d, 2H, J=8.8 Hz), 7.17 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.6
Hz), 6.99 (d, 1H, J=2.5 Hz), 6.82-6.78 (m, 4H), 6.71 (dd, 1H, J=8.8
Hz, J=2.5 Hz), 5.17 (s, 2H), 4.31-4.22 (m, 2H), 3.79 (s, 3H), 3.76
(s, 3H), 3.43-3.36 (m, 4H), 2.97-2.83 (m, 2H), 2.16 (s, 3H),
1.80-1.59 (m, 5H), 1.41-1.26 (m, 1H); IR (KBr), 2920, 1450, 1250
cm-1; MS eI m/z 484 (M+); CHN calc for
C.sub.31H.sub.36N.sub.2O.sub.3+1 HCL.
EXAMPLE NO. 91
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3-methy-
l-1H-indole (HCL)
[0184] Mp=161-163.degree. C.; .sup.1H NMR (DMSO), 10.65 (brs, 1H),
7.27 (d, 2H, J=8.8 Hz), 7.17 (d, 1H, J=8.8 Hz), 7.03 (d, 2H, J=8.6
Hz), 6.99 (d, 1H, J=2.5 Hz), 6.82-6.77 (m, 4H), 6.71 (dd, 1H, J=8.8
Hz, J=2.5 Hz), 5.17 (s, 2H), 4.27 (m, 2H), 3.79 (s, 3H), 3.76 (s,
3H ), 3.44-3.30 (m, 4H), 3.17 (m, 2H), 2.16 (s, 3H), 1.82-1.77 (m,
4H), 1.63-1.48 (m, 4H); MS eI m/z 499 (M+); CHN calc for
C.sub.32H.sub.38N.sub.2O.sub.3+1 HCl.
EXAMPLE NO. 92
2-(4-Ethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-ind-
ol-5-ol
[0185] Mp=173-175.degree. C.; .sup.1H NMR (DMSO), 8.69 (s, 1H),
7.25 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.99 (dd, 2H, J=6.8
Hz, J=2.0 Hz), 6.80 (d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.59 (dd, 1H,
J=8.5 J=2.2), 5.09 (s, 2H), 4.05 (q, 2H, J=7.03 Hz), 3.93 (t, 2H,
J=6.0 Hz), 2.62-2.56 (m, 2H), 2.41-2.36 (m, 4H), 2.09 (s, 3H),
1.45-1.41 (m, 4H), 1.38-1.30 (m, 5H); MS eI m/z 484 (M+); CHN calc
for C.sub.31H.sub.36N.sub.20.sub.3+0.25H.sub.2O.
EXAMPLE NO. 93
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-ethoxy-phenyl)-3-methyl-1H-indol--
5-ol
[0186] Mp=133-135.degree. C.; .sup.1H NMR (DMSO), 8.69 (s, 1H),
7.25 (d, 2H, J=8.8 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.99 (dd, 2H, J=6.8
Hz, J=2.0 Hz), 6.80 (d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.59 (dd, 1H,
J=8.5 Hz, J=2.2 Hz), 5.09 (s, 2H), 4.05 (q, 2H, J=7.03 Hz), 3.90
(t, 2H, J=6.1 Hz), 2.75 (t, 2H, J=6.0 Hz), 2.62-2.58 (m, 4H), 2.09
(s, 3H), 1.58-1.44 (m, 8H), 1.33 (t, 3H, J=7.0 Hz); IR (KBr), 2930,
1470, 1250 CM.sup.-1; MS eI m/z 498 (M+); CHN calc for
C.sub.32H.sub.38N.sub.2O.sub.3.
EXAMPLE NO. 94
4-{5-Fluoro-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-indol-2-yl}-
-phenol (HCl)
[0187] Mp=223-225.degree. C.; .sup.1H NMR (DMSO), 10.30 (br s, 1H),
7.27-7.23 (m, 2H), 7.17 (d, 2H, J=8.6 Hz), 6.88-6.79 (m, 7H), 5.20
(s, 2H), 4.28 (t, 2H, J=5.0 Hz), 3.42-3.35 (m, 4H), 3.00-2.85 (m,
2H), 2.14 (s, 3H), 1.78-1.70 (m, 4H), 1.67-1.59 (m, 1H), 1.40-1.26
(m, 1H); MS eI m/z 458 (M+).
EXAMPLE No. 95
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-3-methyl-2-phenyl-1H-indol-5-ol
(HCl)
[0188] Mp=203-204.degree. C.; .sup.1H NMR (DMSO), 10.50 (brs, 1H),
8.80 (s, 1H), 7.50-7.38 (m, 5H); 7.10 (d, 1H, J=8.8 Hz), 6.83-6.77
(m, 5H), 6.60 (d, 1H, J=6.6 Hz), 5.15 (s, 2H ), 4.26 (t, 2H, J=5.2
Hz), 3.45-3.35 (m, 4H), 3.21-3.10 (m, 2H), 2.12 (s, 3H), 1.85-1.75
(m, 4H), 1.70-1.51 (m, 4H); MS eI m/z 454 (M+); CHN calc for
C.sub.30H.sub.34N.sub.2O.sub.2+1 HCl.
EXAMPLE NO. 96
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-pyrollidin-1-yl-ethoxy)-benzyl]-1H-i-
ndol-5-ol
[0189] Mp=105-110.degree. C.; CHN calc'd for
C.sub.28H.sub.30N.sub.2O.sub.3+0.4 H.sub.2O; .sup.1H NMR (DMSO),
9.65 (s, 1H), 8.67 (s, 1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H,
J=8.6 Hz), 6.84 (d, 2H, J=2H), 6.79 (d, 1H, J=2.4 Hz), 6.56 (dd,
1H, J=8.6, 2.2 Hz), 6.74 (s, 4H), 5.09 (s, 2H), 3.95 (t, 2H, J=5.7
Hz), 3.39-3.23 (m, 4H), 2.80-2.75 (m, 2H), 2.09 (s, 3H), 1.67-1.64
(m, 4H); IR (KBr), 3410 (br), 1620, 1510 cm.sup.-1; MS (EI) m/z
442
EXAMPLE NO. 97
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-
-5-ol (HCl)
[0190] Mp=168-171.degree. C.; .sup.1H NMR (DMSO), 10.11 (brs, 1H),
9.70 (s, 1H), 8.71 (s, 1H); 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H,
J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 6.80-6.77 (m, 5H), 6.56 (dd, 1H,
J=8.8 Hz, 2.2 Hz), 5.11 (s, 2H), 4.26 (t, 2H, J=4.6 Hz), 3.48-3.30
(m, 4H), 3.22-3.08 (m, 2H), 2.09 (s, 3H), 1.83-1.76 (m, 4H),
1.67-1.48 (m, 4H); IR (KBr), 3500 br, 3250 br, 2900, 1610; MS FAB
m/z 471 (M+H+); CHN calcd for C.sub.30H.sub.34N.sub.2O.sub.3+2.5
H.sub.2O+HCl.
EXAMPLE NO. 98
Acetate Salt of Example No. 97
[0191] Made by the precipitation of No. 97 free base from acetone
and acetic acid.
[0192] Mp=174-178.degree. C.
EXAMPLE NO. 99
1-[4-(2-Azocan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-
-5-ol
[0193] Mp=98-102.degree. C.; .sup.1H NMR (DMSO), 9.63 (s, 1H), 8.68
(s, 1H), 7.15-7.13 (m, 2H), 7.05 (d, 1H, J=8.5 Hz), 6.83 (dd, 2H,
J=2.0 Hz, 6.6 Hz), 6.79 (d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.55 (dd,
1H, J=2.2 Hz, 8.6 Hz), 5.08 (s, 2H), 3.89 (t, 2H, J=5.7 Hz), 2.74
(t, 2H, J=5.4 Hz), 2.55 (bs, 4H), 2.08 (s, 3H), 1.55 (s, 2H), 1.46
(s, 8H); IR 3400, 2900, 1250 cm.sup.-1; MS eI m/z 484 (M+); CHN
calcd for C.sub.31H.sub.36N.sub.2O.sub.3+0.30 H.sub.2O.
EXAMPLE NO. 100
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-dimethyl-1-yl-ethoxy)-benzyl]-1H-ind-
ol-5-ol
[0194] Mp=95-105.degree. C.; IR (KBr), 3400 br, 2900, 1610
cm.sup.-1; MS eI m/z 416 (M+); CHN calcd for
C.sub.26H.sub.28N.sub.2O.sub.3+0.5 H.sub.2O.
EXAMPLE NO. 101
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-diethyl-1-yl-ethoxy)-benzyl]-1H-indo-
l-5-ol
[0195] Mp=100-107.degree. C.; CHN calc'd for
C.sub.28H.sub.32N.sub.32N.sub.2O.sub.3+0.25 H.sub.2O; .sup.1H NMR
(DMSO), 9.64 (s, 1H), 8.67 (s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.05
(d, 1H, J=8.8 Hz), 6.84 (d, 2H, J=8.6 Hz), 6.79 (d, 1H, 2.2 Hz),
6.74 (s, 4H), 6.56 (dd, 1H, J=8.8, 2.4 Hz), 5.09 (s, 2H), 3.95-3.85
(m, 2H), 2.80-2.60 (m, 2H), 2.58-2.40 (m, 4H), 2.09 (s, 3H), 0.93
(t, 6H, J=7.0 Hz); IR (KBr), 3410 (br), 2950, 1610, 1510 cm.sup.-1;
MS FAB 445 (M+H+).
EXAMPLE NO. 102
1-[4-(2-Dipropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-ind-
ol-5-ol
[0196] Mp=83-86.degree. C.; .sup.1H NMR (DMSO), 9.64 (s, 1H), 8.67
(s, 1H), 7.14 (d, 2H, J=8.6), 7.04 (d, 1H, J=8.6 Hz), 6.83 (d, 2H,
J=8.6 Hz), 6.78 (d, 1H, J=2.2 Hz), 6.72 (m, 4H), 6.55 (dd, 1H,
J=2.4 Hz, 8.2 Hz), 5.08 (s, 2H), 3.88 (t, 2H, J=6.0 Hz), 2.80-2.63
(m, 2H), 2.59-2.45 (m, 4H), 2.10 (s, 3H), 1.41-1.30 (m, 4H), 0.79
(t 6H, J=7.3 Hz); IR 3400, 2900, 1250; MS FAB m/z 473 [M+H+]; CHN
calcd for C.sub.30H.sub.36N.sub.2O.sub.3+0.20 H.sub.2O.
EXAMPLE NO. 103
1-[4-(2-Dibutylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol
[0197] Foam; .sup.1H NMR (DMSO), 9.63 (s, 1H), 8.66 (s, 1H),
7.15(d, 2H, J=8.6 Hz), 7.05(d, 1H, J=8.8 Hz), 6.83 (d, 2H, J=8.6
Hz), 6.79 (d, 1H, J=4.2 Hz), 6.78-6.71 (m, 4H), 6.55 (dd, 1H, J=8.6
Hz, J=2.4 Hz), 5.10 (s, 2H), 3.88 (t, 2H, J=5.5 Hz), 2.68-2.62 (m,
2H), 2.42-2.34 (m, 4H), 2.08 (s, 3H), 1.38-1.19 (m, 8H), 0.82 (t,
6H, J=7.2 Hz); IR (KBr), 3400, 1450 cm-1; MS eI m/z 501 (M+).
EXAMPLE NO. 104
1-[4-(2-Diisopropylamino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H--
indol-5-ol
[0198] Mp=96-102.degree. C.; .sup.1H NMR (DMSO), 9.64 (s, 1H), 8.67
(s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.04 (d, 1H, J=8.6 Hz), 6.83 (d,
2H, J=8.6 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.77-6.69 (m, 4H), 6.56 (dd,
1H, J=8.6 Hz, 2.2 Hz), 5.08 (s, 2H), 3.75 (t, 2H, J=7.0 Hz),
3.01-2.92 (m, 2H), 2.67 (t, 2H, J=7.0 Hz), 2.09 (s, 3H), 0.93 (d,
12H, 6.6 Hz); IR (KBr), 3400 br, 2940, 1620 cm-1; MS FAB m/z 473
(M+H+); CHN calcd for C.sub.30H.sub.36N.sub.2O.sub.3+0.5
H.sub.2O.
EXAMPLE NO. 105
1-{4-[2-(Butyl-methyl-amino)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-3-methyl-
-1H-indol-5-ol
[0199] Mp=102-107.degree. C.; .sup.1H NMR (DMSO), 9.60 (s, 1H),
8.67 (s, 1H), 7.14 (d, 2H, J=8.4 Hz), 7.04 (d, 1H, J=8.6 Hz), 6.82
(d, 2H, J=8.8 Hz), 6.78 (d, 1H, J=2.3 Hz), 6.73 (s, 4H), 6.55 (dd,
1H, J=8.8 Hz, J=2.4 Hz), 5.08 (s, 2H), 3.92 (t, 2H, J=6.0 Hz),
2.64-2.59 (m, 2H), 2.38-2.29 (m, 2H), 2.20 (br s, 3H), 2.08 (s,
3H), 1.40-1.31 (m, 2H), 1.25-1.19 (m, 2H), 0.83 (t, 3H, 7.2 Hz); IR
(KBr), 3420, 1460, 1230 cm.sup.-1; MS eI m/z 638 (M+).
