U.S. patent application number 10/405308 was filed with the patent office on 2003-11-27 for tetrahydroisoquinoline compounds as estrogen agonists/antagonists.
Invention is credited to Cameron, Kimberly O., Chesworth, Richard, DaSilva-Jardine, Paul A., Day, Robert F., Lefker, Bruce A., Zawistoski, Michael P..
Application Number | 20030220494 10/405308 |
Document ID | / |
Family ID | 22630375 |
Filed Date | 2003-11-27 |
United States Patent
Application |
20030220494 |
Kind Code |
A1 |
Cameron, Kimberly O. ; et
al. |
November 27, 2003 |
Tetrahydroisoquinoline compounds as estrogen
agonists/antagonists
Abstract
This invention relates to compounds useful for treating or
preventing obesity, breast cancer, osteoporosis, endometriosis,
cardiovascular disease, prostatic disease, and the like, and to
pharmaceutical composition, methods, and kits comprising such
compounds.
Inventors: |
Cameron, Kimberly O.; (East
Lyme, CT) ; Chesworth, Richard; (Mystic, CT) ;
DaSilva-Jardine, Paul A.; (Providence, RI) ; Day,
Robert F.; (Groton, CT) ; Lefker, Bruce A.;
(Gales Ferry, CT) ; Zawistoski, Michael P.; (West
Warwick, RI) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
22630375 |
Appl. No.: |
10/405308 |
Filed: |
April 2, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10405308 |
Apr 2, 2003 |
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09745396 |
Dec 21, 2000 |
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6608203 |
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60173063 |
Dec 24, 1999 |
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Current U.S.
Class: |
544/60 ; 544/128;
544/363; 546/148 |
Current CPC
Class: |
A61P 3/04 20180101; A61P
29/00 20180101; A61P 35/00 20180101; A61P 5/30 20180101; A61P 15/00
20180101; C07D 217/14 20130101; C07D 217/06 20130101; A61P 9/00
20180101; C07D 217/18 20130101; A61P 13/08 20180101; A61P 19/10
20180101; A61P 43/00 20180101; C07D 217/04 20130101 |
Class at
Publication: |
544/60 ; 544/128;
544/363; 546/148 |
International
Class: |
C07D 417/02; C07D 43/02;
C07D 413/02; C07D 41/02 |
Claims
1. A compound of the formula: 18wherein: A.sup.1 is hydrogen,
hydroxy, (C.sub.1-C.sub.4)alkoxy, or (C.sub.1-C.sub.4)alkanoyloxy,
said (C.sub.1-C.sub.4)alkoxy or said (C.sub.1-C.sub.4)alkanoyloxy
being optionally substituted by hydroxy, halo, or a partially
saturated, fully saturated, or fully unsaturated five to twelve
membered ring optionally having up to four heteroatoms
independently selected from oxygen, sulfur, and nitrogen, or
A.sup.1 is R.sup.3-(C.sub.1-C.sub.4)alkoxy wherein R.sup.3 is
pyrrolidino, piperidino, morpholino, or dimethylamino; A.sup.2,
A.sup.3, and A.sup.4 are independently selected from hydrogen,
hydroxy, (C.sub.1-C.sub.4)alkoxy, and halo; R.sup.1 is phenyl;
pyridyl; piperidinyl; (C.sub.1-C.sub.7)alkyl; adamantyl; a
partially saturated, fully saturated, or fully unsaturated three to
twelve membered ring optionally having up to four heteroatoms
selected independently from oxygen, sulfur, and nitrogen; a
bicyclic ring consisting of two fused independently partially
saturated, fully saturated, or fully unsaturated five to six
membered rings, wherein said bicyclic ring includes up to four
heteroatoms independently selected from oxygen, sulfur, and
nitrogen; or a bicyclic ring system consisting of two rings joined
by a covalent bond, said rings being independently partially
saturated, fully saturated, or fully unsaturated three to eight
membered rings, wherein said bicyclic ring system includes up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen; wherein each of the above R.sup.1 groups is optionally
substituted with up to seven fluoro atoms, or with up to three
substituents independently selected from Group A, wherein Group A
consists of hydroxy, halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
R.sup.3-(C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.4)alkenyl-COOR.sup.7 wherein R.sup.7 is hydrogen or
(C.sub.1-C.sub.4)alkyl, (C.sub.0-C.sub.4)alkyl-COOR.sup.7,
(C.sub.1-C.sub.4)alkanoyloxy-(C.sub.2-- C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and
R.sup.5 are independently hydrogen, (C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)a- lkylene, or
(C.sub.3-C.sub.8)cycloalkyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form pyrrolidino,
piperidino, morpholino, or hexamethyleneimino,
(C.sub.0-C.sub.4)alkyl-CONR.sup.4R.sup.5,
(C.sub.0-C.sub.4)alkyl-NR.sup.4- R.sup.5,
OCH.sub.2--CH.sub.2--NR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9
are independently methyl or ethyl, or R.sup.8 and R.sup.9 taken
together with the nitrogen atom to which they are attached form
pyrrolidino, piperidino, morpholino, or hexamethyleneimino,
propyl-R.sup.8R.sup.9, and SO.sub.2--R.sup.6 wherein R.sup.6 is
imidazolyl, thienyl, benzathienyl, or isoxazyl, optionally
substituted with up to three substituents independently selected
from (C.sub.1-C.sub.4)alkyl; X is a covalent bond, (CH.sub.2).sub.n
where n is 1, 2, or 3, (C.sub.0-C.sub.1)alkylene-phenyle-
ne-(C.sub.0-C.sub.1)alkylene, CO.sub.2,
(C.sub.0-C.sub.3)alkylene-CO--(C.s- ub.0-C.sub.3)alkylene, or
(C.sub.0-C.sub.4)alkylene-SO.sub.2--(CO-C.sub.4)- alkylene; R.sup.2
is (C.sub.1-C.sub.9)alkyl; (C.sub.2-C.sub.4)alkenyl; benzhydryl; a
partially saturated, fully saturated, or fully unsaturated three to
eight membered ring optionally having up to four heteroatoms
selected independently from oxygen, sulfur, and nitrogen; a
bicyclic ring consisting of two fused independently partially
saturated, fully saturated, or fully unsaturated five to six
membered rings, wherein said bicyclic ring includes up to four
heteroatoms independently selected from oxygen, sulfur, and
nitrogen; or a bicyclic ring system consisting of two rings joined
by a covalent bond, said rings being independently partially
saturated, fully saturated, or fully unsaturated three to eight
membered rings, wherein said bicyclic ring system includes up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen; wherein said (C.sub.1-C.sub.9)alkyl is optionally
substituted with one to seven fluoro substituents, or up to three
substituents independently selected from Group B, wherein Group B
consists of chloro, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; wherein said
(C.sub.2-C.sub.4)alkenyl is optionally substituted with up to three
substituents independently selected from Group C, wherein Group C
consists of halo, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and wherein said benzhydryl, said 5
to 8 membered ring, said bicyclic ring, and said bicyclic ring
system is optionally substituted with up to three substituents
independently selected from Group D, wherein Group D consists of
halo, hydroxy, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
imidazolyl, amino, (C.sub.1-C.sub.4)alkylcarbonylamino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and p is 0, 1, or 2; with the
proviso that when X is (CH.sub.2).sub.2 or (CH.sub.2).sub.3, p is
0, and R.sup.1 is phenyl or phenyl substituted with a single
chloro, fluoro, bromo, hydroxy, methoxy, pyrrolidinoethoxy,
piperidinoethoxy, or morpholinoethoxy substituent, then R.sup.2 is
not phenyl, methoxyphenyl, tert-butyl, or cyclopentyl; when X is
CH.sub.2, (CH.sub.2).sub.2, COCH.sub.2, or CH.sub.2CO, A.sup.1 is
hydrogen, and R.sup.1 is phenyl, then R.sup.2 is not phenyl; and
when X is a covalent bond, p is 0, A.sup.1 is hydrogen or methoxy,
and R.sup.1 is phenyl or phenyl substituted with a single chloro,
fluoro, bromo, methoxy, pyrrolidinoethoxy, or piperidinoethoxy
substituent, then R is not phenyl or m-fluorophenyl.
2. A compound of claim 1 wherein: A.sup.1 is hydroxy; A.sup.2,
A.sup.3, and A.sup.4 are hydrogen; and p is 0.
3. A compound of claim 1 wherein R.sup.1 is phenyl, pyridyl,
(C.sub.1-C.sub.4)alkyl, adamantyl, naphthyl, or a partially
saturated, fully saturated, or fully unsaturated five to six
membered ring optionally having up to two heteroatoms selected
independently from oxygen, sulfur, and nitrogen; wherein each of
said R.sup.1 groups is optionally substituted with up to seven
fluoro atoms, or with up to three substituents independently
selected from Group A.
4. A compound of claim 3 wherein R.sup.1 is phenyl, cyclohexyl,
pyridyl, thienyl, isopropyl, or adamantyl; wherein each of said
R.sup.1 groups is optionally substituted with up to seven fluoro
atoms, or with up to three substituents independently selected from
Group A.
5. A compound of claim 4 wherein R.sup.1 is phenyl or cyclohexyl;
wherein each of said R.sup.1 groups is optionally substituted with
up to seven fluoro atoms, or with up to three substituents
independently selected from Group A.
6. A compound of claim 3 wherein each of said R.sup.1 groups is
optionally substituted with up to three halo atoms, or with one
substituent selected from hydroxy, (C.sub.1-C.sub.2)alkoxy,
pyrrolidino-(C.sub.1-C.sub.4)alkox- y, dimethylamino,
(C.sub.2-C.sub.4)alkenyl-COOR.sup.7, COOR.sup.7,
(C.sub.2-C.sub.4)alkenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and
R.sup.5 are independently hydrogen, (C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, --(CH.sub.2CH.sub.2--O--CH.sub.3),
or (C.sub.5-C.sub.6)cycloalkyl, or R.sup.4 and R.sup.5 taken
together with the nitrogen atom to which they are attached form
piperidino or morpholino, or SO.sub.2--R.sup.6 wherein R.sup.6 is
imidazolyl optionally substituted with up to three substituents
independently selected from (C.sub.1-C.sub.4)alkyl.
7. A compound of claim 6 wherein each of said R.sup.1 groups is
optionally substituted with up to three fluoro atoms, or with one
substituent selected from iodo, chloro, bromo, hydroxy, methoxy,
pyrrolidino-ethoxy, dimethylamino, COOR.sup.7 wherein R.sup.7 is
hydrogen or methyl, or ethenyl-CONR.sup.4R.sup.5 wherein R.sup.4
and R.sup.5 are both methyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form piperidino
or morpholino.
8. A compound of claim 7 wherein each of said R.sup.1 groups is
optionally substituted with one hydroxy or pyrrolidino-ethoxy.
9. A compound of claim 1 wherein X is a covalent bond, CH.sub.2,
CH.sub.2-phenylene, CO.sub.2, CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene.
10. A compound of claim 1 wherein X is a covalent bond, CO, or
SO.sub.2.
11. A compound of claim 1 wherein R.sup.2 is
(C.sub.1-C.sub.7)alkyl; propenyl; a partially saturated, fully
saturated, or fully unsaturated five to seven membered ring
optionally having up to two heteroatoms selected independently from
oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two
fused independently partially saturated, fully saturated, or fully
unsaturated five to six membered rings, wherein said bicyclic ring
includes up to two oxygen atoms; or biphenyl; wherein said
(C.sub.1-C.sub.7)alkyl is optionally substituted with one to seven
fluoro substituents, or up to three substituents independently
selected from Group B; wherein said propenyl is optionally
substituted with up to three substituents independently selected
from Group C; and wherein each of said 5-7 membered ring, said
bicyclic ring, and said biphenyl is optionally substituted with up
to three substituents independently selected from Group D.
12. A compound of claim 11 wherein R.sup.2 is methyl, t-butyl,
phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, or
benzodioxolyl; wherein each of said methyl or t-butyl is optionally
substituted with one to seven fluoro substituents, or up to three
substituents independently selected from Group B; and wherein each
of said phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl,
naphthyl, or benzodioxolyl is optionally substituted with up to
three substituents independently selected from Group D.
13. A compound of claim 12 wherein R2 is trifluoromethyl or phenyl;
wherein said phenyl is optionally substituted with up to three
substituents independently selected from Group D.
14. A compound of claim 11 wherein each of said
(C.sub.1-C.sub.7)alkyl and said propenyl is substituted with one to
three fluoro substituents, or up to two substituents independently
selected from amino and methylcarbonyl; and wherein each of said
5-7 membered ring, said bicyclic ring, and said biphenyl is
substituted with up to three fluoro substituents, or up to two
substituents independently selected from hydroxy,
(C.sub.1-C.sub.3)alkyl, amino, and methylcarbonyl.
15. A compound of claim 1 wherein: A.sup.1 is hydroxy; A.sup.2,
A.sup.3, and A.sup.4 are hydrogen; p is 0; R.sup.1 is phenyl,
cyclohexyl, pyridyl, thienyl, isopropyl, or adamantyl; wherein each
of said R.sup.1 groups is optionally substituted with up to three
fluoro atoms, or with one substituent selected from iodo, chloro,
bromo, hydroxy, methoxy, pyrrolidino-ethoxy, dimethylamino,
COOR.sup.7 wherein R.sup.7 is hydrogen or methyl, or
ethenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are both
methyl, or R.sup.4 and R.sup.5 taken together with the nitrogen
atom to which they are attached form piperidino or morpholino; X is
a covalent bond, CH.sub.2, CH.sub.2-phenylene, CO.sub.2,
CO--(C.sub.0-C.sub.2)alkyle- ne, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene; and R.sup.2 is methyl,
t-butyl, phenyl, cyclohexyl, isoxazolyl, tetrahydrnpyranyl,
naphthyl, or benzodioxolyl; wherein each of said methyl or t-butyl
is optionally substituted with one to three fluoro substituents, or
up to two substituents independently selected from amino and
methylcarbonyl; and wherein each of said phenyl, cyclohexyl,
isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl is
optionally substituted with up to three fluoro substituents, or up
to two substituents independently selected from hydroxy,
(C.sub.1-C.sub.3)alkyl, amino, and methylcarbonyl.
16. A compound of claim 15 wherein R.sup.1 is phenyl or cyclohexyl,
each of which is optionally substituted with up to three fluoro
atoms, or with one substituent selected from iodo, chloro, bromo,
hydroxy, methoxy, pyrrolidino-ethoxy, dimethylamino, COOR.sup.7
wherein R.sup.7 is hydrogen or methyl, or ethenyl-CONR.sup.4R.sup.5
wherein R.sup.4 and R.sup.5 are both methyl, or R.sup.4 and R.sup.5
taken together with the nitrogen atom to which they are attached
form piperidino or morpholino.
17. A compound of claim 15 wherein R.sup.1 is optionally
substituted with one hydroxy or pyrrolidino-ethoxy.
18. A compound of claim 15 wherein X is a covalent bond, CO, or
SO.sub.2.
19. A compound of claim 15 wherein R.sup.2 is trifluoromethyl or
phenyl, wherein said phenyl is optionally substituted with up to
three fluoro substituents, or up to two substituents independently
selected from hydroxy, (C.sub.1-C.sub.3)alkyl, amino, and
methylcarbonyl.
20. A compound of claim 15 wherein: R.sup.1 is phenyl or
cyclohexyl, each of which is optionally substituted with one
hydroxy or pyrrolidino-ethoxy; X is a covalent bond, CO, or
SO.sub.2; and R.sup.2 is trifluoromethyl or phenyl; wherein said
phenyl is optionally substituted with up to three fluoro
substituents, or up to two substituents independently selected from
hydroxy, (C.sub.1-C.sub.3)alkyl, amino, and methylcarbonyl.
21. A compound of claim 15 which is 1920
22. A compound of claim 15 which is
2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethox-
y)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol 21
23. A compound of claim 15 which is
2,2,2-trifluoro-1-[6-hydroxy-1-(4-hydr-
oxyphenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone 22
24. A compound of claim 15 which is
2-benzenesulfonyl-1-[4-(2-pyrrolidin-1-
-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol
232-(4-isopropylbenzenesulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1-
,2,3,4-tetrahydroisoquinolin-6-ol 24
25. A compound of claim 21 which is
1-(4-hydroxy-phenyl)-2-phenyl-1,2,3,4--
tetrahydroisoquinolin-6-ol.
26. A compound of claim 21 which is
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-phenyl]-1-piperidin-1-yl-propenone.
27. A compound of claim 21 which is
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-phenyl]-1-morpholin-4-yl-propenone.
28. A compound of claim 21 which is
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetra-
hydroisoquinolin-1-yl)-phenyl]-N,N-dimethyl-acrylamide.
29. A compound of claim 23 which is
2,2,2-trifluoro-1-[6-hydroxy-1(R)-(4-h-
ydroxyphenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone 25
30. A compound of claim 1 wherein: said compound is of formula (I);
A.sup.1 is hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkanoyloxy- , or pyrrolidino-ethoxy; A.sup.2,
A.sup.3, and A.sup.4 are hydrogen; p is 0 or 1; R.sup.1 is
(C.sub.1-C.sub.4)alkyl, (C.sub.4-C.sub.7)cycloalkyl, adamantyl,
phenyl, pyridyl, or thienyl, wherein each of said phenyl, pyridyl,
or thienyl groups is optionally substituted with up to three fluoro
atoms, or with one substituent selected from iodo, chloro, bromo,
hydroxy, methoxy, dimethylamino, OCH.sub.2CH.sub.2NR.sup.8R.sup.9,
COOR.sup.7, ethenyl-COOR.sup.7, or ethenyl-CONR.sup.4R.sup.5
wherein R.sup.4 and R.sup.5 are both methyl, or R.sup.4 and R.sup.5
taken together with the nitrogen atom to which they are attached
form pyrrolidino, piperidino, hexamethyleneimino, or morpholino; X
is a covalent bond, CH.sub.2, CH.sub.2-phenylene, CO.sub.2,
CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene; and R.sup.2 is
(C.sub.1-C.sub.7)alkyl, phenyl, benzyl, thienyl,
(C.sub.5-C.sub.7)cycloalkyl, isoxazolyl, imidazolyl,
tetrahydropyranyl, naphthyl, or benzodioxolyl, wherein said
(C.sub.1-C.sub.7)alkyl is optionally substituted with one to three
fluoro substituents, or up to two substituents independently
selected from amino and methylcarbonyl, and wherein each of said
phenyl, thienyl, (C.sub.5-C.sub.7)cycloalkyl, isoxazolyl,
tetrahydropyranyl, naphthyl, and benzodioxolyl is optionally
substituted with up to three fluoro substituents, or up to two
substituents independently selected from hydroxy, methoxy,
(C.sub.1-C.sub.3)alkyl, amino, and methylcarbonyl.
31. A compound of claim 30 wherein: p is 0; X is SO.sub.2; R.sup.1
is not substituted with ethenyl-COOR.sup.7; R.sup.2 is phenyl,
benzyl, napthyl, isoxazoyl, (C.sub.5-C.sub.7)cycloalkyl, or
(C.sub.1-C.sub.4)alkyl, wherein each of said phenyl, benzyl,
napthyl, and isoxazoyl is optionally substituted with up two
(C.sub.1-C.sub.3)alkyl groups.
32. A compound of claim 31 wherein R.sup.1 is phenyl or thienyl,
each of which is optionally substituted with up to three fluoro
atoms or with a single OCH.sub.2CH.sub.2NR.sup.8R.sup.9 group.
33. A compound of claim 30 wherein: p is 0; X is CO; R.sup.1 is not
substituted with ethenyl-COOR.sup.7; R.sup.2 is
(C.sub.5-C.sub.7)cycloalk- yl, (C.sub.3-C.sub.7)alkyl, napthyl, or
trifluoromethyl, wherein said (C.sub.3-C.sub.7)alkyl is optionally
subtituted with up to 3 fluoro atoms.
34. A compound of claim 33 wherein R.sup.1 is phenyl or thienyl,
each of which is optionally substituted with up to three fluoro
atoms or with a single OCH.sub.2CH.sub.2NR.sup.8R.sup.9 group.
35. A compound of claim 30 wherein: p is 0; X is CH.sub.2; R.sup.1
is not substituted with ethenyl-COOR.sup.7; R.sup.2 is phenyl,
thienyl, or benzodioxolyl, each of which is optionally substituted
with up to 3 fluoro atoms or an imidazoyl group.
36. A compound of claim 35 wherein R.sup.1 is phenyl or thienyl,
each of which is optionally substituted with up to three fluoro
atoms or with a single OCH.sub.2CH.sub.2NR.sup.8R.sup.9 group.
37. A compound of claim 30 wherein: p is 0; X is a covalent bond;
R.sup.1 is not substituted with chloro, methoxy, or
ethenyl-COOR.sup.7; R.sup.2 is phenyl, thienyl,
(C.sub.5-C.sub.7)cycloalkyl, or tetrahydropyranyl, wherein each of
said R.sup.2 groups is optionally substituted with up to two methyl
groups, or said phenyl and thienyl groups are optionally
substituted with up to 3 fluoro atoms.
38. A compound of claim 30 wherein: p is 0; X is CO.sub.2; R.sup.1
is not substituted with ethenyl-COOR.sup.7; R.sup.2 is phenyl or
(C.sub.1-C.sub.4)alkyl, each of which is optionally subtituted with
up to 3 fluoro atoms.
39. A compound of claim 38 wherein R.sup.1 is phenyl or thienyl,
each of which is optionally substituted with up to three fluoro
atoms or with a single OCH.sub.2CH.sub.2NR.sup.8R.sup.9 group.
40. A compound of claim 1 wherein said compound is of formula
(II).
41. A compound of claim 40 wherein: A.sup.1 is hydroxy,
(C.sub.1-C.sub.4)alkoxy, or (C.sub.1-C.sub.4)alkanoyloxy; A.sup.2,
A.sup.3, and A.sup.4 are hydrogen; p is 0 or 1; R.sup.1 is
(C.sub.1-C.sub.4)alkyl, (C.sub.4-C.sub.7)cycloalkyl, adamantyl,
phenyl, pyridyl, or thienyl, wherein each of said phenyl, pyridyl,
thienyl, or (C.sub.5-C.sub.7)cycloalkyl groups is optionally
substituted with up to three fluoro atoms, or with one substituent
selected from iodo, chloro, bromo, hydroxy, methoxy, dimethylamino,
OCH.sub.2CH.sub.2NR.sup.8R.sup.9, COOR.sup.7, or
ethenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and R.sup.5 are both
methyl, or R.sup.4 and R.sup.5 taken together with the nitrogen
atom to which they are attached form pyrrolidino, piperidino,
hexamethyleneimino, or morpholino; X is a covalent bond, CH.sub.2,
CH.sub.2-phenylene, CO.sub.2, CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene; and R.sup.2 is
(C.sub.1-C.sub.7)alkyl, phenyl, benzyl, thienyl,
(C.sub.5-C.sub.7)cycloal- kyl, isoxazolyl, tetrahydropyranyl,
naphthyl, or benzodioxolyl, wherein said (C.sub.1-C.sub.7)alkyl is
optionally substituted with one to three fluoro atoms, or up to two
substituents independently selected from amino and methylcarbonyl,
and wherein each of said phenyl, thienyl, cyclohexyl, isoxazolyl,
tetrahydropyranyl, naphthyl, and benzodioxolyl is optionally
substituted with up to three fluoro atoms, or up to two
substituents independently selected from hydroxy, methoxy, and
(C.sub.1-C.sub.3)alkyl.
42. A compound of claim 15 wherein said compound is of formula
(II).
43. A compound of claim 42 which is
2,2,2-trifluoro-1-[7-hydroxy-4-(4-hydr-
oxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone 26
44. A compound of the formula: 27wherein: A.sup.1 is hydrogen,
hydroxy, (C.sub.1-C.sub.4)alkoxy, or (C.sub.1-C.sub.4)alkanoyloxy,
said (C.sub.1-C.sub.4)alkoxy or said (C.sub.1-C.sub.4)alkanoyloxy
being optionally substituted by hydroxy, halo, or a partially
saturated, fully saturated, or fully unsaturated five to twelve
membered ring optionally having up to four heteroatoms
independently selected from oxygen, sulfur, and nitrogen, or
A.sup.1 is R.sup.3-(C.sub.1-C.sub.4)alkoxy wherein R.sup.3 is
pyrrolidino, piperidino, morpholino, or dimethylamino; A.sup.2,
A.sup.3, and A.sup.4 are independently selected from hydrogen,
hydroxy, (C.sub.1-C.sub.4)alkoxy, and halo; R.sup.1 is phenyl;
pyridyl; piperidinyl; (C.sub.1-C.sub.7)alkyl; adamantyl; a
partially saturated, fully saturated, or fully unsaturated three to
twelve membered ring optionally having up to four heteroatoms
selected independently from oxygen, sulfur, and nitrogen; a
bicyclic ring consisting of two fused independently partially
saturated, fully saturated, or fully unsaturated five to six
membered rings, wherein said bicyclic ring includes up to four
heteroatoms independently selected from oxygen, sulfur, and
nitrogen; or a bicyclic ring system consisting of two rings joined
by a covalent bond, said rings being independently partially
saturated, fully saturated, or fully unsaturated three to eight
membered rings, wherein said bicyclic ring system includes up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen; wherein each of the above R.sup.1 groups is optionally
substituted with up to seven fluoro atoms, or with up to three
substituents independently selected from Group A, wherein Group A
consists of hydroxy, halo, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy, (C.sub.3-C.sub.8)cycloalkyl,
R.sup.3-(C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.4)alkenyl-COOR.sup.7 wherein R.sup.7 is hydrogen or
(C.sub.1-C.sub.4)alkyl, (C.sub.0-C.sub.4)alkyl-COOR.sup.7,
(C.sub.1-C.sub.4)alkanoyloxy-(C.sub.2-- C.sub.C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and
R.sup.5 are independently hydrogen, (C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)a- lkylene, or
(C.sub.3-C.sub.8)cycloalkyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form pyrrolidino,
piperidino, morpholino, or hexamethyleneimino,
(C.sub.0-C.sub.4)alkyl-CONR.sup.4R.sup.5,
(C.sub.0-C.sub.4)alkyl-NR.sup.4- R.sup.5,
OCH.sub.2CH.sub.2NR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 are
independently methyl or ethyl, or R.sup.8 and R.sup.9 taken
together with the nitrogen atom to which they are attached form
pyrrolidino, piperidino, morpholino, or hexamethyleneimino,
propyl-R.sup.8R.sup.9, and SO.sub.2-R.sup.6 wherein R.sup.6 is
imidazolyl, thienyl, benzathienyl, or isoxazyl, optionally
substituted with up to three substituents independently selected
from (C.sub.1-C.sub.4)alkyl; X is
(C.sub.0-C.sub.1)alkylene-phenylene-(C.sub.0-C.sub.1)alkylene,)
CO.sub.2, CO,
(C.sub.1-C.sub.3)alkylene-CO--(C.sub.1-C.sub.3)alkylene,
(C.sub.0-C.sub.3)alkylene-CO--(C.sub.2-C.sub.3)alkylene,
(C.sub.2-C.sub.3)alkylene-CO--(C.sub.0-C.sub.3)alkylene, or
(C.sub.0-C.sub.4)alkylene-SO.sub.2--(C.sub.0-C.sub.4)alkylene;
R.sup.2 is (C.sub.1-Cg)alkyl; (C.sub.2-C.sub.4)alkenyl; benzhydryl;
a partially saturated, fully saturated, or fully unsaturated three
to eight membered ring optionally having up to four heteroatoms
selected independently from oxygen, sulfur, and nitrogen; a
bicyclic ring consisting of two fused independently partially
saturated, fully saturated, or fully unsaturated five to six
membered rings, wherein said bicyclic ring includes up to four
heteroatoms independently selected from oxygen, sulfur, and
nitrogen; or a bicyclic ring system consisting of two rings joined
by a covalent bond, said rings being independently partially
saturated, fully saturated, or fully unsaturated three to eight
membered rings, wherein said bicyclic ring system includes up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen; wherein said (C.sub.1-C.sub.9)alkyl is optionally
substituted with one to seven fluoro substituents, or up to three
substituents independently selected from Group B, wherein Group B
consists of chloro, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; wherein said
(C.sub.2-C.sub.4)alkenyl is optionally substituted with up to three
substituents independently selected from Group C, wherein Group C
consists of halo, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and wherein said benzhydryl, said 5
to 8 membered ring, said bicyclic ring, and said bicyclic ring
system is optionally substituted with up to three substituents
independently selected from Group D, wherein Group D consists of
halo, hydroxy, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
imidazolyl, amino, (C.sub.1-C.sub.4)alkylcarbonylamino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and p is 0, 1, or2.
45. A method for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen level in a mammal, said method
comprising administering to said mammal a therapeutically effective
amount of a compound of claim 1.
46. A method according to claim 45 wherein said disease, disorder,
condition, or symptom is perimenopausal or postmenopausal syndrome,
osteoporosis, atrophy of skin or vagina, elevated serum cholesterol
levels, cardiovascular disease, Alzheimer's disease, a reduction or
prevention of reduction in cognitive function, an estrogen
dependent cancer, breast or uterus cancer, a prostatic disease,
benign prostatic hyperplasia, or prostate cancer.
47. A method according to claim 45 wherein said disease, disorder,
condition, or symptom is obesity, endometriosis, bone loss, uterine
fibrosis, aortal smooth muscle cell proliferation, lack of birth
control, acne, hirsutism, dysfunctional uterine bleeding,
dysmenorrehea, male infertility, impotence, psychological and
behavioral symptoms during menstruation, ulcerative mucositis,
uterine fibroid disease, restenosis, atherosclerosis,
musculoaponeurotic fibromatosis, alopecia, wound-healing, scarring,
auto immune disease, cartilage degeneration, delayed puberty,
demyelinating disease, dysmyelinating disease, hypoglycemia, lupus
erythematosus, myocardial infarction, ischemia, thromboembolic
disorder, obessive compulsive disorder, ovarian dysgenesis, post
menopausal CNS disorder, pulmonary hypertension, reperfusion
damage, resistant neoplasm, rheumatoid arthritis, seborrhea, sexual
precocity, thyroiditis, Turner's syndrome, or hyperlipidemia.
48. A method according to claim 45 useful for blocking a calcium
channel, inhibiting an environmental estrogen, minimizing the
uterotropic effect of tamoxifen or an analog thereof, removing
fibrin by inhibiting plasminogen activators, inhibiting estrogen
positive primary tumors of the brain and CNS, increasing sphincter
competence, increasing libido, inhibiting fertility, oxidizing low
density lipoprotein, increasing macrophage function, expressing
thrombomodulin, or increasing levels of endogenous growth
hormone.
49. A method for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen level in a mammal, said method
comprising administering to said mammal a therapeutically effective
amount of a compound of claim 1 and an amount of an anabolic agent,
a prodrug thereof, or a pharmaceutically acceptable salt of said
anabolic agent or said prodrug.
50. A method according to claim 49 wherein said disease, disorder,
condition, or symptom is perimenopausal or postmenopausal syndrome,
osteoporosis, atrophy of skin or vagina, elevated serum cholesterol
levels, cardiovascular disease, Alzheimer's disease, a reduction or
prevention of reduction in cognitive function, an estrogen
dependent cancer, breast or uterus cancer, a prostatic disease,
benign prostatic hyperplasia, or prostate cancer.
51. A method according to claim 49 wherein said disease, disorder,
condition, or symptom is obesity, endometriosis, bone loss, uterine
fibrosis, aortal smooth muscle cell proliferation, lack-of birth
control, acne, hirsutism, dysfunctional uterine bleeding,
dysmenorrehea, male infertility, impotence, psychological and
behavioral symptoms during menstruation, ulcerative mucositis,
uterine fibroid disease, restenosis, atherosclerosis,
musculoaponeurotic fibromatosis, alopecia, wound-healing, scarring,
auto immune disease, cartilage degeneration, delayed puberty,
demyelinating disease, dysmyelinating disease, hypoglycemia, lupus
erythematosus, myocardial infarction, ischemia, thromboembolic
disorder, obessive compulsive disorder, ovarian dysgenesis, post
menopausal CNS disorder, pulmonary hypertension, reperfusion
damage, resistant neoplasm, rheumatoid arthritis, seborrhea, sexual
precocity, thyroiditis, Turner's syndrome, or hyperlipidemia.
52. A method according to claim 49 useful for blocking a calcium
channel, inhibiting an environmental estrogen, minimizing the
uterotropic effect of tamoxifen or an analog thereof, removing
fibrin by inhibiting plasminogen activators, inhibiting estrogen
positive primary tumors of the brain and CNS, increasing sphincter
competence, increasing libido, inhibiting fertility, oxidizing low
density lipoprotein, increasing macrophage function, expressing
thrombomodulin, or increasing levels of endogenous growth
hormone.
