U.S. patent application number 12/247263 was filed with the patent office on 2009-04-16 for tetrahydro-indazole cannabinoid modulators.
Invention is credited to Bharat Lagu, Fina Liotta, Meng Pan, Michael P. Wachter, Mingde Xia Xia.
Application Number | 20090099143 12/247263 |
Document ID | / |
Family ID | 34965110 |
Filed Date | 2009-04-16 |
United States Patent
Application |
20090099143 |
Kind Code |
A1 |
Lagu; Bharat ; et
al. |
April 16, 2009 |
TETRAHYDRO-INDAZOLE CANNABINOID MODULATORS
Abstract
This invention is directed to a tetrahydro-indazole cannabinoid
modulator compound of formula I: ##STR00001## and a method for use
in treating, ameliorating or preventing a cannabinoid receptor
mediated syndrome, disorder or disease.
Inventors: |
Lagu; Bharat; (Hillsborough,
NJ) ; Liotta; Fina; (Westfield, NJ) ; Pan;
Meng; (Neshanic Station, NJ) ; Wachter; Michael
P.; (Bloomsbury, NJ) ; Xia; Mingde Xia; (Belle
Mead, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
34965110 |
Appl. No.: |
12/247263 |
Filed: |
October 8, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11087943 |
Mar 23, 2005 |
7452997 |
|
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12247263 |
|
|
|
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60555890 |
Mar 24, 2004 |
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Current U.S.
Class: |
514/170 ;
514/217; 514/242; 514/322; 514/386; 514/406 |
Current CPC
Class: |
A61P 25/02 20180101;
A61P 25/30 20180101; A61P 37/00 20180101; C07D 401/12 20130101;
A61P 3/00 20180101; A61P 3/10 20180101; A61P 25/22 20180101; A61P
29/00 20180101; A61P 11/00 20180101; A61P 21/00 20180101; C07D
409/12 20130101; C07D 405/06 20130101; C07D 409/06 20130101; C07D
451/02 20130101; A61P 15/18 20180101; A61P 27/06 20180101; A61P
3/04 20180101; C07D 231/56 20130101; A61P 25/28 20180101; C07D
453/02 20130101; A61P 25/04 20180101; A61P 25/34 20180101; A61P
1/14 20180101; A61P 25/00 20180101; C07D 403/12 20130101; A61P
43/00 20180101 |
Class at
Publication: |
514/170 ;
514/406; 514/322; 514/217; 514/242; 514/386 |
International
Class: |
A61K 31/416 20060101
A61K031/416; A61K 31/454 20060101 A61K031/454; A61K 31/55 20060101
A61K031/55; A61K 31/56 20060101 A61K031/56; A61K 31/53 20060101
A61K031/53; A61K 31/4164 20060101 A61K031/4164 |
Claims
1-17. (canceled)
18. A method for treating, ameliorating or preventing a cannabinoid
receptor mediated syndrome, disorder or disease in a subject in
need thereof comprising the step of administering to the subject an
effective amount of a compound of claim 1.
19. The method of claim 18 wherein the cannabinoid receptor is a
CB1 or CB2 receptor; and, the compound of claim 1 is an agonist,
antagonist or inverse-agonist of the receptor.
20. The method of claim 18 wherein the syndrome, disorder or
disease is related to appetite, metabolism, diabetes,
glaucoma-associated intraocular pressure, social and mood
disorders, seizures, substance abuse, learning, cognition or
memory, organ contraction or muscle spasm, respiratory disorders,
locomotor activity or movement disorders, immune and inflammation
disorders, unregulated cell growth, pain management or
neuroprotection.
21. The method of claim 18 wherein the effective amount of the
compound of claim 1 is from about 0.001 mg/kg/day to about 300
mg/kg/day.
22. The method of claim 18 further comprising treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
appetite related, obesity related or metabolism related syndrome,
disorder or disease in a subject in need thereof comprising the
step of administering to the subject an effective amount of a CB1
inverse-agonist compound of claim 1.
23. The method of claim 22 wherein the effective amount of the
compound of claim 1 is from about 0.001 mg/kg/day to about 300
mg/kg/day.
