U.S. patent application number 10/435520 was filed with the patent office on 2004-03-11 for rxr modulators with improved pharmacologic profile.
Invention is credited to Ardecky, Robert J., Boehm, Marcus F., Faulkner, Amy L., Hamann, Lawrence G., Jones, Todd K., Mapes, Christopher M., Michellys, Pierre-Yves, Tyhonas, John S..
Application Number | 20040049072 10/435520 |
Document ID | / |
Family ID | 22549155 |
Filed Date | 2004-03-11 |
United States Patent
Application |
20040049072 |
Kind Code |
A1 |
Ardecky, Robert J. ; et
al. |
March 11, 2004 |
RXR modulators with improved pharmacologic profile
Abstract
The present invention provides a novel class of RXR modulator
compounds that exhibit an improved pharmacologic profile relative
to the profile of previously studied RXR modulators, including
those that share common structural features with the presently
claimed modulators. The present invention also provides synthetic
methods for preparing these compounds as well as pharmaceutical
compositions incorporating these novel compounds and methods for
the therapeutic use of such compounds and pharmaceutical
compositions.
Inventors: |
Ardecky, Robert J.;
(Encinitas, CA) ; Boehm, Marcus F.; (San Diego,
CA) ; Faulkner, Amy L.; (San Diego, CA) ;
Hamann, Lawrence G.; (Cherry Hill, NJ) ; Jones, Todd
K.; (Solana Beach, CA) ; Mapes, Christopher M.;
(Del Mar, CA) ; Michellys, Pierre-Yves; (San
Diego, CA) ; Tyhonas, John S.; (San Diego,
CA) |
Correspondence
Address: |
PAUL, HASTINGS, JANOFSKY & WALKER LLP
P.O. BOX 919092
SAN DIEGO
CA
92191-9092
US
|
Family ID: |
22549155 |
Appl. No.: |
10/435520 |
Filed: |
May 9, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10435520 |
May 9, 2003 |
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09662211 |
Sep 14, 2000 |
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6593493 |
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60153890 |
Sep 14, 1999 |
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Current U.S.
Class: |
562/475 ;
546/341; 548/577 |
Current CPC
Class: |
C07C 59/64 20130101;
A61P 17/04 20180101; A61P 35/00 20180101; A61P 3/04 20180101; A61P
3/10 20180101; A61P 5/48 20180101; C07D 213/55 20130101; A61P 17/16
20180101; A61P 9/00 20180101; A61P 3/06 20180101; A61P 5/14
20180101; C07C 59/72 20130101; A61P 17/10 20180101; A61P 25/28
20180101; A61P 17/00 20180101; A61P 25/16 20180101; A61P 43/00
20180101; A61P 25/02 20180101; A61P 17/06 20180101; C07D 333/24
20130101; A61P 17/02 20180101; C07D 307/54 20130101 |
Class at
Publication: |
562/475 ;
546/341; 548/577 |
International
Class: |
C07C 065/03; C07D
213/55; C07D 207/46 |
Claims
What is claimed is:
1. A compound having the structure: 100wherein R.sup.1 is selected
from the group of hydrogen, F, Cl, Br, I, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3
haloalkenyl, C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl,
and C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sup.2 and R.sup.4 are independently
selected from the group of hydrogen, NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted; R.sup.3 is selected from the group of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 haloalkynyl, aryl, heteroaryl, C.sub.1-C.sub.6
alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl,
alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,
alkoxy, aryloxy groups may be optionally substituted; R.sup.5 and
R.sup.6 are independently selected from the group of hydrogen, F,
Cl, Br, I, CN, NH.sub.2, OH, SH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkenyl, C.sub.1-C.sub.6 alkoxy, and aryloxy wherein said
alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy and aryloxy groups
may be optionally substituted; or R.sup.5 and R.sup.6 taken
together form a three- to eight-membered carbocyclic ring, a three-
to eight-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups may be optionally substituted; R.sup.7 is
selected from the group of C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 haloalkyl, wherein said alkyl,
alkenyl, and haloalkyl groups may be optionally substituted;
R.sup.8 is selected from the group of hydrogen, F, Cl, Br, I, CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkynyl, alkoxy and aryloxy groups may be,
optionally substituted; R.sup.9 is selected from the group of
hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R.sup.10 to and R.sup.11 each independently is hydrogen or
optionally substituted C.sub.1-C.sub.6 alkyl; or R.sup.10 and
R.sup.11 taken together with nitrogen form an optionally
substituted five- or six-membered heterocyclic ring; Y is selected
from the group of NR.sup.12, O and S; R.sup.12 is selected from the
group of hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl,
and optionally substituted C.sub.1-C.sub.6 haloalkyl; and
pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein R.sup.1 is selected
from the group of hydrogen, optionally substituted C.sub.1-C.sub.3
alkyl and optionally substituted C.sub.1-C.sub.3 haloalkyl.
3. A compound according to claim 2, wherein R.sup.1 is
hydrogen.
4. A compound according to claim 2, wherein R.sup.3 is selected
from the group of hydrogen, optionally substituted C.sub.1-C.sub.6
alkyl and optionally substituted C.sub.1-C.sub.6 haloalkyl.
5. A compound according to claim 4, wherein R.sup.3 is
hydrogen.
6. A compound according to claim 4, wherein R.sup.8 is selected
from the group of hydrogen, optionally substituted C.sub.1-C.sub.6
alkyl and optionally substituted C.sub.1-C.sub.6 haloalkyl.
7. A compound according to claim 6, wherein R.sup.8 is
hydrogen.
8. A compound according to claim 6, wherein R.sup.9 is hydrogen, F,
Cl, Br, or I.
9. A compound according to claim 8, wherein R.sup.9 is
hydrogen.
10. A compound according to claim 1, wherein R.sup.5 and R.sup.6
each independently is selected from the group of hydrogen, F, Cl,
Br, I, and C.sub.1-C.sub.4 alkyl wherein said alkyl group may be
optionally substituted; or R.sup.5 and R.sup.6 taken together form
a three- to eight-membered carbocyclic ring, a three- to
eight-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups may be optionally substituted.
11. A compound according to claim 10, wherein R.sup.5 is optionally
substituted C.sub.1-C.sub.4 alkyl and R.sup.6 is hydrogen.
12. A compound according to claim 10, wherein R.sup.5 and R.sup.6
taken together form a five- to six-membered carbocyclic ring, a
five- to six-membered heterocyclic ring, an aryl group or a
heteroaryl group, wherein said carbocyclic ring, heterocyclic ring,
aryl and heteroaryl groups may be optionally substituted.
13. A compound according to claim 10, wherein R.sup.7 is selected
from the group of C.sub.2-C.sub.5 alkyl and C.sub.2-C.sub.5
haloalkyl, wherein said alkyl and haloalkyl groups may be
optionally substituted.
14. A compound according to claim 13, wherein R.sup.7 is an
optionally substituted C.sub.2-C.sub.5 alkyl.
15. A compound according to claim 13, wherein R.sup.7 is an
optionally substituted C.sub.2-C.sub.5 haloalkyl.
16. A compound according to claim 1, wherein R.sup.2 and R.sup.4
are independently selected from the group of NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, aryl, and heteroaryl, wherein said alkyl, haloalkyl,
cycloalkyl, aryl and heteroaryl groups may be optionally
substituted.
17. A compound according to claim 16, wherein R.sup.2 and R.sup.4
are independently selected from the group of aryl, C.sub.1-C.sub.6
alkyl and C.sub.1-C.sub.6 haloalkyl, wherein said aryl, alkyl and
haloalkyl groups may be optionally substituted.
18. A compound according to claim 17, wherein R.sup.2 and R.sup.4
each independently is optionally substituted C.sub.1-C.sub.6
alkyl.
19. A compound according to claim 18, wherein R.sup.2 is selected
from the group of ethyl, i-propyl, t-butyl, and t-amyl.
20. A compound according to claim 16, wherein R.sup.4 is selected
from the group of NR.sup.10R.sup.11, i-propyl, t-butyl, and
t-amyl.
21. A compound according to claim 1, wherein R.sup.1 is selected
from the group of hydrogen, optionally substituted C.sub.1-C.sub.3
alkyl, and optionally substituted C.sub.1-C.sub.3 haloalkyl;
R.sup.3, R.sup.6, and R.sup.8 are independently selected from the
group of hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl,
and optionally substituted C.sub.1-C.sub.6 haloalkyl; R.sup.2 and
R.sup.4 are independently selected from the group of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.5-C.sub.6
cycloalkyl, aryl, and heteroaryl, wherein said alkyl, haloalkyl,
cycloalkyl, aryl and heteroaryl groups may be optionally
substituted; R.sup.5 is optionally substituted C.sub.1-C.sub.6
alkyl; R.sup.7 is optionally substituted C.sub.2-C.sub.5 alkyl; and
R.sup.9 is hydrogen, F, Cl, Br, or I.
22. A compound according to claim 1, wherein R.sup.1 is selected
from the group of hydrogen, optionally substituted C.sub.1-C.sub.3
alkyl, and optionally substituted C.sub.1-C.sub.3 haloalkyl;
R.sup.3, R.sup.6, and R.sup.8 are independently selected from the
group of hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl,
and optionally substituted C.sub.1-C.sub.6 haloalkyl; R.sup.2 and
R.sup.4 are independently selected from the group of
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.5-C.sub.6
cycloalkyl, aryl, and heteroaryl, wherein said alkyl, haloalkyl,
cycloalkyl, aryl and heteroaryl groups may be optionally
substituted; R.sup.5 is optionally substituted C.sub.1-C.sub.6
alkyl; and R.sup.7 is optionally substituted C.sub.2-C.sub.5
haloalkyl; R.sup.9 is hydrogen, F, Cl, Br, or I.
23. A compound according to claim 1, wherein R.sup.1, R.sup.3,
R.sup.8 and R.sup.9 are hydrogen; R.sup.2 and R.sup.4 are
independently selected from the group of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, aryl and
heteroaryl, wherein alkyl haloalkyl, cycloalkyl, aryl and
heteroaryl may be optionally substituted; R.sup.5 and R.sup.6 taken
together form a five- to six-membered carbocyclic ring, a five- to
six-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups may be optionally substituted; and R.sup.7 is an
optionally substituted C.sub.2-C.sub.5 alkyl.
24. A compound according to claim 1, wherein R.sup.1, R.sup.3,
R.sup.8 and R.sup.9 are hydrogen; R.sup.2 and R.sup.4 are
independently selected from the group of C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6 cycloalkyl, aryl and
heteroaryl, wherein alkyl, haloalkyl, cycloalkyl, aryl and
heteroaryl may be optionally substituted; R.sup.5 and R.sup.6 taken
together form a five- to six-membered carbocyclic ring, a five- to
six-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups may optionally substituted; and R.sup.7 is
optionally substituted C.sub.2-C.sub.5 haloalkyl.
25. A compound according to claim 1, wherein said compound, when
administered to an individual, decreases blood glucose levels but
does not substantially raise triglyceride levels.
26. A compound according to claim 1 wherein said compound does not
substantially suppress thyroid hormone axis in an individual.
27. A compound according to claim 1 wherein said compound is
non-teratogenic.
28. A compound according to claim 1 wherein said modulator compound
is selected from the group of:
10110210310410510610710810911011111211311411-
5116117118119120121122123124
29. A compound of claim 28 wherein said compound is selected from
the group of: 125126127128129
30. A pharmaceutical composition comprising a compound according to
any one of claims 1, 28 or 29 and a pharmaceutically acceptable
carrier.
31. A method for modulating RXR activity in an individual
comprising administering to said individual a pharmaceutically
effective amount of a compound according to any one of claims 1, 28
or 29.
32. A method for treating an individual having a disease condition
selected from the group of syndrome X, NIDDM, diabetes, obesity and
cardiovascular disease comprising administering to said individual
a pharmaceutically effective amount of a compound according to any
one of claims 1, 28 or 29.
33. A method for treating an individual having a disease condition
selected from the group of breast cancer, photoaging, acne, and
psoriasis comprising administering to said individual a
pharmaceutically effective amount of a compound according to any
one of claims 1, 28 or 29.
34. A method for treating an individual at risk for developing a
disease condition selected from the group of syndrome X, NIDDM,
diabetes, obesity and cardiovascular disease comprising
administering to said individual a pharmaceutically effective
amount of a compound according to any one of claims 1, 28 or
29.
35. A method for treating an individual at risk for developing a
disease condition selected from the group of breast cancer;
photoaging, acne, and psoriasis comprising administering to said
individual a pharmaceutically effective amount of a compound
according to any one of claims 1, 28 or 29.
36. A method for lowering blood glucose levels in an individual
without substantially raising said individual's serum triglyceride
levels comprising administering to said individual a
pharmaceutically effective amount of a compound according to any
one of claims 1, 28 or 29.
37. A method of claim 36 further comprising, administering to said
individual a PPAR.gamma. agonist.
38. A method for increasing HDL cholesterol levels and reducing
triglyceride levels in an individual comprising administering to
said individual a pharmaceutically effective amount of a compound
according to any one of claims 1, 28 or 29.
39. A method for modulating lipid metabolism in an individual
comprising administering to said individual a pharmaceutically
effective amount of a compound according to any one of claims 1, 28
or 29.
40. The method of claim 38 further comprising the administration of
a PPAR.alpha. agonist.
41. A method for modulating RXR:PPAR heterodimer activity in an
individual comprising administering to said individual a
pharmaceutically effective amount a compound according to any one
of claims 1, 28 or 29.
42. The method of claim 41 further comprising administering to said
individual a PPAR agonist.
43. A process for preparing a compound of structural formula 1:
130comprising the step of treating a coumarin intermediate of
structural formula 4: 131with a reducing agent to form a diol of
structural formula 7: 132wherein R.sup.1 is selected from the group
of hydrogen, F, Cl, Br, I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sup.2 and R.sup.4 are independently
selected from the group of hydrogen, NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted; R.sup.3 is selected from the group of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 haloalkynyl, aryl, heteroaryl, C.sub.1-C.sub.6
alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl,
alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,
alkoxy, aryloxy groups may be optionally substituted; R.sup.5 and
R.sup.6 are independently selected from the group of hydrogen, F,
Cl, Br, I, CN, NH.sub.2, OH, SH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkenyl, C.sub.1-C.sub.6 alkoxy, and aryloxy wherein said
alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy and aryloxy groups
may be optionally substituted; or R.sup.5 and R.sup.6 taken
together form a three- to eight-membered carbocyclic ring, a three-
to eight-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups may be optionally substituted; R.sup.7 is
selected from the group of C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 haloalkyl, wherein said alkyl,
alkenyl, and haloalkyl groups may be optionally substituted;
R.sup.8 is selected from the group of hydrogen, F, Cl, Br, 1, CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkynyl, alkoxy and aryloxy groups may be
optionally substituted; R.sup.9 is selected from the group of
hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R.sup.10 and R.sup.11 each independently is hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl; or R.sup.10 and R.sup.11 taken
together with nitrogen form an optionally substituted five- or
six-membered heterocyclic ring; and pharmaceutically acceptable
salts thereof.
44. A process according to claim 43 further comprising the steps
of: (a) selectively alkylating the phenol oxygen of the diol of
structural formula 7 with R.sup.7X in the presence of a base to
form a primary allylic alcohol of structural formula 8: 133(b)
treating the allylic alcohol of structural formula 8 with an
oxidant to form an aldehyde of structural formula 9: 134(c)
treating the aldehyde of structural formula 9 with a phosphonate of
structural formula 10: 135to form an ester of formula 1-E: 136and
hydrolyzing the ester, 1-E; wherein: R'" and R"" each independently
is alkyl or aryl; X is a halogen.
45. A process according to claim 44 wherein R'" and R"" each
independently is methyl, ethyl or iso-propyl.
46. A process for preparing a compound of structural formula 1:
137comprising the steps of: (a) treating alkoxyarylhalide 12
138with a trialkyl borate and a base under Pd-catalysis to form a
compound of structural formula 14 139(b) treating the compound of
structural formula 14 with a compound of structural formula 15:
140to form a compound of structural formula 16: 141 wherein: A is
COOR' or COP.sup.g, wherein P.sup.g is a protecting group; R and R'
each independently is hydrogen or alkyl; X.sup.a and X.sup.b each
independently is halogen; R.sup.1 is selected from the group of
hydrogen, F, Cl, Br, I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl, C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sup.2 and R.sup.4 are independently
selected from the group of hydrogen, NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 S
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted; R.sup.3 is selected from the group of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, CZ-C.sub.6 alkynyl, C.sub.2-C.sub.6
haloalkynyl, aryl, heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy,
wherein said alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl,
alkynyl, haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may
be optionally substituted; R.sup.5 and R.sup.6 are independently
selected from the group of hydrogen, F, Cl, Br, I, CN, NH.sub.2,
OH, SH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkenyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkoxy and aryloxy groups may be optionally
substituted; or R.sup.5 and R.sup.6 taken together form a three- to
eight-membered carbocyclic ring, a three- to eight-membered
heterocyclic ring, an aryl group or a heteroaryl group, wherein
said carbocyclic ring, heterocyclic ring, aryl and heteroaryl
groups may be optionally substituted; R.sup.7 is selected from the
group of C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and
C.sub.2-C.sub.6 haloalkyl, wherein said alkyl, alkenyl, and
haloalkyl groups may be optionally substituted; R.sup.8 is selected
from the group of hydrogen, F, Cl, Br, I, CN, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkynyl, alkoxy, and aryloxy groups may be
optionally substituted; R.sup.9 is selected from the group of
hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R.sup.10 and R.sup.11 each independently is hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl; or R.sup.10 and R.sup.11 taken
together with nitrogen form an optionally substituted five- or
six-membered heterocyclic ring; and pharmaceutically acceptable
salts thereof.
47. A process for preparing a compound of the structural formula 1:
142comprising the step of: (a) treating a ketone of structural
formula VI: 143with a phosphonate of structural formula 10b: 144
wherein: R'" and R"" each independently is alkyl or aryl; R.sup.1
is selected from the group of hydrogen, F, Cl, Br, I,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3
alkenyl, C.sub.2-C.sub.3 haloalkenyl, C.sub.2-C.sub.3 alkynyl,
C.sub.2-C.sub.3 haloalkynyl, and C.sub.1-C.sub.3 alkoxy, wherein
said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,
and alkoxy groups may be optionally substituted; R.sup.2 and
R.sup.4 are independently selected from the group of hydrogen,
NR.sup.10R.sup.11, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 haloalkynyl, aryl, heteroaryl, C.sub.1-C.sub.6
alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl,
alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,
alkoxy, aryloxy groups may be optionally substituted; R.sup.3 is
selected from the group of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted; R.sup.5 and R.sup.6 are independently
selected from the group of hydrogen, F, Cl, Br, I, CN, NH.sub.2,
OH, SH, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 haloalkenyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkoxy and aryloxy groups may be optionally
substituted; or R.sup.5 and R.sup.6 taken together form a three- to
eight-membered carbocyclic ring, a three- to eight-membered
heterocyclic ring, an aryl group or a heteroaryl group, wherein
said carbocyclic ring, heterocyclic ring, aryl and heteroaryl
groups may be optionally substituted; R.sup.7 is selected from the
group of C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and
C.sub.2-C.sub.6 haloalkyl, wherein said alkyl, alkenyl, and
haloalkyl groups may be optionally substituted; R.sup.8 is selected
from the group of hydrogen, F, Cl, Br, I, CN, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkynyl, alkoxy, and aryloxy groups may be
optionally substituted; R.sup.9 is selected from the group of
hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R.sup.10 and R.sup.11 each independently is hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl; or R.sup.10 and R.sup.11 taken
together with nitrogen form an optionally substituted five- or
six-membered heterocyclic ring; and pharmaceutically acceptable
salts thereof.
48. A process according to claim 47, wherein R.sup.9 is F.
49. A process for preparing a compound of structural formula 1b:
145comprising the step of: (a) treating a compound of the
structural formula I: 146with sodium azide to form a triazole of
formula II: 147 wherein: R" is C.sub.1-C.sub.6 alkyl; R.sup.1 is
selected from the group of hydrogen, F, Cl, Br, I, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.2-C.sub.3 alkenyl,
C.sub.2-C.sub.3 haloalkenyl, C.sub.2-C.sub.3 alkynyl,
C.sub.2-C.sub.3 haloalkynyl, and C.sub.1-C.sub.3 alkoxy, wherein
said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl,
and alkoxy groups may be optionally substituted; R.sup.2 and
R.sup.4 are independently selected from the group of hydrogen,
NR.sup.10R.sup.11, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 haloalkynyl, aryl, heteroaryl, C.sub.1-C.sub.6
alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl,
alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,
alkoxy, aryloxy groups may be optionally substituted; R.sup.3 is
selected from the group of hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted; R.sup.7 is selected from the group of
C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6
haloalkyl, wherein said alkyl, alkenyl, and haloalkyl groups may be
optionally substituted; R.sup.8 is selected from the group of
hydrogen, F, Cl, Br, I, CN, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, and aryloxy,
wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,
alkoxy, and aryloxy groups may be optionally substituted; R.sup.9
is selected from the group of hydrogen, F, Cl, Br, I, methyl, and
optionally substituted methyl; R.sup.10 and R.sup.11 each
independently is hydrogen or optionally substituted C.sub.1-C.sub.6
alkyl; or R.sup.10 and R.sup.11 taken together with nitrogen form
an optionally substituted five- or six-membered heterocyclic ring;
and pharmaceutically acceptable salts thereof.
49. A process for preparing a compound of the structural formula
1a: 148comprising the steps of: (a) treating an arylboronic acid of
structural formula I: 149with a compound of structural formula XI:
150to form a compound of structural formula II: 151 wherein: X is
halogen; R.sup.1 is selected from the group of hydrogen, F, Cl, Br,
I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted; R.sup.2 and R.sup.4 are independently
selected from the group of hydrogen, NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted; R.sup.3 is selected from the group of
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.3-C.sub.8 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.2-C.sub.6 haloalkynyl, aryl, heteroaryl, C.sub.1-C.sub.6
alkoxy, and aryloxy, wherein said alkyl, haloalkyl, cycloalkyl,
alkenyl, haloalkenyl, alkynyl, haloalkynyl, aryl, heteroaryl,
alkoxy, aryloxy groups may be optionally substituted; R.sup.5 and
R.sup.6 are independently selected from the group of hydrogen, F,
Cl, Br, I, CN, NH.sub.2, OH, SH, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6
haloalkenyl, C.sub.1-C.sub.6 alkoxy, and aryloxy wherein said
alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy and aryloxy groups
may be optionally substituted; or R.sup.5 and R.sup.6 taken
together form a three- to eight-membered carbocyclic ring, a three-
to eight-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups may be optionally substituted; R.sup.7 is
selected from the group of C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, and C.sub.2-C.sub.6 haloalkyl, wherein said alkyl,
alkenyl, and haloalkyl groups may be optionally substituted;
R.sup.8 is selected from the group of hydrogen, F, Cl, Br, I, CN,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.2-C.sub.6 alkynyl,
C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said alkyl, haloalkyl,
alkenyl, haloalkenyl, alkynyl, alkoxy, and aryloxy groups may be
optionally substituted; R.sup.9 is selected from the group of
hydrogen, F, Cl, Br, I, methyl, and optionally substituted methyl;
R.sup.10 and R.sup.11 each independently is hydrogen or optionally
substituted C.sub.1-C.sub.6 alkyl; or R.sup.10 and R.sup.11 taken
together with nitrogen form an optionally substituted five- or
six-membered heterocyclic ring; Y is selected from the group of
NR.sup.12, O and S; R.sup.12 is selected from the group of
hydrogen, optionally substituted C.sub.1-C.sub.6 alkyl, and
optionally substituted C.sub.1-C.sub.6 haloalkyl; and
pharmaceutically acceptable salts thereof.
50. A process according to claim 50, wherein Y is NR.sup.12.
Description
[0001] This application claims priority to U.S. Provisional
Application Serial No. 60/153,890, filed Sep. 14, 1999, the entire
disclosure of which is incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates to small molecule compounds
that are able to modulate the biological activity of retinoid X
receptors, and to methods for the production and therapeutic use of
such compounds.
BACKGROUND OF THE INVENTION
[0003] The vitamin A metabolite, retinoic acid, has long been
recognized to induce a broad spectrum of biological effects. For
example, retinoic acid-containing products, such as Retin-A.RTM.
and Accutane.RTM., have found utility as therapeutic agents for the
treatment of various pathological conditions. In addition, a
variety of structural analogues of retinoic acid have been
synthesized that also have been found to be bioactive. Many of
these synthetic retinoids have been found to mimic many of the
pharmacological actions of retinoic acid, and thus have therapeutic
potential for the treatment of numerous disease states.
[0004] Medical professionals have become very interested in the
therapeutic applications of retinoids. Among their uses approved by
the FDA is the treatment of severe forms of acne and psoriasis as
well as cancers such as Kaposi's Sarcoma. A large body of evidence
also exists that these compounds can be used to arrest and, to an
extent, reverse the effects of skin damage arising from prolonged
exposure to the sun. Other evidence exists that these compounds
have clear effects on cellular proliferation, differentiation and
programmed cell death (apoptosis), and thus, may be useful in the
treatment and prevention of a variety of cancerous and
pre-cancerous conditions, such as acute promyleocytic leukemia
(APL), epithelial cancers, squamous cell carcinomas, including
cervical and skin cancers and renal cell carcinoma. Furthermore,
retinoids may have beneficial activity in treating and preventing
diseases of the eye, cardiovascular disease and skin disorders.
[0005] Major insight into the molecular mechanism of retinoic acid
signal transduction was gained in 1988, when a member of the
steroid/thyroid hormone intracellular receptor superfamily was
shown to transduce a retinoic acid signal. V. Giguere et al.,
Nature, 330:624-29 (1987); M. Petkovich et al., Nature, 330: 444-50
(1987); for a review, see R. M. Evans, Science, 240:889-95 (1988).
It is now known that retinoids regulate the activity of two
distinct intracellular receptor subfamilies: the Retinoic Acid
Receptors (RARs) and the Retinoid X Receptors (RXRs), including
their subtypes, RAR.alpha., .beta., .gamma. and RXR.alpha., .beta.,
.gamma.. All-trans-retinoic acid (ATRA) is an endogenous
low-molecular-weight ligand that modulates the transcriptional
activity of the RARs, while 9-cis retinoic acid (9-cis) is the
endogenous ligand for the RXRs. R. A. Heyman et al., Cell,
68:397-406 (1992); and A. A. Levin et al., Nature, 355:359-61
(1992).
[0006] Although both the RARs and RXRs respond to ATRA in vivo, due
to the in vivo conversion of some of the ATRA to 9-cis, the
receptors differ in several important aspects. First, the RARs and
RXRs are significantly divergent in primary structure (e.g., the
ligand binding domains of RAR.alpha. and RXR.alpha. have only
approximately 30% amino acid homology). These structural
differences are reflected in the different relative degrees of
responsiveness of RARs and RXRs to various vitamin A metabolites
and synthetic retinoids. In addition, distinctly different patterns
of tissue distribution are seen for RARs and RXRs. For example,
RXR.alpha. mRNA is expressed at high levels in the visceral
tissues, e.g., liver, kidney, lung, muscle and intestine, while
RAR.alpha. mRNA is not. Finally, the RARs and RXRs have different
target gene specificity. In this regard, RARs and RXRs regulate
transcription by binding to response elements in target genes that
generally consist of two direct repeat half-sites of the consensus
sequence AGGTCA. PAR:RXR heterodimers activate transcription ligand
by binding to direct repeats spaced by five base pairs (a DR5) or
by two base pairs (a DR2). However, RXR:RXR homodimers bind to a
direct repeat with a spacing of one nucleotide (a DR1). D. J.
Mangelsdorf et al., "The Retinoid Receptors" in The Retinoids:
Biology, Chemistry and Medicine, M. B. Sporn, A. B. Roberts and D.
S. Goodman, Eds., Raven Press, New York, N.Y., 2nd Edition (1994).
For example, response elements have been identified in the cellular
retinal binding protein type II (CRBPII), which consists of a DR1,
and in Apolipoprotein AI genes that confer responsiveness to RXR,
but not to RAR. Further, RAR has also been shown to repress
RXR-mediated activation through the CRBPII RXR response element (D.
J. Manglesdorf et al., Cell, 66:555-61 (1991)). Also, RAR specific
target genes have been identified, including target genes specific
for RAR.beta. (e.g., PRE), that consist of a DR5. These data
indicate that two retinoic acid responsive pathways are not simply
redundant, but instead manifest a complex interplay.
[0007] RXR agonists in the context of an RXR:RXR homodimer display
unique transcriptional activity in contrast to the activity of the
same compounds through an RXR heterodimer. Activation of a RXR
homodimer is a ligand dependent event, i.e., the RXR agonist must
be present to bring about the activation of the RXR homodimer. In
contrast, RXR working through a heterodimer (e.g., RXR:RAR,
RXR:VDR) is often the silent partner, i.e., no RXR agonist will
activate the RXR-containing heterodimer without the corresponding
ligand for the heterodimeric partner. However, for other
heterodimers, (e.g., PPAR:RXR) a ligand for either or both of the
heterodimer partners can activate the heterodimeric complex.
Furthermore, in some instances, the presence of both an RXR agonist
and the agonist for the other heterodimeric partner (e.g.,
gemfibrizol for PPAR.alpha. and TTNPB for RAR.alpha.) leads to at
least an additive, and often a synergistic enhancement of the
activation pathway of the other IR of the heterodimer pair (e.g.,
the PPAR.alpha. pathway). See e.g., WO 94/15902, published Jul. 21,
1994; R. Mukherjee et al., J. Steroid Biochem. Molec. Biol.,
51:157-166 (1994); and L. Jow and R. Mukherjee, J. Biol. Chem.,
270:3836-40 (1995).
[0008] RAR and RXR retinoid agonists, including both RAR specific
and RXR specific agonists have been previously identified. See
e.g., WO 94/15902, WO 93/21146, WO 94/15901, WO 94/12880, WO
94/17796, WO 94/20093, WO 96/05165 and Application No.
PCT/US93/10166; EPO Patent Application Nos. 87110303.2, 87309681.2
and EP 0718285; U.S. Pat. Nos. 4,193,931, 4,539,134, 4,801,733,
4,831,052, 4,833,240, 4,874,747, 4,879,284, 4,898,864, 4,925,979,
5,004,730, 5,124, 473, 5,198,567, 5,391,569 and Re 33,533; and H.
Kagechika et al., "Retinobenzoic Acids. 2. Structure-Activity
Relationship of Chalcone-4-carboxylic Acids and
Flavone-4'-carboxylic Acids", J. Med. Chem., 32:834 (1989); H.
Kagechika et al., "Retinobenzoic Acids. 3. Structure-Activity
Relationships of Retinoidal Azobenzene-4-carboxylic Acids and
Stilbene-4-carboxylic Acids", J. Med. Chem., 32:1098 (1989); H.
Kagechika et al., "Retinobenzoic Acids. 4. Conformation of Aromatic
Amides with Retinoidal Activity. Importance of trans-Amide
Structure for the Activity", J. Med. Chem., 32:2292 (1989); M.
Boehm et al., J. Med. Chem., 37:2930 (1994); M. Boehm et al., J.
Med. Chem., 38:3146 (1995); E. Allegretto et al., Journal of Biol.
Chem., 270:23906 (1995); R. Bissonnette et al., Mol. & Cellular
Bio., 15:5576 (1995); R. Beard et al., J. Med. Chem., 38:2820
(1995); and M. I. Dawson et al., "Effect of Structural
Modifications in the C7-C11 Region of the Retinoid Skeleton on
Biological Activity in a Series of Aromatic Retinoids", J. Med.
Chem., 32:1504 (1989).
[0009] Further, antagonists to the RAR subfamily of receptors have
been identified. See e.g., C. Apfel et al., Proc. Natl. Acad. Sci.,
89:7129 (1992); S. Keidel et al., Mol. Cell. Biol., 14:287 (1994);
S. Kaneko et al., Med. Chem. Res., 1:220 (1991); L. Eyrolles et
al., Med. Chem. Res., 2:361 (1992); J. Eyrolles et al., J. Med.
Chem., 37:1508 (1994); M-O Lee et al., Proc. Natl. Acad. Sci.,
91:5632 (1994); Yoshimura et al., J. Med. Chem., 38:3163 (1995);
and U.S. Pat. No. 5,391,766. In addition, various polyene compounds
have been disclosed to be useful in the treatment of inflammatory
conditions, psoriasis, allergic reactions, and for use in
sunscreens in cosmetic preparations. See e.g., U.S. Pat. Nos.
4,534,979 and 5,320,833. Also, trienediolates of hexadienoic acids
have proved useful in the synthesis of retinoic and nor-retinoic
acids. See M. J. Aurell, et al., Tetrahedron, 49:6089 (1993).
[0010] Compounds have also been found that are RXR antagonist
(e.g., that bind to RXR and do not activate, but antagonize
transcription) and/or RXR selective compounds that have distinct
heterodimer selective properties, such that they are capable of
manifesting agonist, partial agonist and antagonist properties. See
WO 97/12853, published Apr. 10, 1997. RXR agonists compounds which
have been identified so far have exhibited significant therapeutic
utility, but they have also exhibited some undesirable side
effects, such as elevation of triglycerides and suppression of the
thyroid hormone axis (see, e.g., Sherman, S. I. et al., N. Engl. J.
Med. 340 (14):1075-1079 (1999).
[0011] The entire disclosures of the publications and references
referenced to above and hereafter in this specification are
incorporated herein by reference.
SUMMARY OF THE INVENTION
[0012] The present invention provides a novel class of RXR
modulator compounds having the structure: 1
[0013] wherein
[0014] R.sup.1 is selected from the group of hydrogen, F, Cl, Br,
I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted;
[0015] R.sup.2 and R.sup.4 are independently selected from the
group of hydrogen, NR.sup.10R.sup.11, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted;
[0016] R.sup.3 is selected from the group of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted;
[0017] R.sup.5 and R.sup.6 are independently selected from the
group of hydrogen, F, Cl, Br, I, CN, NH.sub.2, OH, SH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.6 haloalkenyl, C.sub.1-C.sub.6 alkoxy, and
aryloxy wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy
and aryloxy groups may be optionally substituted; or
[0018] R.sup.5 and R.sup.6 taken together form a three- to
eight-membered carbocyclic ring, a three- to eight-membered
heterocyclic ring, an aryl group or a heteroaryl group, wherein
said carbocyclic ring, heterocyclic ring, aryl and heteroaryl
groups may be optionally substituted;
[0019] R.sup.7 is selected from the group of C.sub.2C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 haloalkyl, wherein
said alkyl, alkenyl, and haloalkyl groups may be optionally
substituted;
[0020] R.sup.8 is selected from the group of hydrogen, F, Cl, Br,
I, CN, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, and aryloxy,
wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,
alkoxy, and aryloxy groups may be optionally substituted;
[0021] R.sup.9 is selected from the group of hydrogen, F, Cl, Br,
l, methyl, and optionally substituted methyl;
[0022] R.sup.10 and R.sup.11 each independently is hydrogen or
optionally substituted C.sub.1-C.sub.6 alkyl; or
[0023] R.sup.10 and R.sup.11 taken together with nitrogen form an
optionally substituted five- or six-membered heterocyclic ring;
[0024] Y is selected from the group of NR.sup.12, O and S;
[0025] R.sup.12 is selected from the group of hydrogen, optionally
substituted C.sub.1-C.sub.6 alkyl, and optionally substituted
C.sub.1-C.sub.6 haloalkyl; and
[0026] pharmaceutically acceptable salts thereof.
[0027] Compounds of the present invention exhibit an improved
pharmacologic profile relative to the profile of previously studied
RXR modulators, including those that share common structural
features with the presently disclosed modulator compounds. The
present invention also provides synthetic methods for preparing
these compounds as well as pharmaceutical compositions
incorporating these novel compounds and methods for the therapeutic
use of such compounds and pharmaceutical compositions. These and
various other advantages and features of novelty that characterize
the invention are pointed out with particularity in the claims
annexed hereto and forming a part hereof. However, for a better
understanding of the invention, its advantages, and objects
obtained by its use, reference should be had to the accompanying
descriptive matter, in which there is described preferred
embodiments of the invention.
DETAILED DESCRIPTION OF THE INVENTION
[0028] The present invention is based on the discovery of a group
of compounds that modulate the activity of the RXR receptor and
unexpectedly exhibit a significantly improved pharmacologic
profile. This new group of compounds does not exhibit the
undesirable side effects of substantially raising triglyceride
levels and substantially suppressing thyroid hormone axis, which
have been associated with previously characterized RXR
modulators.
[0029] In accordance with the present invention and as used herein,
the following terms are defined with the following meanings, unless
explicitly stated otherwise.
[0030] The term "alkyl", alone or in combination, refers to a
straight-chain or branched-chain alkyl radical having from 1 to
about 10 carbon atoms. Examples of alkyl radical include methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tert-butyl, tert-amyl, pentyl, hexyl, heptyl, octyl and the
like.
[0031] The term "alkenyl", alone or in combination, refers to a
straight-chain or branched-chain hydrocarbon radical having one or
more carbon-carbon double-bonds and having from 2 to about 18
carbon atoms. Examples of alkenyl radicals include ethenyl,
propenyl, 1,4-butadienyl and the like.
[0032] The term "alkynyl", alone or in combination, refers to a
straight-chain or branched-chain hydrocarbon radical having one or
more carbon-carbon triple-bonds and having from 2 to about 10
carbon atoms. Examples of alkynyl radicals include ethynyl,
propynyl, butynyl and the like.
[0033] The term "aryl", alone or in combination, refers to an
optionally substituted aromatic ring. The term aryl includes
monocyclic aromatic rings, polyaromatic rings and polycyclic ring
systems. The polyaromatic and polycyclic rings systems may contain
from two to four, more preferably two to three, and most preferably
two rings. Preferred aryl groups include five or six-membered
aromatic ring systems. Examples of aryl groups include, without
limitation, phenyl, biphenyl, naphthyl and anthryl ring systems.
Preferably the aryl groups of the present invention contain from
five to about twenty carbon atoms.
[0034] The term "alkoxy", alone or in combination, refers to an
alkyl ether radical wherein the term alkyl is defined as above.
Examples of alkoxy radicals include methoxy, ethoxy, n-propoxy,
isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the
like.
[0035] The term "aryloxy", alone or in combination, refers to an
aryl ether radical wherein the term aryl is defined as above.
Examples of aryloxy radicals include phenoxy, benyloxy and the
like.
[0036] The term "cycloalkyl", alone or in combination, refers to a
saturated or partially saturated monocyclic, bicyclic or tricyclic
alkyl radical wherein each cyclic moiety has about 3 to about 8
carbon atoms. Examples of cycloalkyl radicals include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and the like.
[0037] The term "aralkyl", alone or in combination, refers to an
alkyl radical as defined above in which one hydrogen atom is
replaced by an aryl radical as defined above, such as, for example,
benzyl, 2-phenylethyl and the like.
[0038] The terms alkyl, alkenyl and alkynyl include straight-chain,
branched-chain, saturated and/or unsaturated structures, and
combinations thereof.
[0039] The terms haloalkyl, haloalkenyl and haloalkynyl include
alkyl, alkenyl and alkynyl structures, as described above, that are
substituted with one or more fluorines, chlorines, bromines or
iodines, or with combinations thereof.
[0040] The terms cycloalkyl and cycloalkene include optionally
substituted, saturated and/or unsaturated C.sub.3-C.sub.7
carbocyclic structures.
[0041] The terms cycloalkyl, allyl, aryl, arylalkyl, heteroaryl,
alkynyl, and alkenyl include optionally substituted cycloalkyl,
allyl, aryl, arylalkyl, heteroaryl, alkynyl, and alkenyl
groups.
[0042] The term carbocycle includes optionally substituted,
saturated and/or unsaturated, three- to seven-membered cyclic
structures in which all of the skeletal atoms are carbon.
[0043] The term heterocycle includes optionally substituted,
saturated and/or unsaturated, three- to seven-membered cyclic
structures in which one or more skeletal atoms is oxygen, nitrogen,
sulfur, or combinations thereof.
[0044] The term "heteroaryl" refers to optionally substituted
aromatic ring systems having one or more heteroatoms such as, for
example, oxygen, nitrogen and sulfur. The term heteroaryl may
include five- or six-membered heterocyclic rings, polycyclic
heteroaromatic ring systems, and polyheteroaromatic ring systems
where the ring system has from two to four, more preferably two to
three, and most preferably two, rings. The terms heterocyclic,
polycyclic heteroaromatic, and polyheteroaromatic include ring
systems containing optionally substituted heteroaromatic rings
having more than one heteroatom as described above (e.g., a six
membered ring with two nitrogens), including polyheterocyclic ring
systems from two to four, more preferably two to three, and most
preferably two, rings. The term heteroaryl includes ring systems
such as, for example, pyridine, quinoline, furan, thiophene,
pyrrole, pyrrolidine, piperidine, indole, imidazole, thiazole,
benzthiazole, triazole and pyrazole. Preferably the heteroaryl
groups of the present invention contain from about five to about 20
skeletal ring atoms.
[0045] The term acyl includes alkyl, aryl, heteroaryl, arylalkyl or
heteroarylalkyl substituents attached to a compound via a carbonyl
functionality (e.g., --CO-alkyl, --CO-aryl, --CO-arylalkyl or
heteroarylalkyl etc. . . . ).
[0046] The substituents of an "optionally substituted" structure
may include, without limitation, one or more, preferably one to
four, and more preferably one to two of the following preferred
substituents: alkyl, alkenyl, alkynyl, aryl, heteroaryl, alkoxy,
aryloxy, alkylthio, arylthio, cycloalkyl, arylalkyl, amino,
alkylamino, dialkylamino, F, Cl, Br, I, CN, NO.sub.2, NH.sub.2,
NHCH.sub.3, N(CH.sub.3).sub.2, S, SH, SCH.sub.3, OH, OCH.sub.3,
OCF.sub.3, CH.sub.3, CF.sub.3.
[0047] The term halogen refers to F, Cl, Br or I.
[0048] Protecting groups that may be used in the present invention
include those that are commonly known to those skilled in the art,
such groups include, but are not limited to, TBDMS, TBS, and
BNZ.
[0049] RXR refers to RXR.alpha., RXR.beta., RXR.gamma. and
combinations thereof.
[0050] PPAR refers to PPAR.alpha., PPAR.beta., PPAR.gamma.1,
PPAR.gamma.2 and combinations thereof.
[0051] The term RXR modulator compound refers to a compound that
binds to one or more Retinoid X Receptors and modulates (i.e.,
increases or decreases the transcriptional activity and/or
biological properties of the given receptor dimer) the
transcriptional activity of an RXR homodimer (i.e., RXR:RXR) and/or
RXR in the context of a heterodimer, including but not limited to
heterodimer formation with peroxisome proliferator activated
receptors (e.g., RXR:PPAR.alpha.,.beta.,.gamma.1 or .gamma.2),
thyroid receptors (e.g., RXR:TR.alpha. or .beta.), vitamin D
receptors (e.g., RXR:VDR), retinoic acid receptors (e.g.,
RXR:RAR.alpha.,.beta. or .gamma.), NGFIB receptors (e.g.,
RXR:NGFIB), NURR1 receptors (e.g., RXR:NURR1) LXR receptors (e.g.,
RXR:LXR.alpha.,.beta.), DAX receptors (e.g., RXR:DAX), as well as
other orphan receptors that form heterodimers with RXR, as either
an agonist, partial agonist and/or antagonist. The particular
effect of an RXR modulator as an agonist, partial agonist and/or
antagonist will depend upon the cellular context as well as the
heterodimer partner in which the modulator compounds acts.
[0052] Compounds of the present invention that do not substantially
raise triglyceride levels do not raise triglyceride levels by more
than 50% in individuals having normal triglyceride plasma levels
when such compounds are administered to such individuals in a
pharmaceutically effective amount. Preferably, such compounds do
not raise triglyceride levels by more than 25%. More preferably,
such compounds do not raise triglyceride levels by more than 15%.
Most preferably, such compounds decrease triglyceride levels when
administered to such individuals in a pharmaceutically effective
amount.
[0053] Compounds of the present invention that do not substantially
suppress thyroid hormone axis do not decrease T4 levels in the
blood by more than 50% in individuals having normal T4 levels when
such compounds are administered to such individuals in a
pharmaceutically effective amount. Preferably, such compounds do
not decrease T4 levels in the blood by more than 25%. More
preferably, such compounds do not decrease T4 levels in the blood
by more than 15%. Most preferably, compounds of the present
invention do not substantially increase or decrease T4 levels in
the blood.
[0054] As used herein, the term disease includes, but is not
limited to, syndrome X, NIDDM, diabetes, obesity, and
cardiovascular disease.
[0055] As used herein, persons at risk for developing a disease
condition are those who have one or more, preferably two or more
risk factors for developing such a disease. Such risk factors
include, but are not limited to, insulin resistance, obesity,
hyperlipidemia, hypercholesterolemia, and hypertension.
[0056] In accordance with a first aspect of the present invention,
we have developed compounds of the formulae: 2
[0057] wherein
[0058] R.sup.1 is selected from the group of hydrogen, F, Cl, Br,
I, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl,
C.sub.2-C.sub.3 alkenyl, C.sub.2-C.sub.3 haloalkenyl,
C.sub.2-C.sub.3 alkynyl, C.sub.2-C.sub.3 haloalkynyl, and
C.sub.1-C.sub.3 alkoxy, wherein said alkyl, haloalkyl, alkenyl,
haloalkenyl, alkynyl, haloalkynyl, and alkoxy groups may be
optionally substituted;
[0059] R.sup.2 and R.sup.4 are independently selected from the
group of hydrogen, NR.sup.10R.sup.11, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted;
[0060] R.sup.3 is selected from the group of hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkynyl, aryl,
heteroaryl, C.sub.1-C.sub.6 alkoxy, and aryloxy, wherein said
alkyl, haloalkyl, cycloalkyl, alkenyl, haloalkenyl, alkynyl,
haloalkynyl, aryl, heteroaryl, alkoxy, aryloxy groups may be
optionally substituted;
[0061] R.sup.5 and R.sup.6 are independently selected from the
group of hydrogen, F, Cl, Br, I, CN, NH.sub.2, OH, SH,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.6 haloalkenyl, C.sub.1-C.sub.6 alkoxy, and
aryloxy wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkoxy
and aryloxy groups may be optionally substituted; or
[0062] R.sup.5 and R.sup.6 taken together form a three- to
eight-membered carbocyclic ring, a three- to eight-membered
heterocyclic ring, an aryl group or a heteroaryl group, wherein
said carbocyclic ring, heterocyclic ring, aryl and heteroaryl
groups may be optionally substituted;
[0063] R.sup.7 is selected from the group of C.sub.2-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, and C.sub.2-C.sub.6 haloalkyl, wherein
said alkyl, alkenyl, and haloalkyl groups may be optionally
substituted;
[0064] R.sup.8 is selected from the group of hydrogen, F, Cl, Br,
I, CN, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, and aryloxy,
wherein said alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,
alkoxy, and aryloxy groups may be optionally substituted;
[0065] R.sup.9 is selected from the group of hydrogen, F, Cl, Br,
I, methyl, and optionally substituted methyl;
[0066] R.sup.10 and R.sup.11 each independently is hydrogen or
optionally substituted C.sub.1-C.sub.6 alkyl; or
[0067] R.sup.10 and R.sup.11 taken together with nitrogen form an
optionally substituted five- or six-membered heterocyclic ring;
[0068] Y is selected from the group of NR.sup.12, O and S;
[0069] R.sup.12 is selected from the group of hydrogen, optionally
substituted C.sub.1-C.sub.6 alkyl, and optionally substituted
C.sub.1-C.sub.6 haloalkyl; and
[0070] pharmaceutically acceptable salts thereof.
[0071] In one embodiment, the present invention provides a method
for preparing compounds of formula 1 using a coumarin intermediate.
Such a method includes treating a coumarin intermediate of
structural formula 4: 3
[0072] with a reducing agent to form a diol of structural formula
7: 4
[0073] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, and
R.sup.6 are as previously defined. Preferably, such a method
further includes the step of selectively alkylating the phenol
oxygen of the diol of structural formula 7 with R.sup.7X in the
presence of a base to form a primary allylic alcohol of structural
formula 8: 5
[0074] treating the allylic alcohol of structural formula 8 with an
oxidant to form an aldehyde of structural formula 9: 6
[0075] treating the aldehyde of structural formula 9 with a
phosphonate of structural formula 10: 7
[0076] to form an ester of formula 1-E: 8
[0077] and hydrolyzing the ester, 1-E; wherein R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9
are as previously defined. Preferably, R'" and R"" each
independently is methyl, ethyl or iso-propyl.