53. A method for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen level in a mammal, said method
comprising administering to said mammal a therapeutically effective
amount of a compound of claim 1 and an amount of growth hormone or
a growth hormone secretagogue, a prodrug thereof, or a
pharmaceutically acceptable salt of said growth hormone
secretagogue or said prodrug.
54. A method according to claim 53 wherein said disease, disorder,
condition, or symptom is perimenopausal or postmenopausal syndrome,
osteoporosis, atrophy of skin or vagina, elevated serum cholesterol
levels, cardiovascular disease, Alzheimer's disease, a reduction or
prevention of reduction in cognitive function, an estrogen
dependent cancer, breast or uterus cancer, a prostatic disease,
benign prostatic hyperplasia, or prostate cancer.
55. A method according to claim 53 wherein said disease, disorder,
condition, or symptom is obesity, endometriosis, bone loss, uterine
fibrosis, aortal smooth muscle cell proliferation, lack of birth
control, acne, hirsutism, dysfunctional uterine bleeding,
dysmenorrehea, male infertility, impotence, psychological and
behavioral symptoms during menstruation, ulcerative mucositis,
uterine fibroid disease, restenosis, atherosclerosis,
musculoaponeurotic fibromatosis, alopecia, wound-healing, scarring,
auto immune disease, cartilage degeneration, delayed puberty,
demyelinating disease, dysmyelinating disease, hypoglycemia, lupus
erythematosus, myocardial infarction, ischemia, thromboembolic
disorder, obessive compulsive disorder, ovarian dysgenesis, post
menopausal CNS disorder, pulmonary hypertension, reperfusion
damage, resistant neoplasm, rheumatoid arthritis, seborrhea, sexual
precocity, thyroiditis, Turner's syndrome, or hyperlipidemia.
56. A method of claim 53 useful for blocking a calcium channel,
inhibiting an environmental estrogen, minimizing the uterotropic
effect of tamoxifen or an analog thereof, removing fibrin by
inhibiting plasminogen activators, inhibiting estrogen positive
primary tumors of the brain and CNS, increasing sphincter
competence, increasing libido, inhibiting fertility, oxidizing low
density lipoprotein, increasing macrophage function, expressing
thrombomodulin, or increasing levels of endogenous growth
hormone.
57. A method for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen level in a mammal, said method
comprising administering to said mammal a therapeutically effective
amount of a compound of claim 1 and an amount of a second compound
comprising a prostaglandin agonist/antagonist, a prodrug thereof,
or a pharmaceutically acceptable salt of said prostaglandin
agonist/antagonist or said prodrug.
58. A method according to claim 57 wherein said disease, disorder,
condition, or symptom is perimenopausal or postmenopausal syndrome,
osteoporosis, atrophy of skin or vagina, elevated serum cholesterol
levels, cardiovascular disease, Alzheimer's disease, a reduction or
prevention of reduction in cognitive function, an estrogen
dependent cancer, breast or uterus cancer, a prostatic disease,
benign prostatic hyperplasia, or prostate cancer.
59. A method according to claim 57 wherein said disease, disorder,
condition, or symptom is obesity, endometriosis, bone loss, uterine
fibrosis, aortal smooth muscle cell proliferation, lack of birth
control, acne, hirsutism, dysfunctional uterine bleeding,
dysmenorrehea, male infertility, impotence, psychological and
behavioral symptoms during menstruation, ulcerative mucositis,
uterine fibroid disease, restenosis, atherosclerosis,
musculoaponeurotic fibromatosis, alopecia, wound-healing, scarring,
auto immune disease, cartilage degeneration, delayed puberty,
demyelinating disease, dysmyelinating disease, hypoglycemia, lupus
erythematosus, myocardial infarction, ischemia, thromboembolic
disorder, obessive compulsive disorder, ovarian dysgenesis, post
menopausal CNS disorder, pulmonary hypertension, reperfusion
damage, resistant neoplasm, rheumatoid arthritis, seborrhea, sexual
precocity, thyroiditis, Turner's syndrome, or hyperlipidemia.
60. A method according to claim 57 useful for blocking a calcium
channel, inhibiting an environmental estrogen, minimizing the
uterotropic effect of tamoxifen or an analog thereof, removing
fibrin by inhibiting plasminogen activators, inhibiting estrogen
positive primary tumors of the brain and CNS, increasing sphincter
competence, increasing libido, inhibiting fertility, oxidizing low
density lipoprotein, increasing macrophage function, expressing
thrombomodulin, or increasing levels of endogenous growth
hormone.
61. A method for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen level in a mammal, said method
comprising administering to said mammal a therapeutically effective
amount of a compound of claim 1 and an amount of a second compound
comprising parathyroid hormone or sodium fluoride.
62. A method according to claim 61 wherein said disease, disorder,
condition, or symptom is perimenopausal or postmenopausal syndrome,
osteoporosis, atrophy of skin or vagina, elevated serum cholesterol
levels, cardiovascular disease, Alzheimer's disease, a reduction or
prevention of reduction in cognitive function, an estrogen
dependent cancer, breast or uterus cancer, a prostatic disease,
benign prostatic hyperplasia, or prostate cancer.
63. A method according to claim 61 wherein said disease, disorder,
condition, or symptom is obesity, endometriosis, bone loss, uterine
fibrosis, aortal smooth muscle cell proliferation, lack of birth
control, acne, hirsutism, dysfunctional uterine bleeding,
dysmenorrehea, male infertility, impotence, psychological and
behavioral symptoms during menstruation, ulcerative mucositis,
uterine fibroid disease, restenosis, atherosclerosis,
musculoaponeurotic fibromatosis, alopecia, wound-healing, scarring,
auto immune disease, cartilage degeneration, delayed puberty,
demyelinating disease, dysmyelinating disease, hypoglycemia, lupus
erythematosus, myocardial infarction, ischemia, thromboembolic
disorder, obessive compulsive disorder, ovarian dysgenesis, post
menopausal CNS disorder, pulmonary hypertension, reperfusion
damage, resistant neoplasm, rheumatoid arthritis, seborrhea, sexual
precocity, thyroiditis, Turner's syndrome, or hyperlipidemia.
64. A method according to claim 61 useful for blocking a calcium
channel, inhibiting an environmental estrogen, minimizing the
uterotropic effect of tamoxifen or an analog thereof, removing
fibrin by inhibiting plasminogen activators, inhibiting estrogen
positive primary tumors of the brain and CNS, increasing sphincter
competence, increasing libido, inhibiting fertility, oxidizing low
density lipoprotein, increasing macrophage function, expressing
thrombomodulin, or increasing levels of endogenous growth
hormone.
65. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable vehicle, carrier, or diluent.
66. A pharmaceutical composition comprising a compound of claim 44
and a pharmaceutically acceptable vehicle, carrier, or diluent.
67. A pharmaceutical composition comprising: a compound of claim 1;
an anabolic agent, a prodrug thereof, or a pharmaceutically
acceptable salt of said anabolic agent or a said prodrug; and a
pharmaceutically acceptable vehicle, carrier, or diluent.
68. A pharmaceutical composition comprising: a compound of claim 1;
growth hormone, a growth hormone secretagogue, a prodrug thereof,
or a pharmaceutically acceptable salt of said growth hormone
secretagogue or a said prodrug; and a pharmaceutically acceptable
vehicle, carrier, or diluent.
69. A pharmaceutical composition comprising: a compound of claim 1;
a prostaglandin agonist/antagonist, a prodrug thereof, or a
pharmaceutically acceptable salt of said prostaglandin
agonist/antagonist or a said prodrug; and a pharmaceutically
acceptable vehicle, carrier, or diluent.
70. A pharmaceutical composition comprising: a compound of claim 1;
parathyroid hormone or sodium fluoride; and a pharmaceutically
acceptable vehicle, carrier, or diluent.
71. A kit useful for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen levels, said kit comprising: a compound
of claim 1 and a pharmaceutically acceptable vehicle, carrier, or
diluent in a dosage form; and a container for containing said
dosage form.
72. A kit useful for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen levels, said kit comprising: a compound
of claim 1 and a pharmaceutically acceptable vehicle, carrier, or
diluent in a first unit dosage form; an anabolic agent, a prodrug
thereof, or a pharmaceutically acceptable salt of said anabolic
agent or said prodrug and a pharmaceutically acceptable vehicle,
carrier, or diluent in a second unit dosage form; and a container
for containing said first and second unit dosage forms.
73. A kit useful for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen levels, said kit comprising: a compound
of claim 1 and a pharmaceutically acceptable vehicle, carrier, or
diluent in a first unit dosage form; growth hormone or a growth
hormone secretagogue, a prodrug thereof, or a pharmaceutically
acceptable salt of said growth hormone secretagogue or said prodrug
and a pharmaceutically acceptable vehicle, carrier, or diluent in a
second unit dosage form; and a container for containing said first
and second unit dosage forms.
74. A kit useful for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen levels, said kit comprising: a compound
of claim 1 and a pharmaceutically acceptable vehicle, carrier, or
diluent in a first unit dosage form; a prostaglandin
agonist/antagonist, a prodrug thereof, or a pharmaceutically
acceptable salt of said prostaglandin agonist/antagonist or said
prodrug and a pharmaceutically acceptable vehicle, carrier, or
diluent in a second unit dosage form; and a container for
containing said first and second unit dosage forms.
75. A kit useful for treating or preventing a disease, disorder,
condition, or symptom mediated by an estrogen receptor and/or
caused by lowered estrogen levels, said kit comprising: a compound
of claim 1 and a pharmaceutically acceptable vehicle, carrier, or
diluent in a first unit dosage form; parathyroid hormone or sodium
fluoride and a pharmaceutically acceptable vehicle, carrier, or
diluent in a second unit dosage form; and a container for
containing said first and second unit dosage forms.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application claims priority of U.S. provisional
application number 60/173,063, filed Dec. 24, 1999.
[0002] This invention relates to novel tetrahydroisoquinoline
compounds that are useful as estrogen agonists and antagonists, and
the pharmaceutical uses thereof.
BACKGROUND OF THE INVENTION
[0003] The value of naturally occurring estrogens and synthetic
compositions demonstrating "estrogenic" activity has typically 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, but is not limited to, 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 post-partum lactation (Goodman and Gilman, The
Pharmacological Basis Of Therapeutics (7th Ed.), Macmillan
Publishing Company, 1985, pages 1421-1423). Accordingly, there has
been increasing interest in finding newly synthesized compounds and
new uses for previously known compounds that are demonstrably
estrogenic, that 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 desirable to procure
compounds having demonstrable estrogen-like function, but which are
devoid of unwanted 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 treated chronically with active estrogens, it is
not clinically advisable to treat osteoporosis in intact women with
fully active estrogens for prolonged periods.
[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 injuries cost the nation over $10 billion per year.
Hip fractures are the most serious, with 5-20% of patients dying
within one year, and over 50% of the 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 3-fold over the next 60 years, and one study estimates
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
that 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 remains 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 plasma levels of the beneficial high density lipoproteins
(HDLs). Thus, estrogen can be an effective therapy for
hypercholesterolemia. However, as discussed supra, long-term
estrogen therapy has been implicated in a variety of disorders,
including an increase in the risk of uterine and breast cancer,
causing many women to avoid this treatment. Recently suggested
therapeutic regimens, that seek to lessen the cancer risk, such as
administering combinations of progestogen and estrogen, cause the
patient to experience unacceptable bleeding. Furthermore, combining
progestogen with estrogen seems to blunt the desired serum
cholesterol 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 that exert
selective effects on different tissues in the body. Tamoxifen, or
1-(4-.beta.-dimethylaminoethoxyphenyl)-1,2-diphenyl-but-1-ene, is
an antiestrogen that has a palliative effect on breast cancer, but
is reported to have estrogenic activity in the uterus. Gill-Sharma
et al., J. Repr. Fert., 99:395 (1993), discloses 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 Conf. Scrip No.
1812/13, p. 29 (Apr. 16-20, 1993)) that raloxifene, or
6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]th-
iophene, mimics the favorable action of estrogen on bone and lipids
but, unlike estrogen, has minimal uterine stimulatory effect.
(Jordan et al., Breast Cancer Res. Treat., 10(1):31-36 (1987)).
[0012] Neubauer et al., The Prostate, 23:245 (1993), teaches that
raloxifene treatment of male rats produced regression of the
ventral prostate.
[0013] Raloxifene and related compounds are described as
antiestrogenic and antiandrogenic materials that are effective in
the treatment of certain mammary and prostate cancers. See U.S.
Pat. No. 4,418,068 and Jones et al., J. Med. Chem., 27:1057-66
(1984).
[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 that are useful as
antifertility agents, and also suppress the growth of mammary
tumors.
[0015] Lednicer et al., J. Med. Chem., 12:881 (1969), describes
estrogen antagonists of the structure 1
[0016] wherein R.sup.2 is phenyl or cyclopentyl and R.sup.3 is H,
--CH.sub.2CHOHCH.sub.2OH, or 2
[0017] Bencze et al., J. Med. Chem., 10:138 (1967), prepared a
series of tetrahydronaphthalenes intended to achieve separation of
estrogenic, antifertility, and hypocholesterolemic activities,
although they were only partially successful in doing so. These
structures have the general formula: 3
[0018] 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, and R.sup.3 is H or Cl.
[0019] U.S. Pat. No. 3,234,090 discloses compounds having
estrogenic and antifungal properties, as well as procedures for the
preparation of these compounds. The described compounds have the
formula: 4
[0020] 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 the tertiary amino is separated from the 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 --(C.sub.nH.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 quaternary ammonium compounds thereof.
[0021] U.S. Pat. No. 3,277,106 refers to basic ethers with
estrogenic, hypocholesterolemic, and antifertility effects, those
ethers having the formula: 5
[0022] 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
--(C.sub.nH.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.
[0023] 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 6
[0024] 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.
[0025] PCT publication No. WO 96/09040 A1 discloses a benzofuran
compound useful for treatment of medical indications associated
with post-menopausal syndrome, e.g., uterine fibroid disease,
endometriosis, and aortal smooth muscle cell proliferation.
[0026] European Patent Application EP 0,826,670 A1 discloses
naphthalene compounds and methods for inhibiting estrogen deficient
pathologies such as lack of birth control, postmenopausal syndrome
including osteoporosis, cardiovascular disease, restenosis and
hyperlipidemia, prostate cancer, acne, hirsutism, dysfunctional
uterine bleeding, dysmenorrhea, and atrophic vaginitis.
[0027] European Patent Application EP 0,659,424 A1 discloses
benzothiophene compounds useful for treating male infertility.
[0028] U.S. Pat. No. 5,462,950 discloses the use of benzothiophene
compounds for treating physical menstrual symptoms.
[0029] PCT Publication WO 96/40134 discloses methods of
antagonizing or blocking calcium channels in vascular tissue
comprising administering a benzothiophene compound.
[0030] U.S. Pat. No. 5,521,214 discloses methods of inhibiting
environmental estrogens comprising administering a benzothiophene
compound.
[0031] U.S. Pat. No. 5,554,628 discloses methods for minimizing the
uterotrophic effect of tamoxifen and its analogs by administering a
naphthalene compound.
[0032] PCT Publication WO 97/13764 discloses benzothiophene
compounds useful for inhibiting cardiovascular disease including
restenosis and atherosclerosis.
[0033] PCT Publication WO 97/13511 discloses benzothiophene
compounds useful for inhibiting plasminogen activator inhibitor 1
related conditions such as major tissue damage and trauma, or
multiple organ dysfunction syndrome.
[0034] European Patent Application 0,729,754 A2 discloses
benzothiophene compounds useful for inhibiting estrogen positive
tumors of the brain or CNS.
[0035] U.S. Pat. No. 5,670,523 discloses benzothiophene compounds
useful for inhibiting musculoaponeurotic fibromatoses previously
classified as desmoid tumors.
[0036] U.S. Pat. No. 5,496,828 discloses methods for inhibiting
ulcerative mucositis by administering a benzothiophene
compound.
[0037] PCT Publication WO 97/26876 discloses methods for increasing
sphincter competence by administering a benzothiophene
compound.
[0038] European Patent Application 0,826,679 A2 discloses a
pharmaceutical composition useful for alleviating symptoms of
postmenopausal syndromes, the composition comprising a naphthalene
compound and an additional therapeutic agent such as estrogen or
progestin, a benzothiophene compound such as raloxifene, a naphthyl
compound having antiestrogen activity, a bisphosphonate compound
such as alendronate or tiludronate, parathyroid hormone (PTH),
including truncated and/or recombinant forms of PTH such as PTH
(1-34), calcitonin, bone morphogenic proteins (BMPs), or
combination thereof.
[0039] European Patent Application 0,702,962 A2 discloses a
pharmaceutical agent for treating breast cancer, the agent
comprising tamoxifen and a naphthyl compound useful for inhibiting
hormone-dependent breast cancer.
[0040] U.S. Pat. No. 5,599,822 discloses a pharmaceutical
composition for minimizing the bone loss effect of danazol, the
composition comprising danazol and a benzothiophene compound having
antiestrogen activity.
SUMMARY OF THE INVENTION
[0041] This invention relates to novel tetrahydroisoquinoline
compounds that are useful as estrogen agonists and antagonists, and
the pharmaceutical uses thereof.
[0042] In a first aspect, this invention provides compounds of the
formula: 7
[0043] wherein:
[0044] A.sup.1 is hydrogen, hydroxy, (C.sub.1-C.sub.4)alkoxy, or
(C.sub.1-C.sub.4)alkanoyloxy, said (C.sub.1-C.sub.4)alkoxy or said
(C.sub.1-C.sub.4)alkanoyloxy being optionally substituted by
hydroxy, halo, or a partially saturated, fully saturated, or fully
unsaturated five to twelve membered ring optionally having up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen, or A.sup.1 is R.sup.3--(C.sub.1-C.sub.4)alkoxy wherein
R.sup.3 is pyrrolidino, piperidino, morpholino, or
dimethylamino;
[0045] A.sup.2, A.sup.3, and A.sup.4 are independently selected
from hydrogen, hydroxy, (C.sub.1-C.sub.4)alkoxy, and halo;
[0046] R.sup.1 is phenyl; pyridyl; piperidinyl;
(C.sub.1-C.sub.7)alkyl; adamantyl; a partially saturated, fully
saturated, or fully unsaturated three to twelve membered ring
optionally having up to four heteroatoms selected independently
from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of
two fused independently partially saturated, fully saturated, or
fully unsaturated five to six membered rings, wherein said bicyclic
ring includes up to four heteroatoms independently selected from
oxygen, sulfur, and nitrogen; or a bicyclic ring system consisting
of two rings joined by a covalent bond, said rings being
independently partially saturated, fully saturated, or fully
unsaturated three to eight membered rings, wherein said bicyclic
ring system includes up to four heteroatoms independently selected
from oxygen, sulfur, and nitrogen; wherein each of the above
R.sup.1 groups is optionally substituted with up to seven fluoro
atoms, or with up to three substituents independently selected from
Group A, wherein Group A consists of hydroxy, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.3-C.sub.8)cycloal- kyl, R.sup.3--(C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.4)alkenyl-COOR.sup.7 wherein, R.sup.7 is hydrogen or
(C.sub.1-C.sub.4)alkyl, (C.sub.0-C.sub.4)alkyl-COOR.sup.7,
(C.sub.1-C.sub.4)alkanoyloxy-(C.sub.2-- C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and
R.sup.5 are independently hydrogen, (C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)a- lkylene, or
(C.sub.3-C.sub.8)cycloalkyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form pyrrolidino,
piperidino, morpholino, or hexamethyleneimino,
(C.sub.0-C.sub.4)alkyl-CONR.sup.4R.sup.5,
(C.sub.0-C.sub.4)alkyl-NR.sup.4- R.sup.5,
OCH.sub.2CH.sub.2NR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 are
independently methyl or ethyl, or R.sup.8 and R.sup.9 taken
together with the nitrogen atom to which they are attached form
pyrrolidino, piperidino, morpholino, or hexamethyleneimino,
propyl-R.sup.8R.sup.9, and SO.sub.2--R.sup.6 wherein R.sup.6 is
imidazolyl, thienyl, benzathienyl, or isoxazyl, optionally
substituted with up to three substituents independently selected
from (C.sub.1-C.sub.4)alkyl;
[0047] X is a covalent bond, (CH.sub.2).sub.n where n is 1, 2, or
3, (C.sub.0-C.sub.1)alkylene-phenylene-(C.sub.0-C.sub.1)alkylene,
CO.sub.2, (C.sub.0-C.sub.3)alkylene-CO--(C.sub.0-C.sub.3)alkylene,
or
(C.sub.0-C.sub.4)alkylene-SO.sub.2--(C.sub.0-C.sub.4)alkylene;
[0048] R.sup.2 is (C.sub.1-C.sub.9)alkyl; (C.sub.2-C.sub.4)alkenyl;
benzhydryl; a partially saturated, fully saturated, or fully
unsaturated three to eight membered ring optionally having up to
four heteroatoms selected independently from oxygen, sulfur, and
nitrogen; a bicyclic ring consisting of two fused independently
partially saturated, fully saturated, or fully unsaturated five to
six membered rings, wherein said bicyclic ring includes up to four
heteroatoms independently selected from oxygen, sulfur, and
nitrogen; or a bicyclic ring system consisting of two rings joined
by a covalent bond, said rings being independently partially
saturated, fully saturated, or fully unsaturated three to eight
membered rings, wherein said bicyclic ring system includes up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen; wherein said (C.sub.1-C.sub.9)alkyl is optionally
substituted with one to seven fluoro substituents, or up to three
substituents independently selected from Group B, wherein Group B
consists of chloro, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; wherein said
(C.sub.2-C.sub.4)alkenyl is optionally substituted with up to three
substituents independently selected from Group C, wherein Group C
consists of halo, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and wherein said benzhydryl, said 5
to 8 membered ring, said bicyclic ring, and said bicyclic ring
system is optionally substituted with up to three substituents
independently selected from Group D, wherein Group D consists of
halo, hydroxy, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
imidazolyl, amino, (C.sub.1-C.sub.4)alkylcarbonylamino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and
[0049] p is 0, 1,or2;
[0050] with the proviso that
[0051] when X is (CH.sub.2).sub.2 or (CH.sub.2).sub.3, p is 0, and
R.sup.1 is phenyl or phenyl substituted with a single chloro,
fluoro, bromo, hydroxy, methoxy, pyrrolidinoethoxy,
piperidinoethoxy, or morpholinoethoxy substituent, then R.sup.2 is
not phenyl, methoxyphenyl, tert-butyl, or cyclopentyl;
[0052] when X is CH.sub.2, (CH.sub.2).sub.2, COCH.sub.2, or
CH.sub.2CO, A.sup.1 is hydrogen, and R.sup.1 is phenyl, then
R.sup.2 is not phenyl; and
[0053] when X is a covalent bond, p is 0, A.sup.1 is hydrogen or
methoxy, and R.sup.1 is phenyl or phenyl substituted with a single
chloro, fluoro, bromo, methoxy, pyrrolidinoethoxy, or
piperidinoethoxy substituent, then R.sup.2 is not phenyl or
m-fluorophenyl.
[0054] In a preferred embodiment of the first aspect, A.sup.1 is
hydroxy; A.sup.2, A.sup.3, and A.sup.4 are hydrogen; and p is
0.
[0055] In another preferred embodiment of the first aspect, R.sup.1
is phenyl, pyridyl, (C.sub.1-C.sub.4)alkyl, adamantyl, naphthyl, or
a partially saturated, fully saturated, or fully unsaturated five
to six membered ring optionally having up to two heteroatoms
selected independently from oxygen, sulfur, and nitrogen; wherein
each of said R.sup.1 groups is optionally substituted with up to
seven fluoro atoms, or with up to three substituents independently
selected from Group A.
[0056] In another preferred embodiment of the first aspect, R.sup.1
is phenyl, cyclohexyl, pyridyl, thienyl, isopropyl, or adamantyl;
wherein each of said R.sup.1 groups is optionally substituted with
up to seven fluoro atoms, or with up to three substituents
independently selected from Group A.
[0057] In another preferred embodiment of the first aspect, R.sup.1
is phenyl or cyclohexyl; wherein each of said R.sup.1 groups is
optionally substituted with up to seven fluoro atoms, or with up to
three substituents independently selected from Group A.
[0058] In another preferred embodiment of the first aspect, each of
said R.sup.1 groups is substituted with up to three halo atoms, or
with one substituent selected from hydroxy,
(C.sub.1-C.sub.2)alkoxy, pyrrolidino-(C.sub.1-C.sub.4)alkoxy,
dimethylamino, (C.sub.2-C.sub.4)alkenyl-COOR.sup.7, COOR.sup.7,
(C.sub.2-C.sub.4)alkenyl- -CONR.sup.4R.sup.5 wherein R.sup.4 and
R.sup.5 are independently hydrogen, (C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl, --(CH.sub.2CH.sub.2--O--CH.sub.3),
or (C.sub.5-C.sub.6)cycloalkyl, or R.sup.4 and R.sup.5 taken
together with the nitrogen atom to which they are attached form
piperidino or morpholino, or SO.sub.2--R.sup.6 wherein R.sup.6 is
imidazolyl optionally substituted with up to three substituents
independently selected from (C.sub.1-C.sub.4)alkyl.
[0059] In another preferred embodiment of the first aspect, each of
said R.sup.1 groups is substituted with up to three fluoro atoms,
or with one substituent selected from iodo, chloro, bromo, hydroxy,
methoxy, pyrrolidino-ethoxy, dimethylamino, COOR.sup.7 wherein
R.sup.7 is hydrogen or methyl, or ethenyl-CONR.sup.4R.sup.5 wherein
R.sup.4 and R.sup.5 are both methyl, or R.sup.4 and R.sup.5 taken
together with the nitrogen atom to which they are attached form
piperidino or morpholino.
[0060] In another preferred embodiment of the first aspect, each of
said R.sup.1 groups is substituted with one hydroxy or
pyrrolidino-ethoxy.
[0061] In another preferred embodiment of the first aspect, X is a
covalent bond, CH.sub.2, CH.sub.2-phenylene, CO.sub.2,
CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene.
[0062] In another preferred embodiment of the first aspect, X is a
covalent bond, CO, or SO.sub.2.
[0063] In another preferred embodiment of the first aspect, R.sup.2
is (C.sub.1-C.sub.7)alkyl; propenyl; a partially saturated, fully
saturated, or fully unsaturated five to seven membered ring
optionally having up to two heteroatoms selected independently from
oxygen, sulfur, and nitrogen; a bicyclic ring consisting of two
fused independently partially saturated, fully saturated, or fully
unsaturated five to six membered rings, wherein said bicyclic ring
includes up to two oxygen atoms; or biphenyl; wherein said
(C.sub.1-C.sub.7)alkyl is optionally substituted with one to seven
fluoro substituents, or up to three substituents independently
selected from Group B; wherein said propenyl is optionally
substituted with up to three substituents independently selected
from Group C; and wherein each of said 5-7 membered ring, said
bicyclic ring, and said biphenyl is optionally substituted with up
to three substituents independently selected from Group D. In an
even more preferred embodiment, each of said (C.sub.1-C.sub.7)alkyl
and said propenyl is substituted with one to three fluoro
substituents, or up to two substituents independently selected from
amino and methylcarbonyl; and wherein each of said 5-7 membered
ring, said bicyclic ring, and said biphenyl is substituted with up
to three fluoro substituents, or up to two substituents
independently selected from hydroxy, (C.sub.1-C.sub.3)alkyl, amino,
and methylcarbonyl.
[0064] In another preferred embodiment of the first aspect, R.sup.2
is methyl, t-butyl, phenyl, cyclohexyl, isoxazolyl,
tetrahydropyranyl, naphthyl, or benzodioxolyl; wherein each of said
methyl or t-butyl is optionally substituted with one to seven
fluoro substituents, or up to three substituents independently
selected from Group B; and wherein each of said phenyl, cyclohexyl,
isoxazolyl, tetrahydropyranyl, naphthyl, or benzodioxolyl is
optionally substituted with up to three substituents independently
selected from Group D.
[0065] In another preferred embodiment of the first aspect, R.sup.2
is trifluoromethyl or phenyl; wherein said phenyl is optionally
substituted with up to three substituents independently selected
from Group D.
[0066] In another preferred embodiment of the first aspect,
[0067] A.sup.1 is hydroxy;
[0068] A.sup.2, A.sup.3, and A.sup.4 are hydrogen;
[0069] p is 0;
[0070] R.sup.1 is phenyl, cyclohexyl, pyridyl, thienyl, isopropyl,
or adamantyl;
[0071] wherein each of said R.sup.1 groups is optionally
substituted with up to three fluoro atoms, or with one substituent
selected from iodo, chloro, bromo, hydroxy, methoxy,
pyrrolidino-ethoxy, dimethylamino, COOR.sup.7 wherein R.sup.7 is
hydrogen or methyl, or ethenyl-CONR.sup.4R.sup.5 wherein R.sup.4
and R.sup.5 are both methyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form piperidino
or morpholino;
[0072] X is a covalent bond, CH.sub.2, CH.sub.2-phenylene,
CO.sub.2, CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene; and
[0073] R.sup.2 is methyl, t-butyl, phenyl, cyclohexyl, isoxazolyl,
tetrahydropyranyl, naphthyl, or benzodioxolyl; wherein each of said
methyl or t-butyl is optionally substituted with one to three
fluoro substituents, or up to two substituents independently
selected from amino and methylcarbonyl; and wherein each of said
phenyl, cyclohexyl, isoxazolyl, tetrahydropyranyl, naphthyl, or
benzodioxolyl is optionally substituted with up to three fluoro
substituents, or up to two substituents independently selected from
hydroxy, (C.sub.1-C.sub.3)alkyl, amino, and methylcarbonyl.
[0074] Some of the more preferred compounds of the first aspect of
the present invention include
1-(4-hydroxy-phenyl)-2-phenyl-1,2,3,4-tetrahydr- oisoquinolin-6-ol;
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin--
1-yl)-phenyl]-1-piperidin-1-yl-propenone;
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-
-tetrahydroisoquinolin-1-yl)-phenyl]-1-morpholin-4-yl-propenone;
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenyl]-N,N--
dimethyl-acrylamide;
2-benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3-
,4-tetrahydroisoquinolin-6-ol;
2,2,2-trifluoro-1-[6-hydroxy-1-(4-hydroxyph-
enyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone;
2-benzenesulfonyl-1-[4-(2-
-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol;
and
2-(4-isopropylbenzenesulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2-
,3,4-tetrahydroisoquinolin-6-ol.
[0075] In another preferred embodiment of the first aspect,
[0076] said compound is of formula (I);
[0077] A.sup.1 is hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkanoyloxy, or pyrrolidino-ethoxy;
[0078] A.sup.2, A.sup.3, and A.sup.4 are hydrogen;
[0079] p is 0 or 1;
[0080] R.sup.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.4-C.sub.7)cycloalkyl, adamantyl, phenyl, pyridyl, or
thienyl, wherein each of said phenyl, pyridyl, or thienyl groups is
optionally substituted with up to three fluoro atoms, or with one
substituent selected from iodo, chloro, bromo, hydroxy, methoxy,
dimethylamino, OCH.sub.2CH.sub.2NR.sup.8R.sup.9, COOR.sup.7,
ethenyl-COOR.sup.7, or ethenyl-CONR.sup.4R.sup.5 wherein R.sup.4
and R.sup.5 are both methyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form pyrrolidino,
piperidino, hexamethyleneimino, or morpholino;
[0081] X is a covalent bond, CH.sub.2, CH.sub.2-phenylene,
CO.sub.2, CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene; and
[0082] R.sup.2 is (C.sub.1-C.sub.7)alkyl, phenyl, benzyl, thienyl,
(C.sub.5-C.sub.7)cycloalkyl, isoxazolyl, imidazolyl,
tetrahydropyranyl, naphthyl, or benzodioxolyl, wherein said
(C.sub.1-C.sub.7)alkyl is optionally substituted with one to three
fluoro substituents, or up to two substituents independently
selected from amino and methylcarbonyl, and wherein each of said
phenyl, thienyl, (C.sub.5-C.sub.7)cycloalkyl, isoxazolyl,
tetrahydropyranyl, naphthyl, and benzodioxolyl is optionally
substituted with up to three fluoro substituents, or up to two
substituents independently selected from hydroxy, methoxy,
(C.sub.1-C.sub.3)alkyl, amino, and methylcarbonyl.
[0083] In another preferred embodiment of the first aspect, said
compound is of formula (II).
