U.S. patent application number 13/408309 was filed with the patent office on 2012-07-12 for kappa opioid receptor ligands.
This patent application is currently assigned to RESEARCH TRIANGLE INSTITUTE. Invention is credited to Lawrence E. Brieaddy, Frank Ivy CARROLL, Hernan A. Navarro, Scott P. Runyon, James B. Thomas.
Application Number | 20120178781 13/408309 |
Document ID | / |
Family ID | 36816429 |
Filed Date | 2012-07-12 |
United States Patent
Application |
20120178781 |
Kind Code |
A1 |
CARROLL; Frank Ivy ; et
al. |
July 12, 2012 |
KAPPA OPIOID RECEPTOR LIGANDS
Abstract
Kappa opioid receptor antagonists are provided that yield
significant improvements in functional binding assays to kappa
opioid receptors, and the use of these antagonists in treatment of
disease states that are ameliorated by binding of the kappa opioid
receptor such as heroin or cocaine addictions.
Inventors: |
CARROLL; Frank Ivy;
(Research Triangle Park, NC) ; Navarro; Hernan A.;
(Research Triangle Park, NC) ; Brieaddy; Lawrence E.;
(Research Triangle Park, NC) ; Runyon; Scott P.;
(Research Triangle Park, NC) ; Thomas; James B.;
(Efland, NC) |
Assignee: |
RESEARCH TRIANGLE INSTITUTE
Research Triangle Park
NC
|
Family ID: |
36816429 |
Appl. No.: |
13/408309 |
Filed: |
February 29, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12911244 |
Oct 25, 2010 |
8173678 |
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13408309 |
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11059390 |
Feb 17, 2005 |
7872023 |
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12911244 |
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Current U.S.
Class: |
514/324 ;
514/320; 546/196; 546/202 |
Current CPC
Class: |
C07D 211/22 20130101;
A61P 37/06 20180101; A61P 43/00 20180101; A61P 9/12 20180101; A61P
31/12 20180101; A61P 19/02 20180101; A61P 25/24 20180101; A61P
25/06 20180101; A61P 3/04 20180101; A61P 37/02 20180101; A61K
31/4545 20130101; A61P 13/00 20180101; A61P 25/30 20180101; A61P
9/10 20180101; C07D 405/12 20130101; A61P 25/32 20180101; A61K
31/445 20130101; A61K 31/506 20130101; A61P 37/08 20180101; A61P
1/12 20180101; A61P 25/04 20180101; C07D 409/12 20130101; A61P
25/16 20180101; A61K 31/53 20130101; A61P 25/08 20180101; A61P
25/36 20180101; A61P 25/00 20180101; A61P 25/18 20180101; A61P
11/14 20180101 |
Class at
Publication: |
514/324 ;
546/196; 514/320; 546/202 |
International
Class: |
A61K 31/4535 20060101
A61K031/4535; A61K 31/453 20060101 A61K031/453; A61P 25/06 20060101
A61P025/06; A61P 37/02 20060101 A61P037/02; A61P 37/06 20060101
A61P037/06; A61P 19/02 20060101 A61P019/02; A61P 37/08 20060101
A61P037/08; A61P 31/12 20060101 A61P031/12; A61P 1/12 20060101
A61P001/12; A61P 25/18 20060101 A61P025/18; A61P 25/24 20060101
A61P025/24; A61P 11/14 20060101 A61P011/14; A61P 25/30 20060101
A61P025/30; A61P 9/12 20060101 A61P009/12; A61P 3/04 20060101
A61P003/04; A61P 25/08 20060101 A61P025/08; C07D 211/08 20060101
C07D211/08 |
Claims
1-21. (canceled)
22. A kappa opioid receptor antagonist represented by formula (I):
##STR00007## wherein G is H, OH, OCOC.sub.1-8 alkyl, CONH.sub.2,
NHCHO, NH.sub.2, NHSO.sub.2C.sub.1-8 alkyl, or NHCO.sub.2C.sub.1-8
alkyl; R.sub.1 is C.sub.1-8 alkyl or one of the following
structures: ##STR00008## Y.sub.1 is H, OH, Br, Cl, F, CN, CF.sub.3,
NO.sub.2, N.sub.3, OR.sub.8, CO.sub.2R.sub.9, C.sub.1-6 alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, or CH.sub.2(CH.sub.2).sub.nY.sub.2; Y.sub.2 is
H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6 alkyl, NR.sub.10R.sub.11,
NHCOR.sub.12, NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H, OH, Br, Cl,
F, CN, CF.sub.3, NO.sub.2, N.sub.3, OR.sub.8, CO.sub.2R.sub.9,
C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, or
CH.sub.2(CH.sub.2).sub.nY.sub.2; R.sub.2 is H, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl or CH.sub.2-aryl substituted
by one or more groups Y.sub.1; R.sub.3 is H, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl or CH.sub.2-aryl substituted
by one or more groups Y.sub.1; wherein R.sub.2 and R.sub.3 may be
bonded together to form a C.sub.2-8 alkyl group; R.sub.4 is
hydrogen, C.sub.1-8 alkyl, CO.sub.2C.sub.1-8 alkylaryl substituted
by one or more groups Y.sub.1, CH.sub.2-aryl substituted by one or
more groups Y.sub.1 or CO.sub.2C.sub.1-8 alkyl; Z is O or S; n is
0, 1, 2 or 3; R.sub.6 is a group selected from the group consisting
of structures (a)-(p): ##STR00009## ##STR00010## ##STR00011## Q is
O, S, SO or SO.sub.2; X.sub.1 is hydrogen, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, or C.sub.3-8 alkynyl; X.sub.2 is hydrogen,
C.sub.1-8 alkyl, C.sub.3-8 alkenyl, or C.sub.3-8 alkynyl, or
X.sub.1 and X.sub.2 together form .dbd.O, .dbd.S, or .dbd.NH;
R.sub.7 is H, C.sub.1-8 alkyl, CH.sub.2aryl substituted by one or
more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15,
CH.sub.2(CH.sub.2).sub.nY.sub.2, or C(.dbd.NH)NR.sub.16R.sub.17,
R.sub.8 is H, C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or
more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2',
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.9 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.10 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.11 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.12 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.13 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.14 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.15 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.16 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; and R.sub.17 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl, or a pharmaceutically
acceptable salt thereof.
23. The kappa opioid receptor antagonist of claim 22, wherein
Y.sub.3 is H; and R.sub.2 and R.sub.3 are each, independently, H,
C.sub.1-8 alkyl, C.sub.3-8 alkynyl, C.sub.3-8 alkynyl, or
CH.sub.2-aryl substituted by one or more substituents Y.sub.1.
24. The kappa opioid receptor antagonist of claim 22, wherein
R.sub.1 is C.sub.1-8 alkyl, or one of the following structures:
##STR00012## Y.sub.3 is H; R.sub.2 and R.sub.3 are each,
independently, H or C.sub.1-8 alkyl, wherein R.sub.2 and R.sub.3
cannot both be H at the same time; and R.sub.7 is H, C.sub.1-8
alkyl, CH.sub.2-aryl substituted by one or more substituents
Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.13,
CONR.sub.14R.sub.15, or CH.sub.2(CH.sub.2).sub.nY.sub.2.
25. The kappa opioid receptor antagonist of claim 22, wherein
R.sub.1 is C.sub.1-8 alkyl; Y.sub.2 is H, CF.sub.3,
CO.sub.2R.sub.9, C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H; R.sub.2 and
R.sub.3 are each, independently, H or methyl, wherein R.sub.2 and
R.sub.3 cannot both be H at the same time; R.sub.4 is H, C.sub.1-8
alkyl, CO.sub.2C.sub.1-8 alkyl, or CH.sub.2-aryl substituted by one
or more substituents Y.sub.1 and the stereocenter adjacent to
R.sub.4 is in an (S) configuration; R.sub.6 is a group having a
formula selected from the group consisting of structures (d)-(p);
and R.sub.7 is H, C.sub.1-8 alkyl, CH.sub.2aryl substituted by one
or more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
26. The kappa opioid receptor antagonist of claim 22, wherein
R.sub.1 is methyl, Y.sub.2 is H, CF.sub.3, CO.sub.2R.sub.9,
C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCO.sub.2R.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H; R.sub.2 and
R.sub.3 are each H or methyl, such that when R.sub.2 is H, R.sub.3
is methyl and vice versa; R.sub.4 is C.sub.1-8 alkyl, or
CO.sub.2C.sub.1-8 alkyl, and the stereocenter adjacent to R.sub.4
has a configuration of (S); and R.sub.7 is H, C.sub.1-8 alkyl,
CH.sub.2 aryl substituted by one or more substituents Y.sub.1, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
27. The kappa opioid receptor antagonist of claim 22, which is in
the form of a pharmaceutically acceptable salt.
28. The kappa opioid receptor antagonist of claim 22, wherein
R.sup.6 is structure (a), (b) or (c).
29. The kappa opioid receptor antagonist of claim 22, wherein
R.sup.6 is one of (d)-(p).
30. The kappa opioid receptor antagonist of claim 22, which is
represented by the formula: ##STR00013## ##STR00014## wherein Q is
defined in claim 22.
31. A pharmaceutical composition comprising an effective amount of
a kappa opioid receptor antagonist of claim 22 and a
physiologically acceptable carrier.
32. A kappa opioid receptor antagonist represented by formula (I):
##STR00015## wherein G is H, OH, OCOC.sub.1-8 alkyl, CONH.sub.2,
NHCHO, NH.sub.2, NHSO.sub.2C.sub.1-8 alkyl, or NHCO.sub.2C.sub.1-8
alkyl; R.sub.1 is C.sub.1-8 alkyl or one of the following
structures: ##STR00016## Y.sub.1, is H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, OR.sub.8, CO.sub.2R.sub.9, C.sub.1-6
alkyl, NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, or CH.sub.2(CH.sub.2).sub.nY.sub.2; Y.sub.2 is
H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6alkyl, NR.sub.10R.sub.11,
NHCOR.sub.12, NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H, OH, Br, Cl,
F, CN, CF.sub.3, NO.sub.2, N.sub.3, OR.sub.8, CO.sub.2R.sub.9,
C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, or
CH.sub.2(CH.sub.2).sub.nY.sub.2; R.sub.2 is H, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl or CH.sub.2-aryl substituted
by one or more groups Y.sub.1; R.sub.3 is H, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl or CH.sub.2-aryl substituted
by one or more groups Y.sub.1; wherein R.sub.2 and R.sub.3 may be
bonded together to form a C.sub.2-8 alkyl group; R.sub.4 is
hydrogen, C.sub.1-8 alkyl, CO.sub.2C.sub.1-8 alkylaryl substituted
by one or more groups Y.sub.1, CH.sub.2-aryl substituted by one or
more groups Y.sub.1 or CO.sub.2C.sub.1-8 alkyl; Z is O or S; n is
0, 1, 2 or 3; R.sub.6 is a group selected from the group consisting
of structures (d)-(p): ##STR00017## ##STR00018## ##STR00019## Q is
CH.sub.2; X.sub.1 is hydrogen, C.sub.1-8 alkyl, C.sub.3-8 alkenyl,
or C.sub.3-8 alkynyl; X.sub.2 is hydrogen, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, or C.sub.3-8 alkynyl; or X.sub.1 and X.sub.2
together form .dbd.O, .dbd.S, or .dbd.NH; R.sub.7 is H, C.sub.1-8
alkyl, CH.sub.2-aryl substituted by one or more substituents
Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.13,
CONR.sub.14R.sub.15, CH.sub.2(CH.sub.2).sub.nY.sub.2, or
C(.dbd.NH)NR.sub.16R.sub.17, R.sub.8 is H, C.sub.1-8 alkyl,
CH.sub.2-aryl substituted by one or more substituents H, OH, Br,
Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.9 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.10 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.11 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.12 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.13 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.14 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.15 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; R.sub.16 is H, C.sub.1-8 alkyl, CH.sub.2-aryl
substituted by one or more substituents H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl; and R.sub.17 is H, C.sub.1-8 alkyl,
CH.sub.2-aryl substituted by one or more substituents H, OH, Br,
Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3, C.sub.1-6 alkyl, or
CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein Y.sub.2' is H, CF.sub.3,
or C.sub.1-6 alkyl, or a pharmaceutically acceptable salt
thereof.
