U.S. patent application number 09/820158 was filed with the patent office on 2001-09-27 for estrogen agonists/antagonists for preventing breast cancer.
Invention is credited to Cameron, Kimberly O., Dasilva-Jardine, Paul A., Ke, Hua Zhu, Rosati, Robert L..
Application Number | 20010025051 09/820158 |
Document ID | / |
Family ID | 23457628 |
Filed Date | 2001-09-27 |
United States Patent
Application |
20010025051 |
Kind Code |
A1 |
Cameron, Kimberly O. ; et
al. |
September 27, 2001 |
Estrogen agonists/antagonists for preventing breast cancer
Abstract
Compounds of this formula 1 are useful for preventing breast
cancer.
Inventors: |
Cameron, Kimberly O.; (East
Lyme, CT) ; Dasilva-Jardine, Paul A.; (Providence,
RI) ; Ke, Hua Zhu; (Ledyard, CT) ; Rosati,
Robert L.; (Stonington, CT) |
Correspondence
Address: |
Gregg C. Benson
Pfizer Inc.
Patent Department, MS 4159
Eastern Point Road
Groton
CT
06340
US
|
Family ID: |
23457628 |
Appl. No.: |
09/820158 |
Filed: |
March 28, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09820158 |
Mar 28, 2001 |
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09466034 |
Dec 17, 1999 |
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09466034 |
Dec 17, 1999 |
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08849726 |
Jun 30, 1997 |
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6204286 |
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08849726 |
Jun 30, 1997 |
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PCT/IB95/00286 |
Apr 24, 1995 |
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Current U.S.
Class: |
514/422 |
Current CPC
Class: |
A61K 31/40 20130101;
A61P 5/00 20180101; A61P 5/30 20180101; C07D 217/16 20130101; A61P
9/00 20180101; C07D 213/64 20130101; A61P 5/32 20180101; A61P 35/00
20180101; A61P 19/10 20180101; C07D 401/04 20130101; A61P 7/00
20180101; A61P 3/06 20180101; C07D 295/088 20130101 |
Class at
Publication: |
514/422 |
International
Class: |
A61K 031/40 |
Claims
What is claimed is:
1. A method of preventing breast cancer in a mammal which comprises
administering to a mammal in need of such prevention an effective
amount of a compound of the formula I: 18wherein: A is selected
from CH.sub.2 and NR; B, D and E are independently selected from CH
and N; Y is (a) phenyl, optionally substituted with 1-3
substituents independently selected from R.sup.4; (b) naphthyl,
optionally substituted with 1-3 substituents independently selected
from R.sup.4; (c) C.sub.3-C.sub.8 cycloalkyl, optionally
substituted with 1-2 substituents independently selected from
R.sup.4; (d) C.sub.3-C.sub.8 cycloalkenyl, optionally substituted
with 1-2 substituents independently selected from R.sup.4; (e) a
five membered heterocycle containing up to two heteroatoms selected
from the group consisting of --O--, --NR.sup.2--and --S(O).sub.n--,
optionally substituted with 1-3 substituents independently selected
from R.sup.4; (f) a six membered heterocycle containing up to two
heteroatoms selected from the group consisting of --O--,
--NR.sup.2-- and --S(O).sub.n-- optionally substituted with 1-3
substituents independently selected from R.sup.4; or (g) a bicyclic
ring system consisting of a five or six membered heterocyclic ring
fused to a phenyl ring, said heterocyclic ring containing up to two
heteroatoms selected from the group consisting of --O--,
--NR.sup.2--, NR.sup.2-- and --S(O).sub.n--, optionally substituted
with 1-3 substituents independently selected from R.sup.4; Z.sup.1
is (a) --(CH.sub.2).sub.p W(CH.sub.2).sub.q--; (b)
--O(CH.sub.2).sub.p CR.sup.5R.sup.6--; (c)
--O(CH.sub.2).sub.pW(CH.sub.2)- .sub.q--; (d)
--OCHR.sup.2CHR.sup.3--; or (e) --SCHR.sup.2CHR.sup.3--; G is (a)
--NR.sup.7R.sup.8; (b) 19 wherein n is 0, 1 or 2; m is 1, 2 or 3;
Z.sup.2is --NH--, --O--, --S--, or --CH.sub.2--; optionally fused
on adjacent carbon atoms with one or two phenyl rings and,
optionally independently substituted on carbon with one to three
substituents and, optionally, independently on nitrogen with a
chemically suitable substituent selected from R.sup.4; or (c) a
bicyclic amine containing five to twelve carbon atoms, either
bridged or fused and optionally substituted with 1-3 substituents
independently selected from R.sup.4; Z.sup.1 and G in combination
may be 20W is (a) --CH.sub.2--; (b) --CH.dbd.CH--; (c) --O--; (d)
--NR.sup.2; (e) --S(O).sub.n--; (f) 21(g) --CR.sup.2(OH)--; (h)
--CONR.sup.2--; (i) --NR.sup.2CO--; (j) 22(k) --C.ident.C--; R is
hydrogen or C.sub.1-C.sub.6 alkyl; R and R.sup.3 are independently
(a) hydrogen; or (b) C.sub.1-C.sub.4 alkyl; R.sup.4 is (a)
hydrogen; (b) halogen; (c) C.sub.1-C.sub.6 alkyl; (d)
C.sub.1-C.sub.4 alkoxy; (e) C.sub.1-C.sub.4 acyloxy; (f)
C.sub.1-C.sub.4 alkylthio; (g) C.sub.1-C.sub.4 alkylsulfinyl; (h)
C.sub.1-C.sub.4 alkylsulfonyl; (i) hydroxy (C.sub.1-C.sub.4)alkyl;
(j) aryl (C.sub.1-C.sub.4)alkyl; (k) --CO.sub.2H; (l) --CN; (m)
--CONHOR; (n) --SO.sub.2NHR; (o) --NH.sub.2; (p) C.sub.1-C.sub.4
alkylamino; (q) C.sub.1-C.sub.4 dialkylamino; (r) --NHSO.sub.2R;
(s) --NO.sub.2; (t) --aryl; or (u) --OH. R.sup.5 and R.sup.6 are
independently C.sub.1-C.sub.8 alkyl or together form a
C.sub.3-C.sub.10 carbocyclic ring; R.sup.7 and R.sup.8 are
independently (a) phenyl; (b) a C.sub.3-C.sub.10 carbocyclic ring,
saturated or unsaturated; (c) a C.sub.3-C.sub.10 heterocyclic ring
containing up to two heteroatoms, selected from --O--, --N-- and
--S--; (d) H; (e) C.sub.1-C.sub.6 alkyl; or (f) form a 3 to 8
membered nitrogen containing ring with R.sup.5 or R.sup.6; R.sup.7
and R.sup.8 in either linear or ring form may optionally be
substituted with up to three substituents independently selected
from C.sub.1-C.sub.6 alkyl, halogen, alkoxy, hydroxy and carboxy; a
ring formed by R.sup.7 and R.sup.8 may be optionally fused to a
phenyl ring; e is 0, 1 or 2; m is 1, 2 or 3; n is 0, 1 or 2; p is
0, 1,2or 3; q is 0, 1, 2 or 3; and optical and geometric isomers
thereof; and nontoxic pharmacologically acceptable acid addition
salts, N-oxides, esters, and quaternary ammonium salts thereof.
2. A method of claim 1 wherein the compound is a compound of the
formula: 23
3. A method of preventing breast cancer in a mammal which comprises
administering to a mammal in need of such prevention an effective
amount of
(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetra-
hydro-naphthalen-2-ol, or a nontoxic pharmacologically acceptable
acid addition salt, N-oxide, ester, or quaternary ammonium salt
thereof.
4. A method of preventing breast cancer in a mammal which comprises
administering to a mammal in need of such prevention an effective
amount of
Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrahydr-
o-naphthalen-2-ol, or an optical or geometric isomer thereof; or a
nontoxic pharmacologically acceptable acid addition salt, N-oxide,
ester, or quaternary ammonium salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of 09/466,034, filed Dec.
17, 1999, which is a continuation of 08/849,726, filed Jun. 30,
1997, now U.S. Pat. No. 6,204,286, which is a .sctn. 371
application of International Application no. PCT/IB95100286, filed
Apr. 24, 1995, which claims priority of 08/369,954, filed Jan. 9,
1995, now U.S. Pat. No. 5,552,412.
FIELD OF THE INVENTION
[0002] This invention relates to estrogen agonists and antagonists
and their use to prevent breast cancer.
BACKGROUND OF THE INVENTION
[0003] The value of naturally occurring estrogens and synthetic
compositions demonstrating "estrogenic" activity has been in their
medical and therapeutic uses. A traditional listing of the
therapeutic applications for estrogens alone or in combination with
other active agents includes: oral contraception; relief for the
symptoms of menopause; prevention of threatened or habitual
abortion; relief of dysmenorrhea; relief of dysfunctional uterine
bleeding; an aid in ovarian development; treatment of acne;
diminution of excessive growth of body hair in women (hirsutism);
the prevention of cardiovascular disease; treatment of
osteoporosis; treatment of prostatic carcinoma; and suppression of
postpartum lactation [Goodman and Gilman, The Pharmacological Basis
Of Therapeutics (Seventh Edition) Macmillan Publishing Company,
1985, pages 1421-1423]. Accordingly, there has been increasing
interest in finding newly synthesized compositions and new uses for
previously known compounds which are demonstrably estrogenic, this
is, able to mimic the action of estrogen in estrogen responsive
tissue.
[0004] From the viewpoint of pharmacologists interested in
developing new drugs useful for the treatment of human diseases and
specific pathological conditions, it is most important to procure
compounds with some demonstrable estrogen-like function but which
are devoid of proliferative side-effects. Exemplifying this latter
view, osteoporosis, a disease in which bone becomes increasingly
more fragile, is greatly ameliorated by the use of fully active
estrogens; however, due to the recognized increased risk of uterine
cancer in patients chronically treated with active estrogens, it is
not clinically advisable to treat osteoporosis in intact women with
fully active estrogens for prolonged periods. Accordingly estrogen
agonists are the primary interest and focus.
[0005] Osteoporosis is a systemic skeletal disease, characterized
by low bone mass and deterioration of bone tissue, with a
consequent increase in bone fragility and susceptibility to
fracture. In the U.S., the condition affects more that 25 million
people and causes more than 1.3 million fractures each year,
including 500,000 spine, 250,000 hip and 240,000 wrist fractures
annually. These cost the nation over $10 billion. Hip fractures are
the most serious, with 5-20% of patients dying within one year, and
over 50% of survivors being incapacitated.
[0006] The elderly are at greatest risk of osteoporosis, and the
problem is therefore predicted to increase significantly with the
aging of the population. Worldwide fracture incidence is forecast
to increase three-fold over the next 60 years, and one study
estimates that there will be 4.5 million hip fractures worldwide in
2050.
[0007] Women are at greater risk of osteoporosis than men. Women
experience a sharp acceleration of bone loss during the five years
following menopause. Other factors that increase the risk include
smoking, alcohol abuse, a sedentary lifestyle and low calcium
intake.