[0084] In another preferred embodiment of the first aspect,
[0085] said compound is of formula (II);
[0086] A.sup.1 is hydroxy, (C.sub.1-C.sub.4)alkoxy, or
(C.sub.1-C.sub.4)alkanoyloxy;
[0087] A.sup.2, A.sup.3, and A.sup.4 are hydrogen;
[0088] p is 0 or 1;
[0089] R.sup.1 is (C.sub.1-C.sub.4)alkyl,
(C.sub.4-C.sub.7)cycloalkyl, adamantyl, phenyl, pyridyl, or
thienyl, wherein each of said phenyl, pyridyl, thienyl, or
(C.sub.5-C.sub.7)cycloalkyl groups is optionally substituted with
up to three fluoro atoms, or with one substituent selected from
iodo, chloro, bromo, hydroxy, methoxy, dimethylamino,
OCH.sub.2CH.sub.2NR.sup.8R.sup.9, COOR.sup.7, or
ethenyl-CONR.sup.4R.sup.- 5 wherein R.sup.4 and R.sup.5 are both
methyl, or R.sup.4 and R.sup.5 taken together with the nitrogen
atom to which they are attached form pyrrolidino, piperidino,
hexamethyleneimino, or morpholino;
[0090] X is a covalent bond, CH.sub.2, CH.sub.2-phenylene,
CO.sub.2, CO--(C.sub.0-C.sub.2)alkylene, or
SO.sub.2--(C.sub.0-C.sub.2)alkylene; and
[0091] R.sup.2 is (C.sub.1-C.sub.7)alkyl, phenyl, benzyl, thienyl,
(C.sub.5-C.sub.7)cycloalkyl, isoxazolyl, tetrahydropyranyl,
naphthyl, or benzodioxolyl, wherein said (C.sub.1-C.sub.7)alkyl is
optionally substituted with one to three fluoro atoms, or up to two
substituents independently selected from amino and methylcarbonyl,
and wherein each of said phenyl, thienyl, cyclohexyl, isoxazolyl,
tetrahydropyranyl, naphthyl, and benzodioxolyl is optionally
substituted with up to three fluoro atoms, or up to two
substituents independently selected from hydroxy, methoxy, and
(C.sub.1-C.sub.3)alkyl.
[0092] One of the more preferred compounds of the first aspect of
the present invention, wherein the compound is of formula (II) is
2,2,2-trifluoro-1-[7-hydroxy-4-(4-hydroxy-phenyl)-3,4-dihydro-1H-isoquino-
lin-2-yl]-ethanone.
[0093] In a second aspect, this invention provides compounds of the
formula: 8
[0094] wherein:
[0095] A.sup.1 is hydrogen, hydroxy, (C.sub.1-C.sub.4)alkoxy, or
(C.sub.1-C.sub.4)alkanoyloxy, said (C.sub.1-C.sub.4)alkoxy or said
(C.sub.1-C.sub.4)alkanoyloxy being optionally substituted by
hydroxy, halo, or a partially saturated, fully saturated, or fully
unsaturated five to twelve membered ring optionally having up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen, or A.sup.1 is R.sup.3--(C.sub.1-C.sub.4)alkoxy wherein
R.sup.3 is pyrrolidino, piperidino, morpholino, or
dimethylamino;
[0096] A.sup.2, A.sup.3, and A.sup.4 are independently selected
from hydrogen, hydroxy, (C.sub.1-C.sub.4)alkoxy, and halo;
[0097] R.sup.1 is phenyl; pyridyl; piperidinyl;
(C.sub.1-C.sub.7)alkyl; adamantyl; a partially saturated, fully
saturated, or fully unsaturated three to twelve membered ring
optionally having up to four heteroatoms selected independently
from oxygen, sulfur, and nitrogen; a bicyclic ring consisting of
two fused independently partially saturated, fully saturated, or
fully unsaturated five to six membered rings, wherein said bicyclic
ring includes up to four heteroatoms independently selected from
oxygen, sulfur, and nitrogen; or a bicyclic ring system consisting
of two rings joined by a covalent bond, said rings being
independently partially saturated, fully saturated, or fully
unsaturated three to eight membered rings, wherein said bicyclic
ring system includes up to four heteroatoms independently selected
from oxygen, sulfur, and nitrogen; wherein each of the above
R.sup.1 groups is optionally substituted with up to seven fluoro
atoms, or with up to three substituents independently selected from
Group A, wherein Group A consists of hydroxy, halo,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
(C.sub.3-C.sub.8)cycloal- kyl, R.sup.3--(C.sub.1-C.sub.4)alkoxy,
(C.sub.2-C.sub.4)alkenyl-COOR.sup.7 wherein R.sup.7 is hydrogen or
(C.sub.1-C.sub.4)alkyl, (C.sub.0-C.sub.4)alkyl-COOR.sup.7,
(C.sub.1-C.sub.4)alkanoyloxy-(C.sub.2-- C.sub.4)alkenyl,
(C.sub.2-C.sub.4)alkenyl-CONR.sup.4R.sup.5 wherein R.sup.4 and
R.sup.5 are independently hydrogen, (C.sub.1-C.sub.4)alkyl,
hydroxy(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)a- lkylene, or
(C.sub.3-C.sub.8)cycloalkyl, or R.sup.4 and R.sup.5 taken together
with the nitrogen atom to which they are attached form pyrrolidino,
piperidino, morpholino, or hexamethyleneimino,
(C.sub.0-C.sub.4)alkyl-CONR.sup.4R.sup.5,
(C.sub.0-C.sub.4)alkyl-NR.sup.4- R.sup.5,
OCH.sub.2CH.sub.2NR.sup.8R.sup.9 wherein R.sup.8 and R.sup.9 are
independently methyl or ethyl, or R.sup.8. and R.sup.9 taken
together with the nitrogen atom to which they are attached form
pyrrolidino, piperidino, morpholino, or hexamethyleneimino,
propyl-R.sup.8R.sup.9, and SO.sub.2--R.sup.6 wherein R.sup.6 is
imidazolyl, thienyl, benzathienyl, or isoxazyl, optionally
substituted with up to three substituents independently selected
from (C.sub.1-C.sub.4)alkyl;
[0098] X is
(C.sub.0-C.sub.1)alkylene-phenylene-(C.sub.0-C.sub.1)alkylene,
CO.sub.2, CO,
(C.sub.1-C.sub.3)alkylene-CO--(C.sub.1-C.sub.3)alkylene,
(C.sub.0-C.sub.3)alkylene-CO--(C.sub.2-C.sub.3)alkylene,
(C.sub.2-C.sub.3)alkylene-CO--(C.sub.0-C.sub.3)alkylene, or
(C.sub.0-C.sub.4)alkylene-SO.sub.2--(C.sub.0-C.sub.4)alkylene;
[0099] R.sup.2 is (C.sub.1-C.sub.9)alkyl; (C.sub.2-C.sub.4)alkenyl;
benzhydryl; a partially saturated, fully saturated, or fully
unsaturated three to eight membered ring optionally having up to
four heteroatoms selected independently from oxygen, sulfur, and
nitrogen; a bicyclic ring consisting of two fused independently
partially saturated, fully saturated, or fully unsaturated five to
six membered rings, wherein said bicyclic ring includes up to four
heteroatoms independently selected from oxygen, sulfur, and
nitrogen; or a bicyclic ring system consisting of two rings joined
by a covalent bond, said rings being independently partially
saturated, fully saturated, or fully unsaturated three to eight
membered rings, wherein said bicyclic ring system includes up to
four heteroatoms independently selected from oxygen, sulfur, and
nitrogen; wherein said (C.sub.1-C.sub.9)alkyl is optionally
substituted with one to seven fluoro substituents, or up to three
substituents independently selected from Group B, wherein Group B
consists of chloro, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; wherein said
(C.sub.2-C.sub.4)alkenyl is optionally substituted with up to three
substituents independently selected from Group C, wherein Group C
consists of halo, (C.sub.1-C.sub.4)alkoxy, amino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and wherein said benzhydryl, said 5
to 8 membered ring, said bicyclic ring, and said bicyclic ring
system is optionally substituted with up to three substituents
independently selected from Group D, wherein Group D consists of
halo, hydroxy, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy,
imidazolyl, amino, (C.sub.1-C.sub.4)alkylcarbonylamino, and
(C.sub.1-C.sub.4)alkylcarbonyl; and
[0100] p is 0, 1, or 2.
[0101] In a third aspect, this invention provides methods for
treating or preventing a disease, disorder, condition, or symptom
mediated by an estrogen receptor and/or caused by lowered estrogen
level in a mammal, said method comprising administering to said
mammal a therapeutically effective amount of a compound of the
present invention.
[0102] In preferred embodiments of the third aspect, a
therapeutically effective amount of a compound of the present
invention is combined with a therapeutically effective amount of an
anabolic agent, a prodrug thereof, or a pharmaceutically acceptable
salt of said anabolic agent or said prodrug; a growth hormone or a
growth hormone secretagogue, a prodrug thereof, or a
pharmaceutically acceptable salt of said growth hormone
secretagogue or said prodrug; a prostaglandin agonist/antagonist, a
prodrug thereof, or a pharmaceutically acceptable salt of said
prostaglandin agonist/antagonist or said prodrug; or a parathyroid
hormone or sodium fluoride.
[0103] In another preferred embodiment of the third aspect, said
disease, disorder, condition, or symptom is perimenopausal or
postmenopausal syndrome, osteoporosis, atrophy of skin or vagina,
elevated serum cholesterol levels, cardiovascular disease,
Alzheimer's disease, a reduction or prevention of reduction in
cognitive function, an estrogen dependent cancer, breast or uterus
cancer, a prostatic disease, benign prostatic hyperplasia, or
prostate cancer.
[0104] In another preferred embodiment of the third aspect, said
disease, disorder, condition, or symptom is obesity, endometriosis,
bone loss, uterine fibrosis, aortal smooth muscle cell
proliferation, lack of birth control, acne, hirsutism,
dysfunctional uterine bleeding, dysmenorrehea, male infertility,
impotence, psychological and behavioral symptoms during
menstruation, ulcerative mucositis, uterine fibroid disease,
restenosis, atherosclerosis, musculoaponeurotic fibromatosis,
alopecia, wound-healing, scarring, auto immune disease, cartilage
degeneration, delayed puberty, demyelinating disease,
dysmyelinating disease, hypoglycemia, lupus erythematosus,
myocardial infarction, ischemia, thromboembolic disorder, obessive
compulsive disorder, ovarian dysgenesis, post menopausal CNS
disorder, pulmonary hypertension, reperfusion damage, resistant
neoplasm, rheumatoid arthritis, seborrhea, sexual precocity,
thyroiditis, Turner's syndrome, or hyperlipidemia.
[0105] In another preferred embodiment of the third aspect, said
method is useful for blocking a calcium channel, inhibiting an
environmental estrogen, minimizing the uterotropic effect of
tamoxifen or an analog thereof, removing fibrin by inhibiting
plasminogen activators, inhibiting estrogen positive primary tumors
of the brain and CNS, increasing sphincter competence, increasing
libido, inhibiting fertility, oxidizing low density lipoprotein,
increasing macrophage function, expressing thrombomodulin, or
increasing levels of endogenous growth hormone.
[0106] In a fourth aspect, this invention provides pharmaceutical
compositions comprising a compound of the present invention and a
pharmaceutically acceptable vehicle, carrier, or diluent.
[0107] In a fifth aspect, this invention provides kits useful for
treating or preventing a disease, disorder, condition, or symptom
mediated by an estrogen receptor and/or caused by lowered estrogen
levels, said kit comprising a compound of the present invention and
a pharmaceutically acceptable vehicle, carrier, or diluent in a
dosage form, and a container for containing said dosage form.
[0108] In a preferred embodiment of the fifth aspect, said kit also
comprises an anabolic agent, a prodrug thereof, or a
pharmaceutically acceptable salt of said anabolic agent or said
prodrug; a growth hormone or a growth hormone secretagogue, a
prodrug thereof, or a pharmaceutically acceptable salt of said
growth hormone secretagogue or said prodrug; a prostaglandin
agonist/antagonist, a prodrug thereof, or a pharmaceutically
acceptable salt of said prostaglandin agonist/antagonist or said
prodrug; or a parathyroid hormone or sodium fluoride.
DETAILED DESCRIPTION OF THE INVENTION
[0109] Halo or halogen refers to chloro, bromo, iodo and
fluoro.
[0110] Estrogen agonists are herein defined as chemical compounds
capable of binding to estrogen receptor sites in mammalian tissue
and mimicking the action(s) of estrogen in one or more tissues.
[0111] Estrogen antagonists are herein defined as chemical
compounds capable of binding to estrogen receptor sites in
mammalian tissue and blocking the action(s) of estrogen or estrogen
agonists in one or more tissues.
[0112] As used in this application, prostatic disease means benign
prostatic hyperplasia or prostatic carcinoma.
[0113] A "compound", when used to refer to compounds of the present
invention, includes within its scope not just the specific
compound(s) listed or described, but also alternative forms of the
compound, such as prodrugs, pharmaceutically acceptable salts,
pharmaceutically acceptable salts of the prodrug, solvates,
hydrates, and the like.
[0114] A prodrug is a chemical compound that, in its present form,
has little or reduced pharmaceutical activity, but which, upon
introduction into its biological environment, is readily converted
into an active drug form. An exemplary prodrug is an ester of a
drug, where upon introduction into a patient, the ester is cleaved
to produce the active drug.
[0115] A "therapeutically effective amount" of a compound is an
amount that is sufficient to cure, prevent, or alleviate a disease,
disorder, condition, or symptom.
[0116] An "anabolic agent" is any compound that is capable of
promoting synthetic metabolic reactions in a patient. In a
preferred embodiment, anabolic agents are useful in promoting wound
healing.
[0117] A "growth hormone or growth hormone secretagogue" is a
naturally occurring growth hormone as understood by those skilled
in the art, a compound that mimics one or more actions of a
naturally occurring growth hormone, or a compound that stimulates
the release of naturally occurring growth hormone in a patient.
[0118] A "prostaglandin agonist or antagonist" is any compound that
is capable of agonizing or antagonizing the activity of a
prostaglandin in a patient.
[0119] Those of skill in the art 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 as will
be recognized by those of skill in the art.
[0120] Those of skill in the art will also recognize that certain
compounds of this invention will consist of multiple possible
geometric configurations, or isomers. All such isomers are included
in this invention.
[0121] The pharmaceutical compositions and methods of this
invention comprise, as an active ingredient, a compound of formula
I or II. The pharmaceutically acceptable salts of the compounds of
formula I and II are salts of non-toxic type commonly used, such as
salts with organic acids (e.g., formic, acetic, trifluoroacetic,
citric, maleic, tartaric, methanesulfonic, benzenesulfonic,
toluenesulfonic acids, and the like), inorganic acids (e.g.
hydrochloric, hydrobromic, sulfuric, phosphoric acids, and the
like), amino acids (e.g., aspartic acid, glutamic acid, and the
like), alkali metals (e.g., sodium, potassium, and the like), and
alkaline earth metals (e.g., calcium, magnesium, and the like).
These salts may be prepared by methods known to those of skill in
the art.
[0122] The compounds of this invention may be administered to
animals (including humans) orally, parenterally, topically, or
otherwise, in any conventional form of preparation, such as
capsules, microcapsules, tablets, granules, powder, troches, pills,
suppositories, injections, suspensions, syrups, and the like.
[0123] The pharmaceutical compositions of this invention can be
prepared by methods commonly employed using conventional additives,
such as excipients (e.g., sucrose, starch, mannitol, sorbitol,
lactose, glucose, cellulose, talc, calcium phosphate, calcium
carbonate, and the like), binders (e.g., cellulose,
methylcellulose, hydroxymethylcellulose, polypropylpyrrolidone,
polyvinylprrolidone, gelatin, gum arabic, polyethyleneglycol,
sucrose, starch, and the like), disintegrators (e.g., starch,
carboxymethylcellulose, hydroxypropylstarch, low substituted
hydroxypropylcellulose, sodium bicarbonate, calcium phosphate,
calcium citrate, and the like), lubricants (e.g., magnesium
stearate, light anhydrous silicic acid, talc, sodium lauryl
sulfate, and the like), flavoring agents (e.g., citric acid,
menthol, glycine, orange powder, and the like), preservatives
(e.g., sodium benzoate, sodium bisulfite, methylparaben,
propylparaben, and the like), stabilizers (e.g., citric acid,
sodium citrate, acetic acid, and the like), suspending agents
(e.g., methylcellulose, polyvinylpyrrolidone, aluminum stearate,
and the like), dispersing agents (e.g.,
hydroxypropylmethylcellulose and the like), diluents (e.g., water,
alcohol, glycerin, and the like), and base waxes (e.g., cocoa
butter, white petrolatum, polyethylene glycol, and the like).
[0124] The compounds of this invention may be administered once a
day or in multiple daily doses, with a preferred daily dosage of
about 0.001 to about 100 mg in adult human patients. This dosage
may be properly varied depending on the age, body weight, and
medical condition of the patient, as well as the mode of
administration. A more preferred daily dose is about 1.0 to about
10 mg in human patients. One dose per day is preferred. Controlled
release, sustained release, and/or delayed release oral or
parenteral compositions may be used.
[0125] General Reaction Schemes:
[0126] Compounds of this invention are readily prepared by the
reactions illustrated in the schemes below.
[0127] If required in the following processes, active groups may be
protected with a suitable protecting group such as benzyl,
p-toluenesulfonyl, methyl, p-methoxybenzyl, and the like, and the
protecting group may subsequently be removed at a later stage in
the synthesis. The protection and removal of the protecting groups
may be carried out according to procedures known to those skilled
in the art (e.g., procedures disclosed in Protective Groups in
Organic Synthesis by T. W. Greene, published by John Wiley &
Sons (1991)).
[0128] General Reaction Scheme A
[0129] A compound of formula (Ia) (i.e., a compound of formula (I)
wherein X is CO--(CH.sub.2).sub.y, and y is 0-3) may be prepared
according to the procedures illustrated in Scheme A. 9
[0130] As illustrated in Scheme A, a phenethyl amine of formula
(II) is coupled with a carboxylic acid of formula (III) to give the
benzamide of formula (V). Compound (V) is subjected to
cyclodehydration to give the dihydroisoquinoline of formula (VI).
Dihydroisoquinoline (VI) is reduced to the tetrahydroisoquinoline
of formula (VII). Then, compound (VII) may be reacted with a
desired acid anhydride, acid chloride, or other coupling agent to
give compound (Ia). Alternatively, compound (VII) may be reacted
with a desired acid in the presence of 1-propanephosphonic acid
cyclic anhydride, Et.sub.3N, and DMAP in dichloromethane
(CH.sub.2Cl.sub.2) to yield compound (Ia).
[0131] The coupling of compounds (II) and (III) is carried out in
the presence of a coupling agent for peptide synthesis, preferably
with an additive. Suitable coupling agents include water-soluble
diimides such as
N-cyclohexyl-N'-(4-diethylaminocyclohexyl)-carbodiimide and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), and suitable
additives include 1-hydroxybenzotriazole (HOBt) and
3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine. This reaction
mixture is preferably stirred at a temperature between about
0.degree. C. to room temperature (i.e., about 25.degree. C.), for
about 12 to 60 hours in a reaction inert solvent such as
CH.sub.2Cl.sub.2, preferably under nitrogen.
[0132] Cyclodehydration of the intermediate compound (V) is carried
out in a reaction inert solvent such as 1,2-dichloroethane in the
presence of phosphorus pentachloride under nitrogen, or neat using
phosphorus oxychloride under nitrogen. Phosphorus pentachloride is
added to the solution of compound (V) at about 0.degree. C., then
the reaction mixture is refluxed for about 1 to 24 hours. The
reaction of compound (V) and phosphorus oxychloride is carried out
at about the reflux temperature of the reaction mixture for about 1
to 48 hours.
[0133] The reduction of compound (VI) to compound (VII) is
typically carried out in the presence of sodium borohydride in a
reaction inert solvent such as methanol or tetrahydrofuran, at from
about 0.degree. C. to about room temperature, for about 1 to 12
hours, preferably under nitrogen. The reaction is quenched with
water.
[0134] The intermediate compound (VII) thus obtained is reacted
with a desired acid anhydride or acid chloride to yield compound
(Ia) according to amide formation procedures known to those skilled
in the art. This reaction is performed in the presence of a base
such as triethylamine (Et.sub.3N), in a reaction inert solvent such
as CH.sub.2Cl.sub.2, for about 1 to 72 hours, at about 0.degree. C.
to about room temperature. This reaction is preferably performed
under nitrogen.
[0135] Alternatively, compound (V) may be prepared by reacting
compound (II) with an acyl chloride of formula (IV) in the presence
of a base such as triethylamine in a reaction inert solvent.
Suitable solvents include dichloromethane, tetrahydrofuran (THF),
CHCl.sub.3, 1,2-dichloroethane, dioxane, toluene, benzene, and the
like, with THF being the most preferred. This reaction is
preferably carried out at a temperature of about 0.degree. C. to
30.degree. C., most preferably about 25.degree. C., under nitrogen,
for about 1 to 24 hours, preferably about 12 hours. If required, a
catalyst such as 4-(dimethylamino)pyridine, scandium triflate,
tributyl phosphine, or the like may be added to the reaction
mixture.
[0136] Intermediate compound (VI) may be substituted with a desired
substituent on R.sup.1 and subsequently subjected to the remaining
processes illustrated in Scheme A. This substitution reaction is
performed according to procedures known to those skilled in the
art. For example, compound (VI) wherein R.sup.1 is piperidin-4-yl
may be reacted with a heteroaryl sulfonyl chloride in the presence
of a base such as triethylamine in a reaction inert solvent such as
dichloroethane to yield a sulfonamide. This reaction is preferably
carried out at about room temperature, under nitrogen, for about 1
to 24 hours, preferably about 2 to 20 hours.
[0137] A compound of formula (I) of this invention wherein X is
--(CH.sub.2).sub.z--SO.sub.2-- may be prepared by reacting compound
(VII) with a sulfonyl chloride of formula
R.sup.2--(CH.sub.2).sub.z--SO.sub.2--- Cl according to known
procedures. For example, this reaction may be carried out in the
presence of triethylamine in a reaction inert solvent such as
tetrahydrofuran (THF) at about room temperature for about 1 to 24
hours under nitrogen.
[0138] A compound of formula (I) of this invention wherein X is a
covalent bond, (CH.sub.2).sub.n, or (CH.sub.2).sub.x-phenyl
(wherein x is 0 or 1), may also be prepared by reacting compound
(VII) with an aldehyde of formula R.sup.2--X--CHO according to
known procedures. This reaction is typically performed in the
presence of a reducing agent such as sodium cyanoborohydride in a
suitable solvent such as methanol.
[0139] A compound of formula (I) of this invention wherein X is
CO.sub.2 may be prepared by reacting compound (VII) with either a
dicarbonate of formula (R.sup.2OCO).sub.2O or a chloroformate of
formula R.sup.2OCOCl in the presence of a base such as
triethylamine in a suitable solvent such as THF at about room
temperature for about 1 to 24 hours, preferably under nitrogen.
[0140] General Reaction Scheme B
[0141] A compound of formula (Ib) (i.e., a compound of formula (I)
wherein X is a covalent bond and R.sup.2 is an optionally
substituted ring moiety) may be prepared according to the
procedures illustrated in Scheme B. 10
[0142] A benzyl acid of formula (VIII) is reacted with an amine of
formula (IX) to give an amide, which is then reduced (this step not
shown) to give the phenethyl amine of formula (X) according to
known procedures (see, for example, Nagarajan et al, Ind. J. Chem.,
24B:83-97 (1985)). Compound (X) thus obtained is reacted with a
carboxylic acid of formula (XI) to give the benzamide of formula
(XII). The compound of formula (XII) is subjected to
cyclodehydration followed by reduction, preferably with NaBH.sub.4
in methanol, to give the tetrahydroisoquinoline (Ib).
[0143] The reaction of compound (X) with compound (XI) is carried
out in the presence a base such as triethylamine, in a reaction
inert solvent such as dichloromethane, THF, CHCl.sub.3, or dioxane,
preferably in the presence of a coupling agent such as
1-propanephosphonic acid cyclic anhydride (PPAA), EDC, or a mixture
thereof, and a catalytic amount of an additive such as HOBt or
4-dimethylaminopyridine (DMAP), at about 0.degree. C. to room
temperature for about 1 to 36 hours.
[0144] The cyclodehydration of compound (XII) may be carried out
according to procedures analogous to those described for in Scheme
A.
[0145] Alternatively, compound (X) may be reacted with an acyl
chloride of formula (IV) to give an amide (XII). This reaction may
be performed according to procedures analogous to those described
in Scheme A.
[0146] Compound (XI) may be substituted at its R.sup.1 moiety with
a desired substituent. For example, when R.sup.1 is aryl aldehyde,
compound (XI) is coupled with a carboalkoxytriphenylphosphorane in
the presence of a base such as sodium hydroxide in a reaction inert
solvent such as tetrahydrofuran (THF). This reaction is performed
at about room temperature for about 1 to 12 hours.
[0147] General Reaction Scheme C
[0148] Scheme C illustrates methods to produce a compound of
formula (Ic), namely a compound of formula (I) wherein A.sub.1 is
hydroxy and X is a covalent bond, (CH.sub.2).sub.n, or
(CH.sub.2).sub.x-phenyl (wherein x is 0 or 1), starting from a
compound of formula (Ia). In this scheme, "Pro" is a hydroxy
protecting group. 11
[0149] For example, compound (Ia) wherein A.sub.1 is hydroxy, X is
CO, and R.sup.2 is CF.sub.3 is first protected with a suitable
hydroxy protecting group to obtain the compound of formula (XIII),
which is converted to the compound of formula (XIV), which is
coupled with a suitable acyl chloride of formula R.sup.2COCl to
obtain the compound of formula (XV), which is finally deprotected
to yield the desired compound (Ic).
[0150] While any hydroxy protecting groups known to those skilled
in the art may be used to protect compound (Ia), a benzyl or methyl
group is preferably used. The protection is typically carried out
by reacting compound (Ia) wherein A.sub.1 is hydroxy with benzyl
bromide in the presence of sodium hydride in a reaction inert
solvent such as DMF at about 0.degree. C. to 100.degree. C. under
nitrogen for about 1 to 12 hours, preferably about 4 hours.
[0151] Conversion of compound (XIII) is performed according to
known procedures. This conversion is conveniently carried out in
the presence of an inorganic base such as K.sub.2CO.sub.3, in a
reaction inert solvent such as methanol or ethanol under N.sub.2
for about 1 to 24 hours, preferably about 12 to 24 hours.
[0152] The coupling reaction of compound (XIV) with a desired acyl
chloride of formula R.sup.2COCl is preferably performed in the
presence of triethylamine in THF at about room temperature under
nitrogen for about 1 to 24 hours.
[0153] The hydroxy protecting group of compound (XV) may be removed
by known procedures. For example, this reaction may be performed in
the presence of a source of H.sub.2 and a catalyst such as 20%
Pd(OH).sub.2/C, in a reaction inert solvent such as methanol, under
nitrogen, at about the reflux temperature of the reaction mixture
for about 1 to 4 hours.
[0154] Compound (I) wherein R.sup.1 is aryl substituted by an
alkenylamide group may be obtained by reacting compound (I) wherein
R.sup.1 is iodophenyl with a suitable alkenylamide. This reaction
may be performed in the presence of a catalyst such as
Pd(PPh.sub.3).sub.4 and a base such as triethylamine in a reaction
inert solvent such as N,N-dimethylformamide (DMF) at about
60.degree. C. to 100.degree. C. for about 1 to 12 hours. The
alkenylamide may be prepared by known methods, for example, by
reacting a secondary amine with an acyl halide such as acryloyl
chloride. This reaction is performed in the presence of a base such
as triethylamine in a reaction inert solvent such as dichloroethane
at about room temperature for about 1 to 12 hours.
[0155] Compound (I) wherein A.sub.1 is hydroxy may be obtained by
converting compound (Ia) wherein A.sub.1 is methoxy. This
conversion is performed in the presence of boron tribromide in a
suitable solvent such as dichloromethane at about -78.degree. C. to
room temperature under nitrogen for about 1 to 12 hours. If
required, this conversion may be quenched by adding a suitable
solvent such as methanol.
[0156] The hydroxy group at the 6-position of the
tetrahydroisoquinoline ring of compound (I) may be converted into
an optionally substituted (C.sub.1-C.sub.4 alkyl)-CO. For example,
the hydroxy may be coupled with 1-(2-chloroethyl)pyrrolidine
hydrochloride in the presence of a condensing agent such as sodium
hydride in a reaction inert solvent such as DMF. This reaction is
preferably performed at about room temperature to the reflux
temperature of the reaction mixture, more preferably at about
100.degree. C., under nitrogen, for about 1 to 8 hours, preferably
about 4 to 5 hours.
[0157] A substituent attached to a ring moiety of R.sup.1 of
compound (I) may be converted to another substituent. For example,
the hydroxy substituent on the R.sup.1 ring moiety may be converted
to 2-pyrrolidin-1-yl-ethoxy according to procedures analogous to
those for the coupling reaction of hydroxy at the 6-position of the
tetrahydroisoquinoline ring of compound (I) with
1-(2-chloroethyl)pyrroli- dine hydrochloride.
[0158] Compounds (II), (III), (IV), (VIII), (IX) and (XI) are known
compounds and are readily prepared according to procedures well
known to those skilled in the art.
[0159] General Reaction Scheme D
[0160] A compound of formula (XXI) (i.e., a compound of formula
(II) lacking the R.sup.2 group) may be prepared according to the
procedures illustrated in Scheme D. 12
[0161] Compounds of formula (XXI) can be prepared under standard
reaction conditions analogous to those well known in the art (e.g.,
Grethe et al., J. Org. Chem., 33(2):491 (1968)). For example a
suitably protected dihydro-1H-isoquinolin-4-one of formula (XXII)
can be treated with a nucleophile of formula (XXIII) such as
substituted phenyl lithium to give the alcohol of formula (XXIV).
The reaction is typically run in an inert solvent such as THF, 1,2
dimethoxyethane, or diethyl ether, and a temperature range of
-78.degree. C. to room temperature is preferred.
[0162] The alcohol (XXIV) can be reduced to the
tetrahydroisoquinoline of formula (XXV) under suitable conditions
(e.g., hydrogenation over a metal catalyst such as palladium).
Another option for the reaction is to perform the reduction with a
trialkylsilane in the presence of a strong acid such as
trifluoroacetic acid. The reaction is typically run in an inert
solvent at a temperature range of 0.degree. C. to 60.degree. C.
13
[0163] The compounds of formula (XXI) can be treated with an acid
chloride of formula (XXVI) or an acid anhydride of formula (XXVII)
in the presence a tertiary amine base such as triethylamine or DMAP
to give an amide of formula (XXVIII). The acid chlorides of formula
(XXVI) and acid anhydride of formula (XXVII) are commercially
available or can be prepared from carboxylic acids by procedures
known to those skilled in the art.
[0164] Another,synthetic route for preparing the compounds of
formula (XXVIII) involves treating a compound of formula (XXI),
preferably at room temperature, with a carboxylic acid of formula
(XXIX) in the presence of a coupling agent (e.g.,
dicyclohexylcarbodiimide (DCC),
1-(3'-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), or
1-propanephosphonic acid cyclic anhydride (PPAA)) and a suitable
base (e.g., triethylamine, DMAP, or N-methylmorpholine (NMO)) in a
solvent such as dichloromethane, chloroform, or dimethylformamide.
Optionally, agents such as HOBt maybe added to the reaction. 14
[0165] Compounds of formula (XXX) can be prepared by reacting the
amines of formula (XXI) with a sulfonyl chloride of formula (XXXI)
in the presence of a base such as triethylamine, DMAP, or NMO in a
suitable solvent such as dichloromethane, chloroform, or
dimethylformamide. The reactions can be run in temperature range of
-20.degree. C. to 60.degree. C., though room temperature is
preferred. 15
[0166] Compounds of formula (XXXII) can be prepared by reacting the
amines of formula (XXI) with a chloroformate of formula (XXXIII) in
the presence of a base such as triethylamine, DMAP, NMO, or sodium
hydrogen carbonate in a suitable solvent such as dichloromethane,
chloroform, aqueous or anhydrous tetrahydrofuran, or
dimethylformamide. The reaction can be run at 0.degree. C. to
60.degree. C., though room temperature is preferred.
[0167] General Reaction Scheme E
[0168] A compound of formula (XXI) (i.e., a compound of formula
(II) lacking the R.sup.2 group) may also be prepared according to
the procedures illustrated in Scheme E. 16
[0169] An alternative and more preferable synthesis of compounds of
formula (XXI) involves reacting an alpha halogenated ketone of
formula (XXXIV) with a suitably protected ammonia equivalent,
preferably benzylamine, to give an amino-ketone of formula (XXXV).
It will be obvious to anyone skilled in the art that the order of
some of the next steps may be reversed. The compound of formula
(XXXV) can be reduced with a suitable reducing agent, preferably
sodium borohydride, di-isobutyl aluminum hydride (DIBAL-H), or
lithium aluminum hydride in a suitable solvent. Typically, sodium
borohydride reactions are run in protic solvents such as methanol
or ethanol, in the temperature range of -10.degree. C. to
40.degree. C. (but preferably at about 0.degree. C.), and the
DIBAL-H or lithium aluminum hydride reactions are preferably run in
dichloromethane or THF in the temperature range of -78.degree. C.
to 30.degree. C. (preferably at about 0.degree. C.) to give the
amino alcohol of formula (XXXVI). In the next step, the amino
alcohol of formula (XXXVI) is condensed with an aldehyde of formula
(XXXVII) to give initially an iminium salt of formula (XXXVIII).