33. The kappa opioid receptor antagonist of claim 32, wherein
Y.sub.3 is H; and R.sub.2 and R.sub.3 are each, independently, H,
C.sub.1-8 alkyl, C.sub.3-8 alkynyl, C.sub.3-8 alkynyl, or
CH.sub.2-aryl substituted by one or more substituents Y.sub.1.
34. The kappa opioid receptor antagonist of claim 32, wherein
R.sub.1 is C.sub.1-8 alkyl, or one of the following structures:
##STR00020## Y.sub.3 is H; R.sub.2 and R.sub.3 are each,
independently, H or C.sub.1-8 alkyl, wherein R.sub.2 and R.sub.3
cannot both be H at the same time; and R.sub.7 is H, C.sub.1-8
alkyl, CH.sub.2-aryl substituted by one or more substituents
Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.13,
CONR.sub.14R.sub.15, or CH.sub.2(CH.sub.2).sub.nY.sub.2.
35. The kappa opioid receptor antagonist of claim 32, wherein
R.sub.1 is C.sub.1-8 alkyl; Y.sub.2 is H, CF.sub.3,
CO.sub.2R.sub.9, C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H; R.sub.2 and
R.sub.3 are each, independently, H or methyl, wherein R.sub.2 and
R.sub.3 cannot both be H at the same time; R.sub.4 is H, C.sub.1-8
alkyl, CO.sub.2C.sub.1-8 alkyl, or CH.sub.2-aryl substituted by one
or more substituents Y.sub.1 and the stereocenter adjacent to
R.sub.4 is in an (S) configuration; R.sub.6 is a group having a
formula selected from the group consisting of structures (d)-(p);
and R.sub.7 is H, C.sub.1-8 alkyl, CH.sub.2aryl substituted by one
or more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
36. The kappa opioid receptor antagonist of claim 32, wherein
R.sub.1 is methyl, Y.sub.2 is H, CF.sub.3, CO.sub.2R.sub.9,
C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCO.sub.2R.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H; R.sub.2 and
R.sub.3 are each H or methyl, such that when R.sub.2 is H, R.sub.3
is methyl and vice versa; R.sub.4 is C.sub.1-5 alkyl, or
CO.sub.2C.sub.1-8 alkyl, and the stereocenter adjacent to R.sub.4
has a configuration of (S); and R.sub.7 is H, C.sub.1-8 alkyl,
CH.sub.2 aryl substituted by one or more substituents Y.sub.1, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
37. The kappa opioid receptor antagonist of claim 32, wherein
R.sup.6 is structure (d), (e), (f) or (g).
38. The kappa opioid receptor antagonist of claim 32, wherein
R.sup.6 is one of (h)-(p).
39. A pharmaceutical composition comprising an effective amount of
a kappa opioid receptor antagonist of claim 32 and a
physiologically acceptable carrier.
40. A method of binding a kappa opioid receptor in a subject in
need thereof, comprising administering to the subject an effective
amount of the kappa opioid receptor antagonist represented by the
formula (I): ##STR00021## wherein G is H, OH, OCOC.sub.1-8 alkyl,
CONH.sub.2, NHCHO, NH.sub.2, NHSO.sub.2C.sub.1-8 alkyl, or
NHCO.sub.2C.sub.1-8 alkyl; R.sub.1 is C.sub.1-8 alkyl or one of the
following structures: ##STR00022## Y.sub.1 is H, OH, Br, Cl, F, CN,
CF.sub.3, NO.sub.2, N.sub.3, OR.sub.8, CO.sub.2R.sub.9, C.sub.1-6
alkyl, NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, or CH.sub.2(CH.sub.2).sub.nY.sub.2; Y.sub.2 is
H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6 alkyl, NR.sub.10R.sub.11,
NHCOR.sub.12, NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, CH.sub.2OH,
CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H, OH, Br, Cl,
F, CN, CF.sub.3, NO.sub.2, N.sub.3, OR.sub.8, CO.sub.2R.sub.9,
C.sub.1-6 alkyl, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, or
CH.sub.2(CH.sub.2).sub.nY.sub.2; R.sub.2 is H, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl or CH.sub.2-aryl substituted
by one or more groups Y.sub.1; R.sub.3 is H, C.sub.1-8 alkyl,
C.sub.3-8 alkenyl, C.sub.3-8 alkynyl or CH.sub.2-aryl substituted
by one or more groups Y.sub.1; wherein R.sub.2 and R.sub.3 may be
bonded together to form a C.sub.2-8 alkyl group; R.sub.4 is
hydrogen, C.sub.1-8 alkyl, CO.sub.2C.sub.1-8 alkylaryl substituted
by one or more groups Y.sub.1, CH.sub.2-aryl substituted by one or
more groups Y.sub.1 or CO.sub.2C.sub.1-8 alkyl; Z is N, O or S,
wherein when Z is S or O there is no R.sub.5; R.sub.5 is H,
C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl,
CH.sub.2CO.sub.2C.sub.1-8 alkyl, CO.sub.2C.sub.1-8 alkyl or
CH.sub.2-aryl substituted by one or more groups Y.sub.1; n is 0, 1,
2 or 3; R.sub.6 is a group selected from the group consisting of
structures (a)-(p): ##STR00023## ##STR00024## ##STR00025## Q is O,
S, SO or SO.sub.2; X.sub.1 is hydrogen, C.sub.1-8 alkyl, C.sub.3-8
alkenyl, or C.sub.3-8 alkynyl; X.sub.2 is hydrogen, C.sub.1-8
alkyl, C.sub.3-8 alkenyl, or C.sub.3-8 alkynyl, or X.sub.1 and
X.sub.2 together form .dbd.O, .dbd.S, or .dbd.NH; R.sub.7 is H,
C.sub.1-8 alkyl, CH.sub.2aryl substituted by one or more
substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15,
CH.sub.2(CH.sub.2).sub.nY.sub.2, or C(.dbd.NH)NR.sub.16R.sub.17,
R.sub.8 is H, C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or
more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2',
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.9 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.10 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.11 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.3-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.12 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.13 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.14 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.15 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; R.sub.16 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl; and R.sub.17 is H,
C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2, N.sub.3,
C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2', wherein
Y.sub.2' is H, CF.sub.3, or C.sub.1-6 alkyl, or a pharmaceutically
acceptable salt thereof.
41. The method of claim 40, wherein administration of the compound
provides an effect in the subject selected from the group
consisting of cytostatic, antimigraine, immunomodulator,
immunosuppressive, antiarthritic, antiallergic, virucidal,
anti-diarrheal, antipsychotic, antischizophrenic, antidepressant,
uropathic, antitussive, antiaddictive, anti-smoking, hypotensive
agents, treating and/or preventing paralysis resulting from
traumatic ischemia, general neuroprotection against ischemic
trauma, anti-diuretic, stimulant, anti-convulsants, and
anti-obesity.
42. The method of claim 40, wherein the subject has a disease state
selected from the group consisting of opiate addiction, cocaine
addiction, nicotine addiction and ethanol addiction.
43. The method of claim 40, wherein Y.sub.3 is H; and R.sub.2 and
R.sub.3 are each, independently, H, C.sub.1-8 alkyl, C.sub.3-8
alkynyl, C.sub.3-8 alkynyl, or CH.sub.2-aryl substituted by one or
more substituents Y.sub.1.
44. The method of claim 40, wherein R.sub.1 is C.sub.1-8 alkyl, or
one of the following structures: ##STR00026## Y.sub.3 is H; R.sub.2
and R.sub.3 are each, independently, H or C.sub.1-8 alkyl, wherein
R.sub.2 and R.sub.3 cannot both be H at the same time; and R.sub.7
is H, C.sub.1-8 alkyl, CH.sub.2-aryl substituted by one or more
substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
45. The method of claim 40, wherein R.sub.1 is C.sub.1-8 alkyl;
Y.sub.2 is H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6 alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, CH.sub.2OH, CH.sub.2OR.sub.8, or
COCH.sub.2R.sub.9; Y.sub.3 is H; R.sub.2 and R.sub.3 are each,
independently, H or methyl, wherein R.sub.2 and R.sub.3 cannot both
be H at the same time; R.sub.4 is H, C.sub.1-8 alkyl,
CO.sub.2C.sub.1-8 alkyl, or CH.sub.2-aryl substituted by one or
more substituents Y.sub.1 and the stereocenter adjacent to R.sub.4
is in an (S) configuration; R.sub.5 is H, C.sub.1-8 alkyl, or
CH.sub.2CO.sub.2C.sub.1-8 alkyl; R.sub.6 is a group having a
formula selected from the group consisting of structures (d)-(p);
and R.sub.7 is H, C.sub.1-8 alkyl, CH.sub.2aryl substituted by one
or more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
46. The method of claim 40, wherein R.sub.1 is methyl, Y.sub.2 is
H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6 alkyl, NR.sub.10R.sub.11,
NHCO.sub.2R.sub.12, NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14,
CH.sub.2OH, CH.sub.2OR.sub.8, or COCH.sub.2R.sub.9; Y.sub.3 is H;
R.sub.2 and R.sub.3 are each H or methyl, such that when R.sub.2 is
H, R.sub.3 is methyl and vice versa; R.sub.4 is C.sub.1-8 alkyl, or
CO.sub.2C.sub.1-8 alkyl, and the stereocenter adjacent to R.sub.4
has a configuration of (S); R.sub.5 is H; and R.sub.7 is H,
C.sub.1-8 alkyl, CH.sub.2 aryl substituted by one or more
substituents Y.sub.1, or CH.sub.2(CH.sub.2).sub.nY.sub.2.
47. The method of claim 40, which is in the form of a
pharmaceutically acceptable salt.
48. The method of claim 40, wherein R.sup.6 is structure (a), (b),
(c) or (d).
49. The method of claim 40, wherein R.sup.6 is one of (e)-(p).
50. The method of claim 40, which is represented by the formula:
##STR00027## ##STR00028## wherein Q is defined in claim 40.
Description
CONTINUATION DATA
[0001] This application is a Continuation of U.S. application Ser.
No. 12/911,244, filed on Oct. 25, 2010, which is a Divisional of
U.S. application Ser. No. 11/059,390, tiled Feb. 17, 2005.
BACKGROUND OF THE INVENTION
[0002] 1. Field of Invention
[0003] The present invention relates to compounds that bind with
high affinity and/or specificity to kappa opioid receptors.