EXAMPLE NO. 108
2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(2-methyl-piperidin-1-yl)-ethoxy]-be-
nzyl}-1H-indol-5-ol
[0200] Mp=121-123.degree. C.; .sup.1H NMR (DMSO), 9.65 (s, 1H),
8.68 (s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.84
(d, 2H, J=8.6 Hz), 6.79 (d, 1H, J=2.0 Hz), 6.74 (s, 4H), 6.56 (dd,
1H, J=8.8 Hz, 2.4 Hz), 5.09 (s, 2H), 3.97-3.86 (m, 2H), 2.95-2.73
(m, 2H), 2.62-2.53 (m, 1H), 2.36-2.14 (m, 2H), 2.09 (s, 3H),
1.61-1.30 (m, 4H), 1.28-1.09 (m, 2H, 0.98 (d, 3H, J=5.1 Hz); IR
(KBr), 3400, 2920, 2850, 1610 cm.sup.-; CHN calcd for
H.sub.30N.sub.34N.sub.2O.sub.3+0.25 H.sub.2O.
EXAMPLE NO. 109
2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(3-methyl-piperdin-1-yl)-ethoxy]-ben-
zyl}-1H-indol-5-ol
[0201] Mp=121-123.degree. C.; .sup.1H NMR DMSO), 9.64 (s, 1H), 8.67
(s, 1H), 7.14 (dd, 2H, J=8.3 Hz, 1.4 Hz), 7.04 (dd, 1H, J=8.6 Hz,
1.2 Hz), 6.84 (dd, 2H, J=8.6 Hz, 1.7 Hz), 6.79 (s, 1H), 6.79 (s,
4H), 6.56 (d, 1H, J=8.6 Hz), 5.08 (s, 2H), 3.94 (t, 2H, J=5.0 Hz),
2.86-2.71 (m, 2H), 2.63-2.50 (m, 2H), 2.48 (s, 3H), 1.92-1.79 (m,
2H), 1.63-1.35 (m, 5H), 0.79 (d, 3H, J=5.2 Hz); IR (KBr), 3400,
2910, 1625 cm.sup.-1; CHN calcd for
C.sub.30H.sub.34N.sub.2O.sub.3+0.25 H.sub.2O.
EXAMPLE NO. 110
2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(4-methyl-piperidin-1-yl)-ethoxy]-be-
nzyl}1H-indol-5-ol (HCl)
[0202] Mp=154-162.degree. C.; .sup.1H NMR (DMSO), 10.00 (brs, 1H),
9.71 (s, 1H), 8.71 (s, 1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H,
J=8.6 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.83-6.77 (m, 4H), 6.57 (dd, 1H,
J=8.6 Hz, 2.2 Hz), 5.11 (s, 2H), 4.27 (t, 2H, J=4.8 Hz), 3.51-3.35
(m, 4H), 3.01-2.87 (m, 2H), 2.09 (s, 3H), 1.74 (d, 2H, J=13.4 Hz),
1.61-1.37 (m, 4H), 0.88 (d, 3H, J=6.4 Hz); IR (KBr), 3410, 2910,
1620 cm.sup.-1; MS eI m/z 470 (M+H+); CHN calcd for
C.sub.30H.sub.34N.sub.2O.sub.3+HCl+2 H.sub.2O.
EXAMPLE NO. 111
1-{4-[2-(3,3-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-phenyl)-
-3-methyl-1H-indol-5-ol
[0203] Mp=100.degree. C.; .sup.1H NMR (DMSO), 9.65 (s, 1H), 8.67
(s, 1H), 7.15 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.84 (d,
2H, J=8.6 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.74 (s, 4H), 6.56 (dd, 1H,
J=8.8, 2.4 Hz), 5.09 (s, 2H), 3.93 (t, 2H, J=5.7 Hz), 2.60-2.50 (m,
2H), 2.37-2.25 (m, 2H), 2.09 (s, 3H), 2.10-1.99 (m, 2H), 1.46 (t,
2H, J=5.9 Hz), 1.13 (t, 2H, J=6.4 Hz), 0.86 (s, 6H); MS eI m/z
484.
EXAMPLE NO. 112
1-{4-[2-((cis)-2,6-Dimethyl-piperidin-1-yl)-ethoxy]-benzyl}-2-(4-hydroxy-p-
henyl)-3-methyl-1H-indol-5-ol
[0204] Mp=114-121.degree. C.; .sup.1H NMR (DMSO), 9.62(s, 1H), 8.64
(s, 1H), 7.11 (d, 2H, J=8.6 Hz), 7.01 (d, 1H, J=8.6 Hz), 6.81 (d,
2H, J=8.8 Hz), 6.76 (d, 1H, J=2.2 Hz), 6.72-6.66 (m, 4H), 6.53 (dd,
1H, J=8.6 Hz, 2.2 Hz), 5.06 (s, 2H), 3.86-3.72 (m, 2H), 2.86-2.76
(m, 2H), 2.43-2.35 (m, 2H), 2.06 (s, 3H), 1.78-1.59 (m, 3H),
1.29-1.17 (m, 1H), 1.12-0.92 (m, 8H); IR (KBr), 3400 br, 2920, 1630
cm-1; MS FAB m/z 485 (M+H+); CHN calcd for
C.sub.31H.sub.36N.sub.2O.sub.3+0.1 acetone+0.75 H.sub.2O.
EXAMPLE NO. 113
2-(4-Hydroxy-phenyl)-1-{4-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-benzyl}-3--
methyl-1H-indol-5-ol
[0205] Mp=80-90.degree. C.; 1H NMR (DMSO), 9.66 (s, 1H), 8.68 (s,
1H), 7.15 (d, 2H, J=7.6 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.84 (dd, 2H,
J=2.0 Hz, 6.6 Hz), 6.78 (d, 1H, 2.2 Hz), 6.73 (s, 4H), 6.55 (dd,
1H, J=2.2 Hz, 8.6 Hz), 5.09 (s, 2H), 4.50 (d, 1H, J=4.2 Hz), 3.92
(t, 2H, J=5.8 Hz), 3.40 (m, 2H), 2.72 (m, 2H), 2.60 (m, 2H), 2.10
(s, 3H), 2.15-2.05 (m, 1H), 1.75-1.63 (m, 2H), 1.42-1.28 (m, 2H);
IR (KBr), 3400, 2900, 1250 cm.sup.-1; MS eI m/z 472 (M+); CHN
calcd. for C.sub.29H.sub.32N.sub.2O.sub.4+0.11
CH.sub.2Cl.sub.2.
EXAMPLE NO. 114
(1S,4R)-1-{4-[2-(2-Aza-bicyclo[2.2.1]hept-2-yl)-ethoxy]-benzyl}-2-(4-hydro-
xy-phenyl)-3-methyl-1H-indol-5-ol
[0206] Mp=125-130.degree. C.; .sup.1H NMR (DMSO), 965 (s, 1H), 8.67
(s, 1H), 7.13 (d, 2H, J=8.6 Hz), 7.04 (d, 1H, J=8.5 Hz), 6.83 (dd,
2H, J=2.0 Hz, 6.6 Hz); 6.78 (d, 1H, J=2.2 Hz), 6.73 (s, 4H), 6.55
(dd, 1H, J=2.2 Hz, 8.6 Hz), 5.08 (s, 2H), 3.95-3.8 (m, 2H),
2.90-2.70 (3H), 2.30-2.20 (m, 2H), 2.10 (s, 3H), 1.70-1.60 (m, 1H),
1.60-1.30 (m, 4H), 1.25-1.15 (m, 2H); IR (KBr), 3400, 2950, 1500;
MS (+), FAB m/z 469 [M+H]+; CHN calcd for
C.sub.30H.sub.32N.sub.2O.sub.3+0.34 EtOAc.
EXAMPLE NO. 115
2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[2-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1-
]-oct-6-yl-ethoxy]-benzyl}-1H-indol-5-ol
[0207] Mp=98-10020 C.; .sup.1H NMR (DMSO), 9.64 (s, 1H), 8.67 (s,
1H), 7.14 (d, 2H, J=8.6 Hz), 7.05 (d, 1H, J=8.6 Hz), 6.84 (d, 2H,
J=8.6 Hz), 6.79 (d, 1H, J=2.4 Hz), 6.75-6.69 (m, 4H), 6.56 (dd, 1H,
J=8.6 Hz, 2.4 Hz), 5.08 (s, 2H), 3.83 (t, 2H, J=5.9 Hz), 3.12-3.07
(m, 1H), 2.94-2.87 (m, 1H), 2.85 (d, 1H, J=9.2 Hz), 2.78-2.70 (m,
1H), 2.17 (d, 1H, J=9.2 Hz), 2.09 (s, 3H), 1.55-1.42 (m, 2H), 1.29
(q, 2H, J=13.6 Hz), 1.14 (s, 3H), 1.11-1.02 (m, 2H), 0.96 (s, 3H),
0.82 (s, 3H); IR (KBr), 3400 br, 2940, 2900, 1630 cm.sup.-1; MS ESI
m/z 525 (M+H+); CHN calcd for C.sub.34H.sub.40N.sub.2O.sub.3+0.5
H.sub.2O.
EXAMPLE NO. 116
2-(4-Fluoro-phenyl)-3-methyl-1-[4-(2-piperidine-1-yl-ethoxy)-benzyl]-1H-in-
dol-5-ol (HCl)
[0208] Mp=201-203.degree. C.; .sup.1H NMR (DMSO), 10.22 (s, 1H),
8.78 (s, 1H), 7.45-7.35 (m, 2H), 7.34-7.25 (m, 2H), 7.11 (d, 1H,
J=8.6 Hz), 6.90-6.70 (m, 5H), 6.61 (dd, 1H, J=2.4 Hz, 8.8 Hz), 5.15
(s, 2H), 4.27 (t, 2H, 4.8 Hz), 3.50-3.34 (m, 4H), 3.0-2.85 (m, 2H),
2.10 (s, 3H), 1.80 (m, 5H), 1.40-1.25 (m, 1H); MS eI m/z 458 (M+);
CHN calcd for C.sub.29H.sub.31FN.sub.2O.sub.2+1 HCl.
EXAMPLE NO. 117
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-fluoro-phenyl)-3-methyl-1H-indol--
5-ol
[0209] Mp=181-184.degree. C.; .sup.1H NMR (DMSO), 10.68 (s, 1H),
8.80 (s, 1H), 7.50-7.36 (m, 2H), 7.34-7.26 (m, 2H), 7.12 (d, 1H,
J=8.8 Hz), 6.86-6.73 (m, 5H), 6.63 (dd, 1H, J=2.2 Hz, 8.5 Hz), 5.13
(s, 2H), 4.29 (t, 2H, J=5.2 Hz), 3.50-3.30 (m, 4H), 3.20-3.08 (m,
2H), 2.11 (s, 3H), 1.90-1.70 (m, 4H), 1.68-1.45 (m, 4H); IR (KBr),
3500, 3100, 2910, 1450, 1250 cm.sup.-1; MS e/I m/z 472 (M+); CHN
calcd for C.sub.30H.sub.33FN.sub.2O.sub.2+1 HCl.
EXAMPLE NO. 118
2-(3-Methoxy-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-ben-
zyl]-1H-indol-5-ol (HCl)
[0210] Mp=161-163.degree. C.; .sup.1H NMR (DMSO), 10.12 (brs, 1H),
9.25 (s, 1H), 8.71 (s, 1H), 7.05 (d, 1H, J=8.5 Hz), 6.85-6.79 (m,
8H), 6.57 (dd, 1H, J=8.5 Hz, J=2.2 Hz), 5.13 (s, 2H), 4.27 (t, 2H,
J=5.0 Hz), 3.64 (s, 3H), 3.44-3.37 (m, 4H), 2.93-2.85 (m, 2H), 2.11
(s, 3H), 1.80-1.60 (m, 5H), 1.40-1.25 (m, 1H); MS eI m/z 486 (M+);
CHN calc for C.sub.30H.sub.34N.sub.2O.sub.4+1 HCL+1 H.sub.2O; IR
(KBr), 3190, 1470, 1230 cm.sup.-1.
EXAMPLE NO. 119
2-Benzo[1.3]dioxol-5-yl-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-
-indol-5-ol (HCL)
[0211] Mp=122-125.degree. C.; .sup.1H NMR (DMSO), 9.80 (brs, 1H),
8.73 (s, 1H), 7.07 (d, 1H, J=8.7 Hz), 7.02 (d, 1H, J=8.0 Hz), 6.89
(d, 1H, J=1.7 Hz), 6.80-6.75 (m, 6H), 6.58 (dd, 1H, J=6.4 Hz, J=2.2
Hz), 6.06 (s, 2H), 5.13 (s, 2H), 4.30-4.19 (m, 2H), 3.51-3.30 (m,
4H), 2.99-2.85 (m, 2H), 2.10 (s, 3H), 1.81-1.59 (m, 5H), 1.41-1.26
(m, 1H); MS eI m/z 484 (M+); CHN calc for
C.sub.30H.sub.32N.sub.2O.sub.4+HCl+0.26 H.sub.2O.