[0008] Estrogen is the agent of choice in preventing osteoporosis
or post menopausal bone loss in women; it is the only treatment
which unequivocally reduces fractures. However, estrogen stimulates
the uterus and is associated with an increased risk of endometrial
cancer. Although the risk of endometrial cancer is thought to be
reduced by a concurrent use of a progestogen, there is still
concern about possible increased risk of breast cancer with the use
of estrogen.
[0009] Black, et al. in EP 0605193A1 report that estrogen,
particularly when taken orally, lowers plasma levels of LDL and
raises those of the beneficial high density lipoproteins (HDL's).
Long-term estrogen therapy, however, has been implicated in a
variety of disorders, including an increase in the risk of uterine
cancer and possibly breast cancer, causing many women to avoid this
treatment. Recently suggested therapeutic regimens, which seek to
lessen the cancer risk, such as administering combinations of
progestogen and estrogen, cause the patient to experience
unacceptable bleeding. Furthermore, combining progesterone with
estrogen seems to blunt the serum cholesterol lowering effects of
estrogen. The significant undesirable effects associated with
estrogen therapy support the need to develop alternative therapies
for hypercholesterolemia that have the desirable effect on serum
LDL but do not cause undesirable effects.
[0010] There is a need for improved estrogen agonists which exert
selective effects on different tissues in the body. Tamoxifen,
1-(4-.beta.-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is
an antiestrogen which has a palliative effect on breast cancer, but
is reported to have estrogenic activity in the uterus. Gill-Sharma,
et al., J. Reproduction and Fertility (1993) 99, 395, disclose that
tamoxifen at 200 and 400 mg/kg/day reduces the weights of the
testes and secondary sex organs in male rats.
[0011] Recently it has been reported (Osteoporosis Conference Scrip
No. 1812/13 Apr. 16/20, 1993, p. 29) that raloxifene,
6-hydroxy-2-(4-hydroxyp- henyl)-3-[4-(2-piperidinoethoxy) benzoyl]
benzo[b] thiophene, mimics the favorable action of estrogen on bone
and lipids but, unlike estrogen, has minimal uterine stimulatory
effect. (Breast Cancer Res. Treat. 10(1). 1987 p 31-36 Jordan, V.C.
et al.).
[0012] Neubauer, et al., The Prostate 23:245 (1993) teach that
raloxifene treatment of male rats produced regression of the
ventral prostate.
[0013] Raloxifene and related compounds are described as
antiestrogen and antiandrogenic materials which are effective in
the treatment of certain mammary and prostate cancers. See U.S.
Pat. No. 4,418,068 and Charles D. Jones, et al., J. Med. Chem.
1984, 27, 1057-1066.
[0014] Jones, et al in U.S. Pat. No. 4,133,814 describe derivatives
of 2-phenyl-3-aroyl-benzothiophene and
2-phenyl-3-aroylbenzothiophene-1-oxid- es which are useful as
antifertility agents as well as suppressing the growth of mammary
tumors.
[0015] Lednicer, et al., J. Med. Chem., 12, 881 (1969) described
estrogen antagonists of the structure 2
[0016] wherein R.sup.2 is phenyl or cyclopentyl and R.sup.3 is H,
3
[0017] or --CH.sub.2CHOHCH.sub.2OH.
[0018] Bencze, et al., J. Med. Chem., 10, 138 (1967) prepared a
series of tetrahydronaphthalenes intended to achieve separation of
estrogenic, antifertility and hypocholesterolemic activities. These
structures are the general formula 4
[0019] wherein R.sup.1 is H or OCH.sub.3; R.sup.2 is H, OH,
OCH.sub.3, OPO(OC.sub.2H.sub.5).sub.2,
OCH.sub.2CH.sub.2N(C.sub.2H.sub.5).sub.2, OCH.sub.2COOH or
OCH(CH.sub.3) COOH.
[0020] U.S. Pat. No. 3,234,090 refers to compounds which have
estrogenic and antifungal properties of the formula 5
[0021] in which Ph is a 1,2-phenylene radical, Ar is a monocyclic
carbocyclic aryl group substituted by tertiary amino-lower
alkyl-oxy, in which tertiary amino is separated from oxy by at
least two carbon atoms, R is hydrogen, an aliphatic radical, a
carbocyclic aryl radical, a carbocyclic aryl-aliphatic radical, a
heterocyclic aryl radical or a heterocyclic aryl aliphatic radical,
the group of the formula--(CnH.sub.2n-2)--stands for an unbranched
alkylene radical having from three to five carbon atoms and
carrying the groups Ar and R, salts, N-oxides, salts of N-oxides or
quatemary ammonium compounds thereof, as well as procedure for the
preparation of such compounds.
[0022] U.S. Pat. No. 3,277,106 refers to basic ethers with
estrogenic, hypocholesterolemic and antifertility effects which are
of the formula 6
[0023] in which Ph is a 1,2-phenylene radical, Ar is a monocyclic
aryl radical substituted by at least one amino-lower alkyl-oxy
group in which the nitrogen atom is separated from the oxygen atom
by at least two carbon atoms, R is an aryl radical, and the portion
--(CnH.sub.2n-2)--stands for lower alkylene forming with Ph a six-
or seven-membered ring, two of the ring carbon atoms thereof carry
the groups Ar and R, salts, N-oxides, salts of N-oxides and
quaternary ammonium compounds thereof.
[0024] Lednicer, et al., in J. Med. Chem. 10, 78 (1967) and in U.S.
Pat. No. 3,274,213 refer to compounds of the formula 7
[0025] wherein R.sub.1 and R.sub.2 are selected from the class
consisting of lower alkyl and lower alkyl linked together to form a
5 to 7 ring member saturated heterocyclic radical.
SUMMARY OF THE INVENTION
[0026] This invention provides compounds of the formula 8
[0027] wherein:
[0028] A is selected from CH.sub.2 and NR;
[0029] B, D and E are independently selected from CH and N;
[0030] Y is
[0031] (a) phenyl, optionally substituted with 1-3 substituents
independently selected from R.sup.4;
[0032] (b) naphthyl, optionally substituted with 1-3 substituents
independently selected from R.sup.4;
[0033] (c) C.sub.3-C.sub.8 cycloalkyl, optionally substituted with
1-2 substituents independently selected from R.sup.4;
[0034] (d) C.sub.3-C.sub.8 cycloalkenyl, optionally substituted
with 1-2 substituents independently selected from R.sup.4;
[0035] (e) a five membered heterocycle containing up to two
heteroatoms selected from the group consisting of --O--,
--NR.sup.2--and --S(O).sub.n--, optionally substituted with 1-3
substituents independently selected from R.sup.4;
[0036] (f) a six membered heterocycle containing up to two
heteroatoms selected from the group consisting of --O--,
--NR.sup.2-- and --S(O).sub.n-- optionally substituted with 1-3
substituents independently selected from R.sup.4; or
[0037] (g) a bicyclic ring system consisting of a five or six
membered heterocyclic ring fused to a phenyl ring, said
heterocyclic ring containing up to two heteroatoms selected from
the group consisting of --O--, --NR .sup.2-- and --S(O).sub.n--,
optionally substituted with 1-3 substituents independently selected
from R.sup.4;
[0038] Z.sup.1 is
[0039] (a) --(CH.sub.2).sub.p W(CH.sub.2).sub.q--;
[0040] (b) --O(CH.sub.2).sub.p CR.sup.5R.sup.6--;
[0041] (c) --O(CH.sub.2).sub.pW(CH.sub.2).sub.q--;
[0042] (d) --OCHR.sup.2CHR.sup.3--; or
[0043] (e) --SCHR.sup.2CHR.sup.3--;
[0044] G is
[0045] (a) --NR.sup.7R.sup.8;
[0046] (b) 9
[0047] wherein n is 0, 1 or 2; m is 1, 2 or 3; Z.sup.2 is --NH--,
--O--, --S--, or --CH.sub.2--; optionally fused on adjacent carbon
atoms with one or two phenyl rings and, optionally independently
substituted on carbon with one to three substituents and,
optionally, independently on nitrogen with a chemically suitable
substituent selected from R.sup.4; or
[0048] (c) a bicyclic amine containing five to twelve carbon atoms,
either bridged or fused and optionally substituted with 1-3
substituents independently selected from R.sup.4; or
[0049] Z.sup.1 and G in combination may be 10
[0050] W is
[0051] (a) --CH.sub.2--;
[0052] (b) --CH.dbd.CH--;
[0053] (c) --O--;
[0054] (d) --NR.sup.2--;
[0055] (e) --S(O).sub.n--;
[0056] (f) 11
[0057] (g) --CR.sup.2(OH)--;
[0058] (h) --CONR.sup.2--;
[0059] (i) --NR.sup.2CO--;
[0060] (j) 12
[0061] (k) --C.ident.C--;
[0062] R is hydrogen or C.sub.1-C.sub.6 alkyl;
[0063] R.sup.2 and R.sup.3 are independently
[0064] (a) hydrogen; or
[0065] (b) C.sub.1-C.sub.4 alkyl;
[0066] R.sup.4is
[0067] (a) hydrogen;
[0068] (b) halogen;
[0069] (c) C.sub.1-C.sub.6 alkyl;
[0070] (d) C.sub.1-C.sub.4 alkoxy;
[0071] (e) C.sub.1-C.sub.4 acyloxy;
[0072] (f) C.sub.1-C.sub.4 alkylthio;
[0073] (g) C.sub.1-C.sub.4 alkylsulfinyl;
[0074] (h) C.sub.1-C.sub.4 alkylsulfonyl;
[0075] (i) hydroxy (C.sub.1-C.sub.4)alkyl;
[0076] (j) aryl (C.sub.1-C.sub.4)alkyl;
[0077] (k) --CO.sub.2H;
[0078] (l) --CN;
[0079] (m) --CONHOR;
[0080] (n) --SO.sub.2NHR;
[0081] (o) --NH.sub.2;
[0082] (p) C.sub.1-C.sub.4 alkylamino;
[0083] (q) C.sub.1-C.sub.4 dialkylamino;
[0084] (r) --NHSO.sub.2R;
[0085] (s) --NO.sub.2;
[0086] (t) -aryl; or
[0087] (u) --OH.
[0088] R.sup.5 and R.sup.6 are independently C.sub.1-C.sub.8 alkyl
or together form a C.sub.3-C.sub.10 carbocyclic ring;
[0089] R.sup.7 and R.sup.8 are independently
[0090] (a) phenyl;
[0091] (b) a C.sub.3-C.sub.10 carbocyclic ring, saturated or
unsaturated;
[0092] (c) a C.sub.3-C.sub.10 heterocyclic ring containing up to
two heteroatoms, selected from --O--, --N-- and --S--;
[0093] (d) H;
[0094] (e) C.sub.1-C.sub.6 alkyl; or
[0095] (f) form a 3 to 8 membered nitrogen containing ring with
R.sup.5 or R.sup.6;
[0096] R.sup.7 and R.sup.8 in either linear or ring form may
optionally be substituted with up to three substituents
independently selected from C.sub.1-C.sub.6 alkyl, halogen, alkoxy,
hydroxy and carboxy;
[0097] a ring formed by R.sup.7 and R.sup.8 may be optionally fused
to a phenyl ring;
[0098] e is 0, 1 or 2;
[0099] m is 1, 2 or 3;
[0100] n is 0, 1 or 2;
[0101] p is 0, 1, 2 or 3;
[0102] q is 0, 1, 2 or 3;
[0103] and optical and geometric isomers thereof; and nontoxic
pharmacologically acceptable acid addition salts, N-oxides, and
quaternary ammonium salts thereof.