[0004] 2. Discussion of the Background
[0005] The study of compounds exerting their actions via the opioid
receptor system has continued for nearly eight decades. Though this
has been a broad effort, the fundamental driving force for this
endeavor relates to the elimination or reduction of the side-effect
profile produced by the most frequently used or abused opiates
morphine (1) and heroin (2) in FIG. 1. Among the many side effects
produced by compounds 1 and 2, addiction, tolerance and respiratory
depression are of greatest concern when heroin abuse is considered.
Though its use waned in the late 70s, increases in both the purity
and availability of this drug have promoted a serious resurgence of
illegal use. In the study and treatment of substance abuse,
antagonists for the opioid receptors like naltrexone (3) (FIG. 1)
have played a prominent role. In recent years, researchers studying
the physiological mechanisms underlying addiction have sought
antagonists selective for each of the three opioid receptor
subtypes mu, delta and kappa. Extensive research efforts along
these lines lead to the discovery of several such compounds with
examples including cyprodime (mu, 4), naltrindole (delta, 5) and
nor-binaltorphimine (kappa, 6) (FIG. 1). Of the three, the kappa
receptor has only begrudgingly yielded antagonists and, of the
known examples, all stem from modification of the prototype,
nor-binaltorphimine (nor-BNI, 6).
[0006] Portoghese in his pioneering work provided not only the
second and third generation kappa antagonists
5'-[(N2-butylamidino)methyl]naltrindole (7) and
C5'-guanidinylnaltrindole (GNTI, 8) but also convincing evidence
that the Glu297 residue in transmembrane helix 6 of the kappa
receptor is the principle address site influencing the kappa
selectivity found in 6-8 (FIG. 1). In terms of the message address
concept as applied by Portoghese to opioid small-molecules, it is
the pendant amine functionality (noted by asterisks in the chart)
that functions as the kappa address element for compounds 6-8 by
interacting with the Glu297 residue which is present in the kappa
but not in the mu receptor.
[0007] In terms of substance abuse treatment, antagonists selective
for the kappa receptor have been the least studied primarily due to
the limited bio-availability of 6 and its analogs. However,
mounting evidence that the endogenous kappa opioid system opposes
the actions of mu agonists like 2 suggests that antagonists
selective for the kappa receptor system could suppress or eliminate
the symptoms of withdrawal which arise from an overactive kappa
receptor system and thus could promote abstinence and prevent
relapse. Therefore, the development of novel kappa antagonists
possessing improved pharmacokinetic profiles would be of great
value.
[0008] As is obvious from the examples above, the morphinan
substructure of 3 has served as the preeminent template upon which
selective antagonists have been constructed. Contrary to these
efforts, our work in this field started from the relatively
unstudied N-substituted
trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine class of opioid
antagonist discovered by Zimmerman et al. Compounds like 9a and 9b
(FIG. 1) were novel opioid antagonists because their intrinsic
antagonist activity was not mediated by the structure of their
N-substituent (i.e. the N-methyl (9a) and N-cyclopropylmethyl (9b)
analogs in the phenylpiperidine series are both pure antagonists).
Indeed, no N-substituent has been discovered which converts this
series of compound into an agonist. Compounds 10-12 (FIG. 1)
represent some of the structures tried to date. In this connection
we recently demonstrated that compounds bearing the trans-cinnamyl
N-substituent, as found in 13 (FIG. 1), most closely reproduced the
potency at the mu opioid receptor of the flexible N-substituted
analogs (10-12). In fact, the comparable mu receptor potencies
demonstrated by analogs
trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine possessing the
trans-cinnamyl moiety lead us to speculate that in their
biologically active conformation, compounds such as 10-12 have the
connecting chain and appended ring in their N-substituent extended
away from the piperidine nitrogen in a manner consistent with the
trans-cinnamyl skeleton like that found in 13.
[0009] In more recent studies comparing opioid receptor potency and
selectivity to N-substituent changes in this series of antagonists,
we discovered 14-18, where Q is CH.sub.2, O, S, SO, or SO.sub.2
(FIG. 1). These compounds were obtained from the screening of
libraries of compounds which were biased for opioid antagonist
activity by incorporation of
trans-(3,4)-dimethyl-4-(3-hydroxyphenyl)piperidine into each
ligand. In biological testing those compounds (14-18) were found to
possess kappa opioid receptor subtype selectivity in functional
binding assays.
SUMMARY OF THE INVENTION
[0010] It is an object of the invention to provide compounds which
bind to kappa opioid receptors with high affinity.
[0011] It is another object of the invention to provide compounds
which bind to kappa opioid receptors with high specificity.
[0012] It is another object of the invention to provide compounds
which bind to kappa opioid receptors with high affinity and
specificity in functional assays.
[0013] The objects of the present invention, and others, are
accomplished with compounds of the structures described herein,
particularly compounds 14-18, which have the above advantages.
BRIEF DESCRIPTION OF THE FIGURES
[0014] A more complete appreciation of the invention and many of
the attendant advantages thereof will be readily obtained as the
same becomes better understood by reference to the following
detailed description when considered in connection with the
accompanying drawings, wherein:
[0015] FIG. 1: chemical structure of compounds (I)-(18);
[0016] FIGS. 2-4: examples of synthetic routes to compound
(14-18).
[0017] Reagents and Conditions for FIG. 2:
[0018] (a) diethylcarbonate, THF, NaH; (b) H.sub.2, Pd/C, EtOH,
FeCl.sub.3; (c) MeOH, NaOH; (d) SOCl.sub.2, Toluene; (e) EtLi,
(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (2.10),
THF; (f) LiOOH, 3:1 THF/H.sub.2O, (g) BOP, TEA, THF, room temp; (h)
BBr.sub.3, CH.sub.2Cl.sub.2, -78.degree. C.
[0019] Reagents and Conditions for FIG. 3:
[0020] (a) NaH, DMF; (b) MeOH, KOH; (c) P.sub.2O.sub.5, toluene,
Celite; (d) methylcyanoformate, LDA, HMPA, THF; (e) TFA,
Et.sub.3SiH; (f) KOH, MeOH; (g) oxalyl chloride, CH.sub.2Cl.sub.2;
(h) EtLi,
(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (3.9),
THF; (i) LiOH, 3:1 THF/H.sub.2O, (j)
N-[(2'S)-Amino-3'-methylbutyl]-(3R,4R)-trans-dimethyl-4-(3-hydroxyphenyl)-
piperidine (3.13), BOP, TEA, THF, room temp; (h) BBr.sub.3,
CH.sub.2Cl.sub.2, -78.degree. C. to 0.degree. C.
[0021] Reagents and Conditions for FIG. 4:
[0022] (a) NaH, THF; (b) oxalyl chloride, CH.sub.2--Cl.sub.2; (c)
SnCl.sub.4, chlorobenzene, 0 .sub.iC; (d) NaSEt, DMF, reflux; (e)
pivaloyl chloride, TEA; (f) methyl cyanoformate, LDA, HMPA, THF;
(g) TFA, Et.sub.3SiH; (h) NaHCO.sub.3, MeOH; (i) oxalyl chloride,
CH.sub.2Cl.sub.2; (j) EtLi,
(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (4.9),
THF; (k) LiOH, 3:1 THF/H.sub.2O, 0.degree. C. (1)
N-[(2'S)-amino-3'-methylbutyl]-(3R,4R)-trans-dimethyl-4-(3-hydroxyphenyl)-
piperidine (4.13), BOP, TEA, THF, room temp; (m) 3M HCl,
dioxane.
[0023] FIG. 5: graphical representation of effect of compound 160
(one of compounds 14 or 15) on U50,488-stimulated urine output.
[0024] FIG. 6: graphical representation of long-term effect of
compound 160 (one of compounds 14 or 15) on U50,488 urine
output.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention provides kappa opioid antagonists that
bind to kappa opioid receptors with high affinity and/or
specificity. Compounds of the present invention are those
represented by the formula (I):
##STR00001##
[0026] wherein G is H, OH, OCOC.sub.1-8 alkyl, CONH.sub.2, NHCHO,
NH.sub.2, NHSO.sub.2C.sub.1-8 alkyl, or NHCO.sub.2C.sub.1-8
alkyl
R.sub.1 is C.sub.1-8 alkyl, or one of the following structures:
##STR00002##
[0027] Y.sub.1 is H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, OR.sub.8, CO.sub.2R.sub.9, C.sub.1-6 alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, or
CH.sub.2(CH.sub.2).sub.nY.sub.2;
[0028] Y.sub.2 is H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, CH.sub.2OH, CH.sub.2OR.sub.8, or
COCH.sub.2R.sub.9;
[0029] Y.sub.3 is H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, OR.sub.8, CO.sub.2R.sub.9, C.sub.1-6 alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.12, CONR.sub.13R.sub.14, or
CH.sub.2(CH.sub.2).sub.nY.sub.2;
[0030] R.sub.2 is H, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-8
alkynyl or CH.sub.2aryl substituted by one or more groups
Y.sub.1;
[0031] R.sub.3 is H, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-8
alkynyl or CH.sub.2aryl substituted by one or more groups
Y.sub.1,
[0032] wherein R.sub.2 and R.sub.3 may be bonded together to form a
C.sub.2-8 alkyl group;
[0033] R.sub.4 is hydrogen, C.sub.1-8 alkyl, CO.sub.2C.sub.1-8
alkylaryl substituted by one or more groups Y.sub.1, CH.sub.2aryl
substituted by one or more groups Y.sub.1 or CO.sub.2C.sub.1-8
alkyl;
[0034] Z is N, O or S; when Z is O or S, there is no R.sub.5
[0035] R.sub.5 is H, C.sub.1-8 alkyl, C.sub.3-8 alkenyl, C.sub.3-8
alkynyl, CH.sub.2CO.sub.2C.sub.1-8 alkyl, CO.sub.2C.sub.1-8 alkyl
or
[0036] CH.sub.2aryl substituted by one or more groups Y.sub.1;
(when Z is O or S, there is no R.sub.5)
[0037] n is 0, 1, 2 or 3;
[0038] R.sub.6 is a group selected from the group consisting of
structures (a)-(p):
##STR00003## ##STR00004## ##STR00005##
[0039] Q is CH.sub.2, O, S, SO, or SO.sub.2;
[0040] X.sub.1 is hydrogen, C.sub.1-8 alkyl, C.sub.3-8alkenyl, or
C.sub.3-8alkynyl;
[0041] X.sub.2 is hydrogen, C.sub.1-8alkyl, C.sub.3-8alkenyl, or
C.sub.3-8alkynyl;
[0042] or X.sub.1 and X.sub.2 together form .dbd.O, .dbd.S, or
.dbd.NH;
[0043] R.sub.7 is H, C.sub.1-8alkyl, CH.sub.2aryl substituted by
one or more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15,
CH.sub.2(CH.sub.2).sub.nY.sub.2, or
C(.dbd.NH)NR.sub.16R.sub.17,
[0044] R.sub.8 is H, C.sub.1-8alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0045] R.sub.9 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0046] R.sub.10 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0047] R.sub.11 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0048] R.sub.12 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0049] R.sub.13 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0050] R.sub.14 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0051] R.sub.15 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl;
[0052] R.sub.16 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl; and
[0053] R.sub.17 is H, C.sub.1-8 alkyl, CH.sub.2 aryl substituted by
one or more substituents H, OH, Br, Cl, F, CN, CF.sub.3, NO.sub.2,
N.sub.3, C.sub.1-6 alkyl, or CH.sub.2(CH.sub.2).sub.nY.sub.2';
wherein Y.sub.2' is H, CF.sub.3, or C.sub.1-6alkyl
[0054] and pharmaceutically acceptable salts thereof.