[0078] In another embodiment, the present invention provides a
method for preparing compounds of formula 1, which includes the
steps of treating alkoxyarylhalide 12 9
[0079] with a trialkyl borate and a base under Pd-catalysis to form
a compound of structural formula 14 10
[0080] treating a compound of structural formula 14 with a compound
of structural formula 15: 11
[0081] to form a compound of structural formula 16: 12
[0082] wherein A is COOR' or COP.sup.g, P.sup.g is a protecting
group, R and R' each is hydrogen or alkyl; X.sup.a and X.sup.b each
independently is halogen; and R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and R.sup.7 are as previously defined. In this
embodiment, it is preferred where R is hydrogen and R' is methyl or
ethyl.
[0083] In yet another embodiment, the present invention provides a
method for preparing compounds of formula 1, which includes the
steps of treating a ketone of structural formula VI: 13
[0084] with a phosphonate of structural formula 10b: 14
[0085] wherein R'" and R"" each independently is alkyl or aryl and
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and R.sup.9 are as previously defined. In this embodiment,
it is preferred where R.sup.9 is halogen, most preferably F.
[0086] In still another embodiment, the present invention provides
a method for preparing a compound of structural formula 1b: 15
[0087] which includes the step of treating a compound of the
structural formula I: 16
[0088] with sodium azide to form a triazole of formula II: 17
[0089] wherein R" is C.sub.1-C.sub.6 alkyl and R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and R.sup.9
are as previously defined.
[0090] In yet another embodiment, the present invention provides a
method for preparing a compound of structural formula 1a: 18
[0091] which includes the steps of
[0092] (a) treating an arylboronic acid of structural formula I:
19
[0093] with a compound of structural formula XI: 20
[0094] to form a compound of structural formula II: 21
[0095] wherein X is halogen and 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.12, and Y are as
previously defined. In this embodiment, Y is preferably
NR.sup.12.
[0096] Preferred R.sup.1 groups include hydrogen, optionally
substituted C.sub.1-C.sub.3 alkyl, and optionally substituted
C.sub.1-C.sub.3 haloalkyl. Most preferably, R.sup.1 is
hydrogen.
[0097] Preferred R.sup.2 groups include NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, aryl and heteroaryl, wherein the alkyl, haloalkyl,
cycloalkyl, aryl, and heteroaryl groups are optionally substituted.
More preferred R.sup.2 groups include C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, and aryl. Most preferably R.sup.2 is
optionally substituted C.sub.1-C.sub.6 alkyl, such as, for example,
ethyl, iso-propyl, tert-butyl, and tert-amyl.
[0098] Preferred R.sup.3 groups include hydrogen, optionally
substituted C.sub.1-C.sub.6 alkyl, and optionally substituted
C.sub.1-C.sub.6 haloalkyl. Most preferably, R.sup.3 is
hydrogen.
[0099] Preferred R.sup.4 groups include NR.sup.10R.sup.11,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.8
cycloalkyl, aryl and heteroaryl, wherein the alkyl, haloalkyl,
cycloalkyl, aryl, and heteroaryl groups are optionally substituted.
More preferred R.sup.4 groups include C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, and aryl. Most preferably R is
NR.sup.10R.sup.11 or optionally substituted C.sub.1-C.sub.6 alkyl,
such as, for example, iso-propyl, tert-butyl, and tert-amyl.
[0100] Preferred R.sup.5 groups include hydrogen, F, Cl, Br, I, and
optionally substituted C.sub.1-C.sub.4 alkyl. Also preferred are
compounds of formulae I and Ia where R.sup.5 is taken with R.sup.6
to form a five- to six-membered carbocyclic, a five- to
six-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein the carbocyclic, heterocyclic, aryl and heteroaryl
groups are optionally substituted. More preferably R.sup.5 is
optionally substituted C.sub.1-C.sub.4 alkyl or is taken together
with R.sup.6 to form a five- to six-membered carbocyclic, % a five-
to six-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein the carbocyclic, heterocyclic, aryl and heteroaryl
groups are optionally substituted.
[0101] Preferred R.sup.6 groups include hydrogen, F, Cl, Br, I, and
optionally substituted C.sub.1-C.sub.4 alkyl. More preferably,
R.sup.6 is hydrogen or is taken together with R.sup.5 to form a
five- to six-membered carbocyclic, a five- to six-membered
heterocyclic ring, an aryl group or a heteroaryl group, wherein the
carbocyclic, heterocyclic, aryl and heteroaryl groups are
optionally substituted.
[0102] Preferred R.sup.7 groups include C.sub.2-C.sub.5 alkyl and
C.sub.2-C.sub.5 haloalkyl, wherein the alkyl, and haloalkyl groups
are optionally substituted. More preferably R.sup.7 is optionally
substituted C.sub.2-C.sub.5 haloalkyl.
[0103] Preferred R.sup.8 groups include hydrogen, F,
C.sub.1-C.sub.6 alkyl, and C.sub.1-C.sub.6 haloalkyl, wherein the
alkyl and haloalkyl groups are optionally substituted. More
preferably R.sup.8 is hydrogen.
[0104] Preferred R.sup.9 groups include hydrogen and halogen. More
preferably R.sup.9 is hydrogen.
[0105] Preferred R.sup.10 groups include hydrogen and optionally
substituted C.sub.1-C.sub.6 alkyl. Also preferred is R.sup.10 and
R.sup.11 taken with nitrogen to form a five or six membered
heterocyclic ring.
[0106] Preferred R.sup.11 groups include hydrogen and optionally
substituted C.sub.1-C.sub.6 alkyl.
[0107] Preferred Y groups include NR.sup.12, O or S. More
preferably Y is NR.sup.12.
[0108] Preferred R.sup.12 groups include hydrogen and optionally
substituted C.sub.1-C.sub.6 alkyl.
[0109] In one preferred embodiment of the invention, R.sup.1 is
selected from the group of hydrogen, optionally substituted
C.sub.1-C.sub.3 alkyl, and optionally substituted C.sub.1-C.sub.3
haloalkyl; R.sup.3, R.sup.6, and R.sup.8 each independently is
selected from the group of hydrogen, optionally substituted
C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.1-C.sub.6
haloalkyl; R.sup.2 and R.sup.4 each independently is selected from
the group of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.5-C.sub.6 cycloalkyl, aryl, and heteroaryl, wherein said
alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl groups are
optionally substituted; R.sup.5 is optionally substituted
C.sub.1-C.sub.6 alkyl; R.sup.7 is optionally substituted
C.sub.2-C.sub.5 alkyl; and R.sup.9 is hydrogen or halogen.
[0110] In another preferred embodiment of the invention, R.sup.1 is
selected from the group of hydrogen, optionally substituted
C.sub.1-C.sub.3 alkyl, and optionally substituted C.sub.1-C.sub.3
haloalkyl; R.sup.3, R.sup.6, and R.sup.8 each independently is
selected from the group of hydrogen, optionally substituted
C.sub.1-C.sub.6 alkyl, and optionally substituted C.sub.1-C.sub.6
haloalkyl; R.sup.2 and R.sup.4 each independently is selected from
the group of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.5-C.sub.6 cycloalkyl, aryl, and heteroaryl, wherein said
alkyl, haloalkyl, cycloalkyl, aryl and heteroaryl groups are
optionally substituted; R.sup.5 is optionally substituted
C.sub.1-C.sub.6 alkyl; R.sup.7 is optionally substituted
C.sub.2-C.sub.5 haloalkyl; and R.sup.9 is hydrogen or halogen.
[0111] In yet another preferred embodiment of the invention,
R.sup.1, R.sup.3, R.sup.8 and R.sup.9 are hydrogen; R.sup.2 and
R.sup.4 each independently is selected from the group of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, aryl and heteroaryl, wherein the alkyl, haloalkyl,
cycloalkyl, aryl and heteroaryl groups are optionally substituted;
R.sup.5 and R.sup.6 taken together form a five- to six-membered
carbocyclic ring, a five- to six-membered heterocyclic ring, an
aryl group or a heteroaryl group, wherein said carbocyclic ring,
heterocyclic ring, aryl and heteroaryl groups are optionally
substituted; and R.sup.7 is optionally substituted C.sub.2-C.sub.5
alkyl.
[0112] In still another preferred embodiment of the invention,
R.sup.1, R.sup.3, R.sup.8 and R.sup.9 are hydrogen; R.sup.2 and
R.sup.4 each independently is selected from the group of
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.3-C.sub.6
cycloalkyl, aryl and heteroaryl, wherein alkyl, haloalkyl,
cycloalkyl, aryl and heteroaryl; R.sup.5 and R.sup.6 taken together
form a five- to six-membered carbocyclic ring, a five- to
six-membered heterocyclic ring, an aryl group or a heteroaryl
group, wherein said carbocyclic ring, heterocyclic ring, aryl and
heteroaryl groups are optionally substituted; and R.sup.7 is
optionally substituted C.sub.2-C.sub.5 haloalkyl.
[0113] The compounds of formulae 1 and 1a represent a novel group
of compounds. RXR modulator compounds that have insulin sensitizing
activity, but do not substantially suppress the thyroid axis and do
not substantially elevate triglycerides. These compounds are
heterodimer selective modulators of RXR activity. They bind to RXR
with high affinity (K.sub.i<20 nM) and produce potent activation
of the RXR:PPAR.gamma. heterodimer, but preferably do not activate
the RXR:RAR heterodimer. This activation of PPAR.gamma. in vitro is
contemplated to be a major determinant of the antidiabetic efficacy
of the compounds in vivo.
[0114] In a conventional cell-based co-transfection assay, the
compounds of the invention act as partial agonists with respect to
RXR homodimers and, together with PPAR modulators such as BRL,
synergistically activate RXR:PPAR heterodimers. In contrast to
their effect upon RXR:PPAR heterodimers, the compounds of the
present invention do not significantly activate RXR:RAR
heterodimers and in fact exhibit substantial RXR:RAR antagonist
activity. In animal models of diabetes, such as the db/db mouse,
the Sprague-Dawley rat and the ZDF rat, these compounds have been
shown to regulate glucose and triglyceride levels. In contrast to
previously characterized retinoids, these compounds are also
contemplated to be non-teratogenic.
[0115] Applicants have discovered that one feature for achieving
RXR modulator compounds with the desired activity is the length of
the carbon chain at the R.sup.7 position. The preferred length of
the carbon chain at this position is from 2 to 5 carbons. The most
preferred or optimal length of the carbon chain within this range
of 2 to 5 carbons will vary, depending upon the specific
substitutions made at the other positions in Formula 1 or in
Formula 1a. By varying the length of the carbon chain at the
R.sup.7 position, the substituents at R.sup.2 and R.sup.4, and
testing for desired activity, the preferred chain length for any
specific compound within the scope of Formula 1 and 1a can be
determined.
[0116] Table 1 shows a comparison of the activity of compounds of
Formula 1 that are identical except for the length of the carbon
chain at the R.sup.7 position or the presence of an oxygen linking
the R.sup.7 substituent to the ring.
1 TABLE 1 Bind PPAR.gamma. RXR:RXR RXR:RAR db/db mouse RXR.alpha.
CV-1 (%) CV-1 (%) CV-1 (%) Glu. Trigs. Trigs. T4 Compound K.sub.i
(nM) Synergy Ag. Antag. Ag. Antag. (D 14) (D 3) (D 14) (D 3)
LG100268 3 183 73 -- 6 0 73 195 82 43 L1 1.1 166 62 7 21 19 96 300
54 NT L2 13 69 11 62 6 49 91 NC 116 45 L3 1 25 2 90 5 84 75 NC 133
NC L4 1 20 1 92 2 88 50 NC 105 NC L5 0.6 6 0 94 5 68 0 NC NC NT NC
= no change NT = not tested K.sub.i = Determined from IC.sub.50
values by the Cheng-Prussof equation using tritiated LGD1069.
Synergy = Efficacy calculated as the maximal response in presence
of 100 nM BRL49653 (RXR:PPAR.gamma.) relative to maximal response
of BRL49653 alone. Ag. = Efficacy calculated as the maximal
response relative to maximal response of ATRA. Antag. = Efficacy
calculated as the maximal repression (100%) in the presence of 32
nM LGD1069 (RXR:RXR) or 10 nM TTNPB (RXR:RAR). Glu. = Plasma
glucose as a % correction relative to lean values on day 14 of
treatment. Trigs. = Plasma triglycerides as a % correction relative
to lean values on the indicated day of treatment. T4 = Total T4 as
a % of obese control values on day 3 of treatment.
[0117] Table 2 shows an additional comparison of the activity of
compounds of formulae 1 and 1a that have variations of the length
of the carbon chain at the R.sup.7 position, variations of the
substituents at R.sup.2 and R.sup.4 and ring systems incorporated
at R.sup.5 and R.sup.6 taken together. Increased levels of
triglycerides measured using the db/db mouse model were found not
to correlate to increased triglyceride levels measured in the
accepted Sprague-Dawley rat model. Data for Sprague-Dawley rats
were included in Table 2 to indicate the profile of selected
compounds of the invention in an accepted model for triglyceride
measurements.
2TABLE 2 Bind PPAR.gamma. RXR:RAR RXR:RAR db/db mouse SD rat
RXR.alpha. CV-1 (%) CV-1 (%) CV-1 (%) Glu. Trigs. Trigs. Compound
K.sub.i (nM) Synergy Ag. Antag. Ag. (D7) (D3) (H2) LG100268 3 183
73 -- 6 73 195 225 L13 3 54 4 84 1 54 109 NC L14 5 135 3 80 2 45
138 NC L15 6 99 44 39 1 80 156 NT L16 2 64 1 93 2 37 79 NT L17 8 88
3 76 4 29 75 NT L18 29 69 2 90 1 45 134 NC L19 1 47 3 90 2 68 187
NC L23 27 38 1 93 7 53 NT NC NC = no change NT = not tested K.sub.i
= Determined from IC50 values by the Cheng-Prussof equation using
tritiated LGD1069. Synergy = Efficacy calculated as the maximal
response in presence of 100 nM BRL49653 (RXR:PPAR.gamma.) relative
to maximal response of BRL49653 alone. Ag. = Efficacy calculated as
the maximal response relative to maximal response of ATRA. Antag. =
Efficacy calculated as the maximal repression (100%) in the
presence of 32 nM LGD1069 (RXR:RXR) or 10 nM TTNPB (RXR:RAR). Glu.
= Plasma glucose as a % correction relative to lean values on day 7
of treatment with 30 mg/kg/day using db/db mouse study. db/db mouse
Trigs. = Plasma triglycerides as a % of control values on day 3 of
treatment with 30 mg/kg/day using db/db mouse study. SD rat Trigs.
= Plasma triglycerides as a % of control values at hour 2 of
treatment using Sprague Dawley rat study. 22 23 24 25 26 27 28 29
30 31 32 33 34 35
[0118] The rexinoids depicted above where R.sup.7 is less than 2
carbons in length and/or do not have an oxygen linking the R.sup.7
substituent to the ring (LG100268 and L1) are full RXR homodimer
agonists. These compounds are efficacious insulin sensitizers in
rodent models of Type II Diabetes, but they also raise
triglycerides and suppress the thyroid hormone axis in these
animals. On the other hand, a rexinoid such as L5, depicted above,
where R.sup.7 is greater than 5 carbons is a full antagonist and
has no effect on glucose, triglycerides or thyroid status in these
same model systems. The activity of the compounds is dependent on
the chain length of R.sup.7 and on the identity of R.sup.1,
R.sup.2, R.sup.3, and R.sup.4, all of which can be substituted to
affect the behavior of the rexinoid.
[0119] Those compounds that have a carbon chain length at the
R.sup.7 position and appropriate substituents at R.sup.1, R.sup.2,
R.sup.3, and R.sup.4 within the scope of the present invention
maintain the desirable insulin sensitizing activity and eliminate
or reduce both the suppression of the thyroid axis and triglyceride
elevations (e.g., L3, L4, L6, L7). These compounds are heterodimer
selective modulators of RXR activity. They bind to RXR with high
affinity (K.sub.i<20 nM) and produce potent activation of the
RXR:PPAR.gamma. heterodimer. Among these compounds, L3 and L4,
having a chain length of 3 and 4 carbons, respectively, can be
identified as the more preferred embodiments in this group based on
the absence of detectable suppression of the thyroid hormone
axis.
[0120] To minimize the undesirable increases in triglyceride levels
and suppression of thyroid hormone axis, the modulators must not
significantly activate the RXR:RAR heterodimer and must have
substantial RXR:RAR antagonist activity. This requirement is
clearly demonstrated by the two related compounds L2 and L3. The
striking in vitro characteristic for these two compounds is that L3
has approximately twice the RXR:RAR antagonist activity as L2; this
correlates with the distinction in vivo where L2 suppresses thyroid
hormone axis while L3 does not.
[0121] When administered to obese, insulin resistant db/db mice
(100 mg/kg by daily oral gavage for 14 days) these heterodimer
selective RXR modulators lower both plasma glucose and triglyceride
levels. However, unlike either full agonists (e.g., LG100268, L1)
or partial agonists that exhibit less than 50% activity at the
RXR:RAR heterodimer (e.g., L2), they do not substantially suppress
total circulating levels of T4, or substantially increase
triglyceride levels.
[0122] When administered to transgenic mice carrying the human apo
A-I gene all of these compounds increase HDL cholesterol, but both
LG100268 and L1 also raise triglycerides. Among the modulators that
do not significantly activate the RAR:RXR heterodimer are those
which do not raise triglyceride levels in the transgenic mouse
model, consistent with their heterodimer selectivity. This effect
is consistent with activation of PPAR.alpha., and, in fact, in vivo
these compounds synergize with the weak PPAR(X agonist
fenofibrate.
[0123] The compounds of the present invention possess particular
application as RXR modulators and in particular as dimer-selective
RXR modulators including, but not limited to, RXR homodimer
antagonists, and agonists, partial agonists and antagonists of RXRs
in the context of a heterodimer.
[0124] In a second aspect, the present invention provides a method
of modulating processes mediated by RXR homodimers and/or RXR
heterodimers comprising administering to a patient an effective
amount of a compound of the invention as set forth above. The
compounds of the present invention also include all
pharmaceutically acceptable salts, as well as esters and amides. As
used in this disclosure, pharmaceutically acceptable salts include,
but are not limited to: pyridine, ammonium, piperazine,
diethylamine, nicotinamide, formic, urea, sodium, potassium,
calcium, magnesium, zinc, lithium, cinnamic, methylamino,
methanesulfonic, picric, tartaric, triethylamino, dimethylamino,
and tris(hydoxymethyl) aminomethane. Additional pharmaceutically
acceptable salts are known to those skilled in the art.
[0125] The compounds of the present invention are useful in the
modulation of transcriptional activity through RXR in the context
of heterodimers other than RXR:RAR.alpha.,.beta.,.gamma. (e.g.,
RXR:PPAR.alpha.,.beta.,.g- amma.; RXR:TR; RXR:VDR; RXR:NGFIB;
RXR:NURR1; RXR:LXR.alpha.,.beta., RXR:DAX), including any other
intracellular receptors (IRs) that form a heterodimer with RXR. For
example, application of the compounds of the present invention to
modulate a RXR.alpha.:PPAR.alpha. heterodimer is useful to
modulate, i.e. increase, HDL cholesterol levels and reduce
triglyceride levels. Yet, application of many of the same compounds
of the present invention to a RXR.alpha.:PPAR.gamma. heterodimer
modulates a distinct activity, i.e., modulation of adipocyte
biology, including effects on the differentiation and apoptosis of
adipocytes, which will have implications in the treatment and/or
prevention of diabetes and obesity. In addition, use of the
modulator compounds of the present invention with activators of the
other heterodimer partner (e.g., fibrates for PPAR.alpha. and
thiazolidinediones for PPAR.gamma.) can lead to a synergistic
enhancement of the desired response. Likewise, application of the
modulator compounds of the present invention in the context of a
RXR.alpha.:VDR heterodimer will be useful to modulate skin related
processes (e.g., photoaging, acne, psoriasis), malignant and
pre-malignant conditions and programmed cell death (apoptosis).
Further, it will be understood by those skilled in the art that the
modulator compounds of the present invention will also prove useful
in the modulation of other heteromer interactions that include RXR,
e.g., trimers, tetramers and the like.
[0126] In the context of an RXR homodimer, the compounds of the
present invention function as partial agonists. Further, when the
modulator compounds of the present invention are combined with a
corresponding modulator of the other heterodimeric partner, a
surprising synergistic enhancement of the activation of the
heterodimer pathway can occur. For example, with respect to a
RXR.alpha.:PPAR.alpha. heterodimer, the combination of a compound
of the present invention with clofibric acid or gemfibrozil
unexpectedly leads to a greater than additive (i.e. synergistic)
activation of PPAR.alpha. responsive genes, which in turn is useful
to modulate serum cholesterol and triglyceride levels and other
conditions associated with lipid metabolism.
[0127] Whether acting on an RXR heterodimer pathway, or the RXR
homodimer pathway, it will also be understood by those skilled in
the art that the dimer-selective RXR modulator compounds of the
present invention will prove useful in any therapy in which
agonists, partial agonists and/or full antagonists of such pathways
will find application. Importantly, because the compounds of the
present invention can differentially activate RXR homodimers and
RXR heterodimers, their effects will be tissue and/or cell type
specific, depending upon the cellular context of the different
tissue types in a given patient. For example, compounds of the
present invention will exert an RXR antagonist effect in tissues
where RXR homodimers prevail, and partial agonist or full agonist
activity on the PPAR pathway where RXR.alpha.:PPAR.alpha.
heterodimers prevail (e.g., in liver tissue). Thus, the compounds
of the present invention will exert a differental effect in various
tissues in an analogous fashion to the manner in which various
classes of estrogens and antiestrogens (e.g., Estrogen, Tamoxifen,
Raloxifen) exert differential effects in different tissue and/or
cell types (e.g., bone, breast, uterus). See e.g., M. T. Tzukerhan
et al., Mol. Endo, 8:21-30 (1994); D. P. McDonnell et al., Mol.
Endo., 9:659-669 (1995). However, in the present case, it is
believed that the differential effects of the compounds of the
present invention are based upon the particular dimer pair through
which the compound acts, rather than through different
transactiving regions of the estrogen receptor in the case of
estrogens and antiestrogens. However, it is possible that they also
function, in part, by tissue selectivity.
[0128] The particular conditions that may be treated with the
compounds of the present invention include, but are not limited to,
skin-related diseases, such as actinic keratoses, arsenic
keratoses, inflammatory and non-inflammatory acne, psoriasis,
ichthyoses and other keratinization and hyperproliferative
disorders of the skin, eczema, atopic dermatitis, Darriers disease,
lichen planus, prevention and reversal of glucocorticoid damage
(steroid atrophy), as a topical anti-microbial, as skin
pigmentation agents and to treat and reverse the effects of age and
photo damage to the skin. With respect to the modulation of
malignant and pre-malignant conditions, the compounds may also
prove useful for the prevention and treatment of cancerous and
pre-cancerous conditions, including, premalignant and malignant
hyperproliferative diseases and cancers of epithelial origin such
as cancers of the breast, skin, prostate, cervix, uterus, colon,
bladder, esophagus, stomach, lung, larynx, oral cavity, blood and
lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias
and papillomas of the mucous membranes and in the treatment of
Kaposis sarcoma. In addition, the present compounds may be used as
agents to treat and prevent various cardiovascular diseases,
including, without limitation, diseases associated with lipid
metabolism such as dyslipidemias, prevention of restenosis and as
an agent to increase the level of circulating tissue plasminogen
activator (TPA), metabolic diseases such as obesity and diabetes
(i.e., non-insulin dependent diabetes mellitus and insulin
dependent diabetes mellitus), the modulation of differentiation and
proliferation disorders, as well as the prevention and treatment of
neurodegenerative diseases such as Alzheimer's disease, Parkinson's
disease and Amyotrophic Lateral Sclerosis (ALS), and in the
modulation of apoptosis, including both the induction of apoptosis
and inhibition of T-Cell activated apoptosis.
[0129] The RXR modulator compounds, their pharmaceutically
acceptable salts or hydrolyzable esters of the present invention
may be combined with a pharmaceutically acceptable carrier to
provide pharmaceutical compositions useful for treating the
biological conditions or disorders noted herein in mammalian
species, and more preferably, in humans. The particular carrier
employed in these pharmaceutical compositions may vary depending
upon the type of administration desired (e.g. intravenous, oral,
topical, suppository, or parenteral).
[0130] In preparing the compositions in oral liquid dosage forms
(e.g. suspensions, elixirs and solutions), typical pharmaceutical
media, such as water, glycols, oils, alcohols, flavoring agents,
preservatives, coloring agents and the like can be employed.
Similarly, when preparing oral solid dosage forms (e.g. powders,
tablets and capsules), carriers such as starches, sugars, diluents,
granulating agents, lubricants, binders, disintegrating agents and
the like can be employed.
[0131] For parenteral administration, the carrier will typically
comprise sterile water, although other ingredients that aid
solubility or serve as preservatives can also be included.
Furthermore, injectable suspensions can also be prepared, in which
case appropriate liquid carriers, suspending agents and the like
can be employed.
[0132] For topical administration, the compounds of the present
invention can be formulated using bland, moisturizing bases such as
ointments or creams.
[0133] The pharmaceutical compositions and compounds of the present
invention can generally be administered in the form of a dosage
unit (e.g. tablet, capsule, etc.) in an amount from about 1
.mu.g/kg of body weight to about 1 g/kg of body weight, preferably
from about 5 .mu.g/kg of body weight to about 500 mg/kg of body
weight, more preferably from about 10 .mu.g/kg of body weight to
about 250 mg/kg of body weight, most preferably from about 20
.mu.g/kg of body weight to about 100 mg/kg of body weight. Those
skilled in the art will recognize that the particular quantity of
pharmaceutical composition and/or compounds of the present
invention administered to an individual will depend upon a number
of factors including, without limitation, the biological effect
desired, the condition of the individual and the individual's
tolerance for the compound.
[0134] Furthermore, it will be understood by those skilled in the
art that the compounds of the present invention, including
pharmaceutical compositions and formulations containing these
compounds, can be used in a wide variety of combination therapies
to treat the conditions and diseases described above. Thus, the
compounds of the present invention can be used in combination with
modulators of the other heterodimeric partner with RXR (i.e., in
combination with PPAR.alpha. modulators, such as fibrates, in the
treatment of cardiovascular disease, and in combination with
PPAR.gamma. modulators, such thiazolidinediones, in the treatment
of diabetes, including non-insulin dependent diabetes mellitus and
insulin dependent diabetes mellitus, and with agents used to treat
obesity) and with other therapies, including, without limitation,
chemotherapeutic agents such as cytostatic and cytotoxic agents,
immunological modifiers such as interferons, interleukins, growth
hormones and other cytokines, hormone therapies, surgery and
radiation therapy.
[0135] By utilizing the compounds of the present invention with
modulators of the other heterodimeric partner one is able to
utilize lower dosages of either or both modulators, thereby leading
to a significant decrease in the side-effects associated with such
modulators when employed alone at the strengths required to achieve
the desired effect. Thus, the modulator compounds of the present
invention, when utilized in combination therapies, provide an
enhanced therapeutic index (i.e., significantly enhanced efficacy
and/or decrease side-effect profiles) over utilization of the
compounds by themselves.
[0136] Representative modulator compounds of the present invention
include, without limitation those depicted below.
363738394041424344454647484950515253545556575859
[0137] The compounds of the present invention can be obtained by
modification of the compounds disclosed herein or by a total
synthesis approach using techniques known to those skilled in the
art. In this regard, the synthesis of the dimer-specific RXR
modulator compounds of the present invention follow established
retinoid synthesis schemes and techniques as described in U.S. Pat.
Nos. 4,326,055 and 4,578,498, the disclosures of which are herein
incorporated by reference. See also, M. I. Dawson and W. H.
Okamura, "Chemistry and Biology of Synthetic Retinoids", Chapters
3, 8, 14 and 16, CRC Press, Inc., Florida (1990); M. I. Dawson and
P. D. Hobbs, The Synthetic Chemistry of Retinoids, In Chapter 2:
"The Retinoids, Biology, Chemistry and Medicine", M. B. Sporn et
al., eds. (2nd ed.), Raven Press, New York, N.Y., pp. 5-178 (1994);
R. S. H. Liu and A. E. Asato, "Photochemistry and Synthesis of
Stereoisomers of Vitamin A," Tetrahedron, 40:1931 (1984); Cancer
Res., 43:5268 (1983); Eur. J. Med. Chem., 15:9 (1980); M. Boehm et
al., J. Med. Chem., 37:2930 (1994); M. Boehm et al., J. Med. Chem.,
38:3146 (1995); E. Allegretto et al., J. Biol. Chem., 270:23906
(1995); R. Bissonette et al., Mol. & Cellular Bio., 15:5576
(1995); R. Beard et al., J. Med. Chem., 38:2820 (1995); S.
Canan-Koch et al., J. Med. Chem., 39:3229 (1996); WO 97/12853.
Novel Method of Synthesis
[0138] In addition to the synthetic techniques available in the
prior art, the present invention further provides an improved
method for making the claimed compounds, as well as structurally
related RXR modulators, that efficiently and stereospecifically
introduces the desired triene moiety with the correct olefin
geometry. Scheme 1 describes a general method for producing RXR
modulators of the present invention via a coumarin intermediate
which is then ring opened to a diol and then further modified to
the desired compounds. The new synthetic route is versatile, and
can be adapted to the synthesis of an entire class of molecules
with the appropriate variations.
[0139] The key sequence of reactions in this synthetic route
involves utilizing an existing arylalcohol group as a functional
handle to annulate a lactone ring on to the existing aromatic ring,
forming a coumarin. The coumarin, by virtue of its cyclic
structure, necessarily locks the olefin geometry as cis. The
cis-geometry established in this step is then preserved throughout
the remainder of the synthesis, yielding compounds of high isomeric
purity without the need for isomerization of or discarding of the
undesired isomers. Access to coumarin intermediates of the type
required for construction of this important class of RXR modulators
(e.g., Structure 4) can be achieved through either of two distinct
strategies.
[0140] A coumarin such as 4 can be formed directly from an
arylalcohol such as 2 through a von Pechmann or related cyclization
reaction with a .beta.-keto ester such as 3. Alternately, the
coumarin may be introduced from an ortho-hydroxyacetophenone such
as 5 by condensation with a stabilized phosphorous ylide as shown
in Structure 6. For further reference see, S. Sethna and R. Phadke,
Organic Reactions, 7:1-58 (1953); H. J. Bestmann, et al., Angew.
Chem. Int. Ed. Engl. 15(2):115-116 (1976).
[0141] After this cyclization step to form a coumarin such as 4,
the lactone ring of the coumarin is then reductively opened to form
a diol as shown in Structure 7. The diol then undergoes selective
alkylation at the arylalcohol oxygen and mild oxidation of the
allylic alcohol to the corresponding aldehyde (e.g., Structure 9).
The synthesis is then completed by a standard Homer-Emmons/ester
hydrolysis protocol. For further reference see, WO 97/12853, S.
Canan-Koch et al., J. Med. Chem. 39:3229-34 (1996). 60
[0142] Scheme 2 provides an example of the first method for
producing a desired RXR modulator of the present invention.
Beginning with a previously described tetramethyltetrahydronaphthol
(e.g., Structure 2), a classical von Pechmann cyclization strategy
using ethyl acetoacetate in 75% aqueous H.sub.2SO.sub.4 is used to
regioselectively generate the 4-methylcoumarin ring system such as
4 in one step, setting the olefin geometry of the target compound.
For further reference see, S. Canan-Koch et al., J. Med. Chem. 39:
3229-3234 (1996)); S. Sethna and R. Phadke, Organic Reactions,
7:1-58 (1953). Reductive ring opening of the lactone ring in 4 with
LiAlH.sub.4 cleanly provides a diol such as 7. Selective alkylation
of the phenol oxygen under extremely mild conditions is achieved
using excess cesium fluoride and stoichiometric 1-iodopropane in
DMF yields a primary allylic alcohol such as Structure 8. For
further reference see, T. Sato and J. Otera, Syn. Lett., 336
(1995); J. H. Clark and J. M. Miller, Tetrahedron Lett., 18:599
(1977). Oxidation to an aldehyde such as 9 is accomplished with
TPAP and NMO in CH.sub.2Cl.sub.2 (S. V. Ley et al., Synthesis, 639
(1994)). Homer-Wadsworth-Emmons olefination of 9 a with phosphonate
such as 10 provides the remainder of the triene chain (See, B. E.
Maryanoff and A. B. Reitz, Chem. Rev., 89:863 (1989)). Phosphonate
10 may be subjected to saponification with KOH in methanol to
reveal the free acid target compound 1. 61
[0143] Certain related molecules in this series of RXR modulators
(e.g., See, WO 97/12853) that contain branched alkyl-substituted
phenyl moieties in place of the tetramethyltetrahydronaphthyl group
of 1 proved incompatible with the strongly acidic conditions
employed in the von Pechmann cyclization step. Unwanted alkyl
migrations occurred under these reaction conditions. Milder
alternative routes to the coumarin intermediates were explored
using the present substrate as a model. It was reasoned that
construction of the lactone ring under neutral conditions would
circumvent these undesired side reactions. Recently published
routes to coumarins involving montmorillonite clays (e.g., See,
T.-S. Li et al. J. Chem. Res., 38 (1998); G. K. Biswas et al.,
Indian J. Chem., 31B:628 (1992)) or Pd-catalyzed reaction of
unsaturated esters (e.g., See B. M. Trost and F. D. Toste, J. Am.
Chem. Soc., 118:6305 (1996); M. Catellani et al., Tetrahedron
Lett., 35:5923 (1994)) generally required highly electron-rich
aryls for efficient C--C bond formation to close the coumarin ring.
Therefore, a potentially more generally applicable stabilized ylide
approach was investigated. For further reference see, H. J.
Bestmann et al., Angew. Chem. Int. Ed. Eng., 15(2):115 (1976).
[0144] As shown in Scheme 3, treatment of hydroxyacetophenone 5,
which is prepared by acylation/Fries rearrangement of arylalcohol
2, with excess carbethoxymethylenetriphenylphosphorane in refluxing
toluene cleanly produces coumarin 4. See, e.g., K. Fries and G.
Fink, Ber., 41:4271 (1908); K. Fries and W. Pfaffendorf, Ber.,
43:212 (1910); A. H. Blatt, Org. React., 1:342 (1942). This
compound is identical in every respect to the compound obtained by
the von Pechmann cyclization route. Given the ready availability of
acetophenones and related precursors with varied alkyl
substitution, this two-step approach to the key coumarin
intermediate complements the von Pechmann cyclization method.
62
[0145] LG100754, Compound 1 of Scheme 2, was synthesized in six
steps in 61% overall yield from tetrahydronaphthol 2, with
stereospecific introduction of the 6-cis-olefin through a coumarin
intermediate. Employing the alternate synthetic route of Scheme 3,
Compound 1 of Scheme 2 was prepared in seven steps, 66% overall
yield via the stabilized ylide variation of Scheme 3. All of the
reactions in this synthesis are amenable to multigram scale
execution without significant loss of yield or stereochemical
purity, and intermediates require minimal purification.
[0146] Scheme 4 describes a third method for preparation of the
coumarin intermediates described by general Structure 4. The method
involves conversion of a haloarylalcohol such as 11 to its
corresponding arylboronic acid or arylboronate e.g., Structure 13
under Pd-catalysis in DMF. Subsequent Suzuki coupling of the
resultant arylboronic acid or arylboronate with an ethyl
cis-3-halocrotonate represented by Structure 15 produces coumarin
intermediate 4. Concomitant cyclization to the corresponding
coumarin ensues under the basic hydrolytic conditions employed for
the Suzuki coupling chemistry (2 M K.sub.2CO.sub.3).
[0147] In a variant of the above described synthetic scheme, Suzuki
coupling of the same ethyl cis-3-halocrotonate (15) fragment to a
2-alkoxyarylboronate 14 results in Z-ester 16. Alkoxyarylboranate
14 is prepared by alkylation of a 2-haloarylalcohol such as 11 to a
2-alkoxyaryhalide 12 prior to conversion to the arylboronic acid or
arylboronate 14. Z-ester 16 may then be treated with LiAlH.sub.4 to
intercept the coumarin based routes at the stage of allylic alcohol
63
[0148] The concept of using a coumarin intermediate to set the key
cis-olefin geometry of an important new class of RXR modulating
drugs constitutes an efficient general synthetic route, of which
several variations are demonstrated herein.
EXAMPLES
Experimental Section
[0149] General Experimental Chemical Procedures. Proton nuclear
magnetic resonance (.sup.1H NMR) spectra were recorded on a Bruker
AC 400 or a Varian VXR 500 S spectrometer. Chemical shifts are
given in parts per million (ppm) downfield from internal reference
tetramethylsilane in 6-units, and coupling constants (J-values) are
given in hertz (Hz). Selected data are reported in the following
manner: chemical shift, multiplicity, and coupling constants.
Melting points were taken on an Electrothermal IA9100 Digital
apparatus and are uncorrected., "Brine" refers to a saturated
aqueous solution of NaCl. Unless otherwise specified, solutions of
common inorganic salts used in work-ups are aqueous solutions. All
moisture sensitive reactions were carried out using oven-dried or
flame-dried round-bottomed (r.b.) flasks and glassware under an
atmosphere of dry nitrogen.
[0150] General Procedure A: von Pechmann Cyclization/Coumarin
Intermediate Method for Synthesis of RXR Modulators.
[0151]
(2E,4E,6Z)-7-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy-
)-naphthalen-3-yl]-3-methylocta-2,4,6-trienoic Acid (LG100754,
Structure 1 of Schemes 1 and 2, where R.sup.1, R.sup.4, R.sup.6,
R.sup.8=H, R.sup.2 and R.sup.3 Together Form a Tetramethyl
Saturated Six-Membered Carbocyclic Ring, R.sup.5=methyl,
R.sup.7=n-propyl).
[0152] 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (Structure
2 of Schemes 1 and 2, where R.sup.1, R.sup.4=H, R.sup.2 and R.sup.3
together form a tetramethyl saturated six-membered carbocyclic
ring). This compound was prepared as previously described (S. S.
Canan-Koch et al., J. Med. Chem. 39: 3229-34 (1996)): mp
146-149.degree. C. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.17 (d, 1H,
J=8.5 Hz), 6.75 (d, 1H, J=2.8 Hz), 6.62 (dd, 1H, J=8.5, 2.8 Hz),
4.49 (s, 1H), 1.66 (s, 4H), 1.25 and 1.24 (2s, 2.times.3H).
.sup.13C NMR (100 MHz, CDCl.sub.3) 153.0, 146.6, 137.3, 127.7,
113.1, 112.7, 35.2, 35.1, 34.4, 33.7, 32.0, 31.8. IR (thin film)
3143 (br, s), 2917 (m), 1455 (m). Anal. Calcd for
C.sub.14H.sub.20O: C, 82.30; H, 9.87. Found: C, 82.25; H.
10.07.
[0153] 1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin
(Structure 4 of Schemes 1 and 2, Where R.sup.1, R.sup.4, R.sup.6=H,
R.sup.2 and R.sup.3 together form a tetramethyl saturated
six-membered carbocyclic ring, R.sup.5=methyl). To a flame-dried
50-mL r.b. flask containing
5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (2.03 g, 9.94
mmol) in 4 mL 75% H.sub.2SO.sub.4 was added ethyl acetoacetate
(Structure 3 of Scheme 1, where R.sup.5=methyl, R=H, R'=ethyl)
(3.19 mL, 25.0 mmol, 2.52 equiv), and the mixture was heated to
100.degree. C. for 3 h. Upon cooling to room temperature, the
mixture was poured over ice (50 g), diluted with saturated
NaHCO.sub.3 (50 mL), and stirred for 30 mm. The mixture was then
extracted with EtOAc (3.times.50 mL) and the organic layer was
washed with brine (50 mL), dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure. The crude product mixture was
purified by flash column chromatography (silica gel, hexanes/EtOAc,
4:1) to remove residual ethyl acetoacetate, providing the desired
coumarin as a white solid (R.sub.f 0.62, hexanes/EtOAc, 2:1).
Recrystallization from hexanes/EtOAc afforded 2.12 g (79%) of
1,2,3,4-tetrahydro-1,1,4,4,6-penta- methylbenzo[5,6-g]coumarin as
white prisms (mp 126-128.degree. C.). .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.51 (s, 1H), 7.25 (s, 1H), 6.20 (d, 1H, J=0.8 Hz),
2.43 (d, 3H, J=0.9 Hz), 1.72 (s, 4H), 1.33 and 1.31 (2s,
2.times.3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 161.2, 152.2,
151.4, 150.4, 141.5, 122.2, 117.9, 114.3, 107.1, 34.92, 34.84,
34.58, 34.20: 32.22, 31.83, 18.49. IR (thin film) 2923 (m), 1716
(s), 1612 (m). Anal. Calcd for C.sub.18H.sub.22O.sub.2: C, 79.96;
H, 8.20. Found: C, 80.06; H, 8.06.
[0154]
(2Z)-3-(4-Hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hylnaphth-2-ol (Structure 7 of Schemes 1 and 2, where R.sup.1,
R.sup.4, R.sup.6=H, R.sup.2 and R.sup.3 together form a tetramethyl
saturated six-membered carbocyclic ring, R.sup.5=methyl). To a
flame-dried 100-mL r.b. flask containing
1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g- ]coumarin (564
mg, 2.09 mmol) in 30 mL Et.sub.2O at 0.degree. C. was added
LiAlH.sub.4 (79.0 mg, 2.08 mmol, 1.00 equiv), and the mixture was
stirred and allowed to gradually warm to room temperature over 2 h.
The mixture was then cooled to 0.degree. C. before the cautious
addition of 1.0M NaHSO.sub.4 (10 mL). The mixture was extracted
with EtOAc (30 mL) and the organic layer was washed with brine (50
mL), dried (Na.sub.2SO.sub.4), and concentrated under reduced
pressure to afford 568 mg (99%) of
(2Z)-3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnap-
hth-2-ol as a white solid (mp 144-145.degree. C.). .sup.1H NMR (400
MHz, CDCl.sub.3) 6.92 (s, 1H), 6.82 (s, 1H), 5.92 (t, 1H, J=7.4
Hz), 3.96 (d, 2H, J=7.4 Hz), 2.05 (s, 3H), 1.66 (s, 4H), 1.26 and
1.23 (2s, 2.times.3H). .sup.13C NMR (100 MHz, CDCl.sub.3) 149.4,
145.8, 137.3, 137.2, 127.4, 126.6, 124.8, 113.3, 60.4, 35.2, 35.1,
34.2, 33.6, 32.0, 31.8, 25.6. IR (thin film) 3147 (br, m), 2919
(m), 1218 (s). Anal. Calcd for C.sub.18H.sub.26O.sub.2: C, 78.79;
H, 9.55. Found: C, 78.71; H, 9.71.
[0155]
(2Z)-3-(4-Hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramet-
hyl-2-(n-propyloxy)naphthalene (Structure 8 of Schemes 1 and 2,
where R.sup.1, R.sup.4, R.sup.6=H, R.sup.2 and R.sup.3 together
form a tetramethyl saturated six-membered carbocyclic ring,
R.sup.5=methyl, R.sup.7=n-propyl). To a flame-dried 25-mL r.b.
flask containing
3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-
-ol (133 mg, 0.48 mmol) in 2 mL anhydrous DMF at room temperature
was added cesium fluoride (365 mg, 2.40 mmol, 5.00 equiv) and
l-iodopropane (52.0 .mu.L, 0.53 mmol, 1.10 equiv), and the mixture
was stirred for 12 h. The reaction mixture was then diluted with
EtOAc (20 mL) and the resultant organic layer was washed with water
(2.times.10 mL), brine (10 mL), dried (Na.sub.2SO.sub.4), and
concentrated under reduced pressure to afford 150 mg (99%) of
(2Z)-3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-
-5,5,8,8-tetramethyl-2-(n-propyloxy) naphthalene as a colorless
viscous oil. .sup.1H NMR (400 MHz, CDCl.sub.3) 6.91 (s, 1H), 6.77
(s, 1H), 5.78 (dt, 1H, J=6.6, 1.4 Hz), 3.88 (m, 4H), 2.04 (s, 3H),
1.75 (m, 2H), 1.28 and 1.23 (2s, 2.times.3H), 1.01 (t, 3H, J=7.5
Hz). .sup.13C NMR (100 MHz, CDCl.sub.3) 153.3, 144.9, 138.4, 137.0,
127.7, 126.5, 110.1, 70.3, 60.7, 35.2, 35.1, 34.4, 33.6, 31.9,
31.8, 25.1, 22.8, 10.7. IR (thin film) 3336 (br, s), 2919 (s), 1498
(m), 1455 (m). Anal. Calcd for C.sub.21H.sub.32O.sub.2: C, 79.70;
H. 10.19. Found: C, 79.60; H, 10.44.
[0156]
(2Z)-3-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)napht-
halen-3-yl]-but-2-en-1-al (Structure 9 of Schemes 1 and 2, where
R.sup.1, R.sup.4 R.sup.6=H, R.sup.2 and R.sup.3 together form a
tetramethyl saturated six-membered carbocyclic rind,
R.sup.5=methyl, R.sup.7=n-propyl). To an oven-dried 10-mL r.b.
flask containing
(2Z)-3-(4-hydroxy-2-buten-2-yl)-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2--
(n-propyloxy)naphthalene (25.0 mg, 0.08 mmol) and
N-methylmorpholine N-oxide (NMO, 14 mg, 0.12 mmol, 1.5 equiv) in
0.5 mL CH.sub.2Cl.sub.2 at 0.degree. C. was added
tetra-n-propylammonium perruthenate (TPAP, 1.3 mg, 5 mol %), and
the mixture was allowed to warm to room temperature. After 1 h at
room temperature, the reaction mixture was filtered through a pad
of silica gel, washing with an additional 50 mL CH.sub.2Cl.sub.2.
The solvent was then removed under reduced pressure to afford 25 mg
(99%) of
(2Z)-3-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy)naphthalen--
3-yl]-but-2-en-1-al as a colorless low-melting solid. The aldehyde
thus obtained was of greater than 98% purity as judged by the
.sup.1H NMR spectrum, and was used directly in the next step
without further purification. .sup.1H NMR (400 MHz, CDCl.sub.3)
9.36 (d, 1H, J=8.1 Hz), 6.99 (s, 1H), 6.79 (s, 1H), 6.09 (dd, 1H,
J=8.4, 1.1 Hz), 3.90 (t, 2H, J=6.4 Hz), 2.29 (d, 3H, J=1.1 Hz),
1.76 (m, 2H), 1.68 (d, 4H, J=1.6 Hz), 1.30 and 1.23 (2s,
2.times.3H) 1.00 (t, 3H, J=7.5 Hz). .sup.13C NMR (100 MHz,
CDCl.sub.3) 194.0, 161.7, 153.3, 146.9, 136.6, 129.7, 128.6, 125.3,
109.5, 69.7, 35.1, 35.0, 34.6, 33.6, 31.9, 31.8, 25.9, 22.6, 10.7.
IR (thin film) 2922 (br, m), 1674 (s), 1202 (s), 1147 (s).
[0157]
(2E,4E,6Z)-7-[5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-(n-propyloxy-
)-naphthalen-3-yl]-3-methylocta-2,4,6-trienoic acid (LG100754,
Structure 1 of Schemes 1 and 2, where R.sup.1, R.sup.4, R.sup.6,
R.sup.8=H, R.sup.2 and R.sup.3 together form a tetramethyl
saturated six-membered carbocyclic ring, R.sup.5=methyl,
R.sup.7=n-propyl). This compound was prepared from
(2Z)-3-[5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-(n-propylo-
xy)naphthalen-3-yl]-but-2-en-1-al as previously described (S. S.
Canan-Koch et al., J. Med. Chem. 39: 322-934 (1996)). The .sup.1H
NMR spectral data, TLC elution properties, and melting point of
this product thus obtained matched those previously reported.
[0158] General Procedure B: Stabilized Ylide Procedure for
Preparation of a Coumarin Intermediate of General Structure 4.