24. The method of claim 18 further comprising the step of
administering to the subject a combination product and/or therapy
comprising an effective amount of a compound of claim 1 and a
therapeutic agent.
25. The method of claim 24 wherein the therapeutic agent is an
anticonvulsant or a contraceptive agent.
26. The method of claim 25 wherein the anticonvulsant is
topiramate, analogs of topiramate, carbamazepine, valproic acid,
lamotrigine, gabapentin, phenyloin and the like and mixtures or
pharmaceutically acceptable salts thereof.
27. The method of claim 25 wherein the contraceptive agent is a
progestin-only contraceptive, a contraceptive having a progestin
component and an estrogen component, or an oral contraceptive
optionally having a folic acid component.
28. A method of contraception in a subject comprising the step of
administering to the subject a composition, wherein the composition
comprises a contraceptive and a CB1 receptor inverse-agonist or
antagonist compound of claim 1, wherein the composition reduces the
urge to smoke in the subject and/or assists the subject in losing
weight.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This present application claims benefit of U.S. Provisional
Patent Application Ser. No. 60/555,890, filed Mar. 24, 2004, which
is incorporated herein by reference in its entirety and for all
purposes.
FIELD OF THE INVENTION
[0002] This invention is directed to tetrahydro-indazole
cannabinoid (CB) modulator compounds and a method for use in
treating, ameliorating or preventing a cannabinoid receptor
mediated syndrome, disorder or disease.
BACKGROUND OF THE INVENTION
[0003] Before the discovery of the cannabinoid CB1 and CB2
receptors, the term cannabinoid was used to describe the
biologically active components of cannabis sativa, the most
abundant of which are delta-9-tetrahydrocannabinol (THC) and
cannabidiol.
##STR00002##
[0004] THC is a moderately potent partial agonist of the CB1 and
CB2 receptors and is considered the "classical cannabinoid," a term
now used to refer to other analogues and derivatives that are
structurally related to the tricyclic dibenzopyran THC core. The
term "nonclassical cannabinoid" refers to cannabinoid agonists
structurally related to cannabidiol.
[0005] Pharmacological investigations have concentrated on
selective CB receptor modulators of the pyrazole structural class,
which include SR 141716A (the monohydrochloride salt of SR 141716)
and SR 144528. SR 141716A was the first potent and selective CB1
receptor antagonist.
##STR00003##
[0006] Pyrazole cannabinoid modulators are one among the many
different structural classes which have aided the development of CB
pharmacology, have helped to determine the biological effects
mediated by the cannabinoid receptors, will lead to further
refinement of current compounds and will be a source of new
chemical classes in the future.
[0007] Certain compounds (including SR 141716, SR 144528 and the
like) that were originally classified as selective antagonists are
now considered to act as "inverse agonists" rather than pure
antagonists. Inverse agonists have the ability to decrease the
constitutive level of receptor activation in the absence of an
agonist instead of only blocking the activation induced by agonist
binding at the receptor. The constitutive activity of CB receptors
has important implications since there is a level of continuous
signaling by both CB1 and CB2 even in the absence of an agonist.
For example, SR 141716A increases CB1 protein levels and sensitizes
cells toward agonist action, thus indicating that inverse agonists
may be another class of ligands used to modulate the
endocannabinoid system and the downstream signaling pathways
activated by CB receptors.
[0008] Advances in the synthesis of CB and cannabimimetic ligands
have furthered the development of receptor pharmacology and
provided evidence for the existence of additional cannabinoid
receptor sub-types. However, there remains an ongoing need for the
identification and development of CB1 or CB2 receptor cannabinoid
modulators for the treatment of a variety of CB receptor modulated
syndromes, disorders and diseases.