[0055] Preferably, the compounds of the present invention are those
represented by the formula I as shown above, wherein G, R.sub.1,
R.sub.4, R.sub.5, Y.sub.1, Y.sub.2, Z, n, X.sub.1, X.sub.2, Q and
R.sub.7-R.sub.17 are as indicated above;
[0056] Y.sub.3 is H;
[0057] R.sub.2 and R.sub.3 are each, independently, H, C.sub.1-8
alkyl, C.sub.3-8 alkenyl, C.sub.3-8 alkynyl, or CH.sub.2aryl
substituted by one or more substituents Y.sub.1; and
[0058] R.sub.6 is a group having a formula selected from the group
consisting of structures (a)-(p) above.
[0059] More preferably, the compounds of the present invention are
those represented by the formula I as shown above, wherein G,
Y.sub.1, Y.sub.2, R.sub.4, R.sub.5, Z, n, X.sub.1, X.sub.2, Q and
R.sub.8-R.sub.15 are as indicated above;
[0060] R.sub.1 is C.sub.1-8 alkyl, or one of the following
structures
##STR00006##
Y.sub.3 is H;
[0061] R.sub.2 and R.sub.3 are each, independently, H or C.sub.1-8
alkyl, wherein R.sub.2 and R.sub.3 cannot both be H at the same
time;
[0062] R.sub.6 is a formula selected from the structures (a)-(p)
shown above; and
[0063] R.sub.7 is H, C.sub.1-8 alkyl, CH.sub.2aryl substituted by
one or more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
[0064] Still more preferably, the compound of the present invention
are those represented by the formula I as shown above, wherein G,
Y.sub.1, Z, n, X.sub.1, X.sub.2, Q and R.sub.8-R.sub.15 are as
noted above;
[0065] R.sub.1 is C.sub.1-8 alkyl;
[0066] Y.sub.2 is H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6 alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, CH.sub.2OH, CH.sub.2OR.sub.8, or
COCH.sub.2R.sub.9;
[0067] Y.sub.3 is H;
[0068] R.sub.2 and R.sub.3 are each, independently, H or methyl,
wherein R.sub.2 and R.sub.3 cannot both be H at the same time;
[0069] R.sub.4 is H, C.sub.1-8 alkyl, CO.sub.2C.sub.1-8alkyl, or
aryl substituted by one or more substituents Y.sub.1 and the
stereocenter adjacent to R.sub.4 is in an (S) configuration;
[0070] R.sub.5 is H, C.sub.1-8 alkyl, or CH.sub.2CO.sub.2C.sub.1-8
alkyl;
[0071] R.sub.6 is a group having a formula selected from the group
consisting of structures (a)-(c) and (h)-(p); and
[0072] R.sub.7 is H, C.sub.1-8alkyl, CH.sub.2aryl substituted by
one or more substituents Y.sub.1, NR.sub.10R.sub.11, NHCOR.sub.12,
NHCO.sub.2R.sub.13, CONR.sub.14R.sub.15, or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
[0073] Most preferably, the compounds of the present invention are
those represented by the formula I as shown above, wherein G,
Y.sub.1, Z, n, X.sub.1, X.sub.2, Q and R.sub.8-R.sub.14 are as
indicated above;
[0074] R.sub.1 is methyl,
[0075] Y.sub.2 is H, CF.sub.3, CO.sub.2R.sub.9, C.sub.1-6 alkyl,
NR.sub.10R.sub.11, NHCOR.sub.12, NHCO.sub.2R.sub.12,
CONR.sub.13R.sub.14, CH.sub.2OH, CH.sub.2OR.sub.8, or
COCH.sub.2R.sub.9;
[0076] Y.sub.3 is H;
[0077] R.sub.2 and R.sub.3 are each H or methyl, such that when
R.sub.2 is H, R.sub.3 is methyl and vice versa;
[0078] R.sub.4 is C.sub.1-8 alkyl, or CO.sub.2C.sub.1-8 alkyl, and
the stereocenter adjacent to R.sub.4 has a configuration of
(S);
[0079] R.sub.5 is H;
[0080] R.sub.6 is a group having a formula selected from the group
consisting of structures (a) and (b); and
[0081] R.sub.7 is H, C.sub.1-8 alkyl, CH.sub.2aryl substituted by
one or more substituents Y.sub.1 or
CH.sub.2(CH.sub.2).sub.nY.sub.2.
[0082] A most preferred set of compounds are the compounds of
formula 14-18 as shown in FIG. 1, where Q is CH.sub.2, O, S, SO, or
SO.sub.2.
[0083] As used throughout this disclosure, the terms "alkyl group"
or "alkyl radical" encompass all structural isomers thereof, such
as linear, branched and cyclic alkyl groups and moieties. Unless
stated otherwise, all alkyl groups described herein may have 1 to 8
carbon atoms, inclusive of all specific values and subranges
therebetween, such as 2, 3, 4, 5, 6, or 7 carbon atoms.
[0084] The alkenyl group or alkynyl group may have one or more
double or triple bonds, respectively. As will be readily
appreciated, when an alkenyl or alkynyl group is bonded to a
heteroatom a double or triple bond is not formed with the carbon
atom bonded directly to the heteroatom.
[0085] The aryl group is a hydrocarbon aryl group, such as a
phenyl, naphthyl, phenanthryl, anthracenyl group, which may have
one or more C.sub.1-4 alkyl group substituents.
[0086] The compounds of the present invention are opiates which are
preferably antagonists that are selective for the kappa receptor.
The .kappa./.mu. selectivity may be at least 2:1, but is preferably
higher, e.g., at least 5:1, 10:1, 25:1, 50:1, 100:1, 200:1 or even
500:1. The .kappa./.delta. selectivity may be at least 2:1, but is
preferably higher, e.g., at least 5:1, 10:1, 25:1, 50:1, 100:1,
200:1, 250:1, 500:1 or even 1000:1.
[0087] The compounds 14 and 15 Q=CH.sub.2 of the present invention
may be synthesized, for example, in accordance with the reaction
sequence shown in FIG. 2. Condensation of the tetralone 2.1 with
diethylcarbonate gives the keto carboethoxy ester 2.2. Subjection
of 2.2 to catalytic reduction gives 2.3. Hydrolysis of 2.3 affords
the acid 2.4. Treatment of 2.4 with thionyl chloride followed by
the lithium salt of 2.10 gives a mixture of 2.5 and 2.6, which are
separated by chromatography. Treatment of 2.5 with lithium peroxide
in a THF/H.sub.2O mixture gives the acid 2.7. Coupling the acid
with 2.10 gives the phenol-protected analog 2.9. Subjection of 2.9
to boron tribromide in methylene chloride at -78.degree. C. gives
the desired 14 (Q=CH.sub.2). Compound 15 (Q=CH.sub.2) is prepared
by a similar route starting with 2.6.
[0088] The compounds 14 and 15 (Q=S) of the present invention may
be synthesized, for example, in accordance with the reaction
sequence shown in FIG. 3. Nucleophilic displacement of benzyl
chloride 3.1 with ethyl mercaptoacetate 3.2 affords sulfide 3.3.
Hydrolysis of the ester with KOH in MeOH provides the acid 3.4.
Cyclodehydration of the acid 3.4 using phosphorous pentoxide gives
isothiochromanone 3.5. Condensation of the isothiochromanone 3.5
with methyl cyanoformate gives the keto carbomethoxy ester 3.6.
Reduction of the ketone to give 3.7 is accomplished using
triethylsilane in TFA. Hydrolysis of the ester with KOH provides
the acid 3.8. Treatment of 3.8 with oxalyl chloride followed by the
lithium salt of 3.9 gives a mixture of 3.10 and 3.11 which are
separated by chromatography. Hydrolysis of 3.10 with lithium
hydroxide gives the acid 3.12. Coupling of the acid 3.12 with the
amino compound 3.13 gives the phenol protected analog 3.14.
Subjection of 3.14 to boron tribromide in methylene chloride at
-78.degree. C. gives the desired 14 (Q=S). Compound 15 (Q=S) is
prepared by a similar route starting with 3.11.
[0089] The compounds 14 and 15 (Q=O) of the present invention may
be synthesized, for example in accordance with the reaction
sequence shown in FIG. 4. Alkylation of benzyl alcohol 4.1 with
bromoacetic acid 4.2 in THF provides the ether 4.3. Acid halide
formation of 4.3 followed by intramolecular acylation using
SnCl.sub.4 at 0.degree. C. gives the isochromanone 4.4.
Deprotection to give the phenol 4.5 is accomplished using sodium
ethanethiolate in DMF at reflux. Reprotection of phenol 4.5 with
pivaloyl chloride and TEA in THF followed by condensation of the
resulting isochromanone with methyl cyanoformate gives the keto
carbomethoxy ester 4.6. Reduction of the ketone to give 4.7 is
accomplished using triethylsilane in TFA. Selective hydrolysis of
the methyl ester provides the acid 4.8. Treatment of 4.8 with
oxalyl chloride followed by the lithium salt of 4.9 gives a mixture
of 4.10 and 4.11 which are separated by chromatography. Hydrolysis
of 4.10 with lithium hydroxide gives the acid 4.12. Coupling of the
acid 4.12 with the amino compound 4.13 gives the phenol protected
analog 4.14. Cleavage of the pivaloyl protecting group is
accomplished with 3M HCl in dioxane to give 14 (Q=O). Compound 15
(Q=O) is prepared by a similar route starting with 4.11.
[0090] The compounds of the present invention may be in the form of
a pharmaceutically acceptable salt via protonation of the amines
with a suitable acid. The acid may be an inorganic acid or an
organic acid. Suitable acids include, for example, hydrochloric,
hydroiodic, hydrobromic, sulfuric, phosphoric, citric, acetic,
fumaric, tartaric, and formic acids.
[0091] The receptor selectivities discussed above are determined
based on the binding affinities at the receptors indicated or their
selectivity in opioid functional assays.
[0092] The compounds of the present invention may be used to bind
opioid receptors. Such binding may be accomplished by contacting
the receptor with an effective amount of the inventive compound. Of
course, such contacting is preferably conducted in an aqueous
medium, preferably at physiologically relevant ionic strength, pH,
etc.
[0093] The inventive compounds may also be used to treat patients
having disease states which are ameliorated by binding opioid
receptors or in any treatment wherein temporary suppression of the
kappa opioid receptor system is desired. Such diseases states
include opiate addiction (such as heroin addiction), cocaine,
nicotine, or ethanol addiction. The compounds of the present
invention may also be used as cytostatic agents, as antimigraine
agents, as immunomodulators, as immunosuppressives, as
antiarthritic agents, as antiallergic agents, as virucides, to
treat diarrhea, as antipsychotics, as antischizophrenics, as
antidepressants, as uropathic agents, as antitussives, as
antiaddictive agents, as anti-smoking agents, to treat alcoholism,
as hypotensive agents, to treat and/or prevent paralysis resulting
from traumatic ischemia, general neuroprotection against ischemic
trauma, as adjuncts to nerve growth factor treatment of
hyperalgesia and nerve grafts, as anti-diuretics, as stimulants, as
anti-convulsants, or to treat obesity. Additionally, the present
compounds can be used in the treatment of Parkinson's disease as an
adjunct to L-dopa for treatment of dyskinesia associated with the
L-dopa treatment.