[0159] 1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin
(Structure 4 of Schemes 1 and 3, Where R.sup.1, R.sup.4, R.sup.6=H,
R.sup.2 and R.sup.3 Together Form a Tetramethyl Saturated
Six-Membered Carbocyclic Ring, R.sup.5=methyl).
[0160] 3-Acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol
(Structure 5 of Schemes 1 and 3, where R.sup.1, R.sup.4=H, R.sup.2
and R.sup.3 together form a tetramethyl saturated six-membered
carbocyclic ring, R.sup.5=methyl). This compound was prepared as
previously described (S. S. Canan-Koch et al., J. Med. Chem. 39:
3229-34 (1996)): mp 101-103.degree. C. .sup.1H NMR (400 MHz,
CDCl.sub.3) 11.65 (folded over s, 1H), 7.65 (s, 1H), 6.90 (s, 1H),
2.61 (s, 3H), 1.68 (s, 4H), 1.29 and 1.27 (2s, 2.times.3H).
.sup.13C NMR (100 MHz, CDCl.sub.3) 203.9, 159.5, 136.2, 128.7,
118.3, 115.4, 107.1, 35.1, 34.9, 34.6, 33.7, 32.2, 31.6, 26.4. IR
(thin film) 2923 (m), 1654 (s), 1459 (m). Anal. Calcd for
C.sub.16H.sub.22O: C, 78.01; H, 9.00. Found: C, 78.28; H, 9.09.
[0161] 1,2,3,4-Tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin
(Structure 4 of Schemes 1 and 3, where R.sup.1, R.sup.4, R.sup.6=H,
R.sup.2 and R.sup.3 together form a tetramethyl saturated
six-membered carbocyclic ring, R.sup.5=methyl). To a flame-dried
50-mL r.b. flask containing
3-acetyl-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphth-2-ol (1.579
g, 6.41 mmol) in 10 mL toluene was added carbethoxymethylenetriphe-
nylphosphorane (Structure 6 of Scheme 1, where R.sup.6=H, R"=ethyl)
(3.35 g, 9.62 mmol, 1.50 equiv), and the mixture was heated to
reflux for 24 h. Upon cooling to room temperature, the solvent was
removed under diminished pressure, and the remaining solid was
purified by trituration with cold hexanes (3.times.50 mL) to afford
1.54 g (90%) of
1,2,3,4-tetrahydro-1,1,4,4,6-pentamethylbenzo[5,6-g]coumarin as a
white solid. The .sup.1H NMR spectral data, TLC elution properties,
and melting point of this compound thus obtained matched those of
the same compound obtained using General Procedure A (von Pechmann
cyclization).
[0162] General Procedure C: Suzuki Coupling Procedure for
Preparation of a Coumarin Intermediate of General Structure 4.
[0163] Variant 1: 6,8-Di-(tert)-butyl-4-methylcoumarin (Structure 4
of Scheme 1, where R.sup.1, R.sup.3, R.sup.6=H, R.sup.2,
R.sup.4=tert-butyl, R.sup.5=methyl). To a 100-mL r.b. flask
containing 4,6-di-tert-butyl-2-iodophenol (Structure 11 of Scheme
4, where R.sup.1, R.sup.3=H, R.sup.2, R.sup.4=tert-butyl,
R.sup.7=H) (1.10 g, 3.00 mmol) in 30 mL DMF was added
bis(pinacolato)diboron (0.83 g, 3.30 mmol, 1.10 equiv), and
potassium acetate (0.88 g, 9.00 mmol), and a stream of nitrogen gas
was bubbled through the solution for 15 min. To this solution was
added PdCl.sub.2 (dppf) (0.22 g, 0.33 mmol, 10 mol %), and the
reaction was heated to 80.degree. C. for 2 h. The reaction mixture
was then cooled to room temperature, ethyl cis-3-iodocrotonate
(Compound 15 of Scheme 4, where R.sup.5=methyl, R.sup.6=H) (1.44 g,
6.00 mmol) and 15 mL of 2 M K.sub.2CO.sub.3 was added, and the
reaction was heated to 80.degree. C. overnight. The mixture was
cooled, concentrated under reduced pressure, water was added, and
the organics were extracted with 200 mL CH.sub.2Cl.sub.2. The
organic layer was washed successively with water then brine, dried
(MgSO.sub.4), concentrated under reduced pressure, and purified by
flash column chromatography (silica gel, CH.sub.2Cl.sub.2/hexanes,
1:1) to give 0.38 g (47%) of 6,8-di-(tert)-butyl-4-methylcoumarin.
.sup.1H NMR (500 MHz, CDCl.sub.3) 7.59 (d, 1H, J=2.0 Hz), 7.44 (d,
1H, J=2.0 Hz), 6.27 (s, 1H), 2.45 (s, 3H), 1.51 (s, 9H), 1.36 (s,
9H).
[0164] Variant 2: 6,8-Di-(tert)-butyl-4-methylcoumarin (Structure 4
of Scheme 1, where R.sup.1, R.sup.3, R.sup.6=H, R.sup.2,
R.sup.4=tert-butyl, R.sup.5=methyl). To a 100-mL r.b. flask
containing 3,5-di-(tert)-butyl-2-hydroxyphenylboronic acid
(Structure 13 of Scheme 4, where R.sup.1 and R.sup.3=H, R.sup.2 and
R.sup.4=tert-butyl, R.sup.7=H) (0.54 g, 1.9 mmol) in 20 mL of
ethanol and 20 mL of toluene was added (Ph.sub.3P).sub.4Pd (0.1 g,
0.1 mmol, 5 mol %), ethyl cis-3-iodocrotonate (Compound 15 of
Scheme 4, where R.sup.5=methyl, R.sup.6=H) (0.70 g, 2.9 mmol, 1.5
equiv), and 10 mL of 2 M K.sub.2CO.sub.3, and a stream of nitrogen
gas was bubbled through the solution for 10 min. The reaction
mixture was then heated to reflux overnight. The reaction mixture
was then cooled to room temperature, concentrated under reduced
pressure, water was added, and the organics were extracted with 200
mL CH.sub.2Cl.sub.2. The organic layer was washed successively with
water then brine, dried (MgSO.sub.4), concentrated under reduced
pressure, and purified by flash column chromatography (silica gel,
CH.sub.2Cl.sub.2/hexanes, 1:1) to give 0.33 g (55%) of
6,8-di-(tert)-butyl-4-methylcoumarin. .sup.1H NMR (500 MHz,
CDCl.sub.3) 7.59 (d, 1H, J=2.0 Hz), 7.44 (d, 1H, J=2.0 Hz), 6.27
(s, 1H), 2.45 (s, 3H), 1.51 (s, 9H), 1.36 (s, 9H).
[0165] General Procedure D: Preparation of a Z-3-Arylbutenoate of
General Structure 16.
[0166] (2Z)-Ethyl
3-[4,6-di-(tert)-butyl-1-methoxyphen-2-yl]but-2-enoate (Structure
16 of Scheme 4, where R.sup.1, R.sup.3, R.sup.6=H, R.sup.2,
R.sup.4=tert-butyl, R.sup.5, R.sup.7=methyl). To a 50-mL r.b. flask
containing 3,5-di-(tert)-butyl-2-methoxyphenylboronic acid
(Structure 14 of Scheme 4, where R, R.sup.1, R.sup.3=H, R.sup.2,
R.sup.4=tert-butyl, R.sup.7=methyl) (0.97 g, 3.20 mmol) in 10 mL of
EtOH and 6 mL of toluene was added (Ph.sub.3P).sub.4Pd (0.1 g, 0.1
mmol, 3 mol %), ethyl cis-3-iodocrotonate (Compound 15 of Scheme 4,
where R.sup.5=methyl, R.sup.6=H) (1.01 g, 4.2 mmol, 1.31 equiv),
and 6 mL of 2 M K.sub.2CO.sub.3, and a stream of nitrogen gas was
bubbled through the solution for 10 min. The reaction mixture was
then heated to reflux overnight. The reaction mixture was then
cooled to room temperature, concentrated under reduced pressure,
water was added, and the organics were extracted with 200 mL of
CH.sub.2Cl.sub.2. The organic layer was washed successively with
water then brine), dried (MgSO.sub.4), concentrated under reduced
pressure, and purified by flash column chromatography (silica gel,
CH.sub.2Cl.sub.2/hexanes, 1:1) to give 0.35 g (56%) of (2Z)-ethyl
3-[4,6-di-(tert)-butyl-1-methoxyphen-2-yl]but-2-enoat- e. .sup.1H
NMR (500 MHz, CDCl.sub.3) 7.11 (d, 1H, J=2.0 Hz), 5.91 (s, 1H),
4.16 (q, 2H), 3.71 (s, 3H), 2.19 (s, 3H), 1.51 (s, 9H), 1.36 (s,
9H), 0.84 (t, 3H).
[0167] (2'Z)-4,6-Di-(tert)-butyl-2-(4-hydroxy-2-buten-2-yl)anisole
(Structure 8 of Schemes 1 and 4, where R.sup.1, R.sup.3, R.sup.6=H,
R.sup.2, R.sup.4=tert-butyl, R.sup.5, R.sup.7=methyl). To a 50 mL
r.b. flask containing (2Z)-ethyl
3-[4,6-di-(tert)-butyl-1-methoxyphen-2-yl]but- -2-enoate (Structure
16, where R.sup.1, R.sup.3, R.sup.6=H, R.sup.2, R.sup.4=tert-butyl,
R.sup.5, R.sup.7=methyl) (0.35 g, 0.72 mmol) in 5 mL of Et.sub.2O
at -78.degree. C. was added LiAlH.sub.4 (0.03 g, 0.7 mmol), and the
reaction was warmed to room temperature and stirred for 1 h. Ethyl
acetate (20 mL) and 2 mL of 6 N HCl were added and stirred for 1 h.
The organic layer was then washed successively with water then
brine, dried (MgSO.sub.4), concentrated under reduced pressure, and
purified by flash column chromatography (silica gel,
CH.sub.2Cl.sub.2/hexanes, 1:1) to give 0.20 g (90%) of
(2Z)-4,6-di-(tert)-butyl-3-(4-hydroxy-2-buten-2-y- l)anisole.
.sup.1H NMR (500 MHz, CDCl.sub.3) 7.26 (d, 1H, J=2.0 Hz), 6.91 (d,
1H, J=2.0 Hz), 5.82 (dt, 1H, J=7.0 Hz, 2.0 Hz), 3.81 (m, 2H), 3.79
(s, 3H,), 2.16 (d, 3H, J=2.0 Hz), 1.41 (s, 9H), 1.30 (s, 9H).
6465
[0168] Scheme 5 shows a general synthetic method for the production
of coumarin intermediates (e.g., Structure III). This synthetic
method is also described in Scheme I. The synthetic process of
these schemes describes the production of a coumarin from a
hydroxyacetophenone by condensation with a phosphorous ylide. The
coumarin intermediates are then ring opened and alkylated to
produce the desired RXR modulator compounds. Examples 1-13 show a
preferred embodiment for the synthetic method shown in Schemes 1
and 5.
Example 1
[0169] (Compound II of Scheme 5, where R=tert-butyl). To 110 gm
(0.44 mol) of 3,5 Di-tert-butyl-4-hydroxybenzoic acid I in 500 mL
of THF at 0.degree. C. was added 1.6 L (1.76 mol) of 1.4 M MeLi.
The reaction was stirred for 2 h while slowly warming to room
temperature. One liter of EtOAc was slowly added to the reaction
mixture which was subsequently washed (1 L of 1 N HCl, 1 L of water
and 500 mL of brine), dried (MgSO.sub.4), concentrated and purified
by SiO.sub.2 chromatography (10% EtOAc-hexanes) to give 83.0 gm
(0.33 mol) of II. .sup.1H-NMR (CDCl.sub.3) .delta. 7.56 (m, 2H,
Ar--H), 2.65 (s, 3H, CH.sub.3), 1.42 (s, 9H, t-butyl), 1.32 (s, 9H,
t-butyl).
Example 1a
[0170] (Compound IIa of Scheme 5, where R=isobutyl). To a mixture
of 15.64 g (0.0625 mol) of 2-hydroxy-2,4-di-tert-isopropylbenzoic
acid and 300 ml of dry THF at -78.degree. C. was added 100 ml of
2.5 M n-butyllithium slowly (Note: Scheme 5 demonstrates use of
methyl lithium, however in this synthesis butyl lithium was used).
The resulting mixture was warmed to room temperature. The reaction
was checked by TLC and after 3 hours 100 ml of EtOAc and 20 ml of
water were added. The reaction was stirred for 30 minutes and then
extracted with 500 ml of ETOAc. The organic fractions were combined
and dried over MgSO.sub.4. The solvents were evaporated under
reduced pressure and the resulting oil was purified over silica gel
(eluent: methylene chloride/hexane: 50/50) to give 17.82 g (yield:
98%) of IIa. .sup.1H NMR (CDCl.sub.3): 7.62 (s, 1H), 7.54 (s, 1H),
2.98 (t, 2H), 1.76 (m, 2H), 1.55 (m, 4H), 1.54 (d, 6H), 1.43 (d,
6H), 0.96 (t, 3H).
Example 2
[0171] (Compound III of Scheme 5, where R=tert-butyl, R"=H). To
83.0 gm (0.34 mol) of methyl ketone II suspended in 500 mL of
toluene was added 232.9 gm (0.67 mol) of
(carbethoxymethylene)triphenylphosphorane. The mixture was heated
to reflux. and allowed to stir overnight. The mixture was cooled,
water was added, and the organics were extracted with 500 mL of
EtOAc. The organic layer was washed (water then brine), dried
(MgSO.sub.4), concentrated and purified by SiO.sub.2 chromatography
(10% EtOAc-hexanes) to give 73.4 gm (0.27 mol) of III. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.59 (d, J=2.0 Hz, 1H, Ar--H), 7.44 (d, J=2.0
Hz, 1H, Ar--H), 6.27 (s, 1H, .dbd.CH), 2.45 (s, 3H, CH.sub.3), 1.51
(s, 9H, t-butyl), 1.36 (s, 9H, t-butyl).
Example 3
[0172] (Compound IV of Scheme 5, where R=tert-butyl, R"=H). To 9.3
gm (34.2 mmol) of coumarin III in 120 mL of Et.sub.2O at
-78.degree. C. was added 34.2 mL (34.2 mmol) of 1.0 M lithium
aluminum hydride (LAH). The reaction was stirred for 3 h or until
complete by TLC (20% EtOAc-hexanes) while slowly warming to room
temperature. Upon completion, the mixture was cooled to 0.degree.
C. and quenched with water. The organics were extracted (250 mL of
EtOAc), washed (50 mL of brine), dried (MgSO.sub.4), concentrated
and purified by SiO.sub.2 chromatography (20% EtOAC-hexanes) to
give 9.1 g (32.97 mmol) of IV. .sup.1H-NMR (CDCl.sub.3) .delta.
7.26 (d, J=2.0 Hz, 1H, Ar--H), 6.91 (d, J=2.0 Hz, 1H, Ar--H), 5.98
(dt, J=7.0 Hz, J=2.0 Hz, 1H, .dbd.CH), 3.94 (m, 2H, CH.sub.2--OH),
2.14 (d, J=1 Hz, 3H, .dbd.CHCH.sub.3), 1.30 (s, 9H, t-butyl), 1.41
(s, 9H, t-butyl).
Example 4
[0173] (Compound V of Scheme 5, where R=tert-butyl, R'=ethyl,
R"=H). To 9.00 g (32.0 mmol) of diol IV in 120 mL of DMF was added
14.58 g (96.0 mmol) of cesium fluoride. The solution was stirred
for 15 min and then 2.8 mL (35.2 mmol) of iodoethane was added and
the mixture was allowed to stir overnight. Water was added (250 mL)
and the organics were extracted (500 mL EtOAc), dried (MgSO.sub.4),
concentrated and purified by SiO.sub.2 chromatography (10%
EtOAc-hexanes) to give 9.2 g (30.5 mmol) of V. .sup.1H-NMR
(CDCl.sub.3)) .delta. 7.26 (d, J=2.0 Hz, 1H, Ar--H), 6.91 (d, J=2.0
Hz, 1H, Ar--H), 5.82 (dt, J=7.0 Hz, J=7.0 Hz, 2.0 Hz, 1H.dbd.CH),
3.81 (m, 4H, CH.sub.2--OH, --OCH.sub.2CH.sub.3), 2.16 (d, J=2.0 Hz,
3H, CH.sub.3), 1.41 (s, 9H, t-butyl), 1.36 (t, J=7.0 Hz, 3H,
--OCH.sub.2CH.sub.3), 1.30 (s, 9H, t-butyl)
Example 5
[0174] (Compound VI of Scheme 5, where R=tert butyl, R'=ethyl,
R"=H). To 10.3 g (33.9 mmol) of the alcohol V stirring in 150 mL of
CH.sub.2Cl.sub.2 was added 600 mg (1.69 mmol) of
tetrapropylammonium perruthenate (TPAP) and 5.95 g (50.82 mmol) of
4-methylmorpholine-N-oxide (MMNO). The reaction stirred overnight
and the filtered through a SiO.sub.2 plug and washed with
CH.sub.2Cl.sub.2. In vacuo concentration gave 8.49 g (28.11 mmol)
of VI. .sup.1H-NMR (CDCl.sub.3) .delta. 9.47 (d, J=8.5 Hz, 1H,
HCO), 7.37 (d, J=2.0 Hz, 1H, Ar--H), 6.96 (d, J=2.0 Hz, 1H. Ar--H),
6.10 (d, J=8.5 Hz, 1H, .dbd.CH), 3.87 (t, J=6.3 Hz, 1H,
CH.sub.2CH.sub.3), 3.73 (t, J=6.3 Hz, 1H, CH.sub.2CH.sub.3), 2.36
(s, 3H, .dbd.CCH.sub.3), 1.41 (s, 9H, t-butyl), 1.31 (t, 6.3 Hz,
3H, --OCH2CH.sub.3), 1.308 (s, 9H, t-butyl).
Example 6
[0175] (Compound VII of Scheme 5, where R=tert-butyl, R'=ethyl,
R"=H, R'"=H).
[0176] To 20.5 mL (84.34 mmol) of triethyl
3-methyl-4-phosphonocrotonate in 50 mL of THF at -78.degree. C.,
was added 52.7 mL (84.34 mmol) of 1.6 M n-BuLi. This solution was
stirred for 30 min and then 8.49 g (28.11 mmol) of aldehyde VI was
added in 50 mL of THF. The reaction was slowly warmed to room
temperature while stirring overnight. Water (300 mL) was added, and
extracted with EtOAc (300 mL), dried (MgSO.sub.4), concentrated and
purified by SiO.sub.2 chromatography (10% EtOAc-hexanes) to give
10.5 gm (24.53 mmol) of VII. .sup.1H-NMR (CDCl.sub.3) .delta. 7.29
(d, J=2.0 Hz, 1H, Ar.dbd.H), 6.92 (d, J=2.0 Hz, 1H, Ar--H), 6.68
(dd, J=15.0 Hz, J=11 Hz, 1H, .dbd.CH), 6.26 (d, J=15 Hz, 1H,
.dbd.CH), 6.23 (d, J=11 Hz, 1H, .dbd.CH), 5.76 (s, 1H, .dbd.CH),
4.15 (m, 2H, CO.sub.2CH.sub.2CH.sub.3), 3.87 (t, J=6.3 Hz, 1H,
.dbd.OCH.sub.2CH.sub.3)- , 3.69 (t, J=6.3 Hz, 1H,
OCH.sub.2CH.sub.3), 2.21 (s, 3H, CH.sub.3), 1.41 (s, 9, t-butyl),
1.31 (s, 3H, t-butyl), 1.25 (m, 6H, CO.sub.2CH.sub.2CH.sub.3,
OCH.sub.2CH.sub.3).
Example 7
[0177] (L2, Compound VIII of Scheme 5, where R=tert-butyl,
R'=ethyl, R"=H, R'"=H). To 10.00 g (23.36 mmol) of the ethyl ester
VII in 80 mL of MeOH, was added 23.4 mL (70.1 mmol) of 3N aqueous
KOH and the suspension was refluxed overnight. After acidification
(20% aqueous HCl), the organics were extracted with EtOAc (300 mL),
dried (MgSO.sub.4), concentrated and the solid recrystallized from
EtOH to give 3.8 gm (9.90 mmol) of the carboxylic acid VIII.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.29 (d, J=2.0 Hz, 1H, Ar--H),
6.92 (d, J=2.0 Hz, 1H, Ar--H), 6.68 (dd, J=15 Hz, J=11 Hz, 1H,
.dbd.CH), 6.26 (d, J=15 Hz, 1H, .dbd.CH), 6.23 (d, J=11 Hz, 1H,
.dbd.CH), 5.77 (s, 1H, COCH), 3.87 (t, J=6.3 Hz, TH,
CH.sub.2CH.sub.3), 3.69 (t, J=6.3 Hz, 1H, CH.sub.2CH.sub.3), 2.24
(s, 3H, CH.sub.3), 2.16 (d, J=1 Hz, 3H, CH.sub.3), 1.42 (s, 9H,
t-butyl), 1.31 (s, 9H, t-butyl), 1.28 (t, J=6.3 Hz, 3H,
CH.sub.3)
Example 8
[0178] (L1, Compound VIII of Scheme 5, where R=tert-butyl,
R'=methyl, R"=H, R'"=H). This compound was prepared in the manner
previously described for compound VIII in Example 7, except that
iodomethane was used instead of iodoethane in Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.29 (d, J=2.2 Hz, 1H, Ar--H),
6.95 (d, J=2.0 Hz, 1H, Ar--H), 6.67 (dd, J=15 Hz, J=11 Hz, 1H,
.dbd.CH), 6.26 (d, J=15 Hz, 1H, .dbd.CH), 6.23 (d, J=11 Hz, 1H,
.dbd.CH), 5.79 (s, 1H, COCH), 3.62 (s, 3H, CH.sub.3), 2.30 (s, 3H,
CH), 2.16 (s, 3H, CH.sub.3), 1.42 (s, 9H, t-butyl), 1.29 (s, 9H,
t-butyl).
Example 9
[0179] (L3, Compound VIII of Scheme 5, where R=tert-butyl,
R'=n-propyl, R"=H, R'"=H). This compound was prepared in the manner
previously described for Compound VIII in Example 7, except that
Iodopropane was used instead of Iodoethane in Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (d, J=2.0 Hz, 1H, Ar--H),
6.92 (d, J=2.0 Hz, 1H, Ar--H), 6.67 (dd, J=15 Hz, J=11 Hz, TH,
.dbd.CH), 6.26 (d, J=15 Hz, 1H, .dbd.CH), 6.23 (d, J=11 Hz, 1H,
.dbd.CH), 5.75 (s, 1H, COCH), 3.89 (m, 1H, CH.sub.2CH.sub.3), 3.69
(m, 1H, CH.sub.2CH.sub.3), 2.27 (s, 3H, CH.sub.3), 2.18 (s, 3H,
CH.sub.3), 1.68 (m, 2H, CH.sub.3), 1.42 (s, 9H, t-butyl), 1.29 (s,
9H, t-butyl), 0.97 (t, J=6.3 Hz, 3H, CH.sub.3)
Example 10
[0180] (L4, Compound VIII of Scheme 5, where R=tert-butyl,
R'=n-butyl, R"=H, R'"=H). This compound was prepared in the manner
previously described for Compound VIII in Example 7, except that
iodobutane (or bromobutane) was used instead of iodoethane in
Example 4. .sup.1H-NMR (CDCl.sub.3) .delta. 7.29 (d, J=2.2 Hz, 1H,
ArH), 6.96 (d, J=2.2. Hz, 1H, Ar--H), 6.60:(dd, J=15 Hz, J=11 Hz,
1H, .dbd.CH), 6.26 (d, J=15 Hz; 1H, .dbd.CH), 6.23 (d, J=11 Hz, 1H,
.dbd.CH), 5.70 (s, 1H, COCH), 3.87 (m, 1H, CH.sub.2CH.sub.3), 3.63
(m, 1H, CH.sub.2CH.sub.3), 2.30 (s, 3H, CH.sub.3), 2.21 (s, 3H,
CH.sub.3), 1.62 (m, 2H, CH.sub.3), 1.42 (s, 9H, t-butyl), 1.29 (s,
9H, t-butyl), 1.27 (m, 2H, CH.sub.3), 0.91 (t, J=6.3 Hz, 3H,
CH.sub.3).
Example 11
[0181] (L5, Compound VIII of Scheme 5, where R=tert-butyl,
R'=n-heptyl, R"=H, R'"=H). This compound was prepared in the manner
previously described for Compound VIII in Example 7, except that
bromoheptane was used instead of iodoethane in Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.30 (d, J=2.2 Hz, 1H, Ar--H),
6.90 (d, J=2.2 Hz, 1H, Ar--H), 6.66 (dd, J=15 Hz, J=11 Hz, 1H,
.dbd.CH), 6.26 (d, J=15 Hz, 1H, .dbd.CH), 6.23 (d, J=11 Hz, 1H,
.dbd.CH), 5.70 (s, 1H, COCH), 3.90 (m, 1H, CH.sub.2CH.sub.3), 3.60
(m, 1H, CH.sub.2CH.sub.3), 2.22 (s, 3H, CH.sub.3), 2.16 (s, 3H,
CH.sub.3), 1.68-1.29 (m, 8.degree. H, CH.sub.2), 1.40 (s, 9H,
t-butyl), 1.30 (s, 9H, t-butyl), 1.27 (m, 2H, CH.sub.3), 0.86 (t,
J=6.3 Hz, 3H, CH.sub.3).
Example 11a
[0182] (L104, Compound VIIa of Scheme 5 where R=isopropyl,
R'=heptyl, R"=H, and R'"=H). Note: This compound was synthesized
using the procedures illustrated in Scheme 5 starting from Compound
IIa from Example 1a, the synthesis of which employed n-butyl
lithium instead of methyl lithium as in Example 1. To a mixture of
710 mg of the ester of Compound VIIa in 10 ml of ethanol was added
1 ml of 6 N NaOH. The solution was heated to reflux until
completion (TLC monitoring). After cooling, water was added and the
mixture as extracted with ethyl acetate. The organic layer was
washed with water and brine and dried over MgSO.sub.4. The solvents
were evaporated under reduced pressure, and the residual oil was
crystallized from acetonitrile to yield 120 mg of Compound VIIIa.
.sup.1H NMR (CDCl.sub.3): 6.92 (d, 1H), 6.66 (m, 1H), 6.22 (m, 3H),
6.72 (s, 1H), 3.88 (m, 1H), 3.62 (m, 1H), 2.68 (m, 1H), 2.44 (m,
1H), 1.77 (m, 2H), 1.53 (d, 6H), 1.44 (m, 6H), 2.98 (t, 2H), 1.76
(m, 2H), 1.55 (m, 4H), 1.54 (d, 6H), 1.43 (d, 6H), 1.27 (d, 6H),
0.96 (m, 6H).
Example 12
[0183] (L6, Compound VIII of Scheme 5, where R=isopropyl,
R'=n-butyl, R"H, R'"=H). This compound was prepared in the manner
previously described for Compound VIII in Example 7, except that
3,5 di-isopropyl-4-hydroxybenzoic acid was used instead of 3,5
di-tert-butyl-4-hydroxybenzoic acid in Example 1, and iodobutane
was used instead of iodoethane in Example 4. .sup.1H-NMR
(CDCl.sub.3) .delta. 7.02 (d, J=2.2 Hz, 1H, Ar--H), 6.72 (d, J=2.2
Hz, 1H, Ar--H), 6.57 (dd, J=15 Hz, J=11 Hz, 1H, .dbd.CH), 6.24 (d,
1=15 Hz, 1H, .dbd.CH), 6.18 (d, J=11 Hz, 1H, .dbd.CH), 5.73 (s, 1H,
COCH), 3.62 (mb, 2H, CH.sub.2CH.sub.3), 3.37 (m, 1H, CH), 2.85 (m,
1H, CH), 2.20 (s, 3H, CH.sub.3), 2.13 (s, 3H, CH.sub.3), 1.62 (m,
2H, CH.sub.2), 1.44 (m, 2H, CH.sub.2), 1.27 (d, 6H, CH.sub.3), 1.24
(d, 6H, CH.sub.3), 0.91 (t, J=6.3 Hz, 3H, CH.sub.3).
Example 13
[0184] (L7, Compound VIII of Scheme 5, where R=isopropyl,
R'=n-pentyl, R"=H, R'"=H) This compound was prepared in the manner
previously described for Compound VIII in Example 7, except that
3,5 di-isopropyl-4-hydroxybenzoic acid was used instead of 3,5
di-tert-butyl-4-hydroxybenzoic acid in Example 1, and iodopentane
(or bromopentane) was used instead of iodoethane in Example 4.
.sup.1H-NMR (CDCl.sub.3) .delta. 7.04 (d, J=2.2 Hz, 1H, Ar--H),
6.74 (d, J=2.2 Hz, 1H, Ar--H), 6.57 (dd, J=15 Hz, J=11 Hz, 1H,
.dbd.CH), 6.24 (d, J=15 Hz, 1H, .dbd.CH), 6.18 (d, J=11 Hz, 1H,
.dbd.CH), 5.73 (s, 1H, COCH), 3.62 (mb, 2H, CH.sub.2CH.sub.3), 3.33
(n, 1H, CH), 2.89 (m, 1H, CH), 2.20 (s, 3H, CH.sub.3), 2.13 (s, 3H,
CH.sub.3), 1.62 (m, 2H, CH.sub.2), 1.44 (m, 4H, CH.sub.2), 1.27 (d,
6H, CH.sub.3), 1.24 (d, 6H, CH.sub.3), 0.91. (t, J=6.3 Hz, 3H,
CH.sub.3).
Example 14
[0185] (Compound III of Scheme 5, where R=tert-butyl, R"=F). This
compound was prepared in the manner previously described for
Compound III in Example 2, except that triethyl-2-fluoro phosphono
acetate was used instead of
(carbethoxymethylene)triphenylphosphorane. .sup.1H-NMR (CDCl.sub.3)
.delta. 7.56 (d, J=2.1 Hz, 1H, Ar--H), 7.40 (d, J=2.1 Hz, 1H,
Ar--H), 2.42 (d, J=3 Hz, 3H, CH.sub.3), 1.51 (s, 9H, t-butyl), 1.36
(s, 9H, t-butyl).
Example 15
[0186] (L20, Compound VIII of Scheme 5, where R=tert-butyl,
R'=1,1,1-trifluoroethyl, R"=F, R'"=H). This compound was prepared
in the manner previously described for Compound VIII in Example 7,
except that 1,1,1-trifluoro, 2-iodoethane was used instead of
Iodoethane in Example 4. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.35 (d,
J=2.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.59 (d, J=15.6 Hz, 1H),
6.41 (dd, J=25.9, 15.6 Hz, 1H), 5.90 (s, 1H), 4.15 (quintet, J=8.4
Hz, 1H), 4.02 (quintet, J=8.4 Hz, 1H), 2.17 (d, J=3.5 Hz, 3H), 2.14
(s, 3H), 1.41 (s, 9H), 1.30 (s, 9H).
Example 16
[0187] (Compound IV of Scheme 5, where R=tert-butyl, R"=F). This
compound was prepared in the manner previously described for
Compound IV in Example 3, except that
3-fluoro-4-methyl-7,9-di-tert-butyl coumarin was used instead
4-methyl-7,9-di-tert-butyl coumarin in Example 2. IV was directly
used in the next step. .sup.1H NMR (400 MHz, CDCl.sub.3), .delta.:
7.25 (d, J=2.1 Hz, 1H), 6.90 (d, J=2.1 Hz, 1H), 4.95 (broad s, 1H),
4.09 (m, 2H), 2.00 (d, J=3.6 Hz, 3H), 1.98 (broad m, 1H), 1.41 (s,
9H), 1.28 (s, 9H).
Example 17
[0188] (Compound V of Scheme 5, where R=tert-butyl,
R'=1,1-difluoroethyl, R"=F). This compound was prepared in the
manner previously described for Compound V in Example 4, except
that of Z-2-fluoro-3-[2-(2,2-difluoroetho-
xy)-3,5-di-tert-butylbenzene]crotyl alcohol was used instead of
3-[2-(2,2-difluoroethoxy)-3,5-di-tertbutylbenzene]crotyl alcohol IV
in Example 3 (4.7 mmol, yield=88%) of V. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.29 (d, J=2.1 Hz, 1H), 6.99 (d, J=2.1 Hz,
1H), 6.08 (dt, J=55.3, 4.0 Hz, 1H), 4.00 (m, 4H), 2.08 (d, J=3.6
Hz, 3H), 2.01 (broad s, 1H), 1.39 (s, 0.9H), 1.29 (s, 9H).
Example 18
[0189] (Compound VII of Scheme 5, where R=tert-butyl,
R'=1,1-difluoroethyl, R"=F, R'"=H). To a mixture of 365 mg (1.02
mmol) of VI and 179 mg (1.52 mmol) of NMO in 10 ml of
CH.sub.2Cl.sub.2 was added 18 g (0.05 mmol) of TPAP in one time.
The mixture was stirred at room temperature until the reaction was
complete (TLC analysis). The mixture is filtrated over a short pad
of silica gel and the solvent evaporated. The crude aldehyde was
directly treated with the anion of ethyl-3-methylphosphono
crotonate (prepared from 1.0 g 3.8 mmol of
triethyl-3-methylphosphonocrotonate and 2.9 ml of nBuLi in a 10/1
THF/DMPU mixture at -78.degree. C.) at -78.degree. C. The mixture
is allowed to warn-up to room temperature and the solvents are
evaporated. The crude ester was purified over a short silica gel
plug (eluent: 5/95 ethyl acetate/hexane) to afford 414 mg (0.89
mmol, yield=87%, 2 steps) of VII. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.33 (d, J=2.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.56 (d,
J=15.7 Hz, 1H), 6.37 (dd, J=26.3, 15.7 Hz, 1H), 5.97 (dt, J=55.1,
3.9 Hz, 1H), 5.87 (s, 1H), 4.15 (dd, J=15.6, 7.2 Hz, 2H), 4.07 (m,
1H), 3.89 (m, 1H), 2.16 (d, J=3.5 Hz, 3H), 2.12 (s, 3H), 1.40 (s,
9H), 1.26 (s, 9H), 1.24 (t, J=7.2H, 3H).
Example 19
[0190] (L21, Compound VIII of Scheme 5, where R=tert-butyl,
R'=1,1-difluoroethyl, R"=F, R'"=H). This compound was prepared in
the manner previously described for Compound VIII in Example 7,
except that ethyl (2E, 4E,
6E)-3-methyl-6-fluoro-7-[2-(2,2-difluoroethoxy)-3,5-di-ter-
t-butylbenzene]octatrienoate was used instead of ethyl (2E, 4E,
6E)-3-methyl-7-[2-(2,2-difluoroethoxy)-3,5-di-tertbutyl-benzene]octatrien-
oate in Example 6 (yield: 58%) of VII. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.34 (d, J=2.5 Hz, 1H), 6.99 (d, J=2.4 Hz,
1H), 6.59 (d, J=15.7 Hz, 1H), 6.44 (dd, J=25.8, 15.7 Hz, 1H), 5.97
(dt, J=55.1, 3.9 Hz, 1H), 5.90 (s, 1H), 4.05 (m, 1H), 3.88 (m, 1H),
2.18 (d, J=3.6 Hz, 3H), 2.13 (s, 3H), 1.40 (s, 9H), 1.30 (s,
9H).
Example 20
[0191] (L22, Compound VIII of Scheme 5, where R=tert-amyl,
R'=1,1-difluoroethyl, R"=F, R'"=H). This compound was prepared in
the manner previously described for Compound VIII in Example 7,
except that 3,5 di-tert-amyl-4-hydroxybenzoic acid was used instead
of 3,5 di-tert-butyl-4-hydroxybenzoic acid in Example 1, and
difluoroethyl bromide was used instead of iodoethane in Example 4.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.19 (d, J=2.4 Hz, 1H),
6.91 (d, J=2.3 Hz, 1H), 6.58 (d, J=15.6 Hz, 1H), 6.39 (dd, J=26.1,
15.7 Hz, 1H), 5.96 (dt, J=55.2, 3.9 Hz, 1H), 5.89 (s, 1H), 3.99 (m,
1H), 3.81 (m, 1H), 2.16 (d, J=3.5 Hz, 3H), 2.11 (.sctn., 3H), 1.78
(dd, J=15.0, 7.5 Hz, 2H), 1.59 (dd, J=15.0, 7.5 Hz, 2H), 1.37 (s,
3H), 1.36 (s, 3H), 1.26 (s, 3H), 1.25 (s, 3H), 0.67 (dd, J=7.5, 2.8
Hz, 3H), 0.65 (dd, J=7.5, 2.8 Hz, 3H).
Example 20a
[0192] (L18, Compound VIII of Scheme 5, where R=tert-amyl,
R'=1,1-difluoroethyl, R"=H, R'"=H). This compound was prepared in
the manner previously described for Compound VIII in Example 7,
except that 3,5 di-tert-amyl-4-hydroxybenzoic acid was used instead
of 3,5 di-tert-butyl-4-hydroxybenzoic acid in Example 1, and
difluoroethyl bromide was used instead of iodoethane in Example 4.
.sup.1H NMR (CDCl.sub.3): 6.92 (s, 1H), 6.96 (s, 1H), 6.66 (m, 3H),
6.28 (m, 3H), 6.06 (m, 1H), 5.95 (m, 1H), 5.42 (m, 1H), 3.88 (bm,
2H),2.22 (s, 3H), 2.07 (s, 3H), 1.77 (m, 2H), 1.64 (m, 2H),), 1.38
(s, 6H), 1.28 (s, 6H), 0.68 (m, 6H).
Example 21
[0193] (L23, Compound VIII of Scheme 5, where R=tert-butyl,
R'=1,1,1-trifluoroethyl, R"=H, R'"=H). This compound was prepared
in the manner previously described for Compound VIII in Example 7,
except that 2,2,2-difluoro-bromoethane was used instead of
iodoethane in Example 4. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.31 (d, J=2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.59 (dd, J=15.3
Hz, 11.0 Hz, 1H), 6.29 (d, J=4.3 Hz, 1H), 6.28 (d, J=14.7 Hz, 1H),
5.96 (dt, J=55.3 Hz, 4.3 Hz, 1H), 5.78 (s, 1H), 3.95 (m, 2H), 2.22
(s, 3H), 2.15 (s, 3H), 1.41 (s, 9H), 1.30 (s, 9H)
Example 22
[0194] (L13, Compound VIII of Scheme 5, where R=tert-butyl,
R'=1,1-difluoroethyl, R"=H, R'"=H). This compound was prepared in
the manner previously described for Compound VIII in Example 7,
except that 2,2-difluoro-bromoethane was used instead of iodoethane
in Example 4. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.31 (d,
J=2.4 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.59 (dd, J=15.3 Hz, 11.0
Hz, 1H), 6.29 (d, J=4.3 Hz, 1H), 6.28 (d, J=14.7 Hz, 1H), 5.96 (dt,
J=55.3 Hz, 4.3 Hz, 1H), 5.78 (s, 1H), 3.95 (m, 2H), 2.22 (s, 3H),
2.15 (s, 3H), 1.41 (s, 9H), 1.30 (s, 9H)
Example 23
[0195] (L24, Compound VIII of Scheme 5, where R=isopropyl,
R'=1-fluoropropyl, R"=H, R'"=H). This compound was prepared in the
manner previously described for Compound VIII in Example 7, except
that 3,5 di-isopropyl-4-hydroxybenzoic acid was used instead of 3,5
di-tert-butyl-4-hydroxybenzoic acid in Example 1, and
3-fluoro-1-bromopropane was used instead of iodoethane in Example
4., .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (d, J=2.2 Hz, 1H, Ar--H),
6.72 (d, J=2.2 Hz, 1H, Ar--H), 6.57 (dd, J=15 Hz, J=11 Hz, 1H,
.dbd.CH), 6.24 (d, J=15 Hz, 1H, .dbd.CH), 6.20 (d, J=11 Hz, 1H,
.dbd.CH), 5.73 (s, 1H, COCH), 4.65 (m, 1H), 4.55 (m, 1H), 3.75 (m,
2H),), 3.25 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.85 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.22 (s, 3H), 2.22 (s, 3H), 2.01 (m, 2H),
1.25 (m, 12H).
Example 24
[0196] (L25, Compound VIII or Scheme 5, where R=isopropyl,
R'=3-hydroxypropyl, R"=H; R'"=H). This compound was prepared in the
manner previously described for Compound VIII in Example 7, except
that 3,5 di-isopropyl-4-hydroxybenzoic acid was used instead of 3,5
di-tert-butyl-4-hydroxybenzoic acid in Example 1, and
3-fluoro-1-bromopropane was used instead of iodoethane in Example
4. .sup.1H-NMR (CDCl.sub.3) .delta. 7.02 (d, J=2.2 Hz, 1H, Ar--H),
6.72 (d, J=2.2 Hz, 1H, Ar--H), 6.57 (dd, J=15 Hz, J=11 Hz, 1H,
.dbd.CH), 6.24 (d, J=15 Hz, 1H, .dbd.CH), 6.20 (d, J=11 Hz, 1H,
.dbd.CH), 5.73 (s, 1H, COCH), 3.75 (m, 2H),), 3.25 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.85 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.22
(s, 3H), 2.22 (s, 3H), 2.01 (m, 2H), 1.25 (m, 12H).
Example 25
[0197] (L26, Compound VIII of Scheme 5, where R=isopropyl,
R'=1,1,2,2-tetrafluoropropyl, R"=H, R'"=H). This compound was
prepared in the manner previously described for Compound VIII in
Example 7, except that 3,5 di-isopropyl-4-hydroxybenzoic acid was
used instead of 3,5 di-tert-butyl-4-hydroxybenzoic acid in Example
1, and 1,1,2,2-tetrafluoro-bromo-propane was used instead of
iodoethane in Example 4. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.07 (d, J=2.1 Hz, 1H, Ar--H), 6.79 (d, J=2.1 Hz, 1H, Ar--H), 6.51
(dd, J=15.3 Hz, J=10.9 Hz, 1H, C.dbd.C--H), 6.30 (d, J=15.3 Hz, 1H,
C.dbd.CH), 6.28 (d, J=15.3 Hz, 1H, C.dbd.C--H), 5.98 (tt, J=53.1
Hz, J=5.2 Hz, 1H, R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 5.78 (s,
1H, C.dbd.C--H), 3.99 (m, 2H, R--O--CH.sub.1--CF.sub.2--CF.sub.2H),
3.27 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.88 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.19 (s, 3H, CH.sub.3), 2.13 (s, 3H,
CH.sub.3), 1.25 (d, J=5.3 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.23 (d,
J=7.4 Hz, 6H, CH.sub.3--CHCH.sub.3).
Example 26
[0198] (L27, Compound VIII of Scheme 5, where R=tert-butyl,
R'=1,1,2,2-tetrafluoropropyl, R"=H, R'"=H). This compound was
prepared in the manner previously described for Compound VIII in
Example 7, except that 1,1,2,2-tetrafluoro-bromo-propane was used
instead of iodoethane in Example 4. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.32 (d, J=2.4 Hz, 1H, Ar--H), 6.95 (d, J=2.4
Hz, 1H, Ar--H), 6.52 (dd, J=14.9 Hz, J=11.3 Hz, 1H, C.dbd.C--H),
6.29 (d, J=15.3 Hz, 1H, C.dbd.CH), 6.28 (d, J=9.3 Hz, 1H,
C.dbd.C--H), 5.91 (tt, J=53.0 Hz, J=5.0 Hz, 1H,
R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 5.79 (s, 1H, C.dbd.C--H),
4.10 (m, 2H, R--O--CH, --CF.sub.2--CF.sub.2H), 2.21 (s, 3H,
CH.sub.3), 2.13 (s, 3H, CH.sub.3), 1.41 (s, 9H, .sup.tbutyl), 1.30
(s, 9H, .sup.tbutyl).
Example 27
[0199] (L28, Compound VIII of Scheme 5, where R=isopropyl,
R'=1,1,1-trifluoroethyl, R"=H, R'"=H). This compound was prepared
in the manner previously described for Compound VIII in Example 7,
except that 3,5 di-isopropyl-4-hydroxybenzoic acid was used instead
of 3,5 di-tert-butyl-4-hydroxybenzoic acid in Example 1, and
1,1,1-trifluoro-bromo-ethane was used instead of iodoethane in
Example 4. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.07 (d, J=2.1
Hz, 1H, Ar--H), 6.77 (d, J=2.0 Hz, 1H, Ar--H), 6.55 (dd, J=15.3 Hz,
J=11.0 Hz, 1H, C.dbd.C--H), 6.30 (d, J=10.3 Hz, 1H, C.dbd.CH), 6.28
(d, J=15.3 Hz, 1H, C.dbd.C--H), 5.78 (s, 1H, C.dbd.C--H), 3.99 (m,
2H, R--O--CH.sub.2--CF.sub.3), 3.35 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.87 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.21
(s, 3H, CH.sub.3), 2.14 (s, 3H, CH.sub.3), 1.25 (d, J=6.1 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 28
[0200] (L29, Compound VIII of Scheme 5, where R=tert-amyl,
R'=1,1,1-trifluoroethyl, R"=H, R'"=H). This compound was prepared
in the manner previously described for Compound VIII in Example 7,
except that 3,5 di-isoamyl-4-hydroxybenzoic acid was used instead
of 3,5 di-tert-butyl-4-hydroxybenzoic acid in Example 1, and
1,1,1-trifluoro-bromo-ethane was used instead of iodoethane in
Example 4. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.19 (d, J=2.4
Hz, 1H, Ar--H), 6.86 (d, J=2.4 Hz, 1H, Ar--H), 6.58 (dd, J=15.4 Hz,
J=10.9 Hz, 1H, C.dbd.C--H), 6.29 (d, J=1.0 Hz, 1H, C.dbd.CH), 6.28
(d, J=15.4 Hz, 1H, C.dbd.C--H), 5.78 (s, 1H, C.dbd.C--H), 4.09 (m,
2H, R--O--CH.sub.2--CF.sub.3), 2.20 (s, 3H, CH.sub.3), 2.13 (s, 3H,
CH.sub.3), 1.79 (m, 2H, .sup.tamyl-CH.sub.2--CH.sub.3), 1.60 (q,
J=7.4 Hz, 2H, .sup.tamyl-CH.sub.2--CH.sub.3), 1.38 (s, 3H,
.sup.tamyl-CH.sub.3), 1.37 (s, 3H, .sup.tamyl-CH.sub.3), 1.26 (s,
3H, .sup.tamyl-CH.sub.3), 1.25 (s, 3H, .sup.tamyl-CH.sub.3), 0.66
(t, J=7.46, 6H, .sup.tamyl-CH.sub.2--CH.sub.3). 6667
[0201] Scheme 6 is an alternate route to that suggested in Scheme 5
for introduction of fluorine at the R.sup.9 position of the
modulator compound.
Example 29
[0202] (Compound II of Scheme 6, where R=tert-butyl,
R'=1,1-difluoropropyl). To 0.103 g of sodium hydride (2.14 mmol)
suspended in anhydrous DMF (10 ml) in a flame dried 25 ml r.b.
flask at 0.degree. C. is added triethyl-phosphonoacetate (0.449 g,
2.01 mmol) dropwise. The mixture is allowed to stir for 0.2 hours.
Compound I is then added dropwise (0.452 g, 1.34 mmol) via
salvation in anhydrous DMF (5.0 ml). The resultant mixture is
allowed to warm to ambient temperature, and stirred for 18.0 hours.
After such time, water (10.0 ml) is added and the mixture is
allowed to stir for 0.3 hours. The aqueous layer was extracted with
EtOAc. All organic layers were combined, washed (brine), dried
(MgSO.sub.4), and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, hexanes/EtOAc, 9:1)
yielded 0.47 g of II (86%) in a 9:1 E to Z isomer ratio. Data for
compound II. .sup.1H NMR (400 MHz, CDCl.sub.3) S 7.32 (d, J=2.4 Hz,
1H), 7.25 (dd, J=15.3 Hz, J=10.5 Hz, 1H), 6.90 (d, J=2.5 Hz, 1H),
6.30 (d, J=1, 1.5 Hz, 1H), 5.98 (tt, J=55.2 Hz, 4.1 Hz, 1H), 5.87
(d, J=15.4 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.95 (m, 2H), 2.24 (s,
3H), 1.41 (s, 9H), 1.30 (s, 9H), 1.25 (t, J=7.1 Hz, 3H).