[0104] Preferred compounds of the invention are of the formula:
13
[0105] R.sup.4 is H, OH, F, or Cl; and B and E are independently
selected from CH and N.
[0106] Especially preferred compunds are:
[0107]
Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6
,7,8-tetrahydro-naphthalen-2-ol;
[0108]
(-)-Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yI-ethoxy)-phenyl]-5,6,7,8-te-
trahydro-naphthalen-2-ol;
[0109]
Cis-6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tetrah-
ydro-naphthalen-2-ol;
[0110]
Cis-1-[6'-pyrrolodinoethoxy-3'-pyridyl]-2-phenyl-6-hydroxy-1,
2,3,4-tetrahydrohaphthalene;
[0111]
1-(4'-Pyrrolidinoethoxyphenyl)-2-(4"-fluorophenyl)-6-hydroxy-1
,2,3,4-tetrahydroisoquinoline;
[0112]
Cis-6-(4-hydroxyphenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,-
7,8-tetrahydro-naphthalen-2-ol; and
[0113]
1-(4'-Pyrrolidinolethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahyd-
roisoquinoline.
[0114] In another aspect this invention provides methods of
treating or preventing a condition selected from breast cancer,
osteoporosis, endometriosis and cardiovascular disease and
hypercholesterolemia in male or female mammals and benign prostatic
hypertrophy and prostatic carcinomas in male mammals which
comprises administering to said mammal an amount of a compound of
formula I and preferably a preferred compound of formula I
compounds as described above which is effective in treating or
preventing said condition.
[0115] In another aspect this invention provides a method of
treating or preventing obesity in mammals which comprises
administering to said mammal an amount of a compound of formula I
and preferably a preferred compound of formula I as described above
which is effective in treating or preventing obesity.
[0116] In yet another aspect this invention provides a
pharmaceutical composition for treating or preventing breast
cancer, osteoporosis, obesity, cardiovascular disease,
hypercholesterolemia, endometriosis and prostatic disease
comprising a compound of formula I and a pharmaceutically
acceptable carrier.
[0117] In another aspect, this invention provides intermediate
compounds useful in preparing compounds of formula I. These are
1-{2-[4-(6-Methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrrolidine
and 1-{2-[4-(2-Bromo-6-methoxy-3,
4-dihydronaphthalen-1-yl)phenoxy]ethyl}- pyrrolidine.
DETAILED DESCRIPTION OF THE INVENTION
[0118] The terms C.sub.1-C.sub.3 chloroalkyl and C.sub.1-C.sub.3
fluoroalkyl include methyl, ethyl, propyl and isopropyl substituted
to any desired degree with chlorine or fluorine atoms, from one
atom to full substitution. The term C.sub.5-C.sub.7 cycloalkyl
includes cyclopentyl, cyclohexyl and cycloheptyl.
[0119] Halo means chloro, bromo, iodo and fluoro. Aryl (Ar)
includes phenyl and naphthyl optionally substituted with one to
three substituents independently selected from R.sup.4 as defined
above. DTT means dithiothreitol. DMSO means dimethyl sulfoxide.
EDTA means ethylene diamine tetra acetic acid.
[0120] Estrogen agonists are herein defined as chemical compounds
capable of binding to the estrogen receptor sites in mammalian
tissue, and mimicking the actions of estrogen in one or more
tissues.
[0121] Estrogen antagonists are herein defined as chemical
compounds capable of binding to the estrogen receptor sites in
mammalian tissue, and blocking the actions of estrogen in one or
more tissues.
[0122] One of ordinary skill will recognize that certain
substituents listed in this invention will be chemically
incompatible with one another or with the heteroatoms in the
compounds, and will avoid these incompatibilities in selecting
compounds of this invention. Likewise certain functional groups may
require protecting groups during synthetic procedures which the
chemist of ordinary skill will recognize.
[0123] The chemist of ordinary skill will recognize that certain
compounds of this invention will contain atoms which may be in a
particular optical or geometric configuration. All such isomers are
included in this invention; exemplary levorotatory isomers in the
cis configuration are preferred. Likewise, the chemist will
recognize that various pharmaceutically acceptable esters and salts
may be prepared from certain compounds of this invention. All of
such esters and salts are included in this invention.
[0124] As used in this application, prostatic disease means benign
prostatic hyperplasia or prostatic carcinoma.
[0125] The remedies for the prostatic diseases, breast cancer,
obesity, cardiovascular disease, hypercholesterolemia and
osteoporosis of this invention comprise, as active ingredient, a
compound of formula I or a salt or ester thereof. The
pharmaceutically acceptable salts of the compounds of formula I are
salts of non-toxic type commonly used, such as salts with organic
acids (e.g., formic, acetic, trifluoroacetic, citric, maleic,
tartaric, methanesulfonic, benzenesulfonic or toluenesulfonic
acids), inorganic acids (e.g. hydrochloric, hydrobromic, sulfuric
or phosphoric acids), and amino acids (e.g., aspartic or glutamic
acids). These salts may be prepared by the methods known to
chemists of ordinary skill.
[0126] The remedies for prostatic diseases, breast cancer, obesity,
cardiovascular disease, hypercholesterolemia and osteoporosis of
this invention may be administered to animals including humans
orally or parenterally in the conventional form of preparations,
such as capsules, microcapsules, tablets, granules, powder,
troches, pills, suppositories, injections, suspensions and
syrups.
[0127] The remedies for prostatic diseases, breast cancer, obesity,
cardiovascular disease, hypercholesterolemia and osteoporosis of
this invention can be prepared by the methods commonly employed
using conventional, organic or inorganic additives, such as an
excipient (e.g., sucrose, starch, mannitol, sorbitol, lactose,
glucose, cellulose, talc, calcium phosphate or calcium carbonate),
a binder (e.g., cellulose, methylcellulose, hydroxymethylcellulose,
polypropylpyrrolidone, polyvinylprrolidone, gelatin, gum arabic,
polyethyleneglycol, sucrose or starch), a disintegrator (e.g.,
starch, carboxymethylcellulose, hydroxypropylstarch, low
substituted hydroxypropylcellulose, sodium bicarbonate, calcium
phosphate or calcium citrate), a lubricant (e.g., magnesium
stearate, light anhydrous silicic acid, talc or sodium lauryl
sulfate), a flavoring agent (e.g., citric acid, menthol, glycine or
orange powder), a preservative (e.g., sodium benzoate, sodium
bisulfite, methylparaben or propylparaben), a stabilizer (e.g.,
citric acid, sodium citrate or acetic acid), a suspending agent
(e.g., methylcellulose, polyvinylpyrrolidone or aluminum stearate),
a dispersing agent (e.g., hydroxypropylmethylcellulose), a diluent
(e.g., water), and base wax (e.g., cocoa butter, white petrolatum
or polyethylene glycol). The amount of the active ingredient in the
medical composition may be at a level that will exercise the
desired therapeutical effect; for example, about 0.1 mg to 50 mg in
unit dosage for both oral and parenteral administration.
[0128] The active ingredient may be usually administered once to
four times a day with a unit dosage of 0.1 mg to 50 mg in human
patients, but the above dosage may be properly varied depending on
the age, body weight and medical condition of the patient and the
type of administration. A preferred dose is 0.25 mg to 25 mg in
human patients. One dose per day is preferred.
[0129] Compounds of this invention are readily prepared by the
reactions illustrated in the schemes below.
[0130] Certain compounds of formula I are conveniently prepared
from an unsaturated intermediate 14
[0131] by hydrogenation with a noble metal catalyst in a reaction
inert solvent. Pressure and temperatures are not critical and
hydrogenation is normally accomplished in a few hours at room
temperatures at 20-80 psi hydrogen pressure.
[0132] The hydrogenated product is isolated, purified if desired,
and the ether group is cleaved with an acidic catalyst in a
reaction inert solvent at a temperature between 0.degree. C. to
100.degree. C. depending on the acidic catalyst used . Hydrogen
bromide at elevated temperatures, boron tribromide and aluminum
chloride at 0.degree. C. to ambient temperature have been found to
be effective for this reaction.
[0133] The product, Formula I is isolated and purified by standard
procedures.
[0134] Intermediates of Formula II where A is CH.sub.2, and B, D
and E are CH are described in U.S. Pat. No. 3,274,213; J. Med. Chem
10, 78 (1967); J. Med. Chem 10, 138 (1967); and J. Med. Chem. 12,
881 (1969), the disclosures of which are herein incorporated by
reference. They can also be prepared by procedures described
below.
[0135] The preparation of the compounds of Formula I where e=1,
A=CH.sub.2, Z.sup.1=OCH.sub.2CH.sub.2, G=cycloalkylamine, B=CH is
shown in Scheme 1. Compounds 1-2, where D and E are CH are made by
alkylation of 4-bromophenol with the corresponding
N-chloroethylamine using potassium carbonate as base in a polar
aprotic solvent like dimethylformamide at elevated temperatures. A
preferred temperature is 100.degree. C. Compounds 1-2 where D or E
or both are N are synthesized using a nucleophilic displacement
reaction performed on dibromides (1-1) using hydroxy ethyl
cycloalkylamines under phase transfer conditions to afford bromo
amines (1-2). Synthesis, 77, 573 (1980). Following halogen metal
exchange using n-butyllithium or magnesium metal, bromo amines
(1-2) yield the corresponding lithium or magnesium reagents which
are allowed to react at low temperature in the presence of cesium
chloride preferably (without cesium chloride the reaction also
proceeds) with 6-methoxy-1-tetralone to afford either carbinols
(1-3) or styrenes (1-4) after acidic workup. Treatment of either
carbinols (1-3) or styrenes (1-4) with a brominating agent such as
pyridinium bromide perbromide affords bromo styrenes (1-5). Aryl or
heteroaryl zinc chlorides or aryl or heteroaryl boronic acids react
with bromides (1-5) in the presence of a palladium metal catalyst
like tetrakis triphenyl phosphine palladium (0) to yield diaryl
styrenes (1-6). [Pure & Applied Chem. 63, 419,(1991) and Bull.
Chem. Soc. Jpn. 61, 3008-3010, (1988)] To prepare the preferred
compounds the substituted phenyl zinc chlorides or substituted
phenylboronic acids are used in this reaction. The aryl zinc
chlorides are prepared by quench of the corresponding lithium
reagent with anhydrous zinc chloride. The aryl boronic acids, that
are not commercially available, are prepared by quenching the
corresponding aryl lithium reagent with trialkyl borate, preferably
the trimethyl or triisopropyl borate, followed by aqueous acid
workup. Acta Chemica Scan. 47, 221-230 (1993). The lithium reagents
that are not commercially available are prepared by halogen metal
exchange of the corresponding bromide or halide with n-butyl or
t-butyllithium. Alternately, the lithium reagent is prepared by
heteroatom facilitated lithiations as described in Organic
Reactions, Volume 27, Chapter 1. Catalytic hydrogenation of 1-6 in
the presence of palladium hydroxide on charcoal, for example,
affords the corresponding dihydro methoxy intermediates which were
subsequently demethylated using boron tribromide at 0.degree. C. in
methylene chloride or 48% hydrogen bromide in acetic acid at
80-100.degree. C. to afford target structures (1-7). These
compounds are racemic and can be resolved into the enantiomers via
high pressure liquid chromatography using a column with a chiral
stationary phase like the Chiralcel OD columns. Alternately optical
resolution can be carried out by recrystallization of the
diastereomeric salts formed with optically pure acids like
1,1'-binapthyl-2,2'-diyl hydrogen phosphate (see Example 8).