[0094] The compounds may be administered in an effective amount by
any of the conventional techniques well-established in the medical
field. For example, the compounds may be administered orally,
intraveneously, or intramuscularly. When so administered, the
inventive compounds may be combined with any of the well-known
pharmaceutical carriers and additives that are customarily used in
such pharmaceutical compositions. For a discussion of dosing forms,
carriers, additives, pharmacodynamics, etc., see Kirk-Othmer
Encyclopedia of Chemical Technology, Fourth Edition, Vol. 18, 1996,
pp. 480-590, incorporated herein by reference. The patient is
preferably a mammal, with human patients especially preferred.
Effective amounts are readily determined by those of ordinary skill
in the art. Studies by the present inventors show no toxicity and
no lethality for the present compounds at amounts up to 300 mg/kg
in mice.
[0095] The compounds of the present invention can be administered
as a single dosage per day, or as multiple dosages per day. When
administered as multiple dosages, the dosages can be equal doses or
doses of varying amount, based upon the time between the doses
(i.e. when there will be a longer time between doses, such as
overnight while sleeping, the dose administered will be higher to
allow the compound to be present in the bloodstream of the patient
for the longer period of time at effective levels). Preferably, the
compound and compositions containing the compound are administered
as a single dose or from 2-4 equal doses per day.
[0096] Suitable compositions containing the present compounds
further comprise a physiologically acceptable carrier, such as
water or conventional pharmaceutical solid carriers, and if
desired, one or more buffers and other excipients.
EXAMPLES
[0097] Having generally described this invention, a further
understanding can be obtained by reference to certain specific
examples which are provided herein for purposes of illustration
only and are not intended to be limiting unless otherwise
specified.
Chemistry
Synthesis of 14 and 15 (Q=CH.sub.2)
[0098] 6-Methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic
acid ethyl ester. NaH (3.4 g, 60% in mineral oil, 83.3 mmol) was
washed with hexanes (3.times.70 mL) and THF (1.times.30 mL) in an
oven dried 3 neck round-bottomed flask. Diethyl carbonate (5.5 mL,
45.4 mmol) was added to the NaH/THF suspension in anhydrous THF (20
mL) and the slurry was heated at reflux under N.sub.2.
6-Methoxy-1-tetralone (4 g, 22.7 mmol) in THF (40 mL) was added
dropwise via an addition funnel to the suspension at reflux. The
reaction mixture was then heated at reflux for 2 days. The solution
was cooled to room temperature and glacial AcOH (3.6 mL) was added
in a dropwise manner. Et.sub.2O (150 mL) was then added and the
organic layer was washed with saturated NaCl solution (5.times.25
mL), dried (MgSO.sub.4), and concentrated under reduced pressure to
provide a crude brown oil (6.0 g). The oil was subjected to medium
pressure chromatography on silica (CHCl.sub.3) to provide a dark
oil which solidified upon standing (5.17 g, 91.8% yield). The solid
was recrystallized from EtOAc/hexane to provide a white solid. mp
58-60.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.
1.27-1.36 (t, 3H), 2.20-3.56 (m, 5H), 3.85 (s, 3H), 4.23-4.28 (m,
2H), 6.70 (s, 1H), 6.77-6.85 (d, 1H), 7.72-8.03 (d, 1H).
[0099] 6-Methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid
ethyl ester. 10% Pd/C (195 mg) was added to a suspension of
6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
ethyl ester (1.07 g, 4.32 mmol) and FeCl.sub.3, (5 mg) in EtOH (30
mL) under N.sub.2. The suspension was hydrogenated at 40 psi for 3
days. The suspension was filtered through a Celite pad and the
filtrate was concentrated to a leave crude oil. The oil was
purified using medium pressure chromatography on silica
(CHCl.sub.3) to provide a colorless oil (886 mg, 88.3% yield).
.sup.1H-NMR (300 MHz, CDCl.sub.3) .delta. 1.28 (t, J=7.2 Hz, 3H).
1.84 (m, 1H), 2.19 (m, 1H), 2.70 (m, 1H), 2.83 (m, 2H), 2.93 (m,
2H), 3.77 (s, 3H), 4.17 (q, J=7.2 Hz, 2H), 6.62 (s, 1H), 6.69 (dd,
J=8.4, 2.4 Hz, 1H), 7.01 (d, J=8.4 Hz, 1H).
[0100] 6-Methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid.
6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid ethyl
ester (868 mg, 3.74 mmol) oil was dissolved in 10 mL of 10%
methanolic NaOH and heated at reflux for 18 hours. The hydrolyzed
product was filtered upon cooling to provide the sodium carboxylate
salt (445 mg, 1.97 mmol). The filtrate was acidified with 1N HCl,
extracted with CHCl.sub.3 (3.times.100 mL), dried
(Na.sub.2SO.sub.4), and concentrated under reduced pressure to
provide 6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid
as a white flaky solid (361 mg, 99%). The solid was recrystallized
from EtOAc/hexane to provide fine white cubes. mp 151-152.degree.
C. .sup.1H-NMR (300 MHz CDCl.sub.3) .delta. 1.89 (m, 1H), 2.22 (m,
1H), 2.75-2.89 (m, 3H), 2.95-2.99 (m, 2H), 3.78 (s, 3H), 6.63 (s,
1H), 6.72 (dd, J=8.4, 2.7 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H).
[0101] 6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carbonyl chloride.
A 2.0 M solution of thionyl chloride (7.25 mL, 14.3 mmol) in
CH.sub.2Cl.sub.2 was added to a solution of
6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (0.29 g,
1.43 mmol) in toluene (20 mL). The solution was heated at reflux
for 8 hours, cooled to room temperature and concentrated under
reduced pressure to provide a tan solid. The acid halide was used
in the next step without further purification.
[0102] (3aR-cis)-3-(6-Methoxy-1,2,3,4-tetrahydronaphthalene-2(+ and
-)-carbonyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one. A
0.50 M solution of ethyl lithium (3.0 mL, 1.50 mL) in
benzene/cyclohexane 90:10 was added to a solution of
(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (0.25
g, 1.43 mmol) in THF (20 mL) at 0.degree. C. under N.sub.2. The
suspension was allowed to stir at 0.degree. C. for 0.5 hours and
was then cooled to -78.degree. C. A solution of
6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carbonyl chloride (0.29
g, 1.43 mmol) in THF (10 mL) was then added in a dropwise manner to
the -78.degree. C. slurry. The resulting slurry was allowed to warm
to room temperature over 2 hours and water (100 mL) was then added.
The suspension was extracted with CH.sub.2Cl.sub.2 (3.times.100
mL). The organic extracts were combined, dried (MgSO.sub.4), and
concentrated under reduced pressure to provide a tan solid. The
solid was purified on silica with medium pressure column
chromatography (70:30 petroleum ether/Et.sub.20) to provide each of
the diastereomers in approximately 50% theoretical yield. The yield
improves with additional chromatography. The less polar spot was
later identified as the (+) isomer while the more polar was
(-).
[0103] Analysis for:
(3a(R)-cis)-3-(6-Methoxy-1,2,3,4-tetrahydronaphthalene-2(+)-carbonyl)-3,3-
a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one. The solid was
recrystallized from ethyl acetate/petroleum ether to provide a
white solid (0.12 g, 46%). mp. 168-169.degree. C. .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 1.80-1.85 (m, 1H), 2.10-2.21 (m, 1H),
2.71-3.13 (m, 4H), 3.38 (d, J=3.3 Hz, 2H), 3.76 (s, 3H), 3.84 (m,
1H), 5.27 (m, 1H), 5.96-5.99 (d, J=9 Hz, 1H), 6.62 (s, 1H),
6.70-6.71 (dd, J=2.4, 8.1 Hz, 1H), 6.99-7.04 (dd, J=3.6, 8.4 Hz,
1H), 7.24-7.32 (m, 3H), 7.57-7.60 (d, J=7.5 Hz, 1H).
[0104] Analysis for:
(3aR-cis)-3-(6-Methoxy-1,2,3,4-tetrahydronaphthalene-2(-)-carbonyl)-3,3a,-
8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one. The solid was
recrystallized from ethyl acetate/petroleum ether to provide a
white solid (0.13 g, 50%). mp. 162-164.degree. C. .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 1.85-1.98 (m, 1H), 2.12-2.18 (m, 1H),
2.84-2.95 (m, 4H), 3.40-3.41 (d, J=3.3 Hz, 2H), 3.77 (s, 3H),
3.85-3.95 (m, 1H), 5.28-5.33 (m, 1H), 5.97-5.99 (d, J=6.9 Hz, 1H),
6.57-6.69 (m, 2H), 6.95-6.98 (d, J=8.4 Hz, 1H), 7.26-7.42 (m, 3H),
7.60-7.62 (d, J=7.5 Hz, 1H).
[0105] 2(+)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic
acid. A 30% solution of hydrogen peroxide (6.96 mmol, 0.24 mL) in
H.sub.2O was added at 0.degree. C. to a solution of
(3aR-cis)-3-(6-methoxy-1,2,3,4-tetrahydronaphthalene-2(+)-carbonyl)-3,3a,-
8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (0.42 g, 1.16 mmol) in
3:1 THF/H.sub.2O (25 mL). Lithium hydroxide hydrate (0.098 g, 2.32
mmol) was then added to the solution in portions. The suspension
was allowed to stir for 0.5 hours at 0.degree. C. and then for 2
hours at room temperature. A 1.5 N solution of Na.sub.2SO.sub.3 (15
mL) was added in a dropwise manner and the biphasic solution was
basified (pH.apprxeq.10) with saturated sodium bicarbonate
solution. The solution was extracted (2.times.50 mL) with EtOAc,
made acidic to pH 3 with HCl (10 M solution) and extracted
(3.times.100 mL) with CH.sub.2Cl.sub.2. The organic extracts were
combined, dried (MgSO.sub.4), and concentrated under reduced
pressure to provide a white solid. The solid was recrystallized
from EtOAc/petroleum ether to provide
2(+)-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid as
white needles (0.219 g, 92%). mp. 129-130.degree. C.
[a].sup.22.sub.D+57.27.degree. (c 0.22, CHCl.sub.3) .sup.1H-NMR
(300 MHz, CDCl.sub.3) .delta. 1.87-1.90 (m, 1H), 2.20-2.25 (m, 1H),
2.74-2.98 (m, 5H), 3.77 (s, 3H), 6.63 (s, 1H), 6.68-6.72 (dd,
J=2.7, 8.4 Hz, 1H), 7.0-7.03 (d, J=8.4 Hz, 1H).
