U.S. patent application number 11/057827 was filed with the patent office on 2005-06-23 for estrogen receptor modulators.
Invention is credited to Parker, Dann R. JR., Ratcliffe, Ronald W., Wildonger, Kenneth J., Wilkening, Robert R..
Application Number | 20050137192 11/057827 |
Document ID | / |
Family ID | 22668169 |
Filed Date | 2005-06-23 |
United States Patent
Application |
20050137192 |
Kind Code |
A1 |
Parker, Dann R. JR. ; et
al. |
June 23, 2005 |
Estrogen receptor modulators
Abstract
The present invention relates to compounds and derivatives
thereof, their synthesis, and their use as estrogen receptor
modulators. The compounds of the instant invention are ligands for
estrogen receptors and as such may be useful for treatment or
prevention of a variety of conditions related to estrogen
functioning including: bone loss, bone fractures, osteoporosis,
cartilage degeneration, endometriosis, uterine fibroid disease, hot
flashes, increased levels of LDL cholesterol, cardiovascular
disease, impairment of cognitive functioning, cerebral degenerative
disorders, restinosis, gynacomastia, vascular smooth muscle cell
proliferation, obesity, incontinence, and cancer, in particular of
the breast, uterus and prostate.
Inventors: |
Parker, Dann R. JR.;
(Cranford, NJ) ; Ratcliffe, Ronald W.; (Matawan,
NJ) ; Wilkening, Robert R.; (Maplewood, NJ) ;
Wildonger, Kenneth J.; (Bridgewater, NJ) |
Correspondence
Address: |
MERCK AND CO., INC
P O BOX 2000
RAHWAY
NJ
07065-0907
US
|
Family ID: |
22668169 |
Appl. No.: |
11/057827 |
Filed: |
February 14, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11057827 |
Feb 14, 2005 |
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09782855 |
Feb 14, 2001 |
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60182372 |
Feb 14, 2000 |
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Current U.S.
Class: |
514/232.2 ;
514/319; 514/408; 514/640; 514/651; 514/690; 544/155; 546/204;
548/528; 564/257; 564/346 |
Current CPC
Class: |
A61P 19/08 20180101;
C07C 49/755 20130101; C07C 49/84 20130101; C07C 49/755 20130101;
C07C 49/755 20130101; C07C 49/755 20130101; C07C 49/755 20130101;
C07C 49/84 20130101; C07C 49/755 20130101; C07C 49/755 20130101;
C07C 49/755 20130101; C07C 45/65 20130101; C07D 333/22 20130101;
C07C 45/72 20130101; C07C 45/28 20130101; C07C 45/73 20130101; C07C
2603/18 20170501; C07C 45/63 20130101; C07C 45/46 20130101; A61P
19/10 20180101; C07C 251/44 20130101; A61P 25/22 20180101; C07C
45/72 20130101; C07C 45/73 20130101; A61P 13/02 20180101; A61P
25/28 20180101; C07C 45/28 20130101; C07C 45/71 20130101; C07C
45/75 20130101; A61P 9/00 20180101; C07C 49/755 20130101; C07C
49/755 20130101; A61P 15/00 20180101; C07C 45/46 20130101; C07C
45/63 20130101; C07C 45/68 20130101; C07C 45/71 20130101; C07D
295/088 20130101; A61P 43/00 20180101; C07C 45/65 20130101; C07C
39/42 20130101; A61P 35/00 20180101; C07C 45/75 20130101; C07C
45/74 20130101; C07C 255/47 20130101; A61P 3/04 20180101; A61P
25/24 20180101; C07C 59/90 20130101; C07C 45/69 20130101; C07C
45/69 20130101; C07C 45/68 20130101; C07C 49/747 20130101; C07C
45/74 20130101; C07C 205/45 20130101 |
Class at
Publication: |
514/232.2 ;
514/408; 514/319; 514/651; 514/690; 514/640; 544/155; 546/204;
548/528; 564/257; 564/346 |
International
Class: |
A61K 031/537; A61K
031/445; A61K 031/40; A61K 031/138; A61K 031/135; A61K 031/15 |
Claims
1-21. (canceled)
22. A method of treating depression in a mammal in need thereof by
administering to the mammal a therapeutically effective amount of a
compound of the formula: 79wherein X is selected from the group
consisting of: O, N--OR.sup.a, N--NR.sup.aR.sup.b and
C.sub.1-6alkylidene, wherein said alkylidene group is unsubstituted
or substituted with hydroxy, amino, O(C.sub.1-4 alkyl),
NH(C.sub.1-4 alkyl), or N(C.sub.1-4alkyl).sub.2; R.sup.1 is
selected from the group consisting of hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein said alkyl, alkenyl
and alkynyl groups are either unsubstituted or substituted
OR.sup.c, SR.sup.c, NR.sup.bR.sup.c, C(.dbd.O)R.sup.c,
C(.dbd.O)CH.sub.2OH, or phenyl, wherein said phenyl group can
either be unsubstituted or substituted with 1-3 substituents
independently selected from the group consisting of C.sub.1-4alkyl,
OH, O(C.sub.1-4alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2, halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), C(O)H, and C(O)(C.sub.1-4alkyl); R.sup.2
is selected from the group consisting of hydrogen, hydroxy, iodo,
O(C.dbd.O)R.sup.c, C(.dbd.O)R.sup.c, CO.sub.2R.sup.c,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
said alkyl, alkenyl and alkynyl groups are either unsubstituted or
substituted with OR.sup.c, SR.sup.c, NR.sup.bR.sup.c,
C(.dbd.O)R.sup.c, C(.dbd.O)CH.sub.2OH, or phenyl, wherein said
phenyl group can either be unsubstituted or substituted with 1-3
substituents independently selected from the group consisting of
C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl), NH.sub.2,
NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2- , halo, CN, NO.sub.2,
CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl); or R.sup.1 and R.sup.2, when taken together
with the carbon atom to which they are attached, form a carbonyl
group; or R.sup.1 and R.sup.2, when taken together, form a
C.sub.1-6 alkylidene group, wherein said alkylidene group is either
unsubstituted or substituted with a group selected from the group
consisting of hydroxy, O(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
and phenyl, wherein said phenyl group can either be unsubstituted
or substituted with 1-3 substituents independently selected from
the group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl); R.sup.3 is selected from the group consisting
of hydrogen, fluoro, chloro, bromo, iodo, cyano, NR.sup.aR.sup.c,
OR.sup.a, C(.dbd.O)R.sup.a, CO.sub.2R.sup.c, CONR.sup.aR.sup.c,
SR.sup.a, S(.dbd.O)R.sup.a, SO.sub.2R.sup.a, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl, 4-7
membered heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, and heteroarylalkyl, wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, aryl and heteroaryl groups are either
unsubstituted or independently substituted with 1, 2 or 3 groups
selected from the group consisting of fluoro, chloro, bromo, iodo,
cyano, OR.sup.a, NR.sup.aR.sup.c, O(C.dbd.O)R.sup.a,
O(C.dbd.O)NR.sup.aR.sup.c, NR.sup.a (C.dbd.O)R.sup.c, NR.sup.a
(C.dbd.O)OR.sup.c, C(.dbd.O)R.sup.a, CO.sub.2R.sup.a,
CONR.sup.aR.sup.c, CSNR.sup.aR.sup.c, SR.sup.a, S(O)R.sup.a,
SO.sub.2R.sup.a, SO.sub.2NR.sup.aR.sup.c, YR.sup.d, and ZYR.sup.d;
R.sup.4 is selected from the group consisting of hydrogen, hydroxy,
amino, methyl, CF.sub.3, fluoro, chloro, and bromo; R.sup.5 and
R.sup.6 are each independently selected from the group consisting
of hydrogen, fluoro, chloro, bromo, methyl, amino, OR.sup.b,
OR.sup.a, O(C.dbd.O)R.sup.c, O(C.dbd.O)OR.sup.c, and
NH(C.dbd.O)R.sup.c; R.sup.7 is selected from the group consisting
of hydrogen, OR.sup.b, NR.sup.bR.sup.c, fluoro, chloro, bromo,
iodo, cyano, nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, CF.sub.3, and
CHF.sub.2; R.sup.8 and R.sup.9 are each independently selected from
the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl,
and C.sub.2-6alkynyl, or R.sup.8 and R.sup.9, when taken together
with the carbon atom to which they are attached, form a 3-5
membered cycloalkyl ring, or R.sup.8 and R.sup.9, when taken
together with the carbon atom to which they are attached, form a
carbonyl group; R.sup.10 is selected from the group consisting of
hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.3-6cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl
and heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and
heteroarylalkyl groups can be optionally substituted with chloro,
bromo, iodo, OR.sup.b, SR.sup.b, C(.dbd.O)R.sup.b, or 1-5 fluoro,
or R.sup.10 and R.sup.1, when taken together with the three
intervening carbon atoms to which they are attached, form a 5-6
membered cycloalkyl ring which can be optionally substituted with
C.sub.1-6alkyl; R.sup.11 is selected from the group consisting of
hydrogen and C.sub.1-4alkyl; R.sup.a is selected from the group
consisting of hydrogen, C.sub.1-10alkyl, and phenyl, wherein said
alkyl group can be optionally substituted with hydroxy, amino,
O(C.sub.1-4alkyl), NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
phenyl, or 1-5 fluoro, and wherein said phenyl groups can either be
unsubstituted or substituted with 1-3 substituents independently
selected from the group consisting of C.sub.1-4alkyl, OH,
O(C.sub.1-4alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2, halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), C(O)H, and C(O)(C.sub.1-4alkyl); R.sup.b
is selected from the group consisting of hydrogen, C.sub.1-10alkyl,
benzyl and phenyl, wherein said phenyl group can either be
unsubstituted or substituted with 1-3 substituents independently
selected from the group consisting of C.sub.1-4alkyl, OH,
O(C.sub.1-4alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2- , halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), C(O)H, and C(O)(C.sub.1-4alkyl); R.sup.c
is selected from the group consisting of hydrogen, C.sub.1-10 alkyl
and phenyl, wherein said phenyl group can either be unsubstituted
or substituted with 1-3 substituents independently selected from
the group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2- , halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl); or R.sup.a and R.sup.c, whether or not on the
same atom, can be taken together with any attached and intervening
atoms to form a 4-7 membered ring; R.sup.d is selected from the
group consisting of NR.sup.bR.sup.c, OR.sup.a, CO.sub.2R.sup.a,
O(C.dbd.O)R.sup.a, CN, NR.sup.c(C.dbd.O)R.sup.b, CONR.sup.aR.sup.c,
SO.sub.2NR.sup.aR.sup.c, and a 4-7 membered N-heterocycloalkyl ring
that can be optionally interrupted by O, S, NR.sup.c, or C.dbd.O; Y
is selected from the group consisting of CR.sup.bR.sup.c,
C.sub.2-6alkylene and C.sub.2-6alkenylene, wherein said alkylene
and alkenylene linkers can be optionally interrupted by O, S, or
NR.sup.c; Z is selected from the group consisting of O, S,
NR.sup.c, C.dbd.O, O(C.dbd.O), (C.dbd.O)O, NR.sup.c(C.dbd.O) and
(C.dbd.O)NR.sup.c; or a pharmaceutically acceptable salt
thereof.
23. The method of claim 22 wherein the compound is of the formula:
80wherein X is selected from the group consisting of O and
N--OR.sup.a; R.sup.1 is selected from the group consisting of
hydrogen and C.sub.1-6alkyl, wherein said alkyl group is either
unsubstituted or substituted with OR.sup.c or C(.dbd.O)R.sup.c;
R.sup.2 is selected from the group consisting of hydrogen, hydroxy,
iodo, and C.sub.1-6alkyl, wherein said alkyl group is either
unsubstituted or substituted with OR.sup.c or C(.dbd.O)R.sup.c;
R.sup.3 is selected from the group consisting of hydrogen, chloro,
bromo, iodo, cyano, C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl and
heteroaryl, wherein said alkyl, alkenyl, aryl and heteroaryl groups
are either unsubstituted or independently substituted with 1, 2 or
3 groups selected from the group consisting of fluoro, chloro,
bromo, iodo, cyano, OR.sup.a, NR.sup.aR.sup.c, C(.dbd.O)R.sup.a,
CO.sub.2R.sup.c, NR.sup.aC(.dbd.O)R.sup.c, CONR.sup.aR.sup.c,
CSNR.sup.aR.sup.c, SR.sup.a, YR.sup.d, and ZYR.sup.d; R.sup.4 is
selected from the group consisting of hydrogen, fluoro, hydroxy and
methyl; R.sup.5 and R.sup.6 are each independently selected from
the group consisting of hydrogen, fluoro, O(C.dbd.O)R.sup.c and
OR.sup.a; R.sup.7 is selected from the group consisting of
hydrogen, NR.sup.bR.sup.c, chloro, bromo, nitro and C.sub.1-6alkyl;
R.sup.8 and R.sup.9 are each independently selected from the group
consisting of hydrogen and C.sub.1-6alkyl; or R.sup.8 and R.sup.9,
when taken together with the carbon atom to which they are
attached, form a carbonyl group; R.sup.10 is selected from the
group consisting of hydrogen, C.sub.1-10alkyl, C.sub.2-10alkenyl,
C.sub.3-6cycloalkyl and cycloalkylalkyl, wherein said alkyl,
alkenyl, cycloalkyl and cycloalkylalkyl groups can be optionally
substituted with OR.sup.b, SR.sup.b, C(.dbd.O)R.sup.b, or 1-5
fluoro; or R.sup.10 and R.sup.1, when taken together with the three
intervening carbon atoms to which they are attached, form a 5-6
membered cycloalkyl ring which can be optionally substituted with
C.sub.1-6alkyl; R.sup.11 is selected from the group consisting of
hydrogen and C.sub.1-4alkyl; R.sup.a is selected from the group
consisting of hydrogen, C.sub.1-10alkyl, and phenyl, wherein said
alkyl group can be optionally substituted with hydroxy, amino,
O(C.sub.1-4alkyl), NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
phenyl, or 1-5 fluoro; R.sup.b is selected from the group
consisting of hydrogen, C.sub.1-10alkyl, benzyl and phenyl; R.sup.c
is selected from the group consisting of hydrogen and
C.sub.1-10alkyl and phenyl; or R.sup.a and R.sup.c, whether or not
on the same atom, can be taken together with any attached and
intervening atoms to form a 4-7 membered ring; R.sup.d is selected
from the group consisting of NR.sup.bR.sup.c, OR.sup.a,
CO.sub.2R.sup.a, O(C.dbd.O)R.sup.a, CN, NR.sup.c(C.dbd.O)R.sup.b,
CONR.sup.aR.sup.c, SO.sub.2NR.sup.aR.sup.c, and a 4-7 membered
N-heterocycloalkyl ring that can be optionally interrupted by O, S,
NR.sup.c, or C.dbd.O; Y is selected from the group consisting of
CR.sup.bR.sup.c, C.sub.2-6alkylene and C.sub.2-6alkenylene, wherein
said alkylene and alkenylene linkers can be optionally interrupted
by O, S, or NR.sup.c; Z is selected from the group consisting of O,
S, NR.sup.c, C.dbd.O, O(C.dbd.O), (C.dbd.O)O, NR.sup.c(C.dbd.O) and
(C.dbd.O)NR.sup.c; or a pharmaceutically acceptable salt
thereof.
24. The method of claim 23 wherein X is selected from the group
consisting of O, N--OH and N--OCH.sub.3; or a pharmaceutically
acceptable salt thereof.
25. The method of claim 24 wherein R.sup.6 is selected from the
group consisting of OR.sup.a and O(C.dbd.O)R.sup.c; or a
pharmaceutically acceptable salt thereof.
26. The method of claim 25 wherein R.sup.3 is selected from the
group consisting of hydrogen, chloro, bromo, iodo, cyano,
C.sub.1-10alkyl, aryl and heteroaryl, wherein said alkyl, aryl and
heteroaryl groups are either unsubstituted or independently
substituted with 1, 2 or 3 groups selected from the group
consisting of fluoro, chloro, bromo, cyano, NR.sup.aR.sup.c,
C(.dbd.O)R.sup.a, CO.sub.2R.sup.c, CONR.sup.aR.sup.c, SR.sup.a,
YR.sup.d, and ZYR.sup.d; or a pharmaceutically acceptable salt
thereof.
27. The method of claim 22 wherein the compound is selected from
the group consisting of:
4-bromo-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren- -3-one;
9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(3E)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
oxime;
9a-[(1E)-1-butenyl]-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one- ;
4-bromo-9a-butyl-3-methylene-2,3,9,9a-tetrahydro-1H-fluoren-7-ol;
9a-butyl-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4-benzyl-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a
butyl-7-hydroxy-4-(2-thienyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-ene;
9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one hydrochloride;
9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-
-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(2E)-3-[4-(9a-butyl-7-hydroxy-3-oxo-
-2,3,9,9a-tetrahydro-1H-fluoren-4-yl)phenyl]-2-propenoic acid;
9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-3H-tetrahydro-fluoren-3-one;
4-bromo-9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a
butyl-4,8-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-8-chloro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one;
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-hydroxy-2-propyl-1,2,9,9a-tetr-
ahydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one;
(2SR,9aRS)-9a-butyl-7-hydroxy-2-iodo-4-methyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one;
(2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-meth-
yl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(-
2-hydroxyethyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(2SR,9aSR)-2-allyl-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-flu-
oren-3-one;
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(3-hydroxy-2-oxopropyl)-4-meth-
yl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(9SR,9aSR)-7-hydroxy-4-methyl-9-p-
ropyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-8-chloro-7-hydroxy-4--
(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4-acetyl-9a-butyl-8-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
9a-butyl-8-chloro-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
9a-butyl-4-ethyl-6-fluoro-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one;
9a-butyl-8-chloro-4-ethyl-6-fluoro-7-hydroxy-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one;
4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-
-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-8-chloro-6-fluoro-7-hydrox-
y-4-(trifluoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
2-hydroxy-5-methylgibba-1 (10a),2,4,4b-tetraen-6-one;
4-bromo-9a-butyl-3-oxo-2,3,9,9a-1H-fluoren-7-yl pivalate;
7-hydroxy-4,9a-dimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
7-hydroxy-4-methyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
7-hydroxy-9a-isobutyl-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-4-ethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-4-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4,9a-dibutyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-4-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-4-iodo-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-4-trifluoromethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
; 9a-butyl-7-hydroxy-4-phenyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-4-(2-furyl)-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
7-hydroxy-9a-(3-iodopropyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
7-hydroxy-4-methyl-9a-(2-methyl-1-propenyl)-1,2,9,9a-tetrahydro-3H-fluor-
en-3-one;
9a-butyl-4-{4-[2-(dimethylamino)ethoxy]phenyl}-7-hydroxy-1,2,9,9-
a-tetrahydro-3H-fluoren-3-one hydrochloride;
9a-butyl-4-{4-[2-(diethylamin-
o)ethoxy]-phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
hydrochloride;
9a-butyl-7-hydroxy-4-{4-[2-(1-pyrrolidinyl)ethoxy]phenyl}--
1,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride;
9a-butyl-7-hydroxy-4-{4-[2-(4-morpholinyl)ethoxy]phenyl}-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one hydrochloride;
9a-butyl-4-{4-[3-(dimethylamino)propox-
y]-phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
hydrochloride;
9a-butyl-7-hydroxy-4-{4-[3-(1-piperidinyl)propoxy]phenyl}-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one hydrochloride;
(3E)-9a-butyl-7-hydroxy-4-methyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one O-methyloxime;
(2SR,9aSR)-9a-butyl-2-ethy-
l-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(2SR,9aSR)-9a-butyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne;
(2SR,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-propyl-1,2,9,9a-tetrahydro-3H-
-fluoren-3-one;
(2SR,9aSR)-4,9a-dibutyl-7-hydroxy-2-propyl-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one;
(2SR,9aSR)-4-bromo-9a-butyl-7-hydroxy-2-propyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one;
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-oxoet-
hyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(2SR,9aSR)-2,9a-dibutyl-7-hydro-
xy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
(2RS,9aRS)-9a-butyl-7-hy-
droxy-2,4-dimethyl-2-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-2,2-dipropyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-4-methyl-2,2-dipropyl-1,2,9,9a-tetrahydro-3H-fluoren-3-
-one;
(2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-2-propyl-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one;
4-bromo-9a-butyl-2,2-diethyl-7-hydroxy-1,2,9,9a-tetr-
ahydro-3H-fluoren-3-one;
(2SR,9aSR)-7-hydroxy-2,4,9a-trimethyl-1,2,9,9a-te-
trahydro-3H-fluoren-3-one;
(2SR,9aSR)-7-hydroxy-4,9a-dimethyl-2-propyl-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one;
(2SR,9aSR)-9a-butyl-8-chloro-2-ethyl-7--
hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
8-chloro-9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
8-bromo-9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
9a-ethyl-7-hydroxy-4,8-dimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
8-chloro-7-hydroxy-4-methyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-on-
e;
8-bromo-7-hydroxy-4-methyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne;
7-hydroxy-4,8-dimethyl-9a-propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
8-chloro-7-hydroxy-4-methyl-9a-[(1
E)-1-propenyl]-1,2,9,9a-tetrahydro-3H-- fluoren-3-one;
8-bromo-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H--
fluoren-3-one;
9a-butyl-7-hydroxy-4,8-dimethyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
9a-butyl-7-hydroxy-4-methyl-8-nitro-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
8-amino-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-8-methyl-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one;
9a-butyl-7-hydroxy-8-methyl-4-{4-[2-piperidinyl)-et-
hoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4-bromo-7-hydroxy-9a-pr- opyl-1H-fluorene-3,9(2H,9aH)-dione;
4,8-dibromo-7-hydroxy-9a-propyl-1H-flu- orene-3,9(2H,9aH)-dione;
4-bromo-9a-butyl-7-hydroxy-6-methyl-1,2,9,9a-tetr-
ahydro-3H-fluoren-3-one;
9a-butyl-8-chloro-4-methyl-3-oxo-2,3,9,9a-tetrahy-
dro-1H-fluoren-7-yl pivalate;
9a-butyl-6,8-difluoro-7-hydroxy-4-methyl-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-4-ethyl-6,8-difluoro-7-hydroxy-
-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4-bromo-9a-butyl-6,8-difluoro-7-hyd-
roxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
8-bromo-9a-butyl-4-chloro-8-dif-
luoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-butyl-4,8-dibromo-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3--
one;
9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-
-one;
9a-ethyl-6,8-difluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
8-chloro-9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one;
8-bromo-9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one;
9a-ethyl-6-fluoro-7-hydroxy-4,8-dimethyl-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one;
4,9a-diethyl-6,8-difluoro-7-hydroxy-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one;
4-bromo-8-chloro-9a-ethyl-6-fluoro-7-hy-
droxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4-bromo-8-chloro-9a-(cyclopent-
ylmethyl)-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
9a-ethyl-5-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one-
;
8-bromo-9a-ethyl-5-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
9a-ethyl-6,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren--
3-one;
8-bromo-9a-ethyl-6,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one;
9a-ethyl-6-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-on- e;
9a-ethyl-6-hydroxy-4-vinyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
4-allyl-9a-ethyl-6-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
2-hydroxy-5-methyl-7,8,9,10-tetrahydro-7,10a-methanocycloocta[.alpha.]ind-
en-6(11H)-one;
7-amino-4-bromo-9a-butyl-1,2,9,9a-tetrahydro-3H-fluoren-3-o- ne;
7-amino-4,8-dibromo-9a-ethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one;
and the pharmaceutically acceptable salts thereof.
28. The method of claim 27 wherein the compound is
4-bromo-9a-butyl-8-chlo-
ro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one, or a
pharmaceutically acceptable salt thereof.
29. The method of claim 28 wherein the compound is
4-bromo-9a-butyl-8-chlo-
ro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one.
30. The method of claim 22 further comprising an organic
bisphosphonate or a cathepsin K inhibitor, or a pharmaceutically
acceptable salt or mixture thereof.
31. The method of claim 30 wherein the bisphosphonate is selected
from alendronate, clodronate, etidronate, ibandronate, incadronate,
minodronate, neridronate, risedronate, piridronate, pamidronate,
tiludronate, zoledronate, pharmaceutically acceptable salts, esters
or mixtures thereof.
32. The method of claim 31 wherein the bisphosphonate is
alendronate.
Description
BACKGROUND OF THE INVENTION
[0001] Naturally occurring and synthetic estrogens have broad
therapeutic utility, including: relief of menopausal symptoms,
treatment of acne, treatment of dysmenorrhea and dysfunctional
uterine bleeding, treatment of osteoporosis, treatment of
hirsutism, treatment of prostatic cancer, treatment of hot flashes
and prevention of cardiovascular disease. Because estrogen is very
therapeutically valuable, there has been great interest in
discovering compounds that mimic estrogen-like behavior in estrogen
responsive tissues.
[0002] For example, estrogen-like compounds would be beneficial in
the treatment and prevention of bone loss. Bone loss occurs in a
wide range of subjects, including women that are post-menopausal or
have had a hysterectomy, patients who were or are currently being
treated with corticosteroids, and patient's having gonadal
dysgenesis. The current major bone diseases of public concern are
osteoporosis, hypercalcemia of malignancy, osteopenia due to bone
metastases, periodontal disease, hyperparathyroidism, periarticular
erosions in rheumatoid arthritis, Paget's disease,
immobilization-induced osteopenia, and glucocorticoid-induced
osteoporosis. All of these conditions are characterized by bone
loss, resulting from an imbalance between bone resorption, i.e.
breakdown, and bone formation, which continues throughout life at
the rate of about 14% per year on the average. However, the rate of
bone turnover differs from site to site, for example, it is higher
in the trabecular bone of the vertebrae and the alveolar bone in
the jaws than in the cortices of the long bones. The potential for
bone loss is directly related to turnover and can amount to over 5%
per year in vertebrae immediately following menopause, a condition
which leads to increased fracture risk.
[0003] In the U.S., there are currently about 20 million people
with detectable fractures of the vertebrae due to osteoporosis. In
addition, there are about 250,000 hip fractures per year attributed
to osteoporosis. This clinical situation is associated with a 12%
mortality rate within the first two years, while 30% of the
patients require nursing home care after the fracture.
[0004] Osteoporosis affects approximately 20 to 25 million
post-menopausal women in the U.S. alone. It has been theorized that
the rapid loss of bone mass in these women is due to the cessation
of estrogen production of the ovaries. Since studies have shown
that estrogen slows the reduction of bone mass due to osteoporosis,
estrogen replacement therapy is a recognized treatment for
post-menopausal osteoporosis.
[0005] In addition to bone mass, estrogen appears to have an effect
on the biosynthesis of cholesterol and cardiovascular health.
Statistically, the rate of occurrence of cardiovascular disease is
roughly equal in postmenopausal women and men; however,
premenopausal women have a much lower incidence of cardiovascular
disease than men. Because postmenopausal women are estrogen
deficient, it is believed that estrogen plays a beneficial role in
preventing cardiovascular disease. The mechanism is not well
understood, but evidence indicates that estrogen can upregulate the
low density lipid (LDL) cholesterol receptors in the liver to
remove excess cholesterol.
[0006] Postmenopausal women given estrogen replacement therapy
experience a return of lipid levels to concentrations comparable to
levels associated with the premenopausal state. Thus, estrogen
replacement therapy could be an effective treatment for such
disease. However, the side effects associated with long term
estrogen use limit the use of this alternative.
[0007] In models, estrogen has been shown to have beneficial
effects on cognitive functioning, such as relieveing anxiety and
depression and treating and/or preventing Alzheimer's disease.
Estrogen affects the central nervous system by increasing
cholinergic functioning, neurotrophin and neurotrophin receptor
expression. Estrogen also increases glutamergic synaptic
transmission, alters amyloid precursor protein processing and
provides neuroprotection. Thus, the estrogen receptor modulators of
the present invention could be beneficial for improving cognitive
functioning.
[0008] Other disease states that affect postmenopausal women
include estrogen-dependent breast cancer and uterine cancer.
Anti-estrogen compounds, such as tamoxifen, have commonly been used
as chemotherapy to treat breast cancer patients. Tamoxifen, a dual
antagonist and agonist of estrogen receptors, is beneficial in
treating estrogen-dependent breast cancer. However, treatment with
tamoxifen is less than ideal because tamoxifen's agonist behavior
enhances its unwanted estrogenic side effects. For example,
tamoxifen and other compounds that agonize estrogen receptors tend
to increase cancer cell production in the uterus. A better therapy
for such cancers would be an anti-estrogen compound that has
negligible or nonexistent agonist properties.
[0009] Although estrogen can be beneficial for treating pathologies
such as bone loss, increased lipid levels, and cancer, long-term
estrogen therapy has been implicated in a variety of disorders,
including an increase in the risk of uterine and endometrial
cancers. These and other side effects of estrogen replacement
therapy are not acceptable to many women, thus limiting its
use.
[0010] Alternative regimens, such as a combined progestogen and
estrogen dose, have been suggested in an attempt to lessen the risk
of cancer. However, such regimens cause the patient to experience
withdrawal bleeding, which is unacceptable to many older women.
Furthermore, combining estrogen with progestogen reduces the
beneficial cholesterol-lowering effect of estrogen therapy. In
addition, the long term effects of progestogen treatment are
unknown.
[0011] In addition to post-menopausal women, men suffering from
prostatic cancer can also benefit from anti-estrogen compounds.
Prostatic cancer is often endocrine-sensitive; androgen stimulation
fosters tumor growth, while androgen suppression retards tumor
growth. The administration of estrogen is helpful in the treatment
and control of prostatic cancer because estrogen administration
lowers the level of gonadotropin and, consequently, androgen
levels.
[0012] The estrogen receptor has been found to have two forms:
ER.alpha. and ER.beta.. Ligands bind differently to these two
forms, and each form has a different tissue specificity to binding
ligands. Thus, it is possible to have compounds that are selective
for ER.alpha. or ER.beta., and therefore confer a degree of tissue
specificity to a particular ligand.
[0013] What is needed in the art are compounds that can produce the
same positive responses as estrogen replacement therapy without the
negative side effects. Also needed are estrogen-like compounds that
exert selective effects on different tissues of the body.
[0014] The compounds of the instant invention are ligands for
estrogen receptors and as such may be useful for treatment or
prevention of a variety of conditions related to estrogen
functioning including: bone loss, bone fractures, osteoporosis,
cartilage degeneration, endometriosis, uterine fibroid disease, hot
flashes, increased levels of LDL cholesterol, cardiovascular
disease, impairment of cognitive functioning, cerebral degenerative
disorders, restinosis, gynacomastia, vascular smooth muscle cell
proliferation, obesity, incontinence, and cancer, in particular of
the breast, uterus and prostate.
SUMMARY OF THE INVENTION
[0015] The present invention relates to compounds of the following
chemical formula: 1
[0016] wherein X is selected from the group consisting of: O,
N--OR.sup.a, N--NR.sup.aR.sup.b and C.sub.1-6 alkylidene, wherein
said alkylidene group is unsubstituted or substituted with a group
selected from hydroxy, amino, O(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl), or N(C.sub.1-4alkyl).sub.2;
[0017] R.sup.1 is selected from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
said alkyl, alkenyl and alkynyl groups are either unsubstituted or
substituted with a group selected from OR.sup.c, SR.sup.c,
NR.sup.bR.sup.c, C(.dbd.O)R.sup.c, C(.dbd.O)CH.sub.2OH, or phenyl,
wherein said phenyl group can either be unsubstituted or
substituted with 1-3 substituents independently selected from the
group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2- , halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0018] R.sup.2 is selected from the group consisting of hydrogen,
hydroxy, iodo, O(C.dbd.O)R.sup.c, C(.dbd.O)R.sup.c,
CO.sub.2R.sup.c, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl, wherein said alkyl, alkenyl and alkynyl groups
are either unsubstituted or substituted with a group selected from
OR.sup.c, SR.sup.c, NR.sup.bR.sup.c, C(.dbd.O)R.sup.c,
C(.dbd.O)CH.sub.2OH, or phenyl, wherein said phenyl group can
either be unsubstituted or substituted with 1-3 substituents
independently selected from the group consisting of C.sub.1-4alkyl,
OH, O(C.sub.1-4alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2- , halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), C(O)H, and C(O)(C.sub.1-4alkyl);
[0019] or R.sup.1 and R.sup.2, when taken together with the carbon
atom to which they are attached, form a carbonyl group;
[0020] or R.sup.1 and R.sup.2, when taken together, form a
C.sub.1-6 alkylidene group, wherein said alkylidene group is either
unsubstituted or substituted with a group selected from the group
consisting of hydroxy, O(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
and phenyl, wherein said phenyl group can either be unsubstituted
or substituted with 1-3 substituents independently selected from
the group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0021] R.sup.3 is selected from the group consisting of hydrogen,
fluoro, chloro, bromo, iodo, cyano, NR.sup.aR.sup.c, OR.sup.a,
C(.dbd.O)R.sup.a, CO.sub.2R.sup.c, CONR.sup.aR.sup.c, SR.sup.a,
S(.dbd.O)R.sup.a, SO.sub.2R.sup.a, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl, 4-7
membered heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, and heteroarylalkyl, wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, aryl and heteroaryl groups are either
unsubstituted or independently substituted with 1, 2 or 3 groups
selected from fluoro, chloro, bromo, iodo, cyano, OR.sup.a,
NR.sup.aR.sup.c, O(C.dbd.O)R.sup.a, O(C.dbd.O)NR.sup.aR.sup.c,
NR.sup.a (C.dbd.O)R.sup.c, NR.sup.a (C.dbd.O)OR.sup.c,
C(.dbd.O)R.sup.a, CO.sub.2R.sup.a, CONR.sup.aR.sup.c,
CSNR.sup.aR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a,
SO.sub.2NR.sup.aR.sup.c, YR.sup.d, and ZYR.sup.d;
[0022] R.sup.4 is selected from the group consisting of hydrogen,
hydroxy, amino, methyl, CF.sub.3, fluoro, chloro, and bromo;
[0023] R.sup.5 and R.sup.6 are each independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, methyl, amino,
OR.sup.b, OR.sup.a, O(C.dbd.O)R.sup.c, O(C.dbd.O)OR.sup.c, and
NH(C.dbd.O)R.sup.c;
[0024] R.sup.7 is selected from the group consisting of hydrogen,
OR.sup.b, NR.sup.bR.sup.c, fluoro, chloro, bromo, iodo, cyano,
nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, CF.sub.3, and
CHF.sub.2;
[0025] R.sup.8 and R.sup.9 are each independently selected from the
group consisting of hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl,
[0026] or R.sup.8 and R.sup.9, when taken together with the carbon
atom to which they are attached, form a 3-5 membered cycloalkyl
ring,
[0027] or R.sup.8 and R.sup.9, when taken together with the carbon
atom to which they are attached, form a carbonyl group;
[0028] R.sup.10 is selected from the group consisting of hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.3-6cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl
and heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and
heteroarylalkyl groups can be optionally substituted with a group
selected from chloro, bromo, iodo, OR.sup.b, SR.sup.b,
C(.dbd.O)R.sup.b, or 1-5 fluoro,
[0029] or R.sup.10 and R.sup.1, when taken together with the three
intervening carbon atoms to which they are attached, form a 5-6
membered cycloalkyl or cycloalkenyl ring which can be optionally
substituted with 1 or 2 groups selected from oxo, hydroxy, or
C.sub.1-6alkyl;
[0030] R.sup.11 is selected from the group consisting of hydrogen
and C.sub.1-4alkyl;
[0031] R.sup.a is selected from the group consisting of hydrogen,
C.sub.1-10alkyl, and phenyl,
[0032] wherein said alkyl group can be optionally substituted with
a group selected from hydroxy, amino, O(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, phenyl, or 1-5 fluoro,
and
[0033] wherein said phenyl groups can either be unsubstituted or
substituted with 1-3 substituents independently selected from the
group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0034] R.sup.b is selected from the group consisting of hydrogen,
C.sub.1-10alkyl, benzyl and phenyl,
[0035] wherein said phenyl group can either be unsubstituted or
substituted with 1-3 substituents independently selected from the
group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0036] R.sup.c is selected from the group consisting of hydrogen,
C.sub.1-10alkyl and phenyl, wherein said phenyl group can either be
unsubstituted or substituted with 1-3 substituents independently
selected from the group consisting of C.sub.1-4alkyl, OH,
O(C.sub.1-4 alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2, halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), C(O)H, and C(O)(C.sub.1-4alkyl);
[0037] or R.sup.a and R.sup.c, whether or not on the same atom, can
be taken together with any attached and intervening atoms to form a
4-7 membered ring;
[0038] R.sup.d is selected from the group consisting of
NR.sup.bR.sup.c, OR.sup.a, CO.sub.2R.sup.a, O(C.dbd.O)R.sup.a, CN,
NR.sup.c(C.dbd.O)R.sup.- b, CONR.sup.aR.sup.c,
SO.sub.2NR.sup.aR.sup.c, and a 4-7 membered N-heterocycloalkyl ring
that can be optionally interrupted by O, S, NR.sup.c, or
C.dbd.O;
[0039] Y is selected from the group consisting of CR.sup.bR.sup.c,
C.sub.2-6 alkylene and C.sub.2-6 alkenylene, wherein said alkylene
and alkenylene linkers can be optionally interrupted by O, S, or
NR.sup.c;
[0040] Z is selected from the group consisting of O, S, NR.sup.c,
C.dbd.O, O(C.dbd.O), (C.dbd.O)O, NR.sup.c(C.dbd.O) or
(C.dbd.O)NR.sup.c;
[0041] and the pharmaceutically acceptable salts thereof.
[0042] The present invention also relates to pharmaceutical
compositions comprising the compounds of the present invention and
a pharmaceutically acceptable carrier.
[0043] The present invention also relates to methods for making the
pharmaceutical compositions of the present invention.
[0044] The present invention also relates to methods for eliciting
an estrogen receptor modulating effect in a mammal in need thereof
by administering the compounds and pharmaceutical compositions of
the present invention.
[0045] The present invention also relates to methods for eliciting
an estrogen receptor antagonizing effect in a mammal in need
thereof by administering the compounds and pharmaceutical
compositions of the present invention.
[0046] The present invention also relates to methods for eliciting
an estrogen receptor agonizing effect in a mammal in need thereof
by administering the compounds and pharmaceutical compositions of
the present invention.
[0047] The present invention also relates to methods for treating
or preventing disorders related to estrogen functioning, bone loss,
bone fractures, osteoporosis, cartilage degeneration,
endometriosis, uterine fibroid disease, cancer of the breast,
uterus or prostate, hot flashes, cardiovascular disease, impairment
of cognitive function, cerebral degenerative disorders, restenosis,
gynacomastia, vascular smooth muscle cell proliferation, obesity
and incontinence in a mammal in need thereof by administering the
compounds and pharmaceutical compositions of the present
invention.
[0048] The present invention also relates to methods for reducing
bone loss, lowering LDL cholesterol levels and eliciting a
vasodilatory effect, in a mammal in need thereof by administering
the compounds and pharmaceutical compositions of the present
invention.