[0136] The cis compounds (1-7) can be isomerized to the trans
compounds on treatment with base (see Example 2).
[0137] When D and/or E is nitrogen the intermediates (Formula II)
and compounds of Formula I may be prepared from the corresponding
dihalopyridines or pyrimidines as illustrated in Scheme 1 and as
fully described for 6-phenyl-5-[6-(2-pyrrolidin-1-yl- ethoxy)
pyridin-3-yl]-5,6,7,8-tetrahydronaphthalen-2-ol in Example 6.
[0138] The methyl ether of the compound of Formula I where e=1,
A=CH.sub.2, Z.sup.1=OCH.sub.2CH.sub.2, G=pyrrolidine, D,E, B=CH,
Y=Ph can also be conveniently prepared by a first step of
hydrogenation of nafoxidine (Upjohn & Co., 700 Portage Road,
Kalamazoo, Mich. 49001) in a reaction inert solvent in the presence
of a nobel metal catalyst. Pressure and temperature are not
critical; the reaction is conveniently run in ethanol at room
temperature for approximately 20 hours at 50 psi.
[0139] The second step is cleavage of the methoxy group which is
accomplished conveniently at room temperature with an acidic
catalyst such as boron tribromide in a reaction inert solvent or at
80-100.degree. C. with hydrogen bromide in acetic acid. The product
is then isolated by conventional methods and converted to an acid
salt if desired. 15
[0140] Compounds of formula I wherein B is nitrogen are prepared by
the procedures illustrated in Scheme 2 and 3 and Examples 3-5 and
10-12.
[0141] The synthesis of compounds of Formula I where B=N is shown
in Scheme 2. Aryl acid chlorides (2-1) on treatment with primary
amines afford aryl secondary amides (2-2), which are reduced with
lithium aluminum hydride in ethereal solvents to yield secondary
amines (2-3). Subsequent acylation of (2-3) with aroyl acid
chlorides leads to tertiary amides (2-4), which are cyclized in hot
phosphorus oxychloride to yield dihydro isoquinolinium salts (2-5).
Reduction with sodium borohydride to alkoxytetrahydro
isoquinolines; followed by boron tribromide demethylation in
methylene chloride affords the target structures. 16
[0142] The synthesis of the compounds of Formula I where B=N is
also described below in Scheme 3. Secondary amines (3-1) on
acylation with benzyloxyaroyl chlorides (3-2) afford tertiary
amides (3-3) which on cyclization with hot phosphorous oxychloride
yield dihydro isoquinoline salts (3-4). Sodium borohydride
reduction of (3-4) followed by debenzylation with aqueous
hydrochloric acid affords isoquinolines (3-5), which are alkylated
with the appropriately functionalized chlorides and demethylated
with boron tribromide to yield the desired target structures.
17
[0143] The compounds of this invention are valuable estrogen
agonists and pharmaceutical agents or intermediates thereto. Those
which are estrogen agonists are useful for oral contraception;
relief for the symptoms of menopause; prevention of threatened or
habitual abortion; relief of dysmenorrhea; relief of dysfunctional
uterine bleeding; relief of endometriosis; an aid in ovarian
development; treatment of acne; diminution of excessive growth of
body hair in women (hirsutism); the prevention and treatment of
cardiovascular disease; prevention and treatment of
atherosclerosis; prevention and treatment of osteoporosis;
treatment of benign prostatic hyperplasia and prostatic carcinoma
obesity; and suppression of post-partum lactation, These agents
also have a beneficial effect on plasma lipid levels and as such
are useful in treating and preventing hypercholesterolemia.
[0144] While the compounds of this invention are estrogen agonists
in bone, they are also antiestrogens in breast tissue and as such
would be useful in the treatment and prevention of breast
cancer.
[0145] Control and Prevention of Endometriosis
[0146] The protocol for surgically inducing endometriosis is
identical to that described by Jones, Acta Endoerinol (Copenh)
106:282-8. Adult Charles River Sprague-Dawley CD.RTM. female rats
(200-240 g) are used. An oblique ventral incision is made through
the skin and musculature of the body wall. A segment of the right
uterine horn is excised, the myometrium is separated from the
endometrium, and the segment is cut longitudinally. A 5.times.5 mm
section of the endometrium, with the epithelial lining apposed to
the body wall, is sutured at its four corners to the muscle using
polyester braid (Ethiflex, 7-0.RTM.). The criterion of a viable
graft is the accumulation of fluid similar to that which occurs in
the uterus as a result of oestrogen stimulation.
[0147] Three weeks after transplantation of the endometrial tissue
(+3 weeks) the animals are laparotomized, the volume of the explant
(length.times.width.times.height) in mm was measured with calipers,
and treatment is begun. The animals are injected sc for 3 weeks
with 10 to 1000 .mu.g/kg/day of a compound of Formula I. Animals
bearing endometrial explants are injected sc with 0.1 ml/day of
corn oil for 3 weeks served as controls. At the end of 3 week
treatment period (+6 weeks), the animals are laparotomized and the
volume of the explant determined. Eight weeks after cessation of
treatment (+14 weeks) the animals are sacrificed; the explant are
measured again. Statistical analysis of the explant volume is by an
analysis of variance.
[0148] Effect on Prostate Weight
[0149] Male Sprague-Dawley rats, three months of age are
administered by subcutaneous injection either vehicle (10% ethanol
in water), estradiol (30 .mu.g/kg), testosterone (1 mg/kg) or a
compound of formula I daily for 14 days (n=6/group). After 14 days
the animals are sacrificed, the prostate is removed and the wet
prostate weight is determined. Mean weight is determined and
statistical significance (p<0.05) is determined compared to the
vehicle-treated group using Student's t-test.
[0150] The compounds of formula I significantly (P<0.05)
decrease prostate weight compared to vehicle. Testosterone has no
effect while estrogen at 30 .mu.g/kg significantly reduces prostate
weight.
[0151] Bone Mineral Density
[0152] Bone mineral density, a measure of bone mineral content,
accounts for greater than 80% of a bone's strength. Loss of bone
mineral density with age and/or disease reduces a bone's strength
and renders it more prone to fracture. Bone mineral content is
accurately measured in people and animals by dual x-ray
absorptiometry (DEXA) such that changes as little as 1% can be
quantified. We have utilized DEXA to evaluate changes in bone
mineral density due to estrogen deficiency following ovariectomy
(surgical removal of ovaries) and treatment with vehicle, estradiol
(E2), keoxifen (raloxifen), or other estrogen agonists. The purpose
of these studies is to evaluate the ability of the compounds of
this invention to prevent estrogen deficiency bone loss as measured
by DEXA.
[0153] Female (S-D) rats 4-6 months of age undergo bilateral
ovariectomy or sham surgery and allowed to recover from anesthesia.
Rats are treated by s.c. injection or oral gavage with various
doses (10-1000 .mu.g/kg/day, for example) of compound of Formula I
daily for 28 days. All compounds are weighed and dissolved in 10%
ethanol in sterile saline. After 28 days the rats are killed and
femora removed and defleshed. The femoral are positioned on a
Hologic QDR1000W (Hologic, Inc. Waltham, Mass.) and bone mineral
density is determined in the distal portion of the femur at a site
from 1 cm to 2 cm from the distal end of the femur using the high
resolution software supplied by Hologic. Bone mineral density is
determined by dividing the bone mineral content by the bone area of
the distal femur. Each group contains at least 6 animals. Mean bone
mineral density is obtained for each animal and statistical
differences (p<0.05) from the vehicle-treated ovariectomy and
sham-operated group were determined by t test.
[0154] In vitro Estrogen Receptor Binding Assay
[0155] An in vitro estrogen receptor binding assay, which measures
the ability of the compounds of the present invention to displace
[3H]-estradiol from human estrogen receptor obtained by recombinant
methods in yeast, is used to determine the estrogen receptor
binding affinity of the compounds of this invention. The materials
used in this assay are: (1) Assay buffer, TD-0.3 (containing 10 nM
Tris, pH 7.6, 0.3 M potassium chloride and 5 mM DTT, pH 7.6); (2)
The radioligand used is [3H]-estradiol obtained from New England
Nuclear; (3) the cold ligand used is estradiol obtained from Sigma
(4) recombinant human estrogen receptor, hER.
[0156] A solution of the compound being tested is prepared in
TD-0.3 with 4% DMSO and 16% ethanol. The tritiated estradiol is
dissolved in TD-0.3 such that the final concentration in the assay
was 5nM. The hER is also diluted with TD-0.3 such that 4-10 .mu.g
of total protein was in each assay well. Using microtitre plates,
each incubate received 50 ul of cold estradiol (nonspecific
binding) or the compound solution, 20 uL of the tritiated estradiol
and 30 ul of hER solutions. Each plate contains in triplicate total
binding and varying concentrations of the compound. The plates are
incubated overnight at 4.degree. C. The binding reaction is then
terminated by the addition and mixing of 100 mL of 3%
hydroxylapatite in 10 mM tris, pH 7.6 and incubation for 15 minutes
at 4.degree. C. The mixtures is centrifuged and the pellet washed
four times with 1% Triton-X100 in 10 mM Tris, pH 7.6. The
hydroxylapatite pellets are suspended in Ecoscint A and
radioactivity is assessed using beta scintigraphy. The mean of all
triplicate data points (counts per minute, cpm's) is determined.
Specific binding is calculated by subtracting nonspecific cpm's
(defined as counts that remain following separation of reaction
mixture containing recombinant receptor, radioligand, and excess
unlabeled ligand) from total bound cpm's (defined as counts that
remain following the separation of reaction mixture containing only
recombinant receptor, radioligand). Compound potency is determined
by means of IC50 determinations (the concentration of a compound
needed to inhibition 50% of the of the total specific tritiated
estradiol bound). Specific binding in the presence of varying
concentrations of compound is determined and calculated as percent
specific binding of total specific radioligand bound. Data are
plotted as percent inhibition by compound (linear scale) versus
compound concentration (log scale).
[0157] Effect on Total Cholesterol Levels
[0158] The effect of the compounds of the present invention on
plasma levels of total cholesterol is measured in the following
way. Blood samples are collected via cardiac puncture from
anesthetized female (S-D) rats 4-6 months of age that are
bilaterally ovariectomized and treated with the compound (10-1000
.mu.g/kg/day, for example, sc or orally for 28 days or with vehicle
for the same time), or sham operated. The blood is placed in a tube
containing 30.mu.L of 5% EDTA (10.mu.L EDTA/1 mL of blood). After
centrifugation at 2500 rpm for 10 minutes at 20.degree. C. the
plasma is removed and stored at -20.degree. C. unit assay. The
total cholesterol is assayed using a standard enzymatic
determination kit from Sigma Diagnostics (Procedure No. 352).