[0106] 2(-)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic
acid. A 30% solution of hydrogen peroxide (3.3 mmol, 0.11 mL) in
H.sub.2O was added at 0.degree. C. to a solution of
(3aR-cis)-3-(6-methoxy-1,2,3,4-tetrahydronaphthalene-2(-)-carbonyl)-3,3a,-
8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (0.20 g, 0.55 mmol) in
3:1 THF/H.sub.2O (15 mL). Lithium hydroxide hydrate (0.046 g, 1.10
mmol) was then added to the solution in portions. The suspension
was allowed to stir for 0.5 hours at 0.degree. C. and then for 2
hours at room temperature. A 1.5 N solution of Na.sub.2SO.sub.3 (10
mL) was added in a dropwise manner and the biphasic solution was
basified (pH.apprxeq.10) with saturated sodium bicarbonate
solution. The solution was extracted (2.times.50 mL) with EtOAc,
made acidic to pH 3 with HCl (10 M solution) and extracted
(3.times.100 mL) with CH.sub.2Cl.sub.2. The organic extracts were
combined, dried (MgSO.sub.4), and concentrated under reduced
pressure to provide a white solid. The solid was recrystallized
from EtOAc/petroleum ether to provide
2(-)-6-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid as
white needles (0.102 g, 90%). mp. 121-122.degree. C.
[a].sup.22.sub.D-56.9.degree. (c 0.25, CHCl.sub.3) .sup.1H-NMR (300
MHz, CDCl.sub.3) .delta. 1.87-1.90 (m, 1H), 2.20-2.25 (m, 1H),
2.74-2.98 (m, 5H), 3.77 (s, 3H), 6.63 (s, 1H), 6.68-6.72 (dd,
J=2.7, 8.4 Hz, 1H), 7.0-7.03 (d, J=8.4 Hz, 1H).
[0107] 6-Methoxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide.
2(+)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
(0.22 g, 1.07 mmol) was added under N.sub.2 to a solution of BOP
(0.47 g, 1.07 mmol), TEA (0.23 g, 2.35 mmol) and
N-[(2'S)-Amino-3'-methylbutyl]-(3R,4R)-trans-dimethyl-4-(3-hydroxyphenyl)-
piperidine (0.31 g, 1.07 mmol) in anhydrous THF (50 mL). The
solution was allowed to stir at room temperature for 6 h and sat.
NaHCO.sub.3 solution (100 mL) was added. The biphasic mixture was
extracted with EtOAc (3.times.100 mL). The organic extracts were
combined, dried (MgSO.sub.4), and concentrated under reduced
pressure to provide an oil. The oil was purified using medium
pressure column chromatography on silica
(CHCl.sub.3/MeOH/NH.sub.4OH, 9/0.8/0.2) to provide
6-methoxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic acid
{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(2S)--
methylpropyl}-amide as a colorless oil (0.39 g, 77%). .sup.1H NMR
(300 MHz, CDCl.sub.3) .delta. ppm 0.72 (d, J=6.78 Hz, 3H),
0.82-0.96 (m, 6H), 1.26 (s, 3H), 1.55 (d, J=12.43 Hz, 1H),
1.78-2.07 (m, 4H), 2.18-2.88 (m, 12H), 3.73 (s, 3H), 4.00-4.16 (m,
1H), 6.05 (d, J=7.54 Hz, 1H), 6.57 (d, J=2.64 Hz, 1H), 6.62-6.77
(m, 3H), 6.84 (m, 1H), 6.93 (d, J=8.67 Hz, 1H), 7.11 (t, J=7.91 Hz,
1H).
[0108] 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide Hydrochloride. A 1.0 M solution of
BBr.sub.3 (8.2 mL. 8.2 mmol) in CH.sub.2Cl.sub.2 was added at
-78.degree. C. under N.sub.2 to
6-methoxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide (0.39 g, 0.82 mmol) in CH.sub.2Cl.sub.2 (25
mL). The dark brown solution was allowed to stir at -78.degree. C.
for 0.5 h and allowed to warm to room temperature. A saturated
solution of NaHCO.sub.3 (50 mL) was cautiously added and the
biphasic mixture was extracted with EtOAC (3.times.100 mL). The
organic extracts were combined, dried (MgSO.sub.4) and concentrated
under reduced pressure to provide a brown oil. The oil was purified
using medium pressure column chromatography on silica
(CHCl.sub.3/MeOH/NH.sub.4OH, 8/1.8/0.2) to provide a colorless oil
(0.30 g, 77%). The hydrochloride salt was prepared by adding a 1.0
M soln of HCl in Et.sub.2O to
6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide in MeOH. The solution was concentrated
under reduced pressure and recrystallized from EtOH/Et.sub.2O to
provide 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide hydrochloride as white plates. mp
189-191.degree. C. .sup.1H NMR Free Base (300 MHz, CD.sub.3OD)
.delta. ppm 0.74 (d, J=6.78 Hz, 3H), 0.90 (d, J=6.78 Hz, 3H), 0.93
(d, J=6.78 Hz, 3H), 1.27 (s, 3H), 1.55 (d, J=12.81 Hz, 1H),
1.68-1.89 (m, 2H), 1.95 (m, 2H), 2.36-2.81 (m, 12H), 4.02 (ddd,
J=9.61, 5.09, 4.90 Hz, 1H), 6.50 (d, J=2.26 Hz, 1H), 6.57 (ddd,
J=15.26, 8.10, 2.26 Hz, 2H), 6.70-6.80 (m, 2 H), 6.85 (d, J=8.29
Hz, 1H), 7.10 (t, J=8.10 Hz, 1H), 7.81 (br. s., 1H). Elemental Anal
for C.sub.29H.sub.41N.sub.2ClO.sub.3.0.75 H.sub.2O Calcd. C, 67.68;
H, 8.32; N, 5.44. Found. C, 67.55; H, 8.38, N: 5.31.
[0109] 6-Methoxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl](2-
S)-methylpropyl}-amide.
2(-)-6-Methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid
(0.31 g, 1.48 mmol) was added under N.sub.2 to a solution of BOP
(0.65 g, 1.48 mmol), TEA (0.33 g, 3.26 mmol) and
N-[(2'S)-Amino-3'-methylbutyl]-(3R,4R)-trans-dimethyl-4-(3-hydroxyphenyl)-
piperidine (0.43 g, 1.48 mmol) in anhydrous THF (65 mL). The
solution was allowed to stir at room temperature for 6 h and sat.
NaHCO.sub.3 solution (100 mL) was added. The biphasic mixture was
extracted with EtOAc (3.times.100 mL). The organic extracts were
combined, dried (MgSO.sub.4), and concentrated under reduced
pressure to provide an oil. The oil was purified using medium
pressure column chromatography on silica
(CHCl.sub.3/MeOH/NH.sub.4OH, 9/0.8/0.2) to provide
6-methoxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide as a colorless oil (0.70 g, 98%).1H NMR
(300 MHz, CDCl.sub.3) .delta. ppm 0.66-0.78 (d, J=6.9 Hz, 3H),
0.83-0.97 (m, 6H), 1.25 (s, 3H), 1.53 (d, J=12.43 Hz, 1H),
1.78-2.10 (m, 4H), 2.20-2.97 (m, 12H), 3.73 (s, 3H), 4.03 (m, 1H),
6.03 (d, J=7.54 Hz, 1H), 6.57 (d, J=2.26 Hz, 1H), 6.61-6.75 (m,
3H), 6.82 (m, 1H), 6.90 (d, J=8.29 Hz, 1H), 7.10 (t, J=7.72 Hz,
1H).
[0110] 6-Hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide Hydrochloride. A 1.0 M solution of
BBr.sub.3 (8.2 mL. 8.2 mmol) in CH.sub.2Cl.sub.2 was added at
-78.degree. C. under N.sub.2 to
6-methoxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide (0.70 g, 1.45 mmol) in CH.sub.2Cl.sub.2 (50
mL). The dark brown solution was allowed to stir at -78.degree. C.
for 0.5 h and allowed to warm to room temperature. A saturated
solution of NaHCO.sub.3 (100 mL) was cautiously added and the
biphasic mixture was extracted with EtOAC (3.times.150 mL). The
organic extracts were combined, dried (MgSO.sub.4) and concentrated
under reduced pressure to provide a brown oil. The oil was purified
using medium pressure column chromatography on silica
(CHCl.sub.3/MeOH/NH.sub.4OH, 8/1.8/0.2) to provide a colorless oil
(0.57 g, 83%). The hydrochloride salt was prepared by adding a 1.0
M soln of HCl in Et.sub.2O to
6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide in MeOH. The solution was concentrated
under reduced pressure and recrystallized from EtOH/Et.sub.2O to
provide 6-hydroxy-1,2,3,4-tetrahydro-naphthalene-2(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide hydrochloride as tan cubes. mp
193-195.degree. C. .sup.1H NMR (500 MHz, CD.sub.3OD) .delta. ppm
0.76 (d, J=7.32 Hz, 3H), 0.91 (d, J=6.84 Hz, 3H), 0.95 (d,
J=6.84 Hz, 3H), 1.27-1.30 (s, 3H), 1.57 (d, J=11.23 Hz, 1H),
1.75-1.86 (m, 2H), 1.95-2.03 (m, 2H), 2.29 (td, J=12.57, 4.15 Hz,
1H), 2.34-2.41 (m, 1H), 2.42-2.87 (m, 10H), 4.02 (dt, J=9.77, 4.88
Hz, 1H), 6.49 (m, 1H), 6.52 (dd, J=8.30, 2.44 Hz, 1H), 6.58 (dd,
J=7.81, 1.95 Hz, 1H), 6.74 (m, 1H), 6.77 (d, J=7.81 Hz, 1H), 6.82
(d, J=8.30 Hz, 1H), 7.10 (t, J=8.06 Hz, 1H). Elemental Anal for
C.sub.29H.sub.41N.sub.2ClO.sub.3.1.5 H.sub.2O Calcd. C, 65.95; H,
8.40, N, 5.30. Found. C, 65.71; H, 8.11; N, 5.21.
Synthesis of 14 and 15 (Q=S)
[0111] 7-Methoxy-isothiochroman-4-one-3-carboxylic acid methyl
ester. A 2.0 M solution of LDA in heptane/THF/ethylbenzene (1.61
mL, 3.21 mmol) was added in a dropwise manner to a solution of
7-methoxy-isothiochroman-4-one (0.50 g, 2.57 mmol) in THF (50 mL)
at -78.degree. C. under N.sub.2. After 30 min at -78.degree. C.
HMPA (0.46 g, 2.57 mmol) and methyl cyanoformate (0.27 g, 3.21
mmol) were added and the yellow solution was allowed to stir at
-78.degree. C. for 30 min. The solution was then allowed to warm to
room temperature and a saturated solution of NH.sub.4Cl (100 mL)
was added. The slurry was extracted with EtOAc (3.times.75 mL) and
the organic extracts were combined, dried (MgSO.sub.4) and
concentrated under reduced pressure to provide a bright yellow oil.
The oil was purified on silica using medium pressure chromatography
(9:1 petroleum ether/EtOAc) to provide
7-methoxy-isothiochroman-4-one-3-carboxylic acid methyl ester as a
bright yellow oil (0.51 g, 78%). .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. 3.73 (s, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 6.67 (d, J=3Hz,
1H), 6.45 (dd, J=3, 8.7 Hz, 1H), 7.80 (d, J=8.7 Hz, 1H), 12.52 (s,
1H).
[0112] 7-Methoxy-isothiochroman-3-carboxylic acid methyl ester.
Triethylsilane (8.08 mmol, 0.94 g) was added to a solution of
7-methoxy-isothiochroman-4-one-3-carboxylic acid methyl ester (0.51
g, 2.02 mmol) in trifluoroacetic acid (15 mL) at room temperature
under N.sub.2. The reaction was allowed to stir at room temperature
for 2 h and was concentrated under reduced pressure. The resulting
oil was dissolved in EtOAc (100 mL) and washed with sat.