The iminium salt of formula (XXXVIII) is reduced in situ with a
reducing agent such as sodium borohydride, sodium cyanoborohydride,
or sodium triacetoxyborohydride in a solvent such as
dichloromethane, chloroform, 1,2 dichloroethane, methanol, or
ethanol to give the amino alcohol of formula (XXXIX). For the
latter reduction reaction, a temperature range of -10.degree. C. to
50.degree. C. can be employed but a temperature of about 0.degree.
C. is preferred.
[0170] The amino alcohol of formula (XXXIX) can be cyclodehyrated
in the presence of a strong acid such as sulfuric acid or
trifluoroacetic acid in a solvent such as dichloromethane,
chloroform, or 1,2 dichloroethane in a temperature range of
0.degree. C. to 60.degree. C. to give (after appropriate
deprotection) the tetrahydroisoquinoline of formula (XXI).
[0171] General Reaction Scheme F
[0172] A compound of formula (XXIX) (i.e., the amino alcohol
intermediary shown in Scheme E) may be prepared according to the
alterntive procedures illustrated in Scheme F. 17
[0173] Another option for the synthesis of amino alcohol of formula
(XXXIX) is via the amide of formula (XL), which can be prepared by
methods known to those of ordinary skill from the amino alcohol
(XXXVI). Such methods may include taking the amino-alcohol of
formula (XXXVI) and treating this with an acid chloride of formula
(XLI) in the presence of a tertiary amine base such as
triethylamine or DMAP. The acid chlorides of formula (XLI) are
commercially available or can be prepared from carboxylic acids by
procedures known to those of ordinary skill in the art. Another
method of preparing the amides of formula (XL) involves treating an
amino alcohol of formula (XXXVI) with a carboxylic acid of formula
(XLII) in the presence of a coupling agent (e.g., DCC, EDC, or PPM)
and a suitable base (e.g., triethylamine, DMAP, or NMO) in a
solvent such as dichloromethane, chloroform, or dimethylformamide.
Optionally, agents such as HOBt maybe added to the reaction.
Typically, the reaction is run in the temperature range of
0.degree. C. to 50.degree. C., with room temperature being
preferred.
[0174] The amides of formula (XL) can then be reduced to an
amino-alcohol of formula (XXXIX) by reaction with a reducing agent
such as lithium aluminum hydride or borane in a suitable solvent
such as tetrahydrofuran or 1,2 dimethoxyethane at -10.degree. C. to
100.degree. C. (with 0.degree. C. being preferred).
[0175] Reactive groups not involved in the above processes can be
protected with standard protecting groups during the reactions and
removed by standard procedures (Greene & Wuts, Protecting
Groups in Organic Synthesis, John Wiley and Sons, Inc.,
Interscience, 2nd edition, New York) known to those of ordinary
skill in the art. Presently preferred protecting groups include
methyl and benzyl for the hydroxyl moiety, and trifluoroacetamide
and benzyl for the amino moiety.
[0176] In each of the general reaction schemes discussed or
illustrated above, pressure is not critical unless otherwise
indicated. Pressures from about 0.5 atmospheres (.about.50,000 Pa)
to about 5 atmospheres (.about.500,000 Pa) are generally
acceptable, and ambient pressure, i.e. about 1 atmosphere
(.about.100,000 Pa), is preferred as a matter of convenience.
[0177] The compounds of this invention may be prepared in racemic
form and be resolved into their component enantiomers by standard
techniques such as fractional crystallization or preparative
chromatography. Alternatively, enantiomers of the invention
compounds may be synthesized from the appropriate optically active
intermediates or starting materials using any of the general
processes described herein.
[0178] Further, optically active compounds of this invention may be
prepared using enantioselective reactions or by resolution
techniques such as the preparation of diastereomers by reacting the
racemic material with an optically active reagent.
[0179] The compounds of this invention are valuable estrogen
agonists or antagonists, and thus valuable pharmaceutical agents.
Those that are estrogen agonists are useful for oral contraception,
relief of 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/or 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/or preventing hypercholesterolemia.
[0180] While the compounds of this invention are typically estrogen
agonists in bone, unexpectedly they are also often antiestrogens in
breast tissue and as such would be useful in the treatment and
prevention of breast cancer.
[0181] While the compounds of this invention are expected to be
sufficiently active if administered separately, in many instances
it will be beneficial to combine these compounds with other
compounds in order to even more effectively treat a disease or
condition. Exemplary categories of compounds which will be
beneficial in combination with the compounds of the present
invention include an anabolic agent, a prodrug thereof, or a
pharmaceutically acceptable salt of said anabolic agent or said
prodrug; a growth hormone or a growth hormone secretagogue, a
prodrug thereof, or a pharmaceutically acceptable salt of said
growth hormone secretagogue or said prodrug; a prostaglandin
agonist/antagonist, a prodrug thereof, or a pharmaceutically
acceptable salt of said prostaglandin agonist/antagonist or said
prodrug; or a parathyroid hormone or sodium fluoride.
[0182] It will also be useful to present the compounds of the
present invention in the form of kits useful for treating or
preventing a disease, disorder, condition, or symptom mediated by
an estrogen receptor and/or caused by lowered estrogen levels, said
kit comprising a compound of the present invention and a
pharmaceutically acceptable vehicle, carrier, or diluent in a
dosage form, and a container for containing said dosage form.
[0183] In many instances, it will be preferable for the kit to
include, in addition to a compound of the present invention, an
anabolic agent, a prodrug thereof, or a pharmaceutically acceptable
salt of said anabolic agent or said prodrug; a growth hormone or a
growth hormone secretagogue, a prodrug thereof, or a
pharmaceutically acceptable salt of said growth hormone
secretagogue or said prodrug; a prostaglandin agonist/antagonist, a
prodrug thereof, or a pharmaceutically acceptable salt of said
prostaglandin agonist/antagonist or said prodrug; or a parathyroid
hormone or sodium fluoride.
[0184] Methods for Testing the Activity of Invention Compounds
[0185] Assay 1: Control and Prevention of Endometriosis
[0186] A preferred protocol for surgically inducing endometriosis
is that described by Jones, Acta Endoerinol (Copenh), 106:282-88
(1984). 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 estrogen stimulation.
[0187] 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 is measured with calipers,
and treatment is begun. The animals are injected sc for 3 weeks
with 10 to 1000 mg/kg/day of a test compound according to the
present invention. Control animals bearing endometrial explants are
injected sc with 0.1 ml/day of corn oil for 3 weeks. At the end of
the 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
and the explants are measured again. Statistical analysis of the
explant volume is by an analysis of variance.
[0188] Assay 2: Effect on Prostate Weight
[0189] Three-month-old male Sprague-Dawley rats are administered by
subcutaneous injection control vehicle (10% ethanol in water),
estradiol (30 .mu.g/kg), testosterone (1 mg/kg), or a test compound
according to the present invention 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 the Student's
t-test.
[0190] Active compounds significantly (P<0.05) decrease prostate
weight compared to controls. Testosterone is expected to have no
effect while estrogen at 30 .mu.g/kg is expected to significantly
reduce prostate weight.
[0191] Assay 3: In Vitro Estrogen Receptor Binding
[0192] An in vitro estrogen receptor binding assay that measures
the ability of the compounds of the present invention to displace
[.sup.3H]-estradiol from human estrogen receptor obtained by
recombinant methods in yeast, bacteria, or mammalian cells is used
to determine the estrogen receptor binding affinity of the
compounds of this invention. The materials used in this assay are:
(1) TD-0.3 assay buffer (containing 10 mM Tris, pH 7.6, 0.3 M
potassium chloride, and 5 mM DTT); (2) the radioligand used is
[.sup.3H]-estradiol obtained from New England Nuclear (Boston,
Mass.); (3) the cold ligand used is estradiol obtained from Sigma
(St. Louis, Mo.); and (4) recombinant human estrogen receptor,
hER.
[0193] 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
is 5 nM. The hER is also diluted with TD-0.3 such that 0.2 nM hER
is in each assay well. Using microtitre plates, each incubate
receives 50 .mu.l of cold estradiol (nonspecific binding) or the
test compound solution, 20 .mu.l of the tritiated estradiol, and 30
.mu.l of hER solutions. Each plate contains varying concentrations
of the compound and total binding controls in triplicate. 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, followed by incubation for
15 minutes at 4.degree. C. The mixture 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 Ecolite (+) (ICN
Biomedicals, Inc., Aurora, Ohio) 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). Test compound potency is determined by
means of IC.sub.50 determinations (the concentration of a test
compound needed to inhibit 50% of the of the total specific
tritiated estradiol bound). Specific binding in the presence of
varying concentrations of test compound is determined and
calculated as percent specific binding of total specific
radioligand bound. Data are plotted as percent inhibition by test
compound (linear scale) versus test compound concentration (log
scale).
[0194] Assay 4: Effect on Total Cholesterol Levels
[0195] The effect of the compounds of the present invention on
plasma levels of total cholesterol is measured as follows. Blood
samples are collected via cardiac puncture from anesthetized female
(Sprague-Dawley) rats 4-6 months of age that are bilaterally
ovariectomized and treated with the test compound (10-1000
.mu.g/kg/day, for example, sc or orally for 28 days or with control
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.
The total cholesterol is assayed using a standard enzymatic
determination kit from Sigma Diagnostics (Procedure No. 352).
[0196] Assay 5: Effect on Obesity
[0197] Ten-month-old female Sprague-Dawley rats, weighing
approximately 450 grams, are sham-operated or ovariectomized and
treated orally with vehicle, 17.alpha.-ethynyl-estradiol at 30
mg/kg/day, or a compound according to the present invention at
10-1000 mg/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 via dual energy x-ray absorptiometry using a Hologic
QDR-1000/W (Hologic, Bedford, Mass.) equipped with whole body scan
software that shows the proportions of fat body mass and lean body
mass.
[0198] A decrease in fat body mass indicates that the test compound
is useful in preventing and treating obesity.
ABBREVIATIONS
[0199] Abbreviations used in the following examples and
preparations include:
1 1,2 DCE 1,2-Dichloroethane d Doublet dd Double Doublet DMAP
4-Dimethylamino Pyridine EDC
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide Hydrochloride EtOAc
Ethyl Acetate EtOH Ethyl Alcohol or Ethanol Et.sub.2O Ethyl Ether
Et.sub.3N Triethylamine HOBt 1-Hydroxybenzotriazole HPLC High
Pressure Liquid Chromatography hr Hour(s) m Multiplet MeOH Methyl
Alcohol or Methanol min Minute(s) MS Mass Spectrometry NMR Nuclear
Magnetic Resonance PPAA 1-Propanephosphonic Acid Cyclic Anhydride q
Quartet RT (or rt) room temperature (about 20-25.degree. C.) s
Singlet sat. Saturated t Triplet TBAF Tetrabutyl Ammonium Fluoride
TFA Trifluoroacetic Acid THF Tetrahydrofuran
EXAMPLES AND PREPARATIONS
[0200] The following examples will serve to illustrate, but do not
limit, the invention that is defined by the claims.
Preparation 1
[0201] 4-Benzyloxy-N-[2-(3-methoxyphenyl)ethyl]benzamide P A
mixture of 3-methoxyphenethylamine (16.557 g, 109.5 mmol),
4-benzyloxybenzoic acid (25.000 g, 109.5 mmol),
1-hydroxybenzotriazole hydrate (22.202 g, 164.3 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22.047
g, 115.0 mmol) in anhydrous CH.sub.2Cl.sub.2 (300 ml) was stirred
at 0.degree. C. under N.sub.2 for 1 hr, then warmed to rt and
stirred at rt for 19 hr. The reaction mixture was washed
sequentially with 1M NaOH (150 ml), 1M HCl (150 ml), and H.sub.2O
(150 ml), then dried over MgSO.sub.4 and concentrated in vacuo to
give 39.00 g (99% yield) of yellow solid.
[0202] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.63 (d, J=8.7 Hz,
2H), 7.43-7.30 (m, 5H), 7.21 (d, J=7.7 Hz, 1H), 6.95 (d, J=8.7 Hz,
2H), 6.82-6.78 (m, 2H), 6.76 (s, 1H), 6.02 (m, 1H), 5.08 (s, 2H),
3.77 (s, 3H), 3.68 (dd, J=13.07 Hz, J=6.64 Hz, 2H), 2.90-2.86 (m,
2H); MS m/e 362 (M.sup.30 +1).
Preparation 2
[0203] 1-(4-Benzyloxyphenyl)-6-methoxy-3,4-dihydroisoquinoline
hydrochloride
[0204] Phosphorus pentachloride (58.557 g, 281.2 mmol) was added in
portions to a solution of
4-benzyloxy-N-[2-(3-methoxyphenyl)ethyl]benzami- de (59.775 g,
165.4 mmol) in 1,2-dichloroethane (500 ml) at 0.degree. C. under
N.sub.2. The resulting reaction was stirred at 0.degree. C. for 30
min, then refluxed for 18 hr. After cooling to rt, hexane (1200 ml)
was added and the resulting suspension was cooled to 0.degree. C.
The solvent was decanted off from the oil that separated and the
remaining oil was dried in vacuo to give 54.56 g (87% yield) of
orange residue.
[0205] MS m/e 344 (M.sup.++1-HCl).
Preparation 3
[0206]
1-(4-Benzyloxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline
[0207] Sodium borohydride (10.874 g, 287.3 mmol) was added in small
portions to a solution of
1-(4-benzyloxyphenyl)-6-methoxy-3,4-dihydroisoq- uinoline (54.56 g,
143.6 mmol) in MeOH (600 ml) at 0.degree. C. The reaction mixture
was stirred at 0.degree. C. for 1 hr, then quenched by the dropwise
addition of H.sub.2O (20 ml). The resulting mixture was
concentrated in vacuo to a volume of about 100 ml. The solid that
separated was collected to give 35.926 g (72% yield) of white
solid.
[0208] .sup.1H NMR (400 MHz, CDCl.sub.3) d 7.42-7.28 (m, 5H), 7.16
(d, J=8.72 Hz, 2H), 6.91 (d, J=8.72 Hz, 2H), 6.67-6.58 (m, 2H),
6.64 (s, 1 H), 5.03 (s, 2H), 4.98 (s, 1H), 3.76 (s, 3H), 3.26-3.21
(m, 1H), 3.08-2.95 (m, 2H), 2.79-2.74 (m, 1H); MS m/e 346
(M.sup.++1).
[0209] The remaining filtrate was evaporated in vacuo to give an
additional 23.85 g of crude material.
Preparation 4
[0210]
1-[1-(4-Benzyloxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-
-2,2,2-trifluoroethanone
[0211] Trifluoroacetic anhydride (22.620 g, 107.7 mmol) was added
to a solution of
1-(4-benzyloxyphenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinolin- e
(28.530 g, 82.6 mmol) and Et.sub.3N (15.0 ml, 107.7 mmol) in
anhydrous CH.sub.2Cl.sub.2 (500 ml) at 0.degree. C. under N.sub.2.
The resulting yellow solution was stirred at 0.degree. C. for 3 hr,
diluted with CH.sub.2Cl.sub.2 (150 ml), and washed first with 1M
HCl (2.times.100 ml) then 1M NaOH (100 ml), dried over MgSO.sub.4,
and concentrated in vacuo to give 32.09 g of yellow oil.
Purification by flash chromatography, eluting with hexane:EtOAc
(9:1) gave 26.97 g (74% yield) of yellow oil.
[0212] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.40-7.29 (m, 5H),
7.11 (d, J=8.72 Hz, 2H), 6.94 (d, J=8.51 Hz, 1H), 6.87 (d, J=8.72
Hz, 2H), 6.77-6.69 (m, 3H), 5.01 (s, 2H), 3.91-3.80 (m, 1H), 3.79
(s, 3H), 3.48-3.41 (m, 1H), 3.10-3.02 (m, 1H), 2.85-2.80 (m, 1H);
MS m/e 442 (M.sup.++1).
Preparation 5
[0213]
1-{6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1-
H-isoquinolin-2-yl}-2,2,2-trifluoroethanone
[0214] A solution of
2,2,2-trifluoro-1-{6-hydroxy-1-[4-(2-pyrrolidin-1-yl--
ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}ethanone (1.886 g,
4.3 mmol) in anhydrous DMF (50 ml) was added to a suspension of NaH
(0.104 g, 4.3 mmol) in anhydrous DMF (100 ml) at rt under N.sub.2.
After stirring at rt for 1 hr, a solution of benzyl bromide (0.782
g, 4.6 mmol) in anhydrous DMF (10 ml) was added and the reaction
mixture was heated to 100.degree. C. for 4 hr. The reaction mixture
was cooled to rt, diluted with H.sub.2O (250 ml), and extracted
with EtOAc (4.times.100 ml). The combined extracts were washed with
H.sub.2O (2.times.100 ml), dried over MgSO.sub.4, and concentrated
in vacuo to give 2.71 g of orange oil. Purification by flash
chromatography, eluting with EtOAc:MeOH (7:3) gave 0.745 g (33%
yield) of yellow oil.
[0215] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.42-7.39 (m, 4H),
7.38-7.33 (m, 1H), 7.20-7.10 (m, 2 h), 6.95-6.92 (m, 1H), 6.85-6.79
(m, 4H), 6.72 (br s. 1H), 5.05 (s, 2H), 4.30-4.18 (m, 2H),
3.92-3.88 (m, 1H), 3.47-3.40 (m, 1H), 3.30-2.70 (m, 8H), 1.94 (br
s, 4H);
[0216] MS m/e 525 (M.sup.++1).
Preparation 6
[0217]
6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahyd-
roisoquinoline
[0218] A mixture of
1-{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]--
3,4-dihydro-1H-isoquinolin-2-yl}-2,2,2-trifluoroethanone (1.088 g,
2.1 mmol) and anhydrous K.sub.2CO.sub.3 (2.861 g, 20.7 mmol) in
MeOH (150 ml) was refluxed under N.sub.2 for 18 hr, then evaporated
in vacuo to a yellow residue. This was dissolved in H.sub.2O (25
ml) and extracted with EtOAc (3.times.50 ml). The combined extracts
were dried over MgSO.sub.4, and concentrated in vacuo to give 0.881
g of crude yellow product. Purification by flash chromatography,
eluting first with EtOAc: MeOH (8:2), then with EtOAc:MeOH (1:1)
gave 0.842 g (95% yield) of yellow oil.
[0219] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.41-7.29 (m, 5H),
7.17-7.12 (m, 2H), 6.86-6.52 (m, 5H), 5.07-5.05 (m, 1H), 5.02-4.98
(m, 2H), 4.12-4.10 (m, 2H), 3.24-3.21 (m, 1H), 3.06-2.95 (m, 1H),
2.91-2.90 (m, 3H), 2.78-2.75 (m, 1H), 2.65 (br s, 4H), 1.81-1.80
(m, 4H); MS m/e 429 (M.sup.++1).
Preparation 7
[0220]
{6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-
-isoquinolin-2-yl}phenylmethanone
[0221] Benzoyl chloride (0.013 g, 0.09 mmol) was added to a
solution of
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoq-
uinoline (0.040 g, 0.09 mmol) and Et.sub.3N (0.026 ml, 0.19 mmol)
in anhydrous THF (10 ml) at rt under N.sub.2. The resulting
suspension was stirred at rt for 20 hr, then evaporated in vacuo to
give 0.091 g of white solid. Purification by flash chromatography,
eluting with EtOAc:MeOH (6:4) gave 0.049 g (98% yield) of white
solid.
[0222] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.44-7.32 (m, 10H),
7.00-6.96 (m, 2H), 6.82-6.79 (m, 6H), 5.05 (m, 2H), 4.22-4.20 (m,
2H), 3.62-3.58 (m, 1H), 3.32-3.26 (m, 2H), 3.11-3.09 (m, 2H),
2.96-2.92 (m, 4H), 2.69-2.65 (m, 1H), 1.92 (br s, 4H); MS m/e 533
(M.sup.++1).
Preparation 8
[0223]
1-{6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1-
H-isoquinolin-2-yl}-2,2-dimethylpropan-1-one
[0224] A solution of
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,-
2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et.sub.3N
(0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a
solution of trimethylacetyl chloride (0.04 mmol) in anhydrous THF
(0.4 ml) at rt in a sealed reaction vessel. The resulting
suspension was stirred at rt for 20 hr, then evaporated to dryness.
The product was suspended in a mixture of H.sub.2O (0.4 ml) and
saturated NaHCO.sub.3 solution (0.4 ml), then extracted with
CH.sub.2Cl.sub.2 (3.times.0.75 ml). The combined extracts were
evaporated to dryness to give the crude product., Purification by
reverse-phase HPLC, eluting first with gradient. Purification by
reverse-phase HPLC on a Primesphere (Phenomenex 2320 West
205.sup.th St. Torrance, Calif. 90501) C-18HC (50.0 mm.times.10.0
mm column with 5.quadrature.m particle size) column, eluting with a
linear gradient starting at time 0 min. of
H.sub.2O:CH.sub.3CN:1%TFA/H.sub.2O (85:10:5), increasing to
H.sub.2O:CH.sub.3CN:1%TFA/H.sub.2O (5:90:5) at 8 min., detected on
a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave
material which, after evaporation to dryness, was purified by
reverse-phase HPLC on a Primesphere C-18HC (3.0 mm.times.2.0 mm
column with 5.quadrature.m particle size) column, eluting with a
linear gradient starting at time 0 min. of H.sub.2O:CH.sub.3CN:TFA
(99.9:0:0.1), increasing to H.sub.2O:CH.sub.3CN:TFA (0:99.9:0.1) at
4 min., detected with a UV detector (300 nM .+-.90 nM and 254 nM
.+-.25 nM), gave an eluent that was evaporated to dryness to give
0.012 g (56% yield) of the pure product. MS 513 m/e
(M.sup.++1).
Preparation 9
[0225] 4-Benzyloxy-N-phenethylbenzamide
[0226] A mixture of phenethylamine (5.000 g, 41.3 mmol),
4-benzyloxybenzoic acid (9.427 g, 41.3 mmol),
1-hydroxybenzotriazole hydrate (8.378 g, 62.0 mmol) and
1-(3-dimethylaminopropyl)-3-ethylcarbodi- imide hydrochloride
(8.320 g, 43.4 mmol) in anhydrous CH.sub.2Cl.sub.2 (100 ml) was
stirred at 0.degree. C. under N.sub.2 for 1 hr, then warmed to rt
and stirred at rt for 22 hr. The reaction mixture was washed
sequentially with 1M NaOH (50 ml), 1M HCl (50 ml), and H.sub.2O (50
ml), then dried over MgSO.sub.4 and concentrated in vacuo to give
13.61 g of tan solid. Purification by flash chromatography, eluting
first with hexane:EtOAc (1:1) and then with EtOAc gave 12.20 g (89%
yield) of white solid.
[0227] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.63 (d, J=8.92 Hz,
2H), 7.42-7.36 (m, 4H), 7.35-7.29 (m, 3H), 7.24-7.21 (m, 3H), 6.95
(d, J=8.92 Hz, 2H), 6.00 (br s, 1H), 5.08 (s, 2H), 3.71-3.66 (m,
2H), 2.92-2.89 (m, 2H); MS m/e 332 (M.sup.++1).
Preparation 10
[0228] 1-(4-Benzyloxyphenyl)-3,4-dihydroisoquinoline
[0229] A solution of 4-benzyloxy-N-phenethylbenzamide (1.000 g, 3.0
mmol) in POCl.sub.3 (10 ml, 107.3 mmol) was refluxed under N.sub.2
for 18 hr, then the cooled reaction mixture was slowly added to
ice-water (50 ml) with stirring. The resulting mixture was
extracted with EtOAc (4.times.20 ml), then the remaining aqueous
layer was basified to pH 10 with concentrated ammonia (80 ml). This
was extracted with EtOAc (3.times.50 ml), then the combined
extracts were dried over MgSO.sub.4 and concentrated in vacuo to
give 0.270 g of yellow solid. Purification by flash chromatography,
eluting with hexane: EtOAc (6:4) gave 0.151 g (16% yield) of yellow
solid.
[0230] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.55 (d, J=8.92 Hz,
2H), 7.45-7.43 (d, J=7.06 Hz, 2H), 7.40-7.29 (m, 6H), 7.26-7.24 (m,
1H), 7.00 (d, J=8.92 Hz, 2H), 5.11 (s, 2H), 3.81-3.78 (m, 2H),
2.79-2.75 (m, 2H); MS m/e 314 (M.sup.++1).
Preparation 11
[0231] 1-(4-Benzyloxyphenyl)-1,2,3,4-tetrahydroisoquinoline
[0232] Sodium borohydride (0.34 g, 0.89 mmol), was added in small
portions to a solution of
1-(4-benzyloxyphenyl)-3,4-dihydroisoquinoline (0.139 g, 0.44 mmol)
in MeOH (10 ml) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 30 min, stirred at rt for 1 hr, then quenched by
the dropwise addition of H.sub.2O (1.0 ml). The resulting mixture
was concentrated in vacuo to remove the methanol, and the remaining
aqueous layer was extracted with CHCl.sub.3 (4.times.10 ml). The
combined extracts were dried over MgSO.sub.4 and concentrated in
vacuo to give 0.138 g (99% yield) of colorless oil.
[0233] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.43-7.29 (m, 5H),
7.18-7.16 (m, 2H), 7.13-7.12 (m, 2H), 7.10-7.00 (m, 1H), 6.92 (d,
J=8.72 Hz, 2H), 6.75 (d, J=7.68, 1H), 5.05 (s, 1H), 5.04 (s, 2H),
3.28-3.23 (m, 1H), 3.11-2.98 (m, 2H), 2.82-2.77 (m, 1H); MS m/e 316
(M.sup.++1).
Preparation 12
[0234]
1-[1-(4-Benzyloxyphenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-2,2,2-tri-
fluoroethanone
[0235] Trifluoroacetic anhydride (0.088 g, 0.42 mmol) was added to
a solution of 1-(4-benzyloxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(0.132 g, 0.42 mmol) and Et.sub.3N (0.117 ml, 0.84 mmol) in
anhydrous CH.sub.2Cl.sub.2 (5 ml) at 0.degree. C. under N.sub.2.
The resulting yellow solution was stirred at rt for 5 hr, washed
first with 1 M HCl (5 ml) then 1M HCl (5ml) then 1M NaOH (5 ml),
dried over MgSO.sub.4, and concentrated in vacuo to give 0.186 g of
yellow oil. Purification by flash chromatography, eluting with
hexane : EtOAc (9:1) gave 0.147 g (85% yield) of yellow oil.
[0236] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.41-7.26 (m, 6H),
7.23-7.17 (m, 2H), 7.12 (d, J=8.72 Hz, 2H), 7.03 (d, J=7.26 Hz,
1H), 6.88 (d, J=8.72 Hz, 2H), 6.78 (s, 1H), 5.02 (s, 2H), 3.95-3.91
(m, 1H), 3.52-3.44 (m, 1H), 3.14-3.05 (m, 1H), 2.90-2.86 (m, 1H);
MS m/e 410 (M.sup.+-1).
Preparation 13
[0237] Toluene-4-sulfonic acid
4-(6-methoxy-2-trifluoroacetyl-1,2,3,4-tetr-
ahydroisoquinolin-1-yl)phenyl ester
[0238] A solution of
2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4--
dihydro-1H-isoquinolin-2-yl]ethanone (3.387 g, 9.64 mmol),
p-toluenesulfonyl chloride (2.206 g, 11.6 mmol) and Et.sub.3N (1.6
ml, 11.6 mmol) in acetone (50 ml) was refluxed under N.sub.2 for 5
hr, then concentrated in vacuo. The remaining residue was suspended
in H.sub.2O (100 ml) and extracted with CHCl.sub.3 (4.times.75 ml).
The combined extracts were dried over MgSO.sub.4 and concentrated
in vacuo to give 5.622 g of orange oil. Purification by flash
chromatography, eluting with hexane:EtOAc (8:2) gave 4.383 g (90%
yield) of white solid.
[0239] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.71-7.66 (m, 2H),
7.31-7.25 (m, 2H), 7.12 (d, J=8.72 Hz, 1H), 7.12-7.03 (m, 1H),
6.98-6.88 (m, 3H), 6.78-6.68 (m, 2H), 6.70 (s, 1H), 3.91-3.87 (m,
1H), 3.80 (s, 3H), 3.49-3.43 (m, 1H), 2.95-2.91 (m, 1H), 2.84-2.80
(m, 1H), 2.43 (d, J=9.13 Hz, 3H); MS m/e 506 (M.sup.++1).
Preparation 14
[0240] Toluene-4-sulfonic acid
4-(6-hydroxy-2-trifluoroacetyl-1,2,3,4-tetr-
ahydroisoquinolin-1-yl)phenyl ester
[0241] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (16.2 ml,
16.2 mmol) was added slowly to a solution of toluene-4-sulfonic
acid
4-(6-methoxy-2-trifluoroacetyl-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl
ester (7.459 g, 14.8 mmol) in anhydrous CH.sub.2Cl.sub.2 (500 ml)
at 0.degree. C. under N.sub.2. After stirring at 0.degree. C. for 1
hr, the reaction mixture was warmed to rt and stirred at rt for 18
hr. MeOH (250 ml) was slowly added with stirring and the resulting
solution was concentrated in vacuo to give 9.793 g of brown
residue. Purification by flash chromatography, eluting with
hexane:EtOAc (7:3) gave 2.764 g (38% yield) of white solid.
[0242] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.72-7.69 (m, 2H),
7.30 (d, J=8.51 Hz, 2H), 7.12 (d, J=8.92 Hz, 2H), 6.95-6.85 (m,
3H), 6.72-6.67 (m, 3H), 3.93-3.89 (m, 1), 3.40-3.32 (m, 1H),
3.07-2.94 (m, 1H), 2.81-2.77 (m, 1H), 2.44 (s, 3H); MS m/e 492
(M.sup.++1).
Preparation 15
[0243] Toluene-4-sulfonic acid
4-[6-(2-pyrrolidin-1-yl-ethoxy)-2-trifluoro-
acetyl-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl ester
[0244] A solution of toluene-4-sulfonic acid
4-(6-hydroxy-2-trifluoroacety-
l-1,2,3,4-tetrahydroisoquinolin-1-yl)phenyl ester (1.790 g, 3.64
mmol) in anhydrous DMF (30 ml) was added to a suspension of NaH
(0.175 g, 7.28 mmol) in anhydrous DMF (30 ml) at rt under N.sub.2.
After stirring at rt for 1 hr, a solution of
1-(2-chloroethyl)pyrrolidine hydrochloride (0.619 g, 3.64 mmol) in
anhydrous DMF (20 ml) was added and the reaction mixture was heated
to 100.degree. C. for 5 hr. The reaction mixture was cooled to rt,
diluted with H.sub.2O (200 ml), and extracted with EtOAc
(5.times.50 ml). The combined extracts were washed with H.sub.2O
(2.times.50 ml), dried over MgSO.sub.4, and concentrated in vacuo
to give 2.193 g of brown oil. Purification by flash chromatography,
eluting first with EtOAc:MeOH (9:1), and then with EtOAc:MeOH
(7:3), gave 0.482 g (22% yield) of yellow oil.
[0245] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.70 (d, J=8.30 Hz,
2H), 7.31 (d, J=8.09 Hz, 2H), 7.11 (d, J=8.51 Hz, 2H), 6.92-6.89
(m, 3H), 6.76-6.71 (m, 3H), 4.56-4.51 (m, 2H), 3.93-3.89 (m, 3H),
3.47 (br s, 2H), 3.39-3.33 (m, 1H), 3.08-2.97 (m, 3H), 2.84-2.80
(m, 1H), 2.44 (s, 3H) 2.24-2.21 (m, 2H), 2.16-2.10 (m, 2H); MS m/e
589 (M.sup.++1).
Preparation 16
[0246] 4-Iodo-N-[2-(3-methoxyphenyl)-ethyl]benzamide
[0247] A mixture of 3-methoxyphenethylamine (11.7 g, 77.4 mmol),
4-iodobenzoyl chloride (20.6 g, 77.4 mmol), and Et.sub.3N (8.2 g,
81.2 mmol) in anhydrous CH.sub.2Cl.sub.2 (250 ml) was stirred at
0.degree. C. under N.sub.2 for 1 hr, then warmed to rt and stirred
at rt for 19 hr. The reaction mixture was washed sequentially with
1M HCl (2.times.150 ml), 1M NaOH (2.times.150 ml), and saturated
NaCl solution (150 ml), then dried over Na.sub.2SO.sub.4 and
concentrated in vacuo to give 21 g (72% yield) of white solid.
[0248] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.74 (d, J=8.52 Hz,
2H), 7.39 (d, J=8.52 Hz, 2H), 7.25-7.21 (m, 1H), 6.81-6.75 (m, 3H),
6.06 (br s, 1H), 3.78 (s, 3H), 3.71-3.6 (m, 2H), 2.91-2.87 (m, 2H);
MS m/e 382 (M.sup.++1).