DETAILED DESCRIPTION OF THE INVENTION
[0049] The present invention relates to compounds useful as
estrogen receptor modulators. Compounds of the present invention
are described by the following chemical formula: 2
[0050] wherein X is selected from the group consisting of: O,
N--OR.sup.a, N--NR.sup.aR.sup.b and C.sub.1-6 alkylidene, wherein
said alkylidene group is unsubstituted or substituted with a group
selected from hydroxy, amino, O(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl), or N(C.sub.1-4alkyl).sub.2;
[0051] R.sup.1 is selected from the group consisting of hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl, and C.sub.2-6alkynyl, wherein
said alkyl, alkenyl and alkynyl groups are either unsubstituted or
substituted with a group selected from OR.sup.c, SR.sup.c,
NR.sup.bR.sup.c, C(.dbd.O)R.sup.c, C(.dbd.O)CH.sub.2OH, or phenyl,
wherein said phenyl group can either be unsubstituted or
substituted with 1-3 substituents independently selected from the
group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-14alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.- 2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0052] R.sup.2 is selected from the group consisting of hydrogen,
hydroxy, iodo, O(C.dbd.O)R.sup.c, C(.dbd.O)R.sup.c,
CO.sub.2R.sup.c, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl, wherein said alkyl, alkenyl and alkynyl groups
are either unsubstituted or substituted with a group selected from
OR.sup.c, SR.sup.c, NR.sup.bR.sup.c, C(.dbd.O)R.sup.c,
C(.dbd.O)CH.sub.2OH, or phenyl, wherein said phenyl group can
either be unsubstituted or substituted with 1-3 substituents
independently selected from the group consisting of C.sub.1-4alkyl,
OH, O(C.sub.1-4alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2- , halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-4alkyl), C(O)H, and C(O)(C.sub.1-4alkyl);
[0053] or R.sup.1 and R.sup.2, when taken together with the carbon
atom to which they are attached, form a carbonyl group;
[0054] or R.sup.1 and R.sup.2, when taken together, form a
C.sub.1-6 alkylidene group, wherein said alkylidene group is either
unsubstituted or substituted with a group selected from the group
consisting of hydroxy, O(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2,
and phenyl, wherein said phenyl group can either be unsubstituted
or substituted with 1-3 substituents independently selected from
the group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0055] R.sup.3 is selected from the group consisting of hydrogen,
fluoro, chloro, bromo, iodo, cyano, NR.sup.aR.sup.c, OR.sup.a,
C(.dbd.O)R.sup.a, CO.sub.2R.sup.c, CONR.sup.aR.sup.c, SR.sup.a,
S(.dbd.O)R.sup.a, SO.sub.2R.sup.a, C.sub.1-10alkyl,
C.sub.2-10alkenyl, C.sub.2-10alkynyl, C.sub.3-7cycloalkyl, 4-7
membered heterocycloalkyl, cycloalkylalkyl, aryl, heteroaryl,
arylalkyl, and heteroarylalkyl, wherein said alkyl, alkenyl,
alkynyl, cycloalkyl, aryl and heteroaryl groups are either
unsubstituted or independently substituted with 1, 2 or 3 groups
selected from fluoro, chloro, bromo, iodo, cyano, OR.sup.a,
NR.sup.aR.sup.c, O(C.dbd.O)R.sup.a, O(C.dbd.O)NR.sup.aR.sup.c,
NR.sup.a (C.dbd.O)R.sup.c, NR.sup.a (C.dbd.O)OR.sup.c,
C(.dbd.O)R.sup.a, CO.sub.2R.sup.a, CONR.sup.aR.sup.c,
CSNR.sup.aR.sup.c, SR.sup.a, S(O)R.sup.a, SO.sub.2R.sup.a,
SO.sub.2NR.sup.aR.sup.c, YR.sup.d, and ZYR.sup.d;
[0056] R.sup.4 is selected from the group consisting of hydrogen,
hydroxy, amino, methyl, CF.sub.3, fluoro, chloro, and bromo;
[0057] R.sup.5 and R.sup.6 are each independently selected from the
group consisting of hydrogen, fluoro, chloro, bromo, methyl, amino,
OR.sup.b, OR.sup.a, O(C.dbd.O)R.sup.c, O(C.dbd.O)OR.sup.c, and
NH(C.dbd.O)R.sup.c;
[0058] R.sup.7 is selected from the group consisting of hydrogen,
OR.sup.b, NR.sup.bR.sup.c, fluoro, chloro, bromo, iodo, cyano,
nitro, C.sub.1-6alkyl, C.sub.2-6alkenyl, CF.sub.3, and
CHF.sub.2;
[0059] R.sup.8 and R.sup.9 are each independently selected from the
group consisting of hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, and
C.sub.2-6alkynyl,
[0060] or R.sup.8 and R.sup.9, when taken together with the carbon
atom to which they are attached, form a 3-5 membered cycloalkyl
ring,
[0061] or R.sup.8 and R.sup.9, when taken together with the carbon
atom to which they are attached, form a carbonyl group;
[0062] R.sup.10 is selected from the group consisting of hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.2-10alkynyl,
C.sub.3-6cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl
and heteroarylalkyl, wherein said alkyl, alkenyl, alkynyl,
cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl and
heteroarylalkyl groups can be optionally substituted with a group
selected from chloro, bromo, iodo, OR.sup.b, SR.sup.b,
C(.dbd.O)R.sup.b, or 1-5 fluoro,
[0063] or R.sup.10 and R.sup.1, when taken together with the three
intervening carbon atoms to which they are attached, form a 5-6
membered cycloalkyl or cycloalkenyl ring which can be optionally
substituted with 1 or 2 groups selected from oxo, hydroxy, or
C.sub.1-6alkyl;
[0064] R.sup.11 is selected from the group consisting of hydrogen
and C.sub.1-4alkyl;
[0065] R.sup.a is selected from the group consisting of hydrogen,
C.sub.1-10alkyl, and phenyl,
[0066] wherein said alkyl group can be optionally substituted with
a group selected from hydroxy, amino, O(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl), N(C.sub.1-4alkyl).sub.2, phenyl, or 1-5 fluoro,
and
[0067] wherein said phenyl groups can either be unsubstituted or
substituted with 1-3 substituents independently selected from the
group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0068] R.sup.b is selected from the group consisting of hydrogen,
C.sub.1-10alkyl, benzyl and phenyl,
[0069] wherein said phenyl group can either be unsubstituted or
substituted with 1-3 substituents independently selected from the
group consisting of C.sub.1-4alkyl, OH, O(C.sub.1-4alkyl),
NH.sub.2, NH(C.sub.1-4alkyl), NH(C.sub.1-4alkyl).sub.2, halo, CN,
NO.sub.2, CO.sub.2H, CO.sub.2(C.sub.1-4alkyl), C(O)H, and
C(O)(C.sub.1-4alkyl);
[0070] R.sup.c is selected from the group consisting of hydrogen,
C.sub.1-10alkyl and phenyl, wherein said phenyl group can either be
unsubstituted or substituted with 1-3 substituents independently
selected from the group consisting of C.sub.1-4alkyl, OH,
O(C.sub.1-4alkyl), NH.sub.2, NH(C.sub.1-4alkyl),
NH(C.sub.1-4alkyl).sub.2, halo, CN, NO.sub.2, CO.sub.2H,
CO.sub.2(C.sub.1-14alkyl), C(O)H, and C(O)(C.sub.1-4alkyl);
[0071] or R.sup.a and R.sup.c, whether or not on the same atom, can
be taken together with any attached and intervening atoms to form a
4-7 membered ring;
[0072] R.sup.d is selected from the group consisting of
NR.sup.bR.sup.c, OR.sup.a, CO.sub.2R.sup.a, O(C.dbd.O)R.sup.a, CN,
NR.sup.c(C.dbd.O)R.sup.- b, CONR.sup.aR.sup.c,
SO.sub.2NR.sup.aR.sup.c, and a 4-7 membered N-heterocycloalkyl ring
that can be optionally interrupted by O, S, NR.sup.c, or
C.dbd.O;
[0073] Y is selected from the group consisting of CR.sup.bR.sup.c,
C.sub.2-6alkylene and C.sub.2-6alkenylene, wherein said alkylene
and alkenylene linkers can be optionally interrupted by O, S, or
NR.sup.c;
[0074] Z is selected from the group consisting of O, S, NR.sup.c,
C.dbd.O, O(C.dbd.O), (C.dbd.O)O, NR.sup.c(C.dbd.O) or
(C.dbd.O)NR.sup.c;
[0075] and the pharmaceutically acceptable salts thereof.
[0076] In the compounds of the present invention, X is preferably
selected from the group consisting of O and N--OR.sup.a. More
preferably, X is selected from the group consisting of O, N--OH and
N--OCH.sub.3.
[0077] In the compounds of the present invention, R.sup.1 is
preferably selected from the group consisting of hydrogen and
C.sub.1-6alkyl, wherein said alkyl group is either unsubstituted or
substituted with a group selected from OR.sup.c or
C(.dbd.O)R.sup.c.
[0078] In the compounds of the present invention, R.sup.2 is
preferably selected from the group consisting of hydrogen, hydroxy,
iodo, and C.sub.1-6alkyl, wherein said alkyl group is either
unsubstituted or substituted with a group selected from OR.sup.c or
C(.dbd.O)R.sup.c.
[0079] In the compounds of the present invention, R.sup.3 is
preferably selected from the group consisting of hydrogen, chloro,
bromo, iodo, cyano, C.sub.1-10alkyl, C.sub.2-10alkenyl, aryl and
heteroaryl, wherein said alkyl, alkenyl, aryl and heteroaryl groups
are either unsubstituted or independently substituted with 1, 2 or
3 groups selected from fluoro, chloro, bromo, iodo, cyano,
OR.sup.a, NR.sup.aR.sup.c, C(.dbd.O)R.sup.a, CO.sub.2R.sup.c,
NR.sup.aC(.dbd.O)R.sup.c, CONR.sup.aR.sup.c, CSNR.sup.aR.sup.c,
SR.sup.a, YR.sup.d, and ZYR.sup.d.
[0080] In the compounds of the present invention, R.sup.3 is more
preferably selected from the group consisting of hydrogen, chloro,
bromo, iodo, cyano, C.sub.1-10alkyl and aryl, wherein said alkyl
and aryl groups are either unsubstituted or independently
substituted with 1, 2 or 3 groups selected from fluoro,
NR.sup.aR.sup.c, OR.sup.a, YR.sup.d, and ZYR.sup.d.
[0081] In the compounds of the present invention, R.sup.4 is
preferably selected from the group consisting of hydrogen, fluoro,
hydroxy and methyl;
[0082] In the compounds of the present invention, R.sup.5 and
R.sup.6 are each independently preferably selected from the group
consisting of hydrogen, fluoro, O(C.dbd.O)R.sup.c and OR.sup.a.
[0083] In the compounds of the present invention, R.sup.5 is more
preferably selected from the group consisting of hydrogen and
fluoro.
[0084] In the compounds of the present invention, R.sup.6 is more
preferably selected from the group consisting of OR.sup.a and
O(C.dbd.O)R.sup.c.
[0085] In the compounds of the present invention, R.sup.7 is
preferably selected from the group consisting of hydrogen,
NR.sup.bR.sup.c, chloro, bromo, nitro and C.sub.1-6alkyl.
[0086] In the compounds of the present invention, R.sup.8 and
R.sup.9 are each independently preferably selected from the group
consisting of hydrogen and C.sub.1-6alkyl, or R.sup.8 and R.sup.9,
when taken together with the carbon atom to which they are
attached, form a carbonyl group.
[0087] In the compounds of the present invention, R.sup.10 is
preferably selected from the group consisting of hydrogen,
C.sub.1-10alkyl, C.sub.2-10alkenyl, C.sub.3-6cycloalkyl, and
cycloalkylalkyl, wherein said alkyl, alkenyl, cycloalkyl and
cycloalkylalkyl groups can be optionally substituted with a group
selected from OR.sup.b, SR.sup.b, C(.dbd.O)R.sup.b, or 1-5 fluoro,
or R.sup.10 and R.sup.1, when taken together with three intervening
carbon atoms to which they are attached, form a 5-6 membered
cycloalkyl ring which can be optionally substituted with
C.sub.1-6alkyl.
[0088] In the compounds of the present invention, R.sup.11 is
preferably selected from the group consisting of hydrogen and
C.sub.1-4alkyl.
[0089] An embodiment of the invention is a method of eliciting an
estrogen receptor modulating effect in a mammal in need thereof,
comprising administering to the mammal a therapeutically effective
amount of any of the compounds or any of the above pharmaceutical
compositions described above.
[0090] A class of the embodiment is the method wherein the estrogen
receptor modulating effect is an antagonizing effect.
[0091] A subclass of the embodiment is the method wherein the
estrogen receptor is an ER.alpha. receptor.
[0092] A second subclass of the embodiment is the method wherein
the estrogen receptor is an ER.beta. receptor.
[0093] A third subclass of the embodiment is the method wherein the
estrogen receptor modulating effect is a mixed ER.alpha. and
ER.beta. receptor antagonizing effect.
[0094] A second class of the embodiment is the method wherein the
estrogen receptor modulating effect is an agonizing effect.
[0095] A subclass of the embodiment is the method wherein the
estrogen receptor is an ER.alpha. receptor.
[0096] A second subclass of the embodiment is the method wherein
the estrogen receptor is an ER.beta. receptor.
[0097] A third subclass of the embodiment is the method wherein the
estrogen receptor modulating effect is a mixed ER.alpha. and
ER.beta. receptor agonizing effect.
[0098] A third class of the embodiment is the method wherein the
ER.alpha. receptor is an agonizing and antagonizing effect.
[0099] A fourth class of the embodiment is the method wherein the
ER.beta. receptor is an agonizing and antogonizing effect.
[0100] A fifth class of the embodiment is the method wherein the
estrogen receptor modulating effect is a mixed ER.alpha. and
ER.beta. receptor agonizing and antogonizing effect.
[0101] Another embodiment of the invention is a method of treating
or preventing hot flashes in a mammal in need thereof by
administering to the mammal a therapeutically effective amount of
any of the compounds or pharmaceutical compositions described
above.
[0102] Another embodiment of the invention is a method of treating
or preventing anxiety in a mammal in need thereof by administering
to the mammal a therapeutically effective amount of any of the
compounds or pharmaceutical compositions described above.
[0103] Another embodiment of the invention is a method of treating
or preventing depression in a mammal in need thereof by
administering to the mammal a therapeutically effective amount of
any of the compounds or pharmaceutical compositions described
above.
[0104] Exemplifying the invention is a pharmaceutical composition
comprising any of the compounds described above and a
pharmaceutically acceptable carrier. Also exemplifying the
invention is a pharmaceutical composition made by combining any of
the compounds described above and a pharmaceutically acceptable
carrier. An illustration of the invention is a process for making a
pharmaceutical composition comprising combining any of the
compounds described above and a pharmaceutically acceptable
carrier.
[0105] Further exemplifying the invention is the use of any of the
compounds described above in the preparation of a medicament for
the treatment and/or prevention of osteoporosis in a mammal in need
thereof. Still further exemplifying the invention is the use of any
of the compounds described above in the preparation of a medicament
for the treatment and/or prevention of: bone loss, bone resorption,
bone fractures, cartilage degeneration, endometriosis, uterine
fibroid disease, breast cancer, uterine cancer, prostate cancer,
hot flashes, cardiovascular disease, impairment of congnitive
functioning, cerebral degenerative disorder, restenosis, vascular
smooth muscle cell proliferation, incontinence, and/or disorders
related to estrogen functioning.
[0106] The present invention is also directed to combinations of
any of the compounds or any of the pharmaceutical compositions
described above with one or more agents useful in the prevention or
treatment of osteoporosis. For example, the compounds of the
instant invention may be effectively administered in combination
with effective amounts of other agents such as an organic
bisphosphonate or a cathepsin K inhibitor. Nonlimiting examples of
said organic bisphosphonates include alendronate, clodronate,
etidronate, ibandronate, incadronate, minodronate, neridronate,
risedronate, piridronate, pamidronate, tiludronate, zoledronate,
pharmaceutically acceptable salts or esters thereof, and mixtures
thereof. Preferred organic bisphosphonates include alendronate and
pharmaceutically acceptable salts and mixtures thereof. Most
preferred is alendronate monosodium trihydrate.
[0107] The precise dosage of the bisphonate will vary with the
dosing schedule, the oral potency of the particular bisphosphonate
chosen, the age, size, sex and condition of the mammal or human,
the nature and severity of the disorder to be treated, and other
relevant medical and physical factors. Thus, a precise
pharmaceutically effective amount cannot be specified in advance
and can be readily determined by the caregiver or clinician.
Appropriate amounts can be determined by routine experimentation
from animal models and human clinical studies. Generally, an
appropriate amount of bisphosphonate is chosen to obtain a bone
resorption inhibiting effect, i.e. a bone resorption inhibiting
amount of the bisphosphonate is administered. For humans, an
effective oral dose of bisphosphonate is typically from about 1.5
to about 6000 .mu.g/kg body weight and preferably about 10 to about
2000 .mu.g/kg of body weight.
[0108] For human oral compositions comprising alendronate,
pharmaceutically acceptable salts thereof, or pharmaceutically
acceptable derivatives thereof, a unit dosage typically comprises
from about 8.75 mg to about 140 mg of the alendronate compound, on
an alendronic acid active weight basis, i.e. on the basis of the
corresponding acid.
[0109] For use in medicine, the salts of the compounds of this
invention refer to non-toxic "pharmaceutically acceptable salts."
Other salts may, however, be useful in the preparation of the
compounds according to the invention or of their pharmaceutically
acceptable salts. When the compounds of the present invention
contain a basic group, salts encompassed within the term
"pharmaceutically acceptable salts" refer non-toxic salts which are
generally prepared by reacting the free base with a suitable
organic or inorganic acid. Representative salts include the
following: acetate, benzenesulfonate, benzoate, bicarbonate,
bisulfate, bitartrate, borate, bromide, calcium, camsylate,
carbonate, chloride, clavulanate, citrate, dihydrochloride,
edetate, edisylate, estolate, esylate, fumarate, gluceptate,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate,
hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate,
iodide, isothionate, lactate, lactobionate, laurate, malate,
maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulfate, mucate, napsylate, nitrate, N-methylglucamine
ammonium salt, oleate, oxalate, pamoate (embonate), palmitate,
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, sulfate, subacetate, succinate, tannate, tartrate,
teoclate, tosylate, triethiodide and valerate. Furthermore, where
the compounds of the invention carry an acidic moiety, suitable
pharmaceutically acceptable salts thereof may include alkali metal
salts, e.g., sodium or potassium salts; alkaline earth metal salts,
e.g., calcium or magnesium salts; and salts formed with suitable
organic ligands, e.g., quaternary ammonium salts.
[0110] The compounds of the present invention can have chiral
centers and occur as racemates, racemic mixtures, diastereomeric
mixtures, and as individual diastereomers, or enantiomers with all
isomeric forms being included in the present invention. Therefore,
where a compound is chiral, the separate enantiomers, substantially
free of the other, are included within the scope of the invention;
further included are all mixtures of the two enantiomers. Also
included within the scope of the invention are polymorphs, hydrates
and solvates of the compounds of the instant invention.
[0111] The present invention includes within its scope prodrugs of
the compounds of this invention. In general, such prodrugs will be
functional derivatives of the compounds of this invention which are
readily convertible in vivo into the required compound. Thus, in
the methods of treatment of the present invention, the term
"administering" shall encompass the treatment of the various
conditions described with the compound specifically disclosed or
with a compound which may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
the patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985,
which is incorporated by reference herein in its entirety.
Metabolites of these compounds include active species produced upon
introduction of compounds of this invention into the biological
milieu.
[0112] The term "therapeutically effective amount" shall mean that
amount of a drug or pharmaceutical agent that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought by a researcher or clinician.
[0113] The term "bone resorption," as used herein, refers to the
process by which osteoclasts degrade bone.
[0114] The term "alkyl" shall mean a substituting univalent group
derived by conceptual removal of one hydrogen atom from a straight
or branched-chain acyclic saturated hydrocarbon (i.e., --CH.sub.3,
--CH.sub.2CH.sub.3, --CH.sub.2CH.sub.2CH.sub.3,
--CH(CH.sub.3).sub.2, --CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
--CH.sub.2CH(CH.sub.3).sub.2, --C(CH.sub.3).sub.3, etc.).
[0115] The term "alkenyl" shall mean a substituting univalent group
derived by conceptual removal of one hydrogen atom from a straight
or branched-chain acyclic unsaturated hydrocarbon containing at
least one double bond (i.e., --CH.dbd.CH.sub.2,
--CH.sub.2CH.dbd.CH.sub.2, --CH.dbd.CHCH.sub.3,
--CH.sub.2CH.dbd.C(CH.sub.3).sub.2, etc.).
[0116] The term "alkynyl" shall mean a substituting univalent group
derived by conceptual removal of one hydrogen atom from a straight
or branched-chain acyclic unsaturated hydrocarbon containing at
least one triple bond (i.e., --C.ident.CH, --CH.sub.2C.ident.H,
--C.ident.CCH.sub.3, --CH.sub.2C.ident.CCH.sub.2(CH.sub.3).sub.2,
etc.).
[0117] The term "alkylene" shall mean a substituting bivalent group
derived from a straight or branched-chain acyclic saturated
hydrocarbon by conceptual removal of two hydrogen atoms from
different carbon atoms (i.e., --CH.sub.2CH.sub.2--,
--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--,
--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--, etc.).
[0118] The term "alkylidene" shall mean a substituting bivalent
group derived from a straight or branched-chain acyclic saturated
hydrocarbon by conceptual removal of two hydrogen atoms from the
same carbon atom (i.e., .dbd.CH.sub.2, .dbd.CHCH.sub.3,
.dbd.C(CH.sub.3).sub.2, etc.).
[0119] The term "alkenylene" shall mean a substituting bivalent
group derived from a straight or branched-chain acyclic unsaturated
hydrocarbon by conceptual removal of two hydrogen atoms from
different carbon atoms (i.e., --CH.dbd.CH--, --CH.sub.2CH.dbd.CH--,
CH.sub.2CH.dbd.CHCH.sub.2--, --C(CH.sub.3).dbd.C(CH.sub.3)--,
etc.).
[0120] The term "cycloalkyl" shall mean a substituting univalent
group derived by conceptual removal of one hydrogen atom from a
saturated monocyclic hydrocarbon (i.e., cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, or cycloheptyl).
[0121] The term "cycloalkenyl" shall mean a substituting univalent
group derived by conceptual removal of one hydrogen atom from an
unsaturated monocyclic hydrocarbon containing a double bond (i.e.,
cyclopentenyl or cyclohexenyl).
[0122] The term "heterocycloalkyl" shall mean a substituting
univalent group derived by conceptual removal of one hydrogen atom
from a heterocycloalkane wherein said heterocycloalkane is derived
from the corresponding saturated monocyclic hydrocarbon by
replacing one or two carbon atoms with atoms selected from N, O or
S. Examples of heterocycloalkyl groups include, but are not limited
to, oxiranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
and morpholinyl. Heterocycloalkyl substituents can be attached at a
carbon atom. If the substituent is a nitrogen containing
heterocycloalkyl substituent, it can be attached at the nitrogen
atom.
[0123] The term "aryl" as used herein refers to a substituting
univalent group derived by conceptual removal of one hydrogen atom
from a monocyclic or bicyclic aromatic hydrocarbon. Examples of
aryl groups are phenyl, indenyl, and naphthyl.
[0124] The term "heteroaryl" as used herein refers to a
substituting univalent group derived by the conceptual removal of
one hydrogen atom from a monocyclic or bicyclic aromatic ring
system containing 1, 2, 3, or 4 heteroatoms selected from N, O, or
S. Examples of heteroaryl groups include, but are not limited to,
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl, thiazolyl, pyridyl, pyrimidinyl, pyrazinyl,
benzimidazolyl, indolyl, and purinyl. Heteraryl substituents can be
attached at a carbon atom or through the heteroatom.
[0125] In the compounds of the present invention, alkyl, alkenyl,
alkynyl, alkylidene, alkenylene, cycloalkyl, cycloalkenyl,
heterocycloalkyl, aryl and heteroaryl groups can be further
substituted by replacing one or more hydrogen atoms by alternative
non-hydrogen groups. These include, but are not limited to, halo,
hydroxy, mercapto, amino, carboxy, cyano and carbamoyl.
[0126] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., aryl
C.sub.0-8 alkyl) it shall be interpreted as including those
limitations given above for "alkyl" and "aryl." Designated numbers
of carbon atoms (e.g., C.sub.1-10) shall refer independently to the
number of carbon atoms in an alkyl or cyclic alkyl moiety or to the
alkyl portion of a larger substituent in which alkyl appears as its
prefix root.
[0127] The terms "arylalkyl" and "alkylaryl" include an alkyl
portion where alkyl is as defined above and to include an aryl
portion where aryl is as defined above. Examples of arylalkyl
include, but are not limited to, benzyl, fluorobenzyl,
chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl,
chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
Examples of alkylaryl include, but are not limited to, toluyl,
ethylphenyl, and propylphenyl.
[0128] The term "heteroarylalkyl," as used herein, shall refer to a
system that includes a heteroaryl portion, where heteroaryl is as
defined above, and contains an alkyl portion. Examples of
heteroarylalkyl include, but are limited to, pyridylmethyl,
pyridylethyl and imidazoylmethyl.
[0129] The term "cycloalkylalkyl," as used herein, shall refer to a
system that includes a 3- to 8-membered fully saturated cyclic ring
portion and also includes an alkyl portion, wherein cycloalkyl and
alkyl are as defined above.
[0130] In the compounds of the present invention, R.sup.1 and
R.sup.2 can be taken together with the carbon atom to which they
are attached to form a 3-6 membered ring.
[0131] In the compounds of the present invention, R.sup.a and
R.sup.b can be taken together with any of the atoms to which they
may be attached or are between them to form a 4-6 membered ring
system.
[0132] The term "halo" shall include iodo, bromo, chloro and
fluoro.
[0133] The term "oxy" means an oxygen (O) atom. The term "thio"
means a sulfur (S) atom. The term "oxo" means .dbd.O. The term
"oximino" means the .dbd.N--O group.
[0134] The term "substituted" shall be deemed to include multiple
degrees of substitution by a named substitutent. Where multiple
substituent moieties are disclosed or claimed, the substituted
compound can be independently substituted by one or more of the
disclosed or claimed substituent moieties, singly or plurally. By
independently substituted, it is meant that the (two or more)
substituents can be the same or different.
[0135] Under standard nonmenclature used throughout this
disclosure, the terminal portion of the designated side chain is
described first, followed by the adjacent functionality toward the
point of attachment. For example, a C.sub.1-5 alkylcarbonylamino
C.sub.1-6 alkyl substituent is equivalent to 3
[0136] In choosing compounds of the present invention, one of
ordinary skill in the art will recognize that the various
substituents, i.e. R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5,
R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.a, R.sup.b, R.sup.c,
YR.sup.d and ZYR.sup.d are to be chosen in conformity with
well-known principles of chemical structure connectivity.
[0137] Representative compounds of the present invention typically
display submicromolar affinity for alpha and/or beta estrogen
receptors. Compounds of this invention are therefore useful in
treating mammals suffering from disorders related to estrogen
functioning. Pharmacologically effective amounts of the compound,
including the pharmaceutically effective salts thereof, are
administered to the mammal, to treat disorders related to estrogen
functioning, such as bone loss, hot flashes and cardiovascular
disease.
[0138] The compounds of the present invention are available in
racemic form or as individual enantiomers. For convenience, seom
structures are graphically represented as a single enantiomer but,
unless otherwise indicated, is meant to include both racemic and
enantiomeric forms. 4
[0139] It is generally preferable to administer compounds of
structure (I) as enantiomerically pure formulations since most or
all of the desired bioactivity resides with a single enantiomer.
Racemic mixtures can be separated into their individual enantiomers
by any of a number of conventional methods. These include chiral
chromatography, derivatization with a chiral auxillary followed by
separation by chromatography or crystallization, and fractional
crystallization of diastereomeric salts.
[0140] The compounds of the present invention can be used in
combination with other agents useful for treating estrogen-mediated
conditions. The individual components of such combinations can be
administered separately at different times during the course of
therapy or concurrently in divided or single combination forms. The
instant invention is therefore to be understood as embracing all
such regimes of simultaneous or alternating treatment and the term
"administering" is to be interpreted accordingly. It will be
understood that the scope of combinations of the compounds of this
invention with other agents useful for treating estrogen-mediated
conditions includes in principle any combination with any
pharmaceutical composition useful for treating disorders related to
estrogen functioning.
[0141] As used herein, the term "composition" is intended to
encompass a product comprising the specified ingredients in the
specified amounts, as well as any product which results, directly
or indirectly, from combination of the specified ingredients in the
specified amounts.
[0142] The compounds of the present invention can be administered
in such oral dosage forms as tablets, capsules (each of which
includes sustained release or timed release formulations), pills,
powders, granules, elixers, tinctures, suspensions, syrups and
emulsions. Likewise, they may also be administered in intravenous
(bolus or infusion), intraperitoneal, topical (e.g., ocular
eyedrop), subcutaneous, intramuscular or transdermal (e.g., patch)
form, all using forms well known to those of ordinary skill in the
pharmaceutical arts.
[0143] The dosage regimen utilizing the compounds of the present
invention is selected in accordance with a variety of factors
including type, species, age, weight, sex and medical condition of
the patient; the severity of the condition to be treated; the route
of administration; the renal and hepatic function of the patient;
and the particular compound or salt thereof employed. An ordinarily
skilled physician, veterinarian or clinician can readily determine
and prescribe the effective amount of the drug required to prevent,
counter or arrest the progress of the condition.
[0144] Oral dosages of the present invention, when used for the
indicated effects, will range between about 0.01 mg per kg of body
weight per day (mg/kg/day) to about 100 mg/kg/day, preferably 0.01
to 10 mg/kg/day, and most preferably 0.1 to 5.0 mg/kg/day. For oral
administration, the compositions are preferably provided in the
form of tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0,
10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
patient to be treated. A medicament typically contains from about
0.01 mg to about 500 mg of the active ingredient, preferably, from
about 1 mg to about 100 mg of active ingredient. Intravenously, the
most preferred doses will range from about 0.1 to about 10
mg/kg/minute during a constant rate infusion. Advantageously,
compounds of the present invention may be administered in a single
daily dose, or the total daily dosage may be administered in
divided doses of two, three or four times daily. Furthermore,
preferred compounds for the present invention can be administered
in intranasal form via topical use of suitable intranasal vehicles,
or via transdermal routes, using those forms of transdermal skin
patches well known to those of ordinary skill in the art. To be
administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than
intermittant throughout the dosage regimen.
[0145] In the methods of the present invention, the compounds
herein described in detail can form the active ingredient, and are
typically administered in admixture with suitable pharmaceutical
diluents, excipients or carriers (collectively referred to herein
as `carrier` materials) suitably selected with respect to the
intended form of administration, that is, oral tablets, capsules,
elixirs, syrups and the like, and consistent with conventional
pharmaceutical practices.
[0146] For instance, for oral administration in the form of a
tablet or capsule, the active drug component can be combined with
an oral, non-toxic, pharmaceutically acceptable, inert carrier such
as lactose, starch, sucrose, glucose, methyl cellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol
and the like; for oral administration in liquid form, the oral drug
components can be combined with any oral, non-toxic,
pharmaceutically acceptable inert carrier such as ethanol,
glycerol, water and the like. Moreover, when desired or necessary,
suitable binders, lubricants, disintegrating agents and coloring
agents can also be incorporated into the mixture. Suitable binders
include starch, gelatin, natural sugars such as glucose or
beta-lactose, corn sweeteners, natural and synthetic gums such as
acacia, tragacanth or sodium alginate, carboxymethylcellulose,
polyethylene glycol, waxes and the like. Lubricants used in these
dosage forms include sodium oleate, sodium stearate, magnesium
stearate, sodium benzoate, sodium acetate, sodium chloride and the
like. Disintegrators include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like.
[0147] The compounds of the present invention can also be
administered in the form of liposome delivery systems, such as
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine or
phosphatidylcholines.
[0148] Compounds of the present invention may also be delivered by
the use of monoclonal antibodies as individual carriers to which
the compound molecules are coupled. The compounds of the present
invention may also be coupled with soluble polymers as targetable
drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxy-ethylaspartamide-phen- ol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
Furthermore, the compounds of the present invention may be coupled
to a class of biodegradable polymers useful in achieving controlled
release of a drug, for example, polylactic acid, polyglycolic acid,
copolymers of polyactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters,
polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked
or amphipathic block copolymers of hydrogels.
[0149] The novel compounds of the present invention can be prepared
according to the procedure of the following schemes and examples,
using appropriate materials and are further exemplified by the
following specific examples. The compounds illustrated in the
examples are not, however, to be construed as forming the only
genus that is considered as the invention. The following examples
further illustrate details for the preparation of the compounds of
the present invention. Those skilled in the art will readily
understand that known variations of the conditions and processes of
the following preparative procedures can be used to prepare these
compounds. All temperatures are degrees Celsius unless otherwise
noted.
[0150] The compounds of the present invention are prepared
according to the general methods outlined in Schemes I-VIII. In
these schemes, R.sup.I represents one or more of R.sup.4, R.sup.5,
R.sup.6, and R.sup.7, or precursors thereof; R.sup.Ia and R.sup.Ib
represent non-hydrogen values of R.sup.4, R.sup.5, R.sup.6, or
R.sup.7, or precursors thereof; CHR.sup.IIR.sup.III and
CR.sup.III.dbd.CR.sup.IIaR.sup.IIb represent non-hydrogen values of
R.sup.10, or precursors thereof; R.sup.IV represents R.sup.3 or a
precursor thereof; R.sup.IVa and R.sup.IVb represent non-hydrogen
values of R.sup.3, or precursors thereof; R.sup.Va, R.sup.Vb and
CH(OH)R.sup.Vc represent non-hydrogen values of R.sup.1 and
R.sup.2, or precursors thereof; R.sup.VI represents non-hydrogen
R.sup.11; R.sup.VII represents a non-hydrogen value of R.sup.8 or
R.sup.9; R.sup.VIII represents OR.sup.a and NR.sup.aR.sup.b; and
R.sup.IX represents hydrogen or aC.sub.1-5 alkyl group.
[0151] The fundamental methods for construction of 9a-substituted
1,2,9,9a-tertrahydro-3H-fluoren-3-one compounds are illustrated in
Scheme I, and are based on chemistry described by Cragoe, et al.,
J. Med. Chem. 1986, 29, 825-841. In step 1 of Scheme I, a
2-substituted-1-indanone (1b) is reacted with a vinyl ketone in the
presence of base to provide the diketone (2). The diketone is then
cyclized (step 2) under basic or acidic conditions to provide the
tetrahydrofluorenone product (3a). Alternatively, a
2-alkylidene-1-indanone of type (1a), wherein R.sup.II is a carbon
atom substituted with at least one hydrogen atom, reacts with a
vinyl ketone in the presence of base to give the diketone (4).
Cyclization of this intermediate affords a 9a-vinyl substituted
tetrahydrofluorenone (5). In step 1, if one of R.sup.I is NHAc, it
also reacts with the vinyl ketone to form an
N--CH.sub.2CH.sub.2COCH.sub.2R.su- p.IV derivative. This group, as
well as the acetyl group, can be removed at a later stage using
excess sodium hydroxide in ethanol.
[0152] Representative reagents and reaction conditions indicated in
Scheme I as steps 1 and 2 are as follows:
[0153] Step 1 CH.sub.2.dbd.CHC(O)CH.sub.2R.sup.IV, DBN, THF, rt to
60.degree. C. or CH.sub.2.dbd.CHC(O)CH.sub.2R.sup.IV, NaOMe, MeOH,
rt to 60.degree. C.
[0154] Step 2 NaOH, H.sub.2O, MeOH or EtOH, rt to 85.degree. C. or
pyrrolidine, HOAc, THF or PhMe, 60-85.degree. C. or 6N HCl, HOAc,
90-100.degree. C. 5
[0155] The indanone starting materials (1a) and (1b) of Scheme I
are either known compounds or they can be prepared by conventional
methods as outlined in Scheme II. Steps 1-3 of Scheme II, which
produce the 2-substituted-1-indanones (1b), are described in
Cragoe, et al., J. Med. Chem. 1982, 25, 567-579 and references
cited therein, and in Cragoe, et al., J. Med. Chem. 1986, 29,
825-841. The 2-alkylidene-1-indanones (1a) are prepared by reacting
2-unsubstituted indanones (9) with aldehydes or ketones under basic
conditions. Reduction of the double bond (step 5) affords the
indanone (1b). Steps 4 and 5 of Scheme II can be combined to to
provide (1b) directly from (9). Alternatively, 2-substituted
indanones (1b) are obtained by reacting indanones (9) with suitable
alkylating agents in the presence of a base (step 6, Scheme II).
Numerous 2-unsubstituted-1-indanone starting materials of type (9)
are known and other examples can be prepared by procedures
analogous to those used to prepare the known compounds.
[0156] Representative reagents and reaction conditions indicated in
Scheme II as steps 1-6 are as follows:
[0157] Step 1 R.sup.IIIR.sup.IICHCH.sub.2COCl, AlCl.sub.3,
CH.sub.2Cl.sub.2, 0.degree. C. to rt
[0158] Step 2 CH.sub.2(NMe.sub.2).sub.2, Ac.sub.2O, 95.degree. C.
or HCHO, K.sub.2CO.sub.3, MeOH, rt
[0159] Step 3 H.sub.2SO.sub.4, 0.degree. C. to 50.degree. C.
[0160] Step 4 R.sup.IICOR.sup.III, KOH or NaOMe, EtOH, 0.degree. C.
to rt or LDA, THF, -78.degree. C. then R.sup.IICOR.sup.III,
-78.degree. C. to rt when R.sup.IICOR.sup.III is an aldehyde
[0161] R.sup.IICOR.sup.III, LiN(iPr).sub.2, HMPA, -78.degree. C. to
rt when R.sup.IICOR.sup.III is a ketone
[0162] Step 5H.sub.2, 10% Pd/C or 20% Pd(OH).sub.2/C, EtOH or
EtOAc, rt
[0163] Steps 4 and 5 can be combined
[0164] R.sup.IICOR.sup.III, KOH, H.sub.2, 10% Pd/C, EtOH, rt or
[0165] R.sup.IICOR.sup.III, NaOMe, H.sub.2, 20% Pd(OH).sub.2/C,
EtOH, rt
[0166] Step 6 R.sup.IIIR.sup.IICHX, NaH, DMF, 0.degree. C. to rt
where X is Br, I, or OSO.sub.2CF.sub.3 6
[0167] When the indanones (9) and (1b) contain one or two open
sites adjacent to an electron donating R.sup.I group such as
OCH.sub.3 or NHAc, the aromatic ring can be further functionalized
as outlined in Scheme III. Electrophilic aromatic substitution
(step 1 of Scheme III) introduces one or two new substituents
R.sup.Ia ortho to the R.sup.I group. Certain R.sup.Ia groups can be
further transformed (step 2 of Scheme III) to a wide variety of new
substituents R.sup.Ib using well established methods. For example,
intermediate (11a) wherein R.sup.Ia is bromo is converted to
derivatives (11b) wherein R.sup.Ib is alkyl or alkenyl using Stille
or Suzuki coupling procedures. If R.sup.Ia of (11a) is a nitro
group, catalytic hydrogenation provides the corresponding amino
derivative which can be acetylated to provide intermediate (11b)
wherein R.sup.Ib is NHAc. The substituted indanones (11a) and (11b)
are converted into the tetrahydrofluorenones (3b) and (3c) by the
procedures previously described in Scheme I. Certain R.sup.Ib
groups can be further manipulated. For example, reduction of a
vinyl group affords an alkyl group, and an amino group can be
acylated or diazotized and converted to other R.sup.Ib groups such
as OR.sup.a.
[0168] Representative reagents and reaction conditions indicated in
Scheme III as steps 1 and 2 are as follows:
1 Step 1 NCS, MeCN or DMF, rt to 60.degree. C. or R.sup.Ia = Cl
NBS, MeCN or DMF, rt to 60.degree. C. or R.sup.Ia = Br HNO.sub.3,
H.sub.2SO.sub.4, -20.degree. C. R.sup.Ia = NO.sub.2 or 90%
HNO.sub.3, 0.degree. C. Step 2 Stille and Suzuki couplings on
R.sup.Ia = Br Me.sub.4Sn, PdCl.sub.2(PPh.sub.3).sub.2, LiCl, DMF,
R.sup.Ib = Me 100.degree. C. or Bu.sub.3SnCH.dbd.CH.sub.2,
Pd(PPh.sub.3).sub.4, PhMe, R.sup.Ib = CH.dbd.CH.sub.2 100.degree.
C. or PhB(OH).sub.2, Pd(PPh.sub.3).sub.4, Cs.sub.2CO.sub.3, DMF,
R.sup.Ib = Ph 100.degree. C. Reduction of R.sup.Ia = NO.sub.2
H.sub.2, 10% Pd/C, EtOH or EtOAc, rt R.sup.Ib = NH.sub.2
[0169] 7
[0170] Tetrahydrofluorenones of types (3a), (3b) and (3c) wherein
R.sup.IV is hydrogen can be functionalized at the 4-position by the
methods illustrated in Scheme IV for compound (3a). Bromination or
iodination (step 1) affords the 4-halo intermediates (3d). These
compounds can be converted (step 2) by known methods into a variety
of new derivatives (3e) wherein R.sup.IVb is alkyl, alkenyl,
alkynyl, aryl, heteroaryl, CN, OR.sup.a, NR.sup.aNR.sup.b, and
SR.sup.a. If the group R.sup.IVb is, or contains, a functional
group capable of further modification, this can be carried out to
produce additional derivatives. For example, a R.sup.IVb cyano
group can be hydrolyzed to a carboxyl group which in turn can be
converted to carbamoyl groups.