NaHCO.sub.3 (3.times.75 mL). The organic extracts were combined,
dried (MgSO.sub.4) and concentrated to provide an oil. The oil was
purified on silica using medium pressure chromatography (9:1
petroleum ether/EtOAc) to provide
7-methoxy-isothiochroman-3-carboxylic acid methyl ester (0.34 g,
70%) as a pale yellow oil. .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. 3.14 (m, 2H), 3.58-3.63 (d, J=15 Hz, 1H), 3.73-3.86 (m,
8H), 6.70 (d, J=3Hz, 1H), 6.75 (dd, J=3, 9 Hz, 1H), 7.10 (d, J=9
Hz, 1H).
[0113] 7-Methoxy-isothiochroman-3-carboxylic acid. Potassium
hydroxide (0.80 g, 14.3 mmol) was added to a solution of
7-methoxy-isothiochroman-3-carboxylic acid methyl ester (0.34 g,
1.43 mmol) in MeOH (50 mL). The solution was heated at 60.degree.
C. for 2 h, cooled to room temperature, and diluted with H.sub.2O
(100 mL). The solution was made acidic with 6 M HCl and extracted
with EtOAc (3.times.100 mL). The organic extracts were combined,
dried (MgSO.sub.4) and concentrated to give
7-methoxy-isothiochroman-3-carboxylic acid (0.28 g, 88%) as a pale
yellow solid. The solid was used in the next step without further
purification.
[0114] 7-Methoxy-isothiochroman-3-carbonyl chloride. A 2.0 M
solution of oxalyl chloride (3.57 mL, 7.14 mmol) in
CH.sub.2Cl.sub.2 was added under N.sub.2 to a solution of
7-methoxy-isothiochroman-3-carboxylic acid (0.80 g, 3.57 mmol) and
a drop of DMF in CH.sub.2Cl.sub.2 (100 mL). The solution was
allowed to stir at room temperature for 3 h and was concentrated
under reduced pressure to provide
7-methoxy-isothiochroman-3-carbonyl chloride as a tan oil. The acid
halide was used in the next step without further purification.
[0115] (3aR-cis)-3-(7-Methoxy-isothiochroman-3(+ and
-)-carbonyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one. A
0.50 M solution of ethyl lithium (8.6 mL, 4.28 mmol) in
benzene/cyclohexane 90:10 was added to a solution of
(3aR-cis)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d]oxazol-2-one (0.75
g, 4.28 mmol) in THF (100 mL) at 0.degree. C. under N.sub.2. The
suspension was allowed to stir at 0.degree. C. for 0.5 h and was
then cooled to -78.degree. C. A solution of
7-methoxy-isothiochroman-3-carbonyl chloride (0.86 g, 3.57 mmol) in
THF (10 mL) was then added in a dropwise manner to the -78.degree.
C. slurry. The resulting slurry was allowed to warm to room
temperature over 2 hours and water (150 mL) was then added. The
suspension was extracted with CH.sub.2Cl.sub.2 (3.times.150 mL).
The organic extracts were combined, dried (MgSO.sub.4), and
concentrated under reduced pressure to provide a tan solid. The
solid was purified on silica using medium pressure column
chromatography (60:40 petroleum ether/Et.sub.20) to provide each of
the diastereomers in 62% (+ isomer) and 37% (- isomer) theoretical
yield. The yield improves with additional chromatography. The less
polar spot was later identified as the (+) isomer while the more
polar was (-).
[0116] Analysis for:
(3a(R)-cis)-3-(7-Methoxy-isothiochroman-3(+)-carbonyl)-3,3a,8,8a-tetrahyd-
ro-2H-indeno[1,2-d]oxazol-2-one. The solid was recrystallized from
EtOAc/petroleum ether to provide a white solid (0.42 g, 62%). mp.
146-147.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3) .delta.
3.09-3.16 (dd, J=6, 15.6 Hz, 1H), 3.20-3.28 (dd, J=7.2, 15.3 Hz,
1H), 3.38-3.39 (d, J=3.6 Hz, 2H), 3.59-3.64 (d, J=15 Hz, 1H), 3.79
(s, 3H), 3.85-3.90 (d, J=15 Hz, 1H), 4.97-5.01 (m, 1H), 5.30-5.35
(m, 1H), 5.92-5.95 (d, J=7 Hz, 1H), 6.71-6.72 (d, J=2.7 Hz, 1H),
6.75-6.79 (dd, J=2.4, 8.4 Hz, 1H), 7.06-7.09 (d, J=8.4 Hz, 1H),
7.23-7.38 (m, 3H), 7.58-7.61 (d, J=7.5 Hz, 1H).
[0117] Analysis for:
(3aR-cis)-3-(7-Methoxy-isothiochroman-3(-)-carbonyl)-3,3a,8,8a-tetrahydro-
-2H-indeno[1,2-d]oxazol-2-one. The solid was recrystallized from
ethyl acetate/petroleum ether to provide a white solid (0.25 g,
37%). mp. 176-178.degree. C. .sup.1H-NMR (300 MHz, CDCl.sub.3)
.delta. 3.14-3.19 (dd, J=6, 12.6 Hz, 1H), 3.24-3.29 (dd, J=7.5,
15.3 Hz, 1H), 3.39-3.40 (d, J=3.6 Hz, 2H), 3.48-3.55 (d, J=15 Hz,
1H), 3.79 (s, 3H), 3.83-3.88 (d, J=15 Hz, 1H), 4.91-4.95 (m, 1H),
5.29-5.33 (m, 1H), 5.96-5.99 (d, J=7 Hz, 1H), 6.71-6.72 (d, J=2.7
Hz, 1H), 6.76-6.80 (dd, J=2.4, 8.4 Hz, 1H), 7.10-7.12 (d, J=8.4 Hz,
1H), 7.26-7.38 (m, 3H), 7.58-7.61 (d, J=7.5 Hz, 1H).
[0118] 3(+)-7-Methoxy-isothiochroman-3-carboxylic acid. Lithium
hydroxide hydrate (0.093 g, 2.2 mmol) was added at 0.degree. C. to
a solution of
(3aR-cis)-3-(7-methoxy-isothiochroman-3(+)-carbonyl)-3,3a,8,8a-tetrahydro-
-2H-indeno[1,2-d]oxazol-2-one (0.42 g, 1.10 mmol) in 3:1
THF/H.sub.2O (25 mL). The suspension was allowed to stir for 0.5
hours at 0.degree. C. The reaction was made basic (pH.apprxeq.10)
with saturated sodium bicarbonate solution and the solution was
extracted with Et.sub.2O (1.times.100 mL), made acidic to pH 3 with
HCl (6 M solution) and extracted with EtOAc (3.times.100 mL). The
organic extracts were combined, dried (MgSO.sub.4), and
concentrated under reduced pressure to provide a white solid (0.25
g, 100%). The solid was recrystallized from toluene/petroleum ether
to provide 3(+)-7-methoxy-isothiochroman-3-carboxylic acid as tan
cubes. mp. 117-118.degree. C. [.alpha.].sup.22.sub.D+98.3.degree.
(c 0.24, MeOH) .sup.1H-NMR (300 MHz, CD.sub.3OD) .delta. 2.97-3.01
(dd, J=9.3, 15 Hz, 1H), 3.10-3.17 (dd, J=5.1, 15.3, 1H), 3.63-3.88
(m, 6H), 6.75-6.77 (m, 2H), 7.08-7.11 (d, J=8.2 Hz, 1H).
[0119] 3(-)-7-Methoxy-isothiochroman-3-carboxylic acid. Lithium
hydroxide hydrate (0.055 g, 1.32 mmol) was added at 0.degree. C. to
a solution of
(3aR-cis)-3-(7-methoxy-isothiochroman-3(-)-carbonyl)-3,3a,8,8a-tetrahydro-
-2H-indeno[1,2-d]oxazol-2-one (0.25 g, 0.66 mmol) in 3:1
THF/H.sub.2O (15 mL). The suspension was allowed to stir for 0.5
hours at 0.degree. C. The reaction was made basic (pH.apprxeq.10)
with saturated sodium bicarbonate solution and the solution was
extracted with Et.sub.2O (1.times.100 mL), made acidic to pH 3 with
HCl (6 M solution) and extracted with EtOAc (3.times.100 mL). The
organic extracts were combined, dried (MgSO.sub.4), and
concentrated under reduced pressure to provide a white solid (0.136
g, 92%). The solid was recrystallized from toluene/petroleum ether
to provide 3(-)-7-methoxy-isothiochroman-3-carboxylic acid as pale
yellow needles. mp. 121-122.degree. C.
[.alpha.].sup.22.sub.D-100.8.degree. (c 0.26, MeOH) .sup.1H-NMR
(300 MHz, CD.sub.3OD) .delta. 2.97-3.01 (dd, J=9.3, 15 Hz, 1H),
3.10-3.17 (dd, J=5.1, 15.3, 1H), 3.63-3.88 (m, 6H), 6.75-6.77 (m,
2H), 7.08-7.11 (d, J=8.2 Hz, 1H).
[0120] 7-Methoxy-isothiochroman-3(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide. 3
(+)-7-Methoxy-isothiochroman-3-carboxylic acid (0.25 g, 1.12 mmol)
was added under N.sub.2 to a solution of BOP (0.50 g, 1.12 mmol),
TEA (0.23 g, 2.24 mmol) and
N-[(2'S)-Amino-3'-methylbutyl]-(3R,4R)-trans-dimethyl-4-(3-hydroxyphenyl)-
piperidine (0.33 g, 1.12 mmol) in anhydrous THF (50 mL). The
solution was allowed to stir at room temperature for 6 h and sat.
NaHCO.sub.3 solution (100 mL) was added. The biphasic mixture was
extracted with EtOAc (3.times.100 mL). The organic extracts were
combined, dried (MgSO.sub.4), and concentrated under reduced
pressure to provide an oil. The oil was purified using medium
pressure column chromatography on silica
(CHCl.sub.3/MeOH/NH.sub.4OH, 9/0.8/0.2) to provide
7-methoxy-isothiochroman-3(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide as a pale yellow semisolid (0.45 g, 81%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.49-0.55 (m, 6H),
0.67-0.69 (d, J=6Hz, 3H), 1.24 (s, 3H), 1.48-1.52 (d, J=12Hz, 1H),
1.62-1.70 (m, 1H), 1.86-1.88 (m, 1H), 2.14-2.52 (m, 6H), 2.61-2.71
(m, 2H), 2.89-2.95 (dd, J=5.1, 14.4 Hz, 1H), 3.31-3.38 (dd, J=5.4,
14.4 Hz, 1H), 3.57-3.62 (d, J=13.8 Hz, 1H), 3.65-3.69 (d, J=13.8
Hz, 1H), 3.74 (s, 3H), 3.84-3.87 (m, 1H), 6.70-6.72 (m, 3H),
6.84-6.89 (m, 2H), 7.03-7.12 (m, 2H).