Preparation 17
[0249] 1-(4-Iodophenyl)-6-methoxy-3,4-dihydroisoquinoline
hydrochloride
[0250] Phosphorus pentachloride (11 g, 52.8 mmol) was added in
portions to a solution of
4-iodo-N-[2-(3-methoxyphenyl)-ethyl]benzamide (10.1 g, 26 mmol) in
CHCl.sub.3 (60 ml) at 0.degree. C. under N.sub.2. The resulting
reaction was stirred at 0.degree. C. for 10 min, then warmed to rt
and stirred at rt for 18 hr. After cooling to 0.degree. C., hexane
(500 ml) was added and the resulting suspension was allowed to
settle. The solvent was decanted off from the oil that separated
and the remaining oil was triturated with EtOH (20 ml) to give a
white solid. Et.sub.2O (200 ml) was added, the resulting suspension
was stirred for 1 hr, the solid was collected and dried in vacuo to
give 7.5 g (72% yield) of white solid.
Preparation 18
[0251]
1-(4-Iodophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline
[0252] Sodium borohydride (2 g, 52.9 mmol) was added in small
portions to a solution of
1-(4-iodophenyl)-6-methoxy-3,4-dihydroisoquinoline hydrochloride
(7.5 g, 18.7 mmol) in MeOH (100 ml) at 0.degree. C. The reaction
mixture was stirred at 0.degree. C. for 1 hr, then quenched by the
dropwise addition of H.sub.2O (20 ml). The resulting mixture was
concentrated in vacuo to remove most of the MeOH, then EtOAc was
added. The resulting mixture was extracted with 1M NaOH (2.times.25
ml), then saturated NaCl solution (25 ml), dried over MgSO.sub.4,
and evaporated in vacuo to give 6.2 g (65% yield) of white
solid.
[0253] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.63 (d, J=8.52 Hz,
1H), 7.01 (d, J=8.31 Hz, 2H), 6.66 (d, 1H), 6.61 (d, J=1.45 Hz,
2H), 5.03 (s, 2H), 4.98 (s, 1H), 3.77 (s, 3H), 3.24-3.20 (m, 1H),
3.08-2.96 (m, 2H), 2.80-2.75 (m, 1H); MS m/e 366 (M.sup.++1).
Preparation 19
[0254] Cyclohexanecarboxylic acid
[2-(3-methoxyphenyl)ethyl]amide
[0255] A mixture of 3-methoxyphenethylamine (1.000 g, 6.61 mmol),
cyclohexanecarboxylic acid (0.847 g, 6.61 mmol),
1-hydroxybenzotriazole hydrate (1.340 g, 9.92 mmol), and
1-(3-dimethylaminopropyl)-3-ethylcarbod- iimide hydrochloride
(1.330 g, 6.94 mmol) in anhydrous CH.sub.2Cl.sub.2 (20 ml) was
stirred at 0.degree. C. under N.sub.2 for 1 hr, then warmed to rt
and stirred at rt for 18 hr. The reaction mixture was washed
sequentially with 1M NaOH (10 ml), 1M HCl (10 ml), and H.sub.2O (10
ml), then dried over MgSO.sub.4 and concentrated in vacuo to give
1.301 g of off-white solid. Purification by flash chromatography,
eluting with hexane : EtOAc (6:4) gave 1.107 g (64% yield) of white
solid.
[0256] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.23-7.19 (m, 1H),
6.78-6.71 (m, 3H), 5.44 (br s, 1H), 3.78 (s, 3H), 3.52-3.47 (m,
2H), 2.79-2.75 (m, 2H), 1.81-1.73 (m, 4H), 1.64 (br s, 1H),
1.41-1.33 (m, 2H), 1.26-1.18 (m, 4H); MS m/e 262 (M.sup.++1).
Preparation 20
[0257] 1-Cyclohexyl-6-methoxy-3,4-dihydroisoquinoline
[0258] A solution of cyclohexanecarboxylic acid
[2-(3-methoxyphenyl)ethyl]- amide (1.000 g, 3.8 mmol) in POCl.sub.3
(7.0 ml, 75.1 mmol) was refluxed under N.sub.2 for 24 hr, then the
cooled reaction mixture was slowly added to ice-water (30 ml) with
stirring. The resulting mixture was extracted with EtOAc
(3.times.20 ml), then the remaining aqueous layer was basified to
pH 10 with concentrated ammonia (40 ml). This was extracted with
CHCl.sub.3 (4.times.20 ml), then the combined extracts were dried
over MgSO.sub.4 and concentrated in vacuo to give 0.270 g (93%
yield) of yellow oil.
[0259] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.47 (d, J=8.72 Hz,
1H), 6.79 (dd, J=8.51 Hz, J=2.49 Hz, 1H), 6.70 (d, J=2.28 Hz, 1H),
3.83 (s, 3H), 3.66-3.62 (m, 2H), 2.88-2.82 (m, 1H), 2.65-2.62 (m
2H), 1.87-1.81 (m, 4H), 1.46-1.23 (m, 6H); MS m/e 244
(M.sup.++1).
Preparation 21
[0260] 1-Cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline
[0261] Sodium borohydride (0.512 g, 13.5 mmol) was added in small
portions to a solution of
1-cyclohexyl-6-methoxy-3,4-dihydroisoquinoline (0.822 g, 3.38 mmol)
in MeOH (40 ml) at 0.degree. C. The reaction mixture was stirred at
0.degree. C. for 30 min, warmed to rt and stirred at rt for 15 hr,
then quenched by the dropwise addition of H.sub.2O (5.0 ml). The
resulting mixture was concentrated in vacuo to remove the MeOH and
the remaining aqueous solution was extracted with CHCl.sub.3
(4.times.10 ml). The combined extracts were dried over MgSO.sub.4
and concentrated in vacuo to give 0.775 g (93% yield) of yellow
oil.
[0262] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.05 (d, J=8.51 Hz,
1H), 6.73-6.70 (dd, J=8.72 Hz, J=2.91 Hz, 1H), 6.59 (d, J=2.70 Hz,
1H), 3.86 (d, J=3.94 Hz, 1H), 3.77 (s, 3H), 3.30-3.25 (m, 1H),
2.95-2.88 (m, 1H), 2.86-2.79 (m, 1H), 2.67-2.61 (m, 1H) 1.89-1.79
(m, 2H), 1.71-1.64 (m, 4H), 1.40-1.23 (m, 4H), 1.17-1.05 (m, 4H);
MS m/e 246 (M.sup.++1).
Preparation 22
[0263] N-[2-(3-Methoxyphenyl)ethyl]benzamide
[0264] Benzoyl chloride (0.922 g, 6.61 mmol) was added to a
solution of 3-methoxyphenethylamine (1.000 g, 6.61 mmol) and
Et.sub.3N (2.8 ml, 19.8 mmol) in anhydrous THF (30 ml) at rt under
N.sub.2. The resulting suspension was stirred at rt under N.sub.2
for 20 hr. The reaction mixture was filtered and the filtrate was
concentrated in vacuo to give 1.811 g of white solid. Purification
by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.689
g (100% yield) of white solid.
[0265] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.68-7.66 (m, 2H),
7.49-7.40 (m, 1H), 7.39-7.37 (m, 2H), 7.25-7.19 (m, 1H), 6.83-6.79
(m, 2H), 6.77 (s, 1H), 6.11 (br s, 1H), 3.78 (s, 3H), 3.74-3.69 (m,
2H), 2.92-2.89 (m, 2H); MS m/e 256 (M.sup.++1).
Preparation 23
[0266] 6-Methoxy-1-phenyl-3,4-dihydroisoquinoline
[0267] A solution of N-[2-(3-methoxyphenyl)ethyl]benzamide (1.530
g, 5.99 mmol) in phosphorous oxychloride (10 ml, 107.3 mmol) was
refluxed under N.sub.2 for 24 hours. The cooled reaction mixture
was then slowly added to ice-water (50 ml) with stirring, and
basified to pH 10 with concentrated ammonia (60 ml). This was
extracted with CHCl.sub.3 (4.times.25 ml), and the combined organic
extracts were dried over MgSO.sub.4 then concentrated in vacuo to
give 1.548 g (100% yield) of yellow oil.
[0268] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.60-7.58 (m, 2H),
7.47-7.39 (m, 3H), 7.22 (d, J=8.51 Hz, 1H), 6.80 (d, J=2.70 Hz,
1H), 6.74 (dd, J=8.51 Hz, J=2.49 Hz, 1H), 3.85 (s, 3H), 3.84-3.80
(m, 2H), 2.82-2.79 (m, 2H); MS m/e 238 (M.sup.++1).
Preparation 24
[0269] 6-Methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline
[0270] Sodium borohydride (0.945 g, 24.96 mmol) was added in small
portions to a solution of
6-methoxy-1-phenyl-3,4-dihydroisoquinoline (1.480 g, 6.24 mmol) in
MeOH (50 ml) at 0.degree. C. The reaction mixture was stirred for
30 min, warmed to rt and stirred at rt for 19 hr, then quenched by
the dropwise addition of H.sub.2O (10 ml). Excess MeOH was removed
by evaporation and the resulting aqueous solution was extracted
with CHCl.sub.3 (4.times.10 ml). The combined organic extracts were
dried over MgSO.sub.4 and concentrated in vacuo to give 1.308 g
(88% yield) of white solid.
[0271] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.33-7.26 (m, 5H),
6.66-6.59 (m, 3H), 5.05 (s, 1H), 3.76 (s, 3H), 3.26-3.20 (m, 1H),
3.08-2.99 (m, 2H), 2.84-2.77 (m, 1H); MS m/e 240 (M.sup.++1).
Preparation 25
[0272] Thiophene-2-carboxylic acid
[2-(3-methoxyphenyl)ethyl]amide
[0273] A mixture of 3-methoxyphenethylamine (1.000 g, 6.61 mmol),
2-thiophenecarboxylic acid (0.847 g, 6.61 mmol),
1-hydroxybenzotriazole hydrate (1.340 g, 9.92 mmol), and
1-(3-diethylaminopropyl)-3-ethylcarbodi- imide hydrochloride (1.330
g, 6.94 mmol) in anhydrous CH.sub.2Cl.sub.2 (20 ml) was stirred at
0.degree. C. under N.sub.2 for 1 hr, then warmed to rt and stirred
at rt for 18 hr. The reaction mixture was washed with 1M NaOH (10
ml) followed by 1M HCl (10 ml), dried over MgSO.sub.4, and
concentrated in vacuo to give 1.859 g of yellow oil. Purification
by flash chromatography, eluting with hexane:EtOAc (7:3) gave 1.637
g (95% yield) of yellow oil.
[0274] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.43 (dd, J=4.98
Hz, J=1.04 Hz, 1H), 7.38 (dd, J=3.74 Hz, J=1.25 Hz, 1H), 7.25-7.21
(m, 1H), 7.03 (dd, J=4.98 Hz, J=3.74 Hz, 1H), 6.82-6.76 (m, 3H),
5.97 (br s, 1H), 3.78 (s, 3H), 3.70-3.65 (m, 2H), 2.90-2.87 (m,
2H); MS m/e 262 (M.sup.++1).
Preparation 26
[0275] 6-Methoxy-1-thiophen-2-yl-3,4-dihydroisoquinoline
[0276] A solution of thiophene-2-carboxylic acid
[2-(3-methoxyphenyl)ethyl- ]amide (1.480 g, 5.66 mmol) in
phosphorous oxychloride (10 ml, 107.3 mmol) was refluxed under
N.sub.2 for 24 hr. The cooled reaction mixture was then slowly
added to ice-water (50 ml) with stirring and basified to pH 10 with
concentrated ammonia (60 ml). This was extracted with CHCl.sub.3
(4.times.25 ml) and the combined extracts were dried over
MgSO.sub.4 then concentrated in vacuo to give 1.517 g (96% yield)
of yellow oil.
[0277] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.66 (d, J=8.51 Hz,
1H), 7.48-7.45 (m, 2H), 7.13-7.11 (m, 1H), 6.88-6.81 (m, 2H), 3.87
(s, 3H), 3.80-3.76 (m, 2H), 2.79-2.75 (m, 2H); MS m/e 244
(M.sup.++1).
Preparation 27
[0278] 6-Methoxy-1-thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline
[0279] Sodium borohydride (0.916 g, 24.2 mmol) was added in small
portions to a solution of
6-methoxy-1-thiophen-2-yl-3,4-dihydroisoquinoline (1.470 g, 6.04
mmol) in MeOH (50 ml) at 0.degree. C. The reaction mixture was
stirred for 30 min, warmed to rt and stirred at rt for 21 hr, then
quenched by the dropwise addition of H.sub.2O (10 ml). Excess MeOH
was removed by evaporation and the resulting aqueous solution was
extracted with CHCl.sub.3 (4.times.10 ml). The combined extracts
were dried over MgSO.sub.4 and concentrated in vacuo to give 1.316
g (89% yield) of yellow solid.
[0280] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.23 (d, J=2.91 Hz,
1H), 6.94-6.88 (m, 3H), 6.68-6.65 (m, 2H), 5.39 (s, 1H), 3.77 (s,
3H), 3.28-3.22 (m, 1H), 3.11-3.05 (m, 1H), 2.97-2.90 (m, 1H),
2.87-2.82 (m, 1H); MS m/e 246 (M.sup.++1).
Preparation 28
[0281] 4-Bromo-N-[2-(3-methoxyphenyl)ethyl]benzamide
[0282] To a stirred solution of 3-methoxyphenethylamine (25.0 g,
165 mmol) and Et.sub.3N (30.0 ml, 214.50 mmol) in CH.sub.2Cl.sub.2
(500 ml) at 0.degree. C. was added 4-bromobenzoyl chloride (25 g,
181 mmol) in portions, and the mixture stirred for 30 min. 2N HCl
was added and stirred for 5 min, and the aqueous layer was
separated. The organic phase was washed sequentially with 1N HCl
(1.times.200 ml), H.sub.2O (2.times.100 ml), and saturated
NaHCO.sub.3 solution (100 ml), dried over MgSO.sub.4, and
concentrated in vacuo to give 28.42 g (52% yield) of off-white
solid.
[0283] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.53 (m, 4H), 7.23
(m, 1H), 6.82-6.73 (m, 3H), 3.77 (s, 3H), 3.75-3.69 (m, 2H), 2.89
(t, 2H); MS m/e 334, 336 bromine isotope pattern (M.sup.++1).
Preparation 29
[0284] 1-(4-Bromophenyl)-6-methoxy-3,4-dihydroisoquinoline
hydrochloride
[0285] To a solution of
4-bromo-N-[2-(3-methoxyphenyl)ethyl]benzamide (5.00 g, 15.0 mmol)
in CHCl.sub.3 (30 ml) was added phosphorous pentachloride (5.30 g,
25.0 mmol) and the mixture stirred for 18 hr at rt under N.sub.2.
Hexane was added to the mixture and the liquid was then decanted
off. EtOH (15 ml) was added to the residue and the mixture was
triturated with diethyl ether to give 3.65 g (69% yield) of
off-white solid.
[0286] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta.7.86 (d, J=8.51 Hz,
2H), 7.61 (d, J=8.30 Hz, 2H), 7.47 (d, J=8.92 Hz, 1H), 7.04 (d,
J=2.49 Hz, 1H), 7.04 (dd, J=8.92 Hz, J=2.70 Hz, 1H), 3.98-3.94 (m,
5H), 3.29-3.23 (m, 2H).
Preparation 30
[0287]
1-(4-Bromophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline
[0288] Sodium borohydride (0.720 g, 19.0 mmol) was added in small
portions to a solution of
1-(4-bromophenyl)-6-methoxy-3,4-dihydroisoquinoline, hydrochloride
(3.62 g, 10.2 mmol) in MeOH (30 ml) at 0.degree. C. The reaction
mixture was stirred for 30 min, warmed to rt, and stirred at rt for
1 hr, then quenched by the dropwise addition of H.sub.2O (10 ml).
Acetic acid (10 drops) was added with stirring, and the resulting
mixture was basified to pH 10 with 1N NaOH and extracted with EtOAc
(3.times.25 ml). The combined extracts were washed with 1N NaOH
followed by saturated NaCl solution, dried over Na.sub.2SO.sub.4,
and concentrated in vacuo to give 3.24 g (100% yield) of white
solid.
[0289] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.43 (d, J=8.51 Hz,
1H), 7.15 (d, J=8.51 Hz, 1H), 6.66-6.60 (m, 3H), 5.02 (s, 1H), 3.76
(s, 3H), 3.23-3.17 (m, 1H), 3.07-3.01 (m, 2H), 2.84-2.78 (m,
1H).
Preparation 31
[0290]
2-Benzenesulfonyl-6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl-
]-1,2,3,4-tetrahydroisoquinoline
[0291] Benzenesulfonyl chloride (0.016 g, 0.09 mmol) was added to a
solution of
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-te-
trahydroisoquinoline (0.040 g, 0.09 mmol) and Et.sub.3N (0.026 ml,
0.19 mmol) in anhydrous THF (10 ml) at rt under N.sub.2. The
resulting suspension was stirred at rt for 18 hr, then evaporated
in vacuo to give 0.086 g of yellow residue. Purification by flash
chromatography, eluting with EtOAc:MeOH (6:4) gave 0.045 g (85%
yield) of white solid.
[0292] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.65 (d, J=7.26 Hz,
3H), 7.38 (s, 5H), 7.34-7.32 (m, 1H), 7.28 (d, J=7.06 Hz, 3H), 7.07
(d, J=7.47 Hz, 3H), 6.86 (d, J=7.47 Hz, 1H), 6.76 (d, J=6.64 Hz,
4H), 6.54 (s, 1H), 6.14 (s, 1H), 4.98 (s, 2H), 4.28-4.24 (m, 1H),
3.78-3.74 (m, 1H), 3.33-3.24 (m, 4H), 2.55-2.45 (m, 2H), 1.96 (br
s, 4H); MS m/e 569 (M.sup.++1).
Preparation 32
[0293]
6-Benzyloxy-2-(naphthalene-1-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-etho-
xy)-phenyl]-1,2,3,4-tetrahydroisoquinoline
[0294] A solution of
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,-
2,3,4-tetrahydroisoquinoline (0.015 g, 0.04 mmol) and Et.sub.3N
(0.01 ml, 0.07 mmol) in anhydrous THF (0.35 ml) was added to a
solution of 1-naphthalenesuffonyl chloride (0.04 mmol) in anhydrous
THF (0.4 ml) at rt in a sealed reaction vessel. The resulting
suspension was stirred at rt for 20 hr, then evaporated to dryness.
The product was suspended in a mixture of H.sub.2O (0.4 ml) and
saturated NaHCO.sub.3 solution (0.4 ml), then extracted with
CH.sub.2Cl.sub.2 (3.times.0.75 ml). The combined extracts were
evaporated to dryness to give the crude product. Purification by
reverse-phase HPLC on a Primesphere C-18HC (50.0 mm.times.10.0 mm
column with 5.quadrature.m particle size) column, eluting with a
linear gradient starting at time 0 min. of
H.sub.2O:CH.sub.3CN:1%TFA/H.sub.2O (85:10:5), increasing to
H.sub.2O:CH.sub.3CN:1%TFA/H.sub.2O (5:90:5) at 8 min., detected on
a Micromass Platform 2 mass spectrometer (DAD 190-600 nM) gave
material which, after evaporation to dryness, was purified by
reverse-phase HPLC on a Primesphere C-18HC (3.0 mm.times.2.0 mm
column with 5.quadrature.m particle size) column, eluting with a
linear gradient starting at time 0 min. of H.sub.2O:CH.sub.3CN:TFA
(99.9:0:0.1), increasing to H.sub.2O:CH.sub.3CN:TFA (0:99.9:0.1) at
4 min., detected with a UV detector (300 nM.+-.90 nM and 254
nM.+-.25 nM), gave an eluent that was evaporated to dryness to give
the named product. MS m/e 583 (M.sup.++1).
Preparation 33
[0295]
6-Benzyloxy-2-(3,5-dimethylisoxazole-4-sulfonyl)-1-[4-(2-pyrrolidin-
-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline
[0296] 3,5-Dimethylisoxazole-4-sulfonyl chloride (0.034 g, 0.18
mmol) was added to a solution of
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-
-1,2,3,4-tetrahydroisoquinoline (0.075 g, 0.18 mmol) and Et.sub.3N
(0.037 ml, 0.26 mmol) in anhydrous THF (10 ml) at rt under N.sub.2.
The resulting suspension was stirred at rt for 21 hr, then
evaporated in vacuo to a residue that was suspended in a mixture of
saturated NaHCO.sub.3 solution (4 ml) and H.sub.2O (4 ml). This was
extracted with CHCl.sub.3 (4.times.5 ml) and the combined extracts
were dried over MgSO.sub.4, then concentrated in vacuo to give
0.110 g of yellow oil. Purification by flash chromatography,
eluting with EtOAc:MeOH (1:1) gave 0.078 g (76% yield) of white
solid.
[0297] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.42-7.37 (m, 2H),
7.33 (d, J=6.65 Hz, 1H), 7.19-7.10 (m, 1H), 7.02-6.98 (m, 2H),
6.90-6.87 (m, 2H), 6.81-6.79 (m, 3H), 6.69 (s, 1H), 6.05 (s, 1H),
5.01 (s, 2H), 4.08-4.03 (m, 2H), 3.72-3.67 (m, 1H), 3.35-3.30 (m,
1H), 2.87-2.84 (m, 2H), 2.74-2.71 (m, 1H), 2.67-2.66 (m, 1H), 2.59
(s, 4H), 2.55 (s, 1H), 2.52 (s, 2H), 2.19 (s, 2H), 2.17 (s, 1H),
1.78 (br s, 4H); MS m/e 588 (M.sup.++1).
Preparation 34
[0298]
1-[4-(2-Pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoli-
n-6-ol
[0299] A mixture of
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2-
,3,4-tetrahydroisoquinoline (0.300 g, 0.70 mmol), ammonium formate
(0.883 g, 14.0 mmol), and 20% Pd(OH).sub.2/C (0.050 g) in MeOH (50
ml) was refluxed under N.sub.2 for 1 hr, then filtered through
Celite.RTM.. The filtrate was evaporated in vacuo to a yellow
residue that was suspended in a mixture of H.sub.2O (5 ml) and
saturated NaHCO.sub.3 solution (5 ml), then extracted with
CH.sub.2Cl.sub.2 (4.times.10 ml). The combined organic extracts
were dried over MgSO.sub.4 and concentrated in vacuo to give 0.133
g of yellow oil. The aqueous layer was extracted again with
CH.sub.2Cl.sub.2 (4.times.50 ml) to give an additional 0.083 g of
yellow oil, for a total of 0.216 g (91% yield) of product.
[0300] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.54 (d, J=8.51 Hz,
1H), 7.09 (d, J=8.51 Hz, 1H), 6.83 (d, J=8.72 Hz, 1H), 6.72 (d,
J=8.51 Hz, 1H), 6.57-6.47 (m, 3H), 4.97 (s, 1H), 4.09-4.05 (m, 2H),
3.18-3.15 (m, 1H), 3.01-2.88 (m, 4H), 2.80-2.79 (m, 1H), 2.69 (br
s, 4H), 2.16-2.15 (m, 1H), 1.83 (br s, 4H); MS m/e 339
(M.sup.++1).
Preparation 35
[0301]
6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-i-
soquinoline-2-carboxylic acid tert-butyl ester
[0302] A solution of di-tert-butyl dicarbonate (0.035 g, 0.16
mmol),
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoq-
uinoline (0.069 g, 0.16 mmol), and Et.sub.3N (0.028 ml, 0.20 mmol)
in anhydrous THF (10 ml) was stirred at rt under N.sub.2 for 20 hr.
The reaction mixture was concentrated in vacuo to give 0.081 g of
yellow oil. Purification by flash chromatography, eluting with
EtOAc:MeOH (6:4), gave 0.041 g (48% yield) of white solid.
[0303] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.43-7.27 (m, 5H),
7.20-7.14 (m, 1H), 7.10 (d, J=8.72 Hz, 2H), 6.90 (br s, 1H),
6.80-6.77 (m, 4H), 5.03 (s, 2H), 4.18 (br s, 2H), 3.13-2.65 (m,
10H), 1.89 (br s, 4H), 1.47 (s, 9H); MS, m/e 529 (M.sup.++1).
Preparation 36
[0304]
6-Benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-i-
soquinoline-2-carboxylic acid ethyl ester
[0305] A solution of ethyl chloroformate (0.017 g, 0.16 mmol),
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoq-
uinoline (0.069 g, 0.16 mmol), and Et.sub.3N (0.028 ml, 0.20 mmol)
in anhydrous THF (10 ml) was stirred at rt under N.sub.2 for 20 hr.
The reaction mixture was concentrated in vacuo to give 0.115 g of
tan solid. Purification by flash chromatography, eluting with
EtOAc:MeOH (8:2), gave 0.023 g (28% yield) of white solid.
[0306] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.43-7.29 (m, 6H),
7.12-7.10 (m, 2H), 6.91 (d, J=7.68 Hz, 1H), 6.80-6.77 (m, 4H), 5.04
(s, 2H), 4.29-3.98 (m, 7H), 3.25-2.67 (m, 7H), 1.97 (br s, 4H),
1.30-1.23 (s, 3H); MS, m/e 501 (M.sup.++1).
Preparation 37
[0307] 2-(3-Methoxy-phenyl)-N-phenyl-acetamide
[0308] The title compound was prepared according to the procedure
of Nagarajan et al., Ind. J. Chem., 24B:83-97 (1985).
Preparation 38
[0309] [2-(3-Methoxy-phenyl)-ethyl]-phenyl-amine
[0310] The title compound was prepared according to the procedure
of Nagarajan et al., Ind. J. Chem., 24B:83-97 (1985).
Preparation 39
[0311]
4-Methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide
[0312] To a stirred solution of
2-(3-methoxy-phenyl)-ethyl]-phenyl-amine (0.800 g, 3.52 mmol, 1.0
eq.) in CH.sub.2Cl.sub.2 (4ml) was added Et.sub.3N (2.97 ml, 21.1
mmol, 6.0 eq.), PPAA (50% solution in EtOAc, 7.05 mmol, 2.0 eq.),
para-methoxy benzoic acid (0.803 g, 5.29 mmol, 1.5 eq.), and a
catalytic amount of DMAP. The reaction was stirred at room
temperature for 36 hours. The reaction mixture was diluted with
CH.sub.2Cl.sub.2 (30 ml) and washed successively with 1N HCl
(1.times.20 ml) and saturated NaHCO.sub.3 (1.times.20 ml). The
organic layer was dried over MgSO.sub.4, filtered, and concentrated
in vacuo. Flash chromatography (SiO.sub.2, hexanes:EtOAc 7:1 to
3:1) of the residue afforded the desired compound as a colorless
oil (1.13 g, 3.13 mmol, 89% yield).
[0313] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.95 (2H, t,
J 8.0 Hz) 3.68 (3H, s), 3.73 (3H, s), 4.08 (2H, t, J 8.0 Hz),
6.60-7.24 (13H, overlapping m).
Preparation 40
[0314] Cyclohexanecarboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-amid- e
[0315] The title compound was prepared by analogy to Preparation 39
except that cyclohexane carboxylic acid was used instead of
para-methoxy benzoic acid, and hexanes 7:1 EtOAc was used as the
eluent for flash chromatography purification.
[0316] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 0.84-0.94
(2H, overlapping m), 1.09-1.23 (2H, overlapping m), 1.44-1.77 (6H,
overlapping m), 2.05 (1H, m), 2.81 (2H, m), 3.73 (3H, s), 3.85 (2H,
m), 6.68-6.73 (3H, overlapping m), 7.00-7.02 (2H, overlapping m),
7.13 (1H, m) and 7.31-7.38 (3H overlapping m). MS 338 (M+1).
Preparation 41
[0317] N-[2-(3-Methoxy-phenyl)-ethyl]-N-phenyl-isobutyramide
[0318] The title compound was prepared by analogy to Preparation 39
except that 2-methyl propanoic acid was used instead of
para-methoxy benzoic acid, and hexanes 7:1 EtOAc was used as eluent
for flash chromatography purification.
[0319] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 1.00 (6H, d,
J 6.5 Hz), 2.40 (1H, septet, J 6.5 Hz), 2.85 (2H, t, 7.5 Hz), 3.75
(3H, s), 3.88 (2H, t, 7.5 Hz), 6.72-6.73 (3H, overlapping m) and
7.31-7.41 (9H overlapping m). MS 298 (M+1).
Preparation 42
[0320] N-[2-(3-Methoxy-phenyl)-ethyl]-N-phenyl-benzamide
[0321] To a stirred solution of
2-(3-methoxy-phenyl)-ethyl]-phenyl-amine (1.38 g, 6.08 mmol, 1.0
eq.) in CH.sub.2Cl.sub.2 (30 ml) under an atmosphere of N.sub.2 was
added EDC (1.05 g, 6.69 mmol, 1.1 eq.) and HOBt (1.23 g, 91.2 mmol,
1.5 eq.). Benzoic acid (1.11 g, 9.12 mmol, 1.5 eq.) was added to
this mixture, and stirring was continued at room temperature for 24
hours. Additional EDC (1.1 g, 7.01 mmol, 1.15 eq.) and a catalytic
amount of DMAP were added, and stirring was continued at room
temperature for a further 24 hours. The reaction mixture was
diluted with CH.sub.2Cl.sub.2 (30 ml) and washed sequentially with
sat. NaHCO.sub.3 (1.times.30 ml) and 1N HCl (1.times.30 ml). The
basic aqueous layer was back extracted with CH.sub.2Cl.sub.2
(1.times.20 ml). The combined organics were dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was subjected to
flash chromatography (SiO.sub.2, hexanes:EtOAc 8:1) to give the
desired product (1.41 g, 4.24 mmol, 70% yield).
[0322] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.96 (2H, t,
J 8.0 Hz), 3.74 (3H, s), 4.08 (2H, t, J 8.0 Hz) and 6.73-7.26 (14H,
overlapping m). MS 332 (M+1).
Preparation 43
[0323] 4-(2E-Ethoxycarbonyl-vinyl)-benzoic acid
[0324] To a stirred solution of 4-formyl-benzoic acid (10.0 g, 66.7
mmol) in THF (140 ml) was added carboethoxytriphenylphosphorane
(25.0 g, 71.8 mmol). To this solution was added NaOH (2.50 g, 66.7
mmol) as a solution in water (20 ml). The reaction was stirred at
rt overnight. The reaction mixture was diluted with water (50 ml)
and extracted with EtOAc (3.times.50 ml). The combined extracts
were dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The residue was purified by flash chromatography (SiO.sub.2, 5%
MeOH/CH.sub.2Cl.sub.2) to give the desired compound as a white
solid (11.68 g, 53.1 mmol, 80% yield).
[0325] .sup.1H NMR (400 MHz, d.sub.6-acetone) .delta..sub.H 1.28
(3H, t , J 7.0 Hz), 4.20 (2H, q, J 7.0 Hz), 6.65 (1H, d, J 16.0 Hz)
and 7.67-8.13 (5H, overlapping m).
Preparation 44
[0326]
3-(4-{[2E-(3-Methoxy-phenyl)-ethyl]-phenyl-carbamoyl}-phenyl)-acryl-
ic acid ethyl ester
[0327] The title compound was prepared by analogy to Preparation 39
except that 4-(2E-ethoxycarbonyl-vinyl)-benzoic acid was used
instead of para-methoxy benzoic acid and the crude material was
taken to the next step without any flash chromatography.
[0328] MS 430 (M+1).
Preparation 45
[0329] N-[2-(3-Methoxy-phenyl)-ethyl]-2,N-diphenyl-acetamide
[0330] The title compound was prepared by analogy to Preparation 39
except that phenyl acetic acid was used instead of para-methoxy
benzoic acid, and the crude material was taken to the next step
without any flash chromatography.
[0331] MS 346 (M+1).
Preparation 46
[0332] Thiophene-2-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-ami- de
[0333] The title compound was prepared by analogy to Preparation 39
except that thiophene-2-carboxylic acid was used instead of
para-methoxy benzoic acid, and hexanes 10:1 EtOAc was used as
eluent for flash chromatography purification.
[0334] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.98 (2H,
m), 3.75 (3H, s), 4.05 (2H, m), 6. 65-6.80 (5H, overlapping m) and
7.11-7.39 (7H, overlapping m). MS 337 (M).
Preparation 47
[0335] Naphthalene-2-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-a- mide
[0336] The title compound was prepared by analogy to Preparation 39
except that naphthalene-2-carboxylic acid was used instead of
para-methoxy benzoic acid, and the crude material was taken to the
next step without any flash chromatography.
[0337] MS 382 (M+1).