[0159] Effect on Obesity
[0160] Sprague-Dawley female rats at 10 months of age, weighing
approximately 450 grams, are sham-operated (sham) or ovariectomized
(OVX) and treated orally with vehicle, 17.alpha. ethynyl estradiol
at 30 .mu.g/kg/day or a compound of formula I at 10-1000
.mu.g/kg/day for 8 weeks. There are 6 to 7 rats in each sub group.
On the last day of the study, body composition of all rats is
determined using dual energy x-ray abosorptiometry (Hologic
QDR-1000/W) equipped with whole body scan software which shows the
proportions of fat body mass and lean body mass.
[0161] A decrease in fat body mass indicates that the estrogen
agonists of formula I are useful in preventing and treating
obesity.
[0162] Pharmaceutical chemists will easily recognize that
physiologically active compounds which have accessible hydroxy
groups are frequently administered in the form of pharmaceutically
acceptable esters. The literature concerning such compounds, such
as estradiol, provides a great number of instances of such esters.
The compounds of this invention are no exception in this respect,
and can be effectively administered as an ester, formed on the
hydroxy groups, just as one skilled in pharmaceutical chemistry
would expect. While the mechanism has not yet been investigated, it
is believed that esters are metabolically cleaved in the body, and
that the actual drug, which such form is administered, is the
hydroxy compound itself. It is possible, as has long been known in
pharmaceutical chemistry, to adjust the rate or duration of action
of the compound by appropriate choices of ester groups.
[0163] Certain ester groups are preferred as constituents of the
compounds of this invention. The compounds of formula I may contain
ester groups at various portions as defined herein above, where
these groups are represented as --COOR.sup.9. R.sup.9 is
C.sub.1-C.sub.14 alkyl, C.sub.1-C.sub.3 chloroalkyl,
C.sub.1-C.sub.3 fluoroalkyl, C.sub.5-C.sub.7 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, phenyl, or phenyl mono- or disubstituted
with C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, hydroxy, nitro,
chloro, fluoro or tri(chloro or fluoro)methyl.
[0164] The pharmaceutically acceptable acid addition salts of the
compounds of this invention may be formed of the compound itself,
or of any of its esters, and include the pharmaceutically
acceptable salts which are often used in pharmaceutical chemistry.
For example, salts may be formed with inorganic or organic acids
such as hydrochloric acid, hydrobromic acid, hydroiodic acid,
sulfonic acids including such agents as naphthalenesulfonic,
methanesulfonic and toluenesulfonic acids, sulfuric acid, nitric
acid, phosphoric acid, tartaric acid, pyrosulfuric acid,
metaphosphoric acid, succinic acid, formic acid, phthalic acid,
lactic acid and the like, most preferable with hydrochloric acid,
citric acid, benzoic acid, maleic acid, acetic acid and propionic
acid. It is usually preferred to administer a compound of this
invention in the form of an acid addition salt, as it is customary
in the administration of pharmaceuticals bearing a basic group such
as the pyrrolidino ring.
[0165] The compounds of this invention, as discussed above, are
very often administered in the form of acid addition salts. The
salts are conveniently formed, as is usual in organic chemistry, by
reacting the compound of this invention with a suitable acid, such
as have been described above. The salts are quickly formed in high
yields at moderate temperatures, and often are prepared by merely
isolating the compound from a suitable acidic wash as the final
step of the synthesis. The salt-forming acid is dissolved in an
appropriate organic solvent, or aqueous organic solvent, such as an
alkanol, ketone or ester. On the other hand, if the compound of
this invention is desired in the free base form, it is isolated
from a basic final wash step, according to the usual practice. A
preferred technique for preparing hydrochlorides is to dissolve the
free base in a suitable solvent and dry the solution thoroughly, as
over molecular sieves, before bubbling hydrogen chloride gas
through it.
[0166] The dose of a compound of this invention to be administered
to a human is rather widely variable and subject to the judgement
of the attending physician. It should be noted that it may be
necessary to adjust the dose of a compound when it is administered
in the form of a salt, such as a laureate, the salt forming moiety
of which has an appreciable molecular weight. The general range of
effective administration rates of the compounds is from about 0.05
mg/day to about 50 mg/day. A preferred rate range is from about
0.25 mg/day to 25 mg/day. Of course, it is often practical to
administer the daily dose of compound in portions, at various hours
of the day.
[0167] However, in any given case, the amount of compound
administered will depend on such factors as the solubility of the
active component, the formulation used and the route of
administration.
[0168] The route of administration of the compounds of this
invention is not critical. The compounds are known to be absorbed
from the alimentary tract, and so it is usually preferred to
administer a compound orally for reasons of convenience. However,
the compounds may equally effectively be administered
percutaneously, or as suppositories for absorption by the rectum,
if desired in a given instance.
[0169] The compounds of this invention are usually administered as
pharmaceutical compositions which are important and novel
embodiments of the invention because of the presence of the
compounds. All of the usual types of compositions may be used,
including tablets, chewable tablets, capsules, solutions,
parenteral solutions, troches, suppositories and suspensions.
Compositions are formulated to contain a daily dose, or a
convenient fraction of daily dose, in a dosage unit, which may be a
single tablet or capsule or convenient volume of a liquid.
[0170] Any of the compounds may be readily formulated as tablets,
capsules and the like; it is preferable to prepare solutions from
water-soluble salts, such as the hydrochloride salt.
[0171] In general, all of the compositions are prepared according
to methods usual in pharmaceutical chemistry.
[0172] Capsules are prepared by mixing the compound with a suitable
diluent and filling the proper amount of the mixture in capsules.
The usual diluents include inert powdered substances such as starch
of many different kinds, powdered cellulose, especially crystalline
and microcrystalline cellulose, sugars such as fructose, mannitol
and sucrose, grain flours and similar edible powders.
[0173] Tablets are prepared by direct compression, by wet
granulation, or by dry granulation. Their formulations usually
incorporate diluents, binders, lubricants and disintegrators as
well as the compound. Typical diluents include, for example,
various types of starch, lactose, mannitol, kaolin, calcium
phosphate or sulfate, inorganic salts such as sodium chloride and
powdered sugar. Powdered cellulose derivatives are also useful.
Typical tablet binders are substances such as starch, gelatin and
sugars such as lactose, fructose, glucose and the like. Natural and
synthetic gums are also convenient, including acacia, alginates,
methylcellulose, polyvinylpyrrolidine and the like. Polyethylene
glycol, ethylcellulose and waxes can also serve as binders.
[0174] A lubricant is necessary in a tablet formulation to prevent
the tablet and punches from sticking in the die. The lubricant is
chosen from such slippery solids as talc, magnesium and calcium
stearate, stearic acid and hydrogenated vegetable oils.
[0175] Tablet disintegrators are substances which swell when wetted
to break up the tablet and release the compound. They include
starches, clays, celluloses, algins and gums. More particularly,
corn and potato starches, methylcellulose, agar, bentonite, wood
cellulose, powdered natural sponge, cation-exchange resins, alginic
acid, guar gum, citrus pulp and carboxymethylcellulose, for
example, may be used as well as sodium lauryl sulfate.
[0176] Tablets are often coated with sugar as a flavor and sealant,
or with film-forming protecting agents to modify the dissolution
properties of the tablet. The compounds may also be formulated as
chewable tablets, by using large amounts of pleasant-tasting
substances such as mannitol in the formulation, as is now
well-established in the art.
[0177] When it is desired to administer a compound as a
suppository, the typical bases may be used. Cocoa butter is a
traditional suppository base, which may be modified by addition of
waxes to raise its melting point slightly. Water-miscible
suppository bases comprising, particularly, polyethylene glycols of
various molecular weights are in wide use.
[0178] The effect of the compounds may be delayed or prolonged by
proper formulation. For example, a slowly soluble pellet of the
compound may be prepared and incorporated in a tablet or capsule.
The technique may be improved by making pellets of several
different dissolution rates and filling capsules with a mixture of
the pellets. Tablets or capsules may be coated with a film which
resists dissolution for a predictable period of time. Even the
parenteral preparations may be made long-acting, by dissolving or
suspending the compound in oily or emulsified vehicles which allow
it to disperse only slowly in the serum.
[0179] The following examples will serve to illustrate, but do not
limit, the invention which is defined by the claims.
EXAMPLES
EXAMPLE 1
Cis-6-phenyl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl-5,6,7,8-tetrahvdronaphth-
alen-2-ol
Step A
[0180] cis-1-{2-[4-(6-Methoxy-2-phenyl-1
,2,3,4-tetrahydronaphthalen-1-yl)- phenoxy]ethyl}pyrrolidine.
[0181] A solution of
1-{{2-[4-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1--
yl)phenoxy]ethyl}pyrrolidine hydrochloride (nafoxidene
hydrochloride) (1.0 g, 2.16 mmol) in 20 mL of absolute ethanol
containing 1.0 g of palladium hydroxide on carbon was hydrogenated
at 50 psi at 20.degree. C. for 19 hr. Filtration and evaporation
provided 863 mg (93%) of
cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)phenoxy-
]ethyl}pyrrolidine: .sup.1H-NMR (CDCl.sub.3): .delta. 3.50-3.80 (m,
3H), 3.85 (s, 3H), 4.20-4.40 (m, 3H), 6.80-7.00 (m, 3H); MS 428
(P.sup.++1).
Step B
[0182] To a solution of 400 mg (0.94 mmol) of the product from Step
A in 25 ml of methylene chloride at 0.degree. C. was added,
dropwise with stirring, 4.7 ml (4.7 mmol) of a 1.0 M solution of
boron tribromide in methylene chloride. After 3 hours at room
temperature, the reaction was poured into 100 ml of rapidly
stirring satd aq sodium -20 bicarbonate. The organic layer was
separated, dried over sodium sulfate, filtered, and concentrated to
afford 287 mg (74% yield) of the title substance as the free base.
.sup.1H-NMR (CDCl.sub.3): .delta.3.35 (dd, 1H), 4.00 (t, 2H), 4.21
(d, 1H), 6.35 (ABq, 4H). The corresponding hydrochloride salt was
prepared by treating a solution of the base with excess 4N HCl in
dioxane, followed by evaporation to dryness and ether trituration
(MS: 415 [P.sup.++1]).
[0183] An alternative method useful for the preparation of Example
1 is described below.
Step A
[0184]
1-{2-[4-(6-Methoxy-3,4-dihydronaphthalen-1-yl)phenoxy]ethyl}pyrroli-
dine:
[0185] A mixture of anhydrous CeCl.sub.3 (138 g, 560 mmol) and THF
(500 mL) was vigorously stirred for 2 h. In a separate flask, a
solution of 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (100 g, 370
mmol) in THF (1000 mL) was cooled to -78.degree. C. and n-BuLi (2.6
M in hexanes, 169 mL, 440 mmol) was slowly added over 20 min. After
15 min, the solution was added to the CeCl.sub.3 slurry cooled at
-78.degree. C. via cannula and the reaction was stirred for 2 h at
-78.degree. C. A solution of 6-methoxy-1-tetralone (65.2 g, 370
mmol) in THF (1000 mL) at -78.degree. C. was added to the
arylcerium reagent via cannula. The reaction was allowed to warm
slowly to room temperature and was stirred for a total of 16 h. The
mixture was filtered through a pad of celite. The filtrate was
concentrated in vacuo and 3 N HCl (500 mL) and Et.sub.2O (500 mL)
were added. After stirring for 15 min, the layers were separated.