EXAMPLE NO. 120
2-(4-Isopropoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-
-indol-5-ol (HCl)
[0212] Mp=120-125.degree. C.; .sup.1H NMR (DMSO), 10.18 (s, 1H),
8.73 (s, 1H), 7.25 (d, 2H, J=8.6 Hz), 7.04 (d, 1H, J=8.8 Hz), 6.99
(d, 2H, J=8.8 Hz), 6.82-6.80 (m, 5H), 6.59 (dd, 1H, J=2.2 Hz, 8.6
Hz), 5.12 (s, 2H), 4.67-4.61 (m, 1H), 4.27 (t, 2H, J=4.8 Hz),
3.50-3.35 (m, 4H), 3.0-2.85 (m, 2H), 2.10 (s, 3H), 1.80-1.60 (m,
5H), 1.40-1.25 (m, 7H); IR (KBr), 3400, 3000, 1500, 1250; MS eI m/z
498 (M+); CHN calcd for C.sub.32H.sub.38N.sub.2O.sub.3+1.0 HCl+0.70
H.sub.2O.
EXAMPLE NO. 121
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-isopropoxy-phenyl)-3-methyl-1H-in-
dol-5-ol (HCl)
[0213] Mp=120-125.degree. C.; .sup.1H NMR (DMSO), 10.36 (s, 1H),
8.73 (s, 1H), 7.26-7.23 (m, 2H), 7.05 (d, 1H, J=8.8 Hz), 7.01-6.98
(m, 2H), 6.85-6.75 (m, 5H), 6.57 (dd, 1H, J=2.2 Hz, 8.6 Hz), 5.12
(s, 2H), 4.67-4.61 (m, 1H), 4.27 (t, 2H, J=4.8 Hz), 3.50-3.30 (m,
4H), 3.20-3.10 (m, 2H), 2.10 (s, 3H), 1.85-1.75 (m, 4H), 1.65-1.50
(m, 4H), 1.27 (d, 6H, J=6.1 Hz); IR (KBr), 3400, 1500, 1250: MS eI
m/z 512 (M+); Calcd for C.sub.33H.sub.40N.sub.2O.sub.3+1.0 HCl+0.5
H.sub.2O.
EXAMPLE NO. 122
2-(4-Cyclopenyloxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-
-1H-indol-5-ol
[0214] Mp=121-135.degree. C.; .sup.1H NMR (DMSO), 9.80 (br s, 1H),
8.72 (s, 1H), 7.24 (d, 2H, J=8.8 Hz), 7.05 (d, 1H, J=8.8 Hz), 6.98
(d, 2H, J=8.8 Hz), 6.83-6.78 (m, 5H), 6.57 (dd, 1H, J=8.8 Hz, 2.4
Hz), 5.13 (s, 2H, 4.86-4.82 (m, 1H), 4.25 (t, 2H, J=4.8 Hz),
3.50-3.38 (m, 4H), 2.92 (q, 2H, J=8.8 Hz), 2.11 (s, 3H), 1.98-1.85
(m, 2H), 1.81-1.56 (m, 11H), 1.41-1.29 (m, 1H); IR (KBr), 3400,
2920, 1620 cm-1; MS eI m/z 524 (M+); CHN calcd for
C.sub.34H.sub.40N.sub.2O.sub.3+0.5 H.sub.2O.
EXAMPLE NO. 123
3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethyl-pheny-
l)-1H-indol-5-ol
[0215] Mp=174.degree. C.; .sup.1H NMR (DMSO), 8.8 (s, 1H), 7.82 (d,
2H, J=8.1 Hz), 7.59 (d, 2H, J=7.9 Hz), 7.17 (d, 1H, J=8.6 Hz), 6.86
(d, 1H, J=2.4 Hz), 6.75-6.68 (m, 4H), 6.65 (dd, 1H, J=8.8 Hz, 2.4
Hz), 5.16 (s, 2H), 3.93 (t, 2H, J=5.7 Hz), 2.62-2.56 (m, 2H),
2.42-2.32 (m, 4H), 2.15 (s, 3H), 1.48-1.40 (m, 4H), 1.39-1.29 (m,
2H); IR (KBr), 3410, 2910, 2850, 1620 cm-1; MS eI m/z 508 (M+); CHN
calcd for C.sub.30H.sub.31F.sub.3N.sub.2O.sub.20.25 H.sub.2O.
EXAMPLE NO. 124
3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-p-tolyl-1H-indol-5-ol
[0216] Mp=162-164.degree. C.; .sup.1H NMR (DMSO), 8.70 (s, 1H),
7.28-7.24 (m, 4H), 7.07 (d, 1H, J=8.4 Hz), 6.81 (d, 1H, J=2.2 Hz),
6.73 (s, 4H), 6.58 (dd, 1H, J=2.4 Hz, 8.8 Hz), 5.11 (s, 2H), 3.92
(t, 2H, J=5.9 Hz), 2.55 (t, 2H, J=5.9 Hz), 2.45-2.30 (m, 7H), 2.10
(s, 3H), 1.50-1.40 (m, 4H), 1.48-1.35 (m, 2H); IR (KBr), 3400,
2900, 1200; MS eI m/z 454 (M+); CHN calcd for
C.sub.30H.sub.34N.sub.2O.sub.2.
EXAMPLE NO. 125
2-(4-Chloro-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-ind-
ol-5-ol (HCL)
[0217] Mp=161-164.degree. C.; .sup.1H NMR (DMSO), 10.12 (brs, 1H),
8.80 (s, 1H), 7.53 (d, 2H, J=8.3 Hz), 7.36 (d, 2H, J=8.8 Hz), 7.12
(d, 1H, J=8.8 Hz), 6.85-6.75 (m, 5H), 6.63 (dd, 1H, J=8.8 Hz, J=2.4
Hz), 5.14 (s 2H), 4.29-4.22 (m, 2H), 3.45-3.36 (m, 4H), 2.97-2.84
(m, 2H), 2.11 (s, 3H), 1.83-1.61 (m, 5H), 1.37-1.25 (m, 1H); MS eI
m/z 475 (M+); CHN calc for
C.sub.29H.sub.31ClN.sub.2O.sub.2+HCL+0.25 H.sub.2O.
EXAMPLE NO. 126
2-(2,4-Dimethoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1-
H-indol-5-ol
[0218] Mp=85-92.degree. C.; .sup.1H NMR (DMSO), 8.62 (s, 1H), 7.10
(d, 1H, J=8.4 Hz), 7.01 (d, 1H, J=8.6 Hz), 6.80-6.70 (m, 5H), 6.69
(d, 1H, 2.2 Hz), 6.59 (dd, 1H, J=2.4 Hz, 8.5 Hz), 6.52 (dd, 1H,
J=2.4 Hz, 8.8 Hz), 5.02 (d, 1H, J=6.5 Hz), 4.83 (d, 1H, J=6.3 Hz),
4.0-3.90 (m, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 2.65-2.50 (m, 2H),
2.45-2.30 (m, 4H), 2.0 (s, 3H), 1.55-1.40 (m, 4H), 1.39-1.30 (m,
2H); IR (KBr), 3400, 2900, 1520, 1250; MS eI m/z 500 (M+); CHN
calcd for C.sub.31H.sub.36N.sub.2O.sub.4+0.05 CH.sub.2Cl.sub.2.
EXAMPLE NO. 127
2-(3-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in-
dol-5-ol
[0219] Mp=115-118.degree. C.; .sup.1H NMR (DMSO), 9.57 (s, 1H),
8.71 (s, 1H), 7.27-7.23 (t, 1H, J=8.1 Hz), 7.06-7.04 (d, 1H, J=8.8
Hz), 6.81-6.74 (m, 8H), 6.59-6.56 (dd, 1H, J=2.3 Hz, J=6.3 Hz),
5.12 (s, 2H), 3.94-3.91 (t, 2H, J=5.9 Hz), 2.57-2.54 (t, 2H, J=5.8
Hz), 2.36 (s, 4H), 2.11 (s, 3H), 1.45-1.41 (m, 4H), 1.34-1.33 (m,
2H); IR (KBr), 3400, 2900 cm.sup.-1; MS eI m/z 456 (M+); CHN calcd
for C.sub.29H.sub.32N.sub.2O.sub.3+1.0 H.sub.2O.
EXAMPLE NO. 128
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(3-hydroxy-phenyl)-3-methyl-1H-indol-
e-5-ol
[0220] Mp=94-97.degree. C.; .sup.1H NMR (DMSO), 9.58 (s, 1H), 8.71
(s, 1H), 7.27-7.23 (t, 1H, J=7.9 Hz), 7.07-7.04(d, 1H, J=8.7 Hz),
6.81-6.74 (m, 8H), 6.59-6.56 (dd, 1H, J=2.4 Hz, J=6.3 Hz), 5.12 (s,
2H), 3.9 (m, 2H), 2.80 (s, 2H), 2.65 (s, 4H), 2.11 (s, 3H),
1.54-1.50 (m, 8H); IR 3400, 2900 cm.sup.-1; MS eI m/z 470 (M+); CHN
calcd for C.sub.30H.sub.34N.sub.2O.sub.3+0.75 H.sub.2O+0.23 Ethyl
Acetate.
EXAMPLE NO. 129
2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benz-
yl]-1H-indol-5-ol
[0221] Mp=117-119.degree. C.; .sup.1H NMR (DMSO), 10.1 (s, 1H),
8.71 (s, 1H), 7.10-6.95 (m, 4H), 6.80 (d, 1H, J=2.2 Hz), 6.74 (s,
4H), 6.59 (dd, 1H, J=2.2 Hz, 8.5 Hz), 5.1 (s, 2H), 3.93 (t, 2H,
J=5.9 Hz), 2.56 (t, 2H, J=5.8 Hz), 2.44-2.30 (m, 4H), 2.10 (s, 3H),
1.45-1.40 (m, 4H), 1.36-1.32 (m, 2H); MS eI m/Z 475 (M+); CHN calcd
for C.sub.29H.sub.31FN.sub.2O.sub.3.
EXAMPLE NO. 130
2-(3-Fluoro-4-hydroxy-phenyl)-3-methyl-1-[4-(azepan-1-yl-ethoxy)-benzyl]-1-
H-indol-5-ol
[0222] Mp=88-91.degree. C.; .sup.1NMR (DMSO), 10.10 (s, 1H), 8.71
(s, 1H), 7.12-6.94 (m,4H), 6.80 (d, 1H, J=2.2 Hz), 6.74 (s, 4H),
6.58 (dd, 1H, J=2.2 Hz, 8.5 Hz), 5.10 (s, 2H), 3.91 (t, 2H, J=5.9
Hz), 2.76 (t, 2H, J=5.9), 2.62-2.60 (m, 4H), 2.10 (s, 3H),
1.70-1.40 (m, 8H); MS eI m/Z 488 (M+); CHN calcd for
C.sub.30H.sub.33FN.sub.2O.sub.3.
EXAMPLE NO. 131
2-(3-Methoxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-in-
dole-5-ol
[0223] Mp=120-123.degree. C.; .sup.1H NMR (DMSO), 8.76 (s, 1H),
7.42-7.46 (t, 1H, J=7.9 Hz), 7.12-7.09 (d, 1H, J=8.7 Hz), 6.99-6.92
(m, 2H), 6.86-6.83 (m, 2H), 6.76 (s, 4H), 6.63-6.60 (dd, 1H, J=2.1
Hz, J=6.5 Hz), 5.14 (s, 2H), 3.96-3.92 (t, 2H, J=5.9 Hz), 3.70 (s,
3H), 2.59-2.55 (t, 2H, J=5.9 Hz), 2.37 (s, 4H), 2.14 (s, 3H),
1.49-1.44 (m, 4H), 1.35-1.34 (m, 2H); IR 3400, 2950, 1600
cm.sup.-1; MS eI m/z 471 (M+); CHN calcd for
C.sub.30H.sub.34N.sub.2O.sub.3.
EXAMPLE NO. 132
3-Methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-2-(4-trifluoromethoxy-phen-
yl)-1H-indole-5-ol
[0224] Mp=122-125.degree. C.; .sup.1H NMR (DMSO), 8.80 (s, 1H),
7.51-7.45 (m, 4H), 7.17-7.14 (d, 1H, J=8.7 Hz), 6.85-6.84 (d, 1H,
J=2.0 Hz), 6.75-6.69 (m, 4H), 6.66-6.62 (m, 1H), 5.14 (s, 2H),
3.95-3.92 (t, 2H, J=5.8 Hz), 2.59-2.55 (t, 2H, J=5.6 Hz), 2.49-2.38
(m, 4H), 2.13 (s, 3H), 1.47-1.44 (m, 4H), 1.36-1.34 (d, 2H, J=4.8
Hz); IR 3400, 2900, 1600 cm.sup.-1; MS eI m/z 525 (M+); CHN calcd
for C.sub.30H.sub.31F.sub.3N.sub.2O.sub.3+0.25 H.sub.2O.
[0225] Synthetic Procedures and Physical Data for Compounds
Substituted with Chloro, ethyl or cyano Groups at the 3-Position of
the indole TABLE-US-00008 TABLE 8 ##STR98## Example No. X O Z No.
133 Cl H ##STR99## No. 134 Cl H ##STR100## No. 135 Cl H ##STR101##
No. 136 Cl CH.sub.3 ##STR102## No. 137 Et H ##STR103## No. 138 CN H
##STR104## No. 139 CN H ##STR105##
Synthesis of 3-chloro Analogues No. 133-No. 136
[0226] ##STR106##
EXAMPLE NO. 140
Formation of hydrazone
[0227] 4-Benzyloxyphenylhydrazine CAS No. [51145-58-5] (50.0 g,
233.4 mmol) was mixed with 4-benzyloxyacetophenone CAS No.