[0171] Representative reagents and reaction conditions indicated in
Scheme IV as steps 1 and 2 are as follows:
2 Step 1 NCS, CCl.sub.4, rt R.sup.IVa = Cl Br.sub.2, NaHCO.sub.3,
CH.sub.2Cl.sub.2 or CCl.sub.4, 0.degree. C. to R.sup.IVa = Br rt or
I.sub.2, NaHCO.sub.3, H.sub.2O, CH.sub.2Cl.sub.2, rt R.sup.IVa = I
Step 2 R.sup.IVbSnBu.sub.3, PdCl.sub.2(PPh.sub.3).sub.2, PhMe,
R.sup.IVb = alkenyl, 100-110.degree. C. or aryl, or heteroaryl
R.sup.IVbSnBu.sub.3, Pd(PPh.sub.3).sub.4, PhMe, 100.degree. C. or
R.sup.IVbB(OH).sub.2, PdCl.sub.2(PPh.sub.3).sub.2,
Cs.sub.2CO.sub.3, DMF, 100.degree. C. or R.sup.IVbB(OH).sub.2,
Pd(PPh.sub.3).sub.4, aq Na.sub.2CO.sub.3, PhMe, 80.degree. C.
(R.sup.IVb).sub.3B, PdCl.sub.2(dppf).CH.sub.2Cl.sub.2, R.sup.IVb =
alkyl Ph.sub.3As, Cs.sub.2CO.sub.3, H.sub.2O, THF, DMF, 60.degree.
C. R.sup.IVbSn(CH.sub.2CH.sub.2CH.sub.2).sub.3N,
Pd(PPh.sub.3).sub.4, R.sup.IVb = alkenyl, PhMe, 100.degree. C.
alkyl, or arylalkyl CuCN, NMP, 160.degree. C. R.sup.IVb = CN
[0172] 8
[0173] Methods for introduction of substituents at the 2-position
are illustrated in Scheme V for the tetrahydrofluorenone derivative
(3a). These methods apply equally well to other
tetrahydrofluorenones such as (3b), (3c), (3d), (3e), and (5). In
general terms, the 2-unsubstituted tetrahydrofluorenone is treated
with a strong base and the resulting ketone enolate is trapped with
an appropriate electrophilic reagent (step 1). If the electrophile
is an alkylating agent of the type R.sup.VaX, then both
monoalkylated (12) and dialkylated products (13a) are obtained,
depending on the specifics of the reaction conditions. The
monoalkylated derivatives (12) can be converted to disubstituted
products (13b) by repeating the procedure (step 2) using the same
or a different electrophilic reagent. This well known methodology
leads to a variety of products wherein R.sup.Va and R.sup.Vb are,
inter alia, alkyl, alkenyl, hydroxy, bromo, and iodo. The ketone
enolate can also be trapped with aldehydes (step 3) to afford
2-alkylidene derivatives (14) and 2-hydroxyalkyl derivatives (15).
Where appropriate, the newly introduced 2-substituent can be
further manipulated to produce additional derivatives. For example,
an R.sup.Va allyl group can be oxidized to CH.sub.2CHO which is
reduced in a subsequent step to CH.sub.2CH.sub.2OH.
[0174] Scheme V also illustrates a special case of C-2
functionalization that provides for 2,9a-bridged products of type
(13c). In this case, R.sup.Vd of (12a) is hydrogen or R.sup.Va and
R.sup.III of (12a) is an alkyl group containing an electrophilic
moiety sich as an iodo, bromo, aldehyde, or keto group. Enol
generation at C-2 (step 4) is followed by intramolecular reaction
at the R.sup.III electrophilic center to afford a bridged product
of type (13c). This compund can be deblocked or modified and then
deblocked to provide the final product. For example, if R.sup.IIIa
is a hydroxy group, modifications include acylation, oxidation,
dehydration, and dehydration followed by reduction.
[0175] Representative reagents and reaction conditions indicated in
Scheme V as steps 1-3 are as follows:
3 Step 1 R.sup.VaX, NaH, DMF, 0.degree. C. to rt (X = Br, I) or
R.sup.Va = alkyl, LDA, THF, 0.degree. C. then R.sup.VaX,
-78.degree. C. to rt alkenyl i) LDA, THF, 0.degree. C. then TMSCl,
R.sup.Va = OH -78.degree. C. to rt ii) MCPBA, NaHCO.sub.3,
CH.sub.2Cl.sub.2, rt I.sub.2, pyridine, CH.sub.2Cl.sub.2, rt to
60.degree. C. or R.sup.Va = I LDA, THF, 0.degree. C. then I.sub.2,
-78.degree. C. to rt Step 2 same as step 1 except use R.sup.VbX to
introduce a different alkyl or alkenyl group Step 3 R.sup.VcCHO,
KOH, MeOH or EtOH, rt or LDA, THF, 0.degree. C. then R.sup.VcCHO,
-78.degree. C. to rt or EtOCHO, NaH, PhH, rt (gives 14, R.sup.Vc =
OH) Step 4 LDA, THF, -78.degree. C. to rt or NaH, DMF, 0.degree. C.
to rt
[0176] 9
[0177] Alkyl substituents are introduced at the 1-position of the
tetrahydrofluorenone platform as outlined in Scheme VI for the
derivative (3a). In step 1, oxidation of the cyclohexenone ring
provides the cyclohexadienone (16). Alternatively, (16) is prepared
by base treatment of the 2-bromo or 2-iodo derivatives (12).
Treatment of the dienone intermediate with an appropriate
organometallic species serves to install the C-1 substituent
R.sup.VI.
[0178] Representative reagents and reaction conditions indicated in
Scheme VI as steps 1-3 are as follows:
4 Step 1 DDQ, dioxane, 80-100.degree. C. Step 2 DBN, DMSO,
80-100.degree. C. Step 3 R.sup.VIMgBr.CuBr.SMe.sub.2, THF,
-78.degree. C. to rt or R.sup.VI.sub.2CuLi, Et.sub.2O or THF,
-50.degree. C. to 0.degree. C.
[0179] 10
[0180] 3-Substituted-1-indanones of type (18), which are known or
can be prepared by the route described in J. Med. Chem. 1981, 24,
457-462, are converted to 9-substituted tetrahydrofluorenones of
types (20a) and (20b) by the methods outlined in Scheme VII.
Reductive alkylation (step 1) of (18) with the appropriate aldehyde
affords intermediate (19) which is deblocked and cyclized under
acidic conditions (step 2) to afford the product (20b).
Alternatively, compound (18) can be converted to the 9-substituted
tetrahydrofluorenone product (20a) using procedures previously
described in Schemes I and II. This methodology is also used to
prepare 9,9a-unsubstituted derivatives (20b) wherein R.sup.VII is
hydrogen and, by extension to 3,3-disubstituted-1-indanones,
9,9-disubstituted tetrahydrofluorenone derivatives. Also shown in
Scheme VII is a method for preparing 9-oxo tetrahydrofluorenones
(23) from indan-1,3-diones (22), which are available by
condensation of phthalates (21) with the appropriate ketone.
[0181] Representative reagents and reaction conditions indicated in
Scheme VII as steps 1-3 are as follows:
5 Step 1 OHCCH.sub.2C(OCH.sub.2CH.sub.2O)CH.sub.2R.sup.I- V, KOH,
EtOH, rt, then H.sub.2, 10% Pd/C, EtOH, rt Step 2 6 N HCl, HOAc,
125.degree. C. Step 3 (R.sup.IIIR.sup.IICHCH.sub.2- ).sub.2CO, NaH,
DMF, rt
[0182] 11
[0183] Modifications to the C-3 ketone are outlined in Scheme VIII
for the tetrahydrofluorenone derivative (3a). The methodology also
applies to the other tetrahydrofluorenone products prepared
according to Schemes III-VII. In step 1, the ketone is reacted with
a hydroxylamine, alkoxyamine, or hydrazine reagent to yield the
3-imino product (24). Products are typically obtained as separable
mixtures of E- and Z-isomers about the imino double bond. Ketone
(3a) also reacts with ylide reagents (step 2) to afford
3-alkylidene derivatives (25).
[0184] Representative reagents and reaction conditions indicated in
Scheme VIII as steps 1 and 2 are as follows:
[0185] Step 1 NH.sub.2OR.sup.a.HCl, pyridine, rt to 60.degree. C.
or NH.sub.2NR.sup.aR.sup.b, EtOH, rt
[0186] Step 2 Ph.sub.3P.sup.+CH.sub.2R.sup.IXBr.sup.-, BuLi, THF, 0
to 50.degree. C. 12
[0187] In Schemes I-VIII, the various R groups often contain
protected functional groups which are deblocked by conventional
methods. The deblocking procedure can occur at the last step or at
an intermediate stage in the synthetic sequence. For example, if
one of R.sup.I is a methoxyl group, it can be converted to a
hydroxyl group by any of a number of methods. These include
exposure to BBr.sub.3 in CH.sub.2Cl.sub.2 at -78.degree. C. to room
temperature, heating with pyridine hydrochloride at 190-200.degree.
C., or treatment with EtSH and AlCl.sub.3 in CH.sub.2Cl.sub.2 at
0.degree. C. to room temperature. Another example involves the use
of methoxymethyl (MOM) protection of alcohols and phenols. The MOM
group is conveniently removed by exposure to hydrochloric acid in
aqueous methanol. Other well known protection-deprotection schemes
can be used to prevent unwanted reactions of various functional
groups contained in the various R substituents.
[0188] The following specific examples, while not limiting, serve
to illustrate the methods of preparation of the
1,2,9,9a-tetrahydro-3H-fluor- en-3-one compounds of the present
invention. All compounds prepared are racemic, but could be
resolved if desired using known methodologies.
EXAMPLE 1
Synthesis of
4-bromo-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3h-fluoren-3--
one
[0189] 13
Step 1: 3-hydroxy-2-methyl-1-[4-(methoxy)phenyl]-1-propanone and
2-methyl-1-[4-(methoxy)phenyl]-2-propen-1-one
[0190] A mixture of 1-[4-(methoxy)phenyl]-1-propanone (2.0 g, 12.2
mmol), 37% formaldehyde in water (1.1 mL, 14.6 mmol), and
K.sub.2CO.sub.3 (1.68 g, 12.2 mmol) in methanol (12 mL) was stirred
at room temperature for 4 days, treated with more K.sub.2CO.sub.3
(1.7 g), and stirred at room temperature for an additional 3 days.
The mixture was diluted with EtOAc (50 mL), washed with water (50
mL) and brine (20 mL), dried over MgSO.sub.4, filtered, and
evaporated under vacuum to a clear oil (2.43 g). Proton NMR
revealed a mixture of 3-hydroxy-2-methyl-1-[4-(methoxy)phe-
nyl]-1-propanone (major),
2-methyl-1-[4-(methoxy)phenyl]-2-propen-1-one (minor), and starting
material (minor).
[0191] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.21 (d,
CH.sub.3), 3.45 (m, COCH), 3.76 (m, CH.sub.2OH), 3.89 (s,
OCH.sub.3), 6.96 and 7.99(two m, aryl-H).
Step 2: 5-methoxy-2-methyl-1-indanone
[0192] The crude product from step 1 (2.4 g) was added in portions
over 10 minutes to ice-cold, conc. H.sub.2SO.sub.4. The resulting
yellow-brown solution was stirred at 0.degree. C. for 1.5 hours,
then at room temperature for 1 hour, and finally at 50.degree. C.
for 12 hours. After cooling to room temperature, the mixture was
partitioned between cold EtOAc (200 mL) and cold water (200 mL).
The organic phase was washed with water (200 mL) and brine (100
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum
to afford 5-methoxy-2-methyl-1-indanone (1.5 g) as a solid.
[0193] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.1.31 (d, CH.sub.3),
2.69 and 3.36 (two dd, 3-CH.sub.2), 2.73 (m, H-2), 3.90 (s,
OCH.sub.3), 6.89 (br s, H-4), 6.92 (dd, H-6), and 7.71 (d,
H-7).
Step 3: 5-methoxy-2-methyl-2-(3-oxo-butyl)-1-indanone
[0194] A solution of 5-methoxy-2-methyl-1-indanone (0.5 g, 2.84
mmol) in anhydrous tetrahydrofuran (3 mL) was treated with
1,8-diazabicyclo[5.4.0]- undec-7-ene (0.085 mL, 0.57 mmol) and
methyl vinyl ketone (0.473 mL, 5.68 mmol). The resulting solution
was placed under a nitrogen atmosphere and stirred at room
temperature overnight. The mixture was diluted with EtOAc (25 mL),
washed with 0.2N HCl (25 mL) and brine (10 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to a yellow oil
(800 mg). The oil was dissolved in CH.sub.2Cl.sub.2 (10 mL) and the
solution added to a small column of EM silica gel 60 (8 mL). The
column was eluted with CH.sub.2Cl.sub.2 (30 ml) and the eluant
evaporated under vacuum to afford
5-methoxy-2-methyl-2-(3-oxo-butyl)-1-indanone (467 mg) as an
oil.
[0195] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.24 (s,
CH.sub.3), 1.90 (m, CH.sub.2CH.sub.2CO), 2.11 (s, COCH.sub.3), 2.38
(m, CH.sub.2CH.sub.2CO), 2.89 and 3.00 (two d, 3-CH.sub.2), 3.90
(s, OCH.sub.3), 6.87 (d, H-4), 6.93 (dd, H-6), and 7.70 (d,
H-7).
Step 4:
7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0196] Pyrrolidine (0.159 mL, 1.9 mmol) and acetic acid (0.109 mL,
1.9 mmol) were added to a solution of
5-methoxy-2-methyl-2-(3-oxo-butyl)-1-in- danone (467 mg, 1.9 mmol)
in toluene (5 mL) and the resulting solution was heated in an oil
bath at 85.degree. C. for 2.5 hours. After cooling to room
temperature, the reaction mixture was diluted with EtOAc (20 mL),
washed with water (20 mL), 5% NaHCO.sub.3 (20 mL), and brine (10
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum
to yield 7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
(430 mg) as a light brown solid.
[0197] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.31 (s,
CH.sub.3), 2.11 and 2.17 (two m, 1-CH.sub.2), 2.51 and 2.65 (two m,
2-CH.sub.2), 2.88 (s, 9-CH.sub.2), 3.87 (s, OCH.sub.3), 6.15 (s,
H-4), 6.85-6.89 (m, H-6 and H-8), and 7.52 (d, H-5).
Step 5:
4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0198] A mixture of
7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-o- ne (32 mg,
0.14 mmol) and NaHCO.sub.3 (60 mg, 0.7 mmol) in CH.sub.2Cl.sub.2
(0.5 ml) was treated with bromine (0.008 mL, 0.154 mmol), and the
resulting mixture was stirred at room temperature for 22 hours. The
mixture was diluted with EtOAc (8 ml), washed with dilute aqueous
Na.sub.2S.sub.2O.sub.3 (4 mL) and brine (4 ml), dried over
MgSO.sub.4, filtrered, and evaporated under vacuum to a yellow oil
(43 mg). This material was purified by preparative layer
chromatography on a 0.05.times.20.times.20 cm silica gel GF plate,
developing twice with CH.sub.2Cl.sub.2, to afford
4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahyd- ro-3H-fluoren-3-one
(20 mg) as a gum. The product was contaminated with a trace of
4,6-dibromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-
-one.
[0199] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.33 (s,
CH.sub.3), 2.13 and 2.21 (two m, 1-CH.sub.2), 2.77 and 2.84 (two m,
2-CH.sub.2), 2.86 and 2.97 (two d, 9-CH.sub.2), 3.89 (s,
OCH.sub.3), 6.88 (d, H-8), 6.93 (dd, H-6), and 8.49 (d, H-5).
Step 6:
4-bromo-7-hydroxy-9a-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0200] 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (0.200 mL, 0.2 mmol) was
added to an ice-cold solution of
4-bromo-7-methoxy-9a-methyl-1,2,9,9a-tetrahydro-3- H-fluoren-3-one
(10 mg, 0.033 mmol) in CH.sub.2CL.sub.2 (0.5 mL). The cooling bath
was removed and the solution was stirred at room temperature for 30
minutes, then treated with more BBr.sub.3 in CH.sub.2CL.sub.2 (0.5
mL, 0.5 mmol) and stirred at room temperature for an additional 60
minutes. The solution was diluted with EtOAc (10 mL), washed with
water (10 mL), 1N HCl (2 mL), and brine (10 ml), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil. The
crude product was purified by preparative layer chromatography on a
0.05.times.20.times.20 cm silica gel GF plate, developing with 5%
CH.sub.3OH in CH.sub.2Cl.sub.2, to afford
4-bromo-7-hydroxy-9a-methyl-1,2,9,9a-tetrahyd- ro-3H-fluoren-3-one
as a gum.
[0201] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.21 (s,
CH.sub.3), 2.02 and 2.12 (two m, 1-CH.sub.2), 2.56 and 2.79 (two m,
2-CH.sub.2), 2.78 and 2.88 (two d, 9-CH.sub.2), 6.79-6.82 (m, H-6
and H-8), and 8.25 (m, H-5).
EXAMPLE 2
Synthesis of
9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3h-fluoren-3--
one
[0202] 14
Step 1: 2-butyl-5-methoxy-1-indanone
[0203] Potassium hydroxide (0.44 g, 85% weight pure, 6.67 mmol) and
10% palladium on activated carbon (0.42 g) were added to a mixture
of 5-methoxy-1-indanone (5.0 g, 30.8 mmol) and butyraldehyde (3.3
mL, 37 mmol) in ethanol (30 mL). The resulting mixture was stirred
under an atmosphere of hydrogen at room temperature for 2 hours.
The mixture was filtered and the filtrate evaporated under vacuum.
The residue was partitioned between EtOAc (200 mL) and water (200
mL) containing 2N HCl (5 mL). The organic phase was washed with
brine (100 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to afford crude 2-butyl-5-methoxy-1-indanone (7.0 g)
as an oil.
[0204] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.93 (t,
CH.sub.3), 1.40 (m, CH.sub.2CH.sub.2), 1.47 and 1.96 (two m,
CH.sub.2), 2.66 (m, H-2), 2.78 and 3.28 (two dd, 3---(CH.sub.2),
3.90 (s, OCH.sub.3), 6.88-6.94 (m, H-4 and H-6), and 7.70 (d,
H-7).
Step 2: 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone
[0205] A solution of crude 2-butyl-5-methoxy-1-indanone (218 mg, 1
mmol) in tetrahydrofuran (THF, 2 mL) was treated with
1,8-diazabicyclo[5.4.0]un- dec-7-ene (DBU, 0.030 mL, 0.2 mmol) and
ethyl vinyl ketone (EVK, 0.200 mL, 2 mmol). The resulting solution
was stirred under a nitrogen atmosphere at room temperature for 16
hours, followed by heating in an oil bath at 60.degree. C. for 24
hours. Evaporation of the solvent under vacuum left a residue that
was shown by NMR to be approximately a 1:1 mixture of starting
material and product. The residue was purified by preparative layer
chromatography on three 0.1.times.20.times.20 cm silica gel GF
plates using 5% EtOAc in CH.sub.2Cl.sub.2 as developing solvent.
The product band was eluted with EtOAc to provide
2-butyl-5-methoxy-2-(3-oxo-- pentyl)-1-indanone (84 mg) as an
oil.
[0206] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.82 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.98 (t, COCH.sub.2CH.sub.3),
1.05 and 1.16 (two m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.23 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.57 (m,
CH.sub.2CH.sub.2CH.sub.2CH.su- b.3), 1.87 (m, CH.sub.2CH.sub.2CO),
2.28 (t, CH.sub.2CH.sub.2CO), 2.33 (m, COCH.sub.2CH.sub.3), 2.85
and 3.00 (two d, 3--CH.sub.2), 3.87 (s, OCH.sub.3), 6.86 (d, H-4),
6.89 (dd, H-6), and 7.65 (d, H-7).
Step 3:
9a-butyl-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0207] A solution of 2-butyl-5-methoxy-2-(3-oxo-pentyl)-1-indanone
(84 mg, 0.28 mmol) in acetic acid (0.5 mL) and 6N HCl (0.5 mL) was
stirred and heated in an oil bath at 100.degree. C. for 21 hours.
After cooling to room temperature, the reaction mixture was
partitioned between EtOAc (20 mL) and water (20 mL). The organic
phase was washed with water (10 mL), 5% NaHCO.sub.3 (20 mL), and
brine (10 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to afford 9a-butyl-7-methoxy-4-meth-
yl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (76 mg) as a gum.
[0208] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.16-1.33 (m, CH.sub.2CH.sub.2), 1.39 and 1.61 (two m,
CH.sub.2), 1.99 and 2.24 (two m, 1-CH.sub.2), 2.48 and 2.59 (two m,
2-CH.sub.2), 2.73 and 2.98 (two d, 9-CH.sub.2), 3.88 (s,
OCH.sub.3), 6.85-6.89 (m, H-6 and H-8), and 7.67 (d, H-5).
Step 4:
9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0209] A solution of
9a-butyl-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fl- uoren-3-one
(76 mg, 0.267 mmol) in anhydrous CH.sub.2Cl.sub.2 (2 mL) was placed
under a nitrogen atmosphere, cooled in an ice bath, and stirred
while 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (0.80 mL, 0.80 mmol) was
added by syringe. The cooling bath was removed and the mixture was
stirred at room temperature for 2 hours. The mixture was
partitioned between EtOAc (20 mL) and water (20 mL) containing 2N
HCl (2 mL). The organic phase was washed with brine (10 mL), dried
over MgSO.sub.4, filtered, and evaporated under vacuum to an oil.
This material was purified by preparative layer chromatography on a
0.1.times.20.times.20 cm silica gel GF plate using 5% MeOH in
CH.sub.2Cl.sub.2 as the developing solvent. The product band was
eluted with 10% MeOH in CH.sub.2Cl.sub.2 and the eluant evaporated
under vacuum to give an oil which was lyophilized from benzene to
afford
9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-on- e
as an amorphous solid.
[0210] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.77 (t,
CH.sub.3), 1.05-1.28 (m, CH.sub.2CH.sub.2 and CHaHb), 1.49 (m,
CHaHb), 1.89 and 2.11 (two m, 1-CH.sub.2), 1.91 (s, 4-CH.sub.3),
2.27 and 2.46 (two m, 2-CH.sub.2), 2.61 and 2.87 (two d,
9-CH.sub.2), 6.72 (dd, H-6), 6.75 (d, H-8), and 7.53 (d, H-5).
EXAMPLE 3
Synthesis of
(3e)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3h-fluor-
en-3-one oxime
[0211] 15
[0212] A solution of
9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fl- uoren-3-one
(60 mg, 0.22 mmol) and hydroxylamine hydrochloride (77 mg, 1.11
mmol) in anhydrous pyridine (0.5 mL) was stirred under a nitrogen
atmosphere at room temperature for 4.3 hours and then heated in an
oil bath at 60.degree. C. for 30 minutes. The reaction mixture was
evaporated under vacuum to an oil which was taken up in EtOAc (10
mL), washed with 1N HCl (2.times.6 ml), water (6 mL) and brine (6
ml), dried over MgSO.sub.4, filtered, and evaporated under vacuum.
The residue was lyophilized from benzene (3 mL) to afford
(3E)-9a-butyl-7-hydroxy-4-methy-
l-1,2,9,9a-tetrahydro-3H-fluoren-3-one oxime as an amorphous
solid.
[0213] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.76 (t,
CH.sub.3), 1.03-1.32 (m, CH.sub.2CH.sub.2CH.sub.2), 1.47 and 1.99
(two m, 1-CH.sub.2), 2.03 (s, 4-CH.sub.3), 2.19 and 2.75 (two m,
2-CH.sub.2), 2.52 and 2.79 (two d, 9-CH.sub.2), 6.63 (dd, H-6),
6.67 (br s, H-8), 7.39 (d, H-5), 9.52 (br s, OH), and 10.75 (s,
OH).
EXAMPLE 4
Synthesis of
9a-[(1e)-1-butenyl]-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3h-
-fluoren-3-one
[0214] 16
Step 1: 2-butylidene-5-methoxy-1-indanone
[0215] A solution of diisopropylamine (0.227 mL, 1.62 mmol) in
anhydrous tetrahydrofuran (THF, 15 mL) was placed under a nitrogen
atmosphere, cooled in an ice bath, and stirred while a 2.0M
solution of butyllithium in pentane (0.771 mL, 1.54 mmol) was added
dropwise over 2 minutes. The solution was stirred at room
temperature for 15 minutes, then cooled in a dry ice-acetone bath
and treated dropwise over 3 minutes with a solution of
5-methoxy-1-indanone (250 mg, 1.54 mmol) in THF (2 mL). After
stirring at -78.degree. C. for 20 minutes, the reaction mixture was
treated with butyraldehyde (0.167 mL, 1.85 mmol). After stirring an
additional 26 minutes at -78.degree. C., the reaction mixture was
removed from the cooling bath and stirred at room temperature for
90 hours. The reaction mixture was treated with saturated aqueous
NH.sub.4Cl solution (10 mL) and extracted with EtOAc (15 mL). The
organic phase was washed with brine (25 ml), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to an oil (353 mg). The crude
product was purified by silica gel chromatography on a Biotage
FLASH 12M column (1.2.times.15 cm), eluting with 7:1 hexanes-EtOAc,
to afford 2-butylidene-5-methoxy-1-indanone (205 mg) as a
solid.
[0216] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 1.00 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.59 (m, CH.sub.2CH.sub.2CH.sub.3), 2.30
(m, CH.sub.2CH.sub.2CH.sub.3), 3.63 (br s, 3-CH.sub.2), 3.91 (s,
OCH.sub.3), 6.82 (m, .dbd.CH), 6.92-6.96 (m, H-4 and H-6), and 7.82
(d, H-7).
Step 2:
2-[(1E)-1-butenyl]-5-methoxy-2-(3-oxo-pentyl)-1-indanone
[0217] A solution of 2-butylidene-5-methoxy-1-indanone (202 mg,
0.934 mmol) in anhydrous tetrahydrofuran (THF, 3.7 mL) was placed
under a nitrogen atmosphere and treated with ethyl vinyl ketone
(EVK, 0.187 mL, 1.87 mmol) followed by
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.028 mL, 0.187 mmol). The
resulting solution was stirred and heated in an oil bath at
60.degree. C. for 5 hours. After cooling to room temperature, the
mixture was diluted with EtOAc (15 mL), washed with 0.2N HCl (10
mL), water (10 mL) and brine (10 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to an oil (270 mg). Proton
NMR of this material showed a 1:1 mixture of product and starting
material. The reaction was rerun using the mixture (270 mg), EVK
(0.187 mL), DBU (0.028 mL), and THF (1.8 mL) with heating at
60.degree. C. for 27 hours. Workup as above gave an oil (448 mg)
which contained no starting material. The crude product was
purified by silica gel chromatography on a Biotage FLASH 12M column
(1.2.times.15 cm), eluting with 4:1 hexanes-EtOAc, to afford
2-[(1E)-1-butenyl]-5-methoxy-2-(3-oxopentyl)-1-indanone (199 mg) as
an oil. The product contained a minor amount of the (Z)-butenyl
isomer as evidenced by proton NMR.
[0218] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.96 (t,
CH.sub.3), 1.03 (t, CH.sub.3), 1.88-2.08 (m, two CH.sub.2),
2.29-2.52 (m, two CH.sub.2), 2.99 and 3.21 (two d, 3-CH.sub.2),
3.90 (s, OCH.sub.3), 5.54 (m, CH.dbd.CHCH.sub.2), 5.60 (td,
CH.dbd.CHCH.sub.2), 6.88 (d, H-4), 6.92 (dd, H-6), and 7.69 (d,
H-7).
Step 3:
9a-[(1E)-1-butenyl]-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one
[0219] A solution of
2-[(1E)-1-butenyl]-5-methoxy-2-(3-oxopentyl)-1-indano- ne (199 mg,
0.663 mmol) in methanol (5 mL) was treated with 2N aqueous NaOH
(1.6 mL) and the resulting mixture was stirred and heated in an oil
bath at 85.degree. C. for 7 hours. After cooling to room
temperature, the brown solution was partitioned between EtOAc (20
mL) and 0.4N HCl (10 mL). The organic phase was separated, washed
with brine (15 ml), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to a brown oil (208 mg). The crude product was
purified by silica gel chromatography on a Biotage FLASH 12S column
(1.2.times.7.5 cm), eluting with 5:1 hexanes:EtOAc, to afford
9a-[(1E)-1-butenyl]-7-methoxy-4-methyl-1,2,9,9a--
tetrahydro-3H-fluoren-3-one (67 mg) as an oil.
[0220] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.87 (t,
CH.sub.3), 1.92 (m, .dbd.CHCH.sub.2CH.sub.3), 2.08-2.19 (m,
1-CH.sub.2), 2.14 (s, 4-CH.sub.3), 2.43 and 2.57 (two m,
2-CH.sub.2), 2.95 (m, 9-CH.sub.2), 3.86 (s, OCH.sub.3), 5.29 (td,
CH.dbd.CHCH.sub.2), 5.42 (td, CH.dbd.CHCH.sub.2), 6.82-6.88 (m, H-6
and H-8), and 7.67 (d, H-5).
Step 4:
9a-[(1E)-1-butenyl]-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one
[0221] A mixture of
9a-[(1E)-1-butenyl]-7-methoxy-4-methyl-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one (31.7 mg, 0.112 mmol) and pyridine
hydrochloride (384 mg, 3.32 mmol) was placed under a nitrogen
atmosphere and heated in an oil bath at 190.degree. C. for 65
minutes. After cooling to room temperature, the reaction mixture
was partitioned between water (4 ml) and EtOAc (10 mL). The organic
phase was recovered, washed with brine (5 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (30
mg). The crude product was purified by silica gel chromatography on
a Biotage FLASH 12S column (1.2.times.7.5 cm), eluting with 3:1
hexanes-EtOAc. The product containing fractions were concentrated
under vacuum and the residue lyophilized from benzene to provide
9a-[(1E)-1-butenyl]-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne as a yellow, amorphous solid.
[0222] .sup.1H NMR (9:1 CDCl.sub.3--CD.sub.3CN, 500 MHz) .delta.
0.85 (t, CH.sub.3), 1.90 (m, .dbd.CHCH.sub.2CH.sub.3), 2.04-2.16
(m, 1-CH.sub.2), 2.12 (s, 4-CH.sub.3), 2.42 and 2.55 (two m,
2-CH.sub.2), 2.91 (m, 9-CH.sub.2), 5.27 (td, CH.dbd.CHCH.sub.2),
5.40 (td, CH.dbd.CHCH.sub.2), 6.68 (br s, OH), 6.77-6.82 (m, H-6
and H-8), and 7.61 (d, H-5).
EXAMPLE 5
Synthesis of
4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne
[0223] 17
Step 1: 2-butyl-5-methoxy-1-indanone
[0224] A mixture of 5-methoxy-1-indanone (25.0 g, 154 mmol), 85%
KOH (2.03 g, 30.8 mmol), 10% palladium on activated carbon (2 g),
and ethanol (150 mL) was placed under a hydrogen atmosphere and
stirred while butyraldehyde (16.7 mL, 185 mmol) was added over 2
minutes. The mixture warmed during the addition. The resulting
mixture was hydrogenated at room temperature for 3 hours, then
filtered to remove the catalyst. The filtrate was acidified with 2N
HCl (15.4 mL, 30.8 mmol) and evaporated under vacuum. The residue
was partitioned between EtOAc (500 mL) and water (500 mL). The
organic phase was washed with water (500 mL) and brine (100 mL),
dried over MgSO.sub.4, filtered, and evaporated under vacuum to an
oil (33.5 g). The crude product was purified by column
chromatography on EM silica gel 60 (230-400 mesh, 670 g), eluting
first with CH.sub.2Cl.sub.2 and then with 5% EtOAc in
CH.sub.2Cl.sub.2, to afford 2-butyl-5-methoxy-1-indanone (17.9 g)
as an oil.
Step 2: 2-butyl-5-methoxy-2-(3-oxo-butyl)-1-indanone
[0225] A mixture of 2-butyl-5-methoxy-1-indanone (17.9 g, 82 mmol),
methyl vinyl ketone (MVK, 8.5 mL, 102 mmol), and
1,8-diazabicylco[5.4.0]undec-7-- ene (2.5 mL, 16.4 mmol) in
anhydrous tetrahydrofuran (45 mL) was stirred under a nitrogen
atmosphere at room temperature for 42 hours. Additional MVK (1.7
mL, 20.5 mmol) was added and the mixture was stirred and heated in
an oil bath at 60.degree. C. for 55 minutes. The resulting solution
of crude 2-butyl-5-methoxy-2-(3-oxo-butyl)-1-indanone was used in
the next step.
Step 3: 9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0226] The solution from step 2 was treated with pyrrolidine (6.9
mL, 82 mmol) and acetic acid (4.7 mL, 82 mmol), placed under a
nitrogen atmosphere, and stirred with heating in a 60.degree. C.
bath for 22 hours. After cooling to room temperature, the reaction
mixture was partitioned between EtOAc (500 mL) and water (500 mL).
The EtOAc phase was washed with 0.8N HCl (500 mL), water (500 mL),
5% NaHCO.sub.3 (500 mL), and brine (200 mL), dried with MgSO.sub.4,
filtered, and evaporated under vacuum to a brown oil (22.8 g). This
material was purified by column chromatography on EM silica gel 60
(230-400 mesh, 684 g), using 5% EtOAc in CH.sub.2Cl.sub.2 as
eluting solvent, to afford
9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (11.2 g) as
a solid.
[0227] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.3), 1.17-1.35 (m, CH.sub.2CH.sub.2), 1.47 and 1.65 (two m,
CH.sub.2), 1.99 and 2.29 (two m, 1-CH.sub.2), 2.47 and 2.58 (two m,
2-CH.sub.2), 2.72 and 3.03 (two d, 9-CH.sub.2), 3.87 (s,
OCH.sub.3), 6.16 (s, H-4), 6.83-6.89 (m, H-6 and H-8), and 7.51 (d,
H-5).
Step 4:
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0228] A solution of
9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-o- ne (11.2 g,
41.4 mmol) in CCl.sub.4 (80 mL) was treated with solid NaHCO.sub.3
(17.4 g, 207 mmol). The mixture was cooled in an ice bath and
rapidly swirled by hand while bromine (2.13 mL, 41.4 mmol) was
added over 6 minutes. After swirling a total of 30 minutes at
0.degree. C., the mixture was diluted with CH.sub.2Cl.sub.2 (100
mL) and water (200 mL), treated with a small scoop of
Na.sub.2SO.sub.3, and shaken. The aqueous phase was re-extracted
with more CH.sub.2Cl.sub.2 (50 mL). The combined CH.sub.2Cl.sub.2
extracts were dried over MgSO.sub.4, filtered, and evaporated under
vacuum. The residue in CH.sub.2Cl.sub.2 (30 mL) was added to a plug
of EM silica gel 60 (230-400 mesh, 50 g) which was eluted with
CH.sub.2Cl.sub.2 to give the product (13.7 g) as a solid. This
material was dissolved in hot 2-propanol (350 mL) and the solution
concentrated under vacuum to a suspension (ca. 100 mL volume). The
solid was collected, washed with 2-propanol (20 mL), and dried
under a nitrogen stream to afford
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluore- n-3-one
(10.4 g).
[0229] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.14-1.32 (m, CH.sub.2CH.sub.2), 1.48 and 1.67 (two m,
CH.sub.2), 2.08 and 2.27 (two m, 1-CH.sub.2), 2.68-2.80 (m,
2-CH.sub.2), 2.80 and 3.03 (two d, 9-CH.sub.2), 3.89 (s,
OCH.sub.3), 6.86 (d, H-8), 6.92 (dd, H-6), and 8.51 (d, H-5).
Step 5:
4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0230] A solution of
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-flu- oren-3-one
(1.00 g, 2.75 mmol) in anhydrous CH.sub.2Cl.sub.2 (27.5 mL) was
cooled in a dry ice-acetone bath and stirred under a nitrogen
atmosphere while 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (8.26 mL, 8.26
mmol) was added dropwise over 14 minutes. The cooling bath was
removed and the solution was stirred at room temperature for 3
hours, during which time it darkened considerably. The mixture was
diluted with EtOAc (150 mL) and shaken with water (150 mL)
containing 2N HCl (10 mL). The organic phase was washed with water
(150 mL) and brine (150 mL), dried with MgSO.sub.4, filtered, and
evaporated under vacuum to a dark green solid (1.1 g). The solid
was dissolved in 10% EtOAc/CH.sub.2Cl.sub.2 (10 mL) and added to a
small column of EM silica gel 60 (230-400 mesh, 12 g). The column
was eluted with 10% EtOAc/CH.sub.2Cl.sub.2. The first 100 mL of
eluant was evaporated under vacuum to a green solid (1.0 g). This
material was further purified by column chromatography on EM silica
gel 60 (230-400 mesh, 30 g) using 5% EtOAc/CH.sub.2Cl.sub.2 as
eluting solvent. The product containing fractions were evaporated
under vacuum to provide a solid (730 mg). This material was treated
with benzene (7 mL) and the mixture heated to reflux. The
suspension was sonicated while cooling to room temperature. The
solid was collected, rinsed with benzene (5 mL), and dried under a
nitrogen stream to afford 4-bromo-9a-butyl-7-hydroxy-1,-
2,9,9a-tetrahydro-3H-fluoren-3-one as a pale green powder.
[0231] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.77 (t,
CH.sub.3), 1.04-1.25 (m, CH.sub.2CH.sub.2), 1.33 and 1.58 (two m,
CH.sub.2), 2.01 and 2.12 (two m, 1-CH.sub.2), 2.52 and 2.70 (two m,
2-CH.sub.2), 2.73 and 2.94 (two d, 9-CH.sub.2), 6.78-6.81 (m, H-6
and H-8), 8.26 (m, H-5), and 10.35 (s, OH).
EXAMPLE 6
Synthesis of
4-bromo-9a-butyl-3-methyene-2,3,9,9a-tetrahydro-1H-fluoren-7--
ol
[0232] 18
[0233] A suspension of methyltriphenylphosphonium bromide (373 mg,
1.04 mmol) in anhydrous tetrahydrofuran (2 mL) was cooled in an ice
bath and stirred under a nitrogen atmosphere while 2.5 N nBuLi in
hexane (0.36 mL, 0.90 mmol) was added by syringe. The mixture was
stirred at 0.degree. C. for 10 minutes to complete formation of the
methylenetriphenylphosporane reagent. A solution of
4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-flu- oren-3-one (50
mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added to the reaction
mixture and the ice bath was removed. The resulting mixture was
stirred at room temperature for 3.2 hours, then at 50.degree. C.
for 1.5 hour, and finally at room temperature for an additional 17
hours. The mixture was partitioned between saturated aqueous
NH.sub.4Cl (5 mL) and EtOAc (9 mL). The organic phase was acidified
with 2N HCl (0.2 mL), washed with brine (4 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (90
mg). The crude product was purified by preparative layer
chromatography on a 0.1.times.20.times.20 cm silica gel GF plate
using 3:1 hexanes-EtOAc as developing solvent. The UV visible band
at R.sub.f 0.50-0.63 was eluted with EtOAc. The eluant was
concentrated under vacuum to a residue which was lyophilized from
benzene to afford
4-bromo-9a-butyl-3-methylene-2,3,9,9a-tetrahydro-1H-fluoren-7-o-
l.
[0234] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.3), 1.1-1.3 (m, CH.sub.2CH.sub.2), 1.36 and 1.55 (two m,
CH.sub.2), 1.70 and 2.06 (two m, 1-CH.sub.2), 2.67 and 2.76 (two m,
2-CH.sub.2), 2.67 and 2.88 (two d, 9-CH.sub.2), 5.02 (s, OH), 5.07
and 5.56 (two m, .dbd.CH.sub.2), 6.75 (m, H-6 and H-8), and 8.25
(d, H-5).