Example 30
[0203] (Compound III of Scheme 6, where R=tert-butyl,
R'=1,1-difluoropropyl). To 0.47 g of II (1.15 mmol) dissolved in
anhydrous diethyl ether (15 ml) in a flame dried 25 ml r.b. flask
at 0.degree. C. is added lithium aluminum hydride (0.043 g, 1.15
mmol) portion wise. The resultant mixture is allowed to slowly warm
to ambient temperature, and stirred for 4.0 hours. After such time,
water (10.0 ml) is added and the mixture is allowed to stir for 0.3
hours. The aqueous layer was extracted with EtOAc. All organic
layers were combined, washed (brine), dried (MgSO.sub.4), and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 9:1) yielded 0.335 g of
III (80%). Data for compound III. .sup.1H NMR (400 MHz, CDCl.sub.3)
c 7.28 (d, J=2.5 Hz, 1H), 6.92 (d, J=2.5 Hz, 1H), 6.15 (m, 1H),
5.99 (tt, J=55.7 Hz, 4.1 Hz, 1H), 5.82 (d, J=10.9 Hz, 1H), 5.81 (d,
J=12.0 Hz, 1H), 3.86 (m, 4H), 2.14 (s, 3H), 1.40 (s, 9H), 1.30 (s,
9H).
Example 31
[0204] (Compound IV of Scheme 6, where R=tert-butyl,
R'=1,1-difluoropropyl). To 0.335 g of compound III (0.914 mmol)
dissolved in anhydrous CH.sub.2Cl.sub.2 (10.0 ml) in a flame dried
25 ml r.b. flask is added 4-Methylmorpholine N-oxide (0.161 g, 1.37
mmol) followed by Tetrapropylammonium perruthenate (0.016 g, 0.046
mmol). The resulting mixture is stirred at ambient temperature for
1.0 hours. After such time, the reaction mixture is filtered
through a plug of silica gel (eluding with CH.sub.2Cl.sub.2) and
concentrated under reduced pressure to yield 0.261 g of IV (80%).
Data for compound IV. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.40 (d, J=8.0 Hz, 1H), 7.37 (d, J=2.5 Hz, 1H), 7.04 (dd, J=15.2
Hz, J=11.4 Hz, 1H), 6.93 (d, J=2.4 Hz, 1H), 6.46 (d, J=11.0 Hz,
1H), 6.15 (dd, J=15.3 Hz, 8.0 Hz, 1H), 5.97 (tt, J=55.1 Hz, J=4.1
Hz, 1H), 3.94 (m, 2H), 2.30 (s, 3H), 1.42 (s, 9H), 1.31 (s,
9H).
Example 32
[0205] (Compound V of Scheme 6, where R=tert-butyl,
R'=1,1-difluoropropyl). To 0.261 g of compound IV (0.717 mmol)
dissolved in anhydrous diethyl ether (15.0 ml) in a flame dried 25
ml r.b. flask at 0.degree. C. is added methyl magnesium bromide
(0.789 mmol, 0.26 ml of 3.0 M solution in ether) dropwise via
syringe. The resultant mixture is kept at 0.degree. C. for 2.0
hours. After such time sat. NH.sub.4Cl (5.0 ml) is added and the
mixture is allowed to warm to room temperature. At room
temperature, the mixture is filtered through a plug of silica gel
(eluding with hexanes/EtOAc 9:1) and concentrated under reduced
pressure to yield the crude product mixture. Purification by flash
column chromatography (silica gel, hexanes/EtOAc, 9:1) yielded
0.232 g of V (85%). Data for compound V. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.28 (d, J=2.5 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H),
6.05 (m, 2H), 5.85 (tt, J=56.3 Hz, J=4.1 Hz, 1H), 5.74 (dd, J=13.9
Hz, J=6.3 Hz, 1H), 4.26 (m, 1H), 3.98 (m, 2H), 2.14 (s, 3H), 1.40
(s, 9H), 1.30 (s, 9H), 1.24 (d, J=6.4 Hz, 3H).
Example 33
[0206] (Compound VI of Scheme 6, where R=tert-butyl,
R'=1,1-difluoropropyl). To 0.232 g of compound V (0.612 mmol)
dissolved in anhydrous CH.sub.2Cl.sub.2 (10.0 ml) in a flame dried
25 ml r.b. flask is added 4-Methylmorpholine N-oxide (0.107 g, 0.92
mmol) followed by Tetrapropylammonium perruthenate (0.011 g, 0.031
mmol). The resulting mixture is stirred at ambient temperature for
1.5 hours. After such time, the reaction mixture is filtered
through a plug of silica gel (eluding with CH.sub.2Cl.sub.2) and
concentrated under reduced pressure to yield 0.120 g of VI (52%).
Data for compound VI. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.34 (d, J=2.5 Hz, 1H), 7.06 (dd, J=15.7 Hz, J=11.2 Hz, 1H), 6.93
(d, J=2.5 Hz, 1H), 6.32 (d, J=11.0 Hz, 1H), 6.12 (d, J=15.7 Hz,
1H), 5.96 (tt, J=55.1 Hz, J=4.1 Hz, 1H), 3.95 (m, 2H), 2.27 (s,
3H), 2.15 (s, 3H), 1.42 (s, 9H), 1.31 (s, 9H).
Example 34
[0207] (Compound VII of Scheme 6, where R=tert-butyl,
R'=1,1-difluoropropyl).
[0208] To 0.019 g of sodium hydride (0.411 mmol) suspended in
anhydrous DMF (2.0 ml) in a flame dried 10 ml r.b. flask at
0.degree. C. is added triethyl-2-fluoro-2-phosphonoacetate (0.092
g, 0.379 mmol) dropwise. The mixture is allowed to stir for 0.3
hours. Compound VI is then added dropwise (0.120 g, 0.316 mmol) via
solvation in anhydrous DMF (3.0 ml). The resultant mixture is
allowed to stir at 0.degree. C. for 2.0 hours. After such time,
water (5.0 ml) is added and the mixture is allowed to stir for 0.3
hours. The aqueous layer was extracted with EtOAc. All organic
layers were combined, washed (brine), dried (MgSO.sub.4), and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 9:1) yielded 0.135 g of
VII (92%) as a 1:1 E to Z isomer ratio. Data for compound VII.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d, J=2.6 Hz, 1H),
6.96 (d, J=2.3 Hz, 1H), 6.79 (d, J=15.5 Hz, 1H), 6.49 (dd, J=15.4
Hz, J=11.1 Hz, 1H), 6.35 (d, J=11.0 Hz, 1H), 5.97 (tt, J=55.3 Hz,
J=4.1 Hz, 1H), 4.30 (q, J=7.3 Hz, 2H), 3.95 (m, 2H), 2.21 (s, 3H),
2.07 (d, J=3.0 Hz, 3H), 1.41 (s, 9H), 1.36 (t, J=7.1 Hz, 3H), 1.31
(s, 9H).
Example 35
[0209] (L30, Compound VII of Scheme 6, where R=tert-butyl.
R'=1,1-difluoroethyl). To 0.135 g of compound VII (0.289 mmol)
dissolved in ethanol (10.0 ml) in a 25.0 ml r.b. flask is added 2 M
aqueous LiOH (0.868 mmol). The resultant mixture is heated to
60.degree. C. for 7.0 hours. After such time, the reaction is
cooled and concentrated under reduced pressure. The residue is
taken up in 1 N aqueous HCl (10.0 ml). The flask is sealed and
shaken for 1.0 minute. The resultant suspension was extracted with
EtOAc. All organic layers were combined, washed (brine), dried
(MgSO.sub.4), and concentrated under reduced pressure. The crude
reaction mixture is purified using HPLC (80:20:0.1 MeOH, H.sub.2O,
TFA). The purified 2-Z isomer is recrystallized from Acetonitrile
to yield VIII as a white crystalline solid. Data for compound VIII.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d, J=2.5 Hz, 1H),
6.95 (d, J=2.4 Hz, 1H), 6.76 (d, J=15.3 Hz, 1H), 6.56 (dd, J=15.4
Hz, J=11.0 Hz, 1H), 6.35 (d, J=10.8 Hz, 1H), 5.96 (tt, J=55.3 Hz,
J=4.1 Hz, 1H), 3.96 (m, 2H), 2.23 (s, 3H), 2.08 (d, J=3.1 Hz, 3H),
1.41 (s, 9H), 1.30 (s, 9H). 686970
[0210] In a preferred embodiment, Scheme 7 shows the synthetic
method employed in Examples 36-46. Scheme 7 corresponds to the
general synthetic method shown in Scheme 4 for the production of
coumarin intermediates (e.g., Structure XIV). The coumarin
intermediates as shown above are then converted to the desired RXR
modulator compounds as previously described and as shown in the
following examples.
Example 36
[0211] (Compound IX of Scheme 7, where R=isopropyl). To
3,5-Diisopropylsalicylic acid I (75.0 g, 0.34 mol) in a 300 mL
round bottom flask was added 150 mL of quinoline. The resulting
mixture was heated to 210.degree. C. for 4.0 hours, cooled to room
temperature, dissolved in EtOAc (500 mL), and extracted with 1N HCl
(2.times.500 mL). The organic layer was washed (water then brine),
dried (MgSO.sub.4), and concentrated under reduced pressure. The
crude product was purified by vacuum distillation (1 mm Hg,
collecting the fraction between 100.degree.-102.degree. C.) to
yield 50.0 g (0.28 mol) of Compound IX as a clear, pale yellow oil
(82% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.05 (d,
J=2.1 Hz, 1H, Ar--H), 6.93 (dd, J=8.2 Hz, J=2.2 Hz, 1H, Ar--H),
6.68 (d, J=8.2 Hz, 1H, Ar--H), 4.53 (s, 1H, R--OH), 3.19 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.85 (m, 1H, CH.sub.3--CH--CH.sub.3), 1.27
(d, J=6.8 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 37
[0212] (Compound X of Scheme 7, where R=isopropyl). To 52.2 g
(0.293 mol) of Compound IX dissolved in 400 mL of CH.sub.2Cl.sub.2
in a 1 liter round bottom flask was added 72.6 g (0.322 mol) of
N-Iodosuccinimide (NIS) and 5.6 g (0.029 mol) of p-toluene sulfuric
acid (pTSOH). The resultant mixture was stirred at ambient
temperature for 3.0 hours. After such time, 500 ml of 10% aqueous
Na.sub.2S.sub.2O.sub.3 was added and the reaction mixture was
stirred for an additional 0.5 hours. The aqueous layer was then
separated and extracted with CH.sub.2Cl.sub.2 (2.times.400 mL). The
organic layers were combined, washed (10% aqueous
Na.sub.2S.sub.2O.sub.3, then water, then brine), dried (MgSO.sub.4)
and concentrated under reduced pressure to give 89.1 g (0.29 mol)
of X as a deep red oil (99% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.33 (d, J=2.1 Hz, 1H, Ar--H), 7.00 (d, J=2.0
Hz, 1H, Ar--H), 4.83 (s, 1H, R--OH), 3.28 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.80 (m, 1H, CH.sub.3--CH--CH.sub.3), 1.23
(d, J=6.8 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.21 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 38
[0213] (Compound XI of Scheme 7, where R=isopropyl). To 1.6 g (0.04
mol) of sodium hydride dissolved in 225 ml of anhydrous
N,N-Dimethyl-formamide (DMF) in a flame dried 500 ml round bottom
flask at 0.degree. C., was added dropwise 10.0 g (0.033 mol) of
Compound X in 25 mL DMF. The Mixture was stirred at 0.degree. C.
for 0.5 hours followed by dropwise addition of 3.22 g (0.04 mol) of
methyl chloromethyl ether. The resultant reaction mixture was
allowed to warm to ambient temperature and stirred for 3.0 hours.
The contents of the flask were poured into iced brine (200 ml) and
stirred for 0.5 hours. The aqueous layer was extracted with diethyl
ether (2.times.200 mL) and the organic layers were combined, washed
(brine), dried (MgS.sub.4) and concentrated under reduced pressure.
The concentrated product was filtered through a silica gel plug
(eluting with diethyl ether) and concentrated under reduced
pressure to give 11.3 g (0.032 mol) of XI as a red oil (97% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.42 (d, J=1.8 Hz, 1H,
Ar--H), 7.06 (d, J=1.8 Hz, 1H, Ar--H), 5.05 (s, 2H, R--O--CH,
--O--CH.sub.3), 3.65 (s, 3H, R--O--CH.sub.2--O--CH.sub.3), 3.40 (m,
1H, CH.sub.3--CH--CH.sub.3), 2.81 (m, 1H, CH.sub.3--CH--CH.sub.3),
1.26 (d, J=6.5, 6H, CH.sub.3--CH--CH.sub.3), 1.21 (d, J=6.6, 6H,
CH.sub.3--CH--CH.sub.3).
Example 39
[0214] (Compound XII of Scheme 7, where R=isopropyl). To 10.0 g
(0.029 mol) of Compound XI dissolved in 150 ml of a 1:2 mixture of
diethyl ether-THF in a flame dried 300 ml round bottom flask at
-78.degree. C., was added 21.9 mL (0.035 mol) of a 1.6 M solution
of nBuLi in hexanes. The mixture was stirred at -78.degree. C. for
0.3 h followed by addition of 6.6 mL (0.058 mol) of trimethyl
borate in one portion via syringe. The resultant mixture is allowed
to stir at -78.degree. C. for 0.5 h, warmed to ambient temperature,
and stirred for a further 2 h. Aqueous HCl was added (30 ml of 1N
HCl) and the mixture stirred for an additional 0.5 h. The organic
layer was separated and the aqueous layer was extracted with EtOAc
(2.times.30 ml). The organic layers were combined, washed (water,
then 10% aqueous Na.sub.2S.sub.2O.sub.3, then brine), dried
(MgSO.sub.4), and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, hexanes/EtOAc, 9:1)
yielded 6.6 g (0.025 mol) of XII as a pale yellow oil (86% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.50 (d, J=2.3 Hz, 1H,
Ar--H), 7.23 (d, J=2.3 Hz, 1H, Ar--H), 5.94 (s, 2H, B(OH).sub.2),
5.00 (s, 2H, R--O--CH.sub.2--O--CH.sub- .3), 3.57 (s, 3H,
R--O--CH.sub.2--O--CH.sub.3), 3.21 (m, 1H, CH.sub.3--CH--CH.sub.3),
2.89 (m, 1H, CH.sub.3--CH--CH.sub.3), 1.25 (d, J=6.9, 6H,
CH.sub.3--CH--CH.sub.3), 1.24 (d, J=6.9, 6H,
CH.sub.3--CH--CH.sub.3).
Example 40
[0215] (Compound XIII of Scheme 7, where R=isopropyl). To 6.6 g
(0.025 mol) of Compound XII dissolved in 300 ml of 1:1
toluene-ethanol in a 500 ml round bottom flask, was added 7.86 g
(0.027 mol) of ethyl-2-(trifluoromethyl
sulfonyloxy)-1-cyclopentene-1-carboxylate, 5.3 g (0.05 mol) of 2 N
aqueous Na.sub.2CO.sub.3 and 2.89 g (0.0025 mol) of
tetrakis(triphenylphosphine) palladium (0). The reaction mixture
was heated to 90.degree. C. for 15.0 hours, then cooled to room
temperature, poured into brine (200 ml), and stirred for 0.3 hours.
The aqueous layer was extracted with EtOAc (2.times.200 mL) and the
organic layers were combined, dried (MgSO.sub.4), and concentrated
under reduced pressure. Purification by flash column chromatography
(silica gel, 9:1 hexanes-EtOAc) gave 8.0 g (0.022 mol) of XIII as a
yellow oil (89% yield). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.03 (d, J=2.2 Hz, 1H, Ar--H), 6.77 (d, J=2.2 Hz, 1H, Ar--H), 4.81
(s, 2H, R--O--CH)--O--CH.sub.3), 3.98 (q, J=7.1 Hz, 2H,
CO.sub.2--CH, --CH.sub.3), 3.49 (s, 3H,
R--O--CH.sub.2--O--CH.sub.3), 3.38 (m, TH, CH.sub.3--CH--CH.sub.3),
2.82 (m, 5H, ring CH.sub.2, ring CH.sub.2, CH.sub.3--CH--CH.sub.3),
1.99 (m, 2H, ring CH.sub.2), 1.22 (d, J=6.8 Hz, 6H,
CH.sub.3--CH-CH.sub.3), 1.21 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.95 (t, J=7.1 Hz, 3H,
CO.sub.2--CH.sub.2--CH.su- b.3).
Example 41
[0216] (Compound XIV of Scheme 7, where R=isopropyl). To 8.0 g
(0.022 mol) of Compound XIII dissolved in 150 ml of THF in a 300 ml
round bottom flask was added 6 N aqueous HCl (25.0 ml, 0.15 mol).
The resulting mixture was stirred at ambient temperature for 65.0
hours. After such time, the solvent was removed under reduced
pressure and the residue was taken up in water (100 ml). The
aqueous layer was extracted with EtOAc (2.times.100 mL) and the
organic layers were combined, washed (water then brine), dried
(MgSO.sub.4), and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, 9:1 hexanes-EtOAc) gave
5.9 g (0.022 mmol) of XIV as a yellow-orange oil which crystallized
upon standing (99% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.28 (d, J=1.7 Hz, 1H, Ar--H), 7.10 (d, J=1.8 Hz, 1H,
Ar--H) 3.65 (m, 1H, CH.sub.3--CH--CH.sub.3), 3.08 (t, J=7.6 Hz, 2H,
ring CH.sub.2) 2.93 (m, 3H, ring CH.sub.2, CH.sub.3--CH--CH.sub.3),
2.21 (m, 2H, ring CH.sub.2), 1.29 (d, J=7.4 Hz, 6H,
CH.sub.3--CHCH.sub.3), 1.28 (d, J=7.2 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 42
[0217] (Compound XV of Scheme 7, where R=isopropyl). To 2.0 g (7.4
mmol) of Compound XIV dissolved in 75 mL of anhydrous THF in a
flame dried 200 ml round bottom flask at 0.degree. C. was added 400
mg (7.4 mmol) of sodium aluminum hydride portion-wise. The
resultant mixture is allowed to warm to ambient temperature and
stirred for 4.0 hours. After such time, water (0.14 ml, 7.4 mmol)
was added, followed by 6 N aqueous sodium hydroxide (2.5 ml, 14.8
mmol). The resultant mixture was allowed to stir for 0.5 hours,
filtered through a plug of silica gel (eluting with diethyl ether)
and concentrated under reduced pressure to give 2.0 g (7.3 mmol) of
XV as a colorless oil (99% yield). .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 6.97 (d, J=2.1 Hz, Ar--H), 6.75 (d, J=2.2 Hz,
1H, Ar--H), 5.55 (s, 1H, Ar--OH), 5.07 (s, 2H, R--CH, --OH), 3.29
(m, 1H, CH.sub.3--CH--CH.sub.3), 2.82 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.70 (m, 4H, ring CH.sub.2), 2.02 (m, 2H,
ring CH.sub.2), 1.62 (br s, 1H, R--CH.sub.2--OH), 1.25 (d, J=6.9
Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.22 (d, J=7.1 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 43
[0218] (Compound XVI of Scheme 7, where R=isopropyl, R'=n-propyl).
To 2.0 g (7.30 mmol) of Compound XV dissolved in 75 mL of anhydrous
N,N-dimethylformamide (DMF) in a flame dried 200 ml round bottom
flask, was added 1.00 g (8.1 mmol) of 1-bromopropane followed by
4.5 g (29.6 mmol) of cesium fluoride. The mixture was allowed to
stir at ambient temperature for 18.0 h. Water (100 ml) was added
and the mixture was allowed to stir for an additional 0.5 h. The
aqueous layer was extracted with EtOAc (2.times.100 mL) and the
organic layers were combined, washed (brine), dried (MgSO.sub.4),
and concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 9:1 hexanes-EtOAc) yielded 2.15
g (6.79 mmol) of XVI as a brown oil (93% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 6.99 (d, J=2.2 Hz, 1H, Ar--H), 6.78 (d,
J=2.2 Hz, 1H, Ar--H), 3.98 (d, J=5.0 Hz, 2H, CH.sub.2--OH), 3.57
(t, J=6.7 Hz, 2H, R--O--CH.sub.3--CH.sub.2--CH.sub.3)- , 3.32 (m,
1H, CH.sub.3--CH--CH.sub.3), 2.84 (m, 1H, CH.sub.3--CH--CH.sub.3),
2.74 (t, J=7.3 Hz, 2H, ring CH.sub.2), 2.64 (t, J=7.3 Hz, 2H, ring
CH.sub.2), 2.00 (m, 2H, ring CH.sub.2), 1.71 (m, 2H,
R--O--CH.sub.2--CH, --CH.sub.3), 1.22 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.17 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.97 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3).
Example 44
[0219] (Compound XVII of Scheme 7, where R=isopropyl R'=n-propyl).
To 2.15 g (6.80 mmol) of Compound XVI dissolved in 70 mL of
anhydrous CH.sub.2Cl.sub.2 in a flame dried 200 ml round bottom
flask, was added 1.19 g (10.2 mmol) of 4-methylmorpholine N-oxide
(MMNO) followed by 0.119 g (0.34 mmol) of tetrapropylammonium
perruthenate (TPAP). The resulting mixture was stirred at ambient
temperature for 1.5 h. After such time, the reaction mixture was
filtered through a plug of silica gel (eluting with
CH.sub.2Cl.sub.2) and concentrated under reduced pressure to yield
2.13 g (6.21 mmol) of XVII as a pale yellow oil (91% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.69 (s, 1H, CHO), 7.11
(d, J=2.1 Hz, 1H, Ar--H), 6.85 (d, J=2.0 Hz, 1H, Ar--H), 3.55 (t,
J=6.4 Hz, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.3), 3.33 (m, 1H,
CH.sub.3--CH--CH.sub.3)- , 2.99 (t, J=7.4 Hz, 2H, ring CH.sub.2),
2.87 (m, 1H, CH.sub.3--CH--CH.sub.2), 2.72 (t, J=7.5 Hz, 2H, ring
CH.sub.2), 2.03 (m, 2H, ring CH.sub.2), 1.67 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.28 (d, J=7.1 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.23 (d, J=7.0 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.96 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2-- -CH.sub.3).
Example 45
[0220] (Compound XVIII of Scheme 7, where R=isopropyl, R'=n-propyl,
R"=H). To 5.38 g (20.4 mmol) of triethyl
3-methyl-4-phosphonocrotonate dissolved in 60.0 ml of a 1:2 mixture
of THF-DMPU in a flame dried 200 ml round bottom flask at
-78.degree. C., was added dropwise 13.6 mL (21.7 mmol) of 1.6 M
nBuLi in hexanes. The mixture was allowed to stir for 0.3 h
followed by dropwise addition of 2.33 g (6.80 mmol) of Compound
XVII in 10 mL of a 1:2 THF-DMPU solution. The reaction mixture was
allowed to stir at -78.degree. C. for 0.5 h, warmed to ambient
temperature, and stirred for an additional 2 h. Water (100 ml) was
added and the mixture was stirred for 0.5 h. The aqueous layer was
separated and extracted with EtOAc (2.times.100 mL), and the
organic layers were combined, washed (brine), dried (MgSO.sub.4),
and concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, 9:1 hexanes-EtOAc) gave 2.74 g
(6.45 mmol) of XVIII as a yellow oil (95% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 7.03 (d, J=2.2 Hz, 1H, Ar--H), 6.85 (d,
J=15.8 Hz, 1H, .dbd.CH) 6.79 (d, J=2.2 Hz, 1H, Ar--H), 6.21 (d,
J=15.8 Hz, 1H, .dbd.CH), 5.79 (s, 1H, .dbd.CH), 4.15 (q, J=7.1 Hz,
2H, --CO.sub.2--CH.sub.2--CH.sub.3) 3.53 (t, J=6.5 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3), 3.34 (m, 1H,
CH.sub.3--CH--CH.sub.3)- , 2.86 (m, 3H, CH.sub.3--CH--CH.sub.3,
ring CH.sub.2), 2.66 (t, J=7.3 Hz, 2H, ring CH.sub.2), 2.22 (s, 3H,
CH.sub.3), 2.01 (m, 2H, ring CH.sub.2), 1.65 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.27 (t, J=7.1 Hz, 3H,
--CO.sub.2--CH.sub.2--CH.sub.3) 1.24 (d, J=7.0 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.950 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3).
Example 46
[0221] (L8, Compound XIX of Scheme 7, where R=isopropyl,
R'=n-propyl, R"=H).
[0222] To 2.74 g (6.45 mmol) of Compound XVIII dissolved in 75 mL
of ethanol in a 200 ml round bottom flask was added 10 mL (20.0
mmol) of a 2 M aqueous LiOH solution. The mixture was heated to
90.degree. C. for 3.0 hours, then cooled and concentrated under
reduced pressure. The residue was taken up in 100 mL of 1 N aqueous
HCl and the flask was shaken for 1 min. The resultant suspension
was extracted with EtOAc (2.times.100 mL) and the organic layers
were combined, washed (brine), dried (MgSO.sub.4), and concentrated
under reduced pressure. The concentrate was filtered through a
short plug of silica gel (eluting with EtOAc), concentrated under
reduced pressure and crystallized from acetonitrile to give 2.41 g
(5.68 mmol) of XIX as light yellow crystals (88% yield). .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (d, J=2.1 Hz, 1H, Ar--H),
6.90 (d, J=15.8 Hz, 1H, .dbd.CH) 6.79 (d, J=2.1 Hz, 1H, Ar--H),
6.23 (d, J=15.7 Hz, 1H, .dbd.CH), 5.81 (s, 1H, .dbd.CH), 3.53 (t,
J=6.5 Hz, 2H, R--O--CH)--CH.sub.2--CH.sub.3), 3.33 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.88 (m, 3H, CH.sub.3--CH--CH.sub.3, ring
CH.sub.2), 2.66 (t, J=7.3 Hz, 2H, ring CH.sub.2), 2.23 (s, 3H,
CH.sub.3), 2.03 (m, 2H, ring CH.sub.2), 1.65 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.24 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.951 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3).
Example 47
[0223] (L9, Compound XIX of Scheme 7, where R=isopropyl,
R'=n-butyl, R"=H). This compound was prepared in the manner
previously described for Compound XIX in Example 46, except that
bromobutane was used instead of bromopropane in Example 43. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (d, J=2.1 Hz, 1H, Ar--H),
6.90 (d, J=15.7 Hz, 1H, .dbd.CH) 6.79 (d, J=2.1 Hz, 1H, Ar--H),
6.23 (d, J=15.8 Hz, 1H, .dbd.CH), 5.81 (s, 1H, .dbd.CH), 3.57 (t,
J=6.4 Hz, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.s- ub.3), 3.33
(m, 1H, CH.sub.3--CH--CH.sub.3), 2.88 (m, 3H,
CH.sub.3--CH--CH.sub.3, ring CH.sub.2), 2.67 (t, J=7.2 Hz, 2H, ring
CH.sub.2), 2.23 (s, 3H, CH.sub.3), 2.02 (m, 2H, ring CH.sub.2);
1.60 (m, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 1.41
(m, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3) 1.24 (d,
J=7.0 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.906 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3).
Example 48
[0224] (L10, Compound XIX of Scheme 7, where R=isopropyl,
R'=n-pentyl, R"=Hl. This compound was prepared in the manner
previously described for Compound XIX in Example 46, except that
bromopentane was used instead of bromopropane in Example 43.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.03 (d, J=2.3 Hz, 1H,
Ar--H), 6.90 (d, J=15.8 Hz, 1H, .dbd.CH) 6.79 (d, J=2.3 Hz, 1H,
Ar--H), 6.23 (d, J=15.8 Hz, 1H, .dbd.CH), 5.82 (s, 1H, .dbd.CH),
3.56 (t, J=6.5 Hz, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.s-
ub.2--CH.sub.3), 3.33 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.88 (m, 3H,
CH.sub.3--CH--CH.sub.3, ring CH.sub.2), 2.67 (t, J=7.4 Hz, 2H, ring
CH.sub.2), 2.22 (s, 3H, CH.sub.3), 2.02 (m, 2H, ring CH.sub.2),
1.63 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 1.32 (m,
4H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3) 1.24
(d, J=6.9 Hz, 6H, CH.sub.3CH--CH.sub.3), 1.23 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.89 (t, J=7.0 Hz, 3H,
R--O--CH.sub.2--CH.sub.2-- -CH.sub.2--CH.sub.2--CH.sub.3).
Example 49
[0225] (L31, Compound XIX of Scheme 7, where R=isopropyl,
R'=1,1,1-trifluorobutyl, R"=H). This compound was prepared in the
manner previously described for Compound XIX in Example 46, except
that 4,4,4-trifluoro-1-bromo-butane was used instead of
bromopropane in Example 43. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.04 (d, J=2.2 Hz, 1H, Ar--H), 6.84 (d, J=15.8 Hz, 1H,
C.dbd.CH), 6.80 (d, J=2.2 Hz, 1H, Ar--H), 6.24 (d, J=15.8 Hz, 1H,
C.dbd.CH), 5.82 (s, 1H, C.dbd.CH), 3.62 (t, J=5.9 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CF.sub.3), 3.26 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.86 (m, 3H, CH.sub.3--CH--CH.sub.3, ring
CH.sub.2), 2.68 (t, J=7.3 Hz, 2H, ring CH.sub.2), 2.22 (s, 3H,
CH.sub.3), 2.21 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CF.sub.3), 2.03 (dt, J=114.9
Hz, J=7.4 Hz, 2H, ring CH.sub.2), 1.87 (dt, J=15.8 Hz, J=5.9 Hz,
2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CF.sub.3), 1.24 (d, J=6.8
Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 50
[0226] (L32, Compound XIX of Scheme 7, where R=isopropyl,
R'=1,1-difluoroethyl, R"=H). This compound was prepared in the
manner previously described for Compound XIX in Example 46, except
that 2,2-difluoro-1-bromo-ethane was used instead of bromopropane
in Example 43. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.06 (d,
J=2.1 Hz, 1H, Ar--H), 6.84 (d, J=16.5 Hz, 1H, C.dbd.CH), 6.81 (d,
J=2.3 Hz, 1H, Ar--H), 6.27 (d, J=15.8 Hz, 1H, C.dbd.CH), 5.90 (tt,
J=55.2 Hz, J=4.1 Hz, 1H, R--O--CH.sub.2--CF.sub.2H), 5.83 (s, 1H,
C.dbd.CH), 3.80 (td, J=13.8 Hz, J=4.1 Hz, 2H,
R--O--CH.sub.2--CF.sub.2H), 3.33 (m, 1H, CH.sub.3--CH--CH.sub.3),
2.87 (m, 3H, CH.sub.3--CH--CH.sub.3, ring CH.sub.2), 2.69 (t, J=7.4
Hz, 2H, ring CH.sub.2), 2.22 (s, 3H, CH.sub.3), 2.04 (dt, J=14.9
Hz, J=7.5 Hz, 2H, ring CH.sub.2), 1.25 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.24 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 51
[0227] (L33, Compound XIX of Scheme 7, where R=isopropyl,
R'=1,1-difluoropropyl, R" H). This compound was prepared in the
manner previously described for Compound XIX in Example 46, except
that 3,3-difluoro-1-bromopropane was used instead of bromopropane
in Example 43. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.05 (d,
J=2.0 Hz, 1H, Ar--H), 6.83 (d, J=14.9 Hz, 1H, C.dbd.CH), 6.81 (d,
J=2.3 Hz, 1H, Ar--H), 6.25 (d, J=15.8 Hz, 1H, C.dbd.CH), 5.99 (tt,
J=56.8 Hz, J=4.8 Hz, 1H, R--O--CH.sub.2--CH.sub.2--CF.sub.2H), 5.83
(s, 1H, C.dbd.CH), 3.71 (t, J=5.8 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CF.sub.2H), 3.24 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.86 (m, 3H, CH.sub.3--CH--CH.sub.3, ring
CH.sub.2), 2.69 (t, J=7.2 Hz, 2H, ring CH.sub.2), 2.21 (s, 3H,
CH.sub.3), 2.10 (m, 4H, R--O--CH.sub.2--CH.sub.2--CF.sub.2H, ring
CH.sub.2), 1.24 (d, J=6.9 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.23 (d,
J=6.8 Hz, 6H, CH.sub.3--CH--CH.sub.3).
Example 52
[0228] (L34, Compound XIX of Scheme 7, where R=isopropyl,
R'=1,1,2,2-tetrafluoropropyl, R"=H). This compound was prepared in
the manner previously described for Compound XIX in Example 46,
except that 1,1,2,2-tetrafluorobromopropane was used instead of
bromopropane in Example 43. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.07 (d, J=2.2 Hz, 1H, Ar--H), 6.82 (d, J=2.2 Hz, 1H,
Ar--H), 6.77 (d, J=15.8 Hz, 1H, C.dbd.CH), 6.27 (d, J=15.8 Hz, 1H,
C.dbd.CH), 5.96 (tt, J=53.2 Hz, J=5.1 Hz, 1H,
R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 5.84 (s, 1H, C.dbd.CH), 3.93
(t, J=12.1 Hz, 2H, R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 3.27 (m,
1H, CH.sub.3--CH--CH.sub.3), 2.87 (m, 3H, CH.sub.3--CH--CH.sub.3,
ring CH.sub.2), 2.69 (t, J=7.5 Hz, 2H, ring CH.sub.2), 2.21 (s, 3H,
CH.sub.3), 2.04 (dt, J=14.9 Hz, J=7.4 Hz, 2H, ring CH.sub.2), 1.25
(d, J=6.9 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.24 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 53
[0229] (L35, Compound XIX of Scheme 7, where R=tert-butyl,
R'=1,1,2,2-tetrafluoropropyl, R"=H). This compound was prepared in
the manner previously described for Compound XIX in Example 46,
except that 3,5-di-tert-butylsalicylic acid was used instead of
3,5-diisopropylsalicylic acid in Example 36 and
1,1,2,2-tetrafluorobromop- ropane was used instead of bromopropane
in Example 43. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.32 (d,
J=2.6 Hz, 1H, Ar--H), 6.97 (d, J=2.5 Hz, 1H, Ar--H), 6.74 (d,
J=15.8 Hz, 1H, C.dbd.CH), 6.26 (d, J=15.8 Hz, 1H, C.dbd.CH), 5.85
(tt, J=53.1 Hz, J=4.9 Hz, 1H, R--O--CH.sub.2--CF.sub.-
2--CF.sub.2H), 5.83 (s, 1H, C.dbd.CH), 4.03 (m, 2H,
R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 2.87 (m, 2H, ring CH.sub.2),
2.68 (m, 2H, ring CH.sub.2), 2.19 (d, J=0.8 Hz, 3H, CH.sub.3), 2.07
(m, 2H, ring CH.sub.2), 1.41 (s, 9H, .sup.tbutyl), 1.31 (s, 9H,
.sup.tbutyl).
Example 54
[0230] (L14, Compound XIX of Scheme 7, where R=isopropyl,
R'=1-fluoropropyl, R"=H). This compound was prepared in the manner
previously described for Compound XIX in Example 46, except that
3-fluoro-1-bromopropane was used instead of bromopropane in Example
43. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.04 (d, J=2.2 Hz,
1H, Ar--H), 6.86 (d, J=15.8 Hz, 1H, C.dbd.CH), 6.81 (d, J=2.2 Hz,
1H, Ar--H), 6.24 (d, J=15.7 Hz, 1H, C.dbd.CH), 5.82 (s, 1H,
C.dbd.CH), 4.57 (dt, J=47.1 Hz, J=5.8 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2, 9), 3.69 (t, J=5.9 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2F), 3.28 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.86 (m, 3H, CH.sub.3--CH--CH.sub.3, ring
CH.sub.2), 2.68 (t, J=7.4 Hz, 2H, ring CH.sub.2), 2.22 (s, 3H,
CH.sub.3), 2.00 (m, 4H, R--O--CH.sub.2--CH.sub.2--CH.sub.2F, ring
CH.sub.2), 1.25 (d, J=6.9 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.24 (d,
J=6.8 Hz, 6H, CH.sub.3--CH--CH.sub.3).
Example 55
[0231] (L36, Compound XIX of Scheme 7, where R=isopropyl,
R'=1-fluoropropyl, R"=F). This compound was prepared in the manner
previously described for Compound XIX in Example 46, except that
triethyl 2-fluoro-3-methyl-4-phosphonocrotonate was used instead of
triethyl 3-methyl-4-phosphonocrotonate in Example 45 and
3-fluoro-1-bromopropane was used instead of bromopropane in Example
43. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.05 (d, J=2.2 Hz,
1H, Ar--H), 6.85 (d, J=15.9 Hz, 1H, C.dbd.CH), 6.81 (d, J=2.1 Hz,
1H, Ar--H), 6.69 (d, J=15.8 Hz, 1H, C.dbd.CH), 4.57 (dt, J=47.2 Hz,
J=5.8 Hz, 2H, R--O--CH.sub.2--CH, --CH.sub.2F), 3.69 (t, J=5.9 Hz,
2H, R--O--CH, --CH.sub.2--CH.sub.2F), 3.29 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.86 (m, 3H, CH.sub.3--CH--CH.sub.3, ring
CH.sub.2), 2.73 (t, J=7.4 Hz, 2H, ring CH.sub.2), 2.16 (d, J=3.2
Hz, 3H, CH.sub.3), 2.01 (m, 4H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2F, ring CH.sub.2), 1.24 (d, J=6.9
Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.23 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3)
Example 55a
[0232] (L37, Compound XX of Scheme 7, where R=tert-butyl,
R'=1-fluoropropyl, R"=H). This compound was prepared in the manner
previously described for Compound XIX in Example 46, except that
3,5-di-tert-butylsalicylic acid was used instead of
3,5-diisopropylsalicylic acid in Example 36 and
3-fluoro-1-bromopropane was used instead of bromopropane in Example
43. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.28 (d, J=2.4 Hz,
1H, Ar--H), 6.97 (d, J=2.4 Hz, 1H, Ar--H), 6.85 (d, J=15.8 Hz, 1H,
C.dbd.CH), 6.23 (d, J=15.8 Hz, 1H, C.dbd.CH), 5.82 (s, 1H,
C.dbd.CH), 4.54 (dt, J=47.1 Hz, J=5.9 Hz, 2H,
R--O--CH.sub.2--CF.sub.2--CH.sub.2F), 3.75 (m, 2H,
R--O--CH.sub.2--CF.sub.2--CH.sub.2F), 2.88 (m, 2H, ring CH.sub.2),
2.68 (t, J=7.3, 2H, ring CH.sub.2), 2.21 (s, 3H, CH.sub.3), 1.99
(m, 4H, R--O--CH.sub.2--CH)--CH.sub.2F, ring CH.sub.2), 1.40 (s,
9H, .sup.tbutyl), 1.30 (s, 9H, .sup.tbutyl). 7172
[0233] Scheme 8 provides an alternate route to that proposed in
Scheme 7 for introduction of fluorine at position R.sup.9 of the
modulator compounds.
Example 56
[0234] (Compound II of Scheme 8, where R=propyl, R'=-fluoropropyl).
To 0.114 g of sodium hydride (2.38 mmol) suspended in anhydrous DMF
(10 ml) in a flame dried 25 ml r.b. flask at 0.degree. C. is added
triethyl-phosphonoacetate (0.501 g, 2.23 mmol) dropwise. The
mixture is allowed to stir for 0.2 hours. Compound I is then added
dropwise (0.495 g, 1.49 mmol) via solvation in anhydrous DMF (5.0
ml). The resultant mixture is allowed to warm to ambient
temperature, and stirred for 2.0 hours. After such time, water
(10.0 ml) is added and the mixture is allowed to stir for 0.3
hours. The aqueous layer was extracted with EtOAc. All organic
layers were combined, washed (brine), dried (MgSO.sub.4), and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 9:1) yielded 0.60 g of
II (100%) as the E-isomer exclusively. Data for compound II.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.48 (d, J=15.6 Hz, 1H),
7.05 (d, J=2.0 Hz, 1H), 6.76 (d, J=2.2 Hz, 1H), 5.80 (d, J=15.7 Hz,
1H), 4.58 (dt, J=47.1 Hz, 5.9 Hz, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.68
(t, J=6.0 Hz, 2H), 3.28 (m, 1H), 2.85 (m, 3H), 2.65 (t, J=7.5 Hz,
2H), 2.01 (m, 4H), 1.25 (t, J=7.1 Hz, 3H), 1.24 (d, J=7.3 Hz, 6H),
1.23 (d, J=7.1 Hz, 6H).
Example 57
[0235] (Compound III of Scheme 8, where R=isopropyl,
R'=1-fluoropropyl). To 0.61 g of 11 (1.51 mmol) suspended in
anhydrous diethyl ether (15 ml) in a flame dried 25 ml r.b. flask
at 0.degree. C. is added lithium aluminum hydride (0.057 g, 1.51
mmol) portion wise. The resultant mixture is allowed to slowly warm
to ambient temperature, and stirred for 4.0 hours. After such time,
water (10.0 ml) is added and the mixture is allowed to stir for 0.3
hours. The aqueous layer was extracted with EtOAc. All organic
layers were combined, washed (brine), dried (MgSO.sub.4), and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 9:1) yielded 0.441 g of
III (83%). Data for compound III. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.05 (d, J=2:2 Hz, 1H), 6.77 (d, J=2.2 Hz, 1H), 6.40 (d,
J=15.4 Hz, 1H), 5.78 (dt, J=15.7 Hz, J=6.2 Hz, 1H),), 5.59 (dt,
J=47.2 Hz, 5.9 Hz, 2H), 4.17 (t, J=5.7 Hz, 2H), 3.70 (t, J=5.9 Hz,
2H), 3.30 (m, 1H) 2.86 (m, 3H), 2.82 (t, J=7.4 Hz, 2H), 2.63 (t,
J=7.3 Hz, 2H), 1.84 (m, 4H), 1.23 (d, J=6.8 Hz, 12H).
Example 58
[0236] (Compound IV of Scheme 8, where R=isopropyl,
R'=1-fluoropropyl). To 0.441 g of compound III (1.22 mmol)
dissolved in anhydrous CH.sub.2Cl.sub.2 (10.0 ml) in a flame dried
25 ml r.b. flask is added 4-Methylmorpholine N-oxide (0.215 g, 1.84
mmol) followed by Tetrapropylammonium perruthenate (0.021 g, 0.061
mmol). The resulting mixture is stirred at ambient temperature for
1.0 hours. After such time, the reaction mixture is filtered
through a plug of silica gel (eluding with CH.sub.2Cl.sub.2) and
concentrated under reduced pressure to yield 0.437 g of IV (100%).
Data for compound IV. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.49 (d, J=8.0 Hz, 1H), 7.28 (d, J=16.1 Hz, 1H), 7.10 (d, J=2.2 Hz,
1H), 6.79 (d, J=2.2 Hz, 1H), 6.09 (dd, J=15.4 Hz, J=8.0 Hz, 1H)),
4.34 (dt, J=47.1 Hz, J=5.7 Hz, 2H), 3.69 (t, J=5.9 Hz, 2H), 3.30
(m, 1H) 2.88 (m, 3H), 2.70 (t, J=7.5 Hz, 2H), 2.20 (m, 4H), 1.25
(d, J=7.0 Hz, 6H), 1.24 (d, J=6.8 Hz, 6H).
Example 59
[0237] (Compound V of Scheme 8, where R=isopropyl,
R'=1-fluoropropyl). To 0.437 g of compound IV (1.22 mmol) dissolved
in anhydrous diethyl ether (15.0 ml) in a flame dried 25 ml r.b.
flask at 0.degree. C. is added methyl magnesium bromide (1.34 mmol,
0.45 ml of 3.0 M solution in ether) dropwise via syringe. The
resultant mixture is kept at 0.degree. C. for 2.0 hours. After such
time sat. NH.sub.4Cl (10 ml) is added and the mixture is allowed to
warm to room temperature. Once at room temperature, the mixture is
filtered through a plug of silica gel (eluding with hexanes/EtOAc
9:1) and concentrated under reduced pressure to yield 0.233 g of V
(51%). Data for compound V. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.01 (d, J=2.0 Hz, 1H), 6.78 (d, J=2.1 Hz, 1H), 6.36 (d,
J=15.7 Hz, 1H), 5.66 (dd, J=15.8 Hz, J=6.8 Hz, 1H),), 4.59 (dt,
J=47.2 Hz, J=5.9 Hz, 2H), 4.32 (m, 1H), 3.70 (t, J=6.0 Hz, 2H),
3.29 (m, 1H) 2.84 (m, 3H), 2.62 (t, J=7.4 Hz, 2H), 2.01 (m, 4H),
1.27 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.9 Hz, 12H).
Example 60
[0238] (Compound VI of Scheme 8, where R=isopropyl,
R'=1-fluoropropyl). To 0.233 g of compound V (0.62 mmol) dissolved
in anhydrous CH.sub.2Cl.sub.2 (10.0 ml) in a flame dried 25 ml rb.
flask is added 4-Methylmorpholine N-oxide (0.109 g, 0.93 mmol)
followed by Tetrapropylammonium perruthenate (0.011 g, 0.031 mmol).
The resulting mixture is stirred at ambient temperature for 1.0
hours. After such time, the reaction mixture is filtered through a
plug of silica gel (eluding with CH.sub.2Cl.sub.2) and concentrated
under reduced pressure to yield 0.204 g of VI (100%). Data for
compound VI. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d,
J=16.1 Hz, 1H), 7.07 (d, J=2.2 Hz, 1H), 6.79 (d, J=2.1 Hz, 1H),
6.06 (d, J=16.1 Hz, 1H), 4.57 (dt, J=47.1 Hz, J=5.8 Hz, 2H), 3.68
(t, J=5.9 Hz, 2H), 3.29 (m, 1H), 2.90 (m, 3H), 2.67 (t, J=7.4 Hz,
2H), 2.21 (s, 3H), 2.01 (m, 4H), 1.25 (d, J=7.0 Hz, 6H), 1.24 (d,
J=6.9 Hz, 6H).
Example 61
[0239] (Compound XVIII of Scheme 8, where R=isopropyl,
R'=1-fluoropropyl). To 0.034 g of sodium hydride (0.713 mmol)
suspended in anhydrous DMF (4.0 ml) in a flame dried 15 ml r.b.
flask at 0.degree. C. is added triethyl-2-fluoro-2-phosphonoacetate
(0.159 g, 0.659 mmol) dropwise. The mixture is allowed to stir for
0.3 hours. Compound VI is then added dropwise (0.204 g, 0.549 mmol)
via solvation in anhydrous DMF (3.0 ml). The resultant mixture is
allowed to stir at 0.degree. C. for 0.75 hours. After such time,
water (10.0 ml) is added and the mixture is allowed to stir for 0.3
hours. The aqueous layer was extracted with EtOAc. All organic
layers were combined, washed (brine), dried (MgSO.sub.4), and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 9:1) yielded 0.267 g of
XVIII (100%) as a 1:1 E to Z isomer ratio. Data for compound XVIII.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.04 (s, 1H), 6.82 (s,
1H), 6.78 (d, J=16.2 Hz, 1H), 6.69 (d, J=16.1 Hz, 1H), 4.58 (dt,
J=47.2 Hz, J=5.9 Hz, 2H), 4.31 (q, J=7.1 Hz, 2H), 3.70 (t, J=5.8
Hz, 2H), 3.30 (m, 1H), 2.85 (m, 3H), 2.73 (t, J=7.1 Hz, 2H), 2.14
(d, J=3.0 Hz, 3H), 2.00 (m, 4H), 1.38 (t, J=7.1 Hz, 3H), 1.25 (d,
J=6.9 Hz, 6H), 1.24 (d, J=6.8 Hz, 6H).
Example 62
[0240] (L36, Compound XIX of Scheme 8, where R=isopropyl,
R'=1-fluoropropyl). To 0.267 g of compound XVIII (0.580 mmol)
dissolved in ethanol (10.0 ml) in a 25.0 ml r.b. flask is added 2 M
aqueous LiOH (1.16 mmol). The resultant mixture is heated to
60.degree. C. for 7.0 hours. After such time, the reaction is
cooled and concentrated under reduced pressure. The residue is
taken up in 1 N aqueous HCl (10.0 ml). The flask is sealed and
shaken for 1.0 minute. The resultant suspension was extracted with
EtOAc. All organic layers were combined, washed (brine), dried
(MgSO.sub.4), and concentrated under reduced pressure. The crude
reaction mixture is purified using HPLC (85:15:0.1 MeOH, H.sub.2O,
TFA). The purified 2-Z isomer is recrystallized from acetonitrile
to yield 0.107 g of XIX (42.8%) as a pale yellow crystalline solid.