[54696-05-8] (63.0 g, 280.0 mmol) in pure ethanol (800 mL). A
catalytic amount of acetic acid (5 drops) was added. The reaction
was heated to reflux for 2.5 hrs. During the course of refluxing,
the condensed product solidified out of the hot solution. The
reaction was cooled down to rt. The desired product was collected
by vacuum filtration as a light yellow solid (85 g, 86%).
Mp=165-174.degree. C.; .sup.1H NMR (DMSO), 8.91 (s, 1H), 7.68 (d,
2H, J=8.8 Hz), 7.48-7.32 (m, 10H), 7.12 (d, 2H, J=9 Hz), 7.00 (d,
2H, J=8.8 Hz), 6.88 (d, 2H, J=9.0 Hz), 5.11 (s, 2H), 5.01 (s, 2H),
2.17 (s, 3H); MS eI m/z 422 (M+).
EXAMPLE NO. 141
Formation of indole from hydrazone
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indole
[0228] A flask was charged with
N-(4-Benzyloxy-phenyl)-N'-[1-(4-benzyloxy-phenyl)-ethylidene]-hydrazine
(No. 140) (10.0 g, 23.7 mmol), ZnCl.sub.2 (8.06 g, 59.17 mmol),
acetic acid (70 mL). The reaction flask was heated to 105.degree.
C. for no more than 20 min. During the heating period, the reaction
was monitored carefully by TLC for the disappearance of the
starting material. The progress of the reaction could be shown as
the product solidified out of the solution while heating. The
reaction was then cooled to rt and more product crashed out was
observed. The reaction content was poured into a separatory funnel
containing ether (100 mL) and H.sub.2O (200 mL), which was shaken
vigorously. The insoluble residue as the desired product stayed in
the ether layer which was collected by vacuum filtration. The
product was further purified by trituration in ether to give a
light gray solid (4.4 g, 46%)
[0229] Mp=202-204.degree. C.; .sup.1H NMR (DMSO), 11.24 (s, 1H),
7.73 (d, 2H, J=8.8 Hz), 7.48-7.41 (m, 4H), 7.45-7.27 (m, 6H), 7.25
(d, 1H, J=8.6 Hz), 7.12-7.04 (m, 3H), 6.77 (dd, 1H, J=2.4 Hz, 8.6
Hz), 6.65 (d, 1H, J=1.5 Hz), 5.14 (s, 2H), 5.08 (s, 2H); IR 3420,
3000, 1625 cm.sup.-1; MS eI m/z 405 (M+); CHN calcd for
C.sub.28H.sub.23NO.sub.2+0.40 H.sub.2O.
EXAMPLE NO. 142
Chlorination of indole to Render
5-Benzyloxy-3-chloro-2-(4-benzyloxy-phenyl)-1H-indole
[0230] A flask was charged with
5-Benzyloxy-2-4-benzyloxy-phenyl)-1H-indole No. 141 (8.0 g, 20.0
nmole) and CH.sub.2Cl.sub.2 (50 ml). The reaction was cooled to
0.degree. C. and n-chlorosuccinimide (2.9 g, 22 mmole) was added.
The reaction was stirred at 0.degree. C. for 20 min. The reaction
was then washed with 10% sodium sulfite solution, dried over
MgSO.sub.4, and concentrated. To the resulting brown solid was
added MeOH and the mixture was stirred for 15 min. The solid was
filtered to give 6.8 g of a tan solid (78%).
[0231] Mp=157-160.degree. C.; .sup.1H NMR (DMSO), 11.5 (s, 1H),
7.80 (d, 2H, J=7.0 Hz), 7.42-7.28 (m, 11H), 7.17 (d, 2H, J=8.7 Hz),
7.01 (d, 1H, J=2.2 Hz), 6.88 (dd, 1H, J=8.8 Hz, J=2.4 Hz), 5.17 (s,
2H), 5.13 (s, 2H); MS eI m/z 439 (M+).
EXAMPLE NO. 143
5-Benzyloxy-3-chloro-2-(2-methyl-4-benzyloxy-phenyl)-1H-indole
[0232] This indole synthesized analogously to indole No. 142
immediately preceding: Mp=.sup.1H NMR (DMSO), 11.34 (s, 1H),
7.48-7.44 (m, 4H), 7.42-7.24 (m, 8H), 7.02 (dd, 2H, J=9.3 Hz, J=2.4
Hz), 6.95 (dd, 1H, J=8.4 Hz, J=2.6 Hz), 6.88 (dd, 1H, J=8.8 Hz,
J=2.4 Hz), 5.16 (s, 2H), 5.14 (s, 2H), 2.23 (s, 3H); MS eI m/z 453
(M+).
EXAMPLE NO. 144
Alkylation of indole to give
{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-indol-1-ylmethyl]-phenoxy-
}-acetic acid ethyl ester
[0233] This procedure was performed analogously to that outlined
for the synthesis of 3-methyl indole acetic acid ethyl esters
outlined in method 3.
[0234] Mp=90-94.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 4H, J=7.8
Hz), 7.41-7.26 (m, 9H), 7.14 (d, 2H, J=8.7 Hz), 7.04 (d, 1H, J=2.4
Hz), 6.91 (dd, 1H, J=9.0 Hz, J=2.5 Hz), 6.80-6.74 (m, 4H), 5.24 (s,
2H), 5.15 (s, 2H), 5.14 (s, 2H), 4.66 (s, 2H), 4.12 (q, 2H, J=7.2
Hz), 1.16 (t, 3H, J=7.5 Hz); MS eI m/z 631 (M+).
EXAMPLE NO. 145
Reduction of No. 144 to render No. 145
2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-indol-1-ylmethyl]-pheno-
xy}-ethanol
[0235] This reaction was performed analogously to that outlined for
the synthesis of 3-methyl indoles outlined in method 4. Compound
was not purified or characterized, but used as obtained for the
next step.
EXAMPLE NO. 146
Bromination of No. 145 to render
Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-chloro-1-
H-indole
[0236] This reaction was performed analogously to that outlined for
the synthesis of 3-methyl indoles outlined in method 5.
Mp=155-158.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 4H, J=7.8 Hz),
7.41-7.25 (m, 9H), 7.14 (d, 2H, J=8.7 Hz), 7.04 (d, 1H, J=2.4 Hz),
6.91 (dd, 1H, J=9.0 Hz, J=2.5 Hz), 6.74 (s, 4H), 5.24 (s, 2H), 5.15
(s, 2H), 5.14 (s, 2H), 4.20 (t, 2H, J=5.3 Hz), 3.74 (t, 2H, J=5.3
Hz); MS eI m/z 651 (M+).
EXAMPLE NO. 147
Substitution of No. 146 with piperidine to render
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1yl-ethoxy)-
-benzyl]-1H-indole
[0237] This reaction performed analogously to that outlined for the
synthesis of 3-methyl indoles outlined in method 6, using
piperidine to substitute the bromide.
[0238] Mp=96-98.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 4H, J=7.8
Hz), 7.40-7.30 (m, 9H), 7.14 (d, 2H, J=8.7 Hz), 7.04 (d, 1H, J=2.4
Hz), 6.91 (dd, 1H, J=9.0 Hz, J=2.5 Hz), 6.74 (s, 4H), 5.24 (s, 2H),
5.15 (s, 2H), 5.14 (s, 2H), 3.93 (t, 2H, J=6.0 Hz), 2.56 (t, 2H,
J=6.0 Hz), 2.41-2.32 (m, 4H), 1.48-1.39 (m, 4H), 1.38-1.31 (m,
2H).
EXAMPLE NO. 148
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-chloro-1-[4-(2-azepan-1-yl-ethoxy)-be-
nzyl]-1H-indole
[0239] Reaction performed the same as above except the substituting
amine used was hexamethyleneamine.
[0240] Mp=94-97.degree. C.; .sup.1H NMR (DMSO), 7.45 (d, 4H, J=7.8
Hz), 7.42-7.30 (m, 9H), 7.14 (d, 2H, J=8.7 Hz), 7.04 (d, 1H, J=2.4
Hz ), 6.91 (dd, 1H, J=9.0 Hz, J=2.5 Hz), 6.74 (s, 4H), 5.24 (s,
2H), 5.15 (s, 2H), 5.14 (s, 2H), 3.93 (t, 2H, J=6.0 Hz), 2.75 (t,
2H, J=6.0 Hz), 2.63-2.59 (m, 4H), 1.58-1.44 (m, 8H); MS eI m/z 671
(M+).
EXAMPLE NO. 149
5-Benzyloxy-2-(2-methyl-4-benzyloxy-phenyl)-3-chloro-1-[4-(2-piperidin-1-y-
l-ethoxy)-benzyl]-1H-indole
[0241] Reactions to make this compound analogous to those used to
make No. 147.
[0242] Oil; .sup.1H NMR (DMSO), 7.50-7.29 (m, 11H), 7.17 (d, 1H,
J=8.4 Hz), 7.05 (d, 1H, J=2.4 Hz), 7.02 (d, 1H, J=2.4 Hz),
6.93-6.85 (m, 2H), 6.75-6.65 (m, 4H), 5.14 (s, 2H), 5.13 (s, 2H),
5.07 (m, 2H), 3.92 (t, 2H, J=5.9 Hz), 2.55 (t, 2H, J=5.9 Hz),
2.42-2.29 (m, 4H), 1.94 (s, 3H), 1.44-1.40 (m, 4H), 1.38-1.34 (m,
2H).
EXAMPLE NO. 133
3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)-benzyl]-1H-i-
ndol-5-ol (Hcl)
[0243] Synthesized as described for example No. 134.
[0244] Mp=233-235.degree. C.; .sup.1H NMR (DMSO), 10.50 (s, 1H),
9.88 (s, 1H), 9.01 (s, 1H), 7.30-7.20 (m, 3H), 6.90-6.80 (m, 7H),
6.68 (dd, 1H, J=2.4, Hz, 8.8 Hz), 5.20 (s, 2H), 4.22 (t, 2H, J=4.8
Hz), 3.47 (t, 2H, J=4.8 Hz), 3.10 (bm, 4H), 1.90 (s, 4H); IR (KBr),
3400, 1625, 1475, 825 cm.sup.-1; MS eI m/z 462 (M+); CHN calcd for
C.sub.2H.sub.27ClN.sub.2O.sub.3+1 HCl+0.75 H.sub.2O.
EXAMPLE NO. 134
Removal of benzyl ethers to render
3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i-
ndol-5ol (HCl)
[0245] Benzyl ethers were removed analogously to that procedure
outlined for 3-methyl indoles outlined in method 7. This compound
was then converted to the hydrochloride salt as described
previously in method 8; Mp=207-209.degree. C.; .sup.1H NMR (DMSO),
10.10 (bs, 1H), 9.86 (s, 1H), 9.07 (s, 1H), 7.26 (d,2H, J=8.6 Hz),
7.22 (d, 1H, J=8.8 Hz), 6.87 (d, 2H, J=8.6 Hz), 6.81-6.78 (m, 5H),
6.65 (dd, 1H, J=8.8 Hz, J=2.2 Hz), 5.20 (s, 2H), 4.27 (t, 2H, J=5.0
Hz), 3.44-3.37 (m, 4H), 3.00-2.85 (m, 2H), 1.81-1.60 (m, 5H),
1.41-1.26 (m, 1H); IR (KBr), 3350, 1470, 1250 CM-1; MS eI m/z 476
(M+); CHN calc for C.sub.28H.sub.29ClN.sub.2O.sub.3+HCL+1.5
H.sub.2O.
EXAMPLE NO. 135
3-Chloro-2-(4-hydroxy-phenyl)-1-[4-(2-azepan-1yl-ethoxy)-benzyl]-1H-indol--
5-ol (Hcl)
[0246] Synthesized as described for No. 134.
[0247] Mp=196-198.degree. C.; .sup.1H NMR (DMSO), 10.10 (brs, 1H),
9.86 (s, 1H), 9.07 (s, 1H), 7.26 (d, 2H, J=8.8 Hz), 7.22 (d, 1H,
J=9.0 Hz), 6.87 (d, 2H, J=8.6 Hz), 6.84-6.78 (m, 5H), 6.65 (dd, 1H,
J=8.8 Hz, J=2.2 Hz), 5.20 (s, 2H), 4.27 (t, 2H, J=5.0 Hz),
3.45-3.30 (m, 4H), 3.21-3.10 (m, 2H), 1.82-1.76 (m, 4H), 1.65-1.46
(m, 4H); MS eI m/z 491 (M+); CHN calc for
C.sub.29H.sub.31ClN.sub.2O.sub.3+1 HCl+0.37 H.sub.2O; IR (KBr),
3400, 3200, 1450, 1125
EXAMPLE NO. 136
3-Chloro-2-(4-hydroxy-2-methyl-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benz-
yl]-1H-indol-5-ol
[0248] Synthesized as described for No. 134 except the compound was
not converted into a salt.
[0249] Foam; .sup.1H NMR (DMSO), 9.64 (s, 1H), 9.01 (s, 1H), 7.25
(d, 1H, J=8.8 Hz), 7.03 (d, 1H, J=8.1 Hz), 6.79 (d, 1H, J=2.4 Hz),
6.78-6.65 (m, 7H), 5.06-4.92 (m, 2H), 3.94 (t, 2H, J=5.9 Hz),
2.62-2.57 (m, 2H), 2.42-2.32 (m, 4H), 1.90 (s, 3H), 1.48-1.40 (m,
4H), 1.40-1.32 (m, 2H); MS eI m/z 490 (M+); IR (KBr), 3430, 2900,
1450 cm.sup.-1; CHN calc for C.sub.29H.sub.31ClN.sub.2O.sub.3+1.0
H.sub.2O.