EXAMPLE 7
Synthesis of
9a-butyl-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne
[0235] 19
Step 1:
9a-butyl-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0236] A solution of
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-flu- oren-3-one
(50 mg, 0.138 mmol) in anhydrous 1-methyl-2-pyrrolidinone (0.276
mL) was treated with copper(I) cyanide (25 mg, 0.275 mmol). The
resulting mixture was stirred under a nitrogen atmosphere and
heated in an oil bath at 160.degree. C. for 40 minutes. The mixture
was partitioned between EtOAc (20 mL) and water (20 ml). The
organic phase was washed with water (2.times.20 mL) and brine (10
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum.
The residue was purified by preparative layer chromatography on a
0.1.times.20.times.20 cm silica gel GF plate, developing with 5%
EtOAc in CH.sub.2Cl.sub.2, to afford
9a-butyl-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (33
mg) as an oil.
[0237] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.3), 1.13-1.35 (m, CH.sub.2CH.sub.2), 1.44 and 1.66 (two m,
CH.sub.2), 2.02 and 2.32 (two m, 1-CH.sub.2), 2.61 (m, 2-CH.sub.2),
2.78 and 3.09 (two d, 9-CH.sub.2), 3.92 (s, OCH.sub.3), 6.91 (br s,
H-8), 6.97 (dd, H-6), and 8.33 (d, H-5).
Step 2:
9a-butyl-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0238] A mixture of
9a-butyl-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluo- ren-3-one
(17 mg) and pyridine hydrochloride (2 g) was placed under a
nitrogen atmosphere and heated in an oil bath at 190-195.degree. C.
for 1 hour. After cooling to room temperature, the mixture was
partitioned between EtOAc (20 ml) and water (30 mL). The organic
portion was washed with brine (10 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to an oil (16 mg). The crude
product was purified by preparative layer chromatography on a
0.05.times.20.times.20 cm silica gel GF plate using 5% CH.sub.3OH n
CH.sub.2Cl.sub.2 as the developing solvent. The UV visible product
band was eluted with 10% CH.sub.3OH in CH.sub.2Cl.sub.2, the
solvent evaporated under vacuum, and the residue lyophilized from
benzene-methanol to afford
9a-butyl-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro- -3H-fluoren-3-one
as an amorphous solid.
[0239] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.78 (t,
CH.sub.3), 1.01-1.33 (m, CH.sub.2CH.sub.2 and CHaHb), 1.61 (m,
CHaHb), 1.99 and 2.15 (two m, 1-CH.sub.2), 2.40 and 2.58 (two m,
2-CH.sub.2), 2.71 and 3.01 (two d, 9-CH.sub.2), 6.87 (s, H-8), 6.89
(d, H-6), and 8.04 (d, H-5).
[0240] IR (KBr) 2223, 1648, 1611, 1558, 1467, 1356, 1316, 1296,
1278, 1107, 1066 cm.sup.-1.
EXAMPLE 8
Synthesis of
4-benzyl-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3--
one
[0241] 20
Step 1:
4-benzyl-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0242] A mixture of
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluo- ren-3-one
(29.6 mg, 0.0847 mmol), 5-benzyl-1-aza-5-stanna-bicyclo[3.3.3]un-
decane (38.5 mg, 85% weight pure, 0.0935 mmol), and
Pd(PPh.sub.3).sub.4 (9.8 mg, 0.00848 mmol) in anhydrous toluene
(1.3 mL) was degassed, placed under a nitrogen atmosphere, stirred,
and heated in an oil bath at 100.degree. C. After heating 4 hours,
the cloudy, dark brown reaction mixture was cooled in an ice bath
and filtered through a pad of celite. The filtrate was evaporated
under vacuum to an orange gum (57 mg). The crude product was
purified by preparative layer chromatography on a
0.1.times.20.times.20 cm silica gel GF plate, using 9:1
hexanes-EtOAc as developing solvent. The major UV visible band at
R.sub.f 0.18-0.26 was removed and eluted with EtOAc to afford
4-benzyl-9a-butyl-7-methoxy-1,2,9- ,9a-tetrahydro-3H-fluoren-3-one
(29 mg) as a pale yellow gum.
[0243] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.3), 1.19-1.36 (m, CH.sub.2CH.sub.2), 1.51 and 1.72 (two m,
CH.sub.2), 2.07 and 2.29 (two m, 1-CH.sub.2), 2.52 and 2.64 (two m,
2-CH.sub.2), 2.77 and 3.01 (two d, 9-CH.sub.2), 3.76 and 4.16 (two
d, CH.sub.2Ph), 3.82 (s, OCH.sub.3), 6.71 (dd, H-6), 6.84 (d, H-8),
7.13-7.27 (m, phenyl-H), and 7.42 (d, H-5).
Step 2:
4-benzyl-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0244] A solution of
4-benzyl-9a-butyl-7-methoxy-1,2,9,9a-tetrahydrofluore- n-3-one
(25.9 mg, 0.718 mmol) in anhydrous CH.sub.2Cl.sub.2 (1.2 mL) was
cooled in a dry ice-acetone bath and stirred under a nitrogen
atmosphere while 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (0.215 mL, 0.215
mmol) was added dropwise by syringe. The cooling bath was removed
and the mixture was stirred at room temperature for 3.5 hours,
after which it was diluted with EtOAc (8 mL), water (3 mL) and 2N
HCl (1 mL) and shaken vigorously. The organic phase was separated,
washed with water (3 mL), 1M pH 3 phosphate (3 mL) and brine (3
mL), dried over MgSO.sub.4, filtered and evaporated under vacuum to
a solid (25 mg). The crude product was purified by preparative
layer chromatography on a 0.1.times.20.times.20 cm silica gel GF
plate, using 5% MeOH in CH.sub.2Cl.sub.2 as developing solvent. The
major UV visible band at R.sub.f 0.40-0.53 gave
4-benzyl-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one as
a yellow solid.
[0245] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.3), 1.18-1.36 (m, CH.sub.2CH.sub.2), 1.51 and 1.71 (two m,
CH.sub.2), 2.06 and 2.28 (two m, 1-CH.sub.2), 2.52 and 2.65 (two m,
2-CH.sub.2), 2.74 and 2.98 (two d, 9-CH.sub.2), 3.75 and 4.15 (two
d, CH.sub.2Ph), 6.62 (dd, H-6), 6.78 (d, H-8), 7.13-7.27 (m,
phenyl-H), and 7.36 (d, H-5).
[0246] IR (neat film) 3138, 2929, 1625, 1572, 1468, 1359, 1329,
1299, 1272, 1184, 1104, 1077, 724, and 695 cm.sup.-1.
EXAMPLE 9
Synthesis of
9a-butyl-7-hydroxy-4-(2-thieny)-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0247] 21
Step 1: 9a
butyl-7-methoxy-4-(2-thienyl)-1,2,9,9a-tetrahydro-3H-fluoren-3--
ene
[0248] A mixture of
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluo- ren-3-one
(30 mg, 0.086 mmol), 2-(tributylstannyl)-thiophene (0.055 mL, 0.172
mmol), tris(dibenzylideneacetone)dipalladium(0)
(Pd.sub.2(dba).sub.3, 16 mg, 0.0172 mmol), and anhydrous toluene
(0.5 mL) was placed under a nitrogen atmosphere, stirred, and
heated in an oil bath at 100-110.degree. C. Three additional
Pd.sub.2(dba).sub.3 portions (20-30 mg each) were added at 7, 8,
and 23 hours. An aliquot of the reaction that was removed after
heating for 23.5 hours showed approximately a 1:1 mixture of
starting material and product. The mixture was treated with
bis(triphenylphosphine)-palladium(II) chloride (30 mg) and heating
was continued for 55 minutes to complete the conversion to product.
After cooling to room temperature, the reaction mixture was
purified by preparative layer chromatography on a
0.1.times.20.times.20 cm silica gel GF plate, developing with
CH.sub.2Cl.sub.2, to afford 9a
butyl-7-methoxy-4-(2-thienyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-ene
(16.5 mg) as an oil.
[0249] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.89 (t,
CH.sub.3), 1.23-1.37 (m, CH.sub.2CH.sub.2), 1.53 and 1.75 (two m,
CH.sub.2), 2.14 and 2.33 (two m, 1-CH.sub.2), 2.62 and 2.71 (two m,
2-CH.sub.2), 2.80 and 3.04 (two d, 9-CH.sub.2), 3.81 (s,
OCH.sub.3), 6.51 (d, H-5), 6.58 (dd, H-6), 6.81 (d, H-8), 6.87 (dd,
thienyl H-3), 7.13 (dd, thienyl H-4), and 7.43 (dd, thienyl
H-5).
Step 2: 9a
butyl-7-hydroxy-4-(2-thienyl)-1,2,9,9a-tetrahydro-3H-fluoren-3--
ene
[0250] A solution of 9a
butyl-7-methoxy-4-(2-thienyl)-1,2,9,9a-tetrahydro--
3H-fluoren-3-ene (16.5 mg, 0.048 mmol) in anhydrous
CH.sub.2Cl.sub.2 was placed under nitrogen, cooled in an ice bath,
stirred, and treated with 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (0.145
mL, 0.145 mmol). The cooling bath was removed and the solution was
stirred at room temperature. The demethylation was slow. After 50
minutes, more BBr.sub.3 in CH.sub.2Cl.sub.2 (1.5 mL) was added and
the solution was stirred at room temperature for an additional 50
minutes. The mixture was diluted with EtOAc (10 mL) and washed with
water (8 mL) containing 2N HCl (2 mL). The organic phase was washed
with brine (5 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum. The residue was purified by preparative layer
chromatography on two successive 0.025.times.20.times.20 cm silica
gel GF plates, developing the first with 5% CH.sub.3OH in
CH.sub.2Cl.sub.2 and the second with 2% CH.sub.3OH in
CH.sub.2Cl.sub.2. The product band waas eluted with 10% CH.sub.3OH
in CH.sub.2Cl.sub.2, the eluant concentrated under vacuum, and the
residue lyophilized from benzene to afford 9a
butyl-7-hydroxy-4-(2-thienyl)-1,2,9-
,9a-tetrahydro-3H-fluoren-3-ene as yellow, amorphous solid.
[0251] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.81 (t,
CH.sub.3), 1.11-1.31 (m, CH.sub.2CH.sub.2), 1.37 and 1.64 (two m,
CH.sub.2), 2.04 and 2.18 (two m, 1-CH.sub.2), 2.39 and 2.58 (two m,
2-CH.sub.2), 2.70 and 2.94 (two d, 9-CH.sub.2), 6.25 (d, H-5), 6.41
(dd, H-6), 6.71 (d, H-8), 6.76 (dd, thienyl H-3), 7.09 (dd, thienyl
H-4), and 7.59 (dd, thienyl H-5).
EXAMPLE 10
Synthesis of
9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]-phenyl}-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one
[0252] 22
Step 1:
9a-butyl-7-methoxy-4-(4-methoxymethoxy-phenyl)-1,2,9,9a-tetrahydro-
-3H-fluoren-3-one
[0253] A mixture of
4-bromo-9a-butyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluo- ren-3-one
(800 mg, 2.29 mmol), Pd(PPh.sub.3).sub.4 (132 mg, 0.114 mmol), and
tributyl-(4-methoxymethoxy-phenyl)-stannane (1.174 g, 2.75 mmol) in
anhydrous toluene (11.5 mL) was placed under a nitrogen atmosphere
and heated with stirring in an oil bath at 100.degree. C. After 22
hours, the mixture was cooled to room temperature and evaporated
under vacuum to a dark oil (2.208 g). This material was purified by
chromatography on EM silica gel 60 (230-400 mesh, 115 mL dry),
using 4:1 hexanes-EtOAc as eluting solvent, to afford
9a-butyl-7-methoxy-4-(4-methoxymethoxy-phenyl)-
-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg) as a yellow gum.
[0254] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.88 (t,
CH.sub.3), 1.21-1.38 (m, CH.sub.2CH.sub.2), 1.52 and 1.74 (two m,
CH.sub.2), 2.12 and 2.31 (two m, 1-CH.sub.2), 2.57 and 2.68 (two m,
2-CH.sub.2), 2.77 and 3.01 (two d, 9-CH.sub.2), 3.52 (s,
OCH.sub.3), 3.78 (s, OCH.sub.3), 5.22 (m, OCH.sub.2O), 6.40 (d,
H-5), 6.49 (dd, H-6), 6.78 (d, H-8), and 6.9-7.2 (br m,
phenyl-H).
Step 2:
9a-butyl-4-(4-hydroxyphenyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one
[0255] A suspension of
9a-butyl-7-methoxy-4-(4-methoxymethoxy-phenyl)-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one (813 mg, 2 mmol) in methanol (12
mL) was warmed in an oil bath at 60.degree. C. and treated with
aqueous 2N HCl (4 mL). The resulting mixture was stirred and heated
at 60.degree. C. for two hours, then cooled to room temperature and
evaporated under vacuum to leave a yellow semi-solid. The residue
was dissolved in EtOAc, washed with water and brine, dried over
MgSO.sub.4, filtered, evaporated under vacuum, and stripped with
toluene to afford 9a-butyl-4-(4-hydroxy-phenyl)-
-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (787 mg, ca. 92%
weight pure) as a yellow foam.
[0256] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.88 (t,
CH.sub.3), 1.21-1.38 (m, CH.sub.2CH.sub.2), 1.52 and 1.73 (two m,
CH.sub.2), 2.11 and 2.32 (two m, 1-CH.sub.2), 2.58 and 2.69 (two m,
2-CH.sub.2), 2.77 and 3.01 (two d, 9-CH.sub.2), 3.78 (s,
OCH.sub.3), 6.40 (d, H-5), 6.49 (dd, H-6), 6.77 (d, H-8), and
6.8-7.1 (br m, phenyl-H).
Step 3:
9a-butyl-7-methoxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a--
tetrahydro-3H-fluoren-3-one
[0257] A mixture of crude
9a-butyl-4-(4-hydroxyphenyl)-7-methoxy-1,2,9,9a--
tetrahydro-3H-fluoren-3-one (787 mg, approx. 2 mmol), cesium
carbonate (1.564 g, 4.8 mmol), and 1-(2-chloroethyl)-piperidine
monohydrochloride (442 mg, 2.4 mmol) in acetone (5 mL) was stirred
and heated in an oil bath at 60.degree. C. for 4 hours. After
cooling to room temperature, the mixture was diluted with EtOAc and
filtered to remove salts. The filtrate was washed with water and
brine, dried over MgSO.sub.4, filtered, and evaporated under vacuum
to a yellow gum (0.95 g). The crude product was purified by
chromatography on EM silica gel 60 (230-400 mesh, 50 mL dry) using
2% MeOH+1% Et.sub.3N in EtOAc as eluting solvent. The product
containing fractions were evaporated under vacuum and the residue
stripped with toluene to provide
9a-butyl-7-methoxy-4-{4-[2-(1-piperidiny-
l)ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one (912 mg, 96%
weight pure) as a pale yellow gum.
[0258] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.88 (t,
CH.sub.3), 1.21-1.38 (m, CH.sub.2CH.sub.2), 1.46 (m, 4-CH.sub.2 of
piperidine), 1.52 and 1.73 (two m, CH.sub.2), 1.62 (m, 3-CH.sub.2
and 5-CH.sub.2 of piperidine), 2.11 and 2.31 (two m, 1-CH.sub.2),
2.53 (m, 2-CH.sub.2 and 6-CH.sub.2 of piperidine), 2.57 and 2.68
(two m, 2-CH.sub.2), 2.76 and 3.00 (two d, 9-CH.sub.2), 2.80 (t,
NCH.sub.2CH.sub.2O), 3.77 (s, OCH.sub.3), 4.15 (t,
NCH.sub.2CH.sub.2O), 6.38 (d, H-5), 6.49 (dd, H-6), 6.77 (d, H-8),
and 6.8-7.2 (br m, phenyl-H).
Step 4:
9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a--
tetrahydro-3H-fluoren-3-one and
9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)-
ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one
hydrochloride
[0259] An ice-cold solution of
9a-butyl-7-methoxy-4-{4-[2-(1-piperidinyl)--
ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg, 96%
weight pure, 0.172 mmol) in anhydrous CH.sub.2Cl.sub.2 (1.2 mL) was
placed under a nitrogen atmosphere and treated with EtSH (0.055 mL,
0.743 mmol). The resulting solution was added by syringe to
AlCl.sub.3 (115.2 mg, 0.864 mmol) contained in an ice-cold flask
and kept under nitrogen. The resulting solution was stirred at
0.degree. C. for 3 minutes, then at room temperature for 35
minutes. The mixture was cooled in an ice bath, treated with 0.5N
HCl (1.6 mL) and tetrahydrofuran (1.0 mL), and stirred at 0.degree.
C. for 10 minutes. The resulting mixture was diluted with EtOAc (20
mL) and water (15 mL) and stirred while basifying with solid
NaHCO.sub.3. The layers were separated and the aqueous portion
extracted with EtOAc. The combined organics were washed with brine,
dried over MgSO.sub.4, filtered, and evaporated under vacuum to
afford
9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one as a yellow semi-solid.
[0260] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.82 (t,
CH.sub.3), 1.14-1.32 (m, CH.sub.2CH.sub.2), 1.38 (m, 4-CH.sub.2 of
piperidine), 1.40 and 1.66 (two m, CH.sub.2), 1.50 (m, 3-CH.sub.2
and 5-CH.sub.2 of piperidine), 2.05 and 2.19 (two m, 1-CH.sub.2),
2.36 and 2.57 (two m, 2-CH.sub.2), 2.44 (br m, 2-CH.sub.2 and
6-CH.sub.2 of piperidine), 2.66 (t, NCH.sub.2CH.sub.2O), 2.68 and
2.92 (two d, 9-CH.sub.2), 4.08 (t, NCH.sub.2CH.sub.2O), 6.18 (d,
H-5), 6.35 (dd, H-6), 6.69 (d, H-8), 6.8-7.0 (br m, phenyl-H), and
9.96 (s, OH).
[0261] The product was converted to the hydrochloride salt as
follows. The free base from above was dissolved in EtOAc, diluted
with Et.sub.2O, and treated with 1N HCl in Et.sub.2O (0.2 mL). The
resulting precipitate was collected, washed with Et.sub.2O, and
dried under vacuum to afford
9a-butyl-7-hydroxy-4-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one hydrochloride as a pale orange solid.
[0262] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.82 (t,
CH.sub.3), 1.13-1.33 (m, CH.sub.2CH.sub.2), 1.40 (m, 2H's), 1.67
(m, 2H's), 1.80 (m, 4H's), 2.05 and 2.20 (two m, 1-CH.sub.2), 2.36
and 2.57 (two m, 2-CH.sub.2), 2.69 and 2.93 (two d, 9-CH.sub.2),
3.01 (br s, 2H's), 3.50 (br m, 4H's), 4.42 (t, NCH.sub.2CH.sub.2O),
6.18 (d, H-5), 6.36 (dd, H-6), 6.72 (d, H-8), 6.85-7.1 (br m,
phenyl-H), 10.07 (s, OH or NH), and 10.20 (br s, NH or OH).
[0263] IR (nujol mull) 1644, 1606, 1580, 1509, 1459, 1355, 1330,
1296, 1274, 1240, 1176, 1100, 999, 955, 870, 822, 723, 590, and 534
cm.sup.-1.
[0264] Mass Spectrum, m/e 460.3.
EXAMPLE 11
Synthesis of
9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-1,2,9,9a-tetrahydro-3H-
-fluoren-3-one
[0265] 23
[0266] An ice-cold solution of
9a-butyl-4-(4-hydroxy-phenyl)-7-methoxy-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one (29 mg, 0.08 mmol) in anhydrous
CH.sub.2Cl.sub.2 (1 mL) was added to AlCl.sub.3 (96 mg, 0.72 mmol)
contained in an ice cooled flask. The mixture was stirred at
0.degree. C. under a nitrogen atmosphere and treated with
2-propanethiol (0.056 mL, 0.6 mmol). The resulting mixture was
stirred at 0.degree. C. for 5 minutes and at room temperature for
3.25 hours, then treated with ice (approx. 2 mL), 2N HCl (2 mL) and
EtOAc (4 mL) and stirred for 15 minutes at room temperature. The
EtOAc layer was separated, washed with 1N HCl and brine, dried over
MgSO.sub.4, filtered, and evaporated under vacuum to give a yellow
gum. This material was triturated with benzene to give, after
filtration and drying under vacuum,
9a-butyl-7-hydroxy-4-(4-hydroxy-
phenyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an off-white
solid.
[0267] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.82 (t,
CH.sub.3), 1.12-1.32 (m, CH.sub.2CH.sub.2), 1.39 and 1.64 (two m,
CH.sub.2), 2.03 and 2.18 (two m, 1-CH.sub.2), 2.35 and 2.55 (two m,
2-CH.sub.2), 2.67 and 2.91 (two d, 9-CH.sub.2), 6.19 (d, H-5), 6.35
(dd, H-6), 6.68 (d, H-8), 6.7-7.9 (br m, phenyl-H), 9.41 (s, OH),
and 9.97 (s, OH).
[0268] IR (nujol mull) 1608, 1572, 1512, 1480, 1359, 1333, 1300,
1270, 1239, 1207, 1101, 821, and 674 cm.sup.-1.
[0269] Mass spectrum, m/e 349.1 (M+1).
EXAMPLE 12
Synthesis of
(2e)-3-[4-(9a-butyl-7-hydroxy-3-oxo-2,3,9,9a-tetrahydro-1H-fl-
uoren-4-yl)phenyl]1-2-propenoic Acid
[0270] 24
Step 1:
9a-butyl-7-methoxy-4-(4-trifluoromethanesulfonyloxy-phenyl)-1,2,9,-
9a-tetrahydro-3H-fluoren-3-one
[0271] A solution of
9a-butyl-4-(4-hydroxyphenyl)-7-methoxy-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one (303 mg, 91% weight pure, 0.76 mmol) and
pyridine (0.307 mL, 3.8 mmol) in anhydrous CH.sub.2Cl.sub.2 (1.2
mL) was cooled in an ice bath and stirred under a nitrogen
atmosphere while trifluoromethanesulfonic anhydride (0.147 mL, 0.87
mmol) was added dropwise by syringe. After stirring at 0.degree. C.
for 45 minutes, the reaction mixture was diluted with
CH.sub.2Cl.sub.2 (20 mL) and shaken with water (10 ml) containing
1N NaOH (5 mL). The organic phase was separated, washed with water
(10 mL), 1M pH 3 phosphate buffer (10 mL), water (10 mL), and brine
(10 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to an orange solid (394 mg). The crude product was purified
by flash chromatography on EM silica gel 60 (230-400 mesh, 25 mL
dry, packed under 4:1 hexanes-EtOAc) using 4:1 hexanes-EtOAc as
eluting solvent. The product containing fractions were evaporated
under vacuum to a yellow solid (345 mg). This material was
triturated with petroleum ether and dried under vacuum to afford
9a-butyl-7-methoxy-4-[4--
(trifluoromethane-sulfonyloxy)-phenyl]-1,2,9,9a-tetrahydro-3H-fluoren-3-on-
e (313 mg) as a pale yellow solid.
[0272] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.88 (t,
CH.sub.3), 1.20-1.38 (m, CH.sub.2CH.sub.2), 1.51 and 1.73 (two m,
CH.sub.2), 2.13 and 2.34 (two m, 1-CH.sub.2), 2.58 and 2.69 (two m,
2-CH.sub.2), 2.79 and 3.03 (two d, 9-CH.sub.2), 3.79 (s,
OCH.sub.3), 6.21 (d, H-5), 6.48 (dd, H-6), 6.79 (d, H-8), and
7.10-7.45 (br m, phenyl-H).
Step 2: methyl
(2E)-3-[4-(9a-butyl-7-methoxy-3-oxo-2,3,9,9a-tetrahydro-1H--
fluoren-4-yl)phenyl]-2-propenoate
[0273] A mixture of
9a-butyl-7-methoxy-4-[4-(trifluoromethane-sulfonyloxy)-
-phenyl]-1,2,9,9a-tetrahydro-3H-fluoren-3-one (98.9 mg, 0.2 mmol),
methyl (E)-3-tributylstannyl-acrylate (112.5 mg, 0.3 mmol) and
lithium chloride (25.4 mg, 0.6 mmol) in anhydrous dimethylformamide
(1.0 mL) was purged with nitrogen and treated with
bis(triphenylphosphine)palladium(II) chloride (7.0 mg, 0.01 mmol).
The resulting mixture was purged with nitrogen then stirred under a
nitrogen atmosphere with heating in an oil bath at 90.degree. C.
for 60 minutes. After cooling, the solvent was evaporated under
vacuum. The residue in EtOAc (10 mL) was washed with water
(2.times.5 mL) and brine (5 ml), dried over MgSO.sub.4, filtered,
and evaporated under vacuum to a gum (194 mg). The crude product
was purified by preparative layer chromatography (PLC) on two
0.1.times.20.times.20 cm silica gel GF plates, developing with
4:1-hexanes-EtOAc. The major UV visible band at R.sub.f 0.15-0.25
was eluted with EtOAc and the solvent evaporated under vacuum to
afford methyl
(2E)-3-[4-(9a-butyl-7-methoxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-
-4-yl)phenyl]-2-propenoate (83 mg) as a pale yellow solid. NMR
showed approximately 7-8% of a Bu.sub.3SnX impurity.
[0274] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.89 (t,
CH.sub.3), 1.21-1.39 (m, CH.sub.2CH.sub.2), 1.53 and 1.74 (two m,
CH.sub.2), 2.13 and 2.33 (two m, 1-CH.sub.2), 2.58 and 2.69 (two m,
2-CH.sub.2), 2.79 and 3.03 (two d, 9-CH.sub.2), 3.78 (s,
OCH.sub.3), 3.82 (s, OCH.sub.3), 6.36 (d, H-5), 6.48 (dd, H-6),
6.48 and 7.75 (two d, CH.dbd.CH), 6.79 (d, H-8), 7.05-7.25 (br m,
two phenyl-H), and 7.5-7.66 (br m, two phenyl-H).
Step 3:
(2E)-3-[4-(9a-butyl-7-hydroxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-
-4-yl)phenyl]-2-propenoic Acid
[0275] A mixture of methyl
(2E)-3-[4-(9a-butyl-7-methoxy-3-oxo-2,3,9,9a-te-
trahydro-1H-fluoren-4-yl)phenyl]-2-propenoate (60 mg, 92% weight
pure, 0.128 mmol) and pyridine hydrochloride (741 mg, 6.41 mmol)
was placed under a nitrogen atmosphere, heated in an oil bath at
190.degree. C., and stirred. The reaction flask was periodically
dipped deeper into the heating bath in order to melt the pyridine
hydrochloride that condensed on the sides of the flask. After 2
hours at 190.degree. C., the reaction mixture was cooled to room
temperature and partitioned between EtOAc (10 mL) and water (10
mL). The aqueous phase was extracted with more EtOAc (2.times.5
mL). The combined EtOAc extracts were washed with brine, dried over
MgSO.sub.4, filtered, and evaporated under vacuum to a yellow solid
(55 mg). The crude product was suspended in EtOAc (10 mL) and
extracted with 5% NaHCO.sub.3 (5 mL). The NaHCO.sub.3 solution was
acidified with 2N HCl (2.5 mL) and extracted with EtOAc (2.times.5
mL). The latter EtOAc extracts were combined, washed with brine,
dried over MgSO.sub.4, filtered, and evaporated under vacuum to a
yellow solid (39.4 mg). This material was triturated with diethyl
ether and dried under vacuum to afford
(2E)-3-[4-(9a-butyl-7-hydroxy-3-oxo-2,3,9,9a-tetrahydro-1H-fluoren-
-4-yl)phenyl]-2-propenoic acid as a pale yellow solid.
[0276] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. 0.89 (t,
CH.sub.3), 1.21-1.41 (m, CH.sub.2CH.sub.2), 1.55 and 1.76 (two m,
CH.sub.2), 2.15 and 2.34 (two m, 1-CH.sub.2), 2.51 and 2.71 (two m,
2-CH.sub.2), 2.76 and 3.01 (two d, 9-CH.sub.2), 6.24 (d, H-5), 6.34
(dd, H-6), 6.53 and 7.73 (two d, CH.dbd.CH), 6.71 (d, H-8), 7.0-7.3
(br m, two phenyl-H), and 7.6-7.72 (br m, two phenyl-H).
[0277] Mass spectrum, m/e 403.3 (M+1).
EXAMPLE 13
Synthesis of
9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3--
one
[0278] 25
Step 1: 4-bromo-2-butyl-5-methoxy-1-indanone
[0279] A solution of 2-butyl-5-methoxy-1-indanone (1.869 g, 8.56
mmol) in anhydrous dimethylformamide (8.6 mL) was treated with
N-bromosuccinamide (1.676 g, 9.42 mmol). The resulting mixture was
stirred under a nitrogen atmosphere and at room temperature for 14
hours, and then heated in an oil bath at 50.degree. C. for 4 hours.
After cooling to room temperature, the mixture was diluted with
EtOAc (100 mL), washed with water (4.times.50 mL) and brine (50
mL), dried over MgSO4, and evaporated under vacuum to a dark amber
oil (2.468 g). The crude product was purified by column
chromatography on EM silica gel 60 (230-400 mesh, 620 mL dry,
packed under CH.sub.2Cl.sub.2), using CH.sub.2Cl.sub.2 as eluting
solvent, to afford 4-bromo-2-butyl-5-methoxy-1-indanone (1.267 g,
contains approx. 3% of the 6-bromo isomer) as a pale tan solid.
Earlier fractions afforded the 6-bromo isomer.
[0280] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.92 (t,
CH.sub.3), 1.30-1.46 (m, CH.sub.2CH.sub.2), 1.47 and 1.95 (two m,
CH.sub.2), 2.68 (m, H-2), 2.72 and 3.25 (two dd, 3-CH.sub.2), 3.99
(s, OCH.sub.3), 6.93 and 7.70 (two d, H-6 and H-7).
Step 2: 2-butyl-5-methoxy-4-methyl-1-indanone
[0281] A solution of 4-bromo-2-butyl-5-methoxy-1-indanone (1.159 g,
3.90 mmol) in anhydrous dimethylformamide (39 mL) was treated with
LiCl (455 mg, 10.73 mmol), PPh.sub.3 (205 mg, 0.78 mmol),
PdCl.sub.2(PPh.sub.3).sub- .2 (205 mg, 0.292 mmol) and Me.sub.4Sn
(1.08 mL, 7.80 mmol). The mixture was placed under a nitrogen
atmosphere, then stirred and heated in an oil bath at 100.degree.
C. for 16.5 hours. After cooling to room temperature, the mixture
was diluted with water (100 mL) and extracted with Et.sub.2O (100
mL, 2.times.25 mL). The ether extracts were washed with brine,
dried over MgSO.sub.4, filtered and evaporated under vacuum to a
yellow solid (1.29 g). This material was purified by chromatography
on EM silica gel 60 (230-400 mesh, 130 mL dry, packed under
CH.sub.2Cl.sub.2), using CH.sub.2Cl.sub.2 as eluting solvent, to
afford a 92:3:5 mixture (0.90 g) of
2-butyl-5-methoxy-4-methyl-1-indanone, the 6-methyl isomer, and the
desmethyl product. This material was used as is in the next
step.
[0282] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.92 (t,
CH.sub.3), 1.30-1.48 (m, CH.sub.2CH.sub.2 and CHaHb), 1.95 (m,
CHaHb), 2.18 (s, 4-CH.sub.3), 2.63 (m, H-2), 2.65 and 3.19 (two dd,
3-CH.sub.2), 3.91 (s, OCH.sub.3), 6.89 and 7.63 (two d, H-6 and
H-7).
Step 3: 2-butyl-5-methoxy-4-methyl-2-(3-oxo-butyl)-1-indanone
[0283] Methyl vinyl ketone (MVK, 0.49 mL, 5.9 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.12 mL, 0.8 mmol) were
added to a solution of impure 2-butyl-5-methoxy-4-methyl-1-indanone
(0.90 g, 3.9 mmol) in anhydrous tetrahydrofuran (THF, 3.9 mL). The
resulting solution was stirred at room temperature for 30 hours,
then diluted with Et.sub.2O (50 mL), washed with water (20 mL), 1N
HCl (20 mL), and brine (20 mL), dried over MgSO.sub.4, filtered,
and evaporated under vacuum to an amber oil (1.23 g). The crude
product was purified by chromatography on EM silica gel 60 (230-400
mesh, 125 mL dry, packed under 4:1 hexanes-EtOAc). The column was
eluted with 4:1 hexanes-EtOAc, collecting 25 mL fractions.
Fractions 14-27 gave a 93:2:5 mixture (0.96 g) of
2-butyl-5-methoxy-4-met- hyl-2-(3-oxo-butyl)-1-indanone, the
6-methyl isomer, and the desmethyl product. This material was used
in the next step.
[0284] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.83 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.07 and 1.17 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.24 (m,
CH.sub.2CH.sub.2CH.sub.2CH.su- b.3), 1.59 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.81-1.95 (m,
CH.sub.2CH.sub.2CO), 2.06 (s, 4-CH.sub.3), 2.17 (s, COCH.sub.3),
2.31 (t, CH.sub.2CH.sub.2CO), 2.75 and 2.91 (two d, 3-CH.sub.2),
3.91 (s, OCH.sub.3), 6.90 and 7.61 (two d, H-6 and H-7).
Step 4:
9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0285] A solution of impure
2-butyl-5-methoxy-4-methyl-2-(3-oxo-butyl)-1-i- ndanone (0.96 g,
3.17 mmol), acetic acid (0.182 mL, 3.18 mmol) and pyrrolidine
(0.265 mL, 3.18 mmol) in anhydrous toluene (15.9 mL) was stirred
and heated in an oil bath at 80.degree. C. for 16 hours. After
cooling, the reaction mixture was diluted with Et.sub.2O (100 mL),
washed with 1N HCl (2.times.25 mL), 5% NaHCO.sub.3 (50 mL), and
brine (50 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to a dark brown oil (0.86 g). The crude product was
purified by chromatography on a Biotage FLASH 40S column, eluting
with 9:1 hexanes-EtOAc, to afford
9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
(0.50 g) as an off-white solid.
[0286] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.3), 1.16-1.32 (m, CH.sub.2CH.sub.2), 1.44 and 1.63 (two m,
CH.sub.2), 1.97 and 2.29 (two m, 1-CH.sub.2), 2.15 (s, 8-CH.sub.3),
2.44 and 2.55 (two m, 2-CH.sub.2), 2.58 and 2.99 (two d,
9-CH.sub.2), 3.88 (s, OCH.sub.3), 6.82 (d, H-6), and 7.41 (d,
H-5).
Step 5:
9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0287] A solution of
9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fl- uoren-3-one
(28.4 mg, 0.1 mmol) in anhydrous CH.sub.2Cl.sub.2 (1.7 mL) was
stirred under a nitrogen atmosphere and cooled in a dry ice-acetone
bath while 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (0.30 mL, 0.3 mmol) was
added dropwise by syringe. The cooling bath was removed and the
reaction mixture was stirred at room temperature for 4 hours. The
mixture was diluted with EtOAc (8 mL), water (3 mL) and 1N HCL (1
mL) and shaken vigorously. The EtOAc layer was separated, washed
with water (3 mL), 1M pH 3 phosphate (3 mL) and brine (3 mL), dried
over MgSO.sub.4, filtered and evaporated under vacuum to give an
ochre solid (26.8 mg). The crude product was suspended in
CDCl.sub.3 (1 mL) and filtered. The solid portion was dried under
vacuum to afford 9a-butyl-7-hydroxy-8-methyl-1,2,-
9,9a-3H-tetrahydro-fluoren-3-one as an olive colored powder.
[0288] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.79 (t,
CH.sub.3), 1.07-1.27 (m, CH.sub.2CH.sub.2), 1.32 and 1.54 (two m,
CH.sub.2), 1.88 and 2.18 (two m, 1-CH.sub.2), 2.04 (s, 8-CH.sub.3),
2.23 and 2.44 (two m, 2-CH.sub.2), 2.54 and 2.92 (two d,
9-CH.sub.2), 6.00 (s, H-4), 6.77 (H-6), 7.38 (d, H-5), and 9.99 (br
s, OH).
[0289] IR (nujol mull) 1624, 1602, 1575, 1452, 1436, 1361, 1291,
1265, 1253, 1236, 1220, 1200, 1062, 1048, 991, 889, and 830
cm.sup.-1.
[0290] Mass spectrum, m/e 271.1 (M+1).
EXAMPLE 14
Synthesis of
4-bromo-9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fl-
uoren-3-one
[0291] 26
Step 1:
4-bromo-9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-
-3-one
[0292] A mixture of
9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-flu- oren-3-one
(133 mg, 0.468 mmol), CCl.sub.4 (0.94 mL), and NaHCO.sub.3 (196 mg,
2.333 mmol) was cooled in an ice bath and stirred. Bromine (0.024
mL, 0.467 mmol) was added while stirring and swirling the reaction
mixture by hand. A gummy, red precipitate formed during the
addition. The mixture was swirled by hand for 5 minutes in order to
break up the gum, which gradually changed to a stirrable orange
solid. The mixture was stirred and swirled a total of 35 minutes at
0.degree. C. The mixture was diluted with CH.sub.2Cl.sub.2 and
water and shaken. The organic phase was separated, washed with
water containing Na.sub.2S.sub.2O.sub.4, washed with brine, dried
over MgSO.sub.4, filtered, and evaporated under vacuum to a yellow
gum (241 mg). The crude product was purified by preparative layer
chromatography on two 0.1.times.20.times.20 cm silica gel GF
plates, developing with 4:1 hexanes-EtOAc. The major UV visible
band at R.sub.f 0.39-0.50 was eluted with EtOAc and evaporated
under vacuum to give
4-bromo-9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-
-one (151 mg) as a white solid.
[0293] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.3), 1.16-1.29 (m, CH.sub.2CH.sub.2), 1.46 and 1.64 (two m,
CH.sub.2), 2.07 and 2.27 (two m, 1-CH.sub.2), 2.16 (s, 8-CH.sub.3),
2.65 and 2.99 (two d, 9-CH.sub.2), 2.68-2.79 (m, 2-CH.sub.2), 3.91
(s, OCH.sub.3), 6.84 (d, H-6), and 8.42 (d, H-5).
Step 3:
4-bromo-9a-butyl-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-
-3-one
[0294] A solution of
4-bromo-9a-butyl-7-methoxy-8-methyl-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one (36.3 mg, 0.1 mmol) in anhydrous
CH.sub.2Cl.sub.2 (1.7 mL) was cooled in a dry ice-acetone bath and
stirred under a N.sub.2 atmosphere. A 1 M solution of BBr.sub.3 in
CH.sub.2Cl.sub.2 (0.30 mL, 0.3 mmol) was added dropwise by syringe.
The cooling bath was removed and the mixture was stirred at room
temperature for 3.5 hours. The mixture was diluted with water (3
mL), 1N HCl (1 mL), and EtOAc (8 mL) and shaken. The EtOAc phase
was separated, washed with water (3 mL), 1M pH 3 phosphate (3 mL)
and brine (3 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to give a dark green gum (38 mg). This material was
purified by preparative layer chromatography on a
0.1.times.20.times.20 cm silica gel GF plate using 5% MeOH in EtOAc
as developing solvent. The major UV visible band at R.sub.f
0.40-0.51 was eluted with EtOAc to give a yellow solid (23.5 mg).
The solid was recrystallized from Et.sub.2O-hexanes to afford
4-bromo-9a-butyl-7-hydrox-
y-8-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an off-white,
fibrous solid.
[0295] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.3), 1.15-1.29 (m, CH.sub.2CH.sub.2), 1.47 and 1.65 (two m,
CH.sub.2), 2.07 and 2.27 (two m, 1-CH.sub.2), 2.20 (s, 8-CH.sub.3),
2.66 and 2.99 (two d, 9-CH.sub.2), 2.69-2.80 (m, 2-CH.sub.2), 6.83
(d, H-6), and 8.33 (d, H-5).
[0296] .sup.13C NMR (CDCl.sub.3, 125 MHz) .delta. 11.78, 13.93,
23.09, 27.56, 31.29, 34.18, 38.00, 42.05, 51.27, 112.36, 114.44,
120.23, 127.11, 127.13, 130.31, 150.37, 157.40, 169.38, and
191.45.