The aqueous layer was further washed with Et.sub.2O (2x). The
combined organic layers were dried (MgSO.sub.4), filtered, and
concentrated to provide 6-methoxy-1-tetralone (22 g). The aqueous
layer was basified to pH 12 with 5 N NaOH and 15% aqueous
(NH.sub.4).sub.2CO.sub.3 (1000 mL) was added. The aqueous mixture
was extracted with CH.sub.2Cl.sub.2 (2.times.). The organic
solution was dried (MgSO.sub.4), filtered, and concentrated to
provide a brown oil. Impurities were distilled off (110-140.degree.
C.@ 0.2 mmHg) to yield the product (74 g, 57%). .sup.1H NMR (250
MHz, CDCl.sub.3): .delta. 7.27 (d, J=8.7 Hz, 2H), 6.92-6.99 (m,
3H), 6.78 (d, J=2.6 Hz, 1H), 6.65 (dd, J=8.6, 2.6 Hz, 1H), 5.92 (t,
J=4.7 Hz, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.80 (s, 3H), 2.94 (t, J=6.0
Hz, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.66 (m, 2H), 2.37 (m, 2H), 1.84
(m, 4H).
Step B
[0186]
1-{2-[4-(2-Bromo-6-methoxV-3,4-dihvdronaphthalen-1-yl)phenoxy]ethyl-
}pyrrolidine:
[0187] Pyridinium bromide perbromide (21.22 g, 60.55 mmol) was
added portionwise to a solution of
1-{2-[4-(6-methoxy-3,4-dihydronaphthalen-1-y-
l)phenoxy]ethyl}pyrrolidine (23 g, 72 mmol) in THF (700 mL). The
reaction was stirred for 60 h. The precipitate was filtered through
a Celite pad with the aid of THF. The off-white solid was dissolved
in CH.sub.2Cl.sub.2 and MeOH and was filtered away from the Celite.
The organic solution was washed with 0.5 N aq HCl followed by satd
NaHCO.sub.3 (aq). The organic solution was dried (MgSO.sub.4),
filtered, and concentrated to provide a brown solid (21.5 g, 83%).
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.14 (d, J=8.7 Hz, 2H),
6.97 (d, J=8.8 Hz, 2H), 6.71 (d, J=2.2 Hz, 1H), 6.55 (m, 2H), 4.17
(t, J=6.0 Hz, 2H), 3.77 (s, 3H), 2.96 (m, 4H), 2.66 (m, 4 H), 1.85
(m, 4H).
Step C
[0188]
1-{2-[4-(6-Methoxv-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethy-
l}pyrrolidine hydrochloride (Nafoxidene hydrochloride):
[0189] To a mixture of
1-{2-[4-(2-bromo-6-methoxy-3,4-dihydronaphthalen-1--
yl)phenoxy]ethyl}pyrrolidine (19 g, 44 mmol), phenylboronic acid
(7.0 g, 57 mmol), and tetrakis(triphenylphosphonium)palladium (1.75
g, 1.51 mmol) in THF (300 mL) was added Na.sub.2CO.sub.3 (13 g, 123
mmol) in H.sub.20 (100 mL). The reaction was heated at reflux for
18 h. The layers were separated and the organic layer was washed
with H.sub.2O followed by brine. The organic solution was dried
(MgSO.sub.4), filtered, and concentrated to yield 17.96 g of a
brown solid. The residue was dissolved in a 1:1 mixture of
CH.sub.2Cl.sub.2 and EtOAc (250 mL) and 1 N HCl in Et.sub.2O (100
mL) was added. After stirring for 2 h, product was allowed to
crystallize from solution and 11 g of material was collected by
filtration. Concentration of the mother liquor to half its volume
provided an additional 7.3 g of product.
Step D
[0190]
cis-1-{2-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydronaphthalen-1-yl)p-
henoxy]ethyl}pyrrolidine:
[0191]
1-{2-[4-(6-Methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)phenoxy]ethy-
l}pyrrolidine hydrochloride (nafoxidene hydrochloride) (75 g, 162
mmol) was dissolved in 1000 mL of EtOH and 300 mL of MeOH. Dry
Pd(OH).sub.2 on carbon was added and the mixture was hydrogenated
on a Parr shaker at 50.degree. C. and 50 psi for 68 h. The catalyst
was filtered off with the aid of celite and the solvents were
removed in vacuo. The resulting white solid was dissolved in
CH.sub.2Cl.sub.2 and the solution was washed with satd NaHCO.sub.3
(aq). The organic solution was dried (MgSO.sub.4), filtered, and
concentrated to yield an off-white solid (62.6 g, 90%).
Step E
[0192]
cis-6-Phenvl-5-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-5,6,7,8-tetrahyd-
ronaphthalene-2-ol:
[0193] A mixture of
cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaph-
thalen-1-yl)phenoxy]ethyl}pyrrolidine (12 g, 28 mmol), acetic acid
(75 mL), and 48% HBr (75 mL) was heated at 100.degree. C. for 15 h.
The solution was cooled and the resulting white precipitate was
collected by filtration. The hydrobromide salt (9.6 g, 69%) was
dissolved in CHCl.sub.3/MeOH and was stirred with satd NaHCO.sub.3
(aq). The layers were separated and the aqueous layer was further
extracted with CHCl.sub.3/MeOH. The combined organic layers were
dried (MgSO.sub.4), filtered, and concentrated to yield product as
an off-white foam. .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.04
(m, 3H), 6.74 (m, 2H), 6.63 (d, J=8.3 Hz, 2H), 6.50 (m, 3H), 6.28
(d, J=8.6 Hz, 2H), 4.14 (d, J=4.9 Hz, 1H), 3.94 (t, J=5.3 Hz, 2H),
3.24 (dd, J=12.5, 4.1 Hz, 1H), 2.95 (m, 4H), 2.78 (m, 4H), 2.14 (m,
1H), 1.88 (m, 4H), 1.68 (m, 1H).
EXAMPLE 2
Trans6-phenyl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,7,8-tetrahydronap-
hthalen-2-ol
Step A
[0194] To a solution of
cis-1-{2-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-
naphthalen-1-yl)phenoxy]ethyl}pyrrolidine (500 mg, 1.17 mmol) in 10
ml of dimethyl sulfoxide at 10.degree. C. was added slowly 4.7 ml
(11.7 mmol) of 2.5 M n-butyl lithium in hexane. The reaction was
allowed to warm to 20.degree. C. and was stirred for 19 hrs. After
addition of water and extraction with ether, the organic layers
were combined, dried over magnesium sulfate, filtered and
concentrated to dryness to yield 363 mg (73%) of the
trans-6-methoxydihydronaphthalene. .sup.1H-NMR (CDCl.sub.3):
.delta. 3.45 (m, 2H), 3.82, (s, 3H), 4.06 (d, 1H), 4.45 (m, 2H),
6.80 (d, 2H).
Step B
[0195] Using the boron tribromide deprotection procedure described
in Example 1 Step B, 363 mg (0.85 mmol) of the product of Step A
was converted to 240 mg (68%) of the title compound. .sup.1H-NMR
(CDCl.sub.3): .delta. 4.02 (d, 1H), 4.45 (m, 2H), 7.00 (d, 2H). The
corresponding hydrochloride salt was prepared as described in Step
B of Example 1 (MS 414 P.sup.++1).
EXAMPLE 3
1-(4'-Pyrrolidinoethoxyphenvl)-2-(4"-hydroxyphenyl)-6-hydroxy-1,2,3,4-tetr-
ahydroisoquinoline hydrochloride
Step A
[0196] 3-Methoxyphenylacet4'-methoxyanilide.
[0197] A solution of 20.0 g (0.120 mole) of 3-methoxyphenylacetic
acid and 40 ml (65.3 g, 0.549 mole) of thionyl chloride in 100 ml
of benzene was heated at reflux for 2 hours and evaporated to
dryness to afford the corresponding acid chloride (assume 0.120
mole). The acid chloride was slurried in 50 ml of ether and added
to a mixture of 4-methoxyaniline in 100 ml of ether at 0.degree. C.
After stirring at 20.degree. C. overnight, the slurry was filtered
to afford a solid which was washed with water, 5.5% aq HCl, water,
and ether. Subsequent drying over P.sub.2O.sub.5 in vacuo for 4 hr.
yielded 19.7 g (60%) of the title substance as a white solid.
.sup.1H-NMR (CDCl.sub.3): .delta. 3.70 (s, 2H), 3.77 (s, 3H), 3.81
(s, 3H).
Step B
[0198] N-(4-Methoxyphenyl)-2'-(3"-methoxy phenethylamine)
hydrochloride:
[0199] A slurry of 19.6 g (0.072 mol) of the product of Step A and
6.04 g (0.159 mol) of lithium aluminum hydride in 130 ml of ether
and 75 ml of dioxane was heated at 35.degree. C. for 48 hrs. Excess
sodium sulfite decahydrate was added and the mixture was filtered
and washed with 5% aq HCl. The organic layer was dried over
anhydrous magnesium sulfate and concentrated to yield 10.84 g of
the title substance as the HCl salt (51%). .sup.1H-NMR
(CDCl.sub.3): .delta. 3.15 (m, 2H), 3.42 (m, 2H), 3.71 (s, 3H),
3.74 (s, 3H).
Step C
[0200]
N-2-(3'-Methoxphenethyl)-4"-benzyloxybenz-4"-methoxyanilide:
[0201] To a slurry of 4.83 g (0.164 mol) of the product of Step B
and 2.12 g (0.0164 mol) of diisopropylethylamine in 50 ml of ether
was added 0.013 mol of 4-benzyloxybenzoyl chloride [prepared from
3.00 g (0.013 mol) of the corresponding benzoic acid and 7.13 g
(0.059 mol) of thionyl chloride in 35 ml of benzene] in 50 ml of
ether at 20.degree. C. and the reaction was stirred overnight.
After decantation from a precipitate, the ether solution was washed
with 5% aq HCl, water, brine, dried over magnesium sulfate,
filtered and evaporated to dryness to yield 5.58 g of the title
substance (73%). .sup.1H-NMR (CDCl.sub.3): .delta. 3.00 (m, 2H),
3.75 (m, 9H), 4.05 (m, 2H).
[0202] Step D
[0203]
1-(4'-Benzyloxvphenvl)-2-(4"-methoxvphenyl)-6-methoxy-3,4-dihydro
isoquinolinium chloride:
[0204] A solution of 1.04 g (2.22 mmol) of the product of step C in
5 ml of phosphorous oxychloride was heated at 100.degree. C. for
2.5 hrs. The reaction was evaporated to dryness and partitioned
between ethyl acetate/water. The ethyl acetate layer was dried over
anhydrous magnesium sulfate and concentrated to yield 1.03 g of the
title substance as an oil (96%). .sup.1H-NMR (CDCl.sub.3): .delta.
3.46 (t, 2H), 3.80 (s, 3H), 4.00 (s, 3H), 4.55 (t, 2H).