Data for compound XIX. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.05 (d, J=2.2 Hz, 1H), 6.85 (d, J=15.9 Hz, 1H), 6.81 (d, J=2.1 Hz,
1H), 6.69 (d, J=15.8 Hz, 1H), 4.57 (dt, J=47.2 Hz, J=5.8 Hz, 2H),
3.69 (t, J=5.9 Hz, 2H), 3.29 (m, 1H), 2.86 (m, 3H), 2.73 (t, J=7.4
Hz, 2H), 2.16 (d, J=3.2 Hz, 3H), 2.01 (m, 4H), 1.24 (d, J=6.9 Hz,
6H), 1.23 (d, J=6.8 Hz). 7374
[0241] Scheme 9 shows the preparation of additional coumarin
intermediates (e.g., Structure III) in another preferred aspect of
the invention. The coumarin intermediates may then be converted to
the desired RXR modulator compounds as previously described and as
further described in Examples 63-69.
Example 63
[0242] (Compound II of Scheme 9, where R=isopropyl). To 0.45 g of
Compound I (1.68 mmol) dissolved in toluene/ethanol (1:1, 20.0 ml)
in a 50 ml r.b. flask was added
Methyl-3-bromothiophene-2-carboxylate (0.37 g, 1.68 mmol), 2 N
aqueous Na.sub.2CO.sub.3 (0.36 g, 3.36 mmol,), and
Tetrakis(triphenylphosphine) palladium(0) (0.194 g, 0.17 mmol). The
reaction mixture was heated to 90.degree. C. for 15.0 hours. The
mixture was then cooled, poured into brine (20.0 ml), and stirred
for 0.3 hours. The aqueous layer was extracted with EtOAc. All
organic layers were combined, dried (MgSO.sub.4), and concentrated
under reduced pressure. Purification by flash column chromatography
(silica gel, hexanes/EtOAc, 9:1) yielded 0.17 g of II (28%) as a
yellow solid. Data for Compound II. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.50 (d, J=5.2 Hz, 1H, thiophene-H), 7.13 (d,
J=5.4 Hz, 1H, thiophene-H), 7.12 (d, J=2.5 Hz, 1H, Ar--H), 6.95 (d,
J=2.2 Hz, 114, Ar--H), 4.55 (s, 2H, R--O--CH.sub.2--O--CH.sub.3),
3.78 (s, 3H, R--O--CH.sub.2--O--CH.sub.3), 3.39 (m, 1H,
CH.sub.3--CH--CH.sub.3), 3.18 (s, 3H, CO.sub.2CH.sub.3), 2.89 (m,
1H, CH.sub.3--CH--CH.sub.3), 1.26 (d, J=6.7 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.25 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 64
[0243] (Compound III of Scheme 9, where R=isopropyl). To 0.17 g of
Compound II (0.46 mmol) dissolved in THF (15.0 ml) in a 25 ml r.b.
flask was added 6 N aqueous HCl (2.0 ml, 0.012 mol). The resulting
mixture is allowed to stir at ambient temperature for 65.0 hours.
After such time, the solvent is removed under reduced pressure. The
residue was taken up in water (25.0 ml). The aqueous layer was
extracted with EtOAc. All organic layers were combined, washed
(water then brine), dried (MgSO.sub.4), and concentrated under
reduced pressure. Purification by flash column chromatography
(silica gel, hexanes/EtOAc, 9:1) yielded 0.101 g of III (77%) as a
yellow oil. Data for Compound III. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.89 (d, J=5.0 Hz, 1H, thiophene-H), 7.67 (d,
J=5.3 Hz, 1H, thiophene-H) 7.51 (d, J=2.1 Hz, 1H, Ar--H), 7.21 (d,
J=1.9 Hz, 1H, Ar--H) 3.70 (m, 1H, CH.sub.3--CH--CH.sub.3), 3.01 (m,
1H, CH.sub.3--CHCH.sub.3), 1.34 (d, J=7.1 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.32 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 65
[0244] (Compound IV of Scheme 9, where R=isopropyl). To 0.101 g of
Compound III (0.35 mmol) dissolved in anhydrous THF (10.0 ml) in a
flame dried 25 ml r.b. flask at 0.degree. C. is added Sodium
aluminum hydride (0.02 g, 0.35 mmol) portion wise. The resultant
reaction mixture is allowed to slowly warm to ambient temperature
and stirred for 2.0 hours. After such time, water (0.01 ml, 0.35
mmol) is added followed by 6 N aqueous sodium hydroxide (0.12 ml,
0.70 mmol). The resultant mixture is allowed to stir for 0.5 hours,
filtered through a plug of silica gel (eluding with diethyl ether)
and concentrated under reduced pressure to yield 0.102 g of IV
(100%) as a clear, colorless oil. Data for Compound IV. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta. 7.40 (d, J=5.1 Hz, 1H, thiophene-H),
7.07 (d, J=2.2 Hz, 1H, Ar--H), 7.03 (d, J=5.1 Hz, 1H, thiophene-H),
6.86 (d, J=2.2 Hz, Ar--H), 5.43 (s, 1H, Ar--OH), 4.69 (d, J=5.2 Hz,
2H, R--CH.sub.2--OH), 3.74 (t, J=6.6 Hz, 1H, R--CH.sub.2--OH), 3.31
(m, 1H, CH.sub.3--CH--CH.sub.3), 2.86 (m, 1H,
CH.sub.3--CH--CH.sub.3), 1.28 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.24 (d, J=7.1 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 66
[0245] (Compound V of Scheme 9, where R=isopropyl, R'=n-butyl). To
0.102 g of Compound IV (0.34 mmol) dissolved in anhydrous
N,N-Dimethylformamide (10.0 ml) in a flame dried 25 ml r.b. flask
is added 1-Bromobutane (0.052 g, 0.378 mmol) followed by Cesium
fluoride (0.21 g, 1.38 mmol). The resulting mixture is allowed to
stir at ambient temperature for 18.0 hours. Water (15.0 ml) is
added and the mixture is allowed to stir for 0.5 hours. The aqueous
layer was extracted with EtOAc. All organic layers were combined,
washed (brine), dried (MgSO.sub.4), and concentrated under reduced
pressure. Purification by flash column chromatography (silica gel,
hexanes/EtOAc, 9:1) yielded 0.0748 g of V (63%) as a pale yellow
oil. Data for Compound V. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.32 (d, J=5.0 Hz, 1H, thiophene-H), 7.10 (d, J=2.2 Hz, 1H, Ar--H),
7.01 (d, J=5.0 Hz, 1H, thiophene-H), 6.92 (d, J=2.3 Hz, 1H, Ar--H),
4.52 (d, J=6.3 Hz, 2H, R--C.sub.1H.sub.2--OH), 3.66 (t, J=6.4 Hz,
1H, R--CH.sub.2--OH), 3.39 (t, J=6.7 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2CH.sub.3), 3.34 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.89 (m, 1H, CH.sub.3--CH--CH.sub.3), 1.44
(m, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 1.25 (m,
14H, CH.sub.3--CH--CH.sub.3,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 0.80 (t, J=7.3 Hz,
3H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3).
Example 67
[0246] (Compound VI of Scheme 9, where R=isopropyl, R'=n-butyl). To
0.0748 g of Compound V (0.22 mmol) dissolved in anhydrous
CH.sub.2Cl.sub.2 (3.0 ml) in a flame dried 10 ml r.b. flask is
added 4-Methylmorpholine N-oxide (0.04 g, 0.32 mmol) followed by
Tetrapropylammonium perruthenate (0.004 g, 0.011 mmol). The
resulting mixture is stirred at ambient temperature for 1.0 hour.
After such time, the reaction mixture is filtered through a plug of
silica gel (eluding with CH.sub.2Cl.sub.2) and concentrated under
reduced pressure to yield 0.075 g of VI (100%) as a yellow oil.
Data for Compound VI. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
9.78 (s, 1H, CHO), 7.71 (d, J=5.0 Hz, 1H, thiophene-H), 7.25 (d,
J=5.5 Hz, 1H, thiophene-H), 7.17 (d, J=2.0 Hz, 1H, Ar--H), 6.99 (d,
J=2.0 Hz, 1H, Ar--H), 3.36 (m, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3,
CH.sub.3--CH--CH.sub.3)- , 2.91 (m, 1H, CH.sub.3--CH--CH.sub.3),
1.45 (m, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 1.26
(m, 14H, CH.sub.3--CH--CH.sub.3,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 0.79 (t, J=7.3 Hz,
3H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3).
Example 68
[0247] (Compound VII of Scheme 9, where R=isopropyl, R'=n-butyl,
R"=H). To 0.17 g of Triethyl 3-methyl-4-phosphonocrotonate (0.65
mmol) dissolved in THF/DMPU (1:2, 2.5 ml) in a flame dried 15 ml
r.b. flask at -78.degree. C. is added .sup.nBuLi (0.69 mmol, in
hexanes) dropwise. The mixture is allowed to stir for 0.1 hours.
Compound VI is then added dropwise (0.075 g, 0.22 mmol) via
solvation in THF/DMPU (1:2, 2.5 ml). The resultant mixture is
allowed to stir at -78.degree. C. for 0.3 hours, warmed to ambient
temperature, and stirred for 2.0 hours. After such time, water
(10.0 ml) is added and the mixture is allowed to stir for 0.3
hours. The aqueous layer was extracted with diethyl ether. All
organic layers were combined, washed (brine), dried (MgSO.sub.4),
and concentrated under reduced pressure. Purification by flash
column chromatography (silica gel, hexanes/EtOAc, 9:1) yielded
0.084 g of VII (85%) as a yellow oil. Data for Compound VII.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23 (d, J=5.2 Hz, 1H,
thiophene-H), 7.16 (d, J=5.0 Hz, 1H, thiophene-H), 7.10 (d, J=2.2
Hz, 1H, ArH), 7.05 (d, J=15.8 Hz, 1H, .dbd.CH) 6.90 (d, J=2.2 Hz,
1H, Ar--H), 6.64 (d, J=15.8 Hz, 1H, .dbd.CH), 5.85 (s, 1H,
.dbd.CH), 4.17 (q, J=7.1 Hz, 2H, R--CO.sub.2--CH.sub.2--CH.sub.3)
3.37 (m, 3H, R--O--CH, --CH.sub.2--CH.sub.2--CH.sub.3,
CH.sub.3--CH--CH.sub.3), 2.89 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.26
(s, 3H, CH.sub.3), 1.43 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 1.26 (m, 15H,
R--CO.sub.2--CH.sub.2--CH.sub.3, CH.sub.3--CH--CH.sub.3), 0.79 (t,
J=7.4 Hz, 3H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3).
Example 69
[0248] (L12, Compound VIII of Scheme 9, where R=isopropyl,
R'=n-butyl, R"=H). To 0.084 g of Compound VII (0.18 mmol) dissolved
in ethanol (5.0 ml) in a 15.0 ml r.b. flask is added 2 M aqueous
LiOH (0.55 mmol). The resultant mixture is heated to 90.degree. C.
for 3.0 hours. After such time, the reaction is cooled and
concentrated under reduced pressure. The residue is taken up in 1 N
aqueous HCl (10.0 ml). The flask is sealed and shaken for 1.0
minute. The resultant suspension was extracted with EtOAc. All
organic layers were combined, washed (brine), dried (MgSO.sub.4),
and concentrated under reduced pressure. The concentrate is
filtered through a short plug of silica gel (eluding with EtOAc),
concentrated under reduced pressure and recrystallized from
Acetonitrile to yield 0.08 g of VIII (100%) as a yellow crystalline
solid. Data for Compound VIII. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.26 (d, J=5.1 Hz, 1H, thiophene-H), 7.17 (d, J=5.0 Hz, 1H,
thiophene-H), 7.11 (d, J=2.0 Hz, 1H, Ar--H), 7.11 (d, J=15.8 Hz,
1H, .dbd.CH), 6.91 (d, J=2.1 Hz, 1H, Ar--H), 6.57 (d, J=15.8 Hz,
1H, .dbd.CH), 5.87 (s, 1H, .dbd.CH), 3.37 (m, 3H, R--O--CH,
--CH.sub.2--CH.sub.2--CH.sub.3, CH.sub.3--CH--CH.sub.3), 2.90 (m,
1H, CH.sub.3--CH--CH.sub.3), 2.28 (s, 3H, CH.sub.3), 1.44 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 1.26 (m, 14H,
CH.sub.3-CH--CH.sub.3,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3), 0.79 (t, J=7.3 Hz,
3H, R--O--CH.sub.2--CH.sub.2--CH.sub.2--CH.sub.3).
Example 70
[0249] (L38, Compound VIII of Scheme 9, where R=isopropyl,
R'=1,1-difluoroethyl, R"=H). This compound was prepared in the
manner previously described for Compound VIII in Example 69, except
that 2,2-difluoro-1-bromoethane was used instead of bromobutane in
Example 66. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.31 (d,
J=5.1 Hz, 1H, thiophene-H), 7.16 (d, J=5.0 Hz, 1H, thiophene-H),
7.13 (d, J=2.1 Hz, 1H, Ar--H), 7.05 (d, J=15.8 Hz, 1H, C.dbd.CH),
6.93 (d, J=2.2 Hz, 1H, Ar--H), 6.69 (d, J=15.8 Hz, 1H, C.dbd.CH),
5.89 (s, 1H, C.dbd.CH), 5.68 (tt, J=55.4 Hz, J=4.2 Hz, 1H,
R--O--CH.sub.2--CF.sub.2H) 3.56 (dt, J=13.7 Hz, J=4.1 Hz, 2H,
R--O--CH.sub.2--CF.sub.2H), 3.37 (m, 1H, CH.sub.3--CH--CH.sub.3),
2.91 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.27 (s, 3H, CH.sub.3), 1.28
(d, J=6.9 Hz, 6H, CH.sub.3-7CH--CH.sub.3), 1.26 (d, J=7.1 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 71
[0250] -L39, Compound VIII of Scheme 9, where R=isopropyl,
R'=1,1,1-trifluorobutyl, R"=H). This compound was prepared in the
manner previously described for Compound VIII in Example 69, except
that 4,4,4-trifluoro-1-bromobutane was used instead of bromobutane
in Example 66. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.28 (d,
J=5.1 Hz, 1H, thiophene-H), 7.13 (d, J=5.2 Hz, 1H, thiophene-H),
7.12 (d, J=2.0 Hz, 1H, Ar--H), 7.04 (d, J=15.8 Hz, 1H, C.dbd.CH),
6.92 (d, J=2.0 Hz, 1H, Ar--H), 6.66 (d, J=15.8 Hz, 1H, C.dbd.CH),
5.88 (s, 1H, C.dbd.CH), 3.42 (t, J=5.8 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CF.sub.3), 3.29 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.90 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.26
(s, 3H, CH.sub.3), 2.02 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CF.sub.3)- , 1.69 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--CF.sub.3), 1.28 (d, J=7.3 Hz,
6H, CH.sub.3--CH--CH.sub.3), 1.26 (d, J=7.4 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 72
[0251] (L40, Compound VIII of Scheme 9, where R=isopropyl,
R'=NHBoc-propyl, R"=H). This compound was prepared in the manner
previously described for Compound VIII in Example 69, except
3-NHBoc-propylbromide was used instead of bromobutane in Example
66. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.29 (d, J=5.0 Hz,
1H, thiophene-H), 7.16 (d, J=5.2 Hz, 1H, thiophene-H), 7.12 (d,
J=2.0 Hz, 1H, Ar--H), 7.05 (d, J=15.8 Hz, 1H, C.dbd.CH), 6.91 (d,
J=2.0 Hz, 1H, Ar--H), 6.67 (d, J=15.8 Hz, 1H, C.dbd.CH), 5.88 (s,
1H, C.dbd.CH), 4.57 (s, 1H, NH), 3.43 (t, J=5.6 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--O--NHBoc)- , 3.30 (m, 1H,
CH.sub.3--CH--CH.sub.3), 3.09 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--NHBoc), 2.90 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.65 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2-- -NHBoc), 2.26 (s, 3H,
CH.sub.3), 1.42 (s, 9H, NHCO.sub.2.sup.tbutyl), 1.27 (d, J=7.6 Hz,
6H, CH.sub.3--CH--CH.sub.3), 1.25 (d, J=7.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3).
Example 73
[0252] (L41, Compound VIII of Scheme 9, where R=isopropyl,
R'=1,1-difluoropropyl, R"=H). This compound was prepared in the
manner previously described for Compound VIII in Example 69, except
that 3,3-difluoro-1-bromopropane was used instead of bromobutane in
Example 66. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.30 (d,
J=5.2 Hz, 1H, thiophene-H), 7.14 (d, J=5.3 Hz, 1H, thiophene-H),
7.12 (d, J=2.4 Hz, 1H, Ar--H), 7.05 (d, J=15.8 Hz, 1H, C.dbd.CH),
6.93 (d, J=2.3 Hz, 1H, Ar--H), 6.81 (d, J=15.8 Hz, 1H, C.dbd.CH),
5.89 (s, 1H, C.dbd.CH), 5.84 (tt, J=56.9 Hz, J=4:8 Hz, 1H,
R--O--CH.sub.2--CH.sub.2--CF.sub.2H), 3.52 (t, J=5.8 Hz, 2H,
R--O--CH, --CH.sub.2--CF.sub.2H), 3.28 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.90 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.26
(d, J=0.8 Hz, 3H, CH.sub.3), 1.28 (d, J=8.2 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.25 (d, J=7.0 Hz, 6H,
CH.sub.3--CH--CH.sub.3). 0.127
Example 74
[0253] (L42, Compound VIII of Scheme 9, where R=isopropyl,
R'=1,1,2,2-tetrafluoropropyl, R"=H). This compound was prepared in
the manner previously described for Compound VIII in Example 69,
except that 3,3,2,2-tetrafluoro-1-bromopropane was used instead of
bromobutane in Example 66. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.32 (d, J=5.2 Hz, 1H, thiophene-H), 7.15 (d, J=2.0 Hz, 1H,
Ar--H), 7.11 (d, J=5.0 Hz, 1H, thiophene-H), 7.00 (d, J=15.8 Hz,
1H, C.dbd.CH), 6.94 (d, J=2.1 Hz, 1H, Ar--H), 6.69 (d, J=15.8 Hz,
1H, C.dbd.CH), 5.89 (s, 1H, C.dbd.CH), 5.82 (tt, J=53.2 Hz, J=5.1
Hz, 1H, R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 3.70 (t, J=12.1 Hz,
2H, R--O--CH.sub.2--CF.sub.2--CF.sub.2H), 3.32 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.91 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.26
(s, 3H, CH.sub.3), 1.28 (d, J=7.3 Hz, 6H, CH.sub.3--CH--CH.sub.3),
1.26 (d, J=7.4 Hz, 6H, CH.sub.3--CH--CH.sub.3).
Example 75
[0254] (L43, Compound VIII of Scheme 9, where R=isopropyl,
R'=3-methoxy-propyl, R"=H). This compound was prepared in the
mariner previously described for Compound VIII in Example 69,
except that 3-methoxy-1-bromopropane was used instead of
bromobutane in Example 66. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.27 (d, J=5.8 Hz, 1H, thiophene-H), 7.15 (d, J=5.1 Hz, 1H,
thiophene-H), 7.11 (d, J=2.1 Hz, 1H, Ar--H), 7.09 (d, J=15.8 Hz,
1H, C.dbd.CH), 6.91 (d, J=2.2 Hz, 1H, Ar--H), 6.66 (d, J=15.8 Hz,
1H, C.dbd.CH), 5.88 (s, 1H, C.dbd.CH), 3.45 (t, J=6.04 Hz, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.3), 3.34 (m, 3H,
CH.sub.3--CH--CH.sub.3,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub- .3), 3.26 (s, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.2--O--CH.sub.3), 2.89 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.27 (s, 3H, CH.sub.3), 1.72 (dt, J=12.6
Hz, J=6.3 Hz, 2H, R--O--CH.sub.2--CH, --CH.sub.2--O--CH.sub.3),
1.27 (d, J=8.1 Hz, 6H, CH.sub.3--CH--CH.sub.3), 1.25 (d, J=7.9 Hz,
6H, CH.sub.3--CH--CH.sub.3). 75
[0255] Scheme 10 describes an alternate synthetic method for
producing the desired RXR modulator compounds in another preferred
aspect of the invention. Scheme 10 shows the coupling of an
arylboronic acid with a haloarylalkoxide (e.g., Structure X). The
resulting alkoxyaryl-formylthiophene compound (e.g., Structure VI)
is then coupled with a phosphonate and reduced to produce the
desired RXR modulator compounds.
Example 76
[0256] (Compound X of Scheme 10, where R=isopropyl, R'=n-propyl).
To 0.48 g of Sodium hydride (0.02 mol) dissolved in anhydrous
N,N-Dimethyl-formamide (150.0 ml) in a flame dried 300 ml r.b.
flask at 0.degree. C. was added dropwise Compound IX (5.0 g. 0.016
mol) via solvation in anhydrous N,N-Dimethyl-formamide (15.0 ml).
The mixture was stirred at 0.degree. C. for 0.5 hours. After such
time, I-Bromopropane (2.22 g, 0.018 mol) was added dropwise via
syringe. The resultant reaction mixture was allowed to warm to
ambient temperature and stirred for 24.0 hours. Upon completion,
the contents of the flask are poured into iced brine (200.0 ml) and
stirred for 0.5 hours. The aqueous layer was extracted with diethyl
ether. All organic layers were combined, washed (brine), dried
(MgSO.sub.4) and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, hexanes/EtOAc, 9:1)
yielded 5.18 g of X (91.2%) as a clear, colorless oil. Data for
Compound X. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.46 (d,
J=1.9 Hz, 1H, Ar--H), 7.05 (d, J=1.9 Hz, 1H, Ar--H), 3.79 (t, J=6.6
Hz, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.3), 3.31 (m, 1H,
CH.sub.3--CH--CH.sub.3), 2.81 (m, 1H, CH.sub.3--CH--CH.sub.3), 1.89
(m, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.22 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.21 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.09 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3).
Example 77
[0257] (Compound VI of Scheme 10, where R=isopropyl, R'=n-propyl).
To 0.20 g of Compound X (0.578 mmol) dissolved in toluene/ethanol
(1:1, 10.0 ml) in a 25 ml r.b. flask was added
2-Formylthiophene-3-boronic acid (0.082 g, 0.525 mmol), 2 N aqueous
Na.sub.2CO.sub.3 (0.11 g, 1.05 mmol), and
Tetrakis(triphenylphosphine) palladium(0) (0.061 g, 0.053 mmol).
The reaction mixture was heated to 90.degree. C. for 15.0 hours.
The mixture was then cooled, poured into brine (25.0 ml), and
stirred for 0.3 hours. The aqueous layer was extracted with EtOAc.
All organic layers were combined, dried (MgSO.sub.4), and
concentrated under reduced pressure. Purification by flash column
chromatography (silica gel, hexanes/EtOAc, 9:1) yielded 0.133 g of
VI (70%) as a yellow oil. Data for Compound VI. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta. 9.79 (d, J=0.9 Hz, 1H, R--COH), 7.71 (dd,
J=4.9 Hz, J=0.9 Hz, 1H, thiophene-H), 7.25 (d, J=4.9 Hz, 1H,
thiophene-H), 7.17 (d, J=2.2 Hz, 1H, Ar--H), 7.00 (d, J=2.2 Hz, 1H,
Ar--H), 3.35 (m, 3H, R--O--CH.sub.2--CH.sub.2--CH.sub.3,
CH.sub.3--CH--CH.sub.3), 9.91 (m, 1H, CH.sub.3--CH--CH.sub.3), 1.47
(m, 2H, R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.26 (d, J=6.9 Hz,
12H, CH.sub.3--CH--CH.sub.3), 0.79 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2-- -CH.sub.3).
Example 78
[0258] (Compound VII of Scheme 10, where R=isopropyl, R'=n-propyl,
R"=H). To 0.319 g of Triethyl 3-methyl-4-phosphonocrotonate (1.21
mmol) dissolved in THF/DMPU (1:2, 5.0 ml) in a flame dried 25 ml
r.b. flask at -78.degree. C. is added .sup.nBuLi (1.29 mmol, in
Hexanes) dropwise. The mixture is allowed to stir for 0.3 hours.
Compound VI is then added dropwise via solvation in THF/DMPU (1:2,
5.0 ml). The resultant mixture is allowed to stir at -78.degree. C.
for 0.5 hours, warmed to ambient temperature, and stirred for 3.0
hours. After such time, water (20.0 ml) is added and the mixture is
allowed to stir for 0.2 hours. The aqueous layer was extracted with
EtOAc. All organic layers were combined, washed (brine), dried
(MgSO.sub.4), and concentrated under reduced pressure. Purification
by flash column chromatography (silica gel, hexanes/EtOAc, 9:1)
yielded 0.154 g of VII (87%) as a yellow oil. Data for Compound
VII. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.23 (d, J=5.2 Hz,
1H, thiophene-H), 7.16 (d, J=4.9 Hz, 1H, thiophene-H), 7.10 (d,
J=2.1 Hz, 1H, Ar--H), 7.05 (d, J=15.8 Hz, 1H, .dbd.CH), 6.91 (d,
J=2.2 Hz, 1H, Ar--H), 6.64 (d, J=15.8 Hz, 1H, .dbd.CH), 5.58 (s,
3H, .dbd.CH), 4.17 (q, J=7.6 Hz, 2H, CO.sub.2--CH.sub.2--CH.sub.3),
3.36 (m, 3H, R--O--CH.sub.2--CH.sub.2--CH.sub.3,
CH.sub.3--CH--CH.sub.3), 2.89 (m, 1H, CH.sub.3--CH--CH.sub.3), 2.26
(s, 3H, CH.sub.3), 1.48 (m, 2H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.28 (m, 15H,
CH.sub.3--CH--CH.sub.3, CO.sub.2--CH.sub.2--CH.sub.3), 0.80 (t,
J=7.4 Hz, 3H, R--O--CH.sub.2--CH.sub.2--CH.sub.3).
Example 79
[0259] (L11, Compound VIII of Scheme 10, where R=isopropyl,
R'=n-propyl, R"=H) To 0.154 g of Compound VII (0.35 mmol) dissolved
in ethanol (10.0 ml) in a 25 ml r.b. flask is added 2 M aqueous
LiOH (1.05 mmol). The resultant mixture is heated to 90.degree. C.
for 3.0 hours. After such time, the reaction is cooled and
concentrated under reduced pressure. The residue is taken up in 1 N
aqueous HCl (25.0 ml). The flask is sealed and shaken for 1.0
minute. The resultant suspension was extracted with EtOAc. All
organic layers were combined, washed (brine), dried (MgSO.sub.4),
and concentrated under reduced pressure. The concentrate is
filtered through a short plug of silica gel (eluding with EtOAc),
concentrated under reduced pressure and recrystallized from
Acetonitrile to yield 0.142 g of VIII (98%) as a light yellow
crystalline solid. Data for Compound VIII. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.25 (d, J=4.8 Hz, 1H, thiophene-H), 7.17 (d,
J=5.0 Hz, 1H, thiophene-H), 7.11 (d, J=2.2 Hz, 1H, Ar--H), 7.10 (d,
J=15.8 Hz, 1H, .dbd.CH), 6.91 (d, J=2.2 Hz, 1H, Ar--H), 6.66 (d,
J=15.8 Hz, 1H, .dbd.CH), 5.87 (s, 3H, .dbd.CH), 3.35 (m, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3, CH.sub.3--CH--CH.sub.3), 2.90
(m, 1H, CH.sub.3--CH--CH.sub.3), 2.28 (s, 3H, CH.sub.3), 1.48 (m,
2H, R--O--CH.sub.2--CH.sub.2--CH.sub.3), 1.27 (d, J=6.8 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 1.26 (d, J=6.9 Hz, 6H,
CH.sub.3--CH--CH.sub.3), 0.80 (t, J=7.4 Hz, 3H,
R--O--CH.sub.2--CH.sub.2--CH.sub.3). 7677
[0260] The following acids were prepared according to Scheme 11a
(procedure described in Schemes 1 and 2). Scheme 11a depicts the
preparation of compound having various cyclic A substituents. The
methodology employed here is similar to that depicted in Scheme
10.
Example 80
[0261] (Compound VI of Scheme 11a, where R=isopropyl, R'=methyl,
A=Al). A mixture of 1.1478 g (3.6 mmol) of
3,5-diisopropyl-2-methoxy iodobenzene. 593 mg (3.97 mmol) of
2-formylbenzeneboronic acid and 208 mg (0.18 mmol) of
tetrakistriphenylphosphine palladium, 2 ml of 2N aqueous sodium
carbonate in 20 ml of toluene and 20 ml ethanol was heated to
reflux. After completion (TLC), 40 mL of 10% EtOAc/hexane was added
and the solution was filtered through a short plug of silica gel
and rinsed with 300 mL of 10% ethyl acetate/hexane. The filtrate
was concentrated in vacuo. The residue was purified by flash column
chromatography (SiO.sub.2, 4.times.20 cm, 10% EtOAc/hexane as
eluent) to afford 931 mg (87% yield, theoretical 1.0692 g) of VI as
a colorless oil. R.sub.f 0.50 (SiO.sub.2, 10% EtOAc-hexane).
.sup.1H NMR (400 MHz, CDCl.sub.3) 9.83 (s, 1H), 8.03 (d, J=7.7 Hz,
1H), 7.65 (dd, J=8.8, 6.3 Hz, 1H), 7.48 (m, 2H), 7.17 (d, J=2.2 Hz,
1H), 7.00 (d, J=2.2 Hz, 1H), 3.34 (septet, J=6.9 Hz, 1H), 3.19 (s,
3H), 2.92 (septet, J=6.9 Hz, 1H), 1.27 (d, J=6.9 Hz, 12H).
Example 81
[0262] (Compound VII of Scheme 11a, where R=isopropyl, R'=methyl,
R"=H, A=Al). A solution of 2.17 g (8.2 mmol) of triethyl
3-methyl-4-phosphonocrotonate in a 2:1 mixture of
tetrahydrofuran/1,3-dim-
ethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (THF/DMPU) (15 mL) was
cooled to -78.degree. C. and treated with 3.3 mL of n-butyllithium
(2.5 M in hexane, 8.25 mmol). The resulting solution was stirred at
-78.degree. C. for 15 min. To this solution was added slowly a
solution of 925 mg (2.7 mmol) of VI in a 2:1 mixture of THF/DMPU
(10 mL) via syringe. The resulting mixture was stirred at
-78.degree. C. for additional 1 h and allowed to warm to 0.degree.
C. After completion (TLC), the reaction mixture was quenched with
water (20 mL) and extracted with EtOAc (3.times.50 mL). The
combined organic layers was washed with saturated aqueous sodium
chloride solution (100 mL), dried (MgSO.sub.4), filtered and
concentrated in vacuo. The crude residue was purified by flash
column chromatography (SiO.sub.2, 4.times.20 cm, 5% ethyl
acetate/hexane as eluent) to afford 467 mg (37% yield, theoretical
1.28 g) of VII as a colorless oil. R.sub.f 0.73 (SiO.sub.2, 10%
EtOAc-hexane). .sup.1H NMR (400 MHz, CDCl.sub.3) 7.70 (dd, J=7.5,
2.1 Hz, 1H), 7.40-7.32 (m, 3H), 7.11 (d, J=2.1 Hz, 1H), 6.87 (d,
J=16 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.74 (d, J=16 Hz, 1H), 5.85
(s, 1H), 4.16 (q, J=7.1 Hz, 2H), 3.34 (septet, J=6.9 Hz, 1H), 3.24
(s, 3H), 2.89 (septet, J=6.9 Hz, 1H), 2.17 (5, 3H), 1.31 (t, J=7.1
Hz, 3H), 1.27 (d, J=6.9 Hz, 6H), 1.24 (d, J=6.9 Hz, 6H).
Example 82
[0263] (L44, Compound VIII of Scheme 11a, where R=isopropyl,
R'=methyl, R"=H, A=Al). To a solution of 295 mg (0.73 mmol) of VII
in a 2:2:1 mixture of THF/EtOH/H.sub.2O (10 mL) was added 91 mg
(2.18 mmol) of LiOH. The resulting mixture was heated to reflux for
3 hours. After cooling to room temperature, the mixture was
acidified with HCl (1N aqueous) to pH 2 and extracted with EtOAc
(2.times.20 mL). The combined organic layers was dried
(MgSO.sub.4), filtered and concentrated in vacuo. The crude acid
was recrystallized from acetonitrile to give 142 mg (52%,
theoretical 275 mg) of VIII as a white solid. .sup.1H NMR (400 MHz,
CDCl.sub.3) 7.71 (dd, J=6.4, 2.6 Hz, 1H), 7.42-7.34 (m, 3H), 7.11
(d, J=2.2 Hz, 1H), 6.92 (d, J=16 Hz, 1H), 6.86 (d, J=2.2 Hz, 1H),
6.76 (d, J=16 Hz, 1H), 5.87 (s, 1H), 3.34 (septet, J=6.9 Hz, 1H),
3.24 (s, 3H), 2.89 (septet, J=6.9 Hz, 1H), 2.18 (s, 3H), 1.24 (d,
J=6.9 Hz, 12H).
Example 83
[0264] (L45, Compound VIII of Scheme 11a, where R=isopropyl,
R'=n-butyl, R"=H, A=Al). This compound was prepared in the manner
previously described for Compound VIII of Example 82, starting from
the intermediate IX where R'=n-butyl, synthesized in the manner
described in Example 76 using 1-bromobutane instead of
1-bromopropane. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.71 (dd, J=6.3,
2.7 Hz, 1H), 7.42-7.32 (m, 3H), 7.11 (d, J=2.1 Hz, 1H), 6.95 (d,
J=16 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.75 (d, J=16 Hz, 1H), 5.87
(s, 1H), 3.40-3.20 (m, 3H), 2.88 (septet, J=6.9 Hz, 1H), 2.19 (s,
3H), 1.27 (m, 2H), 1.24 (d, J=6.9 Hz, 12H), 1.09 (m, 2H), 0.68 (t,
J=7.4 Hz, 3H).
Example 84
[0265] (L46, Compound VIII of Scheme 11a, where R=isopropyl.
R'=n-propyl, R"=H, A=Al). This compound was prepared in the manner
previously described for Compound VIII of Example 82, starting from
the intermediate IX where R'=n-propyl, synthesized in the manner
described in Example 76. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.71
(dd, J=6.3, 2.7 Hz, 1H), 7.42-7.32 (m, 3H), 7.11 (d, J=2.2 Hz, 1H),
6.95 (d, J=16 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.75 (d, J=16 Hz,
1H), 5.87 (s, 1H), 3.40-3.20 (m, 3H), 2.89 (septet, J=6.9 Hz, 1H),
2.19 (s, 3H), 1.34 (m, 2H), 1.24 (d, J=6.9 Hz, 12H), 0.64 (t, J=7.4
Hz, 3H).
Example 85
[0266] (L47, Compound VIII of Scheme 11a, where R=isopropyl,
R'=1-fluoropropyl, R"=H, A=At). This compound was prepared in the
manner previously described for Compound VIII of Example 82,
starting from the intermediate IX where R'=1-fluoropropyl,
synthesized in the manner described in Example 76 using
1-fluoro-3-bromopropane instead of 1-bromopropane. .sup.1H NMR (400
MHz, CDCl.sub.3) 7.71 (d, TH, J=7.5 Hz, 1H), 7.40-7.35 (m, 3H),
7.12 (d, J=2.1 Hz, TH), 6.91 (d, J=16 Hz, 1H), 6.87 (d, J=2.1 Hz,
1H), 6.76 (d, J=16 Hz, 1H), 5.87 (s, 1H), 4.29 (dt, J=17.9, 6.1 Hz,
1H), 4.18 (dt, J=17.9, 6.1 Hz, 1H), 3.45 (t, J=6.0 Hz, 1H), 3.40
(t, J=6.0 Hz, 1H), 3.30 (septet, J=6.9 Hz, 1H), 2.89 (septet, J=6.9
Hz, 1H), 2.18 (s, 3H), 1.69 (m, 2H), 1.25 (d, J=6.9 Hz, 12H).
Example 86
[0267] (L48, Compound VIII of Scheme 11a, where R=isopropyl,
R'=ethyl, R"H, A=Al). This compound was prepared in the manner
previously described for Compound VIII of Example 82, starting from
the intermediate IX where R'=ethyl, synthesized in the manner
described in Example 76 using 1-bromoethane instead of
1-bromopropane. .sup.1H NMR (400 MHz, CDCl.sub.3) 7.72 (dd, J=6.1,
2.7 Hz, 1H), 7.43-7.32 (m, 3H), 7.11 (d, J=2.1 Hz, 1H), 6.95 (d,
J=16 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.75 (d, J=16 Hz, 1H), 5.87
(s, 1H), 3.37 (m, 3H), 2.88 (septet, J=6.9 Hz, 1H), 2.19 (s, 3H),
1.24 (d, J=6.9 Hz, 12H), 0.94 (t J=7.1 Hz, 3H).
Example 87
[0268] (L49, Compound VIII of Scheme 11a, where R=isopropyl,
R'=1,1-difluoroethyl, R"=H, A=Al). This compound was prepared in
the manner previously described for Compound VIII of Example 82,
starting from the intermediate IX where R'=1,1-difluoroethyl,
synthesized in the manner described in Example 76 using
1,1-difluoro-2-bromoethane instead of 1-bromopropane. .sup.1H NMR
(400 MHz, CDCl.sub.3) 7.72 (dd, J=7.2, 2.3 Hz, 1H), 7.43-7.35 (m,
3H), 7.14 (d, J=2.2 Hz, 1H), 6.89 (d, J=2.2 Hz, 14), 6.88 (d, J=16
Hz, 1H), 6.76 (d, J=16 Hz, 1H), 5.88 (s, 1H), 5.48 (tt, J=55.5, 4.2
Hz, 1H), 3.48 (dtd, J=27, 12.8, 4.2 Hz, 2H), 3.35 (septet, J=6.9
Hz, 1H), 2.90 (septet, J=6.9 Hz, 1H), 2.18 (s, 3H), 1.25 (d, J=6.9
Hz, 12H).
Example 88
[0269] (L50, Compound VIII of Scheme 11a, where R=tert-butyl,
R'=methyl, R"=H, A=Al). This compound was prepared in the manner
previously described for Compound VIII in Example 82 except that
3,5-ditertbutyl-2-methoxy iodobenzene was used instead of
3,5-diisopropyl-2-methoxy-iodobenzene in Example 80. .sup.1H NMR
(400 MHz, CDCl.sub.3) 7.73 (dd, J=5.5, 3.7 Hz, 1H), 7.44-7.34 (m,
4H), 7.02 (d, J=2.4 Hz, 1H), 6.96 (d, J=16 Hz, 1H), 6.78 (d, J=16
Hz, 1H), 5.88 (s, 1H), 3.16 (s, 3H), 2.19 (s, 3H), 1.43 (s, 9H),
1.31 (s, 9H).
Example 89
[0270] (L51, Compound VIII of Scheme 11a, where R=tert-butyl,
R'=ethyl, R"=H, A=Al). This compound was prepared in the manner
previously described for Compound VIII in Example 82 except that
3,5-ditertbutyl-2-methoxy iodobenzene was used instead of
3,5-diisopropyl-2-methoxy-iodobenzene in Example 80 and Compound IX
was synthesized in the manner described in Example 76 using
1,1-difluoro-2-bromoethane instead of 1-bromopropane. .sup.1H NMR
(500 MHz, CDCl.sub.3) 7.72 (dd, J=5.6, 3.7 Hz, 1H), 7.42 (dd,
J=5.6, 3.7 Hz, 1H), 7.36 (m, 3H), 7.01 (d, J=2.8 Hz, 1H), 6.99 (d,
J=15.9 Hz, 1H), 6.77 (d, J=15.9 Hz, 1H), 5.88 (s, 1H), 3.35 (dq,
J=, 5.8 Hz, 2H), 2.21 (s, 3H), 1.44 (s, 9H), 1.30 (s, 9H), 0.92 (t,
J=7.0 Hz, 3H).
Example 90
[0271] (L52, Compound VIII of Scheme 11a, where R=tert-butyl,
R'=n-butyl, R"=H, A=Al). This compound was prepared in the manner
previously described for Compound VIII in Example 82 except that
3,5-ditertbutyl-2-methoxy iodobenzene was used instead of
3,5-diisopropyl-2-methoxy-iodobenzene in Example 80 and Compound IX
was synthesized in the manner described in Example 76 using
1-bromobutane instead of 1-bromopropane. .sup.1H NMR (500 MHz,
CDCl.sub.3) 7.71 (m, 1H), 7.40 (m, 1H), 7.36 (m, 3H), 7.00 (d,
J=2.7 Hz, 1H), 6.97 (d, J=16 Hz, 1H), 6.76 (d, J=16 Hz, 1H), 5.88
(s, 1H), 3.31 (m, 2H), 2.20 (d, J=1.0 Hz, 3H), 1.43 (s, 9H), 1.31
(s, 9H), 1.07 (m, 2H), 0.67 (t, J=7.3 Hz, 3H).
Example 91
[0272] (L53, Compound VIII of Scheme 11a, where R=tert-butyl,
R'=1-fluoropropyl, R"=H, A=Al). This compound was prepared in the
manner previously described for Compound VIII in Example 82 except
that 3,5-ditertbutyl-2-methoxy Iodobenzene was used instead of
3,5-diisopropyl-2-methoxy-iodobenzene in Example 80 and Compound IX
was synthesized in the manner described in Example 76 using
1-fluoro-3-bromopropane instead of 1-bromopropane. .sup.1H NMR (500
MHz, CDCl.sub.3) 7.73 (m, 1H), 7.38 (m, 4H), 7.02 (d, J=2.4 Hz,
1H), 6.93 (d, J=15.9 Hz, 1H), 6.78 (d, J=15.9 Hz, 1H), 5.89 (s,
1H), 4.26 (m, 2H), 3.44 (m, 2H), 2.19 (d, J=0.7 Hz, 3H), 1.68 (m,
2H), 1.43 (s, 9H), 1.31 (s, 9H).
Example 92
[0273] (L54, Compound VIII of Scheme 11a, where R=tert-butyl,
R'=n-propyl, R"=H, A=Al). This compound was prepared in the manner
previously described for Compound VIII in Example 82 except that
3,5-ditertbutyl-2-methoxy iodobenzene was used instead of
3,5-diisopropyl-2-methoxy-iodobenzene in Example 80 and Compound IX
was synthesized in the manner described in Example 76. .sup.1H NMR
(500 MHz, CDCl.sub.3) 7.71 (dd, J=5.6, 3.7 Hz, 1H), 7.41 (dd,
J=5.6, 3.7 Hz, 1H), 7.36 (d, J=2.4 Hz, 1H), 7.35 (m, 2H), 7.00 (d,
J=2.4 Hz, 1H), 6.97 (d, J=15.9 Hz, 1H), 6.76 (d, J=15.9 Hz, 1H),
5.87 (s, 1H), 3.27 (me, 2H), 2.20 (d, J=0.9 Hz, 3H), 1.43 (s, 9H),
1.34 (m, 2H), 1.31 (s, 9H), 0.64 (t, J=7.3 Hz, 3H).
Example 93
[0274] (L55, Compound VIII of Scheme 11a, where R=isopropyl.
R'=ethyl, R"=H, A=A6). This compound was prepared in the manner
previously described for Compound VIII in Example 82 except that
Compound IX was synthesized in the manner described in Example 76
using 1-bromoethane instead of 1-bromopropane and 2-formylfuran
boronic acid was used instead of 2-formylbenzene boronic acid in
Example 80. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.49 (d,
J=1.9 Hz, 1H), 7.16 (d, J=2.2. Hz, 1H), 7.09 (d, J=2.2 Hz, 1H),
7.07 (d, J=15.9 Hz, 1H), 6.71 (d, J=1.9 Hz, 1H), 6.57 (d, J=15.9
Hz, 1H), 5.86 (s, 1H), 3.57 (dd, J=14.0, 6.9 Hz, 2H), 3.39 (dt, J
13.9, 6.9 Hz, 1H),2.90 (dt, J=13.9, 6.9 Hz, 1H), 2.33 (s, 3H), 1.26
(d, J=6.9 Hz, 6H), 1.25 (d, J=6.9 Hz, 6H), 1.16 (t, J=7.1 Hz,
3H).
Example 94
[0275] (L56, Compound VIII of Scheme 11a, where R=isopropyl,
R'=1-fluoropropyl, R"=H, A=A6). This compound was prepared in the
manner previously described for Compound VIII in Example 82 except
that Compound IX was synthesized in the manner described in Example
76 using 1-fluoro-3-bromopropane instead of 1-bromopropane and
2-formylfuran boronic acid was used instead of 2-formylbenzene
boronic acid in Example 80. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.50 (d, J=1.9 Hz, 1H), 7.17 (d, J=2.3 Hz, 1H), 7.09 (d,
J=2.3 Hz, 1H), 6.99 (d, J=15.9 Hz, 1H), 6.72 (d, J=1.9 Hz, 1H),
6.57 (d, J=15.9 Hz, 1H), 5.86 (s, 1H), 4.57 (t, J=5.9 Hz, 1H), 4.45
(t, J=5.8 Hz, 1H), 3.63 (t, J=6.0 Hz, 2H), 3.34 (dt, J=13.9, 6.9
Hz, 1H), 2.91 (dt, J=13.9, 6.9 Hz, 1H), 2.31 (s, 3H), 1.95 (m, 1H),
1.90 (m, 1H), 1.27 (d, J=6.9 Hz, 6H--), 1.26 (d, J=6.9 Hz, 6H).
Example 95
[0276] (L57, Compound VIII of Scheme 11a, where R=isopropyl,
R'=n-butyl, R"=H, A=A8). This compound was prepared in the manner
previously described for Compound VIII in Example 82 except that
Compound IX was synthesized in the manner described in Example 76
using 1-bromobutane instead of 1-bromopropane and 2-formylthiophene
boronic acid was used instead of 2-formylbenzene boronic acid in
Example 80. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.33 (m,
2H), 7.13 (d, J=2.2 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.95 (d,
J=15.9 Hz, 1H), 6.68 (d, J=16.0 Hz, 1H), 5.87 (s, 1H), 3.42 (t,
J=6.4 Hz, 2H), 3.35 (dt, J=13.8, 6.9 Hz, 1H), 2.88 (dt, J=13.8, 6.9
Hz, 1H), 2.28 (s, 3H), 1.55 (m, 2H), 1.26 (d, J=6.9 Hz, 6H), 1.25
(d, J=6.9 Hz, 6H), 1.24 (m, 2H), 0.79 (t, J=7.3 Hz, 3H).
Example 96
[0277] (L58, Compound VIII of Scheme 11a, where R=1-ethyl,
1,1-dimethylbutyl, R'=1,1-difluoroethyl, R"H, A=A6). This compound
was prepared in the manner previously described for Compound VIII
in Example 82 except that Compound IX was synthesized in the manner
described in Example 76 using 1, 1-difluoro-2-bromoethane instead
of 1-bromopropane and 2-formylfuran boronic acid was used instead
of 2-formylbenzene boronic acid in Example 80. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.53 (d, J=2.2 Hz, 1H), 7.29 (d, J=2.0
Hz, 1H), 7.19 (d, J=2.0 Hz, 1H), 6.89 (d, J=15.9 Hz, 1H), 6.73 (d,
J=2.2 Hz, 1H), 6.58 (d, J=15.9 Hz, 1H), 5.87 (s, 1H), 5.77 (dt,
J=55.2, 4.0 Hz, 1H), 3.59 (dt, J=13.5, 4.0, 2H), 2.30 (s, 3H), 1.84
(dd, J=15.0, 7.5 Hz, 2H), 1.63 (dd, J=15.0, 7.5 Hz, 2H), 1.40 (s,
3H), 1.28 (s, 6H), 1.27 (d, J=7.2 Hz, 3H), 0.88 (t, J=6.6 Hz, 3H),
0.69 (dd, J=14.4, 7.4 Hz, 3H). 7879
Example 97
[0278] (Compound VI of Scheme 11b where R=isopropyl, R'=ethyl,
A=A3). A mixture of 740 mg (3.0 mmol) of 3-5-diisopropyl-2-ethoxy
benzeneboronic acid, 500 mg (2.7 mmol) of 3-bromo-4-formylpyridine
and 155 mg (0.13 mmol) of tetrakistriphenylphosphine palladium, 1.5
ml of 2N aqueous sodium carbonate in 10 ml of toluene and 10 ml
ethanol was heated to reflux. After completion (TLC), 40 mL of 10%
EtOAc/hexane was added and the solution was filtered through a
short plug of silica gel and rinsed with additional 10% ethyl
acetate/hexane (300 mL). The filtrate was concentrated in vacuo.