Preparation 48
[0338]
3,4,5-Trifluoro-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide
[0339] The title compound was prepared by analogy to Preparation 39
except that 3,4,5-trifluorobenzoic acid was used instead of
para-methoxy benzoic acid, and the crude material was taken to the
next step without any flash chromatography.
[0340] MS 386 (M+1).
Preparation 49
[0341]
4-Chloro-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide
[0342] The title compound was prepared by analogy to Preparation 39
except that 4-chloro-benzoic acid was used instead of para-methoxy
benzoic acid, and the crude material was taken to the next step
without any flash chromatography.
[0343] MS 365 (M+1).
Preparation 50
[0344] Thiazole-2-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-amid- e
[0345] The title compound was prepared by analogy to Preparation 39
except that thiazole-2-carboxylic acid (see Metzger, Bull. Soc.
Chim. Fr., p. 708 (1953)) was used instead of para-methoxy benzoic
acid, and the crude material was taken to the next step without any
flash chromatography.
[0346] MS 338 (M+1).
Preparation 51
[0347] Adamantane-1-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-am- ide
[0348] The title compound was prepared by analogy to Preparation 39
except that adamantane-1-carboxylic acid was used instead of
para-methoxy benzoic acid, and the crude material was taken to the
next step without any flash chromatography.
[0349] MS 389 (M).
Preparation 52
[0350] N-[2-(3-Methoxy-phenyl)-ethyl]-N-phenyl -isonicotinamide
[0351] The title compound was prepared by analogy to Preparation 39
except that isonicotinic acid was used instead of para-methoxy
benzoic acid, and hexanes:EtOAc 4:1 was used as eluent for flash
chromatography purification.
[0352] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.95 (2H,
m), 3.75(3H, s), 4.10 (2H, m), 6.74-6.85 (3H, overlapping m),
7.08-7.23 (8H, overlapping m) and 8.41 (2H, m). MS 333 (M+1).
Preparation 53
[0353] 4-Iodo-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide
[0354] To a stirred suspension of 4-iodobenzoic acid (8.5g, 34.4
mmol, 1.3 eq.) in toluene (21 ml) under an atmosphere of N.sub.2
was added thionyl chloride (17 ml). The suspension was heated at
reflux for 2 hours forming a turbid solution. The reaction was
allowed to cool to RT and the volatiles were removed in vacuo. The
residue was taken up in THF (100 ml) under an atmosphere of
N.sub.2and cooled to 0.degree. C. To the ice cold solution was
added successively Et.sub.3N (14.7 ml, 106.0 mmol, 4.0 eq.), a
catalytic amount of DMAP, and
2-(3-methoxy-phenyl)-ethyl]-phenyl-amine (6.0 g, 26.4 mmol, 1.0
eq.). After 1 hour at 0.degree. C.the ice bath was removed and
stirring was continued at RT overnight. The reaction mixture was
diluted with EtOAc (100 ml) and washed successively with 1N HCl
(2.times.100 ml), water (2.times.100 ml), and 10% K.sub.2CO.sub.3
(2.times.100 ml). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was subjected to
flash chromatography (SiO.sub.2, hexanes:EtOAc 8:1 to 4:1 gradient)
to give the desired product (11.0 g, 24.1 mmol, 91% yield).
[0355] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.96 (2H, t,
J 8.0 Hz), 3.77 (3H, s), 4.10 (2H, t, J 8.0 Hz), 6.75-6.87 (5H,
overlapping m), 6.99 (2H, d, J 8.5 Hz), 7.15-7.24 (4H, overlapping
m) and 7.49 (2H, d, J 8.5 Hz). MS 458 (M+1).
Preparation 54
[0356] 1-Trifluoroacetyl-piperidine-4-carbonyl chloride
[0357] The title compound was prepared according to the procedure
of Hibert et al., J. Med. Chem., 33:1594 (1990). [[Was this done
exactly as described, or analogously? Done exactly]]
Preparation 55
[0358] 1-Trifluoroacetyl-piperidine-4-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-amide
[0359] To a stirred solution of 3-methoxy phenylethylamine (9.3g,
61.6 mmol) and triethylamine (8.1 g, 11.2 ml, 80.1 mmol) in
CH.sub.2Cl.sub.2 (50 ml) at 0.degree. C. under an atmosphere of
N.sub.2 was added 1-trifluoroacetyl-piperidine-4-carbonyl chloride
(15.0 g, 61.6 mmol) as a solution in CH.sub.2Cl.sub.2 (50 ml) in a
dropwise manner. The reaction was allowed to warm to RT overnight.
The reaction was quenched with water (50 ml), the layers were
separated, and the organic layer was washed with water (1.times.50
ml). The combined aqueous layers were back extracted with
CH.sub.2Cl.sub.2 (1.times.75 ml). The combined organic layers were
washed with brine (1.times.75 ml). The organic layer was dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The resulting
solid was triturated with Et.sub.2O and filtered to give the
desired product (18.8 g, 52.3 mmol, 85% yield).
[0360] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 1.58-1.97
(5H, overlapping m), 2.30 (1H, m), 2.79 (2H, t, J 6.5 Hz), 2.91
(1H, m), 3.17 (1H, m), 3.52 (2H, m), 3.79 (3H,s), 3.99 (1H, m),
4.41(1 H, m), 5.45 (1 H, broad s), 6.71-6.79 (3H, overlapping m)
and 7.23 (1H, t, J 8.0 Hz). MS 359 (M+1).
Preparation 56
[0361]
2,2,2-Trifluoro-1-[4-(6-methoxy-3,4-dihydro-isoquinolin-1-yl)-piper-
idin-1-yl]-ethanone
[0362] A stirred solution of
1-trifluoroacetyl-piperidine-4-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-amide (1.04g, 2.9 mmol) in POCl.sub.3
under an atmosphere of N.sub.2 was heated at reflux for 2.5 hours.
The reaction was allowed to cool to RT and the POCl.sub.3 was
removed in vacuo. The residual oil was suspended in toluene (20 ml)
and concentrated in vacuo (this process was repeated twice more),
leaving the desired product as a tan colored solid (0.872 g, 2.56
mmol, 88% yield).
[0363] MS 341 (M+1)
Preparation 57
[0364] 6-Methoxy-1-piperidin-4-yl-3,4-dihydro-isoquinoline
[0365] To a stirred solution of
2,2,2-trifluoro-1-[4-(6-methoxy-3,4-dihydr-
o-isoquinolin-1-yl)-piperidin-1-yl]-ethanone (0.160 g, 0.470 mmol)
was added a solution of 10% K.sub.2CO.sub.3 (2 ml). The cloudy
mixture was stirred at RT overnight. The reaction mixture was
extracted with EtOAc (3.times.5 ml), the combined organic extracts
were washed with brine (1.times.5 ml), dried over MgSO.sub.4,
filtered, and concentrated in vacuo to give the desired compound as
a yellow oil (0.101 g, 0.413 mmol, 88% yield).
[0366] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 1.67-1.81
(2H, overlapping m), 1.83-2.02 (2H overlapping m), 2.60 (2H, t, J
7.5 Hz), 2.86 (2H, m), 3.08 (1H, m), 3.28 (2H, m), 3.61 (2H, t, J
7.5 Hz), 3.81 (3H, s), 5.24 (1 H, broad s), 6.70 (1 H, d, J 3.0
Hz), 6.78 (1H, dd, J 8.0 and 3.0 Hz) and 7.38 (1H, d, J 8.0 Hz). MS
245 (M+1).
Preparation 58
[0367]
6-Methoxy-1-[1-(1-methyl-1H-imidazole4-sulfonyl)-piperidin-4-yl]-3,-
4-dihydro-isoquinoline
[0368] To a stirred solution of
6-methoxy-1-piperidin-4-yl-3,4-dihydro-iso- quinoline (0.094 g,
0.385 mmol) and triethylamine (0.078 g, 0.77 mmol) in
CH.sub.2Cl.sub.2 (3 ml) was added 1-methyl-1H-imidazole-4-sulfonyl
chloride (0.070 g, 0.385 mmol). The reaction mixture was stirred at
RT under an atmosphere of N.sub.2 overnight. The reaction mixture
was diluted with CH.sub.2Cl.sub.2 (10 ml) and washed with water
(2.times.5 ml). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was purified via
radial chromatography (SiO.sub.2, 1 mm, CH.sub.2Cl.sub.2 to 5%
MeOH/CH.sub.2Cl.sub.2) to give the product as an oil (0.084 g,
0.216 mmol, 56% yield).
[0369] MS 389 (M+1).
Preparation 59
[0370]
6-Methoxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-1-
,2,3,4-tetrahydroisoquinoline
[0371] To a stirred solution of
6-methoxy-1-[1-(1-methyl-1H-imidazole-4-su-
lfonyl)-piperidin-4-yl]-3,4-dihydro-isoquinoline (0.077 g, 0.197
mmol) in MeOH (3 ml) cooled to 0.degree. C. was added NaBH.sub.4.
The reaction mixture was then stirred at RT for 2 hours and diluted
with water (5 ml) and sat. NaHCO.sub.3 (5 ml). The mixture was
extracted with EtOAc (3.times.10 ml). The combined organics were
washed with brine (1.times.10 ml), dried over MgSO.sub.4, filtered,
and concentrated in vacuo. The residue was purified by radial
chromatography (SiO.sub.2, 1 mm, CH.sub.2Cl.sub.2 to 5%
MeOH/CH.sub.2Cl.sub.2) to give the product as an oil (0.055 g,
0.141 mmol, 71% yield).
[0372] MS 391 (M+1).
Preparation 60
[0373] 2-Benzylamino-1-(4-methoxy-phenyl)-ethanone
[0374] To a solution of Et.sub.3N (13.55 g, 133.9 mmol) and
benzylamine (11.96 g, 111.6 mmol) in THF (25 ml) was added
2-bromo-1-(4-methoxy-pheny- l)-ethanone (25.56 g, 111.6 mmol). The
reaction was stirred at RT for 60 minutes, then filtered and the
filtrate concentrated in vacuo. The residue was purified via flash
chromatography (SiO.sub.2, gradient column 35% to 80%
EtOAc/hexanes) to give the title product (17.12 g, 67.0 mmol, 60%
yield).
[0375] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 3.85 (3H,
s), 3.94 (s, 2H), 4.11 (s, 2H), 6.91 (2H, d, J=9.0 Hz), 7.20-7.41
(m, 5H) and 7.87 (2H, d, J,9.0 Hz). MS 256 (M+1).
Preparation 61
[0376] 2-Benzylamino-1-(4-methoxy-phenyl)-ethanol
[0377] To a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanone
(1.61 g, 6.30 mmol, see Preparation 60) in MeOH (60 ml) was added
NaBH.sub.4 (0.48 g, 12.6 mmol) in three equal portions. The
reaction was stirred at RT overnight, then it was quenched with a
1:1 mixture of water and sat. NaHCO.sub.3 (30 ml). The mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.40 ml), the organics were
combined, dried over MgSO.sub.4, filtered, and concentrated in
vacuo. The residue was purified via Biotage flash chromatography
(SiO.sub.2, neat EtOAc) to give the title product (1.216 g, 4.72
mmol, 75% yield).
[0378] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.68 (2H,
broad s), 2.71 (1H, dd, J 12.5 and 9.0 Hz), 2.87 (1H, dd, J 12.5
and 3.5 Hz), 3.77 (3H, s), 3.81 (2H, m), 4.67 (1H, dd J 9.0 Hz and
3.5 Hz), 6.85 (2H, d J 8.5 Hz) and 7.19-7.38 (7H, m). MS 258
(M+1).
Preparation 62
[0379]
2-[Benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-phenyl)-ethanone
[0380] To a solution of 2-benzylamino-1-(4-methoxy-phenyl)-ethanone
(12.0 g, 47.0 mmol, see Preparation 60) and 3-methoxy benzaldehyde
(6.09 g, 44.8 mmol) in 1,2 DCE (250 ml) was added NaB(OAc).sub.3H.
The reaction mixture was stirred at RT overnight. The reaction was
poured into sat. NaHCO.sub.3 (150 ml) and extracted with
CH.sub.2Cl.sub.2 (3.times.100 ml). The combined organics were dried
over MgSO.sub.4, filtered, and concentrated in vacuo. Flash
chromatography (SiO.sub.2, gradient elution 20% to 50%
EtOAc/hexanes) gave the title product (13.85 g, 36.9 mmol, 83%
yield).
[0381] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 3.76 (2H,
s), 3.77 (3H,s), 3.78 (2H, s), 3.83 (2H, s), 3.84 (3H, s),
6.83-6.93 (5H, m), 7.19-7.36 (6H, m) and 7.83 (2H, d, J 7.5 Hz). MS
376 (M+1).
Preparation 63
[0382]
2-[Benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-phenyl)-ethanol
[0383] To a solution of
2-[benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-p- henyl)-ethanone
(13.8 g, 36.75 mmol, see Preparation 62) in MeOH (150 ml) cooled to
0.degree. C. was added NaBH.sub.4 in five equal portions over 30
minutes. The reaction was stirred overnight while slowly warming to
RT. Water (100 ml) was added to the reaction mixture, the volume
was reduced by half in vacuo, and the mixture extracted with
CH.sub.2Cl.sub.2 (3.times.100 ml). The combined organics were dried
over MgSO.sub.4, filtered, and concentrated in vacuo. Flash
chromatography of the residue (SiO.sub.2, gradient elution 20%-50%
EtOAc/hexanes) gave the title product (12.87 g, 34.1 mmol, 93%
yield).
[0384] Alternatively, to a solution of
2-benzylamino-1-(4-methoxy-phenyl)-- ethanol (1.20 g, 4.66 mmol,
see Preparation 61) and 3-methoxybenzaldehyde (0.700 g, 5.13 mmol)
in 1,2 DCE (25 ml) was added NaB(OAc).sub.3H. The mixture was
stirred at RT overnight. The reaction mixture was poured into sat.
NaHCO.sub.3 (30 ml) and extracted with CH.sub.2Cl.sub.2 (3.times.50
ml). The combined organics were dried over MgSO.sub.4, filtered,
and concentrated in vacuo. The residue was purified via flash
chromatography (Biotage 15% EtOAc/hexanes) to give the title
product (1.72 g, 4.56 mmol, 98% yield).
[0385] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.58 (1H,
m), 3.44 (1H, m), 3.72 (1H, m), 3.75 (3H, s), 3.78 (3H, s), 3.88
(1H, m), 4.65 (1H, m), 6.79-6.90 (5H, m) and 7.12-7.32 (8H, ).
[0386] MS 378 (M+1).
Preparation 64
[0387]
7-Methoxy4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinoline
[0388] A suspension of 10% Pd/C (3.80 g) and
2-benzyl-7-methoxy-4-(4-metho-
xy-phenyl)-1,2,3,4-tetrahydroisoquinoline (3.87 g, 10.8 mmol, see
Example 80) in EtOH (160 ml) was hydrogenated at 50 p.s.i. for 12
hours. The catalyst was removed viafiltration through diatomaceous
earth and the filtrate was concentrated in vacuo. Purification via
flash chromatography (Biotage, SiO.sub.2, 9:1 EtOAc:MeOH then 1:1
EtOAc:MeOH) gave the title product (2.19 g, 8.13 mmol, 76%
yield).
[0389] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 2.88 (1H,
dd, J 12.5 and 8.5 Hz), 3.21-3.31 (2H, m), 3.71 (3H, s), 3.73 (3H,
s), 3.91-4.06 (2H, m), 6.61 (2H, m), 6.68 (1H, m), 6.81 (2H, d J
8.5 Hz) and 6.98 (2H, d, J 8.5 Hz). MS 270 (M+1).
Preparation 65
[0390]
6-Methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinol-
ine
[0391] A stirred solution of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-ph- enyl-benzamide in
POCl.sub.3 under an atmosphere of N.sub.2 was heated at reflux for
14 hours. The solution was allowed to cool to rt and concentrated
in vacuo. The residue was taken up in CH.sub.2Cl.sub.2 (30 ml) and
washed with sat. NaHCO.sub.3 until CO.sub.2 evolution ceased. The
organic layer was dried over MgSO.sub.4, filtered, and concentrated
in vacuo. The residue was dissolved in MeOH (20 ml), cooled to
0.degree. C., and NaBH.sub.4 (0.105 g, 2.77 mmol) was added in a
portionwise manner. The reaction was stirred for 2 hours at
0.degree. C., then additional NaBH.sub.4 (0.105 g, 2.77 mmol) was
added. The reaction was stirred at rt overnight, diluted with
CH.sub.2Cl.sub.2 (50 ml), and washed with sat. NaHCO.sub.3 solution
(1.times.50 ml). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated in vacuo. The residue was subjected to
flash chromatography (SiO.sub.2, hexanes:EtOAc 10:1) to give the
desired compound as a colorless oil (0.550 g, 1.59 mmol, 58%
yield).
[0392] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.89 (2H,
m,) 3.46 (1H, m), 3.63 (1H, m), 3.73 (3H, s), 3.77 (3H, s), 5.73
(1H, s) 6.69-7.22 (12H, overlapping m).
[0393] See also Nagarajan et al., Ind. J. Chem., 24B:83-97
(1985).
Preparation 66
[0394] 6-Methoxy-1,2-diphenyl-1,2,3,4-tetrahydroisoquinoline
[0395] The title compound was prepared by analogy to Preparation 65
except that N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide was
used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide and the
final residue was subjected to flash column chromatography using
hexanes:EtOAc 10:1.
[0396] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.88 (2H,
m), 3.47 (1H, m), 3.69 (1H, m), 3.77 (3H, s), 5.77 (1H, s),
6.70-7.24 (13H, overlapping m). MS 316 (M+1).
[0397] See also Nagarajan et al., Ind. J. Chem., 24B:83-97
(1985).
Preparation 67
[0398]
1-(4-Chloro-phenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoli-
ne
[0399] The title compound was prepared by analogy to Preparation 65
except that
4-chloro-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide was used
instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and
the final residue was not subjected to flash chromatography.
[0400] MS 349 (M+1).
[0401] See also Nagarajan et al., Ind. J. Chem., 24B:83-97
(1985).
Example 1
[0402]
2,2,2-Trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4-dihydro-1H-iso-
quinolin-2-yl]ethanone
[0403]
1-[1-(4-Benzyloxyphenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-
-2,2,2-trifluoroethanone (26.97 g, 61.1 mmol) was hydrogenated
using 10% Pd/C (1.000 g) in EtOH (300 ml) at an initial pressure of
44 psi (.about.300,000 Pa) at rt for 6 hr. The reaction mixture was
filtered through a pad of Celite to remove the catalyst and the
filtrate was evaporated in vacuo to give 18.98 g (88% yield) of
white solid.
[0404] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.08-7.06 (m, 2H),
6.96-6.92 (m, 1H), 6.79-6.69 (m, 5H), 4.81 (br s, 1H),
3.92.times.3.88 (m, 1H), 3.80 (s, 3H), 3.48-3.40 (m, 1H), 3.10-3.01
(m, 1H), 2.85-2.81 (m, 1H); MS m/e 352 (M.sup.++1).
Example 2
[0405]
2,2,2-Trifluoro-1-6-methoxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]--
3,4-dihydro-1H-isoquinolin-2-yl}ethanone
[0406] A solution of
2,2,2-trifluoro-1-[1-(4-hydroxyphenyl)-6-methoxy-3,4--
dihydro-1H-isoquinolin-2-yl]ethanone (18.98 g, 54.0 mmol) in
anhydrous DMF (200 ml) was added to a suspension of NaH (2.592 g,
108.0 mmol) in anhydrous DMF (400 ml) at rt under N.sub.2. After
stirring at rt for 1 hr, a solution of 1-(2-chloroethyl)pyrrolidine
hydrochloride (9.184 g, 54.0 mmol) in anhydrous DMF (200 ml) was
added and the reaction mixture was heated to 100.degree. C. for 4
hr. The reaction mixture was cooled to rt, diluted with H.sub.2O
(2000 ml), and extracted with EtOAc (4.times.250 ml). The combined
extracts were washed with H.sub.2O (3.times.250 ml), dried over
MgSO.sub.4, and concentrated in vacuo to give 21.15 g of yellow
oil. Purification by flash chromatography, eluting with EtOAc:MeOH
(8:2) gave 10.503 g (43% yield) of yellow oil.
[0407] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.11-7.09 (m, 2H),
6.93 (d, J=8.51 Hz, 1H), 6.81-6.79 (m, 2H), 6.77-6.73 (m, 1H),
6.71-6.69 (m, 2H), 4.16 (br s, 2H), 3.91-3.87 (m, 1H), 3.79 (s,
3H), 3.47-3.40 (m, 1H), 3.10-2.94 (m, 3H), 2.86-2.77 (m, (s, 4H);
MS m/e 449 (M.sup.++1).
Example 3
[0408]
2,2,2-Trifluoro-1-{6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-
-3,4-dihydro-1H-isoquinolin-2-yl}ethanone
[0409] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (35.0 ml,
35.0 mmol) was added slowly to a solution of
2,2,2-trifluoro-1-{6-methoxy-1-[4-(2-py-
rrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-isoquinolin-2-yl}ethanone
(6.26 g, 14.0 mmol) in anhydrous CH.sub.2Cl.sub.2 (400 ml) at
0.degree. C. under N.sub.2. The reaction mixture was warmed to rt
and stirred at rt for 21 hr. MeOH (100 ml) was slowly added with
stirring and the resulting solution was concentrated in vacuo to a
red oil. Purification by flash chromatography, eluting with
EtOAc:MeOH (8:2), gave 1.886 g (31% yield) of yellow solid.
[0410] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.07 (d, J=8.30 Hz,
2H), 6.79 (d, J=8.30 Hz, 1H), 6.71-6.63 (m, 5H), 4.24 (br s, 2H),
3.85-3.81 (m, 1H), 3.37-3.31 (m, 1H), 3.20-2.95 (m, 7H), 2.71-2.66
(m, 1H), 1.98 (s, 4H); MS m/e 435 (M.sup.++1).
Example 4
[0411]
{6-Hydroxy-1-4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-iso-
quinolin-2-yl}-phenylmethanone
[0412] A mixture of
{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3-
,4-dihydro-1H-isoquinolin-2-yl}phenylmethanone (0.043 g, 0.08
mmol), ammonium formate (0.127 g, 2.01 mmol), and 20%
Pd(OH).sub.2/C (0.025 g) in MeOH (10 ml) was refluxed under N.sub.2
for 1 hr, then filtered through Celite. The filtrate was evaporated
in vacuo to a white residue that was dissolved in CH.sub.2Cl.sub.2
(10 ml) and washed with 1M NaOH (5 ml). The aqueous layer was
extracted with CH.sub.2Cl.sub.2 (3.times.10 ml) and all of the
combined organic solutions were dried over MgSO.sub.4 and
concentrated in vacuo to give 0.028 g (78% yield) of colorless
residue.
[0413] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.38-7.34 (m, 6H),
7.18 (d, J=7.48 Hz), 6.91-6.62 (m, 6H), 4.24-4.22 (m, 2H),
3.72-3.52 (m, 1H), 3.26-2.89 (m, 8H), 2.56-2.52 (m, 1H), 1.95 (br
s, 4H); MS m/e 443 (M.sup.++1).
Example 5
[0414]
1-6-Hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-i-
soquinolin-2-yl}-2,2-dimethylpropan-1-one
[0415] A mixture of
1-{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]--
3,4-dihydro-1H-isoquinolin-2-yl}-2,2-dimethylpropan-1-one, ammonium
formate (0.033 g, 0.52 mmol), and 20% Pd(OH).sub.2/C (0.002 g) in
MeOH (10 ml) was refluxed under N.sub.2 for 1.5 hr, then filtered
to remove the catalyst. The filtrate was evaporated in vacuo to a
residue that was suspended in H.sub.2O (0.4 ml) and saturated
NaHCO.sub.3 (0.4 ml). The aqueous mixture was extracted with
CH.sub.2Cl.sub.2 (3.times.0.8 ml) and all of the combined organic
solutions were evaporated to give the crude product. Purification
by reverse-phase HPLC on a Primesphere C-18HC (50.0 mm.times.10.0
mm column with 5 .quadrature.m particle size) column, eluting with
a linear gradient starting at time 0 min. of H.sub.2O:CH.sub.3CN:1%
TFA/H.sub.2O (85:10:5), increasing to H.sub.2O:CH.sub.3CN:1%
TFA/H.sub.2O (5:90:5) at 8 min., detected on a Micromass Platform 2
mass spectrometer (DAD 190-600 nM) gave material which, after
evaporation to dryness, was purified by reverse-phase HPLC on a
Primesphere C-18HC (3.0 mm.times.2.0 mm column with 5 .quadrature.m
particle size) column, eluting with a linear gradient starting at
time 0 min. of H.sub.2O:CH.sub.3CN:TFA (99.9:0:0.1), increasing to
H.sub.2O:CH.sub.3CN:TFA (0:99.9:0.1) at 4 min., detected with a UV
detector (300 nM.+-.90 nM and 254 nM.+-.25 nM), gave an eluent that
was evaporated to dryness to give the pure product.
[0416] MS m/e 423 (M.sup.++1).
Example 6
[0417]
Cyclohexyl-{6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-di-
hydro-1H-isoquinolin-2-yl}methanone
[0418] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with cyclohexanecarbonyl
chloride.
[0419] MS m/e 539 (M.sup.++1).
[0420] The second step was performed by analogy to Example 5.
[0421] MS m/e 449 (M.sup.++1).
Example 7
[0422] 1-6-Hydroxy-l
-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-
-isoquinolin-2-yl}-3-phenyl-propan-1-one
[0423] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with cinnamoyl chloride.
[0424] MS m/e 559 (M.sup.++1).
[0425] The second step was performed by analogy to Example 5.
[0426] MS m/e 471 (M.sup.++1).
Example 8
[0427]
1-6-Hydroxy-1-[4-(2-pyrrolidin-1-yI-ethoxy)phenyl]-3,4-dihydro-1H-i-
soquinolin-2-yl}octan-1-one
[0428] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with octanoyl chloride.
[0429] MS m/e 555 (M.sup.++1).
[0430] The second step was performed by analogy to Example 5.
[0431] MS m/e 465 (M.sup.++1).
Example 9
[0432]
{6-Hydroxy-1-[4-(2-pyrrolidin-1-yI-ethoxy)phenyl]-3,4-dihydro-1H-is-
oquinolin-2-yl}naphthalen-1-yl-methanone
[0433] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with 1-naphthoyl
chloride.
[0434] MS m/e 583 (M.sup.++1).
[0435] The second step was performed by analogy to Example 5.
[0436] MS m/e 493 (M.sup.++1).
Example 10
[0437]
{6-Hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-is-
oquinolin-2-yl}-(3-methoxyphenyl)methanone
[0438] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with 3-methoxybenzoyl
chloride.
[0439] MS m/e 563 (M.sup.++1).
[0440] The second step was performed by analogy to Example 5.
[0441] MS m/e 473 (M.sup.++1).
Example 11
[0442] 3-Cyclopentyl-1
6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,-
4-dihydro-1H-isoquinolin-2-yl}propan-1-one
[0443] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with 3-cyclopentylpropionyl
chloride.
[0444] MS m/e 553 (M.sup.++1).
[0445] The second step was performed by analogy to Example 5.
[0446] MS m/e 463 (M.sup.++1).
Example 12
[0447]
1-6-Hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H--
isoquinolin-2-yl}-2,2-diphenyl-ethanone
[0448] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 8, except that
trimethylacetyl chloride was replaced with diphenylacetyl
chloride.
[0449] MS m/e 633 (M.sup.++1).
[0450] The second step was performed by analogy to Example 5.
[0451] MS m/e 533 (M.sup.++1).
Example 13
[0452]
2,2,2-Trifluoro-1-[6-hydroxy-1-(4-hydroxyphenyl)-3,4-dihydro-1H-iso-
quinolin-2-yl]ethanone
[0453] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (6.0 ml, 6.0
mmol) was added slowly to a solution of
1-[1-(4-benzyloxyphenyl)-6-methoxy-3,4--
dihydro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone (1.054 g, 2.4
mmol) in anhydrous CH.sub.2Cl.sub.2 (100 ml) at 0.degree. C. under
N.sub.2. The reaction mixture was warmed to rt and stirred at rt
for 17 hr. MeOH (50 ml) was slowly added with stirring and the
resulting solution was concentrated in vacuo to a red oil. This was
dissolved in MeOH (20 ml) and 1M HCl (20 ml), and the resulting
solution was stirred at rt for 4 hr, then neutralized with
saturated NaHCO.sub.3 solution (60 ml). The resulting suspension
was concentrated in vacuo and the remaining material was extracted
with EtOAc (4.times.30 ml). The combined extracts were dried over
MgSO.sub.4 and evaporated in vacuo to give 0.775 g of crude brown
solid. Purification by flash chromatography, eluting with
hexane:EtOAc (1:1) gave 0.080 g (10% yield) of white solid.
[0454] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.06 (d, J=8.72 Hz,
2H), 6.88 (d, J=8.30 Hz, 1H), 6.74-6.66 (m, 5H), 3.84-3.81 (m, 1H),
3.45-3.40 (m, 1H), 3.02-2.94 (m, 1H), 2.77-2.73 (m, 1H); MS m/e 336
(M.sup.+-1).
Example 14
[0455]
2,2,2-Trifluoro-1-[6-hydroxy-1-(4-hydroxyphenyl)-3,4-dihydro-1H-iso-
quinolin-2-yl]-ethanone
[0456] The racemic material obtained in Example 13 (0.72 g) was
separated on a Chiralpak AD.RTM. column (Chiral Technologies, Inc.,
Exton, Pa.), eluting with hexane:isopropanol (9:1) to give the two
separate enantiomers. The enantiomer with a retention time of 14.1
minutes was collected and evaporated in vacuo to give 0.018 g (25%
recovery) of white solid.
[0457] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.06 (d, J=8.72 Hz,
2H), 6.88 (d, J=8.30 Hz, 1H), 6.74-6.66 (m, 5H), 3.84-3.81 (m, 1H),
3.45-3.40 (m, 1H), 3.02-2.94 (m, 1H), 2.77-2.73 (m, 1H); MS m/e 336
(M.sup.30 -1).
Example 15
[0458]
2,2,2-Trifluoro-1-[1-(4-hydroxyphenyl)-3,4-dihydro-1H-isoquinolin-2-
-yl]ethanone
[0459] A mixture of
1-[1-(4-benzyloxyphenyl)-3,4-dihydro-1H-isoquinolin-2--
yl]-2,2,2-trifluoroethanone (0.144 g, 0.35 mmol), ammonium formate
(0.441 g, 7.00, mmol), and 20% Pd(OH).sub.2/C (0.100 g) in MeOH (50
ml) was refluxed under N.sub.2 for 1.5 hr, then filtered through
Celite. The filtrate was evaporated in vacuo to a yellow residue
that was suspended in a mixture of H.sub.2O (15 ml) and saturated
NaHCO.sub.3 solution (15 ml), then extracted with CHCl.sub.3
(4.times.15 ml). The combined organic extracts were dried over
MgSO.sub.4 and concentrated in vacuo to give 0.115 g of colorless
oil. Purification by flash chromatography, eluting with
hexane:EtOAc (8:2) gave 0.100 g (89% yield) of colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.29-7.16 (m, 4H),
7.09-7.00 (m, 3H), 6.77-6.72 (m, 2H), 3.96-3.91 (m, 1H), 3.52-3.44
(m, 1H), 3.14-3.05 (m, 1H), 2.90-2.86 (m, 1H);
[0460] MS m/e 320 (M.sup.+-1).
Example 16
[0461]
2,2,2-Trifluoro-1-[1-(4-hydroxyphenyl)-3,4-dihydro-1H-isoquinolin-2-
-yl]ethanone
[0462] The racemic material obtained in Example 15 (0.80 g) was
separated on a Chiralpak AD column, eluting with hexane:isopropanol
(9:1) to give the two separate enantiomers. The enantiomer with a
retention time of 9.7 minutes was collected and evaporated in vacuo
to give 0.030 g (38% recovery) of white solid.
[0463] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.29-7.16 (m, 4H),
7.09-7.00 (m, 3H), 6.77-6.72 (m, 2H), 3.95-3.91 (m, 1H), 3.51-3.43
(m, 1H), 3.14-3.05 (m, 1H), 2.90-2.85 (m, 1H);
[0464] MS m/e 320 (M.sup.+-1).
Example 17
[0465]
2,2,2-Trifluoro-1-[1-(4-hydroxyphenyl)-6-(2-pyrrolidin-1-yl-ethoxy)-
-3,4-dihydro-1H-isoquinolin-2-yl]ethanone
[0466] A solution of 1M TBAF in THF (2.8 ml, 2.82 mmol) and
toluene-4-sulfonic acid
4-[6-(2-pyrrolidin-1-yl-ethoxy)-2-trifluoroacetyl-
-1,2,3,4-tetrahydroisoquinolin-1-yl]phenyl ester (0.415 g, 0.71
mmol) in anhydrous THF (50 ml) was refluxed under N.sub.2 for 18
hr, then concentrated in vacuo to a green oil. This was suspended
in sat. NaHCO.sub.3 solution (25 ml), then extracted with EtOAc
(3.times.40 ml). The combined extracts were dried over MgSO.sub.4
and concentrated in vacuo to give 0.566 g of green oil.