[0297] IR (nujol mull) 1637, 1552, 1458, 1376, 1293, 1251, 1203,
1064, 825, and 735 cm.sup.-1.
[0298] Mass spectrum, m/e 349.0 (M+1), 351.0.
EXAMPLE 15
Synthesis of
9a-butyl-4,8-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0299] 27
Step 1: 2-butyl-5-methoxy-4-methyl-2-(3-oxopentyl)-1-indanone
[0300] A solution of 2-butyl-5-methoxy-4-methyl-1-indanone (100 mg,
0.43 mmol) in tetrahydrofuran (0.43 mL) was treated with ethyl
vinyl ketone (EVK, 0.064 mL, 0.646 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 0.013 mL, 0.086 mmol). The
resulting solution was stirred under a nitrogen atmosphere and
heated in an oil bath at 60.degree. C. After 24 hour, more EVK
(0.064 mL) and DBU (0.013 mL) were added and the solution was
heated an additional 24 hours at 60.degree. C. The reaction mixture
was diluted with EtOAc (10 mL) and washed with water (10 mL)
containing 2N HCl (1 mL). The organic phase was washed with brine
(5 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to provide crude
2-butyl-5-methoxy-4-methyl-2-(3-oxopentyl)-1-indanone.
[0301] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.01 (t, COCH.sub.2CH.sub.3),
1.08 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.26 (m,
CH.sub.2CH.sub.2CH.sub.2CH.su- b.3), 1.61 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.91 (m, CH.sub.2CH.sub.2CO),
2.19 (s, 4-CH.sub.3), 2.30 (m, CH.sub.2CH.sub.2CO), 2.36 (m,
COCH.sub.2CH.sub.3), 2.78 and 2.93 (two d, 3-CH.sub.2), 3.94 (s,
OCH.sub.3), 6.92 (d, H-6), and 7.63 (d, H-7).
Step 2: 9a
butyl-4,8-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne
[0302] A solution of the crude diketone from step 1 in acetic acid
(1 mL) and 6N HCl (1 mL) was stirred and heated in an oil bath at
100.degree. C. for 5 hours. After cooling, the reaction mixture was
diluted with EtOAc (20 mL), washed with water (10 mL) and brine (10
mL), dried over MgSO.sub.4, filtered, and the solvent evaporated
under vacuum. The residue was purified by preparative layer
chromatography on two 0.1.times.20.times.20 cm silica gel GF
plates, using 5% EtOAc in CH.sub.2Cl.sub.2 as developing solvent,
to afford 9a
butyl-4,8-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
(84 mg) as a gum.
[0303] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.3), 1.17-1.31 (m, CH.sub.2CH.sub.2), 1.38 and 1.60 (two m,
CH.sub.2), 1.99 and 2.26 (two m, 1-CH.sub.2), 2.09 (s, 4-CH.sub.3),
2.17 (s, 8-CH.sub.3), 2.48 and 2.59 (two m, 2-CH.sub.2), 2.59 and
2.97 (two d, 9-CH.sub.2), 3.91 (s, OCH.sub.3), 6.84 (d, H-6), and
7.57 (d, H-5).
Step 3: 9a
butyl-4,8-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne
[0304] A solution of 9a
butyl-4,8-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3- H-fluoren-3-one
(84 mg, 0.28 mmol) in anhydrous CH.sub.2Cl.sub.2 (3 mL) was placed
under a nitrogen atmosphere, cooled in an acetone-dry ice bath, and
treated with 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (1.11 mL, 1.11 mmol).
The cooling bath was removed and the reaction mixture was stirred
at room temperature for 4 hours. The reaction mixture was diluted
with EtOAc (20 mL), washed with water (20 ml) containing 2N HCl (2
mL) followed by brine (10 mL), dried over MgSO.sub.4, filtered, and
evaporated under vacuum. The crude product was purified by
preparative layer chromatography on a 0.1.times.20.times.20 cm
silica gel GF plate, developing with 10% EtOAc in CH.sub.2Cl.sub.2.
The UV visible product band was eluted with EtOAc and the solvent
evaporated under vacuum. The residue was lyophilized from
benzene-methanol to afford 9a
butyl-4,8-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
as a solid.
[0305] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.77 (t,
CH.sub.3), 1.15 (m, CH.sub.2CH.sub.2), 1.25 and 1.50 (two m,
CH.sub.2), 1.89 and 2.13 (two m, 1-CH.sub.2), 1.90 (s, 4-CH.sub.3),
2.04 (s, 8-CH.sub.3), 2.27 and 2.47 (two m, 2-CH.sub.2), 2.52 and
2.88 (two d, 9-CH.sub.2), 6.79 (d, H-6), 7.38 (d, H-5), and 9.90
(s, OH).
EXAMPLE 16
Synthesis of
9a-butyl-8-chloro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-f-
luoren-3-one
[0306] 28
[0307] Step 1: 2-butyl-4-chloro-5-methoxy-1-indanone
[0308] N-Chlorosuccinimide (505 mg, 3.8 mmol) was added to a
solution of 2-butyl-5-methoxy-1-indanone (825 mg, 3.8 mmol) in
anhydrous dimethylformamide (3.8 mL) and the resulting solution was
stirred under nitrogen and at room temperature overnight. The
reaction mixture was diluted with EtOAc (50 mL), washed with 5%
aqueous NaHCO.sub.3 (20 ml), water (3.times.50 mL) and brine (10
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum.
The residue was purified by column chromatography on EM silica gel
60 (2320-400 mesh, 2.75.times.29 cm), eluting with
CH.sub.2Cl.sub.2, to afford 2-butyl-4-chloro-5-methoxy-1-ind- anone
(148 mg) as an oil.
[0309] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.0.93 (t, CH.sub.3),
1.31-1.52 (m, CHaHbCH.sub.2CH.sub.2), 1.95 (m,
CHaHbCH.sub.2CH.sub.2), 2.68 (m, H-2), 2.76 and 3.30 (two dd,
3-CH.sub.2), 4.00 (s, OCH.sub.3), 6.98 (d, H-6), and 7.67 (d,
H-7).
Step 2: 2-butyl-4-chloro-5-methoxy-2-(3-oxopentyl)-1-indanone
[0310] A solution of 2-butyl-4-chloro-5-methoxy-1-indanone (200 mg,
0.79 mmol) in anhydrous tetrahydrofuran (0.8 mL) was placed under a
nitrogen atmosphere and treated with ethyl vinyl ketone (0.118 mL,
1.19 mmol) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.024
mL, 0.158 mmol). The resulting solution was stirred and heated in
an oil bath at 60.degree. C. for 47 hours. After cooling to room
temperature, the reaction mixture was diluted with EtOAc (20 mL)
and washed with water (20 mL) containing 2N HCl (2 mL). The organic
phase was washed with brine (10 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to provide crude
2-butyl-4-chloro-5-methoxy-2-(3-oxopentyl)-1-indanone (250 mg) as
an oil.
[0311] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.02 (t, COCH.sub.2CH.sub.3),
1.04-1.25 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.27 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.62 (m,
CH.sub.2CH.sub.2CH.sub.2CH.su- b.3), 1.92 (m, CH.sub.2CH.sub.2CO),
2.31 (m, CH.sub.2CH.sub.2CO), 2.37 (m, COCH.sub.2CH.sub.3), 2.88
and 3.03 (two d, 3-CH.sub.2), 4.02 (s, OCH.sub.3), 7.01 (d, H-6),
and 7.67 (d, H-7).
Step 3:
9a-butyl-8-chloro-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0312] A solution of
2-butyl-4-chloro-5-methoxy-2-(3-oxo-pentyl)-1-indanon- e (250 mg,
0.74 mmol) in acetic acid (2 mL) was diluted with 6N aqueous HCl (2
mL). The resulting mixture was stirred and heated in an oil bath at
90.degree. C. for 18 hours, then kept at room temperature for 2
days. The mixture was diluted with EtOAc (20 mL), washed with water
(30 mL), 5% NaHCO.sub.3 (10 mL) and brine (5 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (250
mg). The crude product was purified by preparative layer
chromatography on three 0.1.times.20.times.20 silica gel GF plates,
developing with 5% EtOAc in CH.sub.2Cl.sub.2, to afford
9a-butyl-8-chloro-7-methoxy-4-methyl-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one (143 mg).
[0313] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.15-1.30 (m, CH.sub.2CH.sub.2), 1.40 and 1.60 (two m,
CH.sub.2), 2.02 and 2.28 (two m, 1-CH.sub.2), 2.08 (s, 4-CH.sub.3),
2.49 and 2.60 (two m, 2-CH.sub.2), 2.70 and 3.11 (two d,
9-CH.sub.2), 3.98 (s, OCH.sub.3), 6.92 (d, H-6), and 7.60 (d,
H-5).
Step 4:
9a-butyl-8-chloro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0314] A mixture of
9a-butyl-8-chloro-7-methoxy-4-methyl-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one (36.6 mg) and pyridine hydrochloride (2.66) was
stirred and heated in an oil bath at 190-200.degree. C. for 80
minutes. After cooling to room temperature, the mixture was
partitioned between EtOAc (20 mL) and water (30 mL). The organic
phase was washed with brine (10 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum. The residue was purified by
preparative layer chromatography on a 0.1.times.20.times.20 cm
silica gel GF plate, developing with 10% EtOAc in CH.sub.2Cl.sub.2.
The UV visible product band was eluted with EtOAc, the eluant
evaporated under vacuum, and the residue lyophilized from benzene
to afford 9a-butyl-8-chloro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one as an amorphous solid.
[0315] .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.77 (t,
CH.sub.3), 1.04-1.23 (m, CH.sub.2CH.sub.2), 1.28 and 1.52 (two m,
CH.sub.2), 1.91 (s, 4-CH.sub.3), 1.96 and 2.14 (two m, 1-CH.sub.2),
2.29 and 2.49 (two m, 2-CH.sub.2), 2.65 and 2.93 (two d,
9-CH.sub.2), 6.95 (d, H-6), and 7.52 (d, H-5).
[0316] IR (KBr) 3416, 2954, 2859, 1610, 1459, 1343, 1270, 1100,
944, 867, and 820 cm.sup.-1. Mass spectrum, m/e 333.0 (M+1),
335.0.
EXAMPLE 17
Synthesis of
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-hydroxy-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one
[0317] 29
Step 1: (2SR,
9aSR)-9a-butyl-2,4-dimethyl-7-methoxy-1,2,9,9a-tetrahydro-3H-
-fluoren-3-one
[0318] A solution of
9a-butyl-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fl- uoren-3-one
(142 mg, 0.5 mmol) in anhydrous tetrahydrofuran (THF, 2.5 mL) was
placed under a nitrogen atmosphere, cooled with stirring in an ice
bath, and treated with lithium diisopropylamide (1.5 mL of a 0.4 M
solution in THF/hexanes, 0.6 mmol). After 40 minutes at 0.degree.
C., the solution was cooled to -78.degree. C. (dry ice-acetone
bath) and iodomethane (0.16 mL, 2.5 mmol) was added. The resulting
solution was allowed to slowly warm to room temperature. After 16
hours at room temperature, the solution was diluted with EtOAc (50
mL) and washed with 1 N HCl (30 mL). The aqueous acid phase was
back-extracted with EtOAc (25 mL). The combined organics were
washed successively with 5% aq. NaHCO.sub.3, water, and brine (30
mL each), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to afford 147 mg of yellow oil. This material was purified
by preparative layer chromatography (0.1.times.20.times.20 cm
silica gel GF plate), using 5:1 hexanes-EtOAc as eluting solvent,
to afford (2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxy--
1,2,9,9a-tetrahydro-3H-fluoren-3-one (112 mg) as a faintly yellow
oil.
[0319] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.20-1.31 (m, CH.sub.2CH.sub.2), 1.23 (d, 2-CH.sub.3)
1.35 and 1.62 (two m, CH.sub.2), 1.74 (t, H-1a), 2.09 (s,
4-CH.sub.3), 2.28 (dd, H-1b), 2.56 (m, H-2), 2.69 and 2.96 (two d,
9-CH.sub.2), 3.87 (s, OCH.sub.3), 6.85-6.87 (m, H-6 and H-8), and
7.65 (d, H-5).
Step 2:
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-hydroxy-1,2,9,9a-tetrahydro-3H--
fluoren-3-one
[0320] A solution of
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxy-1,2,9,9a-t-
etrahydro-3H-fluoren-3-one (112 mg, 0.38 mmol) in dichloromethane
(CH.sub.2Cl.sub.2) was cooled to -78.degree. C. under a nitrogen
and treated with boron tribromide (1.12 mL of a 1M solution in
CH.sub.2Cl.sub.2, 1.12 mmol). The cooling bath was removed after
five minutes and the reaction mixture stirred for 17 hours at room
temperature, after which time additional boron tribromide (1 mL, 1
mmol) was added. After 23 hours, the reaction mixture was diluted
with EtOAc (50 mL), washed with 1 N HCl, 5% aq. NaHCO.sub.3, and
brine (30 mL each), then dried over MgSO.sub.4, filtered and
concentrated under vacuum. The crude product was purified by
preparative layer chromatography (PLC, 0.1.times.20.times.20 cm
silica gel GF plate), developing with 4/1 hexanes-EtOAc, to give
the product as a yellow oil (17 mg). This oil was repurified by
PLC, using the same conditions, and the product lyophilized from
benzene to give
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-hydroxy-1,2,9,9a--
tetrahydro-3H-fluoren-3-one (90% pure).
[0321] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.20-1.31 (m, CH.sub.2CH.sub.2), 1.23 (d, 2-CH.sub.3)
1.36 and 1.60 (two m, CH.sub.2), 1.74 (t, H-1a), 2.08 (s,
4-CH.sub.3), 2.29 (dd, H-1b), 2.57 (m, H-2), 2.68 and 2.94 (two d,
9-CH.sub.2), 5.1 (s, OH), 6.78-6.81 (m, H-6 and H-8), and 7.61 (d,
H-5).
EXAMPLE 18
Synthesis of
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-hydroxy-2-propyl-1,2,9,9a--
tetrahydro-3H-fluoren-3-one
[0322] 30
Step 1:
9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren--
3-one
[0323] A solution of
9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fl- uoren-3-one
(5.30 g, 21 mmol) in anhydrous dimethylformamide (50 mL) was cooled
in an ice bath, stirred under a nitrogen atmosphere, and treated
successively with N,N-diisopropyl-ethylamine (10.5 mL, 60 mmol) and
chloromethyl methyl ether (3.45 mL, 41 mmol). The resulting mixture
was stirred while gradually warming to room temperature over 5
hours. After 5.5 hours, additional N,N-diisopropyl-ethylamine (3
mL) and chloromethyl methyl ether (1 mL) were added. After stirring
an additional 25 minutes at room temperature, the reaction mixture
was diluted with EtOAc (1 L) and washed with 1.3N HCl (1 L). The
aqueous phase was separated and extracted with EtOAc (200 mL). The
combined organics were washed with 5% NaHCO.sub.3 (500 ml) and
brine, dried over MgSO.sub.4, filtered, and concentrated under
vacuum to an orange oil (6.5 g). This material was divided into
three portions and each purified by flash chromatography on silica
gel using Biotage FLASH 40M columns and 10:1 hexanes-EtOAc as
eluting solvent. The product containing fractions were combined and
evaporated under vacuum to afford
9a-butyl-7-methoxymethoxy-4-methyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one (4.98 g) as an oil.
[0324] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.18-1.32 (m, CH.sub.2CH.sub.2), 1.39 and 1.60 (two m,
CH.sub.2), 1.98 and 2.25 (two m, 1-CH.sub.2), 2.09 (s, 4-CH.sub.3),
2.48 and 2.59 (two m, 2-CH.sub.2), 2.72 and 2.98 (two d,
9-CH.sub.2), 3.52 (s, OCH.sub.3), 5.24 (m, OCH.sub.2O), 6.98 (dd,
H-6), 7.02 (d, H-8), and 7.66 (dd, H-5).
Step 2:
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one
[0325] A 0.4M solution of lithium diisopropylamide (LDA) in
tetrahydrofuran (THF) was prepared by dissolving diisopropyl amine
(0.56 mL, 4 mmol) in anhydrous THF (5 mL), cooling the solution to
0.degree. C., adding either 1.6M (2.5 mL) or 2.5M (1.6 mL)
butyllithium in hexanes, diluting the resulting solution to 10.0 mL
total volume with anhydrous THF, and stirring the solution for at
least 30 minutes at 0.degree. C.
[0326] A solution of
9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (162 mg, 0.52 mmol) in anhydrous THF (2.5 mL)
was cooled in an ice bath and stirred under a nitrogen atmosphere
while 0.4M LDA in THF (1.55 mL, 0.62 mmol) was added by syringe.
After stirring at 0.degree. C. for 30 minutes, the solution was
cooled to -78.degree. C. (dry ice-acetone bath) and treated with
iodomethane (0.162 mL, 2.6 mmol). The resulting mixture was allowed
to slowly warm to room temperature, then stirred at room
temperature overnight. The mixture was diluted with EtOAc (60 mL)
and shaken with saturated aqueous NH.sub.4Cl (40 mL). The aqueous
phase was extracted with more EtOAc (20 mL). The combined organics
were washed with 5% NaHCO.sub.3, water, and brine, dried over
MgSO.sub.4, filtered, and concentrated under vacuum to a yellow
oil. The crude product was purified by preparative layer
chromatography (PLC) on a 0.1.times.20.times.20 cm silica gel GF
plate using 4:1 hexanes-EtOAc as developing solvent. The band at
R.sub.f 0.44-0.56 was extracted with EtOAc and the extracts
evaporated under vacuum to provide
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2,9,9a-tetrahydro-3H--
fluoren-3-one (111 mg) as an oil.
[0327] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.3), 1.19-1.34 (m, CH.sub.2CH.sub.2), 1.23 (d, 2-CH.sub.3),
1.37 and 1.61 (two m, CH.sub.2), 1.73 (t, 1-CHaHb), 2.08 (s,
4-CH.sub.3), 2.29 (dd, 1-CHaHb), 2.56 (m, H-2), 2.69 and 2.96 (two
d, 9-CH.sub.2), 3.52 (s, OCH.sub.3), 5.24 (m, OCH.sub.2O), 6.98 (br
d, H-6), 7.01 (br s, H-8), and 7.65 (d, H-5).
Step 3:
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-2-propyl-1,2,9,9-
a-tetrahydro-3H-fluoren-3-one
[0328] A solution of
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one (110 mg, 0.34 mmol) in anhydrous
THF (1.5 mL) was cooled in an ice bath, stirred under a nitrogen
atmosphere, and treated with 0.4M LDA in THF (1 mL, 0.4 mmol).
After stirring at 0.degree. C. for 30 minutes, the solution was
cooled to -78.degree. C. and treated with iodopropane (0.170 mL,
1.7 mmol). The resulting mixture was allowed to gradually warm to
room temperature, then stirred at room temperature overnight.
Workup as described in step 2 afforded a crude product (112 mg)
which was purified by PLC on a 0.1.times.20.times.20 cm silica gel
GF plate, using 10:1 hexanes-EtOAc as developing solvent. The band
at R.sub.f 0.20-0.27 gave recovered starting material (39 mg) and
the band at R.sub.f 0.31-0.38 afforded the product
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-2-propyl-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one (41 mg) as an oil.
[0329] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.83 (t,
CH.sub.3), 0.85 (t, CH.sub.3), 1.00-1.54 (m,
CH.sub.2CH.sub.2CH.sub.3 and CH.sub.2CH.sub.2CH.sub.2CH.sub.3),
1.32 (s, 2-CH.sub.3), 1.91 and 2.13. (two d, 1-CH.sub.2), 2.11 (s,
4-CH.sub.3), 2.70 and 3.00 (two d, 9-CH.sub.2), 3.52 (s,
OCH.sub.3), 5.23 (m, OCH.sub.2O), 6.97-7.01 (m, H-6 and H-8), and
7.67 (d, H-5).
Step 4:
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-hydroxy-2-propyl-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one
[0330] A solution of
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-2-p-
ropyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (40 mg, 0.11 mmol) in
methanol (approx. 0.5-1 mL) was placed under a nitrogen atmosphere
and treated with 2N aqueous HCl (0.165 mL, 0.37 mmol). The
resulting yellow solution was stirred and heated in an oil bath at
85.degree. C. for 60 minutes. On cooling, the mixture deposited
white crystals. The mixture was cooled in an ice bath and filtered.
The crystalline product was washed with ice-cold 5:1 MeOH-2N HCl
(2.times.2 ML) and dried under vacuum to afford
(2SR,9aRS)-9a-butyl-2,4-dimethyl-7-hydroxy-2-propyl-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one.
[0331] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.83 (t,
CH.sub.3), 0.85 (t, CH.sub.3), 1.00-1.55 (m,
CH.sub.2CH.sub.2CH.sub.3 and CH.sub.2CH.sub.2CH.sub.2CH.sub.3),
1.32 (s, 2-CH.sub.3), 1.92 and 2.12. (two d, 1-CH.sub.2), 2.11 (s,
4-CH.sub.3), 2.68 and 2.98 (two d, 9-CH.sub.2), 5.26 (s, OH),
6.78-6.82 (m, H-6 and H-8), and 7.63 (m, H-5).
EXAMPLE 19
Synthesis of
9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-flu-
oren-3-one
[0332] 31
Step 1:
9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-f-
luoren-3-one
[0333] A solution of
(2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one (39 mg, 0.12 mmol) in anhydrous
THF (1.0 mL) was cooled in an ice bath, stirred under a nitrogen
atmosphere, and treated with 0.4M LDA in THF (0.39 mL, 0.16 mmol).
After stirring at 0.degree. C. for 30 minutes, the yellow solution
was cooled to -78.degree. C. and treated with iodomethane (0.037
mL, 0.6 mmol). The resulting mixture was allowed to gradually warm
to room temperature, then stirred at room temperature overnight.
Workup as described in Example 18, step 2, afforded a crude product
which was purified by PLC on a 0.1.times.20.times.20 cm silica gel
GF plate, using 10:1 hexanes-EtOAc as developing solvent. The band
at R.sub.f 0.18-0.24 afforded
9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren--
3-one (28 mg) as an oil.
[0334] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.3), 1.15 and 1.35 (two s, two 2-CH.sub.3), 1.20, 1.39 and
1.55 (three m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.85 and 2.27.
(two d, 1-CH.sub.2), 2.12 (s, 4-CH.sub.3), 2.66 and 2.99 (two d,
9-CH.sub.2), 3.52 (s, OCH.sub.3), 5.23 (m, OCH.sub.2O), 6.97-7.01
(m, H-6 and H-8), and 7.67 (d, H-5).
Step 2:
9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren--
3-one
[0335] A solution of
9a-butyl-7-methoxymethoxy-2,2,4-trimethyl-1,2,9,9a-te-
trahydro-3H-fluoren-3-one (28 mg, 0.08 mmol) in methanol (2 mL) was
placed under a nitrogen atmosphere and treated with 2N aqueous HCl
(0.12 mL, 0.24 mmol). The resulting yellow solution was stirred and
heated in an oil bath at 55-80.degree. C. for 45 minutes. After
cooling to room temperature, the mixture was diluted with EtOAc (60
mL) and shaken with 5% aqueous NaHCO.sub.3. The aqueous portion was
separated and extracted with EtOAc (40 mL). The combined organics
were washed with water and brine, dried over MgSO.sub.4, filtered,
and concentrated under vacuum to an oil. The crude product was
purified by PLC on a 0.1.times.20.times.20 cm silica gel GF plate,
developing twice with 4:1 hexanes-EtOAc. The band at R.sub.f
0.34-0.43 was eluted with EtOAc and the eluant evaporated under
vacuum to a residue which was lyophilized from benzene to afford
9a-butyl-7-hydroxy-2,2,4-trimethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
as an amorphous solid.
[0336] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.3), 1.16 and 1.36 (two s, two 2-CH.sub.3), 1.20, 1.38 and
1.55 (three m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.86 and 2.26.
(two d, 1-CH.sub.2), 2.12 (s, 4-CH.sub.3), 2.65 and 2.97 (two d,
9-CH.sub.2), 5.62 (s, OH), 6.80-6.84 (m, H-6 and H-8), and 7.64 (m,
H-5).
[0337] Mass Spectrum, m/e 299.1 (M+1).
EXAMPLE 20
Synthesis of
(2SR,9aRS)-9a-butyl-7-hydroxy-2-iodo-4-methyl-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one
[0338] 32
Step 1:
(2SR,9aRS)-9a-butyl-2-iodo-7-methoxymethoxy-4-methyl-1,2,9,9a-tetr-
ahydro-3H-fluoren-3-one
[0339] A solution of
9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (134 mg, 0.43 mmol) in anhydrous THF (2.5 mL)
was cooled in an ice bath, stirred under a nitrogen atmosphere, and
treated with 0.4M LDA in THF (1.2 mL, 0.48 mmol). After stirring at
0.degree. C. for 30 minutes, the enolate solution was cooled to
-78.degree. C. and treated with a solution of iodine (540 mg, 2.13
mmol) in THF. The resulting mixture was allowed to gradually warm
to room temperature, then stirred at room temperature overnight.
The mixture was diluted with EtOAc (50 mL), washed with 1N HCl,
saturated aqueous Na.sub.2SO.sub.3 (2.times.30 mL), water, 5%
NaHCO.sub.3, and brine, dried over MgSO.sub.4, filtered, and
evaporated under vacuum to provide crude
(2SR,9aRS)-9a-butyl-2-iodo-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro--
3H-fluoren-3-one as a gum.
[0340] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.17-1.32 (m, CH.sub.2CH.sub.2), 1.38 and 1.59 (two m,
CH.sub.2), 2.15 (s, 4-CH.sub.3), 2.70 (t, 1-CHaHb), 2.74 and 2.95
(two d, 9-CH.sub.2), 2.93 (dd, 1-CHaHb), 3.51 (s, OCH.sub.3), 5.23
(m, OCH.sub.2O), 5.30 (dd, H-2), 6.97-7.02 (m, H-6 and H-8), and
7.65 (d, H-5).
Step 2:
(2SR,9aRS)-9a-butyl-7-hydroxy-2-iodo-4-methyl-1,2,9,9a-tetrahydro--
3H-fluoren-3-one
[0341] A suspension of
(2SR,9aRS)-9a-butyl-2-iodo-7-methoxymethoxy-4-methy-
l-1,2,9,9a-tetrahydro-3H-fluoren-3-one (50 mg, 0.11 mmol) in
methanol (3.5 mL) was placed under a nitrogen atmosphere, heated in
an oil bath at 70.degree. C. to affect solution, then treated with
2N aqueous HCl (0.195 mL, 0.39 mmol). The resulting solution was
stirred and heated in an oil bath at 70.degree. C. for 50 minutes.
After cooling to room temperature, the mixture was diluted with
EtOAc and shaken with 5% aqueous NaHCO.sub.3. The aqueous portion
was separated and extracted with EtOAc. The combined organics were
washed with water and brine, dried over MgSO.sub.4, filtered, and
concentrated under vacuum to an oil. The crude product was purified
by PLC on a 0.1.times.20.times.20 cm silica gel GF plate,
developing twice with 5:1 hexanes-EtOAc. The band at R.sub.f
0.24-0.32 was eluted with EtOAc and the eluant evaporated under
vacuum to provide
(2SR,9aRS)-9a-butyl-7-hydroxy-2-iodo-4-methyl-1,2,9,9a-tetrahydro-
-3H-fluoren-3-one as an oil.
[0342] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.16-1.32 (m, CH.sub.2CH.sub.2), 1.39 and 1.60 (two m,
CH.sub.2), 2.16 (s, 4-CH.sub.3), 2.72 (t, 1-CHaHb), 2.73 and 2.93
(two d, 9-CH.sub.2), 2.93 (dd, 1-CHaHb), 5.31 (dd, H-2), 5.52 (br
s, OH), 6.81-6.84 (m, H-6 and H-8), and 7.63 (m, H-5).
EXAMPLE 21
Synthesis of
(2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one
[0343] 33
Step 1:
9a-butyl-7-methoxymethoxy-4-methyl-3-trimethylsilyloxy-9,9a-dihydr-
o-1H-fluorene
[0344] A solution of
9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (163 mg, 0.52 mmol) in anhydrous THF (2.5 mL)
was cooled in an ice bath and stirred under a nitrogen atmosphere
while 0.4M LDA in THF (1.9 mL, 0.78 mmol) was added by syringe.
After stirring at 0.degree. C. for 30 minutes, the solution was
cooled to -78.degree. C. (dry ice-acetone bath) and treated with
chlorotrimethylsilane (0.100 mL, 0.78 mmol). The resulting mixture
was allowed to slowly warm to room temperature, then stirred at
room temperature overnight. The mixture was diluted with EtOAc (60
mL) and shaken with 5% aqueous NaHCO.sub.3 (30 mL). The aqueous
phase was separated and extracted with more EtOAc (30 mL). The
combined organics were washed with saturated brine, dried over
MgSO.sub.4, filtered, and concentrated under vacuum to an oil (204
mg). The .sup.1H NMR of this material showed a 9:1 mixture of
9a-butyl-7-methoxymethoxy-4-methyl-3-trimethylsilyloxy-9,9a-dihydro-1H-fl-
uorene and starting material.
[0345] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.26 (s,
Si(CH.sub.3).sub.3), 0.82 (t, CH.sub.3), 1.04-1.40 (m,
CH.sub.2CH.sub.2CH.sub.2), 2.07 (s, 4-CH.sub.3), 2.19 and 2.39 (two
dd, 1-CH.sub.2), 2.48 and 2.95 (two d, 9-CH.sub.2), 3.52 (s,
OCH.sub.3), 4.95 (dd, H-2), 5.21 (m, OCH.sub.2O), 6.94 (dd, H-6),
6.99 (d, H-8), and 7.56 (d, H-5).
Step 2:
(2SR,9aRS)-9a-butyl-2-hydroxy-7-methoxymethoxy-4-methyl-1,2,9,9a-t-
etrahydro-3H-fluoren-3-one
[0346] A solution of the crude trimethylsilylenolether from step 1
(204 mg, approx. 0.5 mmol) in anhydrous CH.sub.2Cl.sub.2 (5 mL) was
treated with solid NaHCO.sub.3 (42 mg, 0.5 mmol) then placed under
a nitrogen atmosphere and stirred at room temperature. The mixture
was treated over two minutes with three potions of 96%
m-chloroperoxybenzoic acid (65.69, and 45 mg, 1.0 mmol), purging
with nitrogen after each addition. After stirring overnight at room
temperature, the mixture was diluted with CH.sub.2Cl.sub.2 (5 mL),
treated with saturated aqueous Na.sub.2SO.sub.3 (5 mL), and stirred
at room temperature for 25 minutes. The mixture was partitioned
between CH.sub.2Cl.sub.2 (50 mL) and water (10 mL), and the aqueous
portion extracted with more CH.sub.2Cl.sub.2 (25 mL). The combined
organics were washed with water and brine, dried over MgSO.sub.4,
filtered, and concentrated under vacuum to an oil (221 mg). The
crude product was purified by preparative layer chromatography on
two 0.1.times.20.times.20 cm silica gel GF plates using 4:1
hexanes-EtOAc as the developing solvent. The major UV visible band
at R.sub.f 0.19-0.26 gave
(2SR,9aRS)-9a-butyl-2-hydroxy-7-methoxymethoxy-4-methyl-1,2,9,9a-tet-
rahydro-3H-fluoren-3-one (73 mg) as an oil.
[0347] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.89 (t,
CH.sub.3), 1.22-1.40, 1.48, and 1.65 (three m,
CH.sub.2CH.sub.2CH.sub.2), 1.91 (t, 1-CHaHb), 2.14 (s, 4-CH.sub.3),
2.68 (dd, 1-CHaHb), 2.74 and 2.99 (two d, 9-CH.sub.2), 3.52 (s,
OCH.sub.3), 3.77 (d, OH), 4.35 (ddd, H-2), 5.24 (m, OCH.sub.2O),
7.00 (dd, H-6), 7.03 (d, H-8), and 7.67 (d, H-5).
Step 3:
(2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-methyl-1,2,9,9a-tetrahydro-3H--
fluoren-3-one
[0348] A solution of
(2SR,9aRS)-9a-butyl-2-hydroxy-7-methoxymethoxy-4-meth-
yl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (73 mg, 0.22 mmol) in
methanol (5 mL) was placed under a nitrogen atmosphere, treated
with 2N aqueous HCl (0.33 mL, 0.66 mmol), and stirred with heating
in an oil bath at 80.degree. C. for 30 minutes. After cooling to
room temperature, the reaction mixture was diluted with EtOAc,
washed with 5% aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4, filtered, and concentrated under vacuum to an oil. The
crude product was purified by PLC on a 0.1.times.20.times.20 cm
silica gel GF plate, developing twice with 4:1 hexanes-EtOAc. The
band at R.sub.f 0.12-0.20 was eluted with EtOAc and the eluant
evaporated under vacuum to a gum (50 mg). This material
crystallized from benzene to afford
(2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-m-
ethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as a white solid.
[0349] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.88 (t,
CH.sub.3), 1.22-1.39, 1.47, and 1.64 (three m,
CH.sub.2CH.sub.2CH.sub.2), 1.92 (t, 1-CHaHb), 2.14 (s, 4-CH.sub.3),
2.68 (dd, 1-CHaHb), 2.72 and 2.97 (two d, 9-CH.sub.2), 3.84 (br s,
OH), 4.37 (dd, H-2), 6.80-6.84 (m, H-6 and H-8), and 7.63 (d,
H-5).
EXAMPLE 22
Synthesis of
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-hydroxyethyl)-4-methyl-1,2-
,9,9a-tetrahydro-3H-fluoren-3-one
[0350] 34
Step 1:
(2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tet-
rahydro-3H-fluoren-3-one
[0351] A solution of
9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (230 mg, 0.73 mmol) in anhydrous THF (3.8 mL)
was cooled in an ice bath, stirred under a nitrogen atmosphere, and
treated with freshly prepared 0.4M LDA in THF (2.2 mL, 0.88 mmol).
The resulting solution was stirred at 0.degree. C. for 30 minutes,
then cooled to -78.degree. C. (dry ice-acetone bath) and treated
with allyl bromide (0.316 mL, 3.65 mmol). The reaction mixture was
allowed to gradually warm to room temperature then stirred at room
temperature overnight. The mixture was diluted with EtOAc (60 mL)
and shaken with 1N HCl (35 mL). The aqueous phase was extracted
with EtOAc (20 mL) and the combined organics were washed with 5%
NaHCO.sub.3 and brine, dried over MgSO.sub.4, filtered, and
concentrated under vacuum to a yellow oil. The crude product was
purified by preparative layer chromatography on three
0.1.times.20.times.20 silica gel GF plates using 4:1 hexanes-EtOAc
as developing solvent. The UV visible band at R.sub.f 0.44-0.56 was
eluted with EtOAc and the eluant evaporated under vacuum to afford
(2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-
-3H-fluoren-3-one (193 mg) as an oil.
[0352] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.3), 1.18-1.29 (m, CH.sub.2CH.sub.2), 1.36 and 1.58 (two m,
CH.sub.2), 1.67 (t, 1-CHaHb), 2.09 (s, 4-CH.sub.3), 2.20 and 2.51
(two m, CH.sub.2CH.dbd.), 2.30 (dd, 1-CHaHb), 2.70 and 2.97 (two d,
9-CH.sub.2), 2.80 (m, H-2), 3.52 (s, OCH.sub.3), 5.04-5.12 (m,
CH.dbd.CH.sub.2), 5.23 (m, OCH.sub.2O), 5.79 (m, CH.dbd.CH.sub.2),
6.98 (dd, H-6), 7.01 (d, H-8), and 7.65 (d, H-5).
Step 2:
(2RS,9aSR)-9a-butyl-2-(3-hydroxy-2-oxopropyl)-7-methoxymethoxy-4-m-
ethyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one and
(2RS,9aSR)-9a-butyl-7-metho-
xymethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0353] A solution of
(2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-
-1,2,9,9a-tetrahydro-3H-fluoren-3-one (170 mg, 0.48 mmol) in
dioxane (9 mL) was diluted with water (3 mL) and treated with a
single crystal of OSO.sub.4 followed by NaIO.sub.4 (125 mg, 0.58
mmol). The mixture was stirred at room temperature for 15 minutes,
treated with more NaIO.sub.4 (132 mg, 0.62 mmol), and stirred an
additional 30 minutes at room temperature. Workup provided a gum
which was purified by PLC on two 0.1.times.20.times.20 cm silica
gel GF plates, developing twice with 4:1 hexanes-EtOAc. The minor
UV visible band provided (2RS,9aSR)-9a-butyl-2-(-
3-hydroxy-2-oxopropyl)-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fl-
uoren-3-one (26 mg) as an oil. The major UV visible band afforded
(2RS,9aSR)-9a-butyl-7-methoxymethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tet-
rahydro-3H-fluoren-3-one (85 mg) as an oil.
[0354] .sup.1H NMR (CDCl.sub.3, 500 MHz) of
(2RS,9aSR)-9a-butyl-7-methoxym-
ethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one:
.delta. 0.89 (t, CH.sub.3), 1.27, 1.40 and 1.69 (three m,
CH.sub.2CH.sub.2CH.sub.2), 1.81 (t, 1-CHaHb), 2.09 (s, 4-CH.sub.3),
2.33 (dd, 1-CHaHb), 2.47 and 3.06 (two ddd, CH.sub.2CHO), 2.69 and
2.98 (two d, 9-CH.sub.2), 3.15 (m, H-2), 3.52 (s, OCH.sub.3), 5.24
(m, OCH.sub.2O), 6.99 (dd, H-6), 7.02 (d, H-8), 7.66 (d, H-5), and
9.91 (t, CHO).
Step 3:
(2RS,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tet-
rahydro-3H-fluoren-3-one
[0355] A solution of
(2RS,9aSR)-9a-butyl-7-methoxymethoxy-4-methyl-2-(2-ox-
oethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg) in methanol (1
mL) was diluted with 2N HCl (0.36 mL, 0.72 mmol). The resulting
mixture was stirred at room temperature for 30 minutes followed by
heating in an oil bath at 80.degree. C. for 40 minutes. On cooling
to room temperature, crystals formed. The mixture was diluted with
EtOAc and washed with 5% NaHCO.sub.3 and 1N HCl. The aqueous washes
were back-extracted with EtOAc. The combined organics were washed
with brine, dried over MgSO.sub.4, filtered, and concentrated under
vacuum. The residue was purified by PLC on a 0.1.times.20.times.20
cm silica gel GF plate, using 2:1 hexanes-EtOAc as developing
solvent, to afford
(2RS,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-
-3H-fluoren-3-one (50 mg).
[0356] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.89 (t,
CH.sub.3), 1.27, 1.41 and 1.69 (three m, CH.sub.2CH.sub.2CH.sub.2),
1.82 (t, 1-CHaHb), 2.09 (s, 4-CH.sub.3), 2.33 (dd, 1-CHaHb), 2.48
and 3.06 (two ddd, CH.sub.2CHO), 2.67 and 2.96 (two d, 9-CH.sub.2),
3.15 (m, H-2), 5.12 (s, OH), 6.78-6.82 (m, H-6 and H-8), 7.62 (d,
H-5), and 9.91 (t, CHO).
Step 4:
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-hydroxyethyl)-4-methyl-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one
[0357] A solution of
(2RS,9aSR)-9a-butyl-7-hydroxy-4-methyl-2-(2-oxo-ethyl-
)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (17 mg, 0.05 mmol) in
2-propanol (2 mL) was treated with NaBH.sub.4 (1.9 mg, 0.05 mmol)
and the mixture was stirred at room temperature for 40 minutes. The
solvent was evaporated under vacuum. The residue was taken up in
EtOAc (60 mL), washed with 0.2N HCl (30 mL), 5% NaHCO.sub.3, and
brine, dried over MgSO.sub.4, filtered, and concentrated under
vacuum to a gum (24 mg). This material was purified by PLC on a
0.1.times.20.times.20 cm silica gel GF plate using 2:1
hexanes-EtOAc as developing solvent. The UV visible band at R.sub.f
0.06-0.11 afforded
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-hydroxyethyl)-4-met-
hyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an oil.