The residue was purified by flash column chromatography (SiO.sub.2,
3.times.20 cm, 10% EtOAc/hexane as eluent) to afford 731 mg (91%,
theoretical 805 mg) of VI as a colorless oil. R.sub.f 0.26
(SiO.sub.2, 10% EtOAc-hexane). .sup.1H NMR (400 MHz, CDCl.sub.3)
9.86 (s, 1H), 8.81 (s, 1H), 8.80 (d, J=7.0 Hz, 1H), 7.78 (d, J=4.9
Hz, 1H), 7.23 (d, J=2.2 Hz, 1H), 7.06 (d, J=2.2 Hz, 1H), 3.47 (br.
s, 1H), 3.34 (septet, J=6.9 Hz, 1H), 3.17 (br. s, 1H), 2.95
(septet, J=6.9 Hz, 1H), 1.29 (d, J=6.9 Hz, 12H), 0.94 (t, J=6.9 Hz,
3H).
Example 98
[0279] (Compound VII of Scheme 11b where R=isopropyl, R'=ethyl,
A=A3, R"=H). A solution of 1.935 g (7.3 mmol) of triethyl
3-methyl-4-phosphonocrotonate in a 2:1 mixture of
tetrahydroffuran/1,3-di-
methyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (THF/DMPU) (20 mL) was
cooled to -78.degree. C. and treated with 3.0 mL of n-butyllithium
(2.5 M in hexane, 7.5 mmol). The resulting solution was stirred
under nitrogen atmosphere at -78.degree. C. for 15 min. To this
solution was added slowly a solution of 731 mg (2.4 mmol) of VI in
a 2:1 mixture of THF/DMPU (15 mL) via syringe. The resulting
mixture was stirred at -78.degree. C. for additional 1 hour. After
completion (TLC), the reaction mixture was quenched with water (20
mL) and extracted with EtOAc (3.times.50 mL). The combined organic
layers was washed with saturated aqueous sodium chloride solution
(100 mL), dried (MgSO.sub.4), filtered and concentrated in vacuo.
The crude residue was purified by flash column chromatography
(SiO.sub.2, 4.times.20 cm, 10% ethyl acetate/hexane as eluent) to
afford 766 mg (74%, theoretical 1.029 g) of VII as a colorless oil.
R.sub.f 0.27 (SiO.sub.2, 20% EtOAc-hexane). .sup.1H NMR (400 MHz,
CDCl.sub.3) 8.62 (s, 1H), 8.56 (d, J=5.3 Hz, 1H), 7.52 (d, J=5.3
Hz, 1H), 7.16 (d, J=2.2 Hz, 1H), 6.88 (d, J=16 Hz, 1H), 6.86 (d,
J=2.2 Hz, 1H), 6.81 (d, J=16 Hz, 1H), 5.92 (s, 1H), 4.18 (q, J=7.1
Hz, 2H), 3.36 (m, 3H), 2.90 (septet, J=6.9 Hz, 1H), 2.19 (s, 3H),
1.28 (d, J=6.9 Hz, 6H), 1.25 (d, J=6.9 Hz, 6H), 0.95 (t, J=6.9 Hz,
3H).
Example 99
[0280] (L59, Compound VIII of Scheme 11b where R=isopropyl.
R'=ethyl, R"=H, A=A3). To a solution of 766 mg (1.8 mmol) of VII in
a 2:2:1 mixture of THF/EtOH/H.sub.2O (30 mL) was added 381 mg (9.1
mmol) of LiOH. The resulting mixture was heated to reflux for 3
hours. After cooling to room temperature, the mixture was acidified
with HCl (1N aqueous) to pH=2 and extracted with EtOAc (2.times.50
mL). The combined organic layers was dried (MgSO.sub.4), filtered
and concentrated in vacuo. The crude acid was recrystallized from
acetonitrile to give 372 mg (52%, theoretical 715 mg) of VIII as a
white solid. .sup.1H NMR (400 MHz, CDCl.sub.3) 8.63 (s, 1H), 8.58
(d, J=5.3 Hz, 1H), 7.55 (d, J=5.3 Hz, 1H), 7.16 (d, J=2.2 Hz, 1H),
6.91 (d, J=16 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 6.85 (d, J=16 Hz,
1H), 5.97 (s, 1H), 3.36 (m, 3H), 2.90 (septet, J=6.9 Hz, 1H), 2.21
(s, 3H), 1.25 (d, J=6.9 Hz, 12H), 0.95 (t, J=6.9 Hz, 3H).
Example 100
[0281] (L60, Compound VIII of Scheme 11b where R=isopropyl,
R'=ethyl, R"=H, A=A2). This compound was prepared in the manner
previously described for Compound VIII in Example 99. .sup.1H NMR
(400 MHz, CDCl.sub.3) 8.65 (dd, J=4.7, 1.4 Hz, 1H), 7.99 (dd,
J=8.0, 1.4 Hz, 1H), 7.31 (ddy, J=8.0, 4.7 Hz, 1H), 7.16 (d, J=2.3
Hz, 1H), 7.03 (d, J=2.3 Hz, 1H), 6.86 (d, J=16.1 Hz, 1H), 6.74 (d,
J=16.1 Hz, 1H), 5.88 (s, 1H), 3.47 (br. s, 1H), 3.37 (br., 1H),
3.35 (septet, J=6.9 Hz, 1H), 2.90 (septet, J=, 6.9 Hz, 1H), 2.18
(s, 3H), 1.25 (d, J=6.9 Hz, 12H), 0.92 (t, J=7.0 Hz, 3H).
Example 101
[0282] (L61, Compound VIII of Scheme 11b where R=isopropyl,
R'=ethyl, R"=H, A=A4). This compound was prepared in the manner
previously described for Compound VIII in Example 99. .sup.1H NMR
(400 MHz, CDCl.sub.3) 8.94 (s, 1H), 8.55 (d, J=5.0 Hz, 1H), 7.39
(d, J=5.0 Hz, H), 7.17 (d, J=2.2 Hz, 1H), 6.88 (d, J=16.3 Hz, 1H),
6.84 (d, J=2.2 Hz, 1H), 6.83 (d, J=16.3 Hz, 1H), 5.96 (s, 1H), 3.90
(q, 2H, J=6.9 Hz, 2H), 3.36 (septet, J=6.9 Hz, 1H), 2.89 (septet,
J=6.9 Hz, 1H), 2.24 (s, 3H), 1.27 (d, J=6.9 Hz, 6H), 1.24 (d, J=6.9
Hz, 6H), 0.99 (t, J=6.9 Hz, 3H).
Example 102
[0283] (L62, Compound VIII of Scheme 11b where R=tert-butyl,
R'=ethyl, R"=H, A=A3). This compound was prepared in the manner
previously described for Compound VIII in Example 99. .sup.1H NMR
(400 MHz, CDCl.sub.3) 8.66 (s, 1H), 8.59 (d, J=5.4 Hz, 1H), 7.57
(d, J=5.4 Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H),
6.94 (d, J=16.1 Hz, 1H), 6.89 (d, J=16.1 Hz, 1H), 5.98 (s, 1H),
3.38 (quintet, J=7.0 Hz, 1H), 3.32 (quintet, J=7.0 Hz, 1H), 2.23
(s, 3H), 1.44 (s, 9H), 1.32 (s, 9H), 0.93 (t, J=7.0 Hz, 3H).
8081
[0284] Scheme 12 depicts the preparation of triazole derivatives of
type VI employed in Examples 103-108.
Example 103
[0285] (Compound I of Scheme 12, where R=tert-butyl, R'=methyl). To
a mixture of 5.92 g (0.02474 mol) of 1-methoxy-2,4-di-tert-butyl
benzaldehyde and 4.48 g (0.02474 mol) of
thiophenysulfonylacetonitrile in DMF (20 ml) and benzene (40 ml)
was added 1 ml of piperidine. The resulting mixture was heated to
reflux until completion. After cooling to room temperature, water
was added and the mixture was extracted with ethyl acetate
(2.times.50 ml). The organic fractions were combined and dried over
MgSO.sub.4. The solvents were evaporated under reduced pressure and
the resulting oil was purified over silica gel (eluent: methylene
chloride/hexane: 50/50) to give 6.31 g (yield: 62%) of I. .sup.1H
NMR (CDCl.sub.3): 8.51 (s, 1H), 8.05 (m, 2H), 7.96 (s, 1H), 7.63
(m, 3H), 7.58 (s, 1H), 3.80 (s, 3H), 1.40 (s, 9H), 1.30 (s,
3H).
Example 104
[0286] (Compound II of Scheme 12, where R=tert-butyl, R'=methyl).
To a mixture of 6.31 g (0.0153.3 mol) of Compound I and 1.00 g
(0.01533 mol)) of sodium azide in 40 ml DMIF was heated to
100.degree. C. behind an explosion shield. The mixture was stirred
at this temperature until complexion and the solvents were
evaporated under reduced pressure. Water was added and the solution
was extracted with ethyl acetate. The organic layer was dried over
a MgSO.sub.4 and the residue purified over silica gel (eluent:
ethyl acetate/methylene chloride: 0/100 to 10/90% gradient to give
3.50 g (54% yield) of II. .sup.1H NMR (CDCl.sub.3): 7.95 (m, 2H),
7.66 (b, 1H), 7.53 (m, s, 4H), 3.46 (s, 3H), 1.44 (s, 9H), 1.35 (s,
9H).
Example 105
[0287] (Compound III of Scheme 12 where R=tert-butyl, R'=methyl,
R"=methyl). A mixture of 600 mg (0.06 mmol) of Compound II in 10 ml
of dry THF, 1 ml of methyliodide and 2 g of cesium carbonate was
stirred until complete consumption of starting material. The
solvents were evaporated under reduced pressure and the residue was
purified over silica gel (eluent: methylene chloride/hexane (1/1)
to give 0.38 g (63% yield) of III. .sup.1H NMR.(CDCl.sub.3): 7.82
(s, 1H), 7.66 (b, 1H), 4.46 (s, 3H), 3.46 (s, 3H), 1.38 (s,
9H).
Example 106
[0288] (Compound IV of Scheme 12 where R=tert-butyl, R'=methyl,
R"=methyl). To a mixture of 380 mg of Compound III and 5 ml of dry
THF at -78.degree. C., was added 1.0 ml of 1 M DIBAL. The mixture
was warmed to room temperature and checked by TLC. Ethyl acetate 15
ml and water 10 ml were added to the reaction mixture. The organic
layer was dried over MgSO.sub.4 and evaporated under reduced
pressure. The residual oil was purified over silica gel (eluent:
methylene chloride/hexane (1:1) to give 112 mg (yield: 77%)
Compound IV. .sup.1H NMR (CDCl.sub.3): 10.11 (s, 1H), 7.86 (s, 1H),
7.66 (b, 1H), 4.54 (s, 3H), 3.46 (s, 3H), 1.38 (s, 9H).
Example 107
[0289] (Compound V of Scheme 12, where R=tert-butyl, R'=methyl,
R"=methyl). A mixture of 112 mg (0.367 mmol) of Compound IV, 340 mg
(1.46 mmol,) of triethyl 3-methyl-4-phosophonocrotonate in 10 ml of
THF and 1 ml of DMPU was cooled to -78.degree. C. N-BuLi (1.6M) 0.9
ml was slowly added to the solution. The reaction was warmed to
room temperature and stirred overnight. Water was added (15 ml) and
the solution was extracted with ethyl acetate. The organic layer
was washed with water and brine, then dried over MgSO.sub.4.
Evaporation of the solvents gave a yellow oil. The residual oil was
purified over silica gel (eluent: methylene chloride/hexane (1:1)
to give 170 mg (yield: 47%) Compound V as a mixture of isomers.
.sup.1H NMR (CDCl.sub.3): 7.86 (s, 1H), 7.66 (b, 1H), 7.14 (dd,
2H), 6.59 (s, 1H), 4.46 (s, 3H) 4.18 (m, 2H), 3.46 (s, 3H), 2.32,
2.23 (s, s, 3H), 1.38 (s, 9H), 1.30 (t, 3H).
Example 108
[0290] (L63, Compound VI of Scheme 12, where R=tert-butyl,
R'=methyl, R"=methyl). To a mixture of 170 mg of Compound V in 10
ml of ethanol was added 1 ml of 6 N NaOH. The solution was heated
to reflux until completion (TLC monitoring). After cooling, water
was added and the mixture as extracted with ethyl acetate. The
organic layer was washed with water and brine and dried over
MgSO.sub.4. The solvents were evaporated under reduced pressure,
and the residual oil was crystallized from acetonitrile to yield 20
mg of Compound VI. .sup.1H NMR (CDCl.sub.3): 7.86 (s, 1H), 7.66 (b,
1H), 7.14 (dd, 2H), 6.59 (s, 1H), 4.45 (s, 3H), 3.46 (s, 3H), 2.32,
2.23 (s, s, 3H), 1.38 (s, 9H), 1.30 (t, 3H).
[0291] Synthesis of "Non Symmetrical" RXR Modulators
[0292] In a preferred embodiment, the following Schemes depict the
synthetic method employed in the synthesis of RXR modulators
wherein R.sup.2 differs from R.sup.4. 8283
[0293] Scheme 13 depicts the synthetic method employed in the
preparation of compounds of the type XI, wherein the substituents
of R.sup.2 and R.sup.4 differ.
Example 109
[0294] (Compound II of Scheme 13, where R=tert-butyl). A mixture of
3.02 g (20.1 mmol) of 2-tert-butyl phenol, 5.43 g (24.1 mmol) of
NIS and 0.38 g (2 mmol) of p-toluenesulfonic acid in 30 ml of
CH.sub.2Cl.sub.2 was heated to reflux overnight. After cooling at
room temperature, the purple solution was treated with a 10%
aqueous Na.sub.2S.sub.2O.sub.3 solution and dried over MgSO.sub.4.
After evaporation of the solvents, the phenol was purified over a
short pad of silica gel (eluent: 5/95 ethyl acetate/hexane) to
afford 5 g (18.1 mmol, yield: 90%) of II. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.51 (d, J=2.3 Hz, 1H), 7.34 (dd, J=8.1, 2.0
Hz, 1H), 6.44 (d, J=8.1 Hz, 1H), 2.77 (s, 1H), 1.37 (s, 9H).
Example 110
[0295] (Compound III of Scheme 13, where R=tert-butyl). A mixture
of 3.65 g (13.2 mmol) of II, 6.5 gm (20.0 mmol) of Cs.sub.2CO.sub.3
and 1.9 ml (2.7 g, 15.8 mmol) of benzyl bromide in 20 ml of dry DMF
was stirred at room temperature overnight. Water (100 ml) was added
and the mixture was extracted with ethyl acetate. The organic layer
was dried over MgSO.sub.4. After evaporation of the solvents, the
crude oil was purified over a short pad of silica gel (eluent: 5/95
ethyl acetate/hexane) to afford 4.25 g (11.6 mmol, yield: 88%) of
III. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.55 (d, J=2.2 Hz,
1H), 7.41 (m, 6H), 6.68 (d, J=8.5 Hz, 1H), 5.08 (s, 2H), 1.38 (s,
9H).
Example 111
[0296] (Compound IV of Scheme 13 where R=tert-butyl). A mixture of
1.5 g (4.1 mmol) of III 800 mg (8.2 mmol) of trimethylsilyl
acetylene, 80 mg (0.4 mmol) of CuI and 236 mg (0.2 mmol) of
tetrakistriphenylphosphine palladium in 20 ml of dry Et.sub.3N was
stirred at reflux for an hour and at room temperature overnight.
Aqueous NH.sub.4Cl (100 ml) was added and the mixture was extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4.
After evaporation of the solvents, the crude oil was diluted in 10
ml of methanol, and 100 mg (0.72 mmol) of K.sub.2CO.sub.3 was
added. The suspension was stirred at room temperature overnight and
the solvent was evaporated. Chromatography over silica gel (eluent:
10/90 ethyl acetate/hexane) afford 1.02 g (3.86 mmol, yield: 94%)
of IV .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.69 (d, J=2.0 Hz,
1H), 7.41 (m, 6H), 6.68 (d, J=8.4 Hz, 1H), 5.12 (s, 2H), 2.98 (s,
1H), 1.39 (s, 9H).
Example 112
[0297] (Compound V of Scheme 13 where R=tert-butyl, R'=methyl). To
a solution of 1.0 g (3.8 mmol) of IV in 4 ml of THF and 2 ml of
DMPU, was added 1.8 ml of nBuLi at 0.degree. C. The mixture was
stirred 15 minutes and 0.31 ml (697 mg, 4.9 mmol) of methyl iodide
diluted in 1 ml of dry THF was added dropwise. After complexion of
the reaction (TLC analysis), aqueous NH.sub.4Cl (10 ml) was added
and the mixture was extracted with ethyl acetate. The organic layer
was dried over MgSO.sub.4. After evaporation of the solvents, the
crude oil was purified over a short silica gel pad (eluent: 5/95
ethyl acetate/hexane) to give 1.0 g (3.6 mmol, yield: 94%) of V.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.43 (d, J=7.0 Hz, 2H),
7.39 (t, J=7.4 Hz, 2H), 7.30 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 6.83
(d, J=8.3 Hz, 1H), 5.10 (s, 2H), 2.03 (s, 3H), 1.38 (s, 9H).
Example 113
[0298] (Compound VII of Scheme 13, where R=tert-butyl, R'=methyl).
To a solution of 1.0 g (3.6 mmol) of VI and 100 mg of 10% Pd/C in
10 ml of ethyl acetate was stirred at room temperature overnight
under H.sub.2 atmosphere (balloon). After complexion (TLC
analysis), the solution was filtrated over a celite plug and the
plug washed 3 times with ethyl acetate. After evaporation of the
solvents, the crude oil was directly diluted in 10 ml of
CH.sub.2Cl.sub.2. p-toluenesulfonic acid (75 mg, 0.39 mmol) and NIS
(1.0 g, 4.38 mmol) were successively added and the mixture was
stirred until complexion (TLC analysis) of the reaction. Aqueous
Na.sub.2S.sub.2O.sub.3 was added to the purple solution and the
organic layer was separated and dried over MgSO.sub.4. After
evaporation of the solvents and purification over a short pad of
silica gel (eluent: 15/85 ethyl acetate/hexane), 995 mg (3.12 mmol,
yield: 82%, 2 steps) of VII were isolated as an oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.34 (d, J=1.8 Hz, 1H), 7.03 (d,
J=1.8 Hz, 1H), 5.33 (s, 1H), 2.46 (t, J=7.5 Hz, 2H), 1.61 (m, 2H),
1.38 (s, 9H), 0.93 (t, J=7.3 Hz, 3H).
Example 114
[0299] (Compound VIII of Scheme 13, where R=tert-butyl, R'=methyl,
R"=n-propyl). A mixture of 210 mg (0.58 mmol) of VII, 1.14 g (3.5
mmol) of Cs.sub.2CO.sub.3 and 0.26 ml (344 mg, 2.8 mmol) of bromo
propane in 5 ml of dry DMF was stirred at room temperature
overnight. Water (20 ml) was added and the mixture was extracted
with ethyl acetate. The organic layer was dried over MgSO.sub.4.
After evaporation of the solvents, the crude oil was purified over
a short pad of silica gel (eluent: 5/95 ethyl acetate/hexane) to
afford 720 mg (2.0 mmol, yield: 86%) of VIII. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.50 (d, J=2.1 Hz, 1H), 7.09 (d, J=2.1 Hz,
1H), 3.93 (t, J=6.8 Hz, 2H), 2.47 (t, J=7.3 Hz, 2H), 1.95 (m, 2H),
1.62 (m, 2H), 1.38 (s, 9H), 1.08 (t, J=7.4 Hz, 3H), 0.94 (t, J=7.3
Hz, 3H).
Example 115
[0300] (Compound IX in Scheme 13, where R=tert-butyl, R'=methyl,
R"=propyl, A=A7). A mixture of 710 mg (2.33 mmol) of VIII, 136 mg
(0.87 mmol) of 2-formyl-3-thiophene boronic acid, 34 mg (0.03 mmol)
of Pd(PPh.sub.3).sub.4 in toluene/ethanol/aqueous Na.sub.2CO.sub.3
(5/2.5/1 ml respectively) was refluxed overnight. After cooling at
room temperature, water (30 ml) was added and the mixture was
extracted with ethyl acetate. The organic layer was dried over
MgSc.sub.4. After evaporation of the solvents, the crude oil was
purified over a short pad of silica gel (eluent: 5/95 ethyl
acetate/hexane) to afford 154 mg (0.45 mmol, yield: 77%) IX.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.76 (s, 1H), 7.79 (m,
1H), 7.68 (d, J=2.1 Hz, 1H), 7.21 (m, 2H), 3.32 (t, J=6.2 Hz, 2H),
2.56 (t, J=7.6 Hz, 2H), 1.55 (m, 2H), 1.55 (m, 2H), 1.41 (s, 9H),
0.97 (t, J=7.3 Hz, 3H), 0.77 (t, J=7.2 Hz, 3H).
Example 116
[0301] (Compound X in Scheme 13, where R=tert-butyl, R'=methyl.
R"=n-propyl, A=A7). To a solution of 0.36 ml (384 mg, 1.45 mmol) of
triethyl-3-methylphosphonocrotonate in THF/DMPU (4/1 ml
respectively) was added 0.73 ml of nBuLi at -78.degree. C. After
stirring for 10 minutes, 154 mg (0.45 mmol) of IX (diluted in 1 ml
of dry THF) was added dropwise. After complexion of the reaction,
the solvents were evaporated and the crude product directly
purified over silica gel column chromatography (eluent: 5/95 ethyl
acetate/hexane) to afford 181 mg (0.4 mmol, yield: 89%) X. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.32 (d, J=8.3 Hz, 1H), 7.24 (d,
J=1.9 Hz, 1H), 7.12 (d, J=15.8 Hz, 1H), 7.02 (d, J=15.3 Hz, 1H),
6.89 (d, J=1.9 Hz, 1H), 6.62 (dd, J=15.7, 9.3 Hz, 1H), 5.84 (s,
1H), 4.18 (dd, J=14.7, 7.3 Hz, 2H), 3.34 (t, J=6.1 Hz, 2H), 2.55
(t, J=7.5 Hz, 2H), 2.24 (s, 3H), 1.62 (m, 2H), 1.55 (m, 2H), 1.42
(s, 9H), 1.28 (t, J=7.1 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H), 0.77 (t,
J=7.3 Hz, 3H).
Example 117
[0302] (L64, Compound XI in Scheme 13, where R=tert-butyl,
R'=methyl, R"=propyl, A=A7). Saponification (methanol/THF/aqueous
LiOH, reflux) of 181 mg (0.4 mmol) afford after work-up and
recrystallization from acetonitrile 128 mg (0.3 mmol, yield:
.delta. 7.5%) of X. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.28
(d, J=5.2 Hz, 1H), 7.13 (d, J=2.1 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H),
7.07 (d, J=15.8 Hz, 1H), 6.89 (d, J=2.1 Hz, 1H), 6.64 (d, J=15.8
Hz, 1H), 5.86 (s, 1H), 3.33 (t, J=6.3 Hz, 2H), 2.55 (t, J=7.5 Hz,
2H), 2.25 (s, 3H), 1.62 (m, 2H), 1.42 (s, 9H), 0.96 (t, J=7.3 Hz,
3H), 0.76 (t, J=7.4 Hz, 3H).
Example 118
[0303] (L65, Compound XI of Scheme 13, where R=tert-butyl,
R'=n-propyl, R"=n-propyl, A=A7). This compound was prepared in the
manner previously described for Compound XI in Example 117 except
that propyl iodide was used instead of methyl iodide in Example
112. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.28 (d, J=5.1 Hz,
1H), 7.14 (d, J=2.2 Hz, 1H), 7.11 (d, J=5.0 Hz, 1H), 7.07 (d,
J=15.8 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.64 (d, J=15.8 Hz, 1H),
5.86 (s, 1H), 3.33 (t, J=6.3 Hz, 2H), 2.56 (t, J=7.8 Hz, 2H), 2.26
(s, 3H), 1.62 (m, 2H), 1.42 (s, 9H), 1.41 (m, 2H), 1.36 (m, 4H),
0.90 (t, J=6.8 Hz, 3H), 0.76 (t, J=7.4 Hz, 3H).
Example 119
[0304] (L66, Compound XI of Scheme 13, where R=cyclopentyl, R'=H,
R"=n-butyl, A=A7). This compound was prepared in the manner
previously described for Compound XI in Example 117, except that
2-cyclopentyl phenol was used instead of 2-tert-butyl phenol in
Example 109, Compound VI was synthesized directly from IV, yielding
R'=H and bromobutane was used in Example 114 instead of
bromopropane. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.26 (d,
J=4.4 Hz, 1H), 7.14 (d, J=5.1 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 7.10
(d, J=15.7 Hz), 6.88 (d, J=2.1 Hz, 1H), 6.66 (d, J=15.7 Hz, 1H),
5.87 (s, 1H), 3.41 (m, 1H), 3.37 (t, J=6.5 Hz, 2H), 2.62 (dd,
J=15.2, 7.6 Hz, 2H), 2.27 (s, 3H), 2.09 (m, 2H), 1.82 (m, 2H), 1.72
(m, 2H), 1.60 (m, 2H), 1.43 (m, 2H), 1.25 (t J=7.4 Hz, 3H), 0.78
(t, J=7.3 Hz, 3H).
Example 120
[0305] (L17, Compound XI of Scheme 13, where R=cyclopentyl, R'=H,
R"=fluorobutyl, A=A7). This compound was prepared in the manner
previously described for Compound XI in Example 117, except that
2-cyclopentyl phenol was used instead of 2-tert-butyl phenol in
Example 109, Compound VI was synthesized directly from IV, yielding
R'=H, and 3-fluoropropyl bromide was used instead of bromopropane
in example 114. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.26 (d,
J=5.2 Hz, 1H), 7.25 (d, J=2.2 Hz, 1H), 7.121 (d, J=5.3 Hz, 1H),
7.06 (d, J=15.8 Hz, 1H), 6.89 (d, J=2.2 Hz, 1H), 6.66 (d, J=15.8
Hz, 1H), 5.87 (s, 1H), 4.45 (t, J=6.0 Hz, 1H), 4.34 (t, J=6.0 Hz,
1H), 3.49 (t, J=5.9 Hz, 2H), 3.35 (m, 1H), 2.63 (dd, J=15.1, 7.5
Hz, 2H), 2.26 (s, 3H), 2.16 (m, 2H), 1.72 (m, 6H), 1.24 (t, J=7.5
Hz, 3H).
Example 121
[0306] (L67, Compound XI of Scheme 13, where R=cyclopentyl, R'=H,
R"=propyl, A=A7) This compound was prepared in the manner
previously described for Compound XI in Example 117, except that
2-cyclopentyl phenol was used instead of 2-tert-butyl phenol in
Example 109 and Compound VI was synthesized directly from IV,
yielding R'=H. .sup.1H NMR (400 MHz, CDCl.sub.3): 7.25 (d, J=4.70
Hz, 1H), 7.15 (d, J=5.1 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 7.10 (d,
J=15.8 Hz), 6.89 (d, J=2.1 Hz, 1H), 6.66 (d, J=15.8 Hz, 1H), 5.87
(s, 1H), 3.37 (m, 1H), 3.33 (t, J=6.3 Hz, 2H), 2.63 (dd, J=15.2,
7.5 Hz, 2H), 2.28 (s, 3H), 2.18 (m, 2H), 1.85 (m, 2H), 1.72 (m,
2H), 1.61 (m, 2H), 1.46 (m, 2H), 1.24 (t J=7.5 Hz, 3H), 0.79 (t,
J=7.4 Hz, 3H).
Example 121a
[0307] (L16, Compound XI of Scheme 13 where R=tert-butyl, R'=H,
R"=1,1,1-trifluorobutyl, A=A7). This compound was prepared in the
manner previously described for Compound XI in Example 117, except
that Compound VI was synthesized directly from IV, yielding R'=H
and 1,1,1-trifluoro-4-bromobutane was used instead of bromopropane
in Example 114. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.32 (d,
J=5.10 Hz, 1H), 7.18 (d, J=2.2 Hz, 1H), 7.09 (d, J=5.2 Hz, 1H),
6.99 (d, J=15.9 Hz), 6.93 (d, J=2.1 Hz, 1H), 6.65 (d, J=15.9 Hz,
1H), 5.87 (s, 1H), 3.42 (m, 2H), 2.63 (dd, J=15.1, 7.5 Hz, 1H),
2.00 (m, 2H), 1.72 (m, 2H), 1.42 (s, 9H), 1.24 (t J=7.2 Hz,
3H).
Example 122
[0308] (L68, Compound XI of Scheme 13, where R=tert-butyl,
R'=methyl. R"=1,1-difluoroethyl, A=A7). This compound was prepared
in the manner previously described for Compound XI in Example 117,
except that ethyl iodide was used instead of methyl iodide in
Example 112 and 2-fluoroethyl bromide was used instead of
bromopropane in Example 114. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.33 (d, J=5.2 Hz, 1H), 7.17 (d, J=2.2 Hz, 1H), 7.11 (d,
J=5.2 Hz, 1H), 6.99 (d, J=15.8 Hz, 1H), 6.92 (d, J=2.2 Hz, 1H),
6.67 (d, J=15.8 Hz, 1H), 5.63 (dt, J=55.4, 6.9 Hz, 1H), 3.59 (td,
J=13.3, 5.3 Hz, 1H), 2.56 (t, J=7.4 Hz, 2H), 2.25 (s, 3H), 1.65 (m,
2H), 1.43 (s, 9H), 0.97 (t, J=7.3 Hz, 3H).
Example 123
[0309] (L69, Compound XI of Scheme 13, where R=cyclopentyl,
R'=1-isopropyl, R"=fluoropropyl, A=A7). This compound was prepared
in the manner previously described for Compound XI in Example 117,
except that 2-cyclopentyl phenol was used instead of 2-tert-butyl
phenol in Example 109, isopropyl iodide was used instead of methyl
iodide in Example 112 and 3-fluoroethyl bromide was used instead of
bromopropane in Example 114. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.25 (d, J=5.3 Hz, 1H), 7.12 (d, J=5.3 Hz, 1H), 7.09 (d,
J=2.1 Hz, 1H), 7.01 (d, J=15.9 Hz, 1H), 6.88 (d, J=2.1 Hz, 1H),
6.64 (d, J=15.9 Hz, 1H), 5.89 (s, 1H), 4.46 (t, J=6.0 Hz, 1H), 4.34
(t, J=6.0 Hz, 1H), 3.49 (t, J=5.9 Hz, 2H), 2.54 (m, 2H), 2.28 (s,
3H), 2.09 (m, 2H), 1.76 (m, 4H), 1.5 (8H), 0.95 (s, 6H). 8485
[0310] Scheme 14 depicts a method of preparation of unsymmetrical
modulators wherein various substituents are introduced at R.sup.2
and R.sup.4.
Example 124
[0311] (Compound II of Scheme 14, where R=tert-butyl). A mixture of
593 mg (1.62 mmol) of I (2-tert-butyl-4-benzyloxo-phenol), 94 mg
(0.08 mmol) of Pd(PPh.sub.3).sub.4, 300 mg (2.40 mmol) of
phenylboronic acid dissolved in 6 ml of toluene, 3 ml of ethanol
and 1.7 ml of 2N aqueous Na.sub.2CO.sub.3 was heated to reflux
overnight. After work-up, the crude product was filtrated over a
short plug of silica gel to remove the catalyst impurities and
directly dissolved into 5 ml of ethyl acetate. 100 mg of 10% Pd/C
was added and the mixture was stirred under H.sub.2 atmosphere
overnight. Filtration and purification over silica gel column
chromatography, 332 mg (1.46 mmol, yield: 90%, 2 steps) of II
(2-tert-butyl-4-phenyl phenol) was isolated as a pasty solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.56 (dd, J=7.8, 1.0 Hz,
2H), 7.52 (d, J=2.2 Hz, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.31 (m, 2H),
6.75 (d, J=8.1 Hz, 1H), 4.94 (s, 1H), 1.47 (s, 9H).
Example 125
[0312] (Compound III of Scheme 14, where R=tert-butyl). A mixture
of 332 mg (1.46 mmol) of II (2-tert-butyl-4-phenylphenol), 394 mg
(1.75 mmol) of NIS and 30 mg (0.15 mmol) of P-toluenesulfonic acid
in 5 ml of dry CH.sub.2Cl.sub.2 was stirred at room temperature
until complexion of the reaction (TLC analysis). An aqueous
solution of Na.sub.2S.sub.2O.sub.3 (20 ml) was added and the
mixture was extracted with CH.sub.2Cl.sub.2. The organic layer was
dried over MgSO.sub.4. After evaporation of the solvents, the crude
oil was purified over a short pad of silica gel (eluent: 5/95 ethyl
acetate/hexane) to afford 493 mg (1.4 mmol, yield: 96%) of III.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.76 (d, J=2.0 Hz, 1H),
7.49 (m, 2H), 7.47 (d, J=2.0 Hz, 1H), 7.42 (t, J=7.4 Hz, 2H), 7.32
(t, J=7.2 Hz, 1H), 5.53 (s, 1H), 1.44 (s, 9H).
Example 126
[0313] (Compound IV of Scheme 14, where R=tert-butyl, R'=n-propyl).
A mixture of 205-mg (0.58 mmol) of III, 93 mg (0.76 mmol) of
1-bromopropane and 284 mg (0.87 mmol) of Cs.sub.2CO.sub.3 in 5 ml
of dry DMF was stirred at room temperature until complexion of the
reaction (TLC analysis). After work-up and evaporation of the
solvents, the crude oil was purified over a short pad of silica gel
(eluent: 5/95 ethyl acetate/hexane) to afford 191 mg (0.49 mmol,
yield: 83%) of IV. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.91
(d, J=1.90 Hz, 1H), 7.62 (m, 2H), 7.54 (d, J=1.9 Hz, 1H), 7.50 (m,
1H), 7.44 (m, 2H), 7.38 (t, J=7.2 Hz, 1H), 4.00 (t, J=6.9 Hz, 1H),
1.95 (m, 2H), 1.45 (s, 9H), 1.11 (t, J=7.6 Hz, 3H).
Example 127
[0314] (Compound V of Scheme 14, where R=tert-butyl, R'=n-propyl,
A=A7). A mixture of 191 mg (0.48 mmol) of IV, 113 mg (0.73 mmol) of
2-formyl-3-thiopheneboronic acid, 28 mg (0.02 mmol) of
Pd(PPh.sub.3).sub.4 in toluene/ethanol/aqueous Na.sub.2CO.sub.3
(5/2.5/0.5 ml respectively) was refluxed overnight. After cooling
at room temperature, water (30 ml) was added and the mixture was
extracted with ethyl acetate. The organic layer was dried over
MgSO.sub.4. After evaporation of the solvents, the crude oil was
purified over a short pad of silica gel (eluent: 5/95 ethyl
acetate/hexane) to afford 166 mg (0.44 mmol, yield: 90%) V. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.78 (d, J=4.9 Hz, 1H), 7.65 (d,
J=2.3 Hz, 1H), 7.62 (d, J=4.2 Hz, 1H), 7.58 (m, 2H), 7.44 (m, 2H),
7.39 (d, J=2.3 Hz, 1H), 7.31 (m, 1H), 3.40 (t, J=6.2 Hz, 1H), 1.55
(m, 2H), 1.49 (s, 9H), 0.81 (t, J=7.4 Hz, 3H).
Example 128
[0315] (Compound VI of Scheme 14, where R=tert-butyl, R'=n-propyl,
A=A7). To a solution of 0.27 ml (289 mg, 1.09 mmol) of
triethyl-3-methylphosphon- ocrotonate in THF/DMPU (4/1 ml
respectively) was added 0.57 ml of nBuLi at -78.degree. C. After
stirring for 10 minutes, 166 mg (0.44 mmol) of V (diluted in 1 ml
of dry THF) was added dropwise. After complexion of the reaction,
the solvents were evaporated and the crude directly purified over
silica gel column chromatography (eluent: 5/95 ethyl
acetate/hexane) to afford 197 mg (0.41 mmol, yield: 95%) VI.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.65 (m, 2H), 7.42 (m,
2H), 7.33 (m, 4H), 7.14 (d, J=5.3 Hz, 1H), 7.03 (d, J=15.8 Hz, 1H),
6.64 (d, J=15.8 Hz, 1H), 5.85 (s, 1H), 4.17 (dd, J=14.2, 7.1 Hz,
2H), 3.41 (t, J=6.1 Hz, 2H), 2.26 (s, 3H), 1.50 (m, 2H), 1.49 (s,
9H), 1.29 (t, J=7.1 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H).
Example 129
[0316] (L70, Compound VII of Scheme 14, where R=tert-butyl,
R'=n-propyl, A=A7). Saponification (aqueous LiOH, THF, methanol) of
VI followed by usual acidic work-up and recrystallization from
acetonitrile afford 138 mg (0.3 mmol, yield: 75%) of VII. .sup.1H
NMR (400 MHz, CDCl.sub.3) .delta.: 7.56 (m, 2H), 7.42 (t, J=7.5 Hz,
1H), 7.31 (m, 2H), 7.14 (d, J=5.1 Hz, 1H), 7.09 (d, J=15.8 Hz, 1H),
6.66 (d, J=15.8 Hz, 1H, 5.87 (s, 1H), 3.40 (t, J=4.5 Hz, 2H), 2.27
(s, 3H), 1.51 (m, 2H), 1.49 (s, 9H), 0.79 (t, J=7.4 Hz, 3H).
8687
[0317] Scheme 15 depicts an alternative method of introducing a
variety of substituents at the R.sup.2 and R.sup.4 positions.
Example 130
[0318] (Compound II of Scheme 15, where R=ethyl). A mixture of 12.2
g (0.1 mol) of I (4-ethyl phenol), 1.9 g (0.01 mol) of
p-toluenesulfonic acid and 25 g (0.11 mol) of NIS in 100 ml of
CH.sub.2Cl.sub.2 was stirred at room temperature until complexion
(TLC analysis). Aqueous Na.sub.2S.sub.2O.sub.3 was added to the
purple solution and the organic layer was separated and dried over
MgSO.sub.4. After evaporation of the solvents and purification over
a short pad of silica gel (eluent: 15/85 ethyl acetate/hexane),
22.3 g (0.09 mol, yield: 90%) of II were isolated as an oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.49 (d, J=1.8 Hz, 1H),
7.07 (dd, J=8.3, 1.8 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H), 5.12 (s, 1H),
2.55 (dd, J=13.5, 7.4 Hz, 2H), 1.94 (t, J=7.4 Hz, 3H).
Example 131
[0319] (Compound III of Scheme 15, where R=ethyl, R'=cyclohexene).
A mixture of 2.54 g (10.2 mmol) of II (2-iodo-4-ethyl phenol), 57
mg (0.26 mmol) of Pd(OAc).sub.2, 5.2 ml (4.2 g, 51 mmol) of
cyclohexene, 67 mg (026 mmol) of Pd(PPh.sub.3).sub.4, 3 g (30.6
mmol) of KOAc and 2.8 g (10.2 mmol) of nBu.sub.4NCl in 20 ml of DMF
were heated to 60.degree. C. overnight. Water (100 ml) was added
after cooling to room temperature and the solution was extracted
with ethyl acetate. The organic layer was separated and dried over
MgSO.sub.4. After evaporation of the solvents and column
chromatography purification silica gel (eluent: 15/85 ethyl
acetate/hexane), 1.0 g (4.94 mmol, yield: 48%) of III were isolated
as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.01 (d,
J=1.9 Hz, 1H), 6.92 (dd, J=7.4, 1.9 Hz, 1H), 6.68 (d, J=7.4 Hz,
1H), 5.78 (m, 2H), 4.64 (s, 1H), 3.11 (m, 1H), 2.59 (m, 1H), 2.58
(dd, J=13.5, 7.4 Hz, 2H), 2.31 (m, 1H), 2.25 (m, 4H), 1.92 (m, 1H),
1.85 (m, 1H), 1.21 (t, J=7.3H, 3H).
Example 132
[0320] (Compound III of Scheme 15, where R=ethyl, R'=cyclohexane).
A mixture of 1.0 g (4.9 mmol) of II (2-cyclohexe-2-ene-4-ethyl
phenol) and 100 mg of 10% Pd/C in 10 ml of ethyl acetate was
stirred at room temperature under hydrogen atmosphere (balloon)
overnight. The mixture was filtrated over celite and the solvents
evaporated to give 1.0 g (4.9 mmol, yield: 100%) of III as an oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 6.99 (d, J=1.8 Hz, 1H),
6.88 (dd, 1=8.0, 1.8 Hz, 1H), 6.68 (d, J=8.0 Hz, 1H), 4.56 (s, 1H),
2.78 (m, 1H), 2.57 (dd, J=15.1, 7.6 Hz, 2H), 1.89 (m, 4H), 1.75 (m,
2H), 1.49 (m, 6H), 1.20 (t, J=7.4H, 3H).
Example 133
[0321] (Compound IV of Scheme 15, where R=ethyl, R'=cyclohexane). A
mixture of 1.0 g (1.9 mmol) of III, 94 mg (0.5 mmol) of
p-toluenesulfonic acid and 1.2 g (5.4 mmol) of NIS in 20 ml of
CH.sub.2Cl.sub.2 was stirred at room temperature until complexion
(TLC analysis). Aqueous Na.sub.2S.sub.2O.sub.3 was added to the
purple solution and the organic layer was separated and dried over
MgSO.sub.4. After evaporation of the solvents and purification over
a short pad of silica gel (eluent: 15/85 ethyl acetate/hexane), 1.4
g (4.1 mmol, yield: 83%) of IV were isolated as an oil. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.31 (d, J=1.4 Hz, 1H), 6.97 (d,
J=1.4 Hz, 1H), 5.12 (s, 1H), 2.92 (m, 1H), 2.53 (dd, J=15.2, 7.5
Hz, 2H), 1.88 (m, 4H), 1.72 (m, 2H), 1.40 (m, 4H), 1.19 (t, J=7.9
Hz, 3H).
Example 134
[0322] (L104, Compound VIII of Scheme 15 where R=ethyl,
R'=cyclohexane, R"=n-propyl, A=A7). This compound was prepared as
previously described for Compound VII in Example 129 except that IV
of Example 133 was used in the synthetic route instead of Compound
IV of Example 125. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.25
(d, J=5.1 Hz, 1H), 7.12 (d, J=15.8 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H),
6.88 (d, J=2.3 Hz, 1H), 6.65 (d, J=15.8 Hz, 1H), 5.86 (s, 1H), 3.31
(t, J=6.4 Hz, 2H), 2.97 (m, 1H), 2.62 (dd, J=15.2, 7.6 Hz, 2H),
2.27 (s, 3H), 1.77 (m, 4H), 1.42 (m, 6H), 1.24 (t, J=7.5 Hz, 31H),
0.82 (t, J=7.4 Hz, 3H).
Example 135
[0323] (L72, Compound VII of Scheme 15 where R=ethyl,
R'=cyclohexane, R"=1-fluoropropyl, A=A7). This compound was
prepared in the manner previously described for Compound VI in
Example 134 except that 1-fluoro-3-bromopropane was used instead of
1-bromopropane in Example 126. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.25 (d, J=5.2 Hz, 1H), 7.12 (d, J=5.2 Hz, 1H), 7.08 (d,
J=3.6 Hz, 1H), 7.05 (d, J=15.8 Hz, 1H), 6.89 (d, J=3.6 Hz, 1H),
6.66 (d, J=15.8 Hz, 1H), 5.87 (s, 1H), 4.50 (t, J=6.0 Hz, 2H), 4.39
(t, J=6.0 Hz, 1H), 3.48 (t, J=5.9 Hz, 2H), 2.92 (m, 1H), 263 (dd,
J=15.17.5 Hz, 2H), 2.26 s, 3H), 1.83 (m, 2H), 1.79 (m, 2H), 1.55
(m, 2H), 1.40 (m, 2H), 1.24 (t, J=7.5 Hz, 3H).
Example 136
[0324] (Compound III of Scheme 15 where R=ethyl, R'=phenyl). A
mixture of 2.3 g (9.2 mmol) of II (2-iodo-4-ethyl phenol), 1.4 g
(10 mmol) of phenyl boronic acid and 213 mg of Pd(PPh.sub.3).sub.4
In 20 ml of toluene, 10 ml of ethanol and 10 ml of aqueous 2N
Na.sub.2CO.sub.3 was stirred at reflux overnight. After work-up the
solvents were evaporated and the crude product was purified over
column chromatography (eluent: 10/90 ethyl acetate/hexane) to give
0.7 g (3.8 mmol, yield: 40%) of III as a pasty solid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.49 (m, 4H), 7.42 (m, 1H), 7.08 (m,
2H), 6.90 (d, J=8.1 Hz, 1H), 5.06 (s, 1H), 2.63 (dd, J=15.2, 7.6
Hz, 2H), 1.24 (t, J=7.1H, 3H).
Example 137
[0325] (Compound IV of Scheme 15 where R=ethyl, R'=phenyl). A
mixture of 0.75 g (3.8 mmol) of 111.72 mg (0.4 mmol) of
p-toluenesulfonic acid and 1.0 g (4.6 mmol) of NIS in 10 ml of
CH.sub.2Cl.sub.2 was stirred at room temperature until complexion
(TLC analysis). Aqueous Na.sub.2S.sub.2O.sub.3 was added to the
purple solution and the organic layer was separated and dried over
MgSO.sub.4. After evaporation of the solvents and purification over
a short pad of silica gel (eluent: 15/85 ethyl acetate/hexane), 1.4
g.(4.1 mmol, yield: 83%) of IV were isolated as a pasty yellow
solid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.52 (d, J=1.4
Hz, 1H), 7.48 (m, 4H), 7.40 (m, 1H), 7.08 (d, J=1.4 Hz, 1H), 5.40
(s, 1H), 2.59 (dd, J=15.2, 7.6 Hz, 2H), 1.23 (t, J=7.5 Hz, 3H).
Example 138
[0326] (L72, Compound VII of Scheme 15 where R=ethyl, R'=phenyl,
R"=n-propyl, A=A7). This compound was prepared in the manner
previously described for Compound VI of Example 134 except that
benzene was used instead of cyclohexene in Example 131. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.61 (d, J=7.6 Hz, 2H), 7.42 (t,
J=7.3 Hz, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.27 (m, 1H), 7.21 (d, J=2.1
Hz, 1H), 7.17 (d, J=9.6 Hz, 1H), 7.18 (d, J=15.2 Hz, 1H), 7.07 (d,
J=2.1 Hz, 1H), 6.69 (d, J=15.8 Hz, 1H), 5.90 (s, 1H), 3.13 (t,
J=6.3 Hz, 2H), 2.68 (dd, J=15.2, 7.5 Hz, 2H), 2.34 (s, 3H), 1.28
(t, J=7.6 Hz, 2H), 1.15 (m, 2H), 0.53 (t, J=7.4 Hz, 3H).
Example 139
[0327] (L73, Compound VII of Scheme 15 where R=ethyl, R'=phenyl,
R"=1-fluoropropyl, A=A7). This compound was prepared in the manner
previously, described for Compound VI of Example 134 except that
benzene was used instead of cyclohexene in Example 131 and
1-fluoro-3-bromopropane was used instead of 1-bromopropane in
Example 126. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.57 (d,
J=7.6 Hz, 2H), 7.42 (t, J=7.3 Hz, 2H), 7.36 (d, J=7.3 Hz, 1H), 7.27
(m, 1H), 7.21 (d, J=1.9 Hz, 1H), 7.17 (d, J=5.6 Hz, 1H), 7.09 (d,
J=15.9 Hz, 1H), 7.07 (d, J=1.9 Hz, 1H), 6.69 (d, J=15.9 Hz, 1H),
5.91 (s, 1H), 4.12 (t, J=6.1 Hz, 1H), 4.00 (t, J=6.2 Hz, 1H), 3.28
(t, J=5.8 Hz, 2H), 2.69 (dd, J=15.0, 7.4 Hz, 2H), 2.34 (s, 3H),
1.56 (m, 2H), 1.29 (t, J==7.3 Hz, 3H). 8889
[0328] Scheme 16 depicts another alternative method for preparing
modulators with a variety of substituents at the R.sup.2 and
R.sup.4 positions.