Synthesis of 3-ethylindole Analogue No. 137
[0250] This compound was synthesized in exact analogy to the
example given for 3-methylindoles, supra, using methods a and 2-8.
The only difference is that the starting material used is
4'-(benzyloxy)-Butyrophenone CAS No. [26945-71-1] instead of
4'-(benzyloxy)-Propiophenone. Data for intermediates is as
follows.
EXAMPLE NO. 150
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1H-indole
[0251] Mp=101-108.degree. C.; MS eI m/z 433 (M+).
EXAMPLE NO. 151
{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-indol-1-ylmethyl]-phenoxy}--
acetic acid ethyl ester
[0252] Mp=72-75.degree. C.; MS eI m/z 625 (M+).
EXAMPLE NO. 152
2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-indol-1-ylmethyl]-phenoxy-
}-ethanol
[0253] Mp=105-113.degree. C.; MS eI m/z 583 (M+).
EXAMPLE NO. 153
Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-ethyl-1H--
indole
[0254] Mp=140.degree. C. (decomp.); MS eI m/z 647, 645 (M+, Br
present).
EXAMPLE NO. 154
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)--
benzyl]-1H-indole
[0255] Mp=92-96.degree. C.; .sup.1H NMR (DMSO), 7.47 (d, 4H, J=7.2
Hz), 7.42-7.39 (m, 4H), 7.36-7.30 (m, 2H), 7.27 (d, 2H, J=8.6 Hz),
7.18 (d, 1H, J=8.8 Hz), 7.14 (d, 1H, J=2.4 Hz), 7.10 (d, 2H, J=8.8
Hz), 6.79 (dd, 1H, J=8.8 Hz, 2.2 Hz), 6.73 (s, 4H), 5.13 (s, 2H),
5.11 (s, 4H), 3.93 (t, 2H, J=5.9 Hz), 2.62-2.53 (m, 4H), 2.40-2.33
(m, 4H), 1.49-1.42 (m, 4H), 1.37-1.30 (m, 2H), 1.10 (t, 3H, J=7.2
Hz); MS eI m/z 650 (M+H+).
EXAMPLE NO. 137
2-(4-Hydroxy-phenyl)-3-ethyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-ind-
ol-5-ol (HCl)
[0256] Mp=160-164.degree. C.; .sup.1H NMR (DMSO), 9.78 (br s, 1H),
9.69 (s, 1H), 8.69 (s, 1H), 7.14 (d, 2H, J=8.6 Hz), 7.05 (d, 1H,
J=8.6 Hz), 6.87-6.78 (m, 7H), 6.56 (dd, 1H, J=8.8 Hz, 2.4 Hz), 5.08
(s, 2H), 4.25 (t, 2H, J=4.4 Hz), 3.45-3.38 (m, 5H), 3.00-2.86 (m,
2H), 2.57-2.50 (m, 2H), 1.83-1.59 (m, 5H), 1.41-1.28 (m, 1H), 1.10
(t, 2H, J=7.5 Hz); IR (KBr), 3400 br, 3200 br, 2920, 1610 cm-1; MS
eI m/z 470 (M+); CHN calcd for
C.sub.30H.sub.34N.sub.2O.sub.3+HCl+1.5 H.sub.2O. ##STR107##
EXAMPLE NO. 155
5-Benzyloxy-3-cyano-2-(4-benzyloxy-phenyl)-1H-indole
[0257] In a reaction flask
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1H-indole No. 141 (5.90 g, 14.6
mmol) was mixed with CH.sub.2Cl.sub.2 (90 mL) was cooled down to
0.degree. C. (the starting material did not completely dissolve in
CH.sub.2Cl.sub.2). While stirring vigorously, a solution of
chlorosulfonyl isocyanate (2.26 g, 16.0 mmol) in CH.sub.2Cl.sub.2
(25 mL) was added dropwise over a period of 45 min The reaction was
run at 0.degree. C. for 2 Hrs while detected by TLC for the
formation of the insoluble N-chlorosulfonylamide intermediate.
After this period, Et.sub.3N (1.47 g, 14.6 mL) in CH.sub.2Cl.sub.2
(25 mL) was added dropwise over 45 min at 0.degree. C. The
insoluble residue became soluble in the reaction solvent as the
Et.sub.3N addition was approaching completion. The reaction was let
go for the additional 1 hr at 0.degree. C. and 2 hrs at rt. The
progress of the reaction could be observed by the insoluble solid
formation of the product as the reaction time went on. The solvent
was stripped down and the solid residue purified by trituration
with methanol to yield (4.0 g, 63.8%). Mp=238-242.degree. C.;
.sup.1H NMR (DMSO), 12.31 (s, 1H), 7.88 (d, 2H, J=8.8 Hz), 7.48 (d,
4H, J=7.25 Hz), 7.55-7.30 (m, 7H), 7.23 (d, 2H, J=8.8 Hz), 7.14 (d,
1H, J=2.4 Hz), 6.97 (dd, 1H, J=2.2 Hz, 8.8 Hz), 5.20 (s, 2H), 5.17
(s, 2H); MS eI m/z 430 (M+).
EXAMPLE NO. 156
4-(2-Chloroethoxy)benzylbromide
[0258] To 4-(2-Chloroethoxy)benzylalcohol CAS No. [111728-87-1]
(6.4 g, 34.31 mmol) in dioxane (100 mL) at 0.degree. C. was added
slowly thionylbromide (7.13 g, 34.31 mmol). The reaction was run at
0.degree. C. after 5 min. The reaction mixture was diluted with
ether (200 mL) and washed with H.sub.2O (1.times.30 mL) then
NaHCO.sub.3 (2.times.25 mL), and brine (30 mL). The organic extract
was dried over MgSO.sub.4 and concentrated. The crude product was
purified by silica gel chromatography (15% EtOAc/Hex) to yield 5.0
g (58%) of the desired product. Mp=64-66.degree. C.; .sup.1H NMR
(DMSO), 7.37 (d, 2H, J=8.8 Hz), 6.93 (d, 2H, J=8.8 Hz), 4.68 (s,
2H), 4.24 (t, 2H, J=5.05 Hz), 3.93 (t, 2H, J=5.27 Hz); MS eI m/z
248 (M+).
EXAMPLE NO. 157
Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-chloro-ethoxy)-benzyl]-3-cyano-1H-
-indole
[0259] In a reaction flask the 3-cyano indole starting material No.
155 (2.86 g. 6.64 mmol) was dissolved in DMF (25 mL) at 0.degree.
C. was added NaH (191.2 mg, 8 mmol) slowly. The reaction was
stirred at 0.degree. C. for 20 min. In a separate reaction flask
containing 4-(2-Chloroethoxy)benzylbromide No. 156 (1.81 g, 7.28
mmol) in DMF (15 mL) at 0.degree. C., the above prepared indole
anion solution taken up by syringe was added slowly. The reaction
was stirred at 0.degree. C. for 20 min and promoted to rt for 1 H.
The reaction was quenched with a few drops of H.sub.2O. The
reaction mixture was partitioned between EtOAc (2.times.100 mL) and
H.sub.2O (80 mL). The organic extract was washed with brine (80
mL), dried over MgSO.sub.4, and concentrated. The crude product was
purified by trituration with ether to give the product as a white
solid (2.80 g, 70.4%). Mp=160-162.degree. C.; .sup.1H NMR (DMSO),
7.53-7.28 (m, 13H), 7.23 (m, 3H), 6.97 (dd, 1H, J=2.4 Hz, 9.0 Hz),
6.86-6.78 (m, 4H), 5.37 (s, 2H), 5.18 (s, 4H), 4.15 (t, 2H, J=4.8
Hz), 3.87 (t, 2H, J=5.3 Hz); MS eI m/z 598 (M+).
EXAMPLE NO.'S 158 AND 159
[0260] Substitution of the chloro group with piperidine and
hexamethyleneamine was performed analogously to the procedure
outlined in method 6 using No. 157 as a starting material,
supra.
EXAMPLE NO. 158
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-piperidin-1-yl-ethoxy)--
benzyl]-1H-indole
[0261] Mp=148-150.degree. C.; .sup.1H NMR (DMSO), 7.54-7.30 (m,
13H), 7.25-7.18 (m, 3H), 6.98 (dd, 1H, J=2.4 Hz, 9.0 Hz), 6.84-6.74
(m, 4H), 5.35 (s, 2H), 5.17 (s, 4H), 3.94 (t, 2H, 5.9 Hz), 2.55 (t,
2H, 5.7 Hz), 2.35 (bs, 4H), 1.50-1.40 (m, 4H), 1.38-1.25 (m, 2H);
IR 3400, 2910, 2250, 1250 cm.sup.-1; MS FAB 648 [M+H]+.
EXAMPLE NO. 159
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-cyano-1-[4-(2-azepan-1-yl-ethoxy)-ben-
zyl]-1H-indole
[0262] .sup.1H NMR (DMSO), 8.60 (br s, 1H), 7.60-7.28 (m, 12H),
7.25-7.16 (m, 3H), 6.97 (dd, 1H, J=2.4 Hz, 90 Hz), 6.88-6.75 (m,
4H), 5.35 (s, 2H), 5.17 (s, 4H), 3.92 (t, 2H, J=6.2 Hz), 3.08-3.00
(m, 2H), 2.77 (t, 2H, J=5.9 Hz), 2.63 (t, 4H, J=4.8 Hz), 1.78-1.68
(m, 2H), 1.60-1.40 (m, 4H); MS eI m/z 661 (M+).
EXAMPLES NO. 138 AND NO. 139
[0263] Benzyl ethers were removed by hydrogen transfer using 1,4
cyclohexadiene and 10% Pd/C as described in method 7. Compounds
were converted into their respective hydrochloride salts as
described in method 8.
EXAMPLE NO. 138
5-Hydroxy-2-(4-Hydroxy-phenyl)-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i-
ndole-3-carbonitrile (HCl)
[0264] Mp=173-175.degree. C.; .sup.1H NMR (DMSO), 10.40 (s, 1H),
10.12 (s, 1H), 9.40 (s, 1H), 7.38 (m, 2H), 7.30 (d, 1H, J=8.8 Hz),
7.02-6.90 (m, 3H), 6.88 (s, 4H), 6.75 (dd, 1H, J=2.4 Hz, 9 Hz),
5.33 (s, 2H), 4.30 (t, 2H, J=4.8 Hz), 3.51-3.38 (m, 4H), 2.92 (m,
2H), 1.85-1.73 (m, 4H), 1.68-1.59 (m, 1H), 1.26-1.21 (m, 1H); IR
3400, 2200, 1250 cm-1; MS eI m/z 467 (M+); CHN calcd for
C.sub.29H.sub.29N.sub.3O+1.0 HCl+1.0 H.sub.2O.
EXAMPLE NO. 139
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-hydroxy-2-(4-hydroxy-phenyl)-1H-indo-
le-3-cabonitrile (HCl)
[0265] Mp=160-163.degree. C.; .sup.1H NMR (DMSO), 10.22 (s, 1H),
10.08 (s, 1H), 9.35 (s, 1H), 7.40-7.37 (m, 2H), 7.30 (d, 1H, 8.8
Hz), 7.0-6.90 (m, 3H), 6.87 (s, 4H), 6.74 (dd, 1H, J=2.41 Hz, 9
Hz), 5.33 (s, 2H), 4.27 (t, 2H, J=5.0 Hz), 3.50-3.30 (m, 4H), 3.20
(m, 2H), 1.85-1.70 (m, 4H), 1.65-1.50 (m, 4H); IR 3300, 2200, 1250
cm.sup.-1; MS eI m/z 481 (M+); CHN calc for
C.sub.30H.sub.31N.sub.3O.sub.3+1 HCl+1 H.sub.2O.
[0266] Esters of Indole No.'s 97 and 98 TABLE-US-00009 TABLE 9
##STR108## Example No. R Z No. 160 Et ##STR109## No. 161 t-Bu
##STR110## No. 162 t-Bu ##STR111##
Method 9
EXAMPLE NO. 162
Di-pivalate ester of
2-(4-Hydroxy-phenyl)-3-methyl-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-1H-i-
ndol-5-ol
[0267] Example No. 97 free base was used as the starting material
for this synthesis. No. 97 (1.0 g, 2.5 mmol) in 20 mL
CH.sub.2Cl.sub.2 was treated with diisopropylethylamine (0.7 g, 6.3
mmol) and cataltic DMAP. The reaction was cooled to 0.degree. C.
and treated with pivaloyl chloride (0.7 mL, 5.6 mmol) and allowed
to come to rt and stirred overnight. The reaction was worked up by
diluting with CH.sub.2Cl.sub.2 and washing with water and brine.
After drying over MgSO.sub.4 the solution was concentrated and
chromatographed on silica gel (MeOH/CH.sub.2Cl.sub.2, 1:19) to
yield the desired material as an orange foam (1.08 g). This
material was then taken up in 15 mL ethyl acetate and treated with
2.5 mL of a 1M HCl/Et.sub.2O solution. Hexane was added until the
solution turned cloudy. The product precipitated out as the HCl
salt. This material was recrystallized from ethyl acetate/hexane to
yield 0.42 g of pure No. 162: Mp=182-185.degree. C.; CHN calcd for
C.sub.39H.sub.48N.sub.2O.sub.5+HCl+0.25 H.sub.2O.