Purification by flash chromatography, eluting with EtOAc:MeOH (8:2)
gave 0.241 g (79% yield) of yellow oil.
[0467] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.06-6.99 (m, 2H),
6.94-6.87 (m, 1H), 6.83 (d, J=8.51 Hz, 1H), 6.71 (d, J=8.51 Hz,
1H), 6.66 (m, 1H), 6.64-6.57 (m, 2H), 4.23-4.21 (m, 2H), 3.90-3.85
(m, 1H), 3.46-3.35 (m, 1H), 3.13 (s, 2H), 3.05-2.95 (m, 5H),
2.79-2.74 (m, 1H), 1.95 (s, 4H); MS m/e 435 (M.sup.++1).
Example 18
[0468]
2,2,2-Trifluoro-1-[1-(4-iodophenyl)-6-methoxy-3,4-dihydro-1H-isoqui-
nolin-2-yl]ethanone
[0469] Trifluoroacetic anhydride (1.76 g, 8.36 mmol) was added to a
solution of
1-(4-iodophenyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline (2.35 g,
6.44 mmol) and Et.sub.3N (1.0 ml, 7.1 mmol) in anhydrous
CH.sub.2Cl.sub.2 (50 ml) at 0.degree. C. under N.sub.2. The
resulting yellow solution was stirred at 0.degree. C. for 2 hr,
then washed first with 1M HCl (2.times.25 ml) followed by 50%
saturated NaHCO.sub.3 solution (2.times.25 ml), dried over
Na.sub.2SO.sub.4, and concentrated in vacuo to give a yellow oil.
Purification by flash chromatography, eluting with hexane:EtOAc
(6:1) gave 1.87 g (63% yield) of yellow oil.
[0470] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.62 (d, J=8.31 Hz,
2H), 6.97-6.91 (m, 3H), 6.79-6.76 (m, 1H), 6.71-6.69 (m, 2H),
3.95-3.91 (m, 1H), 3.81 (s, 3H), 3.45-3.37 (m, 1H), 3.07-3.02 (m,
1H), 2.87-2.81 (m, 1H); MS m/e 460 (M.sup.+-1).
Example 19
[0471]
2,2,2-Trifluoro-1-[6-hydroxy-1-(4-iodophenyl)-3,4-dihydro-1H-isoqui-
nolin-2-yl]ethanone
[0472] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (0.49 ml,
0.49 mmol) was added slowly to a solution of
2,2,2-trifluoro-1-[1-(4-iodophenyl)-6-m-
ethoxy-3,4-dihydro-1H-isoquinolin-2-yl]ethanone (0.150 g, 0.33
mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. under
N.sub.2. The reaction mixture was stirred at 0.degree. C. for 1 hr,
then warmed to rt and stirred at rt for 19 hr. MeOH (10 ml) was
slowly added with stirring and the resulting solution was
concentrated in vacuo to a yellow oil. Purification by flash
chromatography, eluting with hexane:EtOAc (8:2) gave 0.121 g (83%
yield) of yellow solid.
[0473] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.62 (d, J=8.51 Hz,
2H), 6.94 (d, J=8.51 Hz, 2H), 6.87 (d, J=8.30 Hz, 1H), 6.71-6.68
(m, 3H), 3.94-3.89 (m, 1H), 3.44-3.36 (m, 1H), 3.08-2.99 (m, 1H),
2.83-2.78 (m, 1H), MS m/e 446 (M.sup.+-1).
Example 20
[0474]
1-(1-Cyclohexyl-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr-
ifluoroethanone
[0475] Trifluoroacetic anhydride (0.128 g, 0.61 mmol) was added to
a solution of 1-cyclohexyl-6-methoxy-1,2,3,4-tetrahydroisoquinoline
(0.150 g, 0.61 mmol) and Et.sub.3N (0.17 ml, 0.1.22 mmol) in
anhydrous CH.sub.2Cl.sub.2 (20 ml) at 0.degree. C. under N.sub.2.
The resulting yellow solution was stirred at rt for 22 hr, washed
first with 1M HCl (5 ml) then 1M NaHCO.sub.3 (5 ml), dried over
MgSO.sub.4, and concentrated in vacuo to give 0.248 g of yellow
oil. Purification by flash chromatography, eluting with
hexane:EtOAc (19:1) gave 0.198 g (95% yield) of yellow oil.
[0476] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.02 (d, J=8.51 Hz,
1H), 6.72 (dd, J=8.51 Hz, J=2.70 Hz, 1H), 6.65 (d, J=2.49 Hz, 1H),
5.16 (d, J=9.13 Hz, 1H), 3.97-3.94 (m, 1H), 3.77 (s, 3H), 3.75-3.68
(m, 1H), 3.09-2.88 (m, 2H), 1.75 (br s, 4H), 1.11-1.02 (m, 5H);
[0477] MS m/e 342 (M.sup.++1).
Example 21
[0478]
1-(1-Cyclohexyl-6-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-tr-
ifluoroethanone
[0479] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (0.77 ml,
0.77 mmol) was added slowly to a solution of
1-(1-cyclohexyl-6-methoxy-3,4-dihydro-1-
H-isoquinolin-2-yl)-2,2,2-trifluoroethanone (0.176 g, 0.52 mmol) in
anhydrous CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. under N.sub.2.
The reaction mixture was stirred at 0.degree. C. for 30 min, then
warmed to rt and stirred at rt for 21 hr. MeOH (10 ml) was slowly
added with stirring and the resulting solution was concentrated in
vacuo to a orange oil. Purification by flash chromatography,
eluting with hexane:EtOAc (8:2) gave 0.193 g (100% yield) of white
solid.
[0480] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.6.97 (d, J=8.52 Hz,
1H), 6.66-6.60 (m, 3H), 5.15 (d, J=8.93 Hz, 1H), 4.69 (br s, 1H),
3.97-3.94 (m, 1H), 3.75-3.67 (m, 1H), 3.04-2.87 (m, 3H), 1.75 (br
s, 4H), 1.12-1.10 (m, 5H); MS m/e 326 (M.sup.+-1).
Example 22
[0481]
2,2,2-Trifluoro-1-(6-methoxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2--
yl)ethanone
[0482] Trifluoroacetic anhydride (0.089 ml, 0.627 mmol) was added
to a solution of 6-methoxy-1-phenyl-1,2,3,4-tetrahydoisoquinoline
(0.150 g, 0.627 mmol) and Et.sub.3N (0.174 ml, 1.25 mmol) in
anhydrous CH.sub.2Cl.sub.2 (20 ml) at 0.degree. C. under N.sub.2.
The resulting solution was warmed to rt and stirred at rt for 68
hr, washed with 1M HCl (5 ml), then with sat. NaHCO.sub.3 solution
(5 ml), dried over MgSO.sub.4, and concentrated in vacuo to give
0.216 g of colorless oil. Purification by flash chromatography,
eluting with hexane:EtOAc (19:1) gave 0.188 g (89% yield) of
colorless oil.
[0483] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.30-7.28 (m, 3H),
7.21-7.18 (m, 2H), 6.96 (d, J=8.72 Hz, 1H), 6.79-6.76 (m, 2H), 6.72
(s, 1H), 3.93-3.90 (m, 1H), 3.81 (s, 3H), 3.50-3.42 (m, 1H),
3.08-3.03 (m, 1H), 2.86-2.82 (m, 1H); MS m/e 334 (M.sup.+-1).
Example 23
[0484]
2,2,2-Trifluoro-1-(6-hydroxy-1-phenyl-3,4-dihydro-1H-isoquinolin-2--
yl)ethanone
[0485] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (0.77 ml,
0.77 mmol) was added slowly to a solution of
2,2,2-trifluoro-1-(6-methoxy-1-phenyl-3-
,4-dihydro-1H-isoquinoline-2-yl)ethanone (0.172 g, 0.513 mmol) in
anhydrous CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. under N.sub.2.
The resulting yellow solution was stirred at 0.degree. C. for 30
min, then warmed to rt and stirred at rt for 22 hr. MeOH (5 ml) was
slowly added to the reaction mixture with stirring and the
resulting solution was concentrated in vacuo to give 0.242 g of
yellow oil. Purification by flash chromatography, eluting with
hexane:EtOAc (8:2) gave 0.143 g (87% yield) of white solid.
[0486] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.30-7.27 (m, 3H),
7.20-7.17 (m, 2H), 6.91 (d, J=8.09 Hz, 1H), 6.76 (s, 1H), 6.70-6.74
(m, 2H), 4.76 (br s, 1H), 3.92-3.88 (m, 1H), 3.49-3.41 (m, 1H),
3.09-2.97 (m, 1H), 2.83-2.79 (m, 1H); MS m/e 320 (M.sup.+-1).
Example 24
[0487]
2,2,2-Trifluoro-1-(6-methoxy-1-thiophen-2-yl-3,4-dihydro-1H-isoquin-
olin-2-yl)ethanone
[0488] Trifluoroacetic anhydride (0.70 ml, 4.97 mmol) was added to
a solution of
6-methoxy-1-thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline (1.220 g,
4.97 mmol) and Et.sub.3N (1.39 ml, 9.94 mmol) in anhydrous
CH.sub.2Cl.sub.2 (40 ml) at 0.degree. C. under N.sub.2. The
resulting solution was warmed to rt and stirred at rt for 68 hr,
washed with 1M HCl (20 ml) followed by sat. NaHCO.sub.3 solution
(20 ml), dried over MgSO.sub.4, then concentrated in vacuo to give
1.863 g of red oil. Purification by flash chromatography, eluting
with hexane:EtOAc (19:1) gave 1.340 g (79% yield) of yellow
oil.
[0489] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.24-7.23 (m, 1H),
7.09 (d, J=8.72 Hz, 1H), 6.92-6.90 (m, 1H), 6.84-6.83 (m, 2H),
6.83-6.77 (m, 1H), 6.69 (s, 1H), 3.98-3.95 (m, 1H), 3.81 (s, 3H),
3.62-3.55 (m, 1H), 3.11-3.02 (m, 1H), 2.88-2.84 (m, 1H); MS m/e 340
(M.sup.+-1).
Example 25
[0490]
2,2,2-Trifluoro-1-(6-hydroxy-1-thiophen-2-yl-3,4-dihydro-1H-isoquin-
olin-2-yl)ethanone
[0491] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (0.66 ml,
0.66 mmol) was added slowly to a solution of
2,2,2-trifluoro-1-(6-methoxy-1-thiophen-
-2-yl-3,4-dihydro-1H-isoquinolin-2-yl)ethanone (0.150 g, 0.439
mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. under
N.sub.2. The resulting red solution was stirred at 0.degree. C. for
30 min, then warmed to rt and stirred at rt for 20 hr. MeOH (5 ml)
was slowly added to the reaction mixture with stirring and the
resulting solution was concentrated in vacuo to give 0.138 g of a
black residue. Purification by flash chromatography, eluting with
hexane:EtOAc (8:2) gave 0.006 g (4% yield) of white solid.
[0492] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.24 (s, 1H), 7.04
(d, J=8.72 Hz, 1H), 6.90-6.89 (m, 1H), 6.82 (m, 2H), 6.69 (d,
J=8.92 Hz, 1H), 6.65 (s, 1H), 3.96-3.93 (m, 1H), 3.60-3.54 (m, 1H),
3.03-3.00 (m, 1H), 2.84-2.80 (m, 1H); MS m/e 326 (M.sup.+-1).
Example 26
[0493]
1-[1-(4-Bromophenyl)-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-2,2-
,2-trifluoroethanone Trifluoroacetic anhydride (0.067 ml, 0.471
mmol) was added to a solution of
1-(4-bromophenyl)-6-methoxy-1,2,3,4-tetrahydroisoq- uinoline (0.150
g 0.471 mmol) and Et.sub.3N (0.13 ml, 0.942 mmol) in anhydrous
CH.sub.2Cl.sub.2 (20 ml) at 0.degree. C. under N.sub.2. The
resulting solution was warmed to rt and stirred at rt for 68 hr,
washed with 1M HCl (5 ml) and then with sat. NaHCO.sub.3 solution
(5 ml), dried over MgSO.sub.4, and concentrated in vacuo to give
0.220 g of yellow oil. Purification by flash chromatography,
eluting with hexane:EtOAc (19:1) gave 0.181 g (93% yield) of white
solid.
[0494] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.41 (d, J=8.51 Hz,
2H), 7.07 (d, J=8.51 Hz, 2H), 6.91 (d, J=8.51 Hz, 1H), 6.77 (dd,
J=8.30 Hz, J=2.49 Hz, 1H), 6.70 (s, 2H), 3.93-3.81 (m, 1H), 3.80
(s, 3H), 3.44-3.67 (m, 1H), 3.11-3.02 (m, 1H), 2.85-2.82 (m, 1H; MS
m/e 412, 414 bromine isotope pattern (M.sup.+-1).
Example 27
[0495]
1-[1-(4-Bromophenyl)-6-hydroxy-3,4-dihydro-1H-isoquinolin-2-yl]-2,2-
,2-trifluoroethanone
[0496] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (0.61 ml,
0.61 mmol) was added slowly to a solution of
1-[1-(4-bromophenyl)-6-methoxy-3,4-dihy-
dro-1H-isoquinolin-2-yl]-2,2,2-trifluoroethanone (0.168 g, 0.406
mmol) in anhydrous CH.sub.2Cl.sub.2 (10 ml) at 0.degree. C. under
N.sub.2. The resulting orange solution was stirred at 0.degree. C.
for 30 min, then warmed to rt and stirred at rt for 21 hr. MeOH (5
ml) was slowly added to the reaction mixture with stirring and the
resulting solution was concentrated in vacuo to give 0.201 g of
yellow residue. Purification by flash chromatography, eluting with
hexane:EtOAc (8:2) gave 0.149 g (92% yield) of white solid.
[0497] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.44-7.41 (m, 2H),
7.09-7.07 (m, 2H), 6.88 (d, J=8.10 Hz, 1H), 6.71-6.68 (m, 3H),
3.94-3.90 (m, 1H), 3.43-3.36 (m, 1H), 3.09-2.98 (m, 1H), 2.83-2.79
(m, 1H); MS m/e 400, 398 bromine isotope pattern (M.sup.+-1).
Example 28
[0498]
2-Benzenesulfonyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-te-
trahydroisoquinolin-6-ol
[0499] A mixture of
2-benzenesulfonyl-6-benzyloxy-1-[4-(2-pyrrolidin-1-yl--
ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline (0.043 g, 0.08 mmol),
ammonium formate (0.096 g, 1.52 mmol), and 20% Pd(OH).sub.2/C
(0.025 g) in MeOH (10 ml) was refluxed under N.sub.2 for 1 hr, then
filtered through Celite. The filtrate was evaporated in vacuo to a
white residue that was dissolved in CH.sub.2Cl.sub.2 (10 ml) and
washed with 1M NaOH (5 ml). The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.10 ml), and all of the combined organic
solutions were dried over MgSO.sub.4 and concentrated in vacuo to
give 0.026 g (72% yield) of colorless residue.
[0500] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.65 (d, J=8.09 Hz,
4H), 7.40-7.38 (m, 2H), 7.29 (d, J=7.47 Hz, 4H), 6.73 (d, J=8.51
Hz, 2H), 6.68 (d, J=8.09 Hz, 2H), 6.56 (d, J=9.13 Hz, 1H), 6.37 (s,
1H), 6.09 (s, 1H), 4.21 (br s, 2H), 3.69-3.65 (m, 1H), 3.1-3.13 (m,
4H), 2.48-2.44 (m, 1H), 2.35-2.29 (m, 1H), 1.96 (br s, 4H); MS m/e
479 (M.sup.+-1).
Example 29
[0501]
2-(Naphthalene-1-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1-
,2,3,4-tetrahydroisoquinolin-6-ol
[0502] A mixture of
6-benzyloxy-2-(naphthalene-1-sulfonyl)-1-[4-(2-pyrroli-
din-1-yl-ethoxy)-phenyl]-1,2,3,4-tetrahydroisoquinoline (0.012 g,
0.019 mmol), ammonium formate (0.033 g, 0.52 mmol), and 20%
Pd(OH).sub.2/C (0.002 g) in MeOH (10 ml) was refluxed under N.sub.2
for 1.5 hr, then filtered to remove the catalyst. The filtrate was
evaporated in vacuo to a residue that was suspended in a mixture of
H.sub.2O (0.4 ml) and sat. NaHCO.sub.3 (0.4 ml). The aqueous
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.0.8 ml), and
all of the combined organic solutions were evaporated to give the
crude product. Purification by reverse-phase HPLC, eluting with
gradient Primesphere C-18HC (3.0 mm.times.2.0 mm column with 5
.quadrature.m particle size) column, eluting with a linear gradient
starting at time 0 min. of H.sub.2O:CH.sub.3CN:TFA (99.9:0:0.1),
increasing to H.sub.2O:CH.sub.3CN:TFA (0:99.9:0.1) at 4 min.,
detected with a UV detector (300 nM.+-.90 nM and 254 nM .+-.25 nM),
gave an eluent that was evaporated to dryness to give the named
product. MS m/e 493 (M.sup.++1).
Example 30
[0503]
2-Phenylmethanesulfonyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,-
3,4-tetrahydroisoquinolin-6-ol
[0504] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with
.alpha.-toluenesulfonyl chloride.
[0505] MS m/e 583 (M.sup.++1).
[0506] The second step was performed by analogy to Example 29.
[0507] MS m/e 493 (M.sup.++1).
Example 31
[0508]
2-(Butane-1-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,-
4-tetrahydroisoquinolin-6-ol
[0509] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with 1-butanesulfonyl
chloride.
[0510] MS m/e 549 (M.sup.++1).
[0511] The second step was performed by analogy to Example 29.
[0512] MS m/e 459 (M.sup.++1).
Example 32
[0513]
2-Methanesulfonyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-te-
trahydroisoquinolin-6-ol
[0514] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with methanesulfonyl
chloride.
[0515] MS m/e 507 (M.sup.++1).
[0516] The second step was performed by analogy to Example 29.
[0517] MS m/e 417 (M.sup.++1).
Example 33
[0518] 2-(4-Propylbenzenesulfonyl)-1-[4-(2-pyrrolidin-1-yl
ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol
[0519] The title-compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with
p-n-propylbenzenesulfony- l chloride.
[0520] MS m/e 611 (M.sup.++1).
[0521] The second step was performed by analogy to Example 29.
[0522] MS m/e 521 (M.sup.++1).
Example 34
[0523]
2-(4-Isopropylbenzenesulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)pheny-
l]-1,2,3,4-tetrahydroisoquinolin-6-ol
[0524] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with
4-isopropylbenzenesulfon- yl chloride.
[0525] MS m/e 611 (M.sup.++1).
[0526] The second step was performed by analogy to Example 29.
[0527] MS m/e 521 (M.sup.++1).
Example 35
[0528]
1-[4-(2-Pyrrolidin-1-yl-ethoxy)phenyl]-2-(toluene-4-sulfonyl)-1,2,3-
,4-tetrahydroisoquinolin-6-ol
[0529] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with
4-methylbenzenesulfonyl chloride.
[0530] MS m/e 583 (M.sup.++1).
[0531] The second step was performed by analogy to Example 29.
[0532] MS m/e 493 (M.sup.++1).
Example 36
[0533]
2-(1-Methyl-1H-imidazole-4-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy-
)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol
[0534] The title compound was prepared in a two-step-sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with
1-methylimidazolesulfony- l chloride.
[0535] MS m/e 573 (M.sup.++1).
[0536] The second step was performed by analogy to Example 29.
[0537] MS m/e 483 (M.sup.++1).
Example 37
[0538]
N-(4-6-Hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1-
H-isoquinoline-2-sulfonyl}phenyl)acetamide
[0539] The title compound was prepared in a two-step sequence. The
first step was performed by analogy to Preparation 32, except that
1-naphthalenesulfonyl chloride was replaced with
p-acetamidobenzenesulfon- yl chloride.
[0540] MS m/e 626 (M.sup.++1).
[0541] The second step was performed by analogy to Example 29.
[0542] MS m/e 536 (M.sup.++1).
Example 38
[0543]
4-Amino-3-6-hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihy-
dro-1H-isoquinoline-2-sulfonyl}pent-3-en-2-one
[0544] A mixture of
6-benzyloxy-2-(3,5-dimethylisoxazole-4-sulfonyl)-1-[4--
(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroisoquinoline
(0.036 g, 0.061 mmol), ammonium formate (0.077 g, 1.22 mmol), and
20% Pd(OH).sub.2/C (0.020 g) in MeOH (20 ml) was refluxed under
N.sub.2 for 1.5 hr, then filtered through Celite. The filtrate was
evaporated in vacuo to a yellow residue that was suspended in a
mixture of H.sub.2O (3 ml) and sat. NaHCO.sub.3 solution (3 ml),
then extracted with CH.sub.2Cl.sub.2 (3.times.3 ml). The combined
organic extracts were dried over MgSO.sub.4 and concentrated in
vacuo to give 0.023 g (76% yield) of yellow oil. Further
purification by preparative TLC, eluting with SiO2, EtOAc:MeOH
(1:1), gave 0.019 g (63% yield) of colorless oil.
[0545] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.11.73-11.65 (m,
1H), 6.95-6.88 (m, 3H), 6.75 (d, J=8.52 Hz, 1H), 6.68 (d, J=8.10
Hz, 1H), 6.67-6.52 (m, 3H), 6.08 (br s, 1H), 5.80 (s, 1H),
4.05-4.02 (m, 2H), 3.55-3.52 (m, 1H), 3.10-2.97 (m, 2H), 2.90-2.84
(m, 1H), 2.79-2.63 (m, 4H), 2.50 (s, 1H), 2.37 (s, 3H), 2.34 (s,
3H), 1.84-1.79 (m, 4H); MS m/e 500 (M.sup.++1).
Example 39
[0546]
2-(3,5-Dimethylisoxazole-4-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy-
)phenyl]-1,2,3,4-tetrahydroisoquinolin-6-ol.
[0547] A 1M solution of BBr.sub.3 in CH.sub.2Cl.sub.2 (0.095 ml,
0.095 mmol) was added slowly to a solution of
6-benzyloxy-2-(3,5-dimethylisoxaz-
ole-4-sulfonyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroi-
soquinoline (0.037 g, 0.063 mmol) in anhydrous CH.sub.2Cl.sub.2 (10
ml) at 0.degree. C. under N.sub.2. The reaction mixture was stirred
at 0.degree. C. for 1 hr, then warmed to rt and stirred at rt for 4
hr. MeOH (5 ml) was slowly added with stirring and the resulting
solution was concentrated in vacuo to an orange residue.
Purification by preparative TLC, eluting with EtOAc:MeOH (1:1), and
then purification again by preparative TLC, eluting with EtOAc:MeOH
(8:2), gave 0.011 g (35% yield) of white solid.
[0548] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.6.99 (d, J=8.72 Hz,
2H), 6.75 (d, J=8.51 Hz, 1H), 6.69 (d, J=8.72 Hz, 2H), 6.61 (dd,
J=8.30 Hz, J=2.49 Hz, 1H), 6.51 (d, J=2.28 Hz, 1H), 6.01 (s, 1H),
4.25 (br s, 2H), 3.62-3.57 (m, 1H), 3.24-3.16 (m, 3H), 3.05 (br s,
4H), 2.66-2.57 (m, 1H), 2.52 (s, 3H), 2.47-2.42 (m, 1H), 2.18 (s,
3H), 2.00 (br s, 4H); MS m/e 498 (M.sup.++1).
Example 40
[0549]
2-(4-Imidazol-1-yl-benzyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1-
,2,3,4-tetrahydroisoquinolin-6-ol
[0550] A solution of
1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrah-
ydroisoquinolin-6-ol (0.023 g, 0.067 mmol),
4-imidazol-1-yl-benzaldehyde (0.011 g, 0.063 mmol), NaOAc (0.011 g,
0.14 mmol), and sodium cyanoborohydride (0.004 g, 0.063 mmol) in
MeOH (2.0 ml) was stirred at rt for 18 hr. The reaction mixture was
evaporated in vacuo to a yellow residue that was dissolved in EtOAc
(5 ml) and washed first with sat. NaHCO.sub.3 solution (5 ml) and
then with H.sub.2O (5 ml). The organic solution was dried over
MgSO.sub.4 and evaporated to give 0.035 g of yellow residue.
Purification by preparative TLC, eluting with EtOAc:MeOH (7:3),
gave 0.007 g (23% yield) of white solid.
[0551] MS m/e 495 (M.sup.++1).
Example 41
[0552]
2-Benzo[1,3]dioxol-5-ylmethyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl-
]-1,2,3,4-tetrahydroisoquinolin-6-ol
[0553] The title compound was prepared by analogy to Example 40,
except that 3,4-(methylenedioxy)benzaldehyde was used in place of
4-imidazol-1-yl-benzaldehyde.
[0554] MS m/e 473 (M.sup.++1).
Example 42
[0555]
1-[4-(2-Pyrrolidin-1-yl-ethoxy)phenyl]-2-(tetrahydropyran-4-yI)-1,2-
,3,4-tetrahydroisoquinolin-6-ol
[0556] The title compound was prepared by analogy to Example 40,
except that tetrahydro-4H-pyran-4-one was used in place of
4-imidazol-1-yl-benzaldehyde.
[0557] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.14 (d, J=8.52 Hz,
2H), 6.81-6.79 (m, 1H), 6.75 (d, J=8.52 Hz, 2H), 6.57 (s, 1H),
6.53-6.47 (m, 1H), 4.80 (s, 1H), 4.28 (br s, 4.00-3.97 (m, 1H),
3.91-3.89 (m, 1H), 3.26-3.18 (m, 5H), 3.11-3.08 (m, 2H), 2.73-2.65
(m, 3H), 2.00 (s, 6H), 1.80-1.77 (m, 3H), 1.60-1.57 (m, 2H),
1.43-1.20 (m, 1H);
[0558] MS m/e 423 (M.sup.++1).
Example 43
[0559]
2-(4,4-Dimethylcyclohexyl)-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1-
,2,3,4-tetrahydroisoquinolin-6-ol
[0560] The title compound was prepared by analogy to Example 40,
except that 4,4-dimethyl-2-cyclohexene-1-one was used in place of
4-imidazol-1-yl-benzaldehyde.
[0561] MS m/e 449 (M.sup.++1).
Example 44
[0562]
2-Cyclohexyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahy-
droisoquinolin-6-ol
[0563] The title compound was prepared by analogy to Example 40,
except that cyclohexanone was used in place of
4-imidazol-1-yl-benzaldehyde.
[0564] MS m/e 421 (M.sup.++1).
Example 45
[0565]
2-Benzyl-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-1,2,3,4-tetrahydroi-
soquinolin-6-ol
[0566] The title compound was prepared by analogy to Example 40,
except that benzaldehyde was used in place of
4-imidazol-1-yl-benzaldehyde.
[0567] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.33-7.21 (m, 9H),
6.76 (d, J=8.51 Hz, 1H), 6.55-6.47 (m, 2H), 4.45 (s, 1H), 4.19 (br
s, 2H), 3.76 (d, J=13.70 Hz, 1H), 3.17 (d=13.70 Hz, 1H), 3.04-2.87
(m, 9H), 2.66 (d, J=16.39 Hz, 1H), 2.47-2.43 (m, 1H), 1.91 (br s,
4H); MS m/e 429 (M.sup.++1).
Example 46
[0568]
6-Hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-iso-
quinoline-2-carboxylic acid tert-butyl ester
[0569] The title compound was prepared by analogy to Example 4,
except that
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-i-
soquinoline-2-carboxylic acid tert-butyl ester was used in place of
{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-isoqu-
inolin-2-yl}phenylmethanone.
[0570] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.22-7.06 (m, 3H),
6.81-6.77 (m, 1H), 6.73 (d, J=8.72 Hz, 1H), 6.63-6.61 (m, 1H),
6.30-6.08 (m, 2H), 4.26 (br s, 2H), 3.97-3.93 (m, 1H), 3.17-2.84
(m, 8H), 2.60-2.56 (m, 1H), 1.98 (br s, 4H), 1.47 (s, 9H); MS m/e
439 (M.sup.++1).
Example 47
[0571]
6-Hydroxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)phenyl]-3,4-dihydro-1H-iso-
quinoline-2-carboxylic acid ethyl ester
[0572] The title compound was prepared by analogy to Example 4,
except that
6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-i-
soquinoline-2-carboxylic acid ethyl ester was used in place of
{6-benzyloxy-1-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3,4-dihydro-1H-isoqu-
inolin-2-yl}phenylmethanone.
[0573] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.7.16-7.14 (m, 1H),
7.03 (br s, 2H), 6.77 (d, J=8.51 Hz, 1H), 6.65 (d, J=8.72 Hz, 2H),
6.59-6.57 (m, 2H), 4.14 (br s, 4H), 3.96-3.90 (m, 2H), 3.10-3.03
(m, 3H), 2.84 (br s, 5H), 2.50 (d, J=16.19 Hz, 1H), 1.89 (br s,
4H), 1.26 (br s, 3H); MS m/e 411 (M.sup.++1).
Example 48
[0574]
1-(4-Hydroxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0575] To a stirred solution of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,-
2,3,4-tetrahydroisoquinoline (0.075 g, 0.217 mmol, 1.0 eq.) in
CH.sub.2Cl.sub.2 (3 ml) cooled to -78 .degree. C. under an
atmosphere of N.sub.2 was added BBr.sub.3 as a 1.0 M solution in
CH.sub.2Cl.sub.2 (0.65 ml, 0.65 mmol, 3.0 eq.). The reaction was
stirred overnight, slowly allowing the reaction mixture to warm to
rt. The reaction was quenched with MeOH (2 ml) and stirring was
continued for 1 hour. The mixture was diluted with EtOAc (20 ml),
water (2 ml), and sat. NaHCO.sub.3 (2 ml, until the pH of the
aqueous layer was approximately 8). The layers were separated and
the aqueous layer diluted with water (10 ml), then extracted with
EtOAc (2.times.20 ml) and CH.sub.2Cl.sub.2 (2.times.20 ml). The
combined organics were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was subjected to flash
chromatography (SiO.sub.2, hexanes:EtOAc 3:2) to give the desired
compound (0.053 g, 0.167 mmol, 77% yield).
[0576] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.85 (2H,
m,) 3.41 (1H, m), 3.62 (1H, m), 5.74 (1H, s) 6.62-7.14 (12H,
overlapping m).
Example 49
[0577]
1-Cyclohexyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
[0578] A stirred solution of cyclohexanecarboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-amide in POCl.sub.3 under an
atmosphere of N.sub.2 was heated at reflux for 14 hours. The
solution was allowed to cool to rt and concentrated in vacuo. The
residue was taken up in CH.sub.2Cl.sub.2 (30 ml) and washed with
sat. NaHCO.sub.3 until CO.sub.2 evolution ceased. The organic layer
was dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
residue was dissolved in MeOH (20 ml), cooled to 0.degree. C., and
NaBH.sub.4 (0.105 g, 2.77 mmol) was added in a portionwise manner.
The reaction was stirred for 2 hours at 0.degree. C., then
additional NaBH.sub.4 (0.105 g, 2.77 mmol) was added. The reaction
was stirred at rt overnight, diluted with CH.sub.2Cl.sub.2 (50 ml),
and washed with sat. NaHCO.sub.3 solution (1.times.50 ml). The
organic layer was dried over MgSO.sub.4, filtered, and concentrated
in vacuo, to give the desired compound as a yellow oil (0.234 g,
0.729 mmol, 73% yield).
[0579] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 0.84-1.18
(6H, overlapping m,) 1.58-1.76 (4H, overlapping m), 1.95 (1H, m),
2.95 (2H, m), 3.43 (1H, m), 3.69 (1H, m), 3.76 (3H, s), 4.35 (1H,
d, J 8.0 Hz), 6.64-7.23 (8H, overlapping m). MS 322 (M+1)
Example 50
[0580] 1-Cyclohexyl-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0581] The title compound was prepared by analogy to Example 48
except that
1-cyclohexyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was
used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydr-
oisoquinoline, and hexanes:EtOAc 6:1 was used as eluent for flash
chromatography purification.
[0582] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 0.90-1.15
(6H, overlapping m,) 1.60-1.70 (4H, overlapping m), 1.93 (1H, m),
2.90 (2H, m), 3.41 (1H, m), 3.66 (1H, m), 4.11 (1H, d, J 7.5 Hz),
4.98 (1H, broad s), 6.55-6.59 (2H, overlapping m), 6.65 (1H, t, J
7.0 Hz), 6.82 (2H, d, J 8.5 Hz), 6.90 (1H, d, J 8.0 Hz) and
7.17-7.23 (2H, overlapping m). MS 308 (M+1).