Example 140
[0329] (Compound XI of Scheme 16 where R=tert-butyl, R'=H, R"=H). A
mixture of 5.2 g (35 mmol) of 4-tert-butyl phenol, 17.0 g (52 mmol)
of Cs.sub.2CO.sub.3 and 3.6 ml (5.0 g, 42.5 mmol) of allyl bromide
in 70 ml of dry DMF was stirred at room temperature overnight.
Water (200 ml) was added and the mixture was extracted with ethyl
acetate. The organic layer was dried over MgSO.sub.4. After
evaporation of the solvents, the crude oil was purified over a
short pad of silica gel (eluent: 5/95 ethyl acetate/hexane) to
afford 9.5 mg (5Q mmol, yield: 96%) of XI. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.30 (d, J=6.9 Hz, 2H), 6.88 (d, J=6.9 Hz,
2H), 6.09 (m, 1H), 5.41 (d, J=17.6 Hz, 1H), 5.27. (d, J=10.6 Hz,
1H), 4.53 (m, 2H), 1.30 (s, 9H).
Example 141
[0330] (Compound I of Scheme 16 where R=tert-butyl, R'=H, R"=H). A
mixture of 1.9 g (10 mmol) of XI in 20 ml of N,N-diethylaniline was
stirred at reflux for 2 hours. After cooling, the solution was
triturated with 2N aqueous solution (200 ml) and extracted with
ethyl acetate. The organic layer was dried over MgSO.sub.4. After
evaporation of the solvents, the crude, oil was purified over a
short pad of silica gel (eluent: hexane and 5/95 ethyl
acetate/hexane) to afford 1.3 g (6.8 mmol, yield: 68%) of I.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.15 (dd, J=8.4, 2.2 Hz,
1H), 7.11 (d, J=2.2 Hz, 1H), 6.75 (d, J=8.4 Hz, 1H), 6.05 (m, 1H),
5.19 (m, 2H), 4.86 (broad s, 1H), 3.41 (d, J=6.3 Hz, 2H), 1.29 (s,
9H), 1.26 (t, J=7.0 Hz, 3H).
Example 142
[0331] (Compound II of Scheme 16 where R=tert-butyl, R'=H, R"=H).
Hydrogenation (Pd/C, ethyl acetate, 1 atm H.sub.2) of 1.3 g (6.8
mmol) of I afford 1.3 g (6.8 mmol, yield: 100 g) of II. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.12 (d, J=2.2 Hz, 1H), 7.09 (dd,
J=8.2, 2.2 Hz, 1H), 6.69 (d, J=8.2 Hz, 1H), 4.54 (broad s, 1H),
2.57 (t, J=7.4 Hz, 2H), 1.65 (m, 2H), 1.29 (s, 9H), 0.98 (t, J=7.1
Hz, 3H).
Example 143
[0332] (L74, Compound VIII of Scheme 16 where R=tert-butyl, R'=H,
R"=H, R'"=n-propyl). Compound was prepared in the manner previously
described for Compound VIII in Example 129, except that Compound II
of Example 142 was used instead of Compound II of Example 124 in
the synthetic route. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.26 (d, J=5.1 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 7.18 (d, J=5.3 Hz,
1H), 7.11 (d, J=15.8 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 6.67 (d,
J=15.8 Hz, 1H), 5.87 (s, 1H), 3.33 (t, J=6.4 Hz, 2H), 2.64 (dd,
J=7.5 Hz, 2H), 2.27 (s, 3H), 1.69 (m, 2H), 1.48 (m, 2H), 1.32 (s,
9H), 1.00 (t, J=7.3 Hz, 3H), 0.82 (t, J=7.4 Hz, 3H).
Example 144
[0333] (L106, Compound XI of Scheme 16 where R=tert-butyl, R'=H,
R'=H R'"=n-butyl). Compound was prepared in the manner previously
described for Compound VII in Example 129, except that
benzyloxo-phenol was used instead of
2-tert-butyl-4-benzyloxo-phenol in Example 124. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 7.34 (dd, J=8.6, 2.5 Hz, 1H), 7.25 (d,
J=5.2 Hz, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.16 (d, J=5.2 Hz, 1H), 7.07
(d, J=15.8 Hz, 1H), 6.92 (d, J=8.6 Hz, 1H), 6.68 (d, J=. 15.8 Hz,
1H), 5.87 (s, 1H), 3.93 (t, J=6.5 Hz, 2H), 2.25 (s, 3H), 1.65 (m,
2H), 1.36 (m, 2H), 1.31 (s, 9H), 0.89 (t, J=7.4 Hz, 3H). 90
[0334] Scheme 17 depicts an alternate method of preparing
unsymmetrical modulators of type VIII, in which R, R', R", R'", and
R"" can all be modified.
Example 145
[0335] (Compound II of Scheme 17 where R=ethyl, R'=tert-butyl,
R"=methyl). To a solution of 5.4 g (17.6 mmol)
2-tert-butyl-4-ethyl-6-iodo phenol in 45 ml of dry ether, was added
18 ml of nBuLi (1.6 M in hexane) at -78.degree. C. The mixture is
warmed-up to room temperature until complete consumption of the
starting material (TLC analysis) and, then cooled to -78.degree. C.
again. N,N-dimethyl acetamide (5 ml) diluted in 5 ml of dry ether
was then added dropwise and the mixture was allowed to warm-up to
room temperature. After complexion of the reaction (2-5 hours),
water was added and the solution was extracted with ethyl acetate.
The organic layers were combined, dried over MgSO.sub.4 and
evaporated after filtration. The crude oil was purified over column
chromatography (eluent: 5/95 ethyl acetate/hexane) to give 1.9 g
(8.4 mmol, yield: 48%) of II. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 10.56 (broad s, 1H), 7.41 (d, J=1.9 Hz, 1H), 7.32 (d,
J=1.9 Hz, 1H), 2.63 (s, 3H), 2.60 (dd, J=15.2, 7.5 Hz, 2H), 1.42
(s, 9H), 1.23 (t, J=7.2 Hz, 3H).
Example 146
[0336] (Compound III of Scheme 17 where R=ethyl, R'=tert-butyl,
R"=methyl, R'"=H) A mixture of 1.9 g (8.4 mmol)
2-hydroxy-3-tert-butyl-5-ethyl acetophenone and 9.0 g (26 mmol) of
(carbethoxy-ethylidene)triphenylphosp- horane in 40 ml of dry
toluene was refluxed overnight. After cooling et room temperature,
the solvents were evaporated and the crude coumarin directly
purified over column chromatography (eluent: 10/90 ethyl
acetate/hexane) to give 1.9 g (7.6 mmol, yield: 90%) of III.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.35 (d, J=1.6 Hz, 1H),
7.28 (d, J=1.6 Hz, 1H)., 6.26 (s, 1H), 2.70 (dd, J=15.2, 7.6 Hz,
2H), 2.43 (s, 3H), 1.49 (s, 9H), 1.27 (t, J=7.7 Hz, 3H).
Example 147
[0337] (L75, Compound VIII of Scheme 17 where R=ethyl,
R'=tert-butyl, R"=methyl, R'"=H, R""=n-propyl, R'""=H). This
compound was prepared in the manner previously described for
Compound VIII in Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.09 (d, J=2.8 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H), 6.62 (dd,
J=15.2, 11.1 Hz, 2H), 6.23 (d, J=15.2 Hz, 1H), 6.19 (d, J=1.1 Hz,
1H), 5.76 (s, 1H), 3.69 (m, 1H), 3.64 (m, 1H), 2.59 (dd, J=15.1,
7.5 Hz, 2H), 2.21 (s, 3H), 2.15 (s, 3H), 1.67 (m, 2H), 1.40 (s,
9H), 1.22 (t, J=7.5 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H).
Example 148
[0338] (L76, Compound VIII of Scheme 17 where R=ethyl,
R'=tert-butyl, R"=methyl, R'"=H, R""=n-butyl, R'""=H). This
compound was prepared in the manner previously described for
Compound VIII in Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.08 (d, J=2.8 Hz, 1H), 6.78 (d, J=2.8 Hz, 1H), 6.62 (dd,
J=15.3, 11.1 Hz, 2H), 6.23 (d, J=15.3 Hz, 1H), 6.20 (d, J=11.1 Hz,
1H), 5.76 (s, 1H), 3.70 (m, 2H), 2.59 (dd, J=15.1, 7.6 Hz, 2H),
2.21 (s, 3H), 2.15 (s, 3H), 1.61 (m, 2H), 1.55 (m, 2H), 1.39 (s,
9H), 1.22 (t, J=7.5 Hz, 3H), 0.91 (t, J=7.4 Hz, 3H).
Example 149
[0339] (L77, Compound VIII of Scheme 17 where R=ethyl,
R'=tert-butyl, R"=methyl, R'"=H, R""=1-fluoropropyl, R'""=H). This
compound was prepared in the manner previously described for
Compound VIII in Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.09 (d, J=2.1 Hz, 1H), 6.80 (d, J=2.1 Hz, 1H), 6.57 (dd,
J=15.2, 11.1 Hz, 2H), 6.24 (d, J=15.2 Hz, 1H), 6.22 (d, J=11.1 Hz,
1H), 5.76 (s, 1H), 4.55 (m, H), 4.50 (m, 1H), 3.82 (m, 2H), 2.60
(dd, J=15.2, 7.5 Hz, 2H), 2.22 (s, 3H), 2.13 (s, 3H), 2.01 (m, 2H),
1.39 (s, 9H), 1.23 (t, J=7.6 Hz, 3H).
Example 150
[0340] (L78, Compound VIII of Scheme 17 where R=ethyl,
R'=tert-butyl, R"=methyl, R'"=H, R""=thiomethoxymethyl, R'""=H).
This compound was prepared in the manner previously described for
Compound VIII in Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.12 (d, J=2.7 Hz, 1H), 6.79 (d, J=2.7 Hz, 1H), 6.59 (dd,
J=15.1, 11.0 Hz, 1H), 6.26 (d, J=15.1 Hz), 6.23 (d, J=11.0 Hz, 1H),
5.77 (s, 1H), 4.80 (d, J=10.1 Hz, 1H),4.71 (d, J=10.1 Hz, 1H), 2.60
(dd, J=15.1, 7.6 Hz, 2H), 2.23 (s, 3H), 2.15 (s, 3H), 1.44 (s, 9H),
1.22 (t, J=7.7 Hz, 3H).
Example 151
[0341] (L79, Compound VIII of Scheme 17 where R=ethyl,
R'=tert-butyl, R"=methyl, R'"=H, R""=1,1-di-fluoroethyl, R'""=H).
This compound was prepared in the manner previously described for
Compound VIII in Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.12 (d, J=2.0 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.56 (dd,
J=15.1, 11.1 Hz, 2H), 6.28 (d, J=15.2 Hz, 1H), 6.27 (d, J=11.1 Hz,
1H), 5.95 (dt, J=55.5, 4.0 Hz, 1H), 5.78 (s, 1H), 3.95 (m, 2H),
2.60 (dd, J=15.1, 7.5 Hz, 2H), 2.21 (s, 3H), 2.14 (s, 3H), 1.40 (s,
9H), 1.23 (t, J=7.5 Hz, 3H).
Example 152
[0342] (L80, Compound VIII of Scheme 17 where R=ethyl,
R'=tert-butyl, R"=* methyl, R'"=H, R""=1,1,2,2-tetrafluoropropyl,
R'""=H). This compound was prepared in the manner previously
described for Compound VIII in Scheme 5. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.26 (d, J=2.0 Hz, 1H), 7.13 (d, J=2.0 Hz,
1H), 6.48 (dd, J=14.9, 11.1 Hz, 2H), 6.28 (d, J=15.2 Hz, 1H), 6.27
(d, J=11.1 Hz, 1H), 5.88 (dt, J=49.1, 4.0 Hz, 1H), 5.79 (s, 1H),
4.10 (m, 2H), 2.61 (dd, J=15.1, 7.5 Hz, 2H), 2.20 (s, 3H), 2.13 (s,
3H), 1.39 (s, 9H), 1.23 (t, J=7.5 Hz, 3H). 9192
Example 153
[0343] (Compound I of Scheme 18, where R'=isopropyl). Into a 1L
round-bottomed flask was added 2-hydroxy-3-isopropylbenzoic acid
(10.0 g, 55.49 mmoles) and THF (500 mL). This solution was cooled
to 0.degree. C. and methyllithium (311 mL of a 1.4 M solution,
435.0 mmoles) was added dropwise via addition funnel. The reaction
was subsequently stirred at 0.degree. C. for 1 h and then gradually
warmed to room temperature for 72 h. At this time, the reaction was
quenched with ethyl acetate, isopropanol, and saturated aqueous
Ammonium Chloride. This crude mixture was concentrated in-vacuo,
extracted with 5% ethyl acetate/hexanes, and filtered over a silica
plug affording 7.9 g of I (43.76 mmoles, 79% yield) .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 10.32 (s, 1H), 7.60 (d, J=8.0 Hz,
1H), 7.42 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.7 Hz, 1H), 3.39 (m, 1H),
2.63 (s, 3H), 1.24 (d, J=6.8 Hz, 6H)
Example 154
[0344] (Compound II of Scheme 18, where R'=isopropyl). Into a 500
mL round-bottomed flask fitted with a reflux condenser was added
hydroxy-3-isopropyl-phenyl)ethanone (7.7 g, 43.20 mmoles),
N-iodosuccinimide (10.69 g, 47.52 mmoles), p-toluenesulfonic acid
(0.822 g, 4.32 mmoles), and chloroform (216 mL). This solution was
heated to reflux for 2 h. At this time, the reaction was quenched
with a saturated aqueous solution of sodium thiosulfate and
extracted with methylene chloride. The organic layer was then
passed directly over a pad of silica gel and washed with methylene
chloride to elute the product. Removal of the solvent in-vaccuo
afforded 12.8 g of II (42.19 mmoles, 98% yield). .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 10.9 (s, 1H), 7.87 (d, J=2.2 Hz, 1H),
7.62 (d, J=2.0 Hz, 1H), 3.32 (m, 1H) 2.61 (s, 3H), 1.21 9d, J=6.6
Hz, 6H)
Example 155
[0345] (Compound III of Scheme 18, where R'=isopropyl, R"=H). Into
a 500 mL round-bottomed flask fitted with a Dean-Stark apparatus
and a reflux condenser was added
1-(2-Hydroxy-5-iodo-3-isopropyl-phenyl)-ethanone (12.8 g, 42.19
mmoles) and Toluene (300 mL). To this was added
(Carbethoxymethylene)triphenylphosphorane (34.0 g, 97.0 mmoles),
and the solution was heated to reflux overnight using a Dean-Stark
trap. The reaction was then passed directly over a pad of silica
gel and washed with hexanes to elute the Toluene. A 10% Ethyl
Acetate/Hexanes solution was then used to elute the product off of
the silica gel. Removal of the Solvent in-vacuo afforded 6.6 g of
III (20.1 mmoles, 47% yield). .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.75 (d, J=1.9 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 6.29 (s,
1H), 3.58 (m, 1H), 2.41 (s, 3H), 1.28 (d, J=6.9 Hz, 6H)
Example 156
[0346] (Compound IV of Scheme 18, where R'=isopropyl,
R=1,1,1,2,2-pentafluoroethyl, R"=H). Into a flame-dried 250 mL
round-bottomed flask equipped with a cold-finger condenser was
added Zinc(s) (3.98 g, 60.95 mmoles) and DMF (50 mL). This mixture
was heated to 40.degree. C. and Perfluoroethyliodide(g) was bubbled
into * reaction mixture until the Zinc dissolution was complete.
This solution was allowed to cool to room temperature. At this
time, the perfluoroethylzinc reagent was slowly cannulated into a
slurry of CuBr (4.81 g, 33.53 mmoles) and DMF (50 mL) making sure
to keep the temperature less than 30.degree. C. III (5.0 g, 15.24
mmoles) was then added and the solution was heated under nitrogen
to 65.degree. C. for 6 h. The resultant mixture was quenched with
NH.sub.4Cl(aq) and extracted 2.times. with EtOAc. The organic layer
was washed with Brine, collected and filtered over a pad of Celite.
The solvent was removed in-vacuo and the crude oil was
chromatographed on Silica gel (10% Ethyl Acetate/Hexanes) affording
3.96 g (12.37 mmoles, 81% yield) of IV. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.67 (s, 1H), 7.64 (s, 1H), 6.39 (s, 1H), 3.67
(m, 1H), 2.49 (s, 3H), 1.33 (d, J=6.8 Hz, 6H)
Example 157
[0347] (Compound V of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=H). Into a
flame-dried 250 mL round-bottomed flask equipped for magnetic
stirring was added of IV (0.820 g, 2.56 mmoles) and Et.sub.2O (25
mL). This solution was cooled to 0.degree. C. and LiAlH.sub.4 (97
mg, 2.56 mmoles) was added and then allowed to stir for 1 h. At
this point, the reaction was complete by TLC analysis, therefore no
additional LiAlH.sub.4 was added. The reaction was quenched with a
10% (w/v) NaOH solution (Only enough to quench the reaction). This
heterogeneous mixture was filtered over a small pad of silica gel
using EtOAc to elute V. The filtrate was concentrated and dried
in-vacuo affording a crude oil that was used without further
purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.32 (s,
1H), 7.10 (s, 1H), 6.12 (broad s, 1H), 6.03 (t, J=7.3 Hz, 1H), 3.92
(d, J=7.3 Hz, 2H), 3.33 (m, 1H), 2.06 (s, 3H), 1.39 (t, J=6.9 Hz,
1H), 1.25 (d, J=7.0 Hz, 6H)
Example 158
[0348] (Compound VI of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=H, R'"=ethyl). Into
a 100 mL round-bottomed flask equipped for magnetic stirring was
added crude V (2.56 mmoles max) and DMIF (20 mL). Cesium Carbonate
(4.17 g, 12.8 mmoles) and Iodoethane (0.215 mL, 2.69 mmoles) were
then added and the solution was stirred at room temperature
overnight. At this point a 10% EtOAc/Hexanes solution was added and
the resultant mixture was filtered over a silica plug using a 10%
EtOAc/Hexanes solution to elute VI. The filtrate was concentrated
and dried in-vacuo affording a yellow oil that was used without
further purification. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.38 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.2 Hz, 1H), 5.87 (t, 7.7 Hz,
1H), 3.83 (m, 4H), 3.37 (m, 1H), 1.37 (t, J=7.2 Hz, 3H), 1.24 (m,
7H)
Example 159
[0349] (Compound VII of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=ethyl). Into a 100
mL round-bottomed flask was added crude V (2.56 mmoles max),
dichloromethane (20 mL), and NMO (1.0 g, 8.54 mmoles). TPAP
(Catalytic, Spatula tip) was then added and the solution was
stirred at RT for 1 h. The crude solution was then passed directly
over a silica plug and the aldehyde was eluted with
dichloromethane. The filtrate was concentrated and dried in-vacuo
affording crude VII which was used without further purification.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.39 (d, J=8.1 Hz, 1H),
7.49 (d, J=2.1 Hz, 1H), 7.22 (d, J.=2.1 Hz, 1H), 6.1.7 (d, J=8.0
Hz, 1H), 3.81 (q, J=7.0 Hz, 2H), 3.39 (m, 1H), 2.35 (s, 3H), 1.34
(t, J=7.0 Hz, 3H), 1.26 (d, J=6.9 Hz, 6H)
Example 160
[0350] (Compound VIII of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=H, R'"=ethyl,
R""=H). Into a flame dried round-bottomed flask was
added-triethyl-3-methyl-4-phosphonocrotonate (2.45 mL, 10.24
mmoles), THF (30 mL), and DMPU (5 mL). This solution was cooled to
-78.degree. C. and n-BuLi (4.0 mL of a 2.5M solution in hexanes,
9.98 mmoles) was added dropwise via syringe. The reaction was then
allowed to stir for 30 min at -78.degree. C. At this time VII (2.56
mmoles max) was added in THF (10 mL) and the solution was allowed
to stir at -78.degree. C. for 2 h. Subsequently, the reaction was
quenched with distilled water and extracted with a 10%
EtOAc/Hexanes solution. The organic layer was directly passed over
a silica gel plug and the ester was eluted using 10% EtOAc/Hexanes.
The filtrate was concentrated and dried in-vacuo affording a yellow
oil that was essentially pure VIII by NMR. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.41 (d, J=2.2 Hz, 1H), 7.14 (d, J=2.2 Hz,
1H), 6.44 (dd, J=15.2 Hz, 11.0, 1H), 6.28 (d, J=9.7, 1H), 6.25 (d,
J=15.0 Hz, 1H), 5.75 (s, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.80 (broad
s, 2H), 3.40 (m, 1H), 2.20 (s, 3H), 2.119 s, 3H), 1.27 (m, 12H)
Example 161
[0351] (L15, Compound IX of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=H, R'"=ethyl,
R""=H). Into a 100 mL round-bottomed flask fitted with a reflux
condenser was added crude VIII (2.56 mmoles max), EtOH (30) mL) and
LiOH (7.68 mL of a 1N solution, 7.68 mmoles). This solution was
then heated to reflux for 2 h. The resultant mixture was quenched
with HCl(aq) and extracted 2.times. with EtOAc. The organic layer
was washed with Brine, collected and filtered over a pad of Celite.
The solvent was removed in-vacuo and the crude product was
crystallized three times using acetonitrile affording IX which was
>99% pure by HPLC and NMR. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.41 (s, 1H), 7.13 (s, 1H), 7.47 (dd, J=15.2 Hz, 11.0 Hz,
1H), 6.28 (d, J=9.1 Hz, 1H), 6.26 (d, J=15.4 Hz, 1H), 5.77 (s, 1H),
3.79 (broad s, 2H), 3.40 (m, 1H), 2.21 (s, 3H), 2.11 (s, 3H), 1.32
(t, J=6.9 Hz, 3H), 1.26 (d, J=6.7 Hz, 6H)
Example 162
[0352] (L81, Compound IX of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=H, R'"=propyl,
R""=H). This compound was prepared as described previously for
Compound IX in Example 161 except that iodopropane was used instead
of iodoethane in Example 158. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.41 (d, J=2.1, Hz, 1H), 7.14 (d, J=2.1 Hz, 1H), 6.48 (dd,
J=15.3 Hz, 10.9 Hz, 1H), 6.29 (d, J=7.9 Hz, 1H), 6.27 (d, J=15.5
Hz, 1H), 5.77 (s, 1H), 3.67 (broad s, 2H), 3.39 (m, 1H), 2.21 (s,
3H), 2.12 (s, 3H), 1.71 (m, 2H), 1.26 (d, J=6.8 Hz, 6H), 0.98 (t,
J=7.5 Hz, 3H)
Example 163
[0353] (L82, Compound IX of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl. R'=isopropyl, R"=H,
R'"=1,1,1-trifluorobutyl, R""=H). This compound was prepared as
described previously for Compound IX in Example 161 except that
1,1,1-trifluoro-4-iodobutane was used instead of iodoethane in
Example 158. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.41 (d,
J=2.1 Hz, 1H), 7.14 (d, J=2.1 Hz, 1H), 6.41 (dd, J=15.2 Hz, 10.8
Hz, 1H), 6.29 (d, J=10.8 Hz, 1H), 6.27 (d, J=15.2 Hz), 5.76 (s,
1H), 3.74 (broad s, 2H), 3.29 (m, 1H), 2.26 (m, 2H), 2.18 (s, 3H),
2.09 (s, 3H), 1.92 (m, 2H), 1.24 (d, J=6.8 Hz, 6H)
Example 164
[0354] (L83, Compound IX of Scheme 18, where
R=1,1,1,2,2-pentafluoroethyl, R'=isopropyl, R"=H, R'"=n-butyl,
R""=H). This compound was prepared as described previously for
Compound IX in Example 161 except that iodobutane was used instead
of iodoethane in Example 158. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.41 (d, J=2.1 Hz, 1H), 7.14 (d, J=2.1 Hz, 1H), 6.48 (dd,
J=15.3 Hz, 10.9 Hz, 1H), 6.28 (d, J=7.6 Hz, 1H), 6.27 (d, J=15.4,
1H), 5.77 (s, 1H), 3.71 (broad s, 2H), 3.38 (m, 1H), 2.20 (s, 3H),
2.12 (s, 3H), 1.67 (m, 2H), 1.43 (m, 2H), 1.25 (d, J=6.8 Hz, 6H),
0.93 (t, J=7.3 Hz, 3H) 93
[0355] Scheme 19 depicts an alternate method to introducing a
variety of substituents at R.sup.2 and R.sup.4 in modulators of
type VIII.
Example 165
[0356] (L84, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=1-fluoropropyl, A=A7). This compound was prepared
as described previously for Compound VIII in Example 82 according
to Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.32 (d,
J=5.1 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.10 (d, J=5.2 Hz, 1H), 7.00
(d, J=15.8 Hz, 1H), 6.93 (d, J=1.9 Hz, 1H), 6.65 (d, J=15.8 Hz,
1H), 5.87 (s, 1H), 4.45 (t, J=5.4, Hz, 1H), 4.32 (t, J=5.4 Hz, 1H),
3.51 (m, 2H), 2.63 (dd, J=15.2, 7.6 Hz, 2H), 2.24 (s, 3H), 1.85 (m,
1H), 1.75 (m, 1H), 1.43 (s, 9H), 1.25 (t, J=7.5 Hz, 3H).
Example 166
[0357] (L85, Compound VIII of Scheme 19, where R=tert-butyl,
R'=methyl, R"=n-butyl, A=A7). This compound was prepared as
described previously for Compound VIII in Example 82 according to
Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.25 (d, J=3.1
Hz, 1H), 7.20 (d, J=2.3 Hz, 1H), 7.18 (d, J=5.3 Hz, 1H), 7.10 (d,
J=15.8 Hz, 1H), 7.05 (d, J=2.4 Hz, 1H), 6.67 (d, J=15.8 Hz, 1H),
5.88 (s, 1H), 3.41 (t, J=6.4 Hz, 2H), 2.33 (s, 3H), 2.26 (s, 3H),
1.45 (m, 2H), 1.31 (s, 9H), 1.28 (m, 2H), 0.79 (t, J=7.3 Hz,
3H).
Example 167
[0358] (L86, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=1,1-difluoroethyl, A=A7). This compound was
prepared as described previously for Compound VIII in Example 82
according to Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.34 (d, J=5.2 Hz, 1H), 7.19 (d, J=1.9 Hz, 1H), 7.11 (d, J=5.0 Hz,
1H), 6.99 (d, J=15.9 Hz, 1H), 6.95 (d, J=1.9 Hz, 1H), 6.68 (d,
J=15.9 Hz, 1H), 5.89 (s, 1H), 5.63 (tt, J=55.4, 4.2 Hz, 1H), 3.58
(m, 2H), 2.64 (dd, J=15.2, 7.6 Hz, 2H), 2.25 (s, 3H), 1.43 (s, 9H),
0.88 (t, J.=6.5 Hz, 3H).
Example 168
[0359] (L87, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=1,1-difluoroethyl, A=Al). This compound was
prepared as described previously for Compound VIII in Example 82
according to Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.73 (m, 1H), 7.39 (m, 3H), 7.20 (s, 1H), 6.89 (d, J=16.1, Hz, 1H),
6.77 (d, J=16.1 Hz, 1H), 5.88 (s, 1H), 5.36 (dt, J=56.3, 4.3 Hz,
1H), 3.52 (m, 2H), 2.64 (dd, J=15.1, 7.6 Hz, 2H), 2.18 (s, 3H),
1.65 (m, 2H), 1.42 (s, 9H), 1.25 (t, J=6.9 Hz, 3H).
Example 169
[0360] (L88, Compound VIII of Scheme 19, where R=ethyl.
R'=tert-butyl. R"=n-butyl, A=Al). This compound was prepared as
described previously for Compound VIII in Example 82 according to
Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.70 (t, J=5.0
Hz, 1H), 7.36 (m, 3H), 7.16 (d, J=1.9 Hz, 1H), 6.96 (d, J=16.1 Hz,
1H), 6.86 (d, J=1.9 Hz, 1H), 6.76 (d, J=16.1 Hz, 1H), 5.87 (s, 1H),
3.34 (m, 1H), 3.29 (m, 1H), 2.62 (dd, J=15.2, 7.6 Hz, 2H), 2.19 (s,
3H), 1.42 (s, 9H), 1.31 (m, 2H), 1.24 (t, J=7.4 Hz, 3H), 1.12 (m,
2H), 0.67 (t, J=7.2 Hz, 3H).
Example 170
[0361] (L89, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=fluoropropyl, A=phenyl). This compound was
prepared as described previously for Compound VIII in Example 82
according to Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.62 (m, 1H), 7.38 (m, 3H), 7.18 (d, J=2.1 Hz, 1H), 6.92 (d, J=16.1
Hz, 1H), 6.89 (d, J=2.1 Hz, 1H), 6.78 (d, J=16.1 Hz, 1H), 5.89 (s,
1H), 4.24 (m, 2H), 3.47 (m, 1H), 3.40 (m, 1H), 2.63 (dd, J=15.2,
7.6 Hz, 2H), 2.19 (s, 3H), 1.62 (m, 2H), 1.42 (s, 9H), 1.25 (t,
J=7.7 Hz, 3H).
Example 171
[0362] (L90, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=propyl, A=Al). This compound was prepared as
described previously for Compound VIII in Example 82 according to
Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.69 (t, J=5.4
Hz, 1H), 7.35 (m, 3H), 7.16 (d, J=2.2 Hz, 1H), 6.96 (d, J=16.0 Hz,
1H), 6.87 (d, J=2.2 Hz, 1H), 6.76 (d, J=16.0 Hz, 1H), 5.87 (s, 1H),
3.34 (m, 1H), 3.32 (m, 2H), 2.62 (dd, J=15.2, 7.6 Hz, 2H), 2.19 (s,
3H), 1.42 (s, 9H), 1.30 (m, 2H), 1.24 (t, J=7.5 Hz, 3H), 0.62 (t,
J=7.5 Hz, 3H).
Example 172
[0363] (L91, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=fluoroethyl, A=phenyl). This compound was
prepared as described previously for Compound VIII in Example 82
according to Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.:
7.71 (m, 1H), 7.37 (m, 3H), 7.19 (d, J=1.9 Hz, 1H), 6.94 (d, J=16.1
Hz, 1H), 6.89 (d, J=1.9 Hz, 1H), 6.76 (d, J=16.0 Hz, 1H), 5.89 (s,
1H), 4.25 (t, J=2.0 Hz, 1H), 4.13 (t, J=2.0 Hz, 1H), 3.55 (m, 2H),
2.62 (dd, J=15.0, 7.6 Hz, 2H), 2.20 (s, 3H), 1.44 (s, 9H), 1.25 (t,
J=7.5 Hz, 3H).
Example 173
[0364] (L92, Compound VIII of Scheme 19, where R=ethyl,
R'=tert-butyl, R"=ethyl, A=Al). This compound was prepared as
described previously for Compound VIII in Example 82 according to
Scheme 5. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.70 (dd,
J=5.5, 3.6 Hz, 1H), 7.36 (m, 3H), 7.16 (d, J=2.1 Hz, 1H), 6.98 (d,
J=16.0 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 6.78 (d, J=16.0 Hz, 1H),
5.88 (s, 1H), 3.35 (m, 2H), 2.62 (dd, J=15.1, 7.6 Hz, 2H), 2.21 (s,
3H), 1.43 (s, 9H), 1.24 (t, J=7.5 Hz, 3H), 0.91 (t, J=7.5 Hz, 3H).
9495
[0365] Scheme 20 depicts a method for introducing amine groups at
the R.sup.4 position of the RXR unsymmetrical modulators.
Example 174
[0366] (Compound III of Scheme 20, where R methyl, R'=methyl). A
mixture of 5.0 g (32.6 mmol) of 2-acetyl-4-methyl-6-nitrophenol and
500 mg of 10% Pd/C in 20 ml of ethyl acetate was stirred under
hydrogen atmosphere for 16 hours. The mixture was filtrated over
celite and the solvents evaporated under reduced pressure. The
crude aniline was directly dissolved into 60 ml of methanol, and
1.4 g (10.3 mmol) of ZnCl.sub.2 followed by 5.2 ml of formaldehyde
(37% in water) were added. The solution was cooled to 0.degree. C.
and NaBH.sub.3CN (excess) was added portionwise. After complexion
of the reaction (TLC analysis), the solvents were removed and he
residue purified over silica gel column chromatography (eluent:
10/90 ethyl acetate/hexane) to afford 2.9 g (15 mmol, yield: 73%)
of III. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 10.75 (s, 1H),
7.15 (d, J=1.7 Hz, 1H), 6.90 (d, J=1.7 Hz, 1H), 2.81 (s, 9H), 2.61
(s, 3H), 2.29 (s, 3H).
Example 175
[0367] (Compound IV of Scheme 20, where R methyl, R'=methyl). A
mixture of 1.9 g (10 mmol) and 8.7 g (25 mmol) of carbethoxy
triphenylphoshonoacetat- e in toluene was refluxed for 16 hours.
After complexion of the reaction (TLC analysis), the solvents were
removed and he residue purified over silica gel column
chromatography (eluent: 15/85 ethyl acetate/hexane) to afford 1.9 g
(8.7 mmol, yield: 87%) of IV. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 6.95 (d, J=1.8 Hz, 1H), 6.89 (d, J=1.8 Hz, 1H), 6.24 (s,
1H), 2.90 (s, 6H), 2.39 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H).
Example 176
[0368] (L93, Compound XII of Scheme 20, where R=methyl, R"=methyl,
R'"=n-butyl). This compound was prepared as described previously
for Compound VII according to Scheme 5. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 6.66 (d, J=2.1 Hz, 1H), 6.57 (dd, J=15.5, 10.9
Hz, 1H), 6.47 (broad s, 1H), 6.21 (d, J=14.6 Hz, 2H), 5.74 (s, 1H),
3.73 (m, 2H), 2.82 (s, 6H), 2.28 (s, 3H), 2.17 (s, 3H), 2.13 (s,
3H), 1.57 (m, 2H), 1.39 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).
Example 177
[0369] (L94, Compound XII of Scheme 20, where R=methyl, R"=methyl,
R'"=n-propyl). This compound was prepared as described previously
for Compound VII according to Scheme 5. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 6.66 (s, 1H), 6.57 (dd, J=15.5, 10.8 Hz, 1H),
6.47 (s, 1H), 6.21 (d, J=15.4 Hz, 1H), 5.74 (s, 1H), 3.70 (m, 2H),
2.81 (s, 6H), 2.17 (s, 3H), 2.14 (s, 3H), 1.61 (m, 2H), 0.93 (t,
J=7.4 Hz, 3H).
Example 178
[0370] (L95, Compound XII of Scheme 20, where R=methyl, R"=methyl,
R'" 1-fluoropropyl). This compound was prepared as described
previously for Compound VII according to Scheme 5. .sup.1H NMR (400
MHz, CDCl.sub.3) .delta.: 6.67 (s, 1H), 6.53 (dd, J=15.3, 10.8 Hz,
1H), 6.50 (d, J=10.8 Hz, 1H), 6.22 (d, J=15.3 Hz, 1H), 6.20 (s,
1H), 5.75 (s, 1H), 4.62 (t, J=6.0 Hz, 1H), 4.50 (t, J=6.0 Hz, 1H),
3.86 (t, J=5.6 Hz, 2H), 2.80 (s, 6H), 2.26 (s, 3H), 2.16 (s, 3H),
2.13 (s, 3H), 1.96 (m, 2H).
Example 179
[0371] (Compound II of Scheme 20, where R=phenyl, R"=methyl). To a
flame dried 250 ml round bottom flask, 1 g (3.85 mmol)
5-Bromo-2-hydroxy-3-nitr- oacetophenone, 0.56 g (4.60 mmol) phenol
boronic acid, 0.22 g (0.15 mmol)
tetrakis(triphenylphosphine)palladium, and 5.77 ml (11.5 mmol) of a
2M sodium carbonate solution was added to 1:1 toluene:ethanol (2M)
and heated to reflux for 12 hrs. The reaction was then diluted with
250 ml of 25% ethyl acetate/hexane solution and filtered through a
silica packed plug using a gradient solvent system (eluent: hexanes
to 20% ethyl acetate/hexanes). The crude fractions were then
combined and concentrated under reduced pressure to a dark brown
solid. The solid was further purified using flash silica gel column
chromatography using a gradient solvent system (eluent: Hexanes
(0.1% acetic acid) to 10% ethyl acetate/hexanes (0.1% acetic acid))
solvent system. The solid was further purified by recrystallization
from 10% ethyl acetate/hexanes resulting in 0.36 g (1.4 mmol) of II
as an orange/yellow solid in 37% yield. .sup.1H NMR (500 MHz,
CDCl.sub.3) 6:12.97 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.26 (d, J=2.4
Hz, 1H), 7.57 (dd, J=8.5 Hz, 1.2, 2H), 7.51 (t, J=7.6 Hz, 2H), 7.44
(t, J=7.0 Hz, 1H), 2.79 (s, 3H).
Example 180
[0372] (Compound III of Scheme 20, where R=phenyl, R'=methyl). To a
100 ml round bottom flask was added 2.0 g (7.8 mmol) of
5-phenyl-2-hydroxy-3-nit- roacetophenone and a catalytic amount
(0.8 mmol) of palladium on activated charcoal in 39 ml ethyl
acetate (0.2M) under a hydrogen balloon. The reaction was allowed
to stir for 12 hrs. at which time the mix was filtered through a
celite packed plug using ethyl acetate as the eluent. The fractions
were collected and concentrated under reduced pressure to a dark
brown oil. Due to low stability the aminophenol was carried on to
the next step without further purification.
[0373] Crude 0.5 g (2.2 mmol)
5-phenyl-2-hydroxy-3-aminoacetophenone was added to a 100 ml round
bottom flask followed by addition of 4.59 ml (44.0 mmol) of a 36%
wt solution of formaldehyde in water, and 0.23 g (3.3 mmol) zinc
chloride in 20 ml (0.2M) methanol. The mixture was cooled to 0C
using an ice water bath and 1.38 g (22.0 mmol) sodium
cyanoborohydride was added to the mix under nitrogen in small 0.2 g
portions. After addition of the reducing agent, the reaction was
allowed to warm to room temperature and stir for 1 hr. The reaction
was quenched with water and pH brought to 7 using 1N HCl. The
reaction was partitioned with ethyl acetate and washed 3.times.
with ethyl acetate. The organic layers were combined and washed
1.times. with brine, dried using sodium sulfate, filtered and
concentrated under reduced pressure to a yellow oil. The oil was
purified using flash column chromatography (eluent: hexanes to 20%
ethyl acetate/hexane) affording 0.16 g (0.6 mmol) of III in 29%
yield. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.: 7.54 (m, 2H),
7.45 (m, 3H), 7.36 (m, 1H), 7.30 (d, J=2.1 Hz, 1H), 2.90 (s, 6H),
2.70 (s, 3H).
Example 181
[0374] Compound IV of Scheme 20, where R=phenyl, R"=methyl). To a
100 ml pear shaped flask was added 0.16 g (0.6 mmol) of
5-phenyl-2-hydroxy-3NN-d- imethyacetophenone and 0.44 g (1.3 mmol)
carbethoxymethylene triphenylphosphorane in 23 ml (0.2 M) toluene.
The reaction was heated to reflux and allowed to stir for 12 hrs.
The reaction was diluted with 250 mLs 10% ethyl acetate/hexanes and
purified using flash silica gel column chromatography (eluent:
hexanes to 20% hexanes/ethyl acetate) affording 0.15 g (0.5 mmol)
of IV as a yellow solid in 86% yield. .sup.1H NMR (500 MHz,
CDCl.sub.3) .delta.: 7.59 (m, 2H), 7.47 (m, 2H), 7.39 (m, 1H), 7.34
(d, J=2.1 Hz, 1H), 7.28 (d, J=2.1 Hz, 1H), 6.33 (d, J=1.2 Hz, 1H),
3.00 (s, 6H), 2.48 (d, J=1.2 Hz, 3H).
Example 182
[0375] (Compound V of Scheme 20 where R=phenyl, R'=methyl). To a
flame dried 100 ml pear shaped flask was added 0.19 g (0.7 mmol)
6-Phenyl-8-NN-dimethyl-4-methyl-chromen-2-one in a 9:1 mixture of
diethyl ether:tetrahydrofuran under nitrogen. The solution was
cooled to 0C using an ice bath and allowed to stir for 15 min. at
which time 0.03 g (0.7 mmol) lithium aluminum hydride was added and
the reaction was allowed to stir for 1.5 hrs at 0C. The reaction
was quenched with 1N sodium hydroxide bringing the pH to 7. The
mixture was filtered through a celite packed plug using ethyl
acetate as the eluent. The organic layers were combined and dried
using sodium sulfate, filtered, and concentrated under reduced
pressure to a white foam. Due to lack of stability, V was carried
on to next step without further purification.
Example 183
[0376] (Compound VI of Scheme 20 where R=phenyl, R'=methyl,
R"=1,1-difluoroethyl). To a flame dried 100 ml pear shaped flask
was added 0.2 g (0.7 mmol) V as a crude white foam in 10 ml (0.1 M)
N,N-Dimethylformamide. 0.1 g (0.8 mmol) Difluorobromoethane was
added, followed by addition of 0.3 g (1.0 mmol) cesium carbonate
under nitrogen. The reaction was allowed to stir for 12 hrs. at
room temperature at which time 250 ml of a 10% ethyl
acetate/hexanes mix was used to dilute the mixture. The reaction
was filtered through a silica packed plug and the organic layers
were combined and concentrated under reduced pressure affording
0.07 g (0.2 mmol) of VI as an oil in 29% yield. .sup.1H NMR (500
MHz, CDCl.sub.3) .delta.: 7.54 (m, 2H), 7.43 (m, 2H), 7.33 (m, 1H),
7.06 (d, J=2.1 Hz, 1H), 6.92 (d, J=2.1 Hz, 1H), 6.03 (m, 1H), 5.87
(m, 1H), 4.11 (m, 2H), 3.94 (d, J=7.3 Hz, 2H), 2.86 (s, 6H), 2.11
(s, 3H).
Example 184
[0377] (Compound VII of Scheme 20 where R=phenyl, R'=methyl,
R"=1,1-difluoroethyl). To a flame dried 100 ml pear shaped flask
0.07 g (0.2 mmol) VI in 3 ml (0.1 M) dichloromethane was added 0.04
g (0.3 mmol) 4-methylmorpholine N-oxide and 7 mg (0.02 mmol)
Tetrapropylammonium perruthenate. The reaction was allowed to stir
for 1.5 hrs at room temperature at which time the reaction was
filtered through a celite packed plug using dichloromethane as the
eluent. The organic layers were combined and concentrated under
reduced pressure to a dark brown oil. Due to lack of stability, the
product was carried on without further purification.
Example 185
[0378] (Compound VIII of Scheme 20 where R=phenyl, R'=methyl,
R"=1,1-difluoroethyl). To a flame dried 100 ml pear shaped flask
under nitrogen was added 0.15 g (0.6 mmol)
triethyl-3-methyl-4-phosphonocrotona- te in 2 ml (0.3 M) 2:1
tetrahydorfuran:DMPU (1,3-dimethyl-3,4,5,6-tetrahyd-
o-2-(1H)-pyrimidinone). The mix was cooled to -78C using an
acetone/dry ice bath. 0.23 ml (0.6 mmol) of n-BuLi (2.5 M solution
in hexanes) was added dropwise via syringe. The reaction was
allowed to stir at -78C for 30 min. at which time 0.07 g (0.2 mmol)
3-[2-(2,2, difluoroethoxy)-3-NN-dimethyl-5-phenyl]-but-2-enal in 1
ml (0.2 M) 2:1 tetrahydrofuran:
DMPU(1,3-dimethyl-3,4,5,6-tetrahydo-2-(1H)-pyrimidinone) was added
to the mix via cannula and the reaction was allowed to warm to -40C
and stir for 2 hrs. The reaction was quenched with water and
extracted 3.times. with ethyl acetate. The organics were combined
and washed with brine, dried using sodium sulfate, filtered, and
concentrated under reduced pressure to a yellow oil. The oil was
purified using flash silica gel column chromatography (eluent: 10%
ethyl acetate/hexanes) affording 18 mgs (0.004 mmol) of VIII as an
oil in 21% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) .delta.: 7.55
(d, J=8.2 Hz, 2H), 7.43 (t, J=7.9 Hz, 2H), 7.34 (m, 1H), 7.10 (s,
1H), 6.93 (d, J=2.1 Hz, 1H), 6.52 (dd, J=15.8, 11.1 Hz, 1H), 6.30
(d, J=10.7 Hz, 1H), 6.25 (d, J=15.3 Hz, 1H), 6.01 (m, 1H), 5.76 (s,
1H), 4.16 (n, 4H), 2.89 (s, 3H), 2.88 (s, 3H), 2.21 (s, 3H), 2.13
(s, 3H), 1.28 (t, J=7.0 Hz, 3H).
Example 186
[0379] (L96 Compound IX of Scheme 20, where R=phenyl, R'=methyl,
R"=1,1-difluoroethyl). In a 50 ml pear shaped flask was added 18
mgs (0.04 mmol) VIII in 2.5 ml (0.02M) of a 2:2:1 mixture of
tetrahydrofuran:ethanol:water. 10 mgs (0.2 mmol) lithium-hydroxide
was added to the mixture and the reaction was heated to reflux and
allowed to stir for 3 hrs. The reaction was quenched with 6N HCl
making the solution acidic (pH around 1) followed by 3.times.
extraction with ethyl acetate. The organic layers were combined and
washed with brine, dried with sodium sulfate, filtered, and
concentrated under reduced pressure to a white solid. The solid was
purified using reverse phase HPLC (eluent: 80/20 methanol/water
(0.1% trifluoroacetic acid) resulting in 9 mgs (0.02 mmol) IX in a
52% yield. .sup.1H NMR (500 MHz, CDCl.sub.3) o: 7.48 (m, 6H), 7.35
(d, J=2.14 Hz, 1H), 6.51 (dd, J=12.07, 10.4 Hz, 1H), 6.43 (d,
J=12.2 Hz, 1H), 6.39 (d, J=15.3 Hz, 1H), 6.18 (tt, J=54.9, 4.5 Hz,
1H), 5.83 (s, 1H), 4.70 (bs, 1H), 4.22 (m, 2H), 3.29 (s, 6H), 2.24
(s, 3H), 2.14 (s, 3H). 9697
Example 187
[0380] (Compound II of Scheme 21, where R=ethyl). To a mixture of
35 g (0.286 mol) of 4-ethyl phenol and 0.5 g (0.029 mol) of
p-toluenesulfonic acid in 300 ml of CH.sub.2Cl.sub.2 was added
portionwise 56 g (0.315 mol) of NBS. After complexion of the
reaction (TLC monitoring), water was added and the aqueous layer
was extracted with CH.sub.2Cl.sub.2. The organic layers were
combined, dried over MgSO.sub.4 and evaporated under reduced
pressure. The crude product was purified over a large pad of silica
gel (eluent: 5/95 ethyl acetate/hexane) to afford 56.3 g (0.28 mol,
yield: 98%) of II. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: A
mettre.
Example 188
[0381] (Compound III of Scheme 21, where R=ethyl). To a mixture of
0.5 g (0.8 mmol) of Yb(Otf).sub.2 in 20 ml of 1,1-dichloroethane
was added 1 ml of concentrated nitric acid at room temperature. The
mixture was stirred for 10 minutes and a white biphasic precipitate
appears on the bottom of the flask. Then 3.24 g (16.1 mmol) of
2-bromo-4-ethyl phenol-diluted in 5 ml of 1,1-dichloroethane was
added via a syringe. The mixture becomes yellow and is stirred
until complexion of the reaction (TLC monitoring). The organic
layer was then separated and dried over MgSO.sub.4 and evaporated
under reduced pressure. The crude product was purified over a large
pad of silica gel (eluent: 10/90 ethyl acetate/hexane) to afford
3.7 g (15 mmol, yield: 93%) of III. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 10.97 (s, 1HH), 7.90 (d, J=2.2 Hz, 1H), 7.71
(d, J=2.2 Hz, 1H), 2.64 (dd, J=15.2, 7.6 Hz, 2H), 1.25 (t, J=7.6
Hz, 3H).