EXAMPLE NO. 160
Di-propionate of
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol (HCl)
[0268] Compound was prepared analogously to example No. 162 except
the starting material used was example No. 98 and the acylating
agent used was propionyl chloride: Mp=170.5-172.degree. C.; CHN
calcd for C.sub.36H.sub.42N.sub.2O.sub.5+HCl+0.75 H.sub.2O; MS FAB
605 (M+Na)+.
EXAMPLE NO. 161
Di-pivalate of
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indo-
l-5-ol (HCl)
[0269] Compound was prepared analogously to example No. 162 except
the starting material used was example No. 98: Mp=143-151.degree.
C.; CHN calcd for C.sub.40H.sub.50N.sub.2O.sub.5+HCl+0.75
H.sub.2O.
Experimental for Example No. 166
[0270] ##STR112## ##STR113##
EXAMPLE No. 166
2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl)-propoxy]-benzyl}-1H-
-indol-5-ol
[0271] The title compound was prepared according to Scheme 16 and
the steps provided below:
Method 11
EXAMPLE NO. 163a
4-(3-chloropropoxy)-benzyl alcohol
[0272] A solution of 4-hydroxy benzyl alcohol CAS No. [623-05-2]
(10 g, 80.5 mmol) in ethanol (70 mL) was treated with 1,3
bromochloro propane (16.0 g, 100 mmol) and potassium hydroxide (5.0
g, 89 mmol) was refluxed for 2 Hours. The solution was cooled and
filtered and then the filtrate concentrated. The concentrate was
taken up in ether and washed with water, brine and dried over
magnesium sulfate. The material was chromatographed on silica gel
using ethyl acetate/hexanes (3:7) to yield 11.6 g of the product as
a white solid: Mp=65.degree. C.; .sup.1H NMR (DMSO), 7.21 (d, 2H,
J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.03 (t, 1H, J=5.7 Hz), 4.40 (d,
2H, J=5.5 Hz), 4.05 (t, 2H, J=6.1 Hz), 3.77 (t, 2H, J=6.4 Hz); MS
eI m/z 200.
Method 12
EXAMPLE NO. 163b
4-(3-chloropropoxy)-benzyl bromide
[0273] A solution consisting of 4-(3-chloropropoxy)-benzyl alcohol
No. 162 (10.6 g, 52.8 mmol) in dioxane (0.125 l) was cooled to
0.degree. C. and treated with a dropwise addition of thionyl
bromide (12.0 g, 58.0 mmol). After 10 minutes the reaction was
complete. The dioxane was diluted with ethyl ether and washed with
water, brine, and then dried over MgSO.sub.4. The material was
concentrated down to yield 15 g of an oil:
[0274] .sup.1H NMR (DMSO), 7.36 (d, 2H, J=8.8 Hz), 6.92 (d, 2H,
J=8.6 Hz), 4.68 (s, 2H), 4.08 (t, 2H, J=5.9 Hz), 3.77 (t, 2H, J=6.4
Hz); MS (FAB) 266 (M+H.sup.+).
Method 13
EXAMPLE NO. 164
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-methy-
l-1H-indole
[0275] A solution consisting of
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole No. 7 (6.5 g,
15.5 mmol) in DMF (60 ML) was cooled to 0.degree. C. and treated
with addition of sodium hydride (0.68 g, 17.0 mmol) and stirred for
20 minutes. A solution of 4-(3-chloropropoxy)-benzyl bromide No.
163 in DMF (10 mL) was then added slowly. The reaction was allowed
to come to rt and stirred for 2 hours. The reaction was poured into
water and extracted with ethyl acetate. The ethyl acetate was
washed with water, brine and dried over magnesium sulfate and
concentrated. The concentrate was treated with methanol and 5 g of
the desired product precipitated as a white solid with a melting
point of 130-132.degree. C.
Method 14
EXAMPLE NO. 165
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl]-
-3-methyl-1H-indole
[0276] A solution of
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-chloro-propoxy)-benzyl]-3-meth-
yl-1H-indole No. 164 (3 g, 5.1 mmol), potassium iodide (2.5 g, 15.3
mmol) and piperidine (3.0 mL, 30.6 mmol) were heated in DMF (30 mL)
at 100.degree. C. for 18 hours. The reaction wag worked up by
pouring into water and extracting with ethyl acetate. The organic
layer was washed with water, brine and dried over magnesium
sulfate. The solution was concentrated to an oil and the product
precipitated out by adding methanol. The product was obtained as a
white solid: Mp=104-106.degree. C.; .sup.1H NMR (DMSO), 7.47 (d,
4H, J=7.5 Hz), 7.38 (q, 4H, J=7.9 Hz), 7.36-7.30 (m, 1H), 7.28 (d,
2H, J=8.3 Hz), 7.19 (d, 1H, J=8.8 Hz), 7.12-7.10 (m, 4H), 6.80 (dd,
1H, J=8.8, 2.0 Hz), 6.72 (s, 4H), 5.14 (s, 2H), 5.13 (s, 2H), 5.11
(s, 2H), 3.86 (t, 2H, J=6.4 Hz), 2.35-2.20 (m, 6H), 2.14 (s, 3H),
1.78-1.75 (m, 2H), 1.47-1.42 (m, 4H), 1.40-1.31 (m, 2H); MS eI m/z
650.
Method 15
EXAMPLE NO. 166
2-(4-Hydroxy-phenyl)-3-methyl-1-{4-[3-(piperidin-1-yl)-propoxy]-benzyl}-1H-
-indol-5-ol
[0277] A solution of
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(3-piperidin-1-yl-propoxy)-benzyl-
]-3-methyl-1H-indole No. 165 (2.35 g) in tetrahydrofuran (25 mL)
and ethanol (25 mL) was added to 2.3 g of 10% palladium on carbon.
Cyclohexadiene (10 mL) was added and the reaction allowed to stir
at room temperature for 18 hours. The catalyst was filtered through
celite and the reaction mixture was concentrated and
chromatographed on silica gel using dichloromethane/methanol (4:1)
to elute the product (0.8 g) as a white foam: Mp=125-130.degree.
C.; .sup.1H NMR 9.68 (s, 1H), 8.70 (s, 1H), 7.15 (d, 2H, J=8.6 Hz),
7.05 (d, 1H, J=8.8 Hz), 6.85 (d, 2H, J=8.6 Hz), 6.80 (d, 1H, J=2.4
Hz), 6.74 (d, 4H, J=2.6 Hz), 6.57 (dd, 1H, J=8.6, 2.2 Hz), 5.09 (s,
2H), 3.88 (t, 2H, J=6.4 Hz), 3.60-3.15 (m, 2H), 2.62-2.38 (m, 4H),
2.09 (s, 3H), 1.92-1.78 (m, 2H), 1.55-1.43 (m, 4H), 1.42-1.30 (ml
2H); IR (KBr), 3400 (br), 2900, 1620, 1515 cm-1; MS eI m/z 470.
[0278] Synthesis of No. 167 and No. 168 TABLE-US-00010 TABLE 10
##STR114## Example No. Z No. 167 ##STR115## No. 168 ##STR116##
[0279] ##STR117##
Synthesis of Example No. 167
2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-me-
thyl-1H-indol-5-ol
EXAMPLE NO. 169
(4-Formyl-2-methoxy-phenoxy)-acetic acid ethyl ester
[0280] A flask containing vanillin (20 g, 0.13 mol), ethyl
bromoacetate (28.4 g, 0.17 mol) and potassium carbonate (32.7 g,
0.24 mol) and acetone 200 mL were heated to reflux for 3 hours. The
reaction was allowed to come to rt. The acetone was stripped off
and the residue partitioned between water and ethyl acetate. The
ethyl acetate was washed with brine and dried over magnesium
sulfate. The organic layer was concentrated and the solid
triturated with hexanes to yield 28.4 grams of example No. 169.
[0281] Mp=56-59.degree. C.; .sup.1H NMR (DMSO), 9.83 (s, 1H), 7.50
(dd, 1H, J=2.0 Hz, 8.3 Hz), 7.42 (d, 1H, J=1.7 Hz), 7.07 (d, 1H,
J=8.4 Hz), 4.91 (s, 2H), 4.16 (q, 2H, J=7.2 Hz), 3.84 (s, 3H), 1.20
(t, 3H, J=7.1 Hz); MS eI m/z 238 (M+); CHN calcd for
C.sub.12H.sub.14O.sub.5.
EXAMPLE NO. 170
(4-Chloromethyl-2-methoxy-phenoxy)-acetic acid ethyl ester
[0282] A solution of example No. 169 (28.8 g, 0.119 mol) in 600 mL
of EtOH/THF(1:1) was treated with sodium borohydride (2.25 g, 0.06
mol) at 0.degree. C. and stirred for 45 minutes. The solvents were
evaporated and the reaction mixture diluted with ethyl acetate and
washed with 1N HCl solution. The product thus obtained (14.2 g,
0.059 mol) as an oil was dissolved in 140 mL of THF and cooled to
0.degree. C. This solution was then treated with dropwise addition
of thionyl chloride (7.38 g, 0.062 mol) at 0.degree. C. After 1
Hour the reaction was poured into 400 mL of water and extracted
with ether. The ether layer was washed with a sodium bicarbonate
solution and dried over magnesium sulfate. This was concentrated
and chromatographed by silica gel chromatography using ethyl
acetate/hexanes (1:9). The product was obtained as 10.5 g of a
white solid. Mp=64-66.degree. C.; .sup.1H NMR (DMSO), 7.06 (d, 1H,
J=2.0 Hz), 6.91 (dd, 1H, J=2.0 Hz, 2.2 Hz), 6.83 (d, 1H, J=2.1 Hz),
4.75 (s, 2H), 4.70 s, 2H), 4.13 (q, 2H, J=7.2 Hz), 3,77 (s, 3H),
1.19 (t, 3H, J=7.1 Hz); MS eI m/z 258 (M+); CHN calcd for
C.sub.12H.sub.15ClO.sub.4.
EXAMPLE NO. 171
{2-Methoxy-4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl-
]-phenoxy}-acetic acid ethyl ester
[0283] Alkylation of the indole No. 7 was performed as described
previously in Method No. 3 using example No. 170 as the
electrophile.
[0284] Mp=120-123.degree. C.; .sup.1H NMR (DMSO), 7.48-7.20 (m,
13H), 7.18-7.10 (m, 3H), 6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d,
1H, J=8.4 Hz), 6.52 (d, 1H, J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1
Hz), 5.13 (s, 4H), 5.10 (s, 2H), 4.61 (s, 2H), 4.10 (q, 2H, J=7.0
Hz), 3.58 (s, 3H), 2.15 (s, 3H), 1.15 (t, 3H, J=7.0 Hz); MS eI m/z
641 (M+).
EXAMPLE NO. 172
2-{2-Methoxy-4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmeth-
yl]-phenoxy}-ethanol
[0285] Reduction of the ester No. 171 was performed as described
previously in Method 4.
[0286] Mp=86-90.degree. C.; .sup.1H NMR (DMSO), 7.48-7.20 (m, 13H),
7.18-7.10 (m, 3H), 6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H,
J=8.4 Hz), 6.52 (d, 1H, J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1 Hz),
5.13 (s, 4H), 5.10 (s, 2H), 4.76 (t, 1H, J=5.5 Hz), 3.83 (t, 2H,
J=5.1 Hz), 3.63 (q, 2H, J=5.3 Hz), 3.56 (s, 3H), 2.15 (s, 3H); MS
eI m/z 599 (M+).
EXAMPLE NO. 173
5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[3-methoxy-4-(2-bromo-ethoxy)-benzyl]-
-3-methyl-1H-indole
[0287] Conversion of the alcohol of example No. 172 to the bromide
was performed analogously to that described in Method 5.
[0288] Mp=150-152.degree. C.; .sup.1H NMR (DMSO), 7.48-7.20 (m,
13H), 7.18-7.10 (m, 3H), 6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d,
1H, J=8.4 Hz), 6.52 (d, 1H, J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1
Hz), 5.13 (s, 4H), 5.10 (s, 2H), 4.15 (t, 2H, J=5.3 Hz), 3.70 (t,
2H, J=5.7 Hz), 3.58 (s, 3H), 2.15 (s, 3H); MS eI m/z 661 (M+).
EXAMPLE NO. 174
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[3-Methoxy-4-(2-piperidin-1--
yl-ethoxy)-benzyl]-1H-indole
[0289] Substitution of the bromide with piperidine was performed as
described previously in Method 6.
[0290] .sup.1H NMR (DMSO), 7.48-7.20 (m, 13H), 7.18-7.10 (m, 3H),
6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52 (d,
1H, J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H), 5.10
(s, 2H), 3.90 (t, 2H, J=5.7 Hz), 3.55 (s, 3H), 2.62-2.50 (bs, 2H),
2.45-2.30 (bs, 4H), 2.15 (s, 3H), 1.50-1.40 (m, 4H), 1.40-1.35 (m,
2H); MS FAB m/z 667 (M+H+).
EXAMPLE NO. 175
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[2-Methoxy-4-(2-azepan-1-yl--
ethoxy)-benzyl]-1H-indole
[0291] Reaction performed exactly as for No. 174 except
hexamethyleneamine was used to displace the bromide in place of
piperidine.