Example 51
[0583]
1-Isopropyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
[0584] The title compound was prepared by analogy to Preparation 65
except that N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-isobutyramide
was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and
the final residue was not subjected to flash chromatography.
[0585] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 0.92 (3H, d,
J 6.5 Hz), 1.05 (3H, d, J 7.0 Hz), 2.11 (1H, m), 2.95 (2H, m), 3.42
(1H, m), 3.70 (1H, m), 3.76 (3H, s), 4.32 (1H, d, J 8.0 Hz) and
6.73-7.23 (8H, overlapping m). MS 282 (M+1).
Example 52
[0586] 1-lsopropyl-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0587] The title compound was prepared by analogy to Example 48
except that
1-isopropyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was
used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydr-
oisoquinoline, and hexanes:EtOAc 6:1 was used as eluent for flash
chromatography purification.
[0588] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 0.90 (3H, d,
J 6.5 Hz), 1.02 (3H, d, J 7.0 Hz), 2.06 (1H, m,), 2.90 (2H, m),
3.42 (1H, m), 3.66 (1H, m), 4.29 (1H, d, J 8.0 Hz), 4.77 (1H, s)
and 6.56-7.23 (8H, overlapping m). MS 268 (M+1).
Example 53
[0589] 1,2-Diphenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0590] The title compound was prepared by analogy to Example 48
except that 6-methoxy-1,2-diphenyl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoq-
uinoline, and hexanes:EtOAc 6:1 was used as eluent for flash
chromatography purification.
[0591] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.84 (2H,
m), 3.45 (1H, m), 3.65 (1H, m), 4.98 (1H, broad s), 5.74 (1H, s),
6.56-7.24 (13H, overlapping m). MS 302 (M+1).
Example 54
[0592]
3-[4-(6-Methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yI)-phenyl-
]-E-acrylic acid methyl/ethyl ester
[0593] The title compound was prepared by analogy to Preparation 65
except that
3-(4-{[2-(3-methoxy-phenyl)-ethyl]-phenyl-carbamoyl}-phenyl)-E-acryl-
ic acid ethyl ester was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-- ethyl]-N-phenyl-benzamide. This
compound was obtained as an approximately 1:1 mixture of methyl and
ethyl esters (as determined by thin layer chromatography and mass
spectrometry) due to transesterification.
[0594] MS 400 (R=Me, M+1) and 414 (R=Et, M+1).
Example 55
[0595]
-3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phen-
yl]-E-acrylic acid methyl/ethyl esters
[0596] The title compound was prepared by analogy to Example 48
except that
E-3-[4-(6-methoxy-2-phenyl-1,2,3,4-tetrahydro-isoquinolin-1-yl)-phen-
yl]-acrylic acid methyl/ethyl esters was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinoline,
and hexanes:EtOAc 3:1 was used as the eluent for flash
chromatography purification.
Example 56
[0597]
3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenyl-
]-E-acrylic acid methyl ester
[0598] To 5 ml of the crude mixture of
E-3-[4-(6-hydroxy-2-phenyl-1,2,3,4--
tetrahydroisoquinolin-1-yl)-phenyl]-acrylic acid methyl/ethyl
esters (0.045 g) in MeOH (see Ex. 55) was added a catalytic amount
of NaOMe (prepared by dissolving Na in MeOH) as a solution in MeOH
(1 ml). The reaction was stirred at rt for 36 hours. The pH of the
solution was adjusted to about 7 to 8 with 1N HCl and the product
was extracted with CH.sub.2Cl.sub.2:EtOAc (4:1, 3.times.15 ml). The
combined organics were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The residue was subjected to flash
chromatography (SiO.sub.2, hexanes:EtOAc 3:1) to give the desired
product (0.012 g, 27% yield). .sup.1 H NMR (400 MHz, CDCl.sub.3)
.delta..sub.H 2.84 (2H, m), 3.44 (1H, m), 3.64 (1H, m), 3.76 (3H,
s), 5.71 (1H, s), 6.34 (1H, d, J 16.0 Hz), 6.63-6.80 (5H,
overlapping m) 7.08-7.35 (5H, overlapping m), 7.36 (2H, d, J 8.5
Hz) and 7.60 (1H, d, J 16.0 Hz). MS 386 (M+1).
Example 57
[0599]
3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phenyl-
]-E-acrylic acid
[0600] To a solution of
3-[4-(6-hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquin-
olin-1-yl)-phenyl]-E-acrylic acid methyl/ethyl esters (0.045 g,
0.115 mmol, 1.0 eq.) in THF (2 ml) was added NaOH (0.009 g, 0.230
mmol, 2.0 eq.) as a solution in water (0.2 ml). Water (1.0 ml) was
added and the reaction mixture was stirred at rt for 12 hours. The
mixture was diluted with water (5 ml) and acidified to a pH of
about 5. The aqueous mixture was extracted with
CH.sub.2Cl.sub.2:EtOAc (4:1, 4.times.25 ml). The combined organics
were dried over MgSO.sub.4, filtered, and concentrated in vacuo.
The residue was subjected to flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2:MeOH 10:1) to give the desired compound (0.035 g,
0.0945 mmol, 82% yield).
[0601] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.87 (2H,
m), 3.47 (1H, m), 3.68 (1H, m), 5.75 (1H, s), 6.37 (1H, d, J 16.0
Hz), 6.65-6.83 (5H, overlapping m), 7.13 (1H, d, J 8.0 Hz),
7.21-7.28 (4H, overlapping m), 7.42 (2H, d, J 8.5 Hz) and 7.72 (1H,
d, J 16.0 Hz). MS 372 (M+H).
Example 58
[0602]
1-Benzyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
[0603] The title compound was prepared by analogy to Preparation 65
except that N-[2-(3-methoxy-phenyl)-ethyl]-2,N-diphenyl-acetamide
was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and
the final residue was not subjected to flash chromatography.
[0604] MS 330 (M+1).
Example 59
[0605] 1-Benzyl-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0606] The title compound was prepared by analogy to Example 48
except that
1-benzyl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline was used
instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoq-
uinoline, and hexanes:EtOAc 6:1 was used as eluent for flash
chromatography purification.
[0607] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.68 (1H,
m), 2.67 (1H, m), 2.94 (1H, dd, 13.5 and 7.5 Hz), 3.21 (1H, dd, J
13.5 and 5.5 Hz), 3.49 (1H, m), 3.58 (1H, m), 4.83 (1H, dd, J 7.5
and 5.5 Hz), 5.18 (1H, broad s), 6.47-6.58 (3H, overlapping m),
6.74 (1H, t, J 7.5 Hz), 6.84 (2H, d, J 8.0 Hz), 7.00 (2H, dd, 7.0
and 1.5 Hz) and 7.17-7.26 (5H, overlapping m). MS 314 (M+1).
Example 60
[0608]
6-Methoxy-2-phenyl-1-thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline
[0609] The title compound was prepared by analogy to Preparation 65
except that thiophene-2-carboxylic acid
(2-(3-methoxy-phenyl)-ethyl]-phenyl-amid- e was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-be- nzamide, and
the final residue was not subjected to flash chromatography.
[0610] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.90 (1H,
m), 2.98 (1H, m), 3.54 (1H, m), 3.60 (1H, m), 3.80 (3H, s), 5.99
(1H, s) and 6.67-7.27 (11H overlapping m). MS 321 (M).
Example 61
[0611]
2-Phenyl-1-thiophen-2-yl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0612] The title compound was prepared by analogy to Example 48
except that
6-methoxy-2-phenyl-1-thiophen-2-yl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetra-
hydroisoquinoline, and hexanes:EtOAc from 4:1 to 1:1 was used as
eluent for flash chromatography purification.
[0613] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.84 (1H,
m), 2.91 (1H, m), 3.50 (1H, m), 3.56 (1H, m), 5.96 (1H, s),
6.61-6.67 (3H, overlapping m), 6.76-6.84 (2H overlapping m), 6.91
(2H, d J 7.5 Hz), 7.09 (2H, m) and 7.23 (2H, m). MS 308 (M+H).
Example 62
[0614]
6-Methoxy-1-naphthalen-2-yl-2-phenyl-1,2,3,4-tetrahydroisoquinoline
[0615] The title compound was prepared by analogy to Preparation 65
except that naphthalene-2-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-am- ide was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-- benzamide, and
the final residue was not subjected to flash chromatography.
[0616] MS (M) 365.
Example 63
[0617]
1-Naphthalen-2-yl-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0618] The title compound was prepared by analogy to Example 48
except that
6-methoxy-1-naphthalen-2-yl-2-phenyl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetra-
hydroisoquinoline, and neat CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 was used as eluent for flash chromatography
purification.
[0619] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 2.86 (2H,
m), 3.44 (1H, m), 3.65 (1H, m), 5.87 (1H, s), 6.60-6.68 (3H,
overlapping m), 6.87 (2H, d J 8.0 Hz), 7.12 (3H, m), 7.37 (3H, m),
7.51 (1H, s) and 3H, m). MS 352 (M+1).
Example 64
[0620]
6-Methoxy-2-phenyl-1-(3,4,5-trifluoro-phenyl)-1,2,3,4-tetrahydroiso-
quinoline
[0621] The title compound was prepared by analogy to Preparation 65
except that
3,4,5-trifluoro-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide
was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-ben- zamide, and
the final residue was not subjected to flash chromatography.
[0622] MS 369 (M+1).
Example 65
[0623]
2-Phenyl-1-(3,4,5-trifluoro-phenyl)-1,2,3,4-tetrahydroisoquinolin-6-
-ol
[0624] The title compound was prepared by analogy to Example 48
except that
6-methoxy-2-phenyl-1-(3,4,5-trifluoro-phenyl)-1,2,3,4-tetrahydroisoq-
uinoline was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3-
,4-tetrahydroisoquinoline, and neat CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 was used as eluent for flash chromatography
purification.
[0625] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 2.83 (2H,
m), 3.38 (1H, m), 3.59 (1H, m), 5.70 (1H, s) and 6.61-7.18 (1 OH,
overlapping m). MS 356 (M+1).
Example 66
[0626]
1-(4-Chloro-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0627] The title compound was prepared by analogy to Example 48
except that
1-(4-chloro-phenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-
e was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetr-
ahydroisoquinoline, and neat CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 was used as eluent for flash chromatography
purification.
[0628] .sup.1H NMR (400 MHz, CD.sub.3OD) 8H 2.83 (2H, m), 3.37 (1H,
m), 3.58 (1H, m), 5.71 (1H, s) and 6.62-7.18 (12H, overlapping m).
MS 336/338 (M+1).
Example 67
[0629]
6-Methoxy-2-phenyl-1-thiazol-2-yl-1,2,3,4-tetrahydroisoquinoline
[0630] The title compound was prepared by analogy to Preparation 65
except that thiazole-2-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-amide was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-ben- zamide, and
the final residue was not subjected to flash chromatography.
[0631] MS 322 (M+1).
Example 68
[0632]
2-Phenyl-1-thiazol-2-yl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0633] The title compound was prepared by analogy to Example 48
except that
6-methoxy-2-phenyl-1-thiazol-2-yl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydr-
oisoquinoline, and neat CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 was used as eluent for flash chromatography
purification.
[0634] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.93 (1H,
m), 3.01 (1H, m), 3.40 (1H, m), 3.77 (1H, m), 5.94 (1H, s),
6.59-6.86 (5H, overlapping m), 7.12 (1H, d J 3.0 Hz), 7.16-7.27
(3H, overlapping m) and 7.64 (1H, d J 3.0 Hz). MS 309 (M+1).
Example 69
[0635]
1-Adamantan-1-yl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
[0636] The title compound was prepared by analogy to Preparation 65
except that adamantane-1-carboxylic acid
[2-(3-methoxy-phenyl)-ethyl]-phenyl-ami- de was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-b- enzamide, and
the final residue was subjected to flash chromatography using
hexanes:EtOAc from 20:1 to 10:1.
[0637] MS (M) 373.
Example 70
[0638]
1-Adamantan-1-yl-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0639] The title compound was prepared by analogy to Example 48
except that
1-adamantan-1-yl-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetra-
hydroisoquinoline, and neat CH.sub.2Cl.sub.2 to 10%
MeOH/CH.sub.2Cl.sub.2 was used as eluent for flash chromatography
purification.
[0640] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 1.54-2.10
(15H, overlapping m), 2.86(1H, m), 3.06 (1H, m), 33.38 (1H, m),
3.84 (1H, m), 4.45(1H, s) and 6.50-7.19 (8H, overlapping m). MS 360
(M+1).
Example 71
[0641]
6-Methoxy-2-phenyl-1-pyridin-4-yl-1,2,3,4-tetrahydroisoquinoline
[0642] The title compound was prepared by analogy to Preparation 65
except that N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-isonicotinamide
was used instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and
the final residue was subjected to flash chromatography using
hexanes:EtOAc from 4:1 to 2:1.
[0643] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.82(1H, m),
2.90 (1H, m), 3.47 (1H, m), 3.66 (1H, m), 3.79 (3H, s), 5.70 (1H,
s), 5.70 (1H, s), 6.71-6.80(5H, overlapping m), 7.18-7.25 (5H,
overlapping m) and 8.46 (2H, m). MS 317 (M+1).
Example 72
[0644]
2-Phenyl-1-pyridin-4-yl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0645] The title compound was prepared by analogy to Example 48
except that
6-methoxy-2-phenyl-1-pyridin-4-yl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetrahydr-
oisoquinoline, and hexanes:EtOAc from 4:1 to 1:1 was used as eluent
for flash chromatography purification.
[0646] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 2.84 (2H,
overlapping m), 3.38 (1H, m), 3.65 (1H, m), 5.77 (1H, s), 6.60-6.71
(4H, overlapping m), 6.79 (2H, d, J 8.0 Hz), 7.15 (4H, m), 7.28
(2H, m) and 8.34 (1H, broad s). MS 303 (M+1).
Example 73
[0647]
1-(4-Iodo-phenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
[0648] The title compound was prepared by analogy to Preparation 65
except that
4-iodo-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide was used
instead of
4-methoxy-N-[2-(3-methoxy-phenyl)-ethyl]-N-phenyl-benzamide, and
the final residue was subjected to flash chromatography using a
gradient from neat CH.sub.2Cl.sub.2 to CH.sub.2Cl.sub.2:MeOH
60:1.
[0649] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.83 (2H,
m,) 3.42 (1H, m), 3.62 (1H, m), 3.75 (3H, s), 5.65 (1H, s)
6.67-6.80 (5H, overlapping m), 6.94 (2H, d, J 8.5 Hz), 7.08-7.11
(3H, overlapping m) and 7.50 (2H, d, J 8.5 Hz). MS 442 (M+1).
Example 74
[0650]
1-(4-Iodo-phenyl)-2-phenyl-1,2,3,4-tetrahydroisoquinolin-6-ol
[0651] The title compound was prepared by analogy to Example 48
except that
1-(4-iodo-phenyl)-6-methoxy-2-phenyl-1,2,3,4-tetrahydroisoquinoline
was used instead of
6-methoxy-1-(4-methoxy-phenyl)-2-phenyl-1,2,3,4-tetra-
hydroisoquinoline, and CH.sub.2Cl.sub.2:MeOH in a gradient from
20:1 to 9:1 was used as eluent for flash chromatography
purification.
[0652] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.80 (2H,
m,) 3.43 (1H, m), 3.61 (1H, m), 5.65 (1H, s) 6.62-6.65 (2H,
overlapping m), 6.74-6.81 (3H, overlapping m), 6.94 (2H, d, J 8.5
Hz), 7.05 (1H, m), 7.18-7.22 (2H, overlapping m) and 7.51 (2H, d, J
8.5 Hz). MS 428 (M+1).
Example 75
[0653]
E-3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phen-
yl]-1-piperidin-1-yl-propenone
[0654] To a stirred solution of piperidine (0.61 ml, 6.19 mmol, 1.0
eq.) and Et.sub.3N (2.58 ml, 18.6 mmol, 3.0 eq.) in toluene (10 ml)
was added acryloyl chloride (1.14 g, 12.4 mmol, 2.0 eq.) in a
dropwise manner. The reaction was stirred overnight at RT. The
reaction mixture was diluted with CH.sub.2Cl.sub.2 (20 ml) and
washed sequentially with 1N HCl (1.times.20 ml) and sat.
NaHCO.sub.3 (1.times.20 ml). The organic layer was dried over
MgSO.sub.4, filtered, and concentrated in vacuo. The resulting
material (1-piperidin-1-yl-propenone) was used without
purification.
[0655] To a stirred solution of
1-(4-iodo-phenyl)-2-phenyl-1,2,3,4-tetrahy- droisoquinolin-6-ol
(0.100 g, 0.234 mmol, 1.0 eq.), 1-piperidin-1-yl-propenone (0.043
g, 0.351 mmol, 1.5 eq.), and Et.sub.3N (0.163 ml, 1.17 mmol, 5.0
eq.) in dry DMF (2 ml) under an atmosphere of N.sub.2 was added
Pd(PPh.sub.3).sub.4 (0.013 g, 11.3 .mu.mol, 0.05 eq.). The reaction
mixture was heated to 100.degree. C. overnight. The reaction
mixture was allowed to cool to RT, diluted with water (10 ml), and
extracted with EtOAc (2.times.10 ml). The combined organics were
dried over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo.
The residue was subjected to flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2 to CH.sub.2Cl.sub.2:MeOH 19:1) to give the desired
compound.
[0656] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 1.53-1.64
(6H, overlapping m), 2.77 (2H, m), 3.44-3.62 (6H, overlapping m),
5.68 (1H, s), 6.19-7.64 (14H, overlapping m). MS 439 (M+1).
Example 76
[0657]
E-3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phen-
yl]-acrylamide
[0658] To a stirred solution of
1-(4-iodo-phenyl)-2-phenyl-1,2,3,4-tetrahy- droisoquinolin-6-ol
(0.100 g, 0.234 mmol), triethylamine (0.163 ml, 1.17 mmol), and
acrylamide (0.082 g, 0.351 mmol) in DMF (2 ml), under an atmosphere
of N.sub.2, was added Pd(PPh.sub.3).sub.4 (0.014 g, 0.012 mmol).
The solution was heated to 100.degree. C. overnight, then cooled to
RT and diluted with water (20 ml). The aqueous mixture was
extracted with EtOAc (3.times.10 ml). The combined organics were
dried over MgSO.sub.4, filtered, and concentrated in vacuo. The
residue was subjected to flash chromatography (SiO.sub.2, 5%
MeOH/CH.sub.2Cl.sub.2) to give the desired product (0.030 g, 0.089
mmol, 35% yield).
[0659] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 2.80 (2H,
m,), 3.19 (1H, m), 3.42 (1H, m) 5.67(1H, s), 5.88 (1H, br s), 6.17
(1H, br s), 6.38 (1H, d, J 15.5 Hz), 6.67-6.78 (5H, overlapping m),
7.04-7.32 (7H, overlapping m) and 7.52 (1H, d, 15. 5 Hz). MS 371
(M+1).
Example 77
[0660]
E-3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phen-
yl]-1-morpholin-4-yl-propenone
[0661] The title compound was prepared by analogy to Example 75
except that morpholine was used instead piperidine.
[0662] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 3.10 (2H,
m), 3.56-3.74 (10H, overlapping m), 5.71 (1H, s), 6.49-7.67 (14H,
overlapping m). MS 441 (M+1).
Example 78
[0663]
E-3-[4-(6-Hydroxy-2-phenyl-1,2,3,4-tetrahydroisoquinolin-1-yl)-phen-
yl]-N,N-dimethyl-acrylamide
[0664] The title compound was prepared by analogy to Example 75
except that dimethylamine was used instead piperidine.
[0665] MS 399 (M+1).
Example 79
[0666]
2,2,2-Trifluoro-1-{6-methoxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl-
)-piperidin-4-yl]-3,4-dihydro-1H-isoquinolin-2-yl}-ethanone
[0667] To a stirred solution of 6-methoxy-1-[1-(1-methyl-i
H-imidazole-4-sulfonyl)-piperidin-4-yl]-1,2,3,4-tetrahydroisoquinoline
(0.049 g, 0.126 mmol) and triethylamine (0.135 g, 0.132 mmol) in
CH.sub.2Cl.sub.2 (5 ml) cooled to 0.degree. C. under an atmosphere
of N.sub.2 was added trifluoroacetic acid anhydride (0.028 g, 0.132
mmol). The reaction mixture was stirred overnight, slowly warming
to RT. The reaction was quenched by the addition of water (1 ml)
and diluted with CH.sub.2Cl.sub.2 (5 ml). The layers were separated
and the organic layer was further diluted with CH.sub.2Cl.sub.2 (15
ml), washed with sat. NaHCO.sub.3 (2.times.3 ml) and brine
(1.times.3 ml), dried over MgSO.sub.4, filtered, and concentrated
in vacuo. The residue was purified by radial chromatography
(SiO.sub.2, 1 mm CH.sub.2Cl.sub.2 to 2% MeOH/CH.sub.2Cl.sub.2) to
give the desired product as an oil (0.043 g, 0.088 mmol, 71%
yield).
[0668] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 1.41-1.80
(5H, overlapping m), 2.53 (2H, m), 2.92 (2H, m), 3.68 (1H, m), 3.73
(3H, s), 3.77 (3H, s), 3.90 (3H, m), 5.23 (1H, d, J 8.0 Hz),
6.65-7.00 (3H, m), 7.39 (1H, d, J 1.5 Hz), and 7.45 (1H, d, J 1.5
Hz).
Example 80
[0669]
2,2,2-Trifluoro-1-{6-hydroxy-1-[1-(1-methyl-1H-imidazole-4-sulfonyl-
)-piperidin-4-yI]-3,4-dihydro-1H-isoquinolin-2-yl}-ethanone
[0670] To a stirred solution of
2,2,2-trifluoro-1-{6-methoxy-1-[1-(1-methy-
l-1H-imidazole-4-sulfonyl)-piperidin-4-yl]-3,4-dihydro-1H-isoquinolin-2-yl-
}-ethanone (0.036 g, 0.074 mmol) in CH.sub.2Cl.sub.2 (3 ml) under
an atmosphere of N.sub.2 cooled to -78.degree. C. was added boron
tribromide as a 1.0 M solution in CH.sub.2Cl.sub.2 (0.3 ml, 0.3
mmol). The reaction mixture was stirred overnight slowly, while
allowing it to warm to RT. MeOH (1 ml) was added to the reaction
mixture and stirring was continued at RT for 10 minutes. Sat.
NaHCO.sub.3 was added to the reaction mixture until the pH of the
aqueous layer was 7. The mixture was then extracted with EtOAc
(3.times.20 ml), the combined organics were washed with brine
(1.times.20 ml), dried over MgSO.sub.4, filtered, and concentrated
in vacuo to give the desired product as an off white solid (0.028
g, 0.059 mmol, 80% yield).
[0671] MS 473 (M+1).
Example 81
[0672]
2-Benzyl-7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoquinol-
ine
[0673] To a solution of
2-[benzyl-(3-methoxy-benzyl)-amino]-1-(4-methoxy-p- henyl)-ethanol
(16.23 g, 43.0 mmol, see Preparation 63) in CH.sub.2Cl.sub.2 (280
ml) was added TFA (40.0 g, 27.0 ml, 350 mmol). The mixture was
refluxed overnight. The reaction mixture was allowed to cool to RT
and poured onto ice-water containing sat. NaHCO.sub.3 (250 ml). The
mixture was extracted with CH.sub.2Cl.sub.2 (3.times.150 ml) and
the combined organics were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. Flash chromatography (SiO.sub.2, gradient
elution 10-40% EtOAc/Hexanes) of the residue afforded the title
product (7.67 g, 21.3 mmol, 50% yield).
[0674] .sup.1H NMR (400 MHIz, CDCl3) .delta..sub.H 2.60 (1H, m),
3.03 (1H, m), 3.67 (2H, m), 3.77 (3H, s), 4.13 (1H, m), 6.54 (1H, d
J 2.5 Hz), 6.62 (1H, dd, J 8.5 and 2.5 Hz), 6.78 (3H, m), 7.08 (2H,
d, J 8.5 Hz) and 7.73-7.28 (5H, m). MS 360 (M+1).
Example 82
[0675]
2,2,2-Trifluoro-1-[7-methoxy4-(4-methoxy-phenyl)-3,4-dihydro-1H-iso-
quinolin-2-yI]-ethanone
[0676] To a solution of
7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroi- soquinoline
(1.43 g, 5.31 mmol, see Preparation 64) and Et.sub.3N (1.08 g, 10.6
mmol) in CH.sub.2Cl.sub.2 (50 ml) cooled to 0.degree. C. was added
trifluoroacetic anhydride (1.89 g, 1.27 ml, 9.03 mmol). The
reaction was stirred at 0.degree. C. for 4 hours, then the reaction
mixture was poured into sat. NaHCO.sub.3 (50 ml). The mixture was
extracted with CH.sub.2Cl.sub.2 (3.times.50 ml). The organics were
combined, dried over MgSO.sub.4, filtered, and concentrated in
vacuo. Flash chromatography (Biotage, SiO.sub.2, 10% EtOAc/hexanes)
gave the title product (1.74 g, 4.76 mmol, 90% yield).
[0677] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta..sub.H 3.69-3.75
(1H, m), 3.78 (3H, s), 3.79 (3H, s), 4.00-4.18 (2H, m), 4.72-4.99
(2H, m), 6.65-6.75 (2H, m), 6.81-6.87 (3H, m) and 6.98-7.02 (2H,
m). MS 366 (M+1).
Example 83
[0678]
2,2,2-Trifluoro-1-[7-hydroxy4-(4-hydroxy-phenyl)-3,4-dihydro-1H-iso-
quinolin-2-yl]-ethanone
[0679] To a solution of
2,2,2-trifluoro-1-[7-methoxy-4-(4-methoxy-phenyl)--
3,4-dihydro-1H-isoquinolin-2-yl]-ethanone (1.74 g, 4.76 mmol, see
Example 82) in CH.sub.2Cl.sub.2 (100 ml) cooled to 0.degree. C. was
added BBr.sub.3 as a 1.0 M solution in CH.sub.2Cl.sub.2 (14.28 ml,
14.28 mmol) in a dropwise manner. The reaction mixture was stirred
at 0.degree. C. for 60 minutes, the ice bath removed, and stirring
continued at RT for 90 minutes. MeOH (10 ml) was added to the
reaction and stirring was continued at RT for 10 minutes. The
reaction mixture was concentrated in vacuo and purified by flash
chromatography (Biotage, SiO.sub.2, 25-40% EtOAc/hexanes) to give
the title product (1.36 g, 4.03 mmol, 85% yield).
[0680] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 3.77-4.13
(3H, m), 4.72-4.86 (2H, m), 6.59-6.76 (5H, m) and 6.86-6.90 (2H,
m). MS 338 (M+1).
Example 84
[0681]
Cyclohexyl-[7-hydroxy-4-(4-hydroxy-phenyl)-3,4-dihydro-1H-isoquinol-
in-2-yl]-methanone
[0682] A solution of
7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoq- uinoline
(0.103 g, 0.382 mmol, 1.0 eq., see Preparation 64) and
triethylamine (0.107 ml, 0.764 mmol, 2.0 eq.) in CH.sub.2Cl.sub.2
(2 ml) was added to a vial containing cyclohexanecarbonyl chloride
(0.084 g, 0.573 mmol, 1.5 eq.). The reaction mixture was stirred
overnight at RT. To this mixture was added BBr.sub.3 as a 1.0M
solution in CH.sub.2Cl.sub.2 (1.15 ml, 1.15 mmol, 3.0 eq.). The
reaction mixture was stirred overnight at rt, then cooled to
-78.degree. C. and quenched with MeOH (1.5 ml). The reaction
mixture was evaporated under a stream of nitrogen and purified by
reverse phase HPLC (gradient elution 98:2 H.sub.2O:0.1% TFA, then
2:98 MeCN:H.sub.2O). The exact yield was not determined.
[0683] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 1.12-1.94
(10H, overlapping m), 2.67 (1H, m), 3.77 (1H, m), 3.94 (1H, m),
4.09 (1H, m), 4.35 (1H, d, J 17.5 Hz), 5.06 (1H, d, J 17.5 Hz) and
6.58-6.88 (7H, overlapping m). MS 352 (M+1).
Example 85
[0684]
[7-Hydroxy-4-(4-hydroxy-phenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-ph-
enyl-methanone
[0685] The title compound was prepared by analogy to Example 84
except benzoyl chloride was used in place of cyclohexanecarbonyl
chloride.
[0686] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 3.68 (2H,
m), 3.84-4.18 (3H, overlapping m), 4.52 (1H, d, J 17.5 Hz), 5.22
(1H, d J 17.5 Hz), 6.57-6.96 (8H, overlapping m) and 7.19-7.46 (4H,
m). MS 346 (M+1).
Example 86
[0687]
2-Benzenesulfonyl-4-(4-hydroxy-phenyl)-1,2,3,4-tetrahydroisoquinoli-
n-7-ol
[0688] A solution of
7-methoxy-4-(4-methoxy-phenyl)-1,2,3,4-tetrahydroisoq- uinoline
(0.103 g, 0.382 mmol, 1.0 eq., see Preparation 64) and
triethylamine (0.107 ml, 0.764 mmol, 2.0 eq.) in CH.sub.2Cl.sub.2
(2 ml) was added to a vial containing benzenesulfonyl chloride
(0.101 g, 0.573 mmol, 1.5 eq.). The reaction mixture was stirred
overnight at RT. To this mixture was added BBr.sub.3 as a 1.0M
solution in CH.sub.2Cl.sub.2 (1.15 ml, 1.15 mmol, 3.0 eq.). The
reaction mixture was again stirred overnight at RT, then cooled to
-78.degree. C. and quenched with MeOH (1.5 ml). The reaction
mixture was evaporated under a stream of nitrogen and purified by
reverse phase HPLC (gradient elution 98:2 H.sub.2O:0.1% TFA, then
2:98 MeCN:H.sub.2O). The exact yield was not determined.
[0689] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 3.04 (1H,
dd, J 12.0 and 7.5 Hz), 3.55 (1H, dd, J 12.0 and 5.0 Hz), 4.02 (1H,
dd J 6.5 and 6.0 Hz), 4.12 (1H, d, J 15.0 Hz), 4.27 (1H, d, J 15.0
Hz), 6.52 (2H, m), 6.65 (3H, m), 6.87 (1H, d, J 8.5 Hz), 7.55 (2H,
m), 7.56 (1H, m) and 7.75 (1H, d, J 8.0 Hz). MS 382 (M+1).
Example 87
[0690]
4-(4-Hydroxy-phenyl)-2-(naphthalene-1-sulfonyl)-1,2,3,4-tetrahydroi-
soquinolin-7-ol
[0691] The title compound was prepared by analogy to Example 86
except naphthalene-1-sulfonyl chloride was used in place of
benzenesulfonyl chloride.
[0692] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 3.34 (1H,
dd, J 12.0 and 7.0 Hz), 3.64 (1H, dd, J 12.0 and 4.5 Hz), 3.93 (1H,
t, J 6.0 Hz), 4.36 (1H, d, 15.5 Hz), 4.42 (1H, d, J 15.5 Hz)
6.45-6.68 (7H, overlapping m), 7.93 (1H, m), 8.10-8.18 (2H,
overlapping m) and 8.54 (1H, m). MS 432 (M+1).
Example 88
[0693]
2-(Biphenyl-4-sulfonyl)-4-(4-hydroxy-phenyl)-1,2,3,4-tetrahydroisoq-
uinolin-7-ol
[0694] The title compound was prepared by analogy to Example 86
except biphenyl-4-sulfonyl chloride was used in place of
benzenesulfonyl chloride.
[0695] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 3.09 (1H,
dd, J 12.0 and 7.5 Hz), 3.59 (1H, dd, J 12.0 and 5.0 Hz), 4.05 (1H,
dd, J 7.5 and 5.0 Hz), 4.17 (1H, d, J 15.0 Hz), 4.32 (1H, J 15.0
Hz), 6.54 (3H, m), 6.64 (3H, m), 6.88 (2H, m), 7.36-7.47 (3H,
overlapping m), 7.66 (2H, m) and 7.80 (2H, m). MS 458 (M+1).
Example 89
[0696]
4-(4-Hydroxy-phenyl)-2-phenylmethanesulfonyl-1,2,3,4-tetrahydroisoq-
uinolin-7-ol
[0697] The title compound was prepared by analogy to Example 86
except phenyl-methanesulfonyl chloride was used in place of
benzenesulfonyl chloride.
[0698] .sup.1H NMR (400 MHz, CD.sub.3OD) .delta..sub.H 3.19 (1H,
m), 3.56 (1H, dd, 12.5 and 5.0 Hz), 3.88 (1H, J 7.5 and 6.0 Hz),
4.20-4.39 (4H, overlapping m), 6.48-6.58 (2H, overlapping m),
6.52-6.71 (3H, overlapping m), 6.85 (2H, m) and 7.22-7.38 (5H,
overlapping m). MS 396 (M+1).
* * * * *