[0358] .sup.1H NMR (CD.sub.3OD, 500 MHz) .delta. 0.82 (t,
CH.sub.3), 1.20, 1.33 and 1.56 (three m, CH.sub.2CH.sub.2CH.sub.2),
1.48 and 2.22 (two m, CH.sub.2CH.sub.2OH), 1.66 (t, 1-CHaHb), 2.01
(s, 4-CH.sub.3), 2.33 (dd, 1-CHaHb), 2.61 (m, H-2), 2.64 and 2.92
(two d, 9-CH.sub.2), 3.68 (m, CH.sub.2CH.sub.2OH), 6.73-6.78 (m,
H-6 and H-8), and 7.57 (d, H-5).
EXAMPLE 23
Synthesis of
(2SR,9aSR)-2-allyl-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one
[0359] 35
[0360] A solution of
(2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-
-1,2,9,9a-tetrahydro-3H-fluoren-3-one (5 mg, 0.015 mmol) in THF
(0.5 mL) was treated with 6N HCl (0.5 mL) and the resulting
solution was heated at 50.degree. C. overnight. The mixture was
diluted with EtOAc (30 mL), washed with 5% NaHCO.sub.3 and brine,
dried over MgSO.sub.4, filtered, and evaporated under vacuum to a
yellow oil. The crude product was purified by PLC on a
0.025.times.20.times.20 cm silica gel GF plate using 2:1
hexanes-EtOAc as developing solvent. The UV visible band at R.sub.f
0.43-0.57 afforded
(2SR,9aSR)-2-allyl-9a-butyl-7-hydroxy-4-methyl-1,2,9,9-
a-tetrahydro-3H-fluoren-3-one as a gum.
[0361] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.3), 1.16-1.30 (m, CH.sub.2CH.sub.2), 1.36 and 1.57 (two m,
CH.sub.2), 1.68 (t, 1-CHaHb), 2.09 (s, 4-CH.sub.3), 2.22 and 2.53
(two m, CH.sub.2CH.dbd.), 2.29 (dd, 1-CHaHb), 2.69 and 2.95 (two d,
9-CH.sub.2), 2.80 (m, H-2), 5.04-5.12 (m, CH.dbd.CH.sub.2), 5.40
(s, OH), 5.79 (m, CH.dbd.CH.sub.2), 6.78-6.83 (m, H-6 and H-8), and
7.62 (d, H-5).
EXAMPLE 24
Synthesis of
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(3-hydroxy-2-oxopropyl)-4-met-
hyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0362] 36
[0363] A solution of
(2RS,9aSR)-9a-butyl-2-(3-hydroxy-2-oxopropyl)-7-metho-
xymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (24 mg,
0,06 mmol) in methanol (1 mL) was treated with 2N HCl (0.36 mL,
0.18 mmol) and the resulting solution was heated at reflux for 20
minutes. After cooling, the mixture was concentrated under vacuum
to a residue that was dissolved in EtOAc (60 mL) and washed with 5%
NaHCO.sub.3 (30 mL). The aqueous phase was back-extracted with
EtOAc (30 mL). The combined organics were washed with brine, dried
over MgSO.sub.4, filtered, and evaporated under vacuum. The residue
was purified by PLC, using 1:1 hexanes-EtOAc as developing solvent,
to afford (2RS,9aSR)-9a-butyl-7-hydroxy-2-(3-hydroxy--
2-oxopropyl).sub.4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as
an oil.
[0364] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.88 (t,
CH.sub.3), 1.26, 1.40 and 1.70 (three m, CH.sub.2CH.sub.2CH.sub.2),
1.84 (t, 1-CHaHb), 2.06 (s, 4-CH.sub.3), 2.30 (dd, 1-CHaHb), 2.37
and 2.97 (two dd, CH.sub.2COCH.sub.2OH), 2.65 and 2.96 (two d,
9-CH.sub.2), 3.22 (t, CH.sub.2COCH.sub.2OH), 3.27 (m, H-2), 4.29
and 4.48 (two dd, CH.sub.2COCH.sub.2OH), 6.03 (s, OH), 6.79-6.83
(m, H-6 and H-8), and 7.61 (d, H-5).
EXAMPLE 25
Synthesis of
(9SR,9aSR)-7-hydroxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-
-fluoren-3-one
[0365] 37
Step 1: 6-methoxy-1-propyl-1H-indene
[0366] A solution of 5-methoxy-1H-indene (0.895 g, 6.12 mmol) in
anhydrous Et.sub.2O (7.5 mL) was treated with 1.4M MeLi in
Et.sub.2O (4.7 mL, 6.58 mmol) added dropwise over 10 minutes. The
resulting hazy solution was stirred at room temperature an
additional 15 minutes, then cooled in an ice bath and treated with
iodopropane (1.00 mL, 10.3 mmol). The mixture was stirred at ice
bath temperature with gradual warming to room temperature. After
stirring at room temperature overnight, the mixture was treated
with saturated aq. NH.sub.4Cl (10 mL) and Et.sub.2O (15 mL) and
shaken. The organic phase was washed with brine, dried over
MgSO.sub.4, filtered, and evaporated under vacuum to afford a
mixture (1.248 g) of 5-methoxy-1-propyl-1H-indene and
6-methoxy-1-propyl-1H-inden- e as an oil.
Step 2: 6-methoxy-1-propyl-indan
[0367] The mixture of indenes from step 1 (1.24 g, approx. 6.1
mmol) was dissolved in ethanol (40 mL), treated with 10% Pd on
carbon (58 mg), and hydrogenated at 40 psi and room temperature for
60 minutes. The catalyst was removed by filtration and the filtrate
was evaporated under vacuum to provide a mixture (1.287 g) of
6-methoxy-1-propyl-indan and 5-methoxy-1-propyl-indan in nearly a
1:1 ratio.
Step 3: 5-methoxy-3-propyl-1-indanone
[0368] The mixture of indans from step 2 (1.287 g, approx. 6.1
mmol) in CH.sub.2Cl.sub.2 (50 mL) was treated with a finely ground
mixture of KMnO.sub.4 (7.00 g) and CuSO.sub.4.xH.sub.2O. The
resulting mixture was heated at reflux for 89 hours, then cooled to
room temperature and filtered through a celite pad. The filtrate
was dried over MgSO.sub.4, filtered and evaporated under vacuum to
an oil (1.155 g). The crude product was purified by chromatography
on a Biotage FLASH 12M column, eluting with 10% EtOAc in hexanes,
to afford 5-methoxy-3-propyl-1-indanon- e (0.188 g) as an oil.
Other column fractions afforded 6-methoxy-3-propyl-1-indanone, the
indan starting materials, and 5-methoxy-1-indanone.
[0369] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 0.99 (t,
CH.sub.3), 1.38-1.54 (m, CHaHbCH.sub.2), 1.89 (m, CHaHb), 2.36 and
2.85 (two dd, 2-CH.sub.2), 3.31 (m, H-3), 3.91 (s, OCH.sub.3),
6.90-6.94 (m, H-4 and H-6), and 7.69 (m, H-7).
Step 4:
2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-ethyl]-5-methoxy-3-propyl-1-inda-
none
[0370] A mixture of 5-methoxy-3-propyl-1-indanone (184 mg, 0.90
mmol) and (2-ethyl-[1,3]dioxolan-2-yl)acetaldehyde (173 mg, 1.20
mmol) was treated with a solution of KOH (85% wt. pure, 20 mg, 0.30
mmol) in ethanol (1.0 mL). The resulting mixture was stirred at
room temperature for 30 minutes, then treated with 10% Pd on carbon
(9 mg), placed under a hydrogen atmosphere, and stirred vigorously
at room temperature for 18 hours. The mixture was acidified with 2N
HCl and partitioned between EtOAc (9 mL) and water (5 mL). The
organic phase was washed with brine, dried over MgSO.sub.4,
filtered, and evaporated under vacuum to an oil (316 mg). The crude
product was purified by chromatography on a Biotage FLASH 12M
column, eluting with 10% EtOAc in hexanes, to afford
2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-ethyl]-5-methoxy-3-propyl-1-indanone
(87 mg) as an oil.
[0371] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.91 (t,
CH.sub.3), 0.97 (t, CH.sub.3), 1.32-1.50 (m, CH.sub.2), 1.53-1.90
(m, four CH.sub.2), 2.35 (m, H-2), 2.99 (m, H-3), 3.91 (s,
OCH.sub.3), 3.93 (s, OCH.sub.2CH.sub.2O), 6.89-6.93 (m, H-4 and
H-6), and 7.66 (d, H-7)
Step 5:
(9SR,9aSR)-7-methoxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one
[0372] A solution of
2-[2-(2-ethyl-[1,3]dioxolan-2-yl)-ethyl]-5-methoxy-3--
propyl-1-indanone (86 mg, 0.26 mmol) in acetic acid (1.5 mL) was
diluted with 6N HCl (1.5 mL) and the resulting mixture was heated
in an oil bath at 125.degree. C. for 4.5 hours. After cooling, the
mixture was evaporated under high vacuum to an oil which was
partitioned between EtOAc and saturated aq. NaHCO.sub.3. The
organic phase was washed with brine, dried over MgSO.sub.4,
filtered, and evaporated under vacuum to a gum (65 mg). The crude
product was purified by flash chromatography on EM silica gel 60
(230-400 mesh, 1.times.16 cm column), eluting with 15% EtOAc in
hexanes. The product containing fractions were concentrated under
vacuum to afford
(9SR,9aSR)-7-methoxy-4-methyl-9-propyl-1,2,9,9a-te-
trahydro-3H-fluoren-3-one (40 mg) as an oil.
[0373] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.03 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.53 (m, CH.sub.2CH.sub.2CH.sub.3), 1.66
and 1.97 (two m, CH.sub.2CH.sub.2CH.sub.3), 1.85 and 2.35 (two m,
1-CH.sub.2), 2.11 (d, 4-CH.sub.3), 2.45 and 2.65 (two m,
2-CH.sub.2), 2.79 (m, H-9a), 2.88 (m, H-9), 3.88 (s, OCH.sub.3),
6.86-6.90 (m, H-6 and H-8), and 7.67 (m, H-5)
Step 6:
(9SR,9aSR)-7-hydroxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one
[0374] A solution of
(9SR,9aSR)-7-methoxy-4-methyl-9-propyl-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one (38.3 mg, 0.142 mmol) in anhydrous
CH.sub.2Cl.sub.2 (1.1 mL) was placed under a nitrogen atmosphere,
cooled in a dry ice-acetone bath, and stirred while 1M BBr.sub.3 in
CH.sub.2Cl.sub.2 (0.354 mL, 0.345 mmol) was added by syringe. The
cooling bath was removed and the reaction mixture was stirred at
room temperature for 2.6 hours, then diluted with 0.2N HCl (5 mL)
and EtOAc (10 mL) and shaken. The organic phase was separated,
washed with brine, dried over MgSO.sub.4, filtered, and evaporated
under vacuum to a solid (35.2 mg). The crude product was purified
by flash chromatography on EM silica gel 60 (230-400 mesh,
1.times.18 cm column) using 3:1 hexanes-EtOAc as eluting solvent,
collecting 3 mL fractions. Fractions 12-26 were combined and
concentrated under vacuum to approximately 1 mL of a suspension.
The suspension was filtered and the solid portion washed with EtOAc
and dried under vacuum to afford
(9SR,9aSR)-7-hydroxy-4-methyl-9-propyl-1,2,9,9a-tetrahydro-3H-f-
luoren-3-one.
[0375] .sup.1H NMR (3:1 CDCl.sub.3--CD.sub.3CN, 500 MHz) .delta.
0.93 (t, CH.sub.2CH.sub.2CH.sub.3), 1.43 (m,
CH.sub.2CH.sub.2CH.sub.3), 1.55 and 1.85 (two m,
CH.sub.2CH.sub.2CH.sub.3), 1.75 and 2.25 (two m, 1-CH.sub.2), 1.99
(d, 4-CH.sub.3), 2.35 and 2.52 (two m, 2-CH.sub.2), 2.68 (m, H-9a),
2.76 (m, H-9), 6.70-6.75 (m, H-6 and H-8), 7.15 (s, OH), and 7.51
(d, H-5)
[0376] IR (KBr) 3168, 2957, 1631, 1580, 1475, 1372, 1358, 1337,
1267, 1237, 1202, 1118, 1088, 866, 821, and 707 cm.sup.-1.
[0377] Mass spectrum, m/e 257.1 (M+1).
EXAMPLE 26
Synthesis of
9a-butyl-8-chloro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a-tetr-
ahydro-3H-fluoren-3-one
[0378] 38
Step 1:
9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0379] A solution 2-butyl-4-chloro-5-methoxy-1-indanone (550 mg,
2.03 mmol) in tetrahydrofuran (4.06 mL) was treated with methyl
vinyl ketone (0.203 mL, 2.44 mmol) and 0.5N sodium methoxide in
methanol (0.812 mL, 0.406 mmol). The mixture was stirred at room
temperature for 90 minutes to effect conversion to
2-butyl-4-chloro-5-methoxy-2-(3-oxobutyl)-1-indan- one. The
reaction mixture was evaporated under vacuum. The residue in
toluene (10 mL) was treated with pyrrolidine (0.170 mL, 2.03 mmol)
and acetic acid (0.140 mmol, 2.44 mmol). The resulting mixture was
stirred and heated in an oil bath at 80.degree. C. for 2.5 hours.
After cooling to room temperature, the mixture was partitioned
between EtOAc and water. The organic phase was washed with 0.1N
HCl, saturated aqueous NaHCO.sub.3 and brine, dried over
MgSO.sub.4, filtered, and evaporated under vacuum. The residue was
purified by preparative layer chromatography on silica gel GF
plates to afford 9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one.
Step 2:
4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-
-3-one
[0380] A solution of
9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fl- uoren-3-one
(555 mg, 1.82 mmol) in anhydrous dichloromethane (18.2 mL) was
treated with sodium bicarbonate (765 mg, 9.1 mmol) and bromine
(0.093 mL, 1.82 mmol). The mixture was stirred at room temperature
for 30 minutes and then diluted with CH.sub.2Cl.sub.2 (50 mL) and
washed with water (50 mL). The organic phase was dried over
MgSO.sub.4, filtered through a pad of silica gel (10 mL) with a 10
mL CH.sub.2Cl.sub.2 rinse, and the solvent evaporated under vacuum.
The residue (0.55 g) was lyophilized from benzene to afford
4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one as an amorphous solid.
Step 3:
9a-butyl-8-chloro-7-methoxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one
[0381] A mixture of
4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (55 mg, 0.143 mmol), copper(I) iodide (32.7 mg,
0.172 mmol), methyl difluoro(fluorosulfonyl)acetate (0.132 mL, 1.04
mmol), and anhydrous N,N-dimethylformamide (6.7 mL) was placed
under a nitrogen atmosphere, stirred, and heated in an oil bath at
75.degree. C. for 4 days. After cooling to room temperature, the
mixture was filtered. The filtrate was diluted with EtOAc (100 mL),
washed with water (6.times.100 mL) and brine (50 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (48
mg). The crude product was purified by preparative layer
chromatography on a 0.1.times.20.times.20 cm silica gel GF plate,
developing with CH.sub.2Cl.sub.2. The product band was eluted with
EtOAc and the eluent evaporated under vacuum to afford
.sup.9a-butyl-8-chloro-7-methoxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydro--
3H-fluoren-3-one (32 mg) as an oil.
Step 4: 9a-butyl-8-chloro-7-hydroxy-4-(trifluoromethyl)
1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0382] A solution of
9a-butyl-8-chloro-7-methoxy-4-(trifluoromethyl)-1,2,9-
,9a-tetrahydro-3H-fluoren-3-one (32 mg, 0.086 mmol) in anhydrous
dichloromethane (0.86 mL) was cooled in a dry ice-acetone bath
(-78.degree. C.) and the solution was treated with 1M boron
tribromide in dichloromethane (0.258 mL, 0.258 mmol). The cooling
bath was removed and the mixture was stirred at room temperature
for 95 minutes. Additional 1M BBr.sub.3 in CH.sub.2Cl.sub.2 (0.5
mL, 0.5 mmol) was added and the mixture was stirred at room
temperature for an additional 100 minutes. The mixture was
partitioned between EtOAc (20 mL) and water (20 mL) containing 2N
HCl (3 mL). The organic phase was washed with brine (10 mL), dried
over MgSO.sub.4, filtered, and evaporated under vacuum. The oily
residue was purified by preparative layer chromatography on a
0.1.times.20.times.20 cm silica gel GF plate, developing with 5%
EtOAc in CH.sub.2Cl.sub.2. The product band was eluted with EtOAc,
the eluent evaporated under vacuum, and the residue lyophilized
from benzene to afford
9a-butyl-8-chloro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one as an amorphous solid.
[0383] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.14-1.28 (m,
CH.sub.2CH.sub.2CH.sub.2- CH.sub.3), 1.32 and 1.54 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.07 and 2.25 (two ddd,
1-CH.sub.2), 2.50-2.63 (m, 2-CH.sub.2), 2.80 and 3.09 (two d,
9-CH.sub.2), 5.94 (s, OH), 7.01 (d, H-6), and 7.69 (qd, H-5).
EXAMPLE 27
Synthesis of
4-acetyl-9a-butyl-8-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-f-
luoren-3-one
[0384] 39
Step 1:
9a-butyl-8-chloro-4-(1-ethoxyvinyl)-7-methoxy-1,2,9,9a-tetrahydro--
3H-fluoren-3-one
[0385] A solution of
4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one (90 mg, 0.235 mmol) in anhydrous toluene (1.2
mL) was treated with tributyl(1-ethoxyvinyl)stannane (0.111 mL,
0.352 mmol) and bis(triphenylphosphine)palladium(II) chloride (33
mg, 0.047 mmol). The mixture was placed under a nitrogen
atmosphere, stirred, and heated in an oil bath at 100.degree. C.
for 3 hours. After cooling to room temperature, the mixture was
purified by preparative layer chromatography on two
0.1.times.20.times.20 cm silica gel GF plates, developing with 5%
EtOAc in CH.sub.2Cl.sub.2. The product band was eluted with EtOAc
and the eluent evaporated under vacuum to afford
9a-butyl-8-chloro-4-(1-ethoxyvin-
yl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (67 mg) as an
oil.
Step 2:
4-acetyl-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0386] The product from step 1 in ethanol (1.0 mL), water (0.2 mL)
and aqueous 2N HCl (0.2 mL) was stirred and heated in an oil bath
at 80.degree. C. for 40 minutes. After cooling, the mixture was
partitioned between EtOAc (20 mL) and water (20 mL). The organic
phase was washed with brine (20 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to provide
4-acetyl-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (54 mg) as an oil.
Step 3:
4-acetyl-9a-butyl-8-chloro-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0387] A mixture of
4-acetyl-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one (54 mg) and pyridine hydrochloride (3.5 g) was
heated in an oil bath at 200.degree. C. for one hour. After cooling
to room temperature, the mixture was partitioned between EtOAc (50
mL) and water (50 mL). The organic phase was washed with brine (20
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum
to an oil (32 mg). The crude product was purified by preparative
layer chromatography on a 0.1.times.20.times.20 cm silica gel GF
plate, developing with 5% MeOH in CH.sub.2Cl.sub.2. The product
band was eluted with 10% MeOH in CH.sub.2Cl.sub.2, the eluant
evaporated under vacuum, and the residue lyophilized from benzene
to afford 4-acetyl-9a-butyl-8-chloro-7-hydroxy-1-
,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous solid.
[0388] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.18-1.31 (m,
CH.sub.2CH.sub.2CH.sub.2- CH.sub.3), 1.45 and 1.66 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.06 and 2.31 (two ddd,
1-CH.sub.2), 2.38 (s, COCH.sub.3), 2.51 and 2.57 (two ddd,
2-CH.sub.2), 2.72 and 3.09 (two d, 9-CH.sub.2), 5.84 (s, OH), 6.92
(d, H-6), and 7.35 (d, H-5); mass spectrum m/z 333.2 (M+1).
EXAMPLE 28
Synthesis of
9a-butyl-8-chloro-4--cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-f-
luoren-3-one
[0389] 40
Step 1:
9a-butyl-8-chloro-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-
-3-one
[0390] A solution of
4-bromo-9a-butyl-8-chloro-7-methoxy-1,2,9,9a-tetrahyd-
ro-3H-fluoren-3-one (103 mg, 0.268 mmol) in anhydrous
1-methyl-2-pyrrolidinone (0.54 mL) was treated with copper(I)
cyanide (24 mg, 0.268 mmol). The mixture was placed under a
nitrogen atmosphere, stirred, and heated in an oil bath at
150.degree. C. for 1.5 hours. After cooling to room temperature,
the mixture was partitioned between EtOAc (50 mL) and water (50
mL). The organic phase was washed with water (5.times.50 mL) and
brine (50 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to an oil. The crude product was purified by
preparative layer chromatography on a 0.1.times.20.times.20 cm
silica gel GF plate, developing with 5% EtOAc in CH.sub.2Cl.sub.2.
The product band was eluted with EtOAc and the eluent evaporated
under vacuum to afford
9a-butyl-8-chloro-4-cyano-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
(65 mg) as an oil.
Step 2:
9a-butyl-8-chloro-4-cyano-7-hydroxy-1,2,9,9a-tetrahydro-3H-fluoren-
-3-one
[0391] A mixture of
9a-butyl-8-chloro-4-cyano-7-methoxy-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one (65 mg) and pyridine hydrochloride (4.2 g) was
heated in an oil bath at 200.degree. C. for 85 minutes. After
cooling to room temperature, the mixture was partitioned between
EtOAc (50 mL) and water (50 mL). The organic phase was washed with
brine (20 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum. The residue was purified by preparative layer
chromatography on two 0.1.times.20.times.20 cm silica gel GF
plates, developing with 5% MeOH in CH.sub.2Cl.sub.2. The product
bands were eluted with 10% MeOH in CH.sub.2Cl.sub.2, the eluant
evaporated under vacuum, and the residue lyophilized from benzene
(3 mL) plus EtOH (0.1 mL) to afford
9a-butyl-8-chloro-4-cyano-7-hydroxy-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one as an amorphous yellow solid.
[0392] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.15-1.33 (m,
CH.sub.2CH.sub.2CH.sub.2- CH.sub.3), 1.45 and 1.66 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.03 and 2.35 (two ddd,
1-CH.sub.2), 2.56-2.65(m, 2-CH.sub.2), 2.76 and 3.14 (two d,
9-CH.sub.2), 6.11 (s, OH), 7.11 (d, H-6), and 8.26 (d, H-5); mass
spectrum m/z 316.1 (M+1).
EXAMPLE 29
Synthesis of
9a-butyl-4-ethyl-6-fluoro-7-hydroxy-8-methyl-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one
[0393] 41
Step 1: 1-(3-fluoro-4-methoxyphenyl)-1-hexanone
[0394] Aluminum chloride (6.5 g, 48.8 mmol) was added to a stirred
mixture of 1-fluoro-2-methoxybenzene (5.0 mL, 44.4 mmol) and
hexanoyl chloride (7.5 mL, 53.3 mmol) at room temperature. The
mixture warmed and HCl evolution occurred. The resulting mixture
was stirred at room temperature for 45 minutes and then partitioned
between EtOAc (100 mL) and water (100 mL). The EtOAc layer was
washed with water (100 mL), aqueous K.sub.2CO.sub.3 (100 mL) and
brine (50 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to yield crude 1-(3-fluoro-4-methoxyphenyl)-1-hexanone
(9 g) as a solid.
Step 2: 2-butyl-6-fluoro-5-methoxy-1-indanone
[0395] A mixture of the crude
1-(3-fluoro-4-methoxyphenyl)-1-hexanone from step 1, methanol (45
mL), 37% aqueous formaldehyde (4.0 mL, 53.3 mmol), and potassium
carbonate (6.1 g, 44.4 mmol) was stirred and heated in an oil bath
at 50.degree. C. for 40 minutes. The mixture was then stirred at
room temperature overnight (20.5 hours), reheated to 50.degree. C.
for one hour, and then cooled to room temperature. The mixture was
evaporated under vacuum and the residue partitioned between EtOAc
(100 mL) and water (100 mL). The organic phase was washed with
brine (100 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to an oil (ca. 11 g) consisting of predominantly
1-(3-fluoro-4-methoxyphenyl)-2-(methoxymethyl- )-1-hexanone.
[0396] The oil was cooled in an ice bath and treated with ice cold
sulfuric acid (40 mL). The cooling bath was removed and the mixture
was stirred at room temperature for 10 minutes and then heated in
an oil bath at 50.degree. C. for 16.3 hours. After cooling to room
temperature, the mixture was partitioned between EtOAc (200 mL) and
ice-water (200 mL). The organic phase was washed with brine (100
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum
to a brown oil (8.8 g). The crude product was purified by
chromatography on EM silica gel 60 (4.5.times.21 cm column),
eluting with CH.sub.2Cl.sub.2 (200 mL forerun followed by 8 mL
fractions). Fractions 8-32 were combined and evaporated under
vacuum to afford 2-butyl-6-fluoro-5-methoxy-1-indanone (6.55 g) as
an oil.
Step 3: 2-butyl-6-fluoro-5-hydroxy-1-indanone
[0397] A mixture of 2-butyl-6-fluoro-5-methoxy-1-indanone (2.0 g)
and pyridine hydrochloride (15.0 g) was heated in an oil bath at
200.degree. C. for 75 minutes. After cooling to room temperature,
the mixture was partitioned between EtOAc (100 mL) and water (75
mL) containing brine (25 mL). The organic phase was washed with
brine (50 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to provide 2-butyl-6-fluoro-5-hydroxy-1-indanone (1.79
g) as a solid.
Step 4: 4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone
[0398] N-Bromosuccinimide (1.41 g, 7.93 mmol) was added to a
solution of 2-butyl-6-fluoro-5-hydroxy-1-indanone (1.76 g, 7.93
mmol) in anhydrous N,N-dimethylformamide (15 mL). The resulting
solution was stirred at room temperature for two hours. The solvent
was evaporated under vacuum and the residue was partitioned between
EtOAc (100 mL) and water (100 ml). The organic phase was washed
with water (4.times.100 mL) and brine (50 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to provide crude
4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone (2.17 g) as an
oil.
Step 5: 4-bromo-2-butyl-6-fluoro-5-methoxy-1-indanone
[0399] A mixture of 4-bromo-2-butyl-6-fluoro-5-hydroxy-1-indanone
(2.17 g, 7.23 mmol), N,N-dimethylformamide (14.5 mL), methyl iodide
(0.675 mL, 10.84 mmol), and sodium bicarbonate (1.50 g, 18.1 mmol)
was stirred at room temperature for 17 hours. The solvent was
evaporated under vacuum. The residue in EtOAc (150 mL) was washed
with water (5.times.100 mL) and brine (50 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (2.29
g). The crude product was dissolved in CH.sub.2CL.sub.2 (5 mL) and
the solution filtered through a pad of EM silica gel 60 (20 mL)
using an additional 60 mL of CH.sub.2Cl.sub.2 to elute the silica
gel. The CH.sub.2Cl.sub.2 filtrate was evaporated under vacuum to
afford 4-bromo-2-butyl-6-fluoro-5-methoxy-1-indanone (1.86 g) as a
pink oil.
Step 6: 2-butyl-6-fluoro-5-methoxy-4-methyl-1-indanone
[0400] A mixture of 4-bromo-2-butyl-6-fluoro-5-methoxy-1-indanone
(1.86 g, 5.94 mmol), bis(triphenylphosphine)palladium(II) chloride
(208 mg, 0.297 mmol), tetramethyltin (0.989 mL, 7.128 mmol),
triphenylphosphine (156 mg, 0.594 mmol), lithium chloride (504 mg,
11.88 mmol), and anhydrous N,N-dimethyl-formamide (11.9 mL) was
placed under a nitrogen atmosphere, stirred, and heated in an oil
bath at 100.degree. C. for 22 hours. After cooling to room
temperature, the mixture was evaporated under vacuum. The residue
in EtOAc (150 mL) was washed with water (4.times.100 mL) and brine
(50 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to an oil (2.15 g). The crude product was purified by
chromatography on EM silica gel 60 (2.5.times.29 cm column),
eluting with CH.sub.2Cl.sub.2 (50 mL fore-run followed by 8 mL
fractions). Fractions 20-28 were combined and evaporated under
vacuum to provide 2-butyl-6-fluoro-5-methoxy-4-methyl-1-indanone
(365 mg) as an oil.
Step 7:
9a-butyl-4-ethyl-6-fluoro-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one
[0401] A solution of 2-butyl-6-fluoro-5-methoxy-4-methyl-1-indanone
(118 mg, 0.47 mmol) in anhydrous tetrahydrofuran (0.47 mL) was
treated with propyl vinyl ketone (0.065 mL, 0.56 mmol) and
1,8-diazabicyclo[5.4.0]unde- c-7-ene (0.0143 mL, 0.094 mmol). The
mixture was stirred and heated in an oil bath at 50.degree. C. for
6 hours and then at room temperature for 64 hours. The solvent was
evaporated under vacuum to give a residue consisting mainly of
2-butyl-6-fluoro-5-methoxy-4-methyl-2-(3-oxohexyl)-1- -indanone.
This material was dissolved in acetic acid (2 mL), treated with
aqueous 6N HCl (1.5 mL), and stirred while heating in an 80.degree.
C. oil bath for 6 hours. After cooling, the mixture was partitioned
between EtOAc (25 mL) and saturated aqueous K.sub.2CO.sub.3 (25
mL). The organic phase was washed with brine (10 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (138
mg). The crude product was purified by preparative layer
chromatography on two 0.1.times.20.times.20 cm silica gel GF
plates, developing with CH.sub.2Cl.sub.2. The product bands were
eluted with EtOAc and the eluent evaporated under vacuum to afford
9a-butyl-4-ethyl-6-fluoro-7-methoxy-8-methyl-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one (93 mg) as an oil.
Step 8:
9a-butyl-4-ethyl-6-fluoro-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one
[0402] A solution of
9a-butyl-4-ethyl-6-fluoro-7-methoxy-8-methyl-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one (93 mg, 0.28 mmol) in anhydrous
dichloromethane (1.4 mL) was cooled in a dry ice-acetone bath
(-78.degree. C.) and the solution treated with 1M boron tribromide
in dichloromethane (1.4 mL, 1.4 mmol). The cooling bath was removed
and the mixture was stirred at room temperature for 90 minutes. The
mixture was partitioned between EtOAc (20 mL) and water (20 mL)
containing 2N HCl (2 mL). The organic phase was washed with brine
(10 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum. The residue was purified by preparative layer
chromatography on two 0.05.times.20.times.20 cm silica gel GF
plates, developing with 5% EtOAc in CH.sub.2Cl.sub.2. The product
bands were eluted with EtOAc, the eluent evaporated under vacuum,
and the residue lyophilized from benzene to afford
9a-butyl-4-ethyl-6-fluoro-7-hydroxy-8-methyl-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one as an amorphous solid.
[0403] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.09 (t, CH.sub.2CH.sub.3),
1.13-1.27 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.38 and 1.55 (two
m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.95 and 2.22 (two ddd,
1-CH.sub.2), 2.21 (s, 8-CH.sub.3), 2.39-2.67 (m, CH.sub.2CH.sub.3
and 2-CH.sub.2), 2.54 and 2.89 (two d, 9-CH.sub.2), 5.72 (two d,
OH), and 7.27 (d, H-5); mass spectrum m/z 317.3 (M+1).
EXAMPLE 30
Synthesis of
9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one
[0404] 42
Step 1:1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone
[0405] Aluminum chloride (1.16 g, 8.72 mmol) was added to a stirred
mixture of 1-chloro-3-fluoro-2-methoxybenzene (1.00 mL, 8.72 mmol)
and hexanoyl chloride (1.47 mL, 10.46 mmol) at room temperature.
The mixture warmed and HCl evolution occurred. The resulting
mixture was stirred at room temperature for 67 hours and then
partitioned between EtOAc (40 mL) and ice cold water (40 mL). The
EtOAc layer was washed with brine (30 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to yield crude
1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexanone as an oil.
Step 2: 2-butyl-4-chloro-6-fluoro-5-methoxy-1-indanone
[0406] A mixture of the crude
1-(3-chloro-5-fluoro-4-methoxyphenyl)-1-hexa- none from step 1,
methanol (8.7 mL), 37% aqueous formaldehyde (0.786 mL, 10.5 mmol),
and potassium carbonate (1.2 g, 8.72 mmol) was stirred and heated
in an oil bath at 50.degree. C. for 7 hours. The mixture was
evaporated under vacuum and the residue partitioned between EtOAc
(100 mL) and water (100 mL) containing 2N HCl (10 mL). The organic
phase was washed with brine (50 mL), dried over MgSO.sub.4,
filtered, and evaporated under vacuum to an oil (1.86 g) consisting
of predominantly
1-(3-chloro-5-fluoro-4-methoxyphenyl)-2-(methoxymethyl)-1-hexanone.
[0407] The oil was cooled in an ice bath and treated with ice cold
sulfuric acid (6 mL). The cooling bath was removed and the mixture
was stirred at room temperature for 5 minutes, then heated in an
oil bath at 50.degree. C. for 35 minutes, kept at room temperature
overnight, heated at 50.degree. C. an additional 3 hours, and
finally cooled to room temperature. The mixture was partitioned
between EtOAc (100 mL) and ice cold water (100 mL). The organic
phase was washed with brine (50 mL) and evaporated under vacuum to
an oil (1.5 g). The .sup.1H NMR spectrum os this material showed a
mixture of 2-butyl-4-chloro-6-fluoro-5-methoxy-1-i- ndanone (major
product) and 2-butyl-6-chloro-4-fluoro-5-methoxy-1-indanone (minor
product).
Step 3:
9a-butyl-8-chloro-6-fluoro-7-methoxy-4-methyl-1,2,9,9a-tetrahydro--
3H-fluoren-3-one
[0408] A sample of the crude product from step 2 (360 mg, 1.33
mmol) in anhydrous tetrahydrofuran (2.7 mL) was treated with ethyl
vinyl ketone (0.160 mL, 1.60 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (0.040 mL, 0.266 mmol). The
mixture was stirred and heated in an oil bath at 60.degree. C. for
two hours. TLC showed very little reaction. The mixture was treated
with 0.5M sodium methoxide in methanol (0.53 mL, 0.266 mmol) and
stirred with heating at 60.degree. C. for an additional 17 hours.
After cooling to room temperature, the solvent was evaporated under
vacuum to give a residue consisting mainly of
2-butyl-4-chloro-6-fluoro-5- -methoxy-2-(3-oxopentyl)-1-indanone.
This material was dissolved in acetic acid (6 mL), treated with
aqueous 6N HCl (3 mL), and stirred while heating in an 80.degree.
C. oil bath for 23.5 hours. After cooling, the mixture was
partitioned between EtOAc (150 mL) and water (150 mL). The organic
phase was washed with aqueous K.sub.2CO.sub.3 (100 mL) and brine
(50 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to a dark oil (480 mg). The crude product was purified by
preparative layer chromatography on four 0.1.times.20.times.20 cm
silica gel GF plates, developing with CH.sub.2Cl.sub.2. The product
bands were eluted with EtOAc and the eluent evaporated under vacuum
to give an oil (208 mg). This material was a mixture of
9a-butyl-8-chloro-6-fluoro-7-methoxy-4-met-
hyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (major product) and
9a-butyl-6-chloro-8-fluoro-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one (minor product) as evidenced by .sup.1H NMR
spectroscopy.
Step 4:
9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro--
3H-fluoren-3-one
[0409] The product mixture from step 3 and pyridine hydrochloride
(5.3 g) were combined and heated in an oil bath at 200.degree. C.
for 90 minutes. After cooling, the mixture was partitioned between
EtOAc (50 mL) and water (50 ml). The organic phase was washed with
brine (50 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to a blue oil. The oil was purified by preparative
layer chromatography on four 0.05.times.20.times.20 silica gel GF
plates, developing with 5% EtOAc in CH.sub.2Cl.sub.2. One of the
plates was discarded due to excessive streaking. The combined
product bands were eluted with EtOAc, the eluent evaporated under
vacuum, and the residue lyophilized from benzene (3 mL) containing
EtOH (2 drops) to afford 9a-butyl-8-chloro-6-fluoro-7-hydroxy--
4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous
solid.
[0410] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.28 (m,
CH.sub.2CH.sub.2CH.sub.2- CH.sub.3), 1.39 and 1.57 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.99 and 2.25 (two ddd,
1-CH.sub.2), 2.04 (s, 4-CH.sub.3), 2.48 and 2.58 (two ddd,
2-CH.sub.2), 2.68 and 3.03 (two d, 9-CH.sub.2), 5.70 (d, OH), and
7.40 (d, H-5); mass spectrum m/z 323.2 (M+1).
EXAMPLE 31
Synthesis of
9a-butyl-8-chloro-4-ethyl-6-fluoro-7-hydroxy-1,29,9a-tetrahyd-
ro-3H-fluoren-3-one
[0411] 43
Step 1:
9a-butyl-8-chloro-4-ethyl-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one
[0412] A sample of the crude product from step 2 in the preceding
example (386 mg, 1.36 mmol) in anhydrous tetrahydrofuran (2.7 mL)
was treated with propyl vinyl ketone (0.188 mL, 1.63 mmol) and
1,8-diazabicyclo[5.4.0]undec-7-ene (0.041 mL, 0.272 mmol). The
mixture was stirred and heated in an oil bath at 60.degree. C. for
two hours. TLC showed very little reaction. The mixture was treated
with 0.5M sodium methoxide in methanol (0.54 mL, 0.272 mmol) and
then stirred with heating at 60.degree. C. for an additional 16.3
hours. After cooling to room temperature, the solvent was
evaporated under vacuum to give a residue consisting mainly of
2-butyl-4-chloro-6-fluoro-5-methoxy-2-(3-oxohexyl)-1- -indanone.
This material was dissolved in acetic acid (6 mL), treated with
aqueous 6N HCl (3 mL), and stirred while heating in an oil bath at
80.degree. C. for 22.3 hours. After cooling, the mixture was
partitioned between EtOAc (150 mL) and water (150 mL). The organic
phase was washed with aqueous K.sub.2CO.sub.3 (100 mL) and brine
(50 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to an oil (420 mg). The crude product was purified by
preparative layer chromatography on four 0.1.times.20.times.20 cm
silica gel GF plates, developing three times with 10% EtOAc in
hexanes. The product bands were combined, eluted with EtOAc, and
the eluent evaporated under vacuum to give
9a-butyl-8-chloro-4-ethyl-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluor-
en-3-one as an oil (153 mg). The product contained trace amounts of
9a-butyl-6-chloro-4-ethyl-8-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluor-
en-3-one as evidenced by .sup.1H NMR spectroscopy.
Step 2:
9a-butyl-8-chloro-4-ethyl-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one
[0413] The product from step 1 and pyridine hydrochloride (5.0 g)
were combined and heated in an oil bath at 200.degree. C. for 80
minutes. After cooling, the mixture was partitioned between EtOAc
(50 mL) and water (50 ml). The organic phase was washed with brine
(50 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum to a blue oil. The oil was purified by preparative layer
chromatography on three 0.05.times.20.times.20 silica gel GF
plates, developing with 10% EtOAc in CH.sub.2Cl.sub.2. The combined
product bands were eluted with EtOAc, the eluent evaporated under
vacuum, and the residue lyophilized from benzene (3 mL) to afford
9a-butyl-8-chloro-4-ethyl-6-fluoro-7-hydroxy-1,2,9,9a-te-
trahydro-3H-fluoren-3-one as an amorphous solid.
[0414] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.09 (t, CH.sub.2CH.sub.3),
1.13-1.28 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.39 and 1.56 (two
m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.98 and 2.25 (two ddd,
1-CH.sub.2), 2.41 and 2.62 (two dq, CH.sub.2CH.sub.3), 2.42 and
2.56 (two ddd, 2-CH.sub.2), 2.65 and 3.02 (two d, 9-CH.sub.2), 5.70
(d, OH), and 7.35 (d, H-5); mass spectrum m/z 337.2 (M+1).
EXAMPLE 32
Synthesis of
4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one
[0415] 44
Step 1:
9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluore-
n-3-one
[0416] A solution of crude
2-butyl-4-chloro-6-fluoro-5-methoxy-1-indanone (386 mg, 1.4 mmol)
in tetrahydrofuran (2.8 mL) was treated with methyl vinyl ketone
(0.150 mL, 1.78 mmol) and 0.5N sodium methoxide in methanol (1.1
mL, 0.56 mmol). The mixture was stirred at room temperature for 5.5
hours to effect conversion to
2-butyl-4-chloro-6-fluoro-5-methoxy-2-(3-ox- obutyl)-1-indanone.