[0292] Foam; .sup.1H NMR (DMSO), 7.48-7.20 (m, 13H), 7.18-7.10 (m,
3H), 6.80 (dd, 1H, J=2.5 Hz, 8.8 Hz), 6.64 (d, 1H, J=8.4 Hz), 6.52
(d, 1H, J=2.0 Hz), 6.24 (dd, 1H, J=1.9 Hz, 8.1 Hz), 5.13 (s, 4H),
5.10 (s, 2H), 3.90 (t, 2H, J=5.7 Hz), 3.55 (s, 3H), 2.85-2.70 (bs,
2H), 2.70-2.55 (s, 4H), 2.10 (s, 3H), 1.60-1.15 (m, 8H); MS FAB m/z
681 (M+H+)
EXAMPLE NO. 167
2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-piperidin-1-yl-ethoxy)-benzyl]-3-me-
thyl-1H-indol-5-ol
[0293] Compound No. 173 was hydrogenated by transfer hydrogenation
as described previously in Method 7. Compound was isolated as the
hydrochloride salt by dissolving in ether and treating with 1.2
equivalents of 1N ether/HCl solution (this is a variation of method
8).
[0294] Mp=123-127.degree. C.; .sup.1H NMR (DMSO), 10.20 (bs, 1H),
9.72 (s, 1H), 8.71 (s, 1H), 7.17 (d, 2H, J=8.6 Hz), 7.11 (d, 1H,
J=8.8 Hz), 6.87 (d, 2H, J=8.6 Hz), 6.79 (m, 2H), 6.57 (dd, 1H,
J=2.4 Hz, 8.8 Hz), 6.55 (d, 1H, J=1.7 Hz), 6.33 (dd, 1H, J=1.7 Hz,
8.1 Hz), 5.11 (s, 2H), 4.23 (t, 2H, J=4.8 Hz), 3.60 (s, 3H), 3.45
(m, 2H), 3.35 (m, 2H), 2.95 (m, 2H), 2.10 (s, 3H), 1.70 (m, 5H),
1.35 (m, 1H); IR 3500, 1500, 1275 cm.sup.-1; MS (+), FAB m/z 487
(M+H).sup.+; CHN calcd for C.sub.30H.sub.34N.sub.2O.sub.4+1 HCl+1.0
H.sub.2O.
EXAMPLE NO. 168
2-(4-Hydroxy-phenyl)-1-[3-methoxy-4-(2-azepan-1-yl-ethoxy)-benzyl]-3-methy-
l-1H-indol-5-ol
[0295] Prepared in the same way as that described for example No.
167.
[0296] Mp=142-146.degree. C.; .sup.1H NMR (DMSO), 10.36 (s, 1H),
9.72 (s, 1H), 8.71 (s, 1H), 7.18 (d, 2H, J=8.3 Hz), 7.11 (d, 1H,
J=8.6 Hz), 6.87 (d, 2H, J=8.3 Hz), 6.82 (d, 1H, J=8.1 Hz), 6.79 (d,
1H, J=2.2 Hz), 6.57 (dd, 1H, J=2.2 Hz, 8.6 Hz), 6.55 (d, 1H, J=1.8
Hz), 6.33 (dd, 1H, J=1.5 Hz, 8.1 Hz), 5.11 (s, 2H), 4.24 (t, 2H,
J=4.6 Hz), 3.60 (s, 3H), 3.40 (m, 4H), 3.20 (m, 2H), 2.10 (s, 3H),
1.75 (m, 4H), 1.55 (m, 4H); IR (KBr), 3300, 1500, 1270, 1200
cm.sup.-1; MS (+), FAB m/z 501 (M+H).sup.+; CHN calcd for
C.sub.31H.sub.36N.sub.2O.sub.4+1.0 HCl+0.12 CH.sub.3OH.
Biological Data
Method 16
In Vitro Estrogen Receptor Binding Assay
Receptor Preparation
[0297] CHO cells overexpressing the estrogen receptor were grown in
150 mm.sup.2 dishes in DMEM+10% dextran coated charcoal, stripped
fetal bovine serum. The plates were washed twice with PBS and once
with 10 mM Tris-HCl, pH 7.4, 1 mM EDTA. Cells were harvested by
scraping the surface and then the cell suspension was placed on
ice. Cells were disrupted with a hand-held motorized tissue grinder
using two, 10-second bursts. The crude preparation was centrifuged
at 12,000 g for 20 minutes followed by a 60 minute spin at 100,000
g to produce a ribosome free cytosol. The cytosol was then frozen
and stored at -80.degree. C. Protein concentration of the cytosol
was estimated using the BCA assay with reference standard
protein.
Binding Assay Conditions
[0298] The competition assay was performed in a 96-well plate
(polystyrene*) which binds <2.0% of the total input
[.sup.3H]-17.beta.-estradiol and each data point was gathered in
triplicate. 100 uG/100 uL of the receptor preparation was aliquoted
per well. A saturating dose of 2.5 nM
[.sup.3H]17.beta.-estradiol+competitor (or buffer) in a 50 uL
volume was added in the preliminary competition when 100.times. and
500.times. competitor were evaluated, only 0.8 nM [.sup.3H]
17.beta.-estradiol was used. The plate was incubated at room
temperature for 2.5 h. At the end of this incubation period 150 uL
of ice-cold dextran coated charcoal (5% activated charcoal coated
with 0.05% 69K dextran) was added to each well and the plate was
immediately centrifuged at 99 g for 5 minutes at 4.degree. C. 200
uL of the supernatant solution was then removed for scintillation
counting. Samples were counted to 2% or 10 minutes, whichever
occurs first. Because polystyrene absorbs a small amount of
[.sup.3H]17.beta.-estradiol, wells containing radioactivity and
cytosol, but not processed with charcoal were included to
quantitate amounts of available isotope. Also, wells containing
radioactivity but no cytosol were processed with charcoal to
estimate unremovable DPM of [.sup.3H] 17.beta.-estradiol. Corning
No. 25880-96, 96-well plates were used because they have proven to
bind the least amount of estradiol.
Analysis of Results
[0299] Counts per minute (CPM) of radioactivity were automatically
converted to disintegrated per minute (DPM) by the Beckman LS 7500
Scintillation Counter using a set of quenched standards to generate
a H No. for each sample. To calculate the % of estradiol binding in
the presence of 100 or fold 500 fold competitor the following
formula was applied: ((DPM sample-DPM not removed by charcoal/(DPM
estradiol-DPM not removed by charcoal)).times.100%=% of estradiol
binding
[0300] For the generation of IC.sub.50 curves, % binding is plotted
vs compound. IC.sub.50's are generated for compounds that show
>30% competition at 500.times. competitor concentration. For a
description of these methods, see Hulme, E. C., ed. 1992.
Receptor-Ligand Interactions: A Practical Approach. IRL Press, New
York. (see especially chapter 8). TABLE-US-00011 TABLE 11 Estrogen
Receptor Binding ##STR118## Receptor Example Binding No. X O Z
IC50's uM No. 85 H H ##STR119## 0.45 No. 86 H 4'-OH ##STR120## 0.12
No. 87 OH H ##STR121## 0.030 No. 88 OMe 4'-OH ##STR122## 0.35 No.
89 OH 4'-OMe ##STR123## 0.30 No. 90 OMe 4'-OMe ##STR124## 0.60 No.
91 OMe 4'-OMe ##STR125## 0.52 No. 92 OH 4'-OEt ##STR126## 0.062 No.
93 OH 4'-OEt ##STR127## 0.090 No. 94 F 4'-OH ##STR128## 0.20 No. 97
OH 4'-OH ##STR129## 0.060 No. 98 OH 4'-OH ##STR130## 0.050 No. 99
OH 4'-OH ##STR131## 0.03 No. 100 OH 4'-OH ##STR132## 0.06 No. 101
OH 4'-OH ##STR133## 0.04 No. 102 OH 4'-OH ##STR134## 0.08 No. 103
OH 4'-OH ##STR135## 0.2 No. 104 OH 4'-OH ##STR136## 0.1 No. 105 OH
4'-OH ##STR137## 0.028 No. 106 OH 4'-OH ##STR138## 0.1 No. 107 OH
4'-OH ##STR139## 0.06 No. 108 OH 4'-OH ##STR140## 0.02 No. 109 OH
4'-OH ##STR141## 0.17 No. 110 OH 4'-OH ##STR142## 0.037 No. 111 OH
4'-OH ##STR143## 0.15 No. 112 OH 4'-OH ##STR144## 0.07 No. 113 OH
4'-OH ##STR145## 0.047 No. 114 OH 4'-OH ##STR146## 0.001 No. 115 OH
4'-OH ##STR147## 0.15 No. 116 OH 4'-F ##STR148## 0.04 No. 117 OH
4'-F ##STR149## 0.10 No. 118 OH 3'-OMe,4'-OH ##STR150## N/A No. 119
OH 3',4'-OCH.sub.2O-- ##STR151## 0.070 No. 120 OH 4'-O-iPr
##STR152## 0.10 No. 121 OH 4'-O-iPr ##STR153## 0.080 No. 122 OH
4'-O-Cp ##STR154## 0.080 No. 123 OH 4'-CF.sub.3 ##STR155## 0.17 No.
124 OH 4'-CH.sub.3 ##STR156## 0.11 No. 125 OH 4'-Cl ##STR157## 0.11
No. 126 OH 2',4',-Dimethoxy ##STR158## N/A No. 127 OH 3'-OH
##STR159## 0.019 No. 128 OH 3'-OH ##STR160## 0.009 No. 129 OH
4'-OH,3'-F ##STR161## 0.0055 No. 130 OH 4'-OH, 3'-F ##STR162##
0.013 No. 131 OH 3'-OMe ##STR163## 0.12 No. 132 OH 4'-OCF.sub.3
##STR164## 0.05
[0301] TABLE-US-00012 TABLE 12 Estrogen Receptor Binding ##STR165##
Example Receptor Binding No. X O Z IC50's uM No. 133 Cl H
##STR166## 0.004 No. 134 Cl H ##STR167## 0.024 No. 135 Cl H
##STR168## 0.029 No. 136 Cl CH.sub.3 ##STR169## 0.013 No. 137 Et H
##STR170## 0.15 No. 138 CN H ##STR171## 0.011 No. 139 CN H
##STR172## 0.023
[0302] TABLE-US-00013 TABLE 13 Estrogen Receptor Binding ##STR173##
Receptor Binding Example No. R Z IC50's uM No. 160 Et ##STR174##
N/A No. 161 E-Bu ##STR175## N/A No. 162 t-Bu ##STR176## Does not
Bind
[0303] TABLE-US-00014 TABLE 14 Estrogen Receptor Binding ##STR177##
Receptor Binding Example No. X O Z IC50's uM No. 166 OH 4'-OH
##STR178## 0.099
[0304] TABLE-US-00015 TABLE 15 Estrogen Receptor Binding ##STR179##
Receptor Binding Example No. Z IC50's uM No. 167 ##STR180## 0.08
No. 168 ##STR181## 0.057
Method 17 Ishikawa Cell Alkaline Phosphatase Assay Cell Maintenance
and Treatment:
[0305] Ishikawa cells were maintained in DMEM/F12 (50%:50%)
containing phenol red+10% fetal bovine serum and the medium was
supplemented with 2 mM Glutamax, 1% Pen/Strap and 1 mM sodium
pyruvate. Five days prior to the beginning of each experiment
(treatment of cells) the medium was changed to phenol red-free
DMEM/F12+10% dextran coated charcoal stripped serum. On the day
before treatment, cells were harvested using 0.5% trypsin/EDTA and
plated at a density of 5.times.10.sup.4 cells/well in 96-well
tissue culture plates. Test compounds were dosed at 10.sup.-6,
10.sup.-7 and 10.sup.-8M in addition to 10.sup.-6 M
(compound)+10.sup.-9 M 17.beta.-estradiol to evaluate the ability
of the compounds to function as antiestrogens. Cells were treated
for 48 h prior to assay. Each 96-well plate contained a
17.beta.-estradiol control. Sample population for at each dose was
n=8.
Alkaline Phosphatase Assay:
[0306] At the end of 43 h the media is aspirated and cells are
washed three times with phosphate buffered saline (PBS). 50 .mu.L
of lysis buffer (0.1 M Tris-HCl, pH 9.8, 0.2% Triton X-100) is
added to each well. Plates are placed at -80.degree. C. for a
minimum of 15 minutes. Plates are thawed at 37.degree. C. followed
by the addition of 150 .mu.L of 0.1 M Tris-HCl, pH 9.8, containing
4 mM para-nitrophenylphosphate (pNPP) to each well (final
concentration, 3 mM pNPP).
[0307] Absorbance and slope calculations were made using the
KineticCalc Application program (Bio-Tek Instruments, Inc.,
Winooski, Vt.). Results are expressed as the mean+/-S.D. of the
rate of enzyme reaction (slope) averaged over the linear portion of
the kinetic reaction curve (optical density readings every 5
minutes for 30 minutes absorbance reading). Results for compounds
are summarized as percent of response related to 1 nM
17.beta.-estradiol.
[0308] Various compounds were assayed for estrogenic activity by
the alkaline phosphatase method and corresponding ED50 values (95%
C.I.) were calculated. The four listed in the following were used
as as reference standards: TABLE-US-00016 17.beta.-estradiol 0.03
nM 17.alpha.-estradiol 1.42 nM estriol 0.13 nM estrone 0.36 nM
[0309] A description of these methods is described by Holinka, C.