Step E
[0205]
1-(4'-Benzyloxvphenyl)-2-(4"-methoxyphenyl)-6-methoxy-1,2,3,4-tetra-
hydroisoguinoline:
[0206] To 1.00 g of the product of Step D (2.07 mmol) in 10 ml of
methanol was added 200 mg (5.28 mmol) of sodium borohydride. After
stirring 19 hrs at 25.degree. C., the precipitate was collected and
dried in vacuo to yield 611 mg (66%) of the title substance as a
foam. .sup.1H-NMR (CDCl.sub.3): .delta. 2.95 (m, 2H), 3.50 (m, 2H),
3.71 (s, 3H), 3.78 (s, 3H), 5.09 (s, 1 H).
Step F
[0207]
1-(4'-Hydroxyphenyl)-2-(4"-methoxyphenyl)-6-methoxy-1,2,3,4-tetrahy-
droisoguinoline hydrochloride:
[0208] A solution of 611 mg (1.35 mmol) of the product of Step E in
6 ml of conc. aq HCl and 6 ml of dioxane was heated at 90.degree.
C. for 5 hrs. The dioxane was removed in vacuo and the aqueous
layer diluted with water. The title compound was isolated (155 mg,
29%) as the precipitated hydrochloride salt. .sup.1H-NMR
(CDCl.sub.3): .delta. 3.72 (s, 3H), 3.76 (s, 3H), 5.94 (s, 1H).
Step G
[0209]
1-(4'-Pyrrolidinoethoxyphenyl)-2-(4"-methoxyphenyl)-6-methoxy-1,2,3-
,4-tetrahvdroisoquinoline:
[0210] To a slurry of 152 mg (0.382 mmol) of the product of Step F
in 5 ml of dioxane and 1 ml of DMF was added 152.8 mg (3.82 mmol)
of 60% sodium hydride mineral oil dispersion. After stirring at
45.degree. C. for 0.5 hr., 65 mg (0.382 mmol) of
2-chloroethylpyrrolidine hydrochloride was added slowly portionwise
and was stirred for 3 hr at 450C. After addition of water, the
reaction was extracted with ethyl acetate. The ethyl acetate layer
was dried over anhydrous magnesium sulfate, filtered, and
concentrated to yield 203 mg of crude product which was
chromatographed on silica gel with chloroform/methanol (99:1) to
afford 78 mg (45%) of the title substance. .sup.1H-NMR
(CDCl.sub.3): .delta. 2.85 (m, 2H), 3.72 (s, 3H), 3.79 (s, 3H),
4.00 (t, 2H), 5.50 (s, 1 H).
Step H
[0211]
1-(4'-Pyrrolidinoethoxyphenyl)-2-(4"-hydroxyphenyl)-6-hydroxy-1,2.3-
,4-tetrahydroiosquinoline hydrochloride:
[0212] To a solution of 75 mg (0.164 mmol) of the product of Step G
in 5 ml of methylene chloride at 0.degree. C. was added dropwise
0.82 ml (0.82 mmol) of 1.0 M boron tribromide in methylene
chloride. After stirring at 0.degree. C. for 0.5 hr, the reaction
was allowed to process at 20.degree. C. for 2 hrs. The reaction was
poured into ice cold satd aq sodium bicarbonate. The supernatant
was filtered off from the gum which was dissolved in methanol,
dried over magnesium sulfate, filtered and evaporated to dryness to
yield 53 mg (75%) of the title substance as a foam. .sup.1H-NMR
(CD.sub.3OD): .delta. 4.02 (m, 2H), 5.50 (s, 1 H), 6.50-7.00 (m, 11
H). The hydrochloride salt prepared in the usual manner was a white
solid: MS 431 (P++1).
EXAMPLE 4
1-(6'-Pyrrolidinoethoxy-3'-pyridyl)-2-(4"-hydroxyphenyl)-6-hydroxy-1,2,3,4-
-tetrahvdroisoquinoline hydrochloride
Step A
[0213]
1-(6'-Chloro-3'-pyridyl)-2-(4"-methoxyphenyl)-6-methoxy-1,2,3,4-tet-
rahydroisoquinoline:
[0214] Using the procedures described for Example 3 described in
step C, substituting 6-chloronicotinoyl chloride for
4-benzyloxybenzoyl chloride, the title compound was obtained.
Step B
[0215]
1-(6'-Pyrrolidinoethoxy-3'-pyridyl)-2-(4"-methoxyphenyl)-6-methoxy--
1,2,3,4-tetrahydroisoquinoline:
[0216] The product of Step A (500 mg, 1.31 mmol) was slurried in 10
ml of toluene and treated with 364 mg (5.52 mmol) of potassium
hydroxide, 346 mg (1.31 mmol) of 18-crown-6, and 318 mg (2.76 mmol)
of 1-(2-hydroxyethyl)pyrrolidine. After heating at 80.degree. C.
for 18 hr, the reaction was cooled, diluted with water, and
extracted with ethyl acetate. The combined organic extracts were
washed with brine, dried over magnesium sulfate, filtered, and
concentrated to dryness to afford 575 mg of a foam Chromatography
on silica gel using 97.5% chloroform/methanol (9:1) and 2.5% conc.
NH.sub.4OH yielded 127 mg (21%) of the title substance. .sup.1H-NMR
(CDCl.sub.3): .delta. 2.50 (m, 4H), 2.90 (m, 4H), 3.42 (m, 2H),
3.72 (s, 3H), 3.79 (s, 3H), 4.39 (t, 2H), 5.05 (s, 1H).
Step C
[0217] The product of Step B was deprotected according to the
procedure of Example 1 and converted to the hydrochloride salt in
the usual manner to afford the title substance. .sup.1H-NMR
(CDCl.sub.3): .delta. 2.55 (m, 2H), 5.45 (s, 1H); MS (P.sup.++1)
432.
EXAMPLE 5
1-(4-Azabicycloheptanoethoxyphenyl)-2-(4"-hydroxyphenyl)-6
-hvdroxy-1,2,3,4-tetrahydroisoguinoline hydrochloride
[0218] Using the procedures of Example 3, substituting in Step C,
4-(2'-azabicyclo[2.2.1]heptanoethoxy)benzoic acid for 4-benzyloxy
benzoic acid, followed by the employment of Steps D, E. and H, the
title substance was obtained as a white solid. .sup.1H-NMR
(CDCl.sub.3): .delta. 2.95 (m, 3H), 3.90 (s, 1H), 4.15 (t, 3H),
5.42 (s, 1H); MS 457 (P.sup.++1).
EXAMPLE 6
(-)-cis-6-Phenyl-5-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-5,6,
7,8-tetrahydronaphthalen-2-ol
Step A
[0219] 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine:
[0220] A solution of 2,5-dibromopyridine (15.0 g, 63.3 mmol),
powdered KOH (6.39 g, 114 mmol), 1-(2-hydroxyethyl)pyrrolidine
(14.58 g, 126.6 mmol), and 18-crown-6 (300 mg, 1.14 mmol) in dry
toluene (100 mL) was heated to 70.degree. C. for I h. The solution
was cooled to room temperature and water and EtOAc were added. The
organic layer was washed with water and brine. The solution was
dried (MgSO.sub.4), filtered, and concentrated in vacuo. Short path
distillation (153.degree. C.@ 0.1 mmHg) provided the title compound
as a colorless oil which solidified upon cooling (14.9 g, 87%).
.sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 8.15 (d, J=2.4 Hz, 1H),
7.65 (dd, J=2.4, 8.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 4.38 (t,
J=5.8 Hz, 2H), 2.84 (t, J=5.8 Hz, 2H), 2.62 (m, 4H), 1.82 (m,
4H).
Step B
[0221] 6-Methoxy-1-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-12,
3,4-tetrahydronaphthalen-1-ol:
[0222] To a solution of 5-Bromo-2-(2-pyrrolidin-1-ylethoxy)pyridine
(7.0 g, 26 mmol) in dry THF (50 mL) at -780C was added n-BuLi (2.5
M in hexanes, 12.4 mL, 31.0 mmol) dropwise. After 30 min,
6-methoxy-1-tetralone (4.55 g, 25.8 mmol) in dry THF was added.
After stirring for 15 min at -78.degree. C., the reaction was
allowed to warm to room temperature. After 30 min, the reaction was
poured into aq NaHCO.sub.3 (satd). The aqueous layer was extracted
with EtOAc (2.times.). The combined organic solutions were dried
(MgSO.sub.4), filtered, and concentrated. Flash chromatography
(CHCl.sub.3: MeOH, 95:5) provided the alcohol (4.23 g, 44%) as a
white solid. .sup.1H NMR (250 MHz, CDCl.sub.3): 68.07 (d, J=2.5 Hz,
1H), 7.49 (dd, J=2.5, 8.7 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H), 6.73 (m,
3H), 4.45 (t, J=5.7 Hz, 2H), 3.79 (s, 3H), 2.92 (t, J=5.7 Hz, 2H),
2.76 (m, 2H), 2.67 (m, 4H), 2.11 (s, 1H), 2.08 (m, 3H), 1.82 (m,
5H).
Step C
[0223]
5-(2-Bromo-6-methoxy-3,4-dihydronaphthalen-1-yl)-2-(2-pyrrolidin-1--
ylethoxy)pyridine:
[0224] Pyridinium bromide perbromide (3.5 g, 12.2 mmol) was added
to a solution of
6-methoxy-1-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-1,2,3,4-
-tetrahydronaphthalen-1-ol (3.3 g, 8.9 mmol) in CH.sub.2Cl.sub.2
(50 mL). The reaction was stirred for 18 h and aqueous NaHCO.sub.3
(satd) was added. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 and the combined organic solution was washed with
water and brine. The organic solution was dried (MgSO.sub.4),
filtered, and concentrated. Flash chromatography (CHCl.sub.3: MeOH,
95:5) provided the desired vinyl bromide (2.65 g, 70%). .sup.1H NMR
(250 MHz, CDCl.sub.3): .delta. 8.0 (d, J=2.4 Hz, 1H), 7.41 (dd,
J=2.4, 8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.69 (m, 1H), 6.55 (m,
2H), 4.92 (t, J=5.8 Hz, 2H), 3.76 (s, 3H), 2.94 (m, 6H), 2.64 (m, 4
H), 1.82 (m, 4H).
Step D
[0225]
5-(6-Methoxy-2-phenyl-3,4-dihvdronaphthalen-1-yl)-2-(2-pyrrolidin-1-
-ylethoxy)pyridine.
[0226] Phenyllithium (1.8 M in cyclohexane/ether, 3.8 mL, 7.0 mmol)
was added slowly to zinc chloride (0.5 M in THF, 14 mL, 7.0 mmol)
at 0.degree. C. After stirring for 15 min,
5-(2-bromo-6-methoxy-3,4-dihydron-
aphthalen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine (1.0 g, 2.3
mmol) in dry THF (20 mL) was added followed by Pd(PPh.sub.3).sub.4
(200 mg, 0.173 mmol). The reaction was warmed to room temperature
and was heated at reflux for 4 h. The reaction was poured into
aqueous NH.sub.4Cl solution (satd). The aqueous layer was washed
with CHCl.sub.3 (2.times.) and the combined organic solutions were
washed with water followed by brine. The organic solution was dried
(MgSO.sub.4), filtered, and concentrated in vacuo. Flash
chromatography (CHCl.sub.3: MeOH, 95:5) provided the title compound
(680 mg, 68%). .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.78 (d,
J=2.1 Hz, 1H), 7.27 (m, 1H), 7.07 (m, 5H), 6.68 (m, 4H), 4.40 (t,
J=5.8 Hz, 2H), 3.80 (s, 3H), 2.88 (m, 6H), 2.71 (m, 4 H), 1.81 (m,
4H).