The reaction mixture was diluted with toluene (10 mL), treated with
pyrrolidine (0.117 mL, 1.4 mmol) and acetic acid (0.112 mmol, 1.46
mmol), and then stirred and heated in an oil bath at 80.degree. C.
for 3 hours. After storing overnight at room temperature, the
mixture was partitioned between EtOAc (50 mL) and water (50 mL).
The organic phase was washed with 0.1N HCl (50 mL), saturated
aqueous NaHCO.sub.3 (50 mL) and brine (20 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum. The oily residue
was purified by preparative layer chromatography on four
0.1.times.20.times.20 cm silica gel GF plates, developing with 5%
EtOAc in CH.sub.2Cl.sub.2. The product bands were combined, eluted
with EtOAc, and the eluent evaporated under vacuum to provide
9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fl-
uoren-3-one (160 mg) as a solid. .sup.1H NMR spectroscopy revealed
that the product contained a minor amount of the isomeric product
9a-butyl-6-chloro-8-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one
which is derived from a minor amount of
2-butyl-6-chloro-4-fluoro-5-metho- xy-1-indanone in the starting
material.
Step 2:
4-bromo-9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one
[0417] A solution of the product from step 1 (160 mg, 0.52 mmol) in
anhydrous dichloromethane (5.2 mL) was cooled in an ice bath and
treated with sodium bicarbonate (218 mg, 2.6 mmol) and bromine
(0.028 mL, 0.52 mmol). The mixture was stirred at 0.degree. C. for
15 minutes and then diluted with CH.sub.2Cl.sub.2 (20 mL) and
washed with water (25 mL). The organic phase was dried over
MgSO.sub.4, filtered and evaporated under vacuum. The residue was
purified by preparative layer chromatography on three
0.05.times.20.times.20 cm silica gel GF plates, developing with 10%
EtOAc in hexanes. The product bands were combined, eluted with
EtOAc, and the eluent evaporated under vacuum to afford
4-bromo-9a-butyl-8-chloro-6--
fluoro-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (110 mg) as a
solid.
[0418] Step 3:
4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetra-
hydro-3H-fluoren-3-one
[0419] A solution of
4-bromo-9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a-
-tetrahydro-3H-fluoren-3-one (31 mg, 0.077 mmol) in anhydrous
dichloromethane (0.5 mL) was cooled in a dry ice-acetone bath
(-78.degree. C.) and the solution treated with 1M boron tribromide
in dichloromethane (0.231 mL, 0.231 mmol). The cooling bath was
removed and the mixture was stirred at room temperature for one
hour. The mixture was partitioned between EtOAc (20 mL) and water
(20 mL) containing 2N HCl (2 mL). The organic phase was washed with
brine (10 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum. The residue was purified by preparative layer
chromatography on a 0.05.times.20.times.20 cm silica gel GF plate,
developing with 10% EtOAc in CH.sub.2Cl.sub.2. The product band was
eluted with EtOAc, the eluent evaporated under vacuum, and the
residue lyophilized from benzene plus a few drops of EtOH to afford
4-bromo-9a-butyl-8-chloro-6-fluoro-7-hydroxy-1,2,9,9a-tetrahydr-
o-3H-fluoren-3-one as an amorphous solid.
[0420] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.30 (m,
CH.sub.2CH.sub.2CH.sub.2- CH.sub.3), 1.49 and 1.64 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 and 2.29 (two ddd,
1-CH.sub.2), 2.70-2.80 (m, 2-CH.sub.2), 2.74 and 3.08 (two d,
9-CH.sub.2), 5.83 (s, OH), and 8.29 (d, H-5); mass spectrum m/z
387.0 (M+1) and 389.0 (M+3).
EXAMPLE 33
Synthesis of
9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-(trifluoromethyl)-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one
[0421] 45
Step 1:
9a-butyl-8-chloro-6-fluoro-7-methoxy-4-(trifluoromethyl)-1,2,9,9a--
tetrahydro-3H-fluoren-3-one
[0422] A mixture of
4-bromo-9a-butyl-8-chloro-6-fluoro-7-methoxy-1,2,9,9a--
tetrahydro-3H-fluoren-3-one (47 mg, 0.117 mmol), copper(I) iodide
(27 mg, 0.14 mmol), methyl difluoro(fluorosulfonyl)acetate (0.108
mL, 0.85 mmol), and anhydrous N,N-dimethylformamide (5.9 mL) was
placed under a nitrogen atmosphere, stirred, and heated in an oil
bath at 75-80.degree. C. for 7 hours. After cooling to room
temperature, the mixture was diluted with EtOAc (50 mL), washed
with water (5.times.100 mL) and brine (50 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to an oil (47
mg). The crude product was purified by preparative layer
chromatography on a 0.1.times.20.times.20 cm silica gel GF plate,
developing with 10% EtOAc in hexanes. The product band was eluted
with EtOAc and the eluent evaporated under vacuum to afford
9a-butyl-8-chloro-6-fluoro-7-methoxy-4-(trifluoromethyl)-1,2,9,9a-tetrahy-
dro-3H-fluoren-3-one (39 mg) as an oil.
Step 2:
9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-(trifluoromethyl)-1,2,9,9a--
tetrahydro-3H-fluoren-3-one
[0423] A solution of
9a-butyl-8-chloro-6-fluoro-7-methoxy-4-(trifluorometh-
yl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (39 mg, 0.10 mmol) in
anhydrous dichloromethane (1.0 mL) was cooled in a dry ice-acetone
bath (-78.degree. C.) and the solution was treated with 1M boron
tribromide in dichloromethane (0.3 mL, 0.3 mmol). The cooling bath
was removed and the mixture was stirred at room temperature for one
hour. The mixture was partitioned between EtOAc (20 mL) and water
(20 mL) containing 2N HCl (1 mL). The organic phase was washed with
brine (10 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum. The residue was purified by preparative layer
chromatography on a 0.1.times.20.times.20 cm silica gel GF plate,
developing with 10% EtOAc in CH.sub.2Cl.sub.2. The product band was
eluted with 10% MeOH in CH.sub.2Cl.sub.2, the eluent evaporated
under vacuum, and the residue lyophilized from benzene plus a few
drops of EtOH to afford
9a-butyl-8-chloro-6-fluoro-7-hydroxy-4-(trifl-
uoromethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an amorphous
solid.
[0424] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.85 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.11-1.28 (m,
CH.sub.2CH.sub.2CH.sub.2- CH.sub.3), 1.32 and 1.53 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.07 and 2.26 (two ddd,
1-CH.sub.2), 2.50-2.64 (m, 2-CH.sub.2), 2.78 and 3.08 (two d,
9-CH.sub.2), 5.89 (br s, OH), and 7.54 (m, H-5); mass spectrum m/z
377.1 (M+1).
EXAMPLE 34
Synthesis of
2-hydroxy-5-methylgibba-1(10a),2,4,4b-tetraen-6-one
[0425] 46
Step 1: 2-(2-hydroxyethyl)-5-methoxy-1-indanone
[0426] A solution of 5-methoxy-1-indanone (500 mg, 3.08 mmol) in
methanol (10 mL) was treated with 10% palladium on carbon (53 mg)
followed by glycoaldehyde dimer (370 mg, 3.08 mmol) and 0.5M sodium
methoxide in methanol (1.3 mL, 0.65 mmol). The mixture was placed
under a hydrogen atmosphere (balloon) and stirred vigorously at
room temperature for 65 hours. After purging with nitrogen, the
mixture was filtered through a 0.45 .mu.m Acrodisc and the disk was
rinsed with methanol (2 mL). The filtrate was diluted with EtOAc
(25 mL), washed with 0.1N HCl (15 mL) and brine (15 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to a solid (436
mg). LC-MS of this material showed a mixture of starting material
(major) and product.
[0427] The mixture was purified by chromatography on a Biotage
Flash 12M KP-Sil column (12 mm.times.15 cm). The column was eluted
with 3:2 EtOAc-hexanes, collecting 6 mL fractions every 30 sec.
Fractions 20-36 were concentrated under vacuum and flashed with
benzene to afford 2-(2-hydroxyethyl)-5-methoxy-1-indanone (106 mg,
17% yield) as an oil.
[0428] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.80 and 2.05 (two
m, CH.sub.2CH.sub.2OH), 2.79 and 3.35 (two dd, 3-CH.sub.2), 2.83
(m, H-2), 3.77-3.90 (m, CH.sub.2CH.sub.2OH), 3.87 (s, OCH.sub.3),
6.86 (d, H-4), 6.89 (dd, H-6), and 7.67 (d, H-7).
Step 2: 2-(2-hydroxyethyl)-5-methoxy-2-(3-oxopentyl)-1-indanone
[0429] A solution of 2-(2-hydroxyethyl)-5-methoxy-1-indanone (105
mg, 0.51 mmol) in methanol (2.0 mL) at room temperature was treated
with ethyl vinyl ketone (EVK, 0.102 mL) and 0.5M sodium methoxide
in methanol (0.204 mL, 0.1 mmol). The mixture was stirred in a
capped flask and heated in an oil bath at 60.degree. C. for 8
hours. After cooling, the reaction mixture was diluted with EtOAc
(25 mL), washed with 0.2N HCl (15 mL), water (15 mL), and brine (15
mL), dried over MgSO.sub.4, filtered, and evaporated under vacuum
to afford 2-(2-hydroxyethyl)-5-methoxy-2-(3-oxope- ntyl)-1-indanone
(138 mg, 93% yield) as an oil.
[0430] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.99 (t,
COCH.sub.2CH.sub.3), 1.84-2.00 (m, CH.sub.2CH.sub.2OH and
CH.sub.2CH.sub.2CO), 2.28 (m, CH.sub.2CH.sub.2CO), 2.33 (m,
COCH.sub.2CH.sub.3), 2.92 and 3.11 (two d, 3-CH.sub.2), 3.63 and
3.72 (two m, CH.sub.2CH.sub.2OH), 3.87 (s, OCH.sub.3), 6.86 (d,
H-4), 6.91 (dd, H-6), and 7.67 (d, H-7).
Step 3:
9a-(2-hydroxyethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluo-
ren-3-one and
9a-(2-acetoxyethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3-
H-fluoren-3-one
[0431] A solution of
2-(2-hydroxyethyl)-5-methoxy-2-(3-oxopentyl)-1-indano- ne (138 mg,
0.475 mmol) in acetic acid (3.0 mL) was diluted with aqueous 6N HCl
(3.0 mL) and the resulting mixture was stirred and heated in an oil
bath at 80.degree. C. for 90 minutes. After cooling to room
temperature, the reaction mixture was diluted with EtOAc (20 mL),
washed with water (10 mL), 1M pH 7 phosphate buffer (15 ml), water
(15 mL), and brine (15 mL), dried over MgSO.sub.4, filtered, and
evaporated under vacuum to an oil (139 mg). LC-MS showed a mixture
of
9a-(2-hydroxyethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-o-
ne and its O-acetyl derivative
9a-(2-acetoxyethyl)-7-methoxy-4-methyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one.
Step 4:
9a-(2-hydroxyethyl)-7-methoxy-4-methyl-1,2,99a-tetrahydro-3H-fluor-
en-3-one
[0432] The mixture of products from step 3 was dissolved in
methanol (5 mL) and the solution treated with 0.5M sodium methoxide
in methanol (4.5 mL). The mixture was stirred at room temperature
for 15 minutes then acidified with aqueous 2N HCl and concentrated
under vacuum. The residue in EtOAc (25 mL) was washed with brine
(20 mL), dried over MgSO.sub.4, filtered, and evaporated under
vacuum. The crude product was purified by chromatography on a
Biotage Flash-12 M KP-Sil column (12 mm.times.15 cm). The column
was eluted with 3:2 EtOAc-hexanes (145 mL) followed by 100% EtOAc,
collecting 4 mL fractions every 30 seconds. Fractions 30-50 were
combined and evaporated under vacuum to give the product as an oil
(54.7 mg, 42% yield). Treatment of this material with Et.sub.2O
gave the product
9a-(2-hydroxyethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-flu-
oren-3-one as a solid.
[0433] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.72-1.86 (m,
CH.sub.2CH.sub.2OH), 1.99 and 2.21 (two ddd, 1-CH.sub.2), 2.04 (s,
4-CH.sub.3), 2.45 and 2.63 (two ddd, 2-CH.sub.2), 2.76 and 3.05
(two d, 9-CH.sub.2), 3.47-3.62 (m, CH.sub.2CH.sub.2OH), 3.82 (s,
OCH.sub.3), 6.81-8.85 (m, H-6 and H-8), and 7.61 (d, H-5).
Step 5:
9a-[2-(methanesulfonyoxy)ethyl]-7-methoxy-4-methyl-1,2,9,9a-tetrah-
ydro-3H-fluoren-3-one
[0434] An ice-cold solution of
9a-(2-hydroxyethyl)-7-methoxy-4-methyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one (39 mg, 0.14 mmol) and
triethylamine (0.030 mL, 0.21 mmol) in anhydrous dichloromethane
(1.5 ml) was treated with methanesulfonyl chloride (0.014 mL, 0.18
mmol) and the resulting solution was stirred at 0.degree. C. for 30
minutes. The mixture was diluted with EtOAc (10 mL), washed with
water (5 mL), 0.2N HCl (5 mL), and brine (5 mL), dried over
MgSO.sub.4, filtered, and evaporated under vacuum to provide
9a-[2-(methanesulfonyoxy)ethyl]-7-methoxy-4-methyl-1,2,-
9,9a-tetrahydro-3H-fluoren-3-one (49.7 mg, 99% yield) as an
oil.
[0435] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 2.03 (m,
CH.sub.2CH.sub.2O), 2.08 (s, 4-CH.sub.3), 2.09 and 2.22 (two ddd,
1-CH.sub.2), 2.53 and 2.61 (two ddd, 2-CH.sub.2), 2.85 and 3.03
(two d, 9-CH.sub.2), 2.89 (s, SO.sub.2CH.sub.3), 3.85 (s,
OCH.sub.3), 4.034.17 (m, CH.sub.2CH.sub.2O), 6.86 (s, H-8), 6.87
(dd, H-6), and 7.64 (d, H-5).
Step 6:
9a-(2-iodoethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-
-3-one
[0436] A solution of
2-(2-methoxy-5-methyl-6-oxo-6,7,8,9-tetrahydro-8aH-fl-
uoren-8a-yl)ethyl methanesulfonate (49.7 mg, 0.142 mmol) in acetone
(2.0 mL) was treated with sodium iodide (85 mg, 0.57 mmol) and the
resulting mixture was stirred and heated in an oil bath at
60.degree. C. for 16 hours. After cooling, the mixture was diluted
with acetone (2 mL) and filtered through a 0.45 .mu.m Acrodisc
filter. The filtrate was evaporated under vacuum and the residue in
CH.sub.2Cl.sub.2 (3 mL) was re-filtered. The filtrate was purified
by chromatography on a Biotage Flash 12M KP-Sil column (12
mm.times.15 cm) which was eluted with 4:1 hexanes-EtOAc, collecting
6 mL fractions every 30 seconds. Fractions 9-11 gave
9a-(2-iodoethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-
-one (34.5 mg, 64% yield) as an oil.
[0437] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 2.03 and 2.20 (two
ddd, 1-CH.sub.2), 2.08 (s, 4-CH.sub.3), 2.24 (m,
CH.sub.2CH.sub.21), 2.51 and 2.61 (two ddd, 2-CH.sub.2), 2.80 and
2.97 (two d, 9-CH.sub.2), 2.85 and 2.95 (two m, CH.sub.2CH.sub.2I),
3.86 (s, OCH.sub.3), 6.86 (br s, H-8), 6.87 (dd, H-6), and 7.64 (d,
H-5).
Step 7: 2-methoxy-5-methylgibba-1 (10a),2,4,4b-tetraen-6-one
[0438] A solution of N,N-diisopropylamine (0.015 mL, 0.107 mmol) in
anhydrous tetrahydrofuran (THF, 1.0 mL) was placed under a nitrogen
atmosphere, cooled in an ice bath, and treated with 1.6 M
n-butyllithium in hexanes (0.061 mL, 0.098 mmol). The solution was
stirred at 0.degree. C. for 35 minutes, then cooled in a dry
ice-acetone bath and, after aging for 5 minutes, treated with a
solution of 9a-(2-iodoethyl)-7-methoxy-4-me-
thyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (34 mg, 0.089 mmol) in
THF (1.0 mL). The reaction mixture was warmed from -78.degree. C.
to room temperature over 4 hours, stirred at room temperature for
21 hours, and then quenched with aqueous 2N HCl (0.5 mL) and
diluted with EtOAc (10 mL). The organic phase was washed with water
(5 mL) and brine (5 mL), dried over MgSO.sub.4, filtered, and
evaporated under vacuum to an oil (27.2 mg). This material was
purified by chromatography on a Biotage Flash 12M KP-Sil column (12
mm.times.15 cm), eluting with 6:1 hexanes-EtOAc and collecting 7 mL
fractions every 30 seconds. Fractions 16-20 were combined and
evaporated under vacuum to give a mixture (21.7 mg) of
2-methoxy-5-methylgibba-1(10a),2,4,4b-tetraen-6-one and the
starting material
9a-(2-iodoethyl)-7-methoxy-4-methyl-1,2,9,9a-tetrahydro-
-3H-fluoren-3-one as an oil.
Step 8: 2-hydroxy-5-methylgibba-1(10a),2,4,4b-tetraen-6-one and
7-hydroxy-9a-(2-iodoethyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
[0439] A solution of the product mixture from step 7 (21.7 mg,
approx. 0.1 mmol) in anhydrous dichloromethane (1.0 mL) was treated
at room temperature with aluminum chloride (75 mg, 0.56 mmol) and
ethanethiol (0.032 mL, 0.43 mmol). After stirring at room
temperature for 58 minutes, the yellow solution was treated with
aqueous 2N HCl (1 mL) and EtOAc (9 ml), washed with water (4 mL)
and brine (5 mL), dried over MgSO.sub.4, filtered, and evaporated
under vacuum to a solid film. The solid in warm EtOH (1 mL) was
applied to two 0.1.times.20.times.20 cm silica gel GF plates which
were developed with 1:1-hexanes-EtOAc. Two UV visible bands were
removed, eluted with EtOAc, concentrated under vacuum, and the
residues lyophilized from benzene containing some acetone. The band
at R.sub.f 0.57-0.67 gave mainly
7-hydroxy-9a-(2-iodoethyl)-4-methyl-1,2,9,9-
a-tetrahydro-3H-fluoren-3-one as an amorphous solid (contains
approx. 11% of the major tetracyclic product). The band at R.sub.f
0.47-0.57 gave mainly
2-hydroxy-5-methylgibba-1(10a),2,4,4b-tetraen-6-one as an amorphous
solid (contains approx. 16% of the minor 9a-iodoethyl product).
9a-Iodoethyl-tetrahydrofluorenone product: .sup.1H NMR (approx. 3:2
CD.sub.3CN:CDCl.sub.3, 500 MHz) .delta. 1.84 (p, CHD.sub.2CN), 1.87
(m, 1-CH.sub.aH.sub.b), 1.92 (s, 4-CH.sub.3), 2.01-2.12 (m,
1-CH.sub.aH.sub.b and CH.sub.2CH.sub.2I), 2.31 and 2.44 (two ddd,
2-CH.sub.2), 2.61 and 2.83 (two d, 9-CH.sub.2), 2.76 and 2.87 (two
m, CH.sub.2CH.sub.2I), 6.63-6.66 (m, H-6 and H-8), 7.20 (br s, OH),
7.29 (s, CHCl.sub.3), and 7.43 (d, H-5); mass spectrum m/z 369.2
(M+1).
[0440] Gibbatetraenone product: .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 1.64, 1.75-1.86, 2.26 (three m, 8-CH.sub.2 and 9-CH.sub.2),
1.88 and 1.95 (dd and d, 11-CH.sub.2), 2.06 (s, 5-CH.sub.3), 2.98
and 3.22 (two d, 10-CH.sub.2), 3.07 (dd, H-7), 5.87 (br s, OH),
6.83 (dd, H-3), 6.86 (br s, H-1), and 7.64 (d, H-4).
EXAMPLE 35
Synthesis of 4-bromo-9a-butyl-3-oxo-2,3,9,9a-1h-fluoren-7-yl
Pivalate
[0441] 47
[0442] A solution of
4-bromo-9a-butyl-7-hydroxy-1,2,9,9a-tetrahydro-3H-flu- oren-3-one
(30 mg, 0.09 mmol) in anhydrous dichloromethane (1.0 mL) was
treated with triethylamine (0.015 mL, 0.108 mmol) and pivaloyl
chloride (0.0123 mL, 0.1 mmol). After stirring at room temperature
for 20 minutes, the reaction mixture was purified by preparative
layer chromatography on a 0.1.times.20.times.20 cm silica gel GF
plate, developing with 5% EtOAc in CH.sub.2Cl.sub.2. The product
band was eluted with EtOAc, the eluent was evaporated under vacuum,
and the residue was lyophilized from benzene to afford
4-bromo-9a-butyl-3-oxo-2,3,9,9a-1H-fluoren-7-yl pivalate as an
amorphous solid.
[0443] .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3),1.15-1.30 (m,
CH.sub.2CH.sub.2CH.sub.2C- H.sub.3), 1.37 (s, C(CH.sub.3).sub.3),
1.47 and 1.64 (two m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.08 and
2.27 (two ddd, 1-CH.sub.2), 2.69-2.77 (m, 2-CH.sub.2), 2.81 and
3.04 (two d, 9-CH.sub.2), 7.05 (dd, H-6), 7.08 (s, H-8), and 8.55
(d, H-5).
EXAMPLES 36-111
[0444] The following compounds were prepared using methods
analogous to those described in the preceding examples:
6 48 36 R.sup.3 = CH.sub.3
7-hydroxy-4,9a-dimethyl-1,2,9,9a-tetrahydro-3H- R.sup.10 = CH.sub.3
fluoren-3-one .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.14 (s,
9a-CH.sub.3), 1.92 (s, 4-CH.sub.3), 1.98-2.06 (m, 1-CH.sub.2), 2.33
and 2.58 (two ddd, 2-CH.sub.2), 2.71 and 2.78 (two d, 9-CH.sub.2),
6.74 (dd, H- 6), 6.79 (d, H-8), and 7.55 (d, H-5). 37 R.sup.3 =
CH.sub.3 9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro- -
R.sup.10 = CH.sub.2CH.sub.3 3H-fluoren-3-one .sup.1H NMR
(DMSO-d.sub.6, 500 MHz) .delta. 0.79 (t, CH.sub.2CH.sub.3), 1.32
and 1.55 (two dq, CH.sub.2CH.sub.3), 1.90 and 2.12 (two m,
1-CH.sub.2), 1.93 (s, 4-CH.sub.3), 2.28 and 2.48 (two m, 2-
CH.sub.2), 2.60 and 2.88 (two d, 9-CH.sub.2), 6.73 (dd, H-6), 6.76
(d, H-8), and 7.55 (d, H-5). 38 R.sup.3 = CH.sub.3
7-hydroxy-4-methyl-9a-propyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one .sup.1H NMR
(DMSO-d.sub.6, 500 MHz) .delta. 0.78 (t, CH.sub.2CH.sub.2CH.sub.3),
1.12 and 1.23 (two m, CH.sub.2CH.sub.2CH.sub.3), 1.27 and 1.49 (two
m, CH.sub.2CH.sub.2CH.sub.3- ), 1.91 and 2.11 (two ddd, 1-
CH.sub.2), 1.92 (s, 4-CH.sub.3), 2.28 and 2.50 (two ddd,
2-CH.sub.2), 2.63 and 2.89 (two d, 9- CH.sub.2), 6.73 (dd, H-6),
6.76 (d, H-8), and 7.54 (d, H-5). 39 R.sup.3 = CH.sub.3
7-hydroxy-9a-isobutyl-4-methyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH(CH.sub.3) tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) 8 0.82 and 0.90 (two d, CH(CH.sub.3).sub.2),
1.34 and 1.53 (two dd, CH.sub.2CH(CH.sub.3).sub.2), 1.62 (m,
CH(CH.sub.3).sub.2), 1.99 and 2.25 (two ddd, 1-CH.sub.2), 2.08 (s,
4- CH.sub.3), 2.52 and 2.65 (two ddd, 2-CH.sub.2), 2.72 and 3.02
(two d, 9-CH.sub.2), 5.30 (s, OH), 6.83-6.87 (m, H-6 and H-8), and
7.61 (d, H-5); mass spectrum m/z 271.1 (M+1). 40 R.sup.3 =
CH.sub.2CH.sub.3 9a-butyl-4-ethyl-7-hydroxy-1,- 2,9,9a-tetrahydro-
R.sup.10 = CH.sub.2CH.sub.2CH.sub.2CH.sub.3 3H-fluoren-3-one
.sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.79 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.97 (t, CH.sub.2CH.sub.3),
1.06-1.26 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.26 and 1.48 (two
m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.89 and 2.10 (two m,
1-CH.sub.2), 2.26 and 2.46 (two m, 2-CH.sub.2), 2.35 and 2.52 (two
m, CH.sub.2CH.sub.3), 2.61 and 2.87 (two d, 9-CH.sub.2), 6.72-6.77
(m, H-6 and H-8), 7.48 (d, H-5). 41 R.sup.3 =
CH.sub.2CH.sub.2CH.sub.3
9a-butyl-7-hydroxy-4-propyl-1,2,9,9a-tetrahydro- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.01 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.22, 1.39. and 1.56 (three m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and CH.sub.2CH.sub.2CH.sub.3),
1.96 and 2.21 (two m, 1-CH.sub.2), 2.38-2.49 and 2.52-2.65 (two m,
2-CH.sub.2 and CH.sub.2CH.sub.2CH.sub.3), 2.68 and 2.93 (two d,
9-CH.sub.2), 6.77-6.81 (m, H-6 and H-8), and 7.51 (dd, H-5). 42
R.sup.3 = CH.sub.2CH.sub.2CH.sub.2CH.sub.3
4,9a-dibutyl-7-hydroxy-1,2,9,9- a-tetrahydro-3H- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 fluoren-3-one 43 R.sup.3 = Cl
9a-butyl-4-chloro-7-hydroxy-1,2,9,9a- -tetrahydro- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 3H-fluoren-3-one .sup.1H NMR
(DMSO-d.sub.6, 500 MHz) .delta. 0.78 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.04-1.27 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.34 and 1.60 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.02 and 2.13 (two m,
1-CH.sub.2), 2.48 and 2.68 (two m, 2-CH.sub.2), 2.73 and 2.96 (two
d, 9-CH.sub.2), 6.76-6.81 (m, H-6 and H-8), 8.07 (d, H-5), and
10.35 (br s, OH). 44 R.sup.3 = I
9a-butyl-7-hydroxy-4-iodo-1,2,9,9a-tetr- ahydro- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 3H-fluoren-3-one .sup.1H NMR
(DMSO-d.sub.6, 500 MHz) .delta. 0.78 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.04-1.26 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.30 and 1.55 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.00 and 2.12 (two ddd,
1-CH.sub.2), 2.56 and 2.74 (two ddd, 2-CH.sub.2), 2.72 and 2.90
(two d, 9-CH.sub.2), 6.80 (d, H-8), 6.84 (dd, H-6), 8.52 (d, H-5),
and 10.36 (s, OH). 45 R.sup.3 = CF.sub.3
9a-butyl-7-hydroxy-4-trifluor- omethyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.83 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.21 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.29 and 1.52 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.04 and 2.21 (two ddd,
1-CH.sub.2), 2.49-2.61 (m, 2-CH.sub.2), 2.79 and 2.97 (two d,
9-CH.sub.2), 5.23 (s, OH), 6.75- 6.79 (m, H-6 and H-8), and 7.73
(d, H-5); mass spectrum m/z 325.1 (M+1). 46 49
9a-butyl-7-hydroxy-4-phenyl-1,2,9,9a-tetrahydro- 3H-fluoren-3-one
.sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.83 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.15-1.33 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.42 and 1.68 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.07 and 2.21 (two ddd,
1-CH.sub.2), 2.38 and 2.59 (two ddd, 2-CH.sub.2), 2.70 and 2.94
(two d, 9-CH.sub.2), 6.04 (d, H-5), 6.30 (dd, H-6), 6.70 (d, H-8),
6.9-7.1 and 7.3-7.43 (two br m, C.sub.6H.sub.5), and 9.96 (brs,
OH). 47 50 9a-butyl-4-(2-furyl)-7-hydroxy-1,2,9,9a-
tetrahydro-3H-fluoren-3-one .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta. 0.81 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.11-1.31 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.38 and 1.64 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.01 and 2.18 (two ddd,
1-CH.sub.2), 2.39 and 2.58 (two ddd, 2-CH.sub.2), 2.71 and 2.96
(two d, 9-CH.sub.2), 6.16 (d, H-5), 6.25 (dd, furyl H-3), 6.51 (dd,
H-6), 6.56 (dd, furyl H-4), 6.74 (d, H-8), 7.69 (dd, furyl H-5),
and 10.18 (br s, OH). 48 R.sup.3 = CH.sub.3
7-hydroxy-9a-(3-iodopropyl- )-4-methyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2I tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 1.47-1.56 and 1.65-1.83 (two m,
CH.sub.2CH.sub.2CH.sub.2I), 2.03 and 2.18 (two ddd, 1-CH.sub.2),
2.08 (s, 4-CH.sub.3), 2.51 and 2.62 (two ddd, 2-CH.sub.2), 2.74 and
2.92 (two d, 9-CH.sub.2), 3.01-3.12 (m, CH.sub.2CH.sub.2CH.sub.2I),
6.80-6.83 (m, H-6 and H-8), and 7.61 (d, H-5); mass spectrum m/z
383.1 (M+1). 49 R.sup.3 = CH.sub.3
7-hydroxy-4-methyl-9a-(2-methyl-1-propenyl)- R.sup.10 =
CH.dbd.C(CH.sub.3).sub.2 1,2,9,9a-tetrahydro-3H-fluoren-3-one
.sup.1H NMR (3:1 CDCl.sub.3--CD.sub.3CN, 500 MHz) .delta. 1.52 and
1.53 (two s, .dbd.C(CH.sub.3).sub.2), 1.96 and 2.28 (two m,
1-CH.sub.2), 1.96 (s, 4-CH.sub.3), 2.28 and 2.47 (two m,
2-CH.sub.2), 2.84 and 3.03 (two d, 9-CH.sub.2), 5.06 (s, CH.dbd.),
6.67 (s, H-8), 6.71 (d, H-6), 7.11 (br s, OH), and 7.48 (d, H-5).
51 50 52 9a-butyl-4-{4-[2-(diineth- ylamino)ethoxy]phenyl}-
7-hydroxy-1 ,2,9,9a-tetrahydro-3H-fluoren-3-one hydrochloride
.sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.82 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.23 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.40 and 1.66 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.05 and 2.20 (two m,
1-CH.sub.2), 2.37 and 2.57 (two m, 2-CH.sub.2), 2.68 and 2.93 (two
d, 9-CH.sub.2), 2.86 (s, N(CH.sub.3).sub.2), 3.51 (t,
NCH.sub.2CH.sub.2O), 4.36 (t, NCH.sub.2CH.sub.2O), 6.17 (d, H-5),
6.35 (dd, H-6), 6.72 (d, H-8), 6.84-7.14 (br m, C.sub.6H.sub.4,
10.08 (s, OH), and 10.22 (br s, NH); mass spectrum m/z 420.2 (M+1
of free base). 51 53 9a-butyl-4-{4-[2-(diethylamin- o)ethoxy]-
phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H- fluoren-3-one
hydrochloride .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.26 (t,
N(CH.sub.2CH.sub.3).sub.2), 3.24 (br m, N(CH.sub.2CH.sub.3).sub.2),
3.52 (br m, NCH.sub.2CH.sub.2O), 4.38 (t, NCH.sub.2CH.sub.20),
6.83-7.10 (br m, C.sub.6H.sub.4), 9.99 (br s, NH), 10.06 (s, OH),
9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.3, 1-CH.sub.2, 2-CH.sub.2,
9-CH.sub.2, H-5, H-6, and H-8 are identical to previous compound.
52 54 9a-butyl-7-hydroxy-4-{4-[2-(1-
pyrrolidinyl)ethoxy]phenyl}-1,2,- 9,9a-tetrahydro-3H- fluoren-3-one
hydrochloride .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.90 and
2.03 (two br s, pyrrolidinyl 3-CH.sub.2and 4- CH.sub.2), 3.13 (br
s, NCH.sub.2CH.sub.2O), 3.59 (m, pyrrolidinyl 2-CH.sub.2and
5-CH.sub.2), 4.35 (t, NCH.sub.2CH.sub.2O), 10.07 (s, OH), 10.44 (br
s, NH), 9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.3, 1-CH.sub.2,
2-CH.sub.2, 9-CH.sub.2, H-5, H-6, H-8 and C.sub.6H.sub.4 are
identical to previous compound; mass spectrum m/z 446.2 (M + 1 of
free base). 53 55 9a-butyl-7-hydroxy-4-{4-[2-(4-
morpholinyl)ethoxy]phenyl}-1,2,9,9a-tetrahydro- 3H-fluoren-3-one
hydrochloride .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 3.22 (br
m, NCH.sub.2CH.sub.2O), 3.54 (br m, morpholinyl 3-CH.sub.2 and
5-CH.sub.2), 10.06 (s, OH), 10.83 (br s, NH),
9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.3, 1-CH.sub.2, 2- CH.sub.2,
9-CH.sub.2, NCH.sub.2CH.sub.2O, H-5, H-6, H-8 and C.sub.6H.sub.4
are identical to previous compound; mass spectrum m/z 462.3 (M+1 of
free base). 54 56 9a-butyl-4-{4-[3-(diinethylam- ino)propoxy]-
phenyl}-7-hydroxy-1,2,9,9a-tetrahydro-3H- fluoren-3-one
hydrochloride .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 2.05 (m,
1-CH.sub.aH.sub.b), 2.12-2.23 (m, 1-CH.sub.aH.sub.b and
NCH.sub.2CH.sub.2CH.sub.2O), 2.79 (s, N(CH.sub.3).sub.2), 3.23 (t,
NCH.sub.2CH.sub.2CH.sub.2O), 4.08 (t, NCH.sub.2CH.sub.2CH.sub.2O),
10.05 (s, OH), 10.23 (br s, NH),
9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.3, 2-CH.sub.2, 9- CH.sub.2, H-5,
H-6, H-8 and C.sub.6H.sub.4 are identical to previous compound;
mass spectrum m/z 434.2 (M+1 of free base). 55 57
9a-butyl-7-hydroxy-4-{4-[3-(1- -
piperidinyl)propoxy]phenyl}-1,2,9,9a- tetrahydro-3H-fluoren-3-one
hydrochloride .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 1.40 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.62-1.85 (m, piperidinyl
3-CH.sub.2, 4-CH.sub.2and 5-CH.sub.2), 2.05 (m, 1-CH.sub.aH.sub.b),
2.19 (m, 1-CH.sub.aH.sub.b and NCH.sub.2CH.sub.2CH.sub.2O), 2.89,
3.20, and 3.47 (three m, NCH.sub.2CH.sub.2CH.sub.2O and piperidinyl
2- CH.sub.2and 6-CH.sub.2), 4.08 (t, NCH.sub.2CH.sub.2CH.sub.2O),
6.85-7.05 (br s, C.sub.6H.sub.4, 9.85 (br s, NH), 10.04 (s, OH),
9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.3, 2-CH.sub.2, 9-CH.sub.2, H-5,
H-6, and H-8 are identical to previous compound; mass spectrum m/z
474.2 (M+1 of free base). 58 56
(3E)-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
O- methyloxime .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.77 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.0-1.2 and 1.2-1.3 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.48 and 1.98 (two m,
1-CH.sub.2), 2.03 (s, 4-CH.sub.3), 2.23 and 2.72 (two m,
2-CH.sub.2), 2.53 and 2.80 (two d, 9-CH.sub.2), 3.83 (s,
OCH.sub.3), 6.65 (dd, H-6), 6.68 (s, H-8), 7.41 (d, H-5), and 9.64
(s, OH). 59 57 R.sup.2 = CH.sub.2CH.sub.3
(2SR,9aSR)-9a-butyl-2-ethyl-7-hydroxy-4-methyl- R.sup.3 = CH.sub.3
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 0.84 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.93 (t,
CH.sub.2CH.sub.3), 1.22, 1.35, 1.48, and 1.57 (four m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and CH.sub.aH.sub.bCH.sub.3), 1.66
and 2.30 (two dd, 1-CH.sub.2), 2.02 (m, CH.sub.aH.sub.bCH.sub.3),
2.06 (s, 4-CH.sub.3), 2.36 (m, H-2), 2.68 and 2.84 (two d,
9-CH.sub.2), 5.49 (br s, OH, 6.79 (dd, H-6), 6.81 (d, H-8), and
7.59 (d, H-5); mass spectrum m/z 299.1 (M+1). 58 R.sup.2 =
CH.sub.2CH.sub.2CH.sub.- 3
(2SR,9aSR)-9a-butyl-7-hydroxy-2-propyl-1,2,9,9a- R.sup.3 = H
tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.84 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.94 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.18-1.47 (m, CH.sub.aH.sub.bCH.sub.2CH-
.sub.2CH.sub.3 and CH.sub.aH.sub.bCH.sub.2CH.sub.3), 1.61 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.65 and 2.35 (two dd,
1-CH.sub.2), 2.01 (m, CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.44 (m,
H-2), 2.67 and 2.98 (two d, 9-CH.sub.2), 6.12 (s, H-4), 6.22 (br s,
OH, 6.87-6.91 (m, H-6 and H-8), and 7.43 (d, H-5); mass spectrum
m/z 299.1 (M+1). 59 R.sup.2 = CH.sub.2CH.sub.2CH.sub.3
(2SR,9aSR)-9a-butyl-7-hydroxy-4-methyl-2- R.sup.3 = CH.sub.3
propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.83 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3) , 0.94 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.16-1.28 and 1.30-1.44 (two m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3 and
CH.sub.aH.sub.bCH.sub.2CH.- sub.3), 1.55 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.64 and 2.30 (two dd,
1-CH.sub.2), 2.00 (m, CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.06 (s,
4-CH.sub.3), 2.41 (m, H-2), 2.65 and 2.93 (two d, 9-CH.sub.2), 5.08
(s, OH, 6.77 (dd, H-6), 6.79 (s, H-8), and 7.59 (d, H-5). 60
R.sup.2 = CH.sub.2CH.sub.2CH.sub.3
(2SR,9aSR)-4,9a-dibutyl-7-hydroxy-2-propyl- R.sup.3 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.83, 0.93 and 0.94 (three t, two
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and CH.sub.2CH.sub.2CH.sub.3),
1.22, 1.36, 1.42, and 1.51 (four m,
9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.3, 4- CH.sub.2CH.sub.2CH.sub.2CH-
.sub.3, and CH.sub.aH.sub.bCH.sub.2CH.sub.3), 1.63 and 2.28 (two
dd, 1-CH.sub.2), 1.97 (m, CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.41
(m, H-2), 2.45 and 2.62 (two ddd,
4-CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.66 and 2.94 (two d,
9-CH.sub.2), 6.21 (s, OH), 6.79-6.84 (m, H-6 and H-8), and 7.52 (d,
H-5). 61 R.sup.2 = CH.sub.2CH.sub.2CH.sub.3
(2SR,9aSR)-4-bromo-9a-butyl-7-hydroxy-2- R.sup.3 = Br
propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.18-1.30 and 1.32-1.49 (two m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3 and
CH.sub.aH.sub.bCH.sub.2CH.- sub.3), 1.63 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.75 and 2.33 (two dd,
1-CH.sub.2), 2.04 (m, CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.61 (m,
H-2), 2.74 and 2.98 (two d, 9-CH.sub.2), 5.41 (s, OH), 6.80 (d,
H-8), 6.83 (dd, H- 6), and 8.43 (d, H-5); mass spectrum m/z 377
(M+1) and 379 (M+3). 62 R.sup.2 = CH.sub.2CHO
(2RS,9aSR)-9a-butyl-7-hydroxy-2-(2-oxoethyl)- R.sup.3 = CH.sub.3
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.86 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.26 and
1.38 (two m, CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.67 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.80 and 2.30 (two dd,
1-CH.sub.2), 2.06 (s, 4-CH.sub.3), 2.46 and 3.04 (two ddd,
CH.sub.2CHO), 2.65 and 2.94 (two d, 9-CH.sub.2), 3.13 (m, H-2),
6.76-6.80 (m, H-6 and H-8), 7.60 (d, H-5), and 9.89 (s, OH); mass
spectrum m/z 313.1 (M+1). 63 R.sup.2 = CH.sub.2CH.sub.2CH.sub.2CH.-
sub.3 (2SR,9aSR)-2,9a-dibutyl-7-hydroxy-4-methyl- R.sup.3 =
CH.sub.3 1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.83 (t,
9a-CH.sub.2CH.sub.2CH.sub.2CH.sub.- 3), 0.91 (t, 2-
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.17-1.44 (m, two
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.55 (m, 9a-
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.65 and 2.30 (two dd,
1-CH.sub.2), 2.02 (m, 2- CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3),
2.07 (s, 4-CH.sub.3), 2.42 (m, il-2), 2.65 and 2.93 (two d,
9-CH.sub.2), 6.30 (br s, OH), 6.82 (dd, H-6), 6.84 (s, H-8), and
7.59 (d, H-5); mass spectrum m/z 2327.2 (M+1). 60 64 R.sup.1 =
CH.sub.2CH.sub.2CH.sub.3 (2RS,9aRS)-9a-butyl-7-hydrox-
y-2,4-dimethyl-2- R.sup.2 = CH.sub.3 propyl-1,2,9,9a-tetrahydro-3H-
-fluoren-3-one R.sup.3 = CH.sub.3 .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.82 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.95 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.05 (s, 2-CH.sub.3), 1.13-1.29 and
1.34-1.54 (two m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and
CH.sub.aH.sub.bCH.sub.2CH.sub.3), 1.61 and 2.41 (two d,
1-CH.sub.2), 1.87 (m, CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.10 (s,
4-CH.sub.3), 2.63 and 2.76 (two d, 9-CH.sub.2), 5.14 (s, OH),
6.76-6.80 (m, H-6 and H-8), and 7.61 (d, H-5); mass spectrum m/z
327.2 (M+1). 65 R.sup.1 = CH.sub.2CH.sub.2CH.sub.3
9a-butyl-7-hydroxy-2,2-dipropyl-1,2,9,- 9a- R.sup.2 =
CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one R.sup.3 = H
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta.