[0121] 7-Hydroxy-isothiochroman-3(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide. A 1.0 M solution of BBr.sub.3 (9.1 mL. 9.1
mmol) in CH.sub.2Cl.sub.2 was added at -78.degree. C. under N.sub.2
to 7-methoxy-isothiochroman-3(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide (0.45 g, 0.91 mmol) in CH.sub.2Cl.sub.2
(100 mL). The dark brown solution was allowed to stir at
-78.degree. C. for 0.5 h and allowed to warm to 0.degree. C. for 2
h. A saturated solution of NaHCO.sub.3 (100 mL) was cautiously
added and the biphasic mixture was extracted with EtOAC
(3.times.150 mL). The organic extracts were combined, dried
(MgSO.sub.4) and concentrated under reduced pressure to provide a
brown oil. The oil was purified using medium pressure column
chromatography on silica (CHCl.sub.3/MeOH/NH.sub.4OH, 8/1.8/0.2) to
provide a tan semisolid (0.43 g, 98%). The solid was recrystallized
from acetone/petroleum ether to afford
7-hydroxy-isothiochroman-3(+)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide as white needles. mp 133-135.degree. C.
.sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 0.69-0.74 (m, 9H),
0.89-0.98 (m, 1H), 1.28 (s, 3H), 1.52-1.59 (d, J=12.9 Hz, 1H),
1.64-1.68 (m, 1H), 1.94-1.96 (m, 1H), 2.17-2.47 (m, 4H), 2.58-2.62
(d, J=11.3 Hz, 1H), 2.72-2.75 (d, J=11.3 Hz, 1H), 2.89-2.96 (dd,
J=5.3, 15 Hz, 1H), 3.11-3.18 (dd, J=7.54, 14.3 Hz, 1H), 3.62-3.77
(m, 3H), 3.83-3.90 (m, 1H), 6.54-6.65 (m, 3H), 6.71-6.76 (m, 2H),
6.91-6.94 (d, J=8.2 Hz, 1H), 7.06-7.11 (t, J=7.9 Hz, 1H).
[0122] 7-Methoxy-isothiochroman-3(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide. 3
(-)-7-Methoxy-isothiochroman-3-carboxylic acid (0.24 g, 1.07 mmol)
was added under N.sub.2 to a solution of BOP (0.47 g, 1.07 mmol),
TEA (0.21 g, 2.14 mmol) and
N-[(2'S)-amino-3'-methylbutyl]-(3R,4R)-trans-dimethyl-4-(3-hydroxyphenyl)-
piperidine (0.31 g, 1.07 mmol) in anhydrous THF (50 mL). The
solution was allowed to stir at room temperature for 6 h and sat.
NaHCO.sub.3 solution (100 mL) was added. The biphasic mixture was
extracted with EtOAc (3.times.100 mL). The organic extracts were
combined, dried (MgSO.sub.4), and concentrated under reduced
pressure to provide an oil. The oil was purified using medium
pressure column chromatography on silica
(CHCl.sub.3/MeOH/NH.sub.4OH, 9/0.8/0.2) to provide
7-methoxy-isothiochroman-3(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide as a pale yellow semisolid (0.44 g, 84%).
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 0.65-0.68 (d, J=6.9 Hz,
3H), 0.77-0.79 (d, J=4.2 Hz, 3H), 0.84-0.86 (d, J=6.6 Hz, 3H), 1.27
(s, 3H), 1.47-1.51 (d, J=12.3 Hz, 1H), 1.80-2.70 (m, 11H),
3.03-3.09 (dd, J=5.4, 14.7 Hz, 1H), 3.17-3.24 (dd, J=6.3, 14.4 Hz,
1H), 3.60-3.65 (d, J=14.1 Hz, 1H), 3.67-3.72 (d, J=14.1 Hz, 1H),
3.77 (s, 3H), 3.83-3.87 (m, 1H), 6.59-6.83 (m, 5H), 7.05-7.16 (m,
2H).
[0123] 7-Hydroxy-isothiochroman-3(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide Hydrochloride. A 1.0 M solution of
BBr.sub.3 (9.0 mL. 9.0 mmol) in CH.sub.2Cl.sub.2 was added at
-78.degree. C. under N.sub.2 to
7-methoxy-isothiochroman-3(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide (0.44 g, 0.90 mmol) in CH.sub.2Cl.sub.2
(100 mL). The dark brown solution was allowed to stir at
-78.degree. C. for 0.5 h and allowed to warm to 0.degree. C. for 2
h. A saturated solution of NaHCO.sub.3 (100 mL) was cautiously
added and the biphasic mixture was extracted with EtOAC
(3.times.150 mL). The organic extracts were combined, dried
(MgSO.sub.4) and concentrated under reduced pressure to provide a
brown oil. The oil was purified using medium pressure column
chromatography on silica (CHCl.sub.3/MeOH/NH.sub.4OH, 8/1.8/0.2) to
provide a tan semisolid (0.40 g, 93%). The hydrochloride salt was
prepared by adding a 1.0 M soln of HCl in Et.sub.2O to
7-hydroxy-isothiochroman-3(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide in MeOH. The solution was concentrated
under reduced pressure and recrystallized from EtOH/Et.sub.2O to
provide 7-hydroxy-isothiochroman-3(-)-carboxylic
acid{1-[4-(3-hydroxyphenyl)-(3R)-(4R)-trans-dimethyl-piperidinylmethyl]-(-
2S)-methylpropyl}-amide hydrochloride as white cubes. mp
224-227.degree. C., (191-194.degree. C. softens). .sup.1H NMR Free
Base (300 MHz, CD.sub.3OD) .delta. 0.71-0.74 (d, J=6.8 Hz, 3H),
0.83-0.85 (d, J=6.8 Hz, 3H), 0.88-0.90 (d, J=6.8 Hz, 3H), 1.06-1.13
(m, 1H), 1.26 (s, 3H), 1.50-1.54 (d, J=12.4 Hz, 1H), 1.79-1.94 (m,
2H), 2.15-2.39 (m, 4H), 2.48 (brs, 1H), 2.71-2.75 (d, J=11 Hz, 1H),
2.97-3.10 (m, 2H), 3.58-3.78 (m, 3H), 3.85-3.91 (m, 1H), 6.57-6.60
(d, J=7.9 Hz, 1H), 6.63 (m, 2H), 6.73 (m, 2H), 6.95-6.98 (d, J=8.2
Hz, 1H), 7.06-7.12 (t, J=7.9 Hz, 1H).
Biological
In Vitro
[0124] Measures of opioid receptor antagonism were obtained by
monitoring selected test compounds ability to inhibit stimulation
of [.sup.35S]GTP.gamma.S binding produced by the selective agonists
(D-Ala.sup.2,MePhe.sup.4,Gly-ol.sup.5)enkephalin (DAMGO, mu
receptor), cyclo[D-Pen.sup.2,D-Pen.sup.5]enkephalin (DPDPE, delta)
and
5,7,8-(-)--N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzene-
acetamide (U69,593, kappa) in cloned human receptors, Table 1.
TABLE-US-00001 TABLE 1 Inhibition of Agonist Stimulated
[.sup.35S]GTP.gamma.S Binding by Compounds in Cloned Human .mu.,
.delta., and .kappa. Opioid Receptors .mu., DAMGO .delta., DPDPE
.kappa., U69,593 RTI-5989- K.sub.e (nM) K.sub.e (nM) K.sub.e (nM)
.mu./.kappa. .delta./.kappa. 160 6.67 .+-. 1.20 44.8 .+-. 7.7 0.18
.+-. 0.03 37 248 161 11.2 .+-. 2.4 205 .+-. 59 1.37 .+-. 0.36 8.2
150
[0125] In Vivo
[0126] These in vivo experiments were used to determine the ability
of a putative kappa antagonist to inhibit kappa agonist-induced
increases in urine output. The experiments were designed to assess
both the acute and long-term affects of the test compound. During
the acute phase, the dose of test compound was immediately followed
by the administration of the kappa agonist, U50,488, and urine
output monitored every hour for five hours. To evaluate the
long-term effects of the test compound, the same rats were given
weekly challenge doses of agonist for three weeks and urine output
monitored.
[0127] Adult male Sprague-Dawley rats (Charles River Laboratory,
Raleigh, N.C.) were used for these studies. The test compound and
U50,488 doses were prepared fresh in distilled deionized water
(vehicle) and administered (1 mL/kg body weight) via subcutaneous
injection. Six groups of four rats were used to evaluate each test
compound: vehicle control (Group 1), agonist control (10 mg/kg,
Group 2), test compound at 3, 10 or 30 mg/kg followed by agonist
(10 mg/kg, Groups 3-5) and a test compound control (30 mg/kg, Group
6). Each rat was weighed prior to dosing. One rat from each group
was dosed in succession and the pattern repeated to distribute any
effects of time of day across all groups. After dosing, each rat
was placed into a metabolic chamber and urine output collected
hourly for five hours. Urine output for each collection period was
calculated as (urine+collection tube weight)-collection tube tare
weight. The effect of test compound on total urine output was
assessed using Analysis of Variance with repeated measures (subject
within Group) using factors of Group and Time and their
interaction, or one-way ANOVA, where appropriate. A univariate
ANOVA was run only if a significant effect was observed following
the multivariate ANOVA. Significance was assumed at p<0.05 for
the individual factors and p<0.1 for their interaction.
RESULTS AND DISCUSSION
[0128] Compounds RTI-5989-160 and RTI-5989-161 (which correspond to
compounds of Formulae 14 and 15, although the exact correspondence
has not yet been determined, Q=CH.sub.2) show high potency for the
kappa opioid receptor in the [.sup.35S]GTP.gamma.S in vitro
functional assay. Note that RTI-5989-160 with a K.sub.c value of
0.18 has subnanomolar potency, and since its K.sub.es at the .mu.
and .delta. opioid receptors are 6.67 and 44.8 nM, it is highly
selective for the kappa opioid receptor.
[0129] FIG. 5 shows the effect of compound 160 on
U50,488-stimulated urine output. The results represent the
mean.+-.SE of data collected from four rats per dose group. Panel A
shows urine output for the five one-hour collection periods on the
first day of dosing. Panel B shows the cumulative urine output for
the first three hours. The three-hour time point was chosen because
after that time, there was no longer any effect of U50, 488 to
inhibit. Bars marked with different letters are significantly
different from each other. On the first day of dosing, compound
RTI-5989-160 caused a dose dependent decrease in U50,488-stimulated
diuresis, with individual significance observed for the 10 and 30
mg/kg dose groups (FIG. 5). FIG. 6 shows the long-term effect of
compound 160 on U50,488 urine output. The results represent the
mean.+-.SE of data collected from four rats per dose group. Note
that urine output returns to control levels by one week after
dosing, but a transient and significant decrease in
agonist-stimulated urine output is observed in the 30 mg/kg dose
group two weeks after antagonist dosing. In keeping with earlier
work, the diuretic effect of U50,488 peaked two hours after
administration, and urine output fell to vehicle control levels by
four hours after dosing. Neither compound RTI-5989-160 nor
RTI-5989-161 affected urine output or caused any observable
toxicity at the top dose of 30 mg/kg (not shown).
CONCLUSIONS
[0130] The compounds of the present invention are potent kappa
opioid receptor antagonists in an in vitro functional test. They
show good selectivity relative to the mu and delta opioid
receptors. Compound RTI-5989-160's ability to antagonize diuresis
induced by the kappa agonist U50,488 in rats shows that these
compounds are also potent kappa opioid receptor antagonists in
vivo.
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[0156] Obviously, numerous modifications and variations of the
present invention are possible in light of the above teachings. It
is therefore to be understood that within the scope of the appended
claims, the invention may be practiced otherwise than as
specifically described herein.
* * * * *