Step E
[0227] cis-5-(6-Methoxy-2-phenyl-1
,2,3,4-tetrahydronaphthalen-1-yl)-2-(2--
pyrrolidin-1-ylethoxy)pyridine:
[0228] Pd(OH).sub.2 (20%, 77 mg) was flame dried under vacuum and
was added to a solution of
5-(6-methoxy-2-phenyl-3,4-dihydronaphthalen-1-yl)--
2-(2-pyrrolidin-1-ylethoxy)pyridine (286.4 mg, 0.6714 mmol) in
acetic acid (50 mL). The mixture was hydrogenated on a Parr shaker
at 50 psi and at 50.degree. C. for 16 h. The catalyst was filtered
off with the aid of celite and the acetic acid was removed in
vacuo. .sup.1H NMR indicated that the reaction was incomplete and
the residue was resubjected to the reaction conditions (50 psi and
60.degree. C.) for an additional 6 h. The catalyst was removed via
filtration through celite and the solvent was removed in vacuo.
Radial chromatography (solvent gradient, CH.sub.2Cl.sub.2 to 10%
MeOH in CH.sub.2Cl.sub.2) provided the desired material (207 mg,
72%). .sup.1H NMR (250 MHz, CDCl.sub.3): .delta. 7.19 (m, 4H), 6.84
(m, 3H), 6.75 (d, J=2.4 Hz, 1 H), 6.68 (dd, J=2.4, 8.4 Hz, 1 H),
6.59 (dd, J=2.4, 8.4 Hz, 1 H), 6.40 (d, J=8.4 Hz, 1 H), 4.35 (t,
J=5.7 Hz, 2H), 4.21 (d, J=4.8 Hz, 1H), 3.82 (s, 3H), 3.38 (m, 1H),
3.06 (m, 2H), 2.90 (t, J=5.7 Hz, 2H), 2.69 (m, 4H), 2.11 (m, 2H),
1.84 (m, 4H).
Step F
[0229]
cis-6-Phenyl-5-[6-(2-pyrrolidin-1-ylethoxy)pyridin-3-yl]-5,6,7,8-te-
trahydronaphthalen-2-ol:
[0230] To a solution of
cis-5-(6-methoxy-2-phenyl-1,2,3,4-tetrahydronaphth-
alen-1-yl)-2-(2-pyrrolidin-1-ylethoxy)pyridine (69.6 mg, 0.162
mmol) in dry CH.sub.2Cl.sub.2 (3 mL) at 0.degree. C. was added
AlCl.sub.3 (110 mg, 0.825 mmol) followed by excess EtSH (400 pL).
After 0.5 h, the reaction was warmed to room temperature and
additional AlCl.sub.3 (130 mg) was added. After 0.5 h, aqueous
NaHCO.sub.3 (satd) was carefully added and the aqueous layer was
extracted with CH.sub.2Cl.sub.2/MeOH (3.times.). The combined
organic layers were dried (MgSO.sub.4), filtered, and concentrated.
Radial chromatography (solvent gradient, CH.sub.2Cl.sub.2 to 15%
MeOH in CH.sub.2C.sub.2) provided the deprotected material (64.6
mg, 96%) as an off-white solid. .sup.1H NMR (250 MHz, CDCl.sub.3):
.delta. 7.18 (m, 3H), 6.96 (d, J=2.4 Hz, 1H), 6.82 (m, 2H), 6.70
(d, J=2.4 Hz, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.62 (dd, J=2.4, 8.5 Hz,
1H), 6.52 (dd, J=2.4, 8.4 Hz, 1H), 5.80 (d, J=8.5 Hz, 1H), 4.45 (m,
2H), 4.18 (d, J=4.8 Hz, 1H), 3.40 (m, 1H), 3.04 (m, 3H), 2.75 (m,
6H), 2.11 (m, 1H), 1.88 (m, 4H). The two enantiomers were isolated
by chromatography on a 5 cm id.times.5 cm Chiracel OD column using
5% ethanol/95% heptane with 0.05% diethylamine. Enantiomer 1:
R.sub.t=17.96 min, [.alpha.].sub.d=+242_(c=1, MeOH); Enantiomer 2:
R.sub.t=25.21 min, [.alpha.].sub.d=-295 (c=1, MeOH).
EXAMPLE 7
Cis-6-(4-fluoro-phenyl)-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5,6,7,8-tet-
rahvdronaphthalen-2-ol
Step A
[0231] 1 g of 1-[4'-piperidino ethoxy phenyl]-2-[4"-fluoro
phenyl]-6-methoxy-3,4-dihydronaphthalene (which can be made as in
Example 1 but replacing phenylboronic acid in Step C with
4-fluorophenylboronic acid) in 35 ml acetic acid was added
palladium hydroxide on carbon (20%, 1 g)(flame dried in vacuo). The
mixture was hydrogenated on a Parr shaker at 50.degree. C. and 50
psi for 4 hours. Filtration through Celite and concentration
yielded 1.2 g of crude reaction product which was used without
further purification in the next step.
[0232] .sup.1H-NMR (250 MHz, CDCl.sub.3): .delta. 1.9 (m), 3.1(m),
3.25(m), 3.8 (s, 3H), 4.2 (d, 1H), 4.25 (bd), 6.35 (d, 2H), 6.5 (d,
2H), 6.65 (m), 6.75 (m), 6.8-6.88 (m). m/z 460 (M+1)
Step B
[0233] A solution of cis-1-[4-piperidinoethoxy phenyl]-2-[4"-fluoro
phenyl]-6-methoxy-1,2,3,4 -tetrahydro naphthalene-1-yl]
phenoxy}-ethyl)-piperidine (540 mg, 1.17 mmol) in anhydrous
CH.sub.2Cl.sub.2was cooled to 0.degree. C. followed by the addition
of BBr.sub.3[5.8 mL (1 M solution in CH.sub.2Cl.sub.2), 5.88 mmol]
dropwise. The reaction was allowed to warm to room temperature and
stirred for another hour. After the reaction was complete, the
reaction was cooled back to 0.degree. C. and aqueous NaHCO.sub.3
was carefully added. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.). The organic layer was dried over
MgSO.sub.4, filtered and concentrated. The crude product was
radially chromatographed (solvent 4:1 ether /hexane, 1%
triethylamine) to provide the deprotected product. The HCl salt
product was form with 1 M HCl/Ether solution followed by
trituration with EtOAc/THF to provide 126 mg of product. .sup.1H
NMR (250 MHz, CDCl.sub.3): .delta. 6.80 (m,4H), 6.63 (m, 4H), 6.50
(dd, 1 H), 6.40 (d, 2H), 4.22 (dd, 3H), 3.72 (m, 2H), 3,48 (dd,
2H), 3.0 (bm, 2H), 1.83 (m, 9H). m/z 446 (M+1)
EXAMPLE 8
(-)Cis-6-phenvl-5-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-5,6,
7,8-tetrahvdronaphthalen-2-ol
[0234] The racemic compound of Example 1 (3 g) was subjected to
enantiomeric separation on a 5 cm.times.5 cm Chiralcell OD column
employing 99.95% (5% EtOH/95% heptane)/0.05% diethylamine as the
element to afford 1 g of a fast eluting (+) enantiomer and 1 g of a
slow (-) eluting enantiomer, both of which possessed identical NMR,
MS and TLC behavior as the racemate. Alternatively, a
crystallization procedure using R-binap phosphoric acid can be
employed to effect resolution. In 20 ml of methanol and 20 ml of
methylene chloride was added 7.6g (0.0184 mol) of the product of
Example 1 and 6.4g (0.0184 mol) of R-(-)-1, 1'-binaphthyl-2,2'-diyl
hydrogen phosphate. After solution was complete, evaporation of
solvent followed by trituration with ether afforded 14.2 g of
racemic salt. This solid was slurried in 500 ml of dioxane and 25
ml of methanol and the resulting mixture was heated until the
initial solid dissolved. On standing for 1 hour, a white
precipitate formed (6.8 g) which was collected and which HPLC
(using the conditions above) indicated to be approximately 73%
enantiomerically pure. This material was slurried in 250 ml of
absolute ethanol and heated until solution was achieved, at which
time the solution was allowed to stand at room temperature
overnight. The collected crystals were washed with cold ethanol
followed by ether to afford 3.1g of 98% enantiomerically pure salt;
a second crop of 588 mg was also obtained. Partitioning between 1:2
methanol/methylene chloride and 1% aqueous sodium hydroxide
afforded the corresponding free base which was converted to the
hydrochloride salt (HCl in dioxane). Recrystallization from
acetonitrile/methylene chloride afforded the levorotatory preferred
enantiomer hydrochloride corresponding to Example 1.
[.alpha..sub.D-330.6 (c=0.05,CH.sub.2Cl.sub.2]; mp 260-263.degree.
C.
EXAMPLE 9
Cis-6-(4'-hydroxyphenyl)-5-[4-(2-piperidin-1-ylethoxy)phenyl]-5,6,7,8-tetr-
ahydro-naphthalen-2-ol.
[0235] Following the procedures described for the preparation of
Example 1, the title compound was obtained. .sup.1H NMR
(CDCl.sub.3): .delta. 3.12 (m, 1H); 3.90 (m, 2H); 4.15 (d, 1H);
6.15-6.72 (m, 11H); FAB MS (M+1)430.
EXAMPLE 10
1-(4'-Piperidinoethoxyphenyl)-2-(4"-hydroxyphenyl)-6-hydroxy-1,2,
3,4-tetrahydroisoquinoline hydrochloride
[0236] Using the procedure of Example 3 described in step G,
substituting N-2-chloroethylpiperidine hydrochloride for
N-2-chloroethylpyrrolidine hydrochloride, the title compound was
obtained. .sup.1H NMR (CDCl.sub.3): .delta. 2.65 (m, 2H); 2.75 (m,
2H); 5.45 (s, 1); 6.50-7.00 (m, 11H); FAB MS(M+1) 445.
EXAMPLE 11
1-(4'-Pyrrolidinoethoxoxyphenvl)-2-(4"-fluorophenyl)-6-hydroxy-1,2,
3,4-tetrahydroisoquinoline hydrochloride
[0237] The title compound was obtained using the procedure of
Example 3 described in step A, substituting 4-fluoroaniline for
4-methoxyaniline. .sup.1H NMR (CDCl.sub.3): .delta. 2.12 (m, 2H);
3.65 (m, 2H); 4.45 (m, 2H); 6.10 (s, 1H); 7.5 (m, 2H); FAB MS(M+1)
433.
EXAMPLE 12
1-(4'-Pyrrolidinoethoxyphenyl)-2-phenyl-6-hydroxy-1,2,3,4-tetrahvdroisoqui-
noline hydrochloride
[0238] The title compound was prepared using the procedure of
Example 3 described in step A, substituting aniline for
4-methoxyaniline. .sup.1H NMR (CDCl.sub.3): .delta. 1.70 (m, 4H);
2.70 (m, 2H); 4.00 (m, 2H); 5.70 (s, 1H); 6.60-7.25 (m, 12H); FAB
MS(M+1) 415.
* * * * *