Example 189
[0382] (Compound IV of Scheme 21 where R=ethyl, R'=n-propyl). A
mixture of 1.47 g (5.97 mmol) of 2-bromo-4-ethyl-6-nitro phenol,
0.9 ml (1.45 g, 7.76 mmol) of 1-iodobutane and 1.23 g (8.9 mmol) of
K.sub.2CO.sub.3 in 8 ml of dry DMF was heated to 60.degree. C.
overnight. After cooling at room temperature, water (50 ml) was
added and the solution was extracted with ethyl acetate. The
organic layer was then separated, dried over MgSO.sub.4 and
evaporated under reduced pressure. The crude product was purified
over a short pad of silica gel (eluent: 5/95 ethyl acetate/hexane)
and directly used in the next step. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.60 (d, J=1.7 Hz, 1H), 7.55 (d, J=1.7 Hz,
1H), 4.09 (t, J=6.4 Hz, 2H), 2.65 (dd, J=15.2, 7.6 Hz, 2H), 1.82
(m, 2H), 4.52 (m, 2H), 1.25 (t, J=7.8 Hz, 3H), 0.98 (t, J=7.5 Hz,
3H).
Example 190
[0383] (Compound V of Scheme 21 where R=ethyl, R'=n-propyl). A
mixture of crude 2-bromo-4-ethyl-6-nitro propyloxyphenol, 6.7 g
(30.0 mmol) of SnCl.sub.2 in 20 ml of ethyl acetate was heated to
reflux. After the reaction was completed (TLC monitoring), and
cooling at room temperature, water (100 ml) was added. The milky
solution was filtrated over a celite plug and extracted with ethyl
acetate. The organic layer was then separated, dried over
MgSO.sub.4 and evaporated under reduced pressure. The crude product
was directly used in the next step. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 8.2 (broad s, 2H), 7.49 (d, J=1.7 Hz, 1H),
7.44 (d, J=1.7 Hz, 1H), 4.19 (t, J=6.8 Hz, 2H), 2.64 (dd, J=14.9,
7.5 Hz, 2H), 1.90 (m, 2H), 1.42 (m, 2H), 1.26 (t, J=7.3 Hz, 3H),
0.97 (t, J=7.4 Hz, 3H).
Example 191
[0384] (Compound VI of Scheme 21 where R=ethyl, R'=n-propyl,
R.sup.a=R.sup.b=methyl). A mixture of crude 2-amino-6-bromo-4-ethyl
propyloxyphenol, 1.65 g (12.0 mmol) of ZnCl.sub.2 7.5 ml of
formaldehyde (37% solution in water) in 20 ml of methanol was
cooled to 0.degree. C. An excess of NaBH.sub.3CN was then added
portionwise, until the reaction was complete (TLC monitoring).
Evaporation of the solvent followed by silica gel column
chromatography afford 1.14 g (3.79 mmol, yield: 64%, 3 steps) of
VI. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 6.95 (d, J=1.8 Hz,
1H), 6.63 (d, J=1.8 Hz, 1H), 3.92 (t, J=6.6 Hz, 2H), 2.81 (s, 6H),
2.54 (dd, J=15.2, 7.6 Hz, 2H), 1.81 (m, 2H), 1.53 (m, 2H), 1.21 (t,
J=7.7 Hz, 3H), 0.98 (t, J=7.4 Hz, 3H).
Example 192
[0385] (Compound VII of Scheme 21, where R=ethyl, R'=n-butyl,
R.sup.a=R.sup.b=methyl, A=A7). A mixture of 380 mg (1.27 mmol) of
1-bromo-2-propyloxy-4-N,N-dimethylamino-5-ethyl benzene, 73 mg
(0.06 mmol) of Pd(PPh.sub.3) 4, 257 mg (1.65 mmol) of
2-formyl-3-thiophene boronic acid dissolved in 5 ml of toluene, 3
ml of ethanol and 1.3 ml of 2N aqueous Na.sub.2CO.sub.3 was heated
to reflux overnight. After work-up and purification over silica gel
column chromatography, 115 mg (0.35 mmol, yield: 27%) of VII was
isolated as an oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 9.78
(s, 1H), 7.68 (d, J=4.9 Hz, 1H), 7.20 (d, J=4.9 Hz, 1H), 6.79 (d,
J=1.9 Hz, 1H), 6.74 (d, J=1.9 Hz, 1H), 3.60 (t, J=6.5 Hz, 2H), 2.85
(s, 6H), 2.62 (dd, J=15.2, 7.6 Hz, 2H), 1.38 (m, 2H), 1.26 (t,
J=7.4 Hz, 3H), 1.17 (m, 2H), 0.75 (t, J=7.5 Hz, 3H).
Example 193
[0386] (Compound VIII of Scheme 21, where R=ethyl, R'=n-butyl,
R.sup.a=R.sup.b=methyl, A=A7). To a solution of 0.22 ml (239 mg,
090 mmol) of triethyl-3-methylphosphonocrotonate in 5 ml of
THF/DMPU (4/1 ml respectively) was added 0.5 ml of nBuLi at
-78.degree. C. After stirring for 10 minutes, 115 mg (0.35 mmol) of
2-formyl-3-(2-butyloxy-4-N,N-dimeth-
ylamino-6-ethylbenzene)-thiophene (diluted in 1 ml of dry THF) was
added dropwise. After complexion of the reaction, the solvents were
evaporated and the crude ester directly purified over silica gel
column chromatography (eluent: 5/95 ethyl acetate/hexane) to afford
150 mg (0.34 mmol, yield: 98%) of VIII. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta.: 7.21 (d, J=5.1 Hz, 1H), 7.09 (d, J=5.1 Hz,
1H), 7.04 (d, J=15.8 Hz, 1H), 6.75 (d, J=1.9 Hz, 1H), 6.62 (d,
J=1.9 Hz, 1H), 6.62 (d, J=15.8 Hz, 1H), 4.17 (dd, J=14.2, 7.6 Hz,
2H), 3.59 (t, J=6.3 Hz, 2H), 2.87 (s, 6H), 2.60 (dd, J=15.1, 7.5
Hz, 2H), 1.39 (m, 2H), 1.28 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.6 Hz,
3H), 1.18 (m, 2H), 0.75 (t, J=7.4 Hz, 3H).
Example 194
[0387] (L97, Compound IX of Scheme 21, where R=ethyl, R'=n-butyl,
R.sup.a=R.sup.b=methyl, A=A7). The compound was prepared in the
manner previously described for Compound IX of Example 186 except
that Compound VIII of Example 194 was employed in the synthesis.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.21 (s, 1H), 7.10 (s,
1H), 7.07 (d, J=16.8 Hz, 1H), 6.74 (s, 1H), 6.65 (s, 1H), 6.64 (d,
J=14.2 Hz, 1H), 5.87 (s, 1H), 3.56 (t, J=6.1 Hz, 2H), 2.86 (s, 6H),
2.61 (m, 2H), 2.25 (s, 3H), 1.41 (m, 2H), 1.28 (m, 4H), 0.74 (t,
J=7.2 Hz, 3H).w 98
[0388] Scheme 22 depicts an alternative method for the preparation
of RXR modulators, wherein aryl or heterocyclic groups can be
independently introduced at the R.sup.2 and R.sup.4 positions.
Example 195
[0389] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=2-fluorobenzene). A mixture of 108 mg (0.329 mmol) of
4-methyl-7-iodo-9-isopropyl coumarin, 70 mg (0493 mmol) of
2-fluorobenzene boronic acid, 19 mg (0.016 mmol) of
Pd(PPh.sub.3).sub.4, 0.33 ml of a 2N aqueous solution of
Na.sub.2CO.sub.3 in 5 ml of toluene and 3 ml of ethanol was
refluxed. After complexion of the reaction (TLC analysis), the
mixture is cooled to room temperature and diluted in water (10 ml).
After extraction with ethyl acetate, the organic layer separated
and dried over MgSO.sub.4. After evaporation, the crude coumarin
was purified over silica gel (eluent: 10/90 ethyl acetate/hexane)
to afford 91 mg (0.307 mmol, yield: 93%) of II as a yellow solid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.62 (m, 2H), 7.45 (td,
J=7.8, 1.7 Hz, 1H), 7.37 (m, 1H), 7.26-(dd, J=7.4, 1.0 Hz, 1H),
7.19 (m, 1H), 6.33 (s, 1H), 3.70 (dt, J=13.8, 6.9 Hz, 1H), 2.47 (s,
3H), 1.34 (d, J=6.9 Hz, 6H).
Example 196
[0390] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=3-fluorobenzene). This compound was prepared in the manner
previously described for Compound II in Example 85 except that
3-fluorobenzene boronic acid was used instead of 2-fluorobenzene
boronic acid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.64 (d,
J=:1.9 Hz, 1H), 7.59 (d, J=1.9 Hz, 1H), 7.45 (m, 1H), 7.38 (m, 1H),
7.28 (m, 1H), 7.09 (m, 1H), 6.34 (s, 1H), 3.68 (dt, J=13.7, 6.8 Hz,
1H), 2.49 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
Example 197
[0391] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=3-fluorobenzene). This compound was prepared in the manner
previously described for Compound II in Example 85 except that
4-fluorobenzene boronic acid was used instead of 2-fluorobenzene
boronic acid. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.61 (d,
J=2.2 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.54 (m, 2H), 7.17 (t, J=8.7
Hz, 2H), 7.28 (m, 1H), 7.09 (m, 1H), 6.34 (s, 1H), 3.69 (dt,
J=13.8, 6.8 Hz, 1H), 2.49 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).
Example 198
[0392] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=3,5-difluorobenzene). This compound was prepared in the manner
previously described for Compound II in Example 85 except that
3,5-difluorobenzene boronic acid was used instead of
2-fluorobenzene boronic acid. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta.: 7.61 (d, J=2.0 Hz, 1H), 7.57 (d, J=2.0 Hz, 1H), 7.11 (m,
2H), 6.88 (m, 1H), 6.35 (s, 1H), 3.69 (dt, J=13.7, 6.8 Hz, 1H),
2.50 (s, 3H), 1.34 (d, J=7.0 Hz, 6H).
Example 199
[0393] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=pyridine). This compound was prepared in the manner previously
described for Compound II in Example 85 except that pyrindyl
boronic acid was used instead of 2-fluorobenzene boronic acid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.72 (dd, J=4.9, 2.0 Hz,
1H), 8.11 (d, J=2.0 Hz, 1H), 8.07 (d, J=2.0 Hz, 1H), 7.78 (m, 2H),
7.18 (m, 1H), 3.60 (dt, J=13.8, 6.9 Hz, 1H), 2.54 (s, 3H), 1.37 (d,
J=7.1 Hz, 6H).
Example 200
[0394] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=thiophene). This compound was prepared in the manner previously
described for Compound II in Example 85 except that thiophene
boronic acid was used instead of 2-fluorobenzene boronic acid.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.68 (d, J=2.1 Hz, 1H),
7.61 (d, J=2.1 Hz, TH), 7.32 (m, 2H), 7.11 (dd, J=4.9, 3.5 Hz, 1H),
6.33 (s, 1H), 3.66 (dt, J=13.8, 6.9 Hz, 1H), 2.49 (s, 3H), 1.34 (d,
J=7.0 Hz, 6H).
Example 201
[0395] (Compound II of Scheme 22, where R=isopropyl, R'=H,
Ar=2-furan). This compound was prepared in the manner previously
described for Compound II in Example 85 except that 2-furan boronic
acid was used instead of 2-fluorobenzene boronic acid. .sup.1H NMR
(400 MHz, CDCl.sub.3) .delta.: 7.75 (d, J=2.0 Hz, 1H), 7.72 (d,
J=2.0 Hz, 1H), 7.33 (m, 2H), 7.15 (m, 1H), 6.69 (s, 1H), 3.66 (dt,
J=13.9, 6.8 Hz, 1H), 2.49 (s, 3H), 1.33 (d, J=7.1 Hz, 6H).
Example 202
[0396] (L98, Compound IV of Scheme 22, where R=isopropyl, R'=H,
R"=difluoroethyl, Ar=pyridine). This compound was prepared as
described previously for Compound VIII according to Scheme 5.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 8.23 (t, J=7.8 Hz, 1H),
7.92 (d, J=8.1 Hz, 1H), 7.85 (J=2.2 Hz, 1H), 7.67 (t, J=6.5 Hz,
1H), 7.49 (J=2.2 Hz, 1H), 6.42 (d, J=14.8 Hz, 1H), 6.40 (dd,
J=14.8, 10.7 Hz, 1H), 6.30 (d, J=14.7 Hz, 1H), 5.97 (dt, J=55.1,
4.0 Hz, 1H), 5.78 (s, 1H), 4.00 (m, 2H), 3.44 (dt, J=13.8, 6.8 Hz,
1H), 2.26 (s, 3H), 2.10 (s, 3H), 1.31 (d, J=7.0 Hz, 6H).
Example 203
[0397] (L99, Compound IV of Scheme 22, where R=isopropyl, R'=H,
R"=difluoroethyl, Ar=4-fluorobenzene). This compound was prepared
as described previously for Compound VIII according to Scheme 5.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.50 (dd, J=8.6, 5.4H,
2H), 7.38 (d, J=2.3 Hz, 1H), 7.13 (dd, J=8.6, 5.4 Hz, 2H), 7.10 (d,
J=2.4 Hz, 1H), 6.56 (dd, J=15.3, 11.0 Hz, 1H), 6.32 (d, J=11.5 Hz,
1H), 5.96 (dt, J=55.2, 4.0 Hz, 1H), 5.79 (s, 1H), 4.17 (td, J=13.6,
4.0 Hz, 2H), 3.40 (dt, J=13.8, 6.9 Hz, 1H), 2.23 (s, 3H), 2.14 (s,
3H), 1.29 (d, J=6.9 Hz, 6H).
Example 204
[0398] (L100, Compound IV of Scheme 22, where R=isopropyl, R'=H,
R"=difluoroethyl, Ar=3-fluorobenzene). This compound was prepared
as described previously for Compound VIII according to Scheme 5:
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.42 (d, J=2.2 Hz, 1H),
7.38 (dd, J=8.1, 5.9 Hz, 1H), 7.23 (m, 1H), 7.14 (d, J=2.2 Hz, 1H),
7.04 (m, 1H), 6.55 (dd, J=15.5, 11.0 Hz, 1H), 6.34 (d, J=11.0 Hz,
1H), 6.30 (J=15.5 Hz, 1H), 5.97 (dt, J=55.3, 3.9 Hz, 1H), 5.97 (s,
1H), 3.93 (td, J=13.4, 3.9 Hz, 2H), 3.40 (dt, J=13.9, 6.9 Hz, 1H),
2.24 (s, 3H), 2.14 (s, 3H), 1.30 (d, J=6.9 Hz, 6H).
Example 205
[0399] (L19, Compound IV of Scheme 22, where R=isopropyl, R'=H,
R"=difluoroethyl, Ar=2-fluorobenzene). This compound was prepared
as described previously for Compound VIII according to Scheme 5.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.39 (m, 2H), 7.31 (m,
1H), 7.20 (t, J=7.4 Hz, 1H), 7.14 (m, 2H), 6.65 (dd, J=15.2, 10.9
Hz, 1H), 6.33 (d, J=10.5 Hz, 1H), 6.30 (d, J=15.1 Hz, 1H), 5.98
(dt, J=55.2, 3.9 Hz, 1H), 5.98 (s, 1H), 3.94 (m, 2H), 3.40 (dt,
J=13.9, 6.9 Hz, 1H), 2.23 (s, 3H), 2.17 (s, 3H), 1.29 (d, J=6.9 Hz,
6H).
Example 206
[0400] (L101, Compound IV of Scheme 22, where R=isopropyl, R'=H,
R"=difluoroethyl, Ar=thiophene). This compound was prepared as
described previously for Compound VIII according to Scheme 5.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta.: 7.45 (d, J=2.2 Hz, 1H),
7.25 (m, 2H), 7.18 (d, J=2.2 Hz, 1H, 7.07 (dd, J=4.8, 3.9 Hz, 1H),
6.56 (dd, J=15.3, 11.0 Hz, 1H), 6.33 (d, J=11.0 Hz, 1H), 6.30 (d,
J=15.3 Hz, 1H), 5.96 (dt, J=55.2, 4.0 Hz, 1H), 5.79 (s, 1H), 3.90
(td, J=13.6, 4.0 Hz, 2H), 3.37 (dt, J=13.9, 6.9 Hz, 1H), 2.23 (s,
3H), 2.14 (s, 3H), 1.28 (d, J=6.9 Hz, 6H). 99
[0401] Scheme 23 depicts the synthesis of compounds of the type
VI.
Example 207
[0402] (Compound II of Scheme 23, where R=ethyl, R'=R"=isopropyl,
Y=NH). To a mixture of 90 mg (0.140 mmol) of 2-iodoaniline and 24
mg (0.02 mmol, 5%) of Pd(PPh.sub.3).sub.4 in toluene (5 ml) was
added 153 mg (0.611 mmol) of 2-ethoxy-3,5-di isopropyl benzene
boronic acid diluted in 3 ml of ethanol. To this yellow solution,
0.41 ml of a 2N Na.sub.2CO.sub.3 solution was added, and the
resulting mixture was heated to reflux until completion. After
cooling at room temperature, water was added and the mixture was
extracted with ethyl acetate. The organic layers were combined and
dried over MgSO.sub.4. The solvents were evaporated under reduced
pressure and the resulting oil was purified over silica gel
(eluent: 10/90 ethyl acetate/hexane) to give 70 mg (0.235 mmol,
yield 57%) of 11 as a clear brown oil. .sup.1H NMR (CDCl.sub.3),
6:7.17 (m, 2H), 7.10 (d, J=2.2 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H),
6.83 (td, J=8.2, 0.9 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 3.90 (broad
s, 2H), 3.54 (dd, J=9.2, 7.1 Hz, 2H), 3.42 (ddd, J=13.9, 6.9, 6.9
Hz, 1H), 2.90 (ddd, J=13.8, 6.8, 6.8 Hz, 1H), 1.25 (d, J=6.9 Hz,
12H), 1.07 (t, J=7.0 Hz, 3H).
Example 208
[0403] (Compound III of Scheme 23, where R=ethyl, R'=R"=isopropyl,
Y=NH). To a mixture of 65 mg (0.218 mmol) of 2-(2-ethoxy-3,5-di
isopropyl benzene)-aniline and 24 mg (0.176 mmol, 0.75 equivalent)
of zinc chloride and 50 .mu.l (50 mg, 0.352 mmol) of
ethyl-3-methyl-4-oxo crotonate in 3 ml of methanol was added 44 mg
(0.705 mmol, 4 equivalents) of NaBH.sub.3CN portionwise at
0.degree. C. The mixture was stirred at this temperature until
complexion and the solvents were evaporated under reduced pressure.
The residue was then purified over silica gel column chromatography
(eluent: ethyl acetate/hexane: 5/95) to give 25 mg (0.06 mmol,
yield: 27%) of III as a clear oil. .sup.1H NMR (CDCl.sub.3),
.delta.: 7.19 (m, 2H), 7.11 (d, J=2.3 Hz, 1H), 6.96 (d, J=2.3 Hz,
1H), 6.77 (t, J=8.2 Hz, 1H), 6.50 (d, J=8.1 Hz, 1H), 5.94 (s, 1H),
4.39 (broad t, J=6.0 Hz, 1H), 4.12 (dd, J=14.1, 7.0 Hz, 2H), 3.79
(d, J=5.9 Hz, 2H), 3.54 (dd, J=14.0, 7.1 Hz, 2H), 3.42 (ddd,
J=13.8, 6.9, 6.9 Hz, 1H), 2.88 (m, 1H), 2.16 (s, 3H), 1.25 (m,
12H), 1.07 (t, J=7.0 Hz, 3H), 1.05 (t, J=7.0 Hz, 3H).
Example 209
[0404] (L102, Compound IV of Scheme 23, where R=ethyl,
R'=R"=isopropyl, Y=NH). A mixture of 25 mg (0.06 mmol) of
2-[(2-ethoxy-3,5-di isopropyl benzene)-4-(ethyl-3-methyl
crotonate)]-aniline, 1 ml of THF, 1 ml of methanol and 0.5 ml of a
2M LiOH aqueous solution was heated to reflux until complete
consumption of starting material. After cooling at room
temperature, the solvents were evaporated under reduced pressure
and the aqueous layer was acidified with 2N aqueous HCl (pH 1-2)
and extracted 2 times with ethyl acetate. The organic layers were
combined and dried over MgSO.sub.4. After removal of the solvents,
the residual oil was purified by preparative plate (1000 U, eluent:
25/75 ethyl acetate/hexane) to give 3 mg (0.008 mmol, yield: 13%)
of IV as a pasty oil. .sup.1H NMR (CDCl.sub.3), .delta.: 7.20 (t,
J=8.1 Hz, 1H), 7.16 (d, J=7.4 Hz, 1H), 7.11 (d, J=1.9 Hz, 1H), 6.95
(d, J=2.1 Hz, 1H), 6.78 (t, J=7.4 Hz, 1H), 6.48 (d, J=8.1 Hz, 1H),
5.98 (s, 1H), 4.41 (broad s, 1H), 3.81 (s, 2H), 3.54 (dd, J=14.0,
7.1 Hz, 2H), 3.41 (ddd, J=13.7, 6.9, 6.9 Hz, 1H), 2.89 (ddd,
J=13.7, 6.8, 6.8 Hz, 1H), 2.16 (s, 3H), 1.26 (d, J=6.9 Hz, 6H),
1.25 (d, J=6.8 Hz, 6H), 1.05 (t, J=7.0 Hz, 3H).
Biological Activity
Example 210
Evaluation of Retinoid Receptor Subfamily Activity In Vitro
[0405] Utilizing the "cis-trans" or "co-transfection" assay
described by Evans et al., Science, 240:889-95 (May 13, 1988), the
disclosure of which is herein incorporated by reference, the
dimer-selective RXR modulator compounds of the present invention
were tested and found to have strong, specific activity as
selective RXR modulators, including activity as full agonists,
partial agonists and/or full antagonists of RXR homodimers and/or
heterodimers. This assay is described in further detail in U.S.
Pat. Nos. 4,981,784 and 5,071,773, the disclosures of which are
incorporated herein by reference.
[0406] The co-transfection assay provides a method for identifying
functional agonists which mimic, or antagonists which inhibit, the
effect of native hormones, and quantifying their activity for
responsive IR proteins. In this regard, the co-transfection assay
mimics an in vivo system in the laboratory. Importantly, activity
in the co-transfection assay correlates very well with known in
vivo activity, such that the co-transfection assay functions as a
qualitative and quantitative predictor of a tested compounds in
vivo pharmacology. See, e.g., T. Berger et al. 41 J. Steroid
Biochem. Molec. Biol. 773 (1992), the disclosure of which is herein
incorporated by reference.
[0407] In the co-transfection assay, cloned cDNA for one or more
IRs (e.g., human RAR.alpha., RXR.alpha., or PPAR.gamma.), alone or
in combination (i.e. for heterodimer assays) under the control of a
constitutive promoter (e.g., the SV 40, RSV or CMV promoter) is
introduced by transfection (a procedure to introduce exogenous
genes into cells) into a background cell substantially devoid of
endogenous IRs. These introduced gene(s) direct the recipient cells
to make the IR protein(s) of interest. A further gene is also
introduced (co-transfected) into the same cells in conjunction with
the IR gene(s). This further gene, comprising the cDNA for a
reporter protein, such as firefly luciferase (LUC), controlled by
an appropriate hormone responsive promoter containing a hormone
response element (HRE). This reporter plasmid functions as a
reporter for the transcriptional-modulating activity of the target
IR(s). Thus, the reporter acts as a surrogate for the products
(mRNA then protein) normally expressed by a gene under control of
the target receptor(s) and their native hormone(s).
[0408] The co-transfection assay can detect small molecule agonists
or antagonists, including partial agonists and antagonist, of
target IRs. Exposing the transfected cells to an agonist ligand
compound increases reporter activity in the transfected cells. This
activity can be conveniently measured, e.g., by increasing
luciferase production and enzymatic activity, which reflects
compound-dependent, IR-mediated increases in reporter
transcription. To detect antagonists, the co-transfection assay is
carried out in the presence of a constant concentration of an known
agonist to the target IR (e.g.,
4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic
acid (LGD1069, Ligand Pharmaceuticals, Inc.) for RXR.alpha.) known
to induce a defined reporter signal. Increasing concentrations of
an antagonist will decrease the reporter signal (e.g., luciferase
production). The co-transfection assay is therefore useful to
detect both agonists and antagonists of specific IRs. Furthermore,
it determines not only whether a compound interacts with a
particular IR, but whether this interaction mimics (agonizes) or
blocks (antagonizes) the effects of native or synthetic regulatory
molecules on target gene expression, as well as the specificity and
strength of this interaction.
[0409] The activity of the dimer-selective RXR retinoid modulator
compounds of the present invention were evaluated utilizing the
co-transfection assay according to the following illustrative
Examples.
Example 210A
RXR Homodimer Co-Transfection Assay
[0410] CV-1 cells (African green monkey kidney fibroblasts) were
cultured in the presence of Dulbecco's Modified Eagle Medium (DMEM)
supplemented with 10% charcoal resin-stripped fetal bovine serum
then transferred to 96-well microtiter plates one day prior to
transfection.
[0411] To determine agonist and antagonist activity of the
modulator compounds of the present invention, the CV-1 cells were
transiently transfected by calcium phosphate coprecipitation
according to the procedure of Berger et al., 41 J. Steroid Biochem.
Mol. Biol., 733 (1992) with the receptor expressing plasmid
pRShRXR.alpha., Mangelsdorf et al., 345 Nature, 224 (1990), the
disclosures of which are herein incorporated by reference at a
concentration of 10 ng/well. The receptor expression plasmid was
cotransfected along with a reporter plasmid at 50 ng/well, the
internal control plasmid pRS-.beta.-Gal at 50 ng/well and filler
DNA, pGEM, at 90 ng/well.
[0412] The reporter plasmid CRBPIITKLUC, which contains an
RXR.alpha. (retinoid X receptor response element, as described in
Mangelsdorf et al., 66 Cell, 555 (1991), the disclosure of which is
herein incorporated by reference, was used in transfections for the
RXR homodimer assay. This reporter plasmid contains the cDNA for
firefly luciferase (LUC) under the control of a promoter containing
the RXR response element. As noted above, pRS-.beta.-Gal, coding
for constitutive expression of E. coli .beta.-galactosidase
(.beta.-Gal), was included as an internal control for evaluation of
transfection efficiency and compound toxicity.
[0413] Six hours after transfection, media was removed and the
cells were washed with phosphate-buffered saline (PBS). Media
containing compounds of the present invention in concentrations
ranging from 10.sup.-10 to 10.sup.-5 M were added to the cells.
Similarly, the reference compounds all-trans retinoic acid
(ATRA)(Sigma Chemical), LGD1069
(4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethenyl]benzoic
acid: Ligand Pharmaceuticals, Inc.) and LG100268
(6-[1-(3,5,5,8,8-pentame-
thyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopropyl]nicotinic acid:
Ligand Pharmaceuticals, Inc.), compounds with known agonist
activity on RXRs, were added at similar concentrations to provide a
reference point for analysis of the agonist activity of the
compounds of the present invention. When determining the antagonist
activity of the compounds of the present invention, the compounds
were added to the cells in the presence of a fixed concentration
(3.2.times.10.sup.-8 M) of the known RXR agonist LGD1069
(4-[(3,5,5,8,8-Pentamethyl-5,6,7,8-tetrahydro-2-napht-
hyl)ethenyl]benzoic acid: Ligand Pharmaceuticals, Inc.). Retinoid
purity was established as greater than 99% by reverse phase
high-performance liquid chromatography. Retinoids were dissolved in
dimethylsulfoxide for use in the transcriptional activation assays.
Two to three replicates were used for each sample. Transfections
and subsequent procedures were performed on a Biomek 1000 automated
workstation.
[0414] After 40 hours, the cells were washed with PBS, lysed with a
detergent-based buffer and assayed for LUC and .beta.-Gal
activities using a luminometer or spectrophotometer, respectively.
For each replicate, the normalized response (NR) was calculated
as:
LUC response/.beta.-Gal rates
[0415] where .beta.-Gal
rate=.beta.-Gal.multidot.1.times.10.sup.5/.beta.-G- al incubation
time.
[0416] The mean and standard error of the mean (SEM) of the NR were
calculated. Data were plotted as the response of the compound
compared to the reference compounds over the range of the
dose-response curve. For the agonist activity of the compounds of
the present invention, the effective concentration that produced
50% of the maximum response (E.sub.50) was quantified. Antagonist
activity was determined by testing the amount of LUC expression in
the presence of the RXR agonists described above at the EC.sub.50
concentration for such known compounds. The concentration of
compounds of the present invention that inhibited 50% of LUC
expression induced by the reference agonist was quantified
(IC.sub.50). In addition, the efficacy of antagonists was
determined as a function (%) of maximal inhibition.
Example 210B
RXR and RAR Binding
[0417] In addition to the cotransfection data, the binding of
selected compounds of the present invention to the RAR and RXR
receptors was also investigated according to the methodology
described in M. F., Boehm, et al., "Synthesis and
Structure-Activity Relation-ships of Novel Retinoid X Receptor
Selective Retinoids", 37 J. Med. Chem., 2930 (1994); M. F. Boehm,
et al., "Synthesis of High Specific Activity [.sup.3H]-9-cis
Retinoic Acid and Its Application for Identifying Retinoids with
Unusual Binding Properties", 37 J. Med. Chem., 408 (1994), and E.
A. Allegretto, et al., "Characterization and Comparison of
Hormone-Binding and Transactivation Properties of Retinoic Acid and
Retinoid X Receptors Expressed in Mammalian Cells and Yeast", 268
J. Biol. Chem., 22625 (1993), the disclosures of which are herein
incorporated by reference.
[0418] Non-specific binding was defined as that binding remaining
in the presence of 500 nM of the appropriate unlabelled compound.
At the end of the incubation period, bound ligand was separated
from free. The amount of bound tritiated retinoid was determined by
liquid scintillation counting of an aliquot (700 .mu.L) of the
supernatant fluid or the hydroxylapatite pellet.
[0419] After correcting for non-specific binding, IC.sub.50 values
were determined. The IC.sub.50 value is defined as the
concentration of competing ligand needed to reduce specific binding
by 50%. The IC.sub.50 value was determined graphically from a
log-logit plot of the data. The K.sub.i values were determined by
application of the Cheng-Prussof equation to the IC.sub.50 values,
the labeled ligand concentration and the K.sub.d of the labeled
ligand.
[0420] The RXR.alpha. binding activity and agonist and antagonist
activity in the RXR.alpha. homodimer cotransfection assay of
selected compounds of the present invention are shown in Table 3
below.
3TABLE 3 Activity in RXR.alpha. binding and RXR.alpha. homodimer
cotransfection assays of selected dimer-selective RXR modulator
compounds of the present invention. EC.sub.50 and IC.sub.50 values
were not calculated (NC) if efficacy was <10%. Values represent
mean of n > 3 independent experiments. RXR.alpha. RXR.alpha.
Homodimer Cotransfection Assay Cmpd. Binding Agonist Agonist
Agonist Antagonist No. K.sub.i (nM) Efficacy (%) EC.sub.50 (nM)
Efficacy (%) IC.sub.50 (nM) ATRA 53 100 919 0 NC LGD1069 36 85 76 0
NC LG100268 3.0 73 15 0 NC L1 1.1 62 33 7 NC L2 13 11 14 62 9 L3
1.1 2 NC 90 5 L4 0.9 1 NC 92 9 L5 0.6 0 NC 94 10
[0421] As can be seen in Table 3, all of the dimer-selective RXR
modulator compounds displayed high affinity binding to RXR.alpha..
Compound L1 displayed agonist activity similar in efficacy and
potency to the known RXR agonist, LG100268, in the context of an
RXR:RXR homodimer in the cotransfection assay. Compound L2 acted as
a partial agonist, demonstrating significant efficacy as both an
agonist and an antagonist. Compounds L3, L4 and L5 displayed highly
efficacious and potent antagonist activity with little or no
agonist activity. Thus, compounds of the present invention display
properties ranging from full agonists to partial agonists to full
antagonists in the context of RXR homodimers.
Example 210C
RXR Heterodimer Co-Transfection Assays
[0422] The RXR modulator compounds of the present invention were
further tested for activity on RXR heterodimers with RAR.alpha.,
RAR.gamma. or PPAR.gamma. utilizing the cotransfection assay in
CV-1 cells as described in Example 210A. The RXR:RAR heterodimer
cotransfection assays utilized the following expression plasmids
and reporter plasmid: pRShRAR.alpha. (10 ng/well, Giguere et al.,
330 Nature, 624 (1987) the disclosure of which is herein
incorporated by reference) or pRShRAR.gamma. (10 ng/well, Ishikawa
et al., 4 Mol. Endocrin., 837 (1990) the disclosure of which is
herein incorporated by reference) with .DELTA.-MTV-LUC (50 ng/well,
Hollenberg and Evans, 55 Cell, 899 (1988), the disclosure of which
is herein incorporated by reference) containing an RAR.alpha. which
is referred to as two copies of the TRE-palindromic response
element described in Umesono et al., 336 Nature, 262 (1988), the
disclosure of which is herein incorporated by reference. For the
RXR:PPAR.gamma. heterodimer cotransfection assay, the RXR.alpha.
receptor expression plasmid, pRShRXR.alpha. (10 ng/well), was
cotransfected with the PPAR.gamma. expression plasmid,
pCMVhPPAR.gamma. (10 ng/well), and a reporter plasmid containing
three copies of a PPAR.gamma. response element (pPREA3-tk-LUC, 50
ng well; Mukherjee et al. 272 Journ. Biol. Chem., 8071-8076 (1997)
and references cited therein, the disclosures of which are herein
incorporated by reference).
[0423] Cotransfections were performed as described in Example 210A.
For determination of agonist activity in the context of the RXR:RAR
heterodimer or the RXR:PPAR.gamma. heterodimer, media containing
compounds of the present invention in concentrations ranging from
10.sup.-10 to 10.sup.-5 M were added to the cells. Similarly, the
reference compounds all-trans retinoic acid (ATRA) (Sigma Chemical)
and TTNPB
((E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-
-propenyl]benzoic acid: Hoffman LaRoche, Inc.), known RAR agonist
compounds, or BRL 49653, a compound with known agonist activity on
PPAR.gamma., were added at similar concentrations to provide a
reference point for analysis of the agonist activity of the
compounds of the present invention. When evaluating the antagonist
activity of the compounds of the present invention on RAR.gamma.,
the compounds were added to the cells in the presence of a fixed
concentration (1.times.10.sup.-8 M) of the known RAR selective
agonist TTNPB
((E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-prope-
nyl]benzoic acid: Hoffman LaRoche, Inc.). Antagonist efficacy and
IC.sub.50 values were determined as in Example 210A.
[0424] Compounds of the present invention were also tested for the
ability to synergize with a PPAR.gamma. agonist in the context of
an RXR heterodimer. For these assays the compounds were added to
the cells with a fixed concentration of BRL 49653
(1.times.10.sup.-7 M) for the RXR:PPAR.gamma. heterodimer assay.
Efficacy of the compounds of the present invention in the agonist
and synergy assays was calculated as the maximum response obtained
over the range of the dose response curve relative to the maximum
response obtained by the reference agonist. Antagonist efficacy was
determined as a function (%) of maximal inhibition.
[0425] RAR suppresses RXR ligand binding and transactivation of
typical RXR agonists (e.g., LGD1069, LG100268) via allosteric
interactions. Forman, B. M., Umesono, K., Chen, J., & Evans, R.
M., Cell 81, 541-550 (1995) and Kurokawa, R., et. al. Nature 371,
528-531 (1994). However, when RAR is occupied, typical RXR agonists
activate the heterodimer. Forman, B. M., Umesono, K., Chen, J.,
& Evans, R. M., Cell 81, 541-550 (1995) and Roy, B., Taneja,
R., & Chambon, P., Mol. Cell. Biol 0.15, 6481-6487 (1995). To
examine the effects of the compounds of the present invention on
the transcriptional properties of the RXR:RAR heterodimer, a
heterodimer cotransfection assay as described above was employed.
Table 4 below shows the activity of selected compounds of the
present invention in terms of agonist or antagonist efficacy in the
RXR:RAR heterodimer cotransfection assay.
4TABLE 4 Activity in RXR.alpha.:RAR heterodimer cotransfection
assays of selected dimer-selective RXR modulator compounds of the
present invention. Values represent mean of n > 3 independent
experiments. RXR.alpha.:RAR Heterodimer Cotransfection Assay Cmpd.
Agonist Antagonist No. Efficacy (%).sup.1 Efficacy (%).sup.2 ATRA
100 -- TTNPB 115 -- LGD1069 33 0 LG100268 6 0 L1 21 19 L2 6 49 L3 5
84 L4 2 88 L5 5 68 .sup.1Efficacy calculated as maximal response
relative to response of ATRA. .sup.2Efficacy calculated relative to
maximal repression (100%) in presence of 10 nM TTNPB.
[0426] As shown in Table 4, whereas RXR agonists, such as LGD1069
and LG100268 by themselves, either weakly activate or are inactive
on the RXR:RAR heterodimer, ATRA and the RAR selective activator
TTNPB strongly transactivate this heterodimer. Compound L1 of the
present invention displayed weak agonist activity alone. Compound
L2, which displayed partial RXR agonist activity, was not active in
the RXR:RAR assay. Compounds L3, L4 and L5 were also not active as
RXR:RAR agonists. In fact, they displayed significant RXR:RAR
antagonist activity as indicated by their efficacy in the
antagonist assay. Thus, there appears to be a continuum of
activities from the dimer-selective RXR modulator compounds of the
present invention on the RXR:RAR heterodimer such that as the
length of the carbon chain at the R.sup.7 position increases the
RXR:RAR agonist activity tends to decrease and the RXR:RAR
antagonist activity tends to increase.
[0427] RXR:PPAR.gamma. heterodimers have previously been shown to
be responsive to both RXR and PPAR ligands. Kliewer, et al., Nature
358, 771-774 (1992). To examine the effects of the compounds of the
present invention on the transcriptional properties of the
RXR:PPAR.gamma., a heterodimer cotransfection assay as described
above was employed. Table 5 below shows the activity of reference
compounds and of selected compounds of the present invention in
terms of agonist or synergy efficacy in the RXR:PPAR.gamma.
heterodimer cotransfection assay. As can be seen in Table 5, the
known RXR agonists LGD1069 and LG100268 when tested alone induce
transactivation of the RXR.alpha.:PPAR.gamma. heterodimer as does a
PPAR.gamma. ligand, the thiazolidinedione BRL 49653. In addition,
when the RXR agonists were tested in combination with the
PPAR.gamma. ligand (i.e. synergy mode), they showed even stronger
agonist activity. The dimer-selective RXR modulator compounds of
the present invention, as was seen for the RXR:RAR heterodimer
assay, also display a continuum of activities on the
RXR.alpha.:PPAR.gamma. heterodimer. Compound L1 displays both
agonist and synergistic activity similar to that seen with LGD1069
and LG100268. L2 is a partial agonist alone and shows stronger
activity in combination with the PPAR.gamma. ligand. Compounds L3
and L4 were only weakly active alone, but they were active in the
presence of the PPAR.gamma. ligand. Finally, Compound L5 was not
active as an agonist on the RXR.alpha.:PPAR.gamma. heterodimer
either alone or in combination the PPAR.gamma. ligand.
5TABLE 5 Activity in RXR.alpha.:PPAR.gamma. heterodimer
cotransfection assays of selected dimer-selective RXR modulator
compounds of the present invention. Values represent mean of n >
3 independent experiments. RXR.alpha.:PPAR.gamma. Heterodimer
Cotransfection Assay Cmpd. Agonist Synerg No. Efficacy (%).sup.1
Efficacy (%).sup.2 BRL 49653 100 -- LGD1069 -- 64 LG100268 59 183
L1 59 166 L2 14 69 L3 6 25 L4 3 20 L5 4 6 .sup.1Efficacy calculated
as maximal response relative to response of BRL 49653.
.sup.2Efficacy calculated as maximal response in presence of 100 nM
BRL relative to response of BRL alone.
[0428] Thus, although all of the compounds of the present invention
directly and specifically bind RXR, they manifest distinct
properties in the RXR:RXR homodimer assay as compared to the
RXR:RAR and RXR:PPAR.gamma. heterodimer assays. The various RXR
modulator compounds of the present invention have a range of
activities when compared with each other and are truly
dimer-selective RXR modulators, such that their actual function as
either agonist, partial agonist and/or antagonist change depending
upon the RXR partner and whether the partner is bound by
ligand.
Example 211
Evaluation of Activity In Vivo
[0429] In Vivo Method:
[0430] Rodents that are genetically defective in the leptin pathway
are commonly used as animal models of NIDDM. db/db mice and ZDF
rats develop frank diabetes that progresses to include .beta.-cell
failure and the accompanying precipitous drop in plasma insulin
levels. Both strains are profoundly obese, hyperglycemic,
hyperinsulinemic, and hypertriglyceridemic. fa/fa rats, on the
other hand, are obese and insulin resistant but do not develop
frank diabetes and the associated hyperglycemia. Using all 3 models
we have examined the efficacy of oral dosing with rexinoid
modulators on diabetes, insulin sensitivity, food consumption and
body weight gain.
[0431] All animal experiments were conducted in a United States
Department of Agriculture registered facility in accordance with
NIH guidelines for the care and use of laboratory animals. The
Ligand Institutional Animal Care and Use committee (IACUC) approved
each study. Mice (obtained from Jackson Laboratory), ZDF rats
(obtained from Genetic Models Inc.) and fa/fa rats (obtained from
either Charles River, or Harlan) were maintained on 12-hour
light/dark cycle. Mice (age 28-42 days) were caged in groups of 5-6
and rats (age 7 weeks) were housed individually. All animals were
allowed ad libitum access to water and food (Purina 5015 for mice
and 5008 for rats). Compounds were administered at the specified
doses by oral gavage on the morning of each day of any experiment.
Blood samples were obtained 3 hours after dosing from fed animals
under anesthesia and collected into heparinized capillary tubes
from the tail vein.
[0432] Mice transgenic for the human apolipoprotein A-I gene
(obtained from Jackson Laboratory) were used to evaluate PPARalpha
mediated effects on HDL cholesterol. The mice were handled as
described above for db/db mice, except that they were fed Purina
5001.
[0433] Rexinoids that are full agonists at the RXR homodimer, such
as LG100268, are efficacious insulin sensitizers in rodent models
of Type II Diabetes. However, such compounds raise triglycerides
and suppress the thyroid hormone axis in these animals. On the
other hand, full antagonists, such as L5, have no effect on
glucose, triglycerides or the thyroid status in these same model
systems. We have identified a specific subset of rexinoids that
maintain the desirable insulin sensitizing activity and minimize
both the suppression of the thyroid axis and triglyceride
elevations (e.g., L3, L4, L6, L7, L8, L9, L13, L14, L15, L16, L17,
L18, L19). These compounds are heterodimer selective modulators of
RXR activity. They bind to RXR with high affinity (K.sub.i<20
nM) and produce potent activation of the RXR:PPARgamma heterodimer.
This activation of PPARgamma in vitro is presumably a major
determinant of the antidiabetic efficacy of the compounds in vivo.
In addition, to minimize the undesirable increases in triglyceride
levels and suppression of thyroid hormone axis, the modulators must
not significantly activate the RXR:RAR heterodimer and must have
substantial RXR:RAR antagonist activity. This requirement is
clearly demonstrated by the two related compounds L2, L3. The
striking in vitro characteristic for these two compounds is that L3
has twice the RXR:RAR antagonist activity as L2; this correlates
with the distinction in vivo where L2 suppresses thyroid hormone
axis while L3 does not. Analogous results are obtained in normal
Sprague Dawley rats where both T4 and TSH can be monitored. In this
acute model these heterodimer selective RXR modulators suppress
neither TSH nor T4.
[0434] When administered to obese, insulin resistant db/db mice
(100 mg/kg by daily oral gavage for 14 days) these heterodimer
selective RXR modulators lower both plasma glucose and
triglycerides. However, unlike either full agonists (e.g.,
LG100268, L1) or partial agonists that exhibit some activity at the
RXR:RAR heterodimer (e.g., L2), they do not substantially suppress
total circulating levels of T4, or substantially increase
triglycerides.
[0435] Four week old db/db mice are essentially normoglycemic, they
have not yet developed hyperglycemia: Treatment of such mice with
1392 (30 mg/kg by daily oral gavage) prevents the development of
hyperglycemia. This treatment has been shown to successfully
control plasma glucose levels for up to 11 weeks (when the mice are
15 weeks old).
[0436] Treatment of 7 week old db/db mice with metformin (300 mg/kg
by daily oral gavage) lowers plasma glucose. However the maximum
effect is seen following the first week of treatment. Over 3
subsequent weeks the efficacy of metformin decreases. At this point
treatment with metformin plus the addition of 1392 (100 mg/kg by
daily oral gavage) lowered plasma glucose to the level of age
matched lean. These data suggest that the RXR modulator could be
efficacious in cases of secondary failure of metformin.
[0437] When administered to obese, insulin resistant fa/fa rats
(100 mg/kg by daily oral gavage for 14 days) these heterodimer
selective RXR modulators (such as 1392) produce insulin
sensitization as demonstrated using an oral glucose tolerance test.
In response to the oral glucose challenge both insulin and glucose
rise significantly less than in untreated control animals. These
1392 treated animals consume the same amount of food and gain the
same amount of weight as vehicle treated control animals. When
fa/fa animals are treated with a thiazolinedione insulin sensitizer
they consume significantly more food and gain significantly more
weight than control animals. In contrast, animals treated with a
combination of the thiazolidinedione and 1392 consume the same
amount of food and gain the same amount of weight as the control
animals; 1392 blocks the thiazolidinedione induced increases in
both food consumption and body weight gain.
[0438] When administered to transgenic mice carrying the human apo
A-I gene all of these compounds increase HDL cholesterol, but both
LG100268 and L1 also substantially raise triglycerides. The
modulators that do not activate the RXR:RAR heterodimer and have
greater than 50% RXR:RAR antagonists activity do not substantially
raise triglycerides in the transgenic mouse model, consistent with
their heterodimer selectivity. This effect is consistent with
activation of PPARalpha, and in fact in vivo these compounds
synergize with the weak PPARalpha agonist fenofibrate.
Example 212
Evaluation of Teratogenicity In Vivo
[0439] Teratogenicity is commonly evaluated by examination of
fetuses obtained by cesarean section from pregnant mice dosed daily
with test compound between gestation days 6-18. We have conducted a
blinded study using time-mated female Crl:CD-1.RTM. (ICR)BR mice to
evaluate potential developmental toxicity (teratogenicity)
following administration of L6 at either 30 or 200 mg/kg-day by
daily oral gavage for the specified 12 days of gestation. Each test
group consisted of 7-8 pregnant females and produced approx. 100
live fetuses per test group. As a positive control, pregnant female
mice were treated with the retinoid LG100268 at a dose of either 30
mg/kg-day or 100 mg/kg-day. Teratogenicity was observed in fetuses
from mice-treated with the LG100268 at both dosage groups. In
contrast, no teratogenic effects were observed in fetuses from mice
treated with L6. Compared to controls dosed with vehicle, no
effects were observed on the number of Corpora lutea, implantation
sites, live or dead fetuses, early or late resorptions, fetal
weight or sex, gross external morphology or visceral morphology of
the cranial region in fetuses from mice treated with L6 at either
dose. The highest dose of L6 tested (200 mg/kg-day) is twice the
dose required to produce maximum antidiabetic activity in db/db
mice (100 mg/kg-day).
[0440] While we have described a number of embodiments of this
invention, it is apparent that our basic constructions may be
altered to provide other embodiments which utilize the processes
and products of this invention. Therefore it will be appreciated
that the scope of this invention is to be defined by the appended
claims, rather than by the specific embodiments which have been
presented by way of example.
* * * * *