F., Hata, H., Kuramoto, H. and Gurpide, E. (1986) Effects of
steroid hormones and antisteroids on alkaline phosphatase activity
in human endometrial cancer cells (Ishikawa Line). Cancer Research,
46:2771-2774, and by Littlefield, B. A., Gurpide, E., Markiewicz,
L., McKinley, B. and Hochberg, R. B. (1990) A simple and sensitive
microtiter plate estrogen bioassay based on stimulation alkaline
phosphatase in Ishikawa cells; Estrogen action of D5 adrenal
steroids. Endocrinology, 6:2757-2762.
[0310] Ishikawa Alkaline Phosphatase Assay TABLE-US-00017 Compound
% Activation 17.beta.-estradiol 100% activity tamoxifen 0% activity
(45% with 1 nM 17.beta.-estradiol) raloxifene 5% activity (5% with
1 nM 17.beta.-estradiol) Example No. 98 1% activity (1% with 1 nM
17.beta.-estradiol)
Method No. 18 233 VIT ERE Infection Assay Cell Maintenance and
Treatment
[0311] Chinese Hamster Ovary cells (CHO) which had been stably
transfected with the human estrogen receptor were maintained in
DMEM+10% fetal bovine serum (FBS). 48 h prior to treatment the
growth medium was replaced with DMEM lacking phenol red+10% dextran
coated charcoal stripped FBS (treatment medium). Cells were plated
at a density of 5000 cells/well in 96-well plates containing 200
.mu.L of medium/well.
Calcium Phoshate Transfection
[0312] Reporter DNA (Promega plasmid pGL2 containing two tandem
copies of the vitellogenin ERE in front of the minimal thymidine
kinase promoter driving the luciferase gene) was combined with the
B-galactosidase expression plasmid pCH110 (Pharmacia) and carrier
DNA (pTZ18U) in the following ratio:
[0313] 10 uG of reporter DNA
[0314] 5 uG of pCH110DNA
[0315] 5 uG of pTZ18U
[0316] 20 uG of DNA/1 mL of transfection solution
[0317] The DNA (20 uG) was dissolved in 500 uL of 250 mM sterile
CaCl.sub.2, and added dropwise to 500 uL of 2.times.HeBS (0.28 M
NaCl, 50 mM HEPES, 1.5 mM Na.sub.2HPO.sub.4, pH 7.05) and incubated
at room temperature for 20 minutes. 20 uL of this mixture was added
to each well of cells and remained on the cells for 16 h. At the
end of this incubation the precipitate was removed, the cells were
washed with media, fresh treatment media was replaced and the cells
were treated with either vehicle, 1 nM 17.beta.-estradiol, 1 uM
compound or 1 uM compound+1 nM 17.beta.-estradiol (tests for
estrogen antagonism). Each treatment condition was performed on 8
wells (n=8) which were incubated for 24 h prior to the luciferase
assay.
Luciferase Assay
[0318] After 24 h exposure to compounds, the media was removed and
each well washed with 2.times. with 125 uL of PBS lacking Mg.sup.++
and Ca.sup.++. After removing the PBS, 25 uL of Promega lysis
buffer was added to each well and allowed to stand at
room-temperature for 15 min, followed by 15 min at -80.degree. C.
and 15 min at 37.degree. C. 20 uL of lysate was transferred to an
opaque 96 well plate for luciferase activity evaluation and the
remaining lysate (5 uL) was used for the B-galactosidase activity
evaluation (normalize transfection). The luciferan substrate
(Promega) was added in 100 uL aliquots to each well automatically
by the luminometer and the light produced (relative light units)
was read 10 seconds after addition.
[0319] Infection Luciferase Assay (Standards) TABLE-US-00018
Compound % Activation 17.beta.-estradiol 100% activity estriol 38%
activity tamoxifen 0% activity (10% with 1 nM 17.beta.-estradiol)
raloxifene 0% activity (0% with 1 nM 17.beta.-estradiol)
B-Galactosidase Assay
[0320] To the remaining 5 uL of lysate 45 uL of PBS was added. Then
50 uL of Promega B-galactosidase 2.times. assay buffer was added,
mixed well and incubated at 37.degree. C. for 1Hour. A plate
containing a standard curve (0.1 to 1.5 milliunits in triplicate)
was set up for each experimental run. The plates were analyzed on a
Molecular Devices spectrophotometric plate reader at 410 nm. The
optical densities for the unknown were converted to milliunits of
activity by mathematical extrapolation from the standard curve.
Analysis of Results
[0321] The luciferase data was generated as relative light units
(RLUs) accumulated during a 10 second measurement and automatically
transferred to a JMP (SAS Inc) file where background RLUs were
subtracted. The B-galactosidase values were automatically imported
into the file and these values were divided into the RLUs to
normalize the data. The mean and standard deviations were
determined from a n=8 for each treatment. Compounds activity was
compared to 17.beta.-estradiol for each plate. Percentage of
activity as compared to 17.beta.-estradiol was calculated using the
formula %=((Estradiol-control)/(compound value)).times.100. These
techniques are described by Tzukerman, M. T., Esty, A.,
Santiso-Mere, D., Danielian, P., Parker, M. G., Stein, R. B., Pike,
J. W. and McDonnel, D. P. (1994). Human estrogen receptor
transactivational capacity was determined by both cellular and
promoter context and mediated by two functionally distinct
intramolecular regions (see Molecular Endocrinology, 8:21-30).
TABLE-US-00019 TABLE 16 Infection Luciferase Activity Example No. 1
uM 1 uM + 17.beta. estradiol No. 85 -2 43 No. 86 -5 2 No. 87 0 0
No. 88 4 44 No. 89 16 18 No. 90 3 58 No. 91 -3 56 No. 92 -4 -2 No.
93 -3 -2 No. 94 -5 15 No. 95 -4 -4 No. 96 12 8 No. 97 -4 -5 No. 98
5 5 No. 99 5 6 No. 100 9 10 No. 101 14 9 No. 102 9 10 No. 103 13 10
No. 104 7 7 No. 105 5 5 No. 106 10 81 No. 107 -1 54 No. 108 11 10
No. 109 6 5 No. 110 8 10 No. 111 25 23 No. 112 10 10 No. 113 14 16
No. 114 1 -1 No. 115 11 10 No. 116 -1 1 No. 117 0 1 No. 118 N/A N/A
No. 119 -1 -1 No. 120 -1 1 No. 121 0 1 No. 122 1 5 No. 123 -1 1 No.
124 -2 -2 No. 125 -3 -2 No. 126 -1 0 No. 127 -3 -4 No. 132 -5 -2
No. 133 7 9 No. 134 9 5 No. 135 7 3 No. 136 16 10 No. 137 6 8 No.
138 -2 -1 No. 139 -12 -13 No. 160 N/A N/A No. 161 N/A N/A No. 162
-14 -13 No. 166 25 23 No. 167 4 10 No. 168 3 7
Method No. 19 Rat Uterotrophic/Antiuterotrophic Bioassay
[0322] The estrogenic and antiestrogenic properties of the
compounds were determined in an immature rat uterotrophic assay (4
day) that (as described previously by L. J. Black and R. L. Goode,
Life Sciences, 26, 1453 (1980)). Immature Sprague-Dawley rats
(female, 18 days old) were tested in groups of six. The animals
were treated by daily ip injection with 10 uG compound, 100 uG
compound, (100 uG compound+1 uG 17.beta.-estradiol) to check
antiestrogenicity, and 1 uG 17.beta.-estradiol, with 50% DMSO/50%
saline as the injection vehicle. On day 4 the animals were
sacrificed by CO.sub.2 asphyxiation and their uteri were removed
and stripped of excess lipid, any fluid removed and the wet weight
determined. A small section of one horn was submitted for histology
and the remainder used to isolate total RNA in order to evaluate
complement component 3 gene expression. TABLE-US-00020 TABLE 17 3
Day Rat Immature Uterine Assay Uterine wt Uterine wt mg Uterine wt
mg 100 uG cmpd + 1 uG mg Uterine wt 100 uG 17.beta.- 1 uG 17.beta.-
mg Example No. cmpd estradiol estradiol Vehicle Tamoxifen 71.4 mg
N/A 98.2 mg 42.7 mg No. 85 41.1 mg 92.4 mg 94.4 mg 26.6 mg No. 94
28.1 mg 93.7 mg 88.5 mg 22.3 mg No. 97 27.4 mg 24.3 mg 63.2 mg 30.7
mg No. 98 29.4 mg 27.9 mg 94.1 mg 35.9 mg No. 100 59.9 mg 68.7 mg
91.9 mg 23.4 mg No. 101 65.1 mg 71.0 mg 113.7 mg 27.7 mg No. 122
46.7 mg 38.7 mg 103.4 mg 30.3 mg No. 123 39.2 mg 61.4 mg 94.4 mg
26.1 mg No. 138 28.4 mg 37.9 mg 93.9 mg 24.6 mg No. 139 30.4 mg
45.0 mg 82.1 mg 20.5 mg No. 168 43.2 mg 81.7 mg 98.9 mg 25.5 mg
Method No. 20 6-Week Ovariectomized Rat Model
[0323] Female Sprague Dawley CD rats, ovx or sham ovx, were
obtained 1 day after surgery from Taconic Farm (weight range
240-275 g). They were housed 3 or 4 rats/cage in a room on a 14/10
(light/dark) schedule and provided with food (Purina 500 rat chow)
and water ad libitum. Treatment for all studies began 1 day after
the animals arrival and dosed 5 or 7 days per week as indicated for
6 weeks. A group of age matched sham operated rats not receiving
any treatment served as an intact, estrogen replete control group
for each study. All treatments were prepared in 1% tween 80 in
normal saline at defined concentrations so that the treatment
volume was 0.1 mL/100 g body weight. 17-beta estradiol was
dissolved in corn oil (20 uG/mL) and delivered subcutaneously, 0.1
mL/rat. All dosages were adjusted at three week intervals according
to group mean body weight measurements.
[0324] Five weeks after the initiation of treatment and one week
prior to the termination of the study, each rat was evaluated for
bone mineral density (BMD). The BMD's of the proximal tibiae (PT)
and fourth lumbar vertabrae (L4) were measured in anesthetized rats
using a dual energy X-ray absorptiometer (Eclipse XR-26, Norland
Corp. Ft. Atkins, Wis.). The dual energy X-ray absorptiometer (DXA)
measurements for each rat were performed as follows: Fifteen
minutes prior to DXA measurements, the rat was anesthetized with an
intraperitoneal injection of 100 mg/kg ketarnine (Bristol
Laboratories, Syracuse, N.Y.) and 0.75 mg/kg acepromazine (Aveco,
Ft. Dodge, Iowa). The rat was placed on an acrylic table under the
DXA scanner perpendicular to its path; the limbs were extended and
secured with paper tape to the surface of the table. A preliminary
scan was performed at a scan speed of 50 mm/second with a scan
resolution of 1.5 mm.times.1.5 mm to determine the region of
interest in PT and L4. Small subject software was employed at a
scan speed of 10 mm/second with resolution of 0.5 mm.times.0.5 mm
for final BMD measurements. The software allows the operator to
define a 1.5 cm wide area to cover the total length of L4. The BMDs
for respective sites were computed by the software as a function of
the attenuation of the dual beam (46.8 KeV and 80 KeV) X-ray
generated by the source underneath the subject and the detector
travelling along the defined area above the subject. The data for
BMD values (expressed in g/cm2) and individual scans were stored
for statistical analysis.
[0325] One week after BMD evaluation the rats were sacrificed by
carbon dioxide suffocation and blood collected for cholesterol
determination. The uteri were removed and the weights taken. Total
cholesterol is determined using a Boehringer-Mannheim Hitachi 911
clinical analyzer using the Cholesterol/HP kit. Statitstics were
compared using one-way analysis of variance with Dunnet's test.
TABLE-US-00021 TABLE 18 6-Week Ovariectomized Rat Study Of Example
No. 98 BMD (mg/cm.sup.2).sup.a,b Body Uterine Proximal Weight
Weight Cholesterol Treatment Tibia L.sub.4 (g).sup.a,c (mg).sup.a,c
(mg/dl).sup.a,c Study.sup.d Sham (Intact) 0.211** .+-. 0.003 0.183*
.+-. 0.003 43.0* .+-. 6.0 426.4** .+-. 25.0 71.6** .+-. 5.0 Vehicle
(Ovx) 0.189 .+-. 0.004 0.169 .+-. 0.004 62.7 .+-. 8.2 118.2 .+-.
7.8 87.2 .+-. 3.0 Example No. 98 0.3 mg/kg, p.o. 0.210** .+-. 0.003
0.173 .+-. 0.003 46.8 .+-. 6.6 149.3 .+-. 4.4 59.0** .+-. 2.2
Raloxifene 0.207** .+-. 0.006 0.170 .+-. 0.003 25.3** .+-. 5.4
191.6** .+-. 9.3 55.0** .+-. 2.4 3 mg/kg, p.o. 17.beta.-Estradiol
0.224** .+-. 0.004 0.169 .+-. 0.004 33.1** .+-. 4.9 426.0** .+-.
18.4 95.5 .+-. 3.9 2 .mu.g/rat, s.c. .sup.aMean .+-. SEM
.sup.bFollowing 5 weeks of treatment .sup.cFollowing 6 weeks of
treatment .sup.dDaily treatment x7 days/week x6 weeks *p < 0.05
vs corresponding Vehicle value **p < 0.01 vs corresponding
Vehicle value
* * * * *