0.82, 0.83 and 0.94 (three t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and
two CH.sub.2CH.sub.2CH.sub.3), 1.08, 1.21, 1.32, 1.43, and 1.54
(five m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.aH.sub.bCH.sub.2CH.sub.3, and CH.sub.2CH.sub.2CH.sub.3),
1.74 and 2.30 (two d, 1-CH.sub.2), 1.86 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.65 and 2.99 (two d,
9-CH.sub.2), 5.82 (s, OH, 6.15 (s, H4), 6.77 (m, H-6 and H-8), and
7.44 (m, H-5); mass spectrum m/z 341.1 (M+1). 66 R.sup.1 =
CH.sub.2CH.sub.2CH.sub.3 9a-butyl-7-hydroxy-4-methyl-2,2-dipropyl-
R.sup.2 = CH.sub.2CH.sub.2CH.sub.3
1,2,9,9a-tetrahydro-3H-fluoren-3-one R.sup.3 = CH.sub.3 .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.79, 0.81 and 0.96 (three t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and two CH.sub.2CH.sub.2CH.sub.3),
1.09-1.68 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.aH.sub.bCH.sub.2CH.sub.3, and CH.sub.2CH.sub.2CH.sub.3),
1.71 and 2.27 (two d, 1-CH.sub.2), 1.92 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.08 (s, 4- CH.sub.3), 2.67 and
2.96 (two d, 9-CH.sub.2), 5.45 (s, OH), 6.76-6.80 (m, H-6 and H-8),
and 7.60 (m, H-5); mass spectrum m/z 355.3 (M+1). 67 R.sup.1 =
CH.sub.2CH.sub.2CH.sub.3 (2SR,9aRS)-9a-butyl-2,7-dihydroxy-4-me-
thyl-2- R.sup.2 = OH propyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one
R.sup.3 = CH.sub.3 .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86
(t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.94 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.23, 1.34, 1.53, 1.66, and 1.74 (five
m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and CH.sub.2CH.sub.2CH.sub.3),
2.03 and 2.65 (two d, 1-CH.sub.2), 2.10 (s, 4-CH.sub.3), 2.64 and
2.98 (two d, 9-CH.sub.2), 3.37 (s, OH, 5.41 (s, OH, 6.76-6.80 (m,
H-6 and H-8), and 7.59 (d, H-5); mass spectrum m/z 329.1 (M+1). 68
R.sup.1 = CH.sub.2CH.sub.3
4-bromo-9a-butyl-2,2-diethyl-7-hydroxy-1,2,- 9,9a- R.sup.2 =
CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one R.sup.3 = Br .sup.1H
NMR (CDCl.sub.3, 500 MHz) .delta. 0.74, 0.80 and 0.98 (three t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and two CH.sub.2CH.sub.3),
1.06-1.26 and 1.38-1.68 (two m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3,
CH.sub.aH.sub.bCH.sub.3, and CH.sub.2CH.sub.3), 1.77 and 2.25 (two
d, 1-CH.sub.2), 2.03 (m, CH.sub.aH.sub.bCH.sub.3), 2.77 and 3.00
(two d, 9-CH.sub.2), 5.78 (s, OH, 6.81 (d, H-8), 6.85 (dd, H-6),
and 8.45 (m, H-5); mass spectrum m/z 391.2 (M+1) and 393.2 (M+3).
61 69 R.sup.2 = CH.sub.3 (2SR,9aSR)-7-hydroxy-2,4,9a-trimethyl-1,2-
,9,9a- tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 1.12 (d, 2-CH.sub.3), 1.14 (s, 9a-CH.sub.3), 1.75 and
2.04 (two dd, 1-CH.sub.2), 1.95 (s, 4-CH.sub.3), 2.53 (m, H-2),
2.64 and 2.72 (two d, 9-CH.sub.2), 6.69 (dd, H-6), 6.72 (s, H-8),
and 7.48 (d, H-5); mass spectrum m/z 243.1 (M+1). 70 R.sup.2 =
CH.sub.2CH.sub.2CH.sub.3
(2SR,9aSR)-7-hydroxy-4,9a-dimethyl-2-propyl-
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.94 (t, CH.sub.2CH.sub.2CH.sub.3), 1.22 (s,
9a-CH.sub.3), 1.31-1.44 (m, CH.sub.aH.sub.bCH.sub.2CH.sub.3), 1.79
and 2.17 (two dd, 1-CH.sub.2), 2.01 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.3), 2.06 (s, 4-CH.sub.3), 2.50 (m,
H-2), 2.75 and 2.84 (two d, 9-CH.sub.2), 5.68 (br s, OH), 6.80 (dd,
H- 6), 6.84 (d, H-8), and 7.59 (d, H-5); mass spectrum m/z 271.1
(M+1). 62 71
(2SR,9aSR)-9a-butyl-8-chloro-2-ethyl-7-hydroxy-4-methyl-1,2,9,9a-
tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 0.85 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 0.94 (t,
CH.sub.2CH.sub.3), 1.23, 1.37, 1.48, and 1.57 (four m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 and CH.sub.aH.sub.bCH.sub.3), 1.69
and 2.33 (two dd, 1-CH.sub.2), 2.01 (m, CH.sub.aH.sub.bCH.sub.3),
2.05 (s, 4-CH.sub.3), 2.37 (m, H-2), 2.68 and 3.05 (two d,
9-CH.sub.2), 5.73 (s, OH, 6.99 (d, H-6), and 7.54 (d, H-5); mass
spectrum m/z 333.1 (M+1). 63 72 R.sup.7 = Cl
8-chloro-9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.87 (t, CH.sub.2CH.sub.3), 1.49 and
1.63 (two dq, CH.sub.2CH.sub.3), 2.00 and 2.26 (two ddd,
1-CH.sub.2), 2.06 (s, 4-CH.sub.3), 2.48 and 2.57 (two ddd,
2-CH.sub.2), 2.67 and 3.05 (two d, 9-CH.sub.2), 5.75 (s, OH, 6.99
(d, H-6), and 7.55 (d, H-5). 73 R.sup.7 = Br
8-bromo-9a-ethyl-7-hydroxy-4-methyl-1,2,9,9a- - R.sup.10 =
CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.86 (t, CH.sub.2CH.sub.3), 1.50 and
1.61 (two dq, CH.sub.2CH.sub.3), 2.00 and 2.26 (two ddd,
1-CH.sub.2), 2.06 (s, 4-CH.sub.3), 2.48 and 2.57 (two ddd,
2-CH.sub.2), 2.67 and 3.00 (two d, 9-CH.sub.2), 5.85 (s, OH), 6.99
(d, H-6), and 7.58 (d, H-5). 74 R.sup.7 = CH.sub.3
9a-ethyl-7-hydroxy-4,8-dimeth- yl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-o- ne .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.85 (t, CH.sub.2CH.sub.3), 1.47 and
1.62 (two dq, CH.sub.2CH.sub.3), 1.98 and 2.25 (two ddd,
1-CH.sub.2), 2.06 (s, 4-CH.sub.3), 2.19 (s, 8-CH.sub.3), 2.47 and
2.58 (two ddd, 2-CH.sub.2), 2.57 and 2.94 (two d, 9-CH.sub.2), 5.45
(s, OH), 6.77 (d, H-6), and 7.46 (d, H-5). 75 R.sup.7 = Cl
8-chloro-7-hydroxy-4-methyl-9a-propyl-1,2,9,- 9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-on- e .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.85 (t, CH.sub.2CH.sub.2CH.sub.3),
1.13-1.32 (m, CH.sub.2CH.sub.2CH.sub.3), 1.42 and 1.56 (two dt,
CH.sub.2CH.sub.2CH.sub.3), 2.01 and 2.25 (two ddd, 1-CH.sub.2),
2.06 (s, 4- CH.sub.3), 2.48 and 2.59 (two ddd, 2-CH.sub.2), 2.70
and 3.05 (two d, 9-CH.sub.2), 7.00 (d, H-6), and 7.55 (d, H-5);
mass spectrum m/z 291.2 (M+1). 76 R.sup.7 = Br
8-bromo-7-hydroxy-4-methyl-9a-propyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.84 (t, CH.sub.2CH.sub.2CH.sub.3),
1.12-1.32 (m, CH.sub.2CH.sub.2CH.sub.3), 1.43 and 1.56 (two dt,
CH.sub.2CH.sub.2CH.sub.3), 2.00 and 2.24 (two ddd, 1-CH.sub.2, 2.06
(s, 4- CH.sub.3), 2.48 and 2.59 (two ddd, 2-CH.sub.2), 2.69 and
3.09 (two d, 9-CH.sub.2), 5.86 (br s, OH), 6.99 (d, H-6), and 7.58
(d, H-5); mass spectrum m/z 335.3 (M+1) and 337.3 (M+3). 77 R.sup.7
= CH.sub.3 7-hydroxy-4,8-dimethyl-9a-propyl-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.83 (t, CH.sub.2CH.sub.2CH.sub.3),
1.13-1.32 (m, CH.sub.2CH.sub.2CH.sub.3), 1.41 and 1.55 (two dt,
CH.sub.2CH.sub.2CH.sub.3), 1.99 and 2.23 (two ddd, 1-CH.sub.2),
2.06 (s, 4- CH.sub.3), 2.19 (s, 8-CH.sub.3), 2.48 and 2.60 (two
ddd, 2-CH.sub.2), 2.60 and 2.94 (two d, 9- CH.sub.2), 5.67 (s, OH),
6.79 (d, H-6), and 7.47 (d, H-5); mass spectrum m/z 271.3 (M+1). 78
R.sup.7 = Cl 8-chloro-7-hydroxy-4-methyl-9a-[(1E)-1- R.sup.10 = (E)
--CH.dbd.CHCH.sub.3 propenyl]-1,2,9,9a-tetrahydro-3H-fluor-
en-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 1.57 (dd,
CH.dbd.CHCH.sub.3), 2.10 (s, 4-CH.sub.3), 2.12 and 2.17 (two ddd,
1-CH.sub.2), 2.43 and 2.54 (two ddd, 2-CH.sub.2), 2.91 and 3.04
(two d, 9- CH.sub.2), 5.25 (dq, CH.dbd.CHCH.sub.3), 5.44 (dq,
CH.dbd.CHCH.sub.3), 7.00 (d, H-6), and 7.56 (d, H- 5); mass
spectrum m/z 289.4 (M+1). 779 R.sup.7 = Br 8-bromo-9a-butyl-7-hydr-
oxy-4-methyl-1,2,9,9a- R.sup.10 = CH.sub.2CH.sub.2CH.sub.2CH.sub.3
tetrahydro-3H-fluoren-3-one .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta. 0.78 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.07 and 1.18
(two m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.30 and 1.54 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.92 (s, 4-CH.sub.3), 1.95 and
2.14 (two m, 1-CH.sub.2), 2.30 and 2.51 (two m, 2-CH.sub.2), 2.65
and 2.90 (two d, 9- CH.sub.2), 6.94 (d, H-6), and 7.55 (d, H-5). 80
R.sup.7 = CH.sub.3 9a-butyl-7-hydroxy-4,8-dimethyl-1,2,9,9a-
R.sup.10 = CH.sub.2CH.sub.2CH.sub.2CH.sub.3
tetrahydro-3H-fluoren-3-one .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta. 0.77 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.16 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.25 and 1.50 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.89 and 2.13 (two m,
1-CH.sub.2), 1.90 (s, 4-CH.sub.3), 2.04 (s, 8-CH.sub.3), 2.27 and
2.47 (two m, 2-CH.sub.2), 2.52 and 2.88 (two d, 9-CH.sub.2), 6.79
(d, H-6), 7.38 (d, H-5), and 9.90 (s, OH). 81 R.sup.7 = NO.sub.2
9a-butyl-7-hydroxy-4-methyl-8-nitro-1,2,9,9a- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 tetrahydro-3H-fluoren-3-one
.sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.77 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.05 and 1.16 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.31 and 1.53 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.93 (s, 4-CH.sub.3), 1.96 and
2.13 (two m, 1-CH.sub.2), 2.32 and 2.51 (two m, 2-CH.sub.2), 2.83
and 2.99 (two d, 9- CH.sub.2), 7.08 (d, H-6), and 7.80 (d, H-5). 82
R.sup.7 = NH.sub.2 8-amino-9a-butyl-7-hydroxy-4-methyl-1,2,9,9a-
R.sup.10 = CH.sub.2CH.sub.2CH.sub.2CH.sub.3
tetrahydro-3H-fluoren-3-on- e .sup.1H NMR (DMSO-d.sub.6, 500 MHz)
.delta. 0.79 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.10-1.27 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.48 (m,
CH.sub.aH.sub.bCH.sub.2CH.sub.2CH.sub.3), 1.89 (s, 4-CH.sub.3),
1.90 and 2.13 (two m, 1-CH.sub.2), 2.27 and 2.46 (two m,
2-CH.sub.2), 2.34 and 2.87 (two d, 9-CH.sub.2), 6.69 (d, H-6 or
H-5), and 6.88 (d, H-5 or H-6). 64 83 R = H
9a-butyl-7-hydroxy-4-(4-hydroxyphenyl)-8-methyl-
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.87 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.27 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.51 and 1.70 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.08 and 2.31 (two m,
1-CH.sub.2), 2.13 (s, 8-CH.sub.3), 2.59 and 2.71 (two m,
2-CH.sub.2), 2.61 and 2.97 (two d, 9- CH.sub.2), 6.09 (d, H-6 or
H-5), 6.29 (d, H-5 or H-6), 6.71 (s, OH), 6.74-6.88 (br m,
C.sub.6H.sub.4, and 7.36 (s, OH); mass spectrum m/z 363.2 (M+1). 84
65 9a-butyl-7-hydroxy-8-methyl-4-{4-[2-piperidinyl)-
ethoxy]phenyl}-1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR
(CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.23-1.36, 1.43-1.51, and
1.61-1.69 (three m, CH.sub.2CH.sub.2CH.sub.2CH3, piperidinyl
3-CH.sub.2, 4-CH.sub.2 and 5-CH.sub.2), 1.52 and 1.72 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.10 and 2.31 (two m,
1-CH.sub.2), 2.13 (s, 8-CH.sub.3), 2.51-2.71 (m, 2-CH.sub.2 and
piperidinyl N(CH.sub.2).sub.2), 2.64 and 2.97 (two d, 9-CH.sub.2),
2.83 (t, NCH.sub.2CH.sub.2O), 4.10 (m, NCH.sub.2CH.sub.2O), 6.19
(d, H-6 or H-5), 6.37 (d, H-5 or H-6), 6.67-7.16 (br m,
C.sub.6H.sub.4, and 7.36 (s, OH; mass spectrum m/z 474.2 (M+1). 66
85 R.sup.7 = H 4-bromo-7-hydroxy-9a-propyl-1H-fluorene-
3,9(2H,9aH)-dione .sup.1H NMR (DMSO-d.sub.6, 500 MHz) .delta. 0.71
(t, CH.sub.2CH.sub.2CH.sub.3), 0.97 (m, CH.sub.2CH.sub.2CH.sub.3),
1.68 and 1.79 (two ddd, CH.sub.2CH.sub.2CH.sub.3), 1.99 and 2.16
(two ddd, 1-CH.sub.2), 2.62 and 2.94 (two ddd, 2-CH.sub.2), 7.12
(d, H-8), 7.34 (dd, H-6), and 8.56 (d, H-5). 86 R.sup.7 = Br
4,8-dibromo-7-hydroxy-9a-propyl-1H-fluorene- 3,9(2H,9aH)-dione
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.80 (t,
CH.sub.2CH.sub.2CH.sub.3), 1.10 (m, CH.sub.2CH.sub.2CH.sub.3), 1.73
and 1.86 (two m, CH.sub.2CH.sub.2CH.sub.3), 2.01 and 2.41 (two ddd,
1-CH.sub.2), 2.80 and 2.90 (two ddd, 2-CH.sub.2), 6.47 (br s, OH,
7.46 (d, H-6), and 8.72 (d, H-5). 67 87
4-bromo-9a-butyl-7-hydroxy-6-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-
-one .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.84 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.14-1.30 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.45 and 1.63 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.04 and 2.23 (two ddd,
1-CH.sub.2), 2.31 (s, 6-CH.sub.3), 2.66-2.79 (m, 2-CH.sub.2), 2.73
and 2.96 (two d, 9-CH.sub.2), 5.59 (s, OH), 6.77 (s, H-8), and 8.36
(s, H-5); mass spectrum m/z 349.0 (M+1) and 351.0 (M+3). 68 88
9a-butyl-8-chloro-4-methyl-3-oxo-2,3,9-
,9a-tetrahydro-1H-fluoren-7-yl pivalate .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 0.85 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3),
1.16-1.29 (m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.40 and 1.58 (two
m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.41 (s, C(CH.sub.3).sub.3),
2.01 and 2.28 (two ddd, 1-CH.sub.2), 2.49 and 2.59 (two ddd,
2-CH.sub.2), 2.71 and 3.10 (two d, 9- CH.sub.2), 7.07 (d, H-6), and
7.60 (d, H-5). 69 89 R.sup.3 = CH.sub.3
9a-butyl-6,8-difluoro-7-hydroxy-4-methyl- R.sup.7 = F
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.85 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.29
(m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.37 and 1.57 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.99 and 2.25 (two ddd,
1-CH.sub.2), 2.04 (s, 4-CH.sub.3), 2.48 and 2.57 (two ddd,
2-CH.sub.2), 2.62 and 3.07 (two d, 9-CH.sub.2), 5.36 (s, OH), and
7.28 (dd, H-5); mass spectrum m/z 307.4 (M+1). 90 R.sup.3 =
CH.sub.2CH.sub.3 9a-butyl-4-ethyl-6,8-difluoro-7-hydroxy-1,2,9,9a-
R.sup.7 = F tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 0.85 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.09
(t, CH.sub.2CH.sub.3), 1.14- 1.30 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3- ), 1.38 and 1.55 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.97 and 2.24 (two ddd,
1-CH.sub.2), 2.41 and 2.63 (two dq, CH.sub.2CH.sub.3), 2.47 and
2.56 (two ddd, 2-CH.sub.2), 2.61 and 3.06 (two d, 9-CH.sub.2), 6.01
(s, OH), and 7.23 (dd, H-5); mass spectrum m/z 321.2 (M+1). 91
R.sup.3 = Br 4-bromo-9a-butyl-6,8-difluoro-7-hydro- xy- R.sup.7 = F
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.86 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.31
(m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.47 and 1.63 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 and 2.29 (two ddd,
1-CH.sub.2), 2.70-2.79 (m, 2-CH.sub.2), 2.71 and 3.12 (two d,
9-CH.sub.2), 5.73 (s, OH), and 8.17 (dd, H-5). 92 R.sup.3 = Cl
8-bromo-9a-butyl-4-chloro-8-difluoro-7-hydroxy- R.sup.7 = Br
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.86 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.31
(m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.50 and 1.65 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 and 2.29 (two ddd,
1-CH.sub.2), 2.66-2.74 (m, 2-CH.sub.2), 2.74 and 3.05 (two d,
9-CH.sub.2), 5.88 (s, OH), and 8.10 (dd, H-5). 93 R.sup.3 = Br
9a-butyl-4,8-dibromo-6-fluoro-7-hydroxy- R.sup.7 = Br
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.86 (t, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.13-1.30
(m, CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.51 and 1.64 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 2.09 and 2.29 (two ddd,
1-CH.sub.2), 2.69-2.80 (m, 2-CH.sub.2), 2.73 and 3.04 (two d,
9-CH.sub.2), 5.88 (d, OH, and 8.32 (d, H-5). 70 94 R.sup.3 =
CH.sub.3 9a-ethyl-6-fluoro-7-hydroxy-4-methyl-1,2- ,9,9a- R.sup.7 =
H tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.85 (t, CH.sub.2CH.sub.3), 1.47 and 1.61 (two dq,
CH.sub.2CH.sub.3), 1.97 and 2.23 (two ddd, 1-CH.sub.2), 2.05 (s,
4-CH.sub.3), 2.47 and 2.56 (two ddd, 2-CH.sub.2), 2.65 and 2.92
(two d, 9-CH.sub.2), 5.38 (d, OH), 6.95 (d, H-8), and 7.43 (d,
H-5); mass spectrum m/z 261.2 (M+1). 95 R.sup.3 = CH.sub.3
9a-ethyl-6,8-difluoro-7-hydroxy-4-methyl- R.sup.7 = F
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.87 (t, CH.sub.2CH.sub.3), 1.47 and 1.61 (two dq,
CH.sub.2CH.sub.3), 1.99 and 2.26 (two ddd, 1-CH.sub.2), 2.04 (s,
4-CH.sub.3), 2.48 and 2.56 (two ddd, 2-CH.sub.2), 2.61 and 3.07
(two d, 9-CH.sub.2), 5.41 (s, OH), and 7.28 (d, H-5). 96 R.sup.3 =
CH.sub.3 8-chloro-9a-ethyl-6-fluoro-7-hydroxy-4-methyl- R.sup.7 =
Cl 1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 0.86 (t, CH.sub.2CH.sub.3), 1.48 and 1.62 (two dq,
CH.sub.2CH.sub.3), 1.99 and 2.27 (two ddd, 1-CH.sub.2), 2.04 (s,
4-CH.sub.3), 2.48 and 2.57 (two ddd, 2-CH.sub.2), 2.64 and 3.03
(two d, 9-CH.sub.2), 5.68 (s, OH), and 7.40 (d, H-5); mass spectrum
m/z 295.3 (M+1). 97 R.sup.3 = CH.sub.3
8-bromo-9a-ethyl-6-fluoro--
7-hydroxy-4-methyl- R.sup.7 = Br 1,2,9,9a-tetrahydro-3H-fluoren-3--
one .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.2CH.sub.3), 1.49 and 1.62 (two dq, CH.sub.2CH.sub.3), 1.99
and 2.26 (two ddd, 1-CH.sub.2), 2.04 (s, 4-CH.sub.3), 2.48 and 2.57
(two ddd, 2-CH.sub.2), 2.64 and 2.99 (two d, 9-CH.sub.2), 5.96 (d,
OH), and 7.43 (d, H-5). 98 R.sup.3 = CH.sub.3
9a-ethyl-6-fluoro-7-hydro- xy-4,8-dimethyl- R.sup.7 = CH.sub.3
1,2,9,9a-tetrahydro-3H-fluoren- -3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.85 (t, CH.sub.2CH.sub.3), 1.47 and 1.61 (two dq,
CH.sub.2CH.sub.3), 1.97 and 2.25 (two ddd, 1-CH.sub.2), 2.04 (s,
4-CH.sub.3), 2.21 (s, 8-CH.sub.3), 2.47 and 2.57 (two ddd,
2-CH.sub.2), 2.54 and 2.90 (two d, 9-CH.sub.2), 5.40 (d, OH), and
7.31 (d, H-5); mass spectrum m/z 275.3 (M+1). 99 R.sup.3 =
CH.sub.2CH.sub.3 4,9a-diethyl-6,8-difluoro-7-hydroxy-1,2,9,9a-
R.sup.7 = F tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3,
500 MHz) .delta. 0.86 (t, 9a-CH.sub.2CH.sub.3), 1.09 (t,
4-CH.sub.2CH.sub.3), 1.48 and 1.60 (two dq, 9a-CH.sub.2CH.sub.3),
1.98 and 2.25 (two ddd, 1-CH.sub.2), 2.42 and 2.63 (two m, 4-
CH.sub.2CH.sub.3), 2.46 and 2.54 (two ddd, 2-CH.sub.2), 2.60 and
3.06 (two d, 9-CH.sub.2), 5.39 (t, OH), and 7.24 (d, H-5); mass
spectrum m/z 293.3 (M+1). 100 R.sup.3 = Br
4-bromo-8-chloro-9a-ethyl-6-fluoro-7-hydroxy- R.sup.7 = Cl
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.89 (t, CH.sub.2CH.sub.3), 1.58 and 1.69 (two dq,
CH.sub.2CH.sub.3), 2.09 and 2.30 (two m, 1-CH.sub.2), 2.69-2.79 (m,
2-CH.sub.2), 2.73 and 3.08 (two d, 9-CH.sub.2), 5.93 (br s, OH),
and 8.29 (d, H-5); mass spectrum m/z 359.2 (M+1), 361.2 (M+3). 71
101
4-bromo-8-chloro-9a-(cyclopentylmethyl)-6-fluoro-7-hydroxy-1,2,9,9a-
tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.94-1.12, 1.38-1.49, 1.51-1.69, and 1.71-1.79 (four m,
cyclopentylmethyl), 2.11 and 2.31 (two ddd, 1-CH.sub.2), 2.72 and
2.81 (two ddd, 2- CH.sub.2), 2.76 and 3.17 (two d, 9-CH.sub.2),
5.97 (d, OH), and 8.29 (d, H-5). 72 102 R.sup.7 = H
9a-ethyl-5-fluoro-7-hydroxy-4-methyl-1,2,9,9a-
tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.85 (t, CH.sub.2CH.sub.3), 1.42 and 1.64 (two dq,
CH.sub.2CH.sub.3), 1.96 (d, 4-CH.sub.3), 1.96 and 2.21 (two ddd,
1-CH.sub.2), 2.44 and 2.54 (two ddd, 2-CH.sub.2), 2.67 and 2.90
(two d, 9-CH.sub.2), 5.81 (br s, OH), 6.46 (dd, H-6), and 6.59 (s,
H-8); mass spectrum m/z 261.2 (M+1). 103 R.sup.7 = Br
8-bromo-9a-ethyl-5-fluoro-7-hydroxy-4-methyl-
1,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.86 (t, CH.sub.2CH.sub.3), 1.46 and 1.67 (two dq,
CH.sub.2CH.sub.3), 1.94 (d, 4-CH.sub.3), 1.99 and 2.25 (two ddd,
1-CH.sub.2), 2.46 and 2.55 (two ddd, 2-CH.sub.2), 2.68 and 2.98
(two d, 9-CH.sub.2), 5.82 (d, OH), and 6.70 (d, H-6). 73 104
R.sup.7 = H 9a-ethyl-6,7-dihydroxy-4-methyl-1,- 2,9,9a-
tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.86 (t, CH.sub.2CH.sub.3), 1.48 and 1.61 (two dq,
CH.sub.2CH.sub.3), 1.97 and 2.22 (two ddd, 1-CH.sub.2), 2.10 (s,
4-CH.sub.3), 2.49 and 2.60 (two ddd, 2-CH.sub.2), 2.64 and 2.89
(two d, 9-CH.sub.2), 5.91 (br s, OH), 6.86 (s, H-5 or H-8), 6.94
(br s, OH), and 7.43 (s, H-S or H-5). 105 R.sup.7 = Br
8-bromo-9a-ethyl-6,7-dihydroxy-4-methyl- 1
,2,9,9a-tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500
MHz) .delta. 0.85 (t, CH.sub.2CH.sub.3), 1.49 and 1.61 (two dq,
CH.sub.2CH.sub.3), 1.98 and 2.24 (two ddd, 1-CH.sub.2), 2.06 (s,
4-CH.sub.3), 2.47 and 2.56 (two ddd, 2-CH.sub.2), 2.62 and 2.93
(two d, 9-CH.sub.2), and 7.28 (s, H-5). 74 106 R.sup.3 = CH.sub.3
9a-ethyl-6-hydroxy-4-methyl-1,2,9,9a-tetra- hydro- 3H-fluoren-3-one
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.2CH.sub.3), 1.48 and 1.60 (two dq, CH.sub.2CH.sub.3), 1.99
and 2.24 (two ddd, 1-CH.sub.2), 2.11 (s, 4-CH.sub.3), 2.49 and 2.59
(two ddd, 2-CH.sub.2), 2.64 and 2.92 (two d, 9-CH.sub.2), 6.01 (s,
OH), 6.89 (dd, H-7), 7.18 (d, H-8), and 7.29 (d, H-5). 107 R.sup.3
= CH.dbd.CH.sub.2 9a-ethyl-6-hydroxy-4-vinyl-1,2,9,9a-tetrahydro-
3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.86 (t,
CH.sub.2CH.sub.3), 1.49 and 1.63 (two dq, CH.sub.2CH.sub.3), 2.01
and 2.23 (two ddd, 1-CH.sub.2), 2.51 and 2.61 (two ddd,
2-CH.sub.2), 2.66 and 2.92 (two d, 9-CH.sub.2), 5.53 (dd, cis
CH.dbd.CH.sub.aH.sub.b), 5.63 (s, OH), 5.82 (dd, trans
CH.dbd.CH.sub.aH.sub.b), 6.53 (dd, CH.dbd.CH.sub.aH.sub.b), 6.89
(dd, H-7), 7.17 (d, H-8), and 7.32 (d, H-5). 108 R.sup.3 =
CH.sub.2CH.dbd.CH.sub.2
4-allyl-9a-ethyl-6-hydroxy-1,2,9,9a-tetrahydro- 3H-fluoren-3-one
.sup.1H NMR (CDCl.sub.3, 500 MHz) .delta. 0.87 (t,
CH.sub.2CH.sub.3), 1.53 and 1.66 (two dq, CH.sub.2CH.sub.3), 2.01
and 2.25 (two ddd, 1-CH.sub.2), 2.49 and 2.60 (two ddd,
2-CH.sub.2), 2.66 and 2.73 (two d, 9-CH.sub.2), 3.13 and 3.49 (two
m, CH.sub.2CH.dbd.CH.sub.2), 5.00-5.07 (m, CH.dbd.CH.sub.2), 5.18
(s, OH), 5.98 (m, CH.dbd.CH.sub.2), 6.87 (dd, H-7), 7.13 (d, H-5),
and 7.17 (d, H-8). 75 109
2-hydroxy-5-methyl-7,8,9,10-tetrahydro-7,10-methanocycloocta[a]inden-
6(11H)-one .sup.1H NMR (2:1 CDCl.sub.3--CD.sub.3CN, 500 MHz)
.delta. 1.30-1.46 (m, 9-CH.sub.2, 10-CH.sub.2, and 8-
CH.sub.aH.sub.b),), 1.64 (m, 8-CH.sub.aH.sub.b), 1.85 and 2.11 (dd
and m, 12-CH.sub.2), 1.98 (s, 5-CH.sub.3), 2.52 (m, H-7), 2.55 and
2.74 (two d, 11-CH.sub.2), 6.66 (d, H-3), 6.68 (s, H-1), 7.28 (s,
CHCl.sub.3), and 7.47 (d, H-4); mass spectrum m/z 255.3 (M+1). 76
110 R.sup.3 = Br R.sup.7 = H
7-amino-4-bromo-9a-butyl-1,2,9,9a-tetrahydro- R.sup.10 =
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 3H-fluoren-3-one .sup.1H NMR
(DMSO-d.sub.6, 500 MHz) .delta. 0.79 (t,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3- ), 1.04-1.27 (m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.32 and 1.57 (two m,
CH.sub.2CH.sub.2CH.sub.2CH.sub.3), 1.96 and 2.09 (two m,
1-CH.sub.2), 2.48 and 2.65 (two m, 2-CH.sub.2), 2.64 and 2.85 (two
d, 9-CH.sub.2), 6.14 (s, NH.sub.2), 6.51 (s, H-8), 6.55 (dd, H-6),
and 8.13 (d, H-5). 111 R.sup.3 = CH.sub.3 R.sup.7 = Br
7-amino-4,8-dibromo-9a-ethyl-1,2,9,9a- R.sup.10 = CH.sub.2CH.sub.3
tetrahydro-3H-fluoren-3-one .sup.1H NMR (CDCl.sub.3, 500 MHz)
.delta. 0.86 (t, CH.sub.2CH.sub.3), 1.50 and 1.63 (two dq,
CH.sub.2CH.sub.3), 1.98 and 2.24 (two ddd, 1-CH.sub.2), 2.05 (s,
4-CH.sub.3), 2.46 and 2.56 (two ddd, 2-CH.sub.2), 2.61 and 2.99
(two d, 9-CH.sub.2), 4.42 (s, NH.sub.2), 6.70 (d, H-6), and 7.48
(d, H-5).
EXAMPLE 112
[0445] The following compounds are prepared using methods analogous
to those described in the preceding examples:
7 77 R.sup.3 R.sup.5 R.sup.7 R.sup.10 CH.sub.3 H OH
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H OH
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CH.sub.3 H F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 H F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CHF.sub.2 H F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CF.sub.3 H F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CF.sub.2CH.sub.3 H F
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CN H F CH.sub.2CH.sub.2CH.sub.2C-
H.sub.3 C(.dbd.O)CH.sub.3 H F CH.sub.2CH.sub.2CH.sub.2CH.sub.3
CHF.sub.2 F Cl CH.sub.2CH.sub.3 CF.sub.3 F Cl CH.sub.2CH.sub.3
CF.sub.2CH.sub.3 F Cl CH.sub.2CH.sub.3 CN F Cl CH.sub.2CH.sub.3
C(.dbd.O)CH.sub.3 F Cl CH.sub.2CH.sub.3 Cl F Cl CH.sub.2CH.sub.3
CH.sub.3 F Cl CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.2CH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.3 CHF.sub.2 F Cl CH.sub.2CH.sub.2CH.sub.3
CF.sub.3 F Cl CH.sub.2CH.sub.2CH.sub.3 CF.sub.2CH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.3 CN F Cl CH.sub.2CH.sub.2CH.sub.3
C(.dbd.O)CF.sub.3 F Cl CH.sub.2CH.sub.2CH.sub.3 Cl F Cl
CH.sub.2CH.sub.2CH.sub.3 Br F Cl CH.sub.2CH.sub.2CH.sub.3 CHF.sub.2
F Cl CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CF.sub.2CH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CN F Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 C(.dbd.O)CH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 C(.dbd.O)CH.sub.2CH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 C(.dbd.O)OCH.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 Cl F Cl CH.sub.2CH.sub.2CH.sub.2-
CH.sub.3 CH.sub.2CH.sub.3 H CHF.sub.2 CH.sub.2CH.sub.2CH.sub.2CH.s-
ub.3 CH.sub.2CH.sub.3 F CHF.sub.2 CH.sub.2CH.sub.2CH.sub.2CH.sub.3
CF.sub.3 F Cl CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CF.sub.3 F Cl
CH.sub.2CH.sub.2CH.sub.2CH.sub.3 CF.sub.3 F Cl CF.sub.3 F Cl
[0446]
8 78 n R R.sup.1 R.sup.3 R.sup.5 R.sup.7 1 CH.sub.2CH.sub.2CH.sub.3
H CH.sub.3 H H 1 CH.sub.2CH.sub.2CH.sub.3 H CH.sub.2CH.sub.3 H H 1
CH.sub.2CH.sub.2CH.sub.3 H Br H H 1 CH.sub.2CH.sub.2CH.sub.3 H
CF.sub.3 H H 1 CH.sub.2CH.sub.2CH.sub.3 CH.sub.3 CH.sub.2CH.sub.3 H
H 1 CH.sub.2CH.sub.2CH.sub.3 CH.sub.2CH.sub.2CH.sub.3
CH.sub.2CH.sub.3 H H 1 CH.sub.2CH.sub.2CH.sub.3 OH CH.sub.2CH.sub.3
H H 1 CH.sub.2CH.sub.2CH.sub.3 H CF.sub.3 F Cl 2 CH.sub.2CH.sub.3 H
CH.sub.2CH.sub.3 H H 2 CH.sub.2CH.sub.3 H Br H H 2 CH.sub.2CH.sub.3
H CF.sub.3 H H 2 CH.sub.2CH.sub.3 H CF.sub.3 F Cl 2
CH.sub.2CH.sub.2CH.sub.3 H CH.sub.3 H H 2 CH.sub.2CH.sub.2CH.sub.3
H CF.sub.3 H H
[0447] Estrogen Receptor Binding Assay
[0448] The estrogen receptor ligand binding assays are designed as
scintillation proximity assays employing the use of tritiated
estradiol and recombinant expressed estrogen receptors. The full
length recombinant human ER-.alpha. and ER-.beta. proteins are
produced in a bacculoviral expression system. ER-.alpha. or
ER-.beta. extracts are diluted 1:400 in phosphate buffered saline
containing 6 mM .alpha.-monothiolglycerol. 200 .mu.L aliquots of
the diluted receptor preparation are added to each well of a
96-well Flashplate. Plates are covered with Saran Wrap and
incubated at 4.degree. C. overnight.
[0449] The following morning, a 20 ul aliquot of phosphate buffered
saline containing 10% bovine serum albumin is added to each well of
the 96 well plate and allowed to incubate at 4.degree. C. for 2
hours. Then the plates are washed with 200 ul of buffer containing
20 mM Tris (pH 7.2), 1 mM EDTA, 10% Glycerol, 50 mM KCl, and 6 mM
.alpha.-monothiolglycerol. To set up the assay in these receptor
coated plates, add 178 ul of the same buffer to each well of the 96
well plate. Then add 20 ul of a 10 nM solution of .sup.3H-estradiol
to each well of the plate.
[0450] Test compounds are evaluated over a range of concentrations
from 0.01 nM to 1000 nM. The test compound stock solutions should
be made in 100% DMSO at 100.times. the final concentration desired
for testing in the assay. The amount of DMSO in the test wells of
the 96 well plate should not exceed 1%. The final addition to the
assay plate is a 2 ul aliquot of the test compound which has been
made up in 100% DMSO. Seal the plates and allow them to equilibrate
at room temperature for 3 hours. Count the plates in a
scintillation counter equipped for counting 96 well plates.
[0451] The compounds of Examples 1-111 exhibit binding affinities
to the estrogen receptor .alpha.-subtype in the range of
IC.sub.50=2.8-5625 nm, and to the estrogen receptor .beta.-subtype
in the range of IC.sub.50=0.6-126 nm.
[0452] Pharmaceutical Composition
[0453] As a specific embodiment of this invention, 25 mg of
tetrahydrofluorenone from Example 17, is formulated with sufficient
finely divided lactose to provide a total amount of 580 to 590 mg
to fill a size 0, hard-gelatin capsule.
* * * * *