DETAILED DESCRIPTION OF THE INVENTION
[0009] This invention is directed to a compound of formula I:
##STR00004##
wherein [0010] the dashed lines between positions 2-3 and positions
3a-7a in formula I represent locations for two double bonds present
when X.sub.1R.sub.1 is present; [0011] the dashed lines between
positions 3-3a and positions 7a-1 in formula I represent locations
for two double bonds present when X.sub.2R.sub.2 is present; [0012]
the dashed line between positions 7 and X.sub.4R.sub.4 in formula I
represents the location for a double bond; [0013] X.sub.1 is
absent, or is lower alkylene; [0014] X.sub.2 is absent, or is lower
alkylene; [0015] wherein only one of X.sub.1R.sub.1 and
X.sub.2R.sub.2 are present; [0016] X.sub.3 is absent, or is lower
alkylene, lower alkylidene or --NH--; [0017] when the dashed line
between positions 7 and X.sub.4R.sub.4 is absent, X.sub.4 is
absent, or is lower alkylene; [0018] when the dashed line between
positions 7 and X.sub.4R.sub.4 is present, X.sub.4 is absent;
[0019] X.sub.5 is absent, or is lower alkylene; [0020] R.sub.1 is
selected from the group consisting of aryl, C.sub.3-C.sub.12
cycloalkyl, or heterocyclyl, any of which are optionally
substituted at one or more positions by halogen, lower alkyl,
hydroxy or lower alkoxy; [0021] R.sub.2 is selected from the group
consisting of aryl, C.sub.3-C.sub.12 cycloalkyl, or heterocyclyl,
any of which are optionally substituted at one or more positions by
halogen, lower alkyl, hydroxy or lower alkoxy; [0022] R.sub.3
is
[0022] ##STR00005## [0023] when the dashed line between positions 7
and X.sub.4R.sub.4 is absent, R.sub.4 is hydrogen; hydroxy; lower
alkyl; lower alkoxy; halogen; aryl optionally substituted at one or
more positions by hydroxy, lower alkyl, lower alkoxy or halogen;
heterocyclyl optionally substituted at one or more positions by
hydroxy, lower alkyl, lower alkoxy or halogen; or C.sub.3-C.sub.12
cycloalkyl optionally substituted at one or more positions by
hydroxy, lower alkyl, lower alkoxy or halogen; [0024] when the
dashed line between positions 7 and X.sub.4R.sub.4 is present,
R.sub.4 is CH-aryl wherein aryl is optionally substituted at one or
more positions by hydroxy, lower alkyl, lower alkoxy or halogen; or
CH-heterocyclyl wherein heterocyclyl is optionally substituted at
one or more positions by hydroxy, lower alkyl, lower alkoxy or
halogen; [0025] R.sub.5 is hydrogen; hydroxy; lower alkyl; lower
alkoxy; hydroxy-lower alkylene-; carboxy; alkoxycarbonyl;
aryloxycarbonyl; aryl-alkoxycarbonyl; NHR.sub.10;
--C(O)NR.sub.11R.sub.11a; --O--C(O)--R.sub.12; oxo; or
--C(O)R.sub.13; [0026] R.sub.6 is absent, or is --CH(R.sub.6a)--;
[0027] R.sub.6a is hydrogen; lower alkyl; or aryl optionally
substituted by one or more of halogen, hydroxy, lower alkoxy,
carboxy or alkoxycarbonyl; [0028] R.sub.7 is lower alkoxy; aryl
optionally substituted by one or more hydroxy, halogen, lower
alkyl, carboxy, alkoxycarbonyl, lower alkoxy, hydroxy-alkylene-,
--NH(R.sub.6a), aryloxy, arylalkoxy, or aryl-lower alkylene;
C.sub.3-C.sub.12 cycloalkyl optionally substituted by one or more
hydroxy, halogen, lower alkyl, lower alkyl-aminocarbonyl, carboxy,
alkoxycarbonyl, lower alkoxy, lower alkoxy-lower alkylene-,
hydroxy-alkylene-, aryloxy, arylalkoxy, arylalkoxy-lower
alkylene-optionally substituted on aryl by one or more hydroxy,
halogen or lower alkyl; or aryl-lower alkylene; heterocyclyl
optionally substituted by one or more hydroxy, halogen, lower
alkyl, carboxy, alkoxycarbonyl, lower alkoxy, lower alkoxy-lower
alkylene-, hydroxy-alkylene-, aryloxy or arylalkoxy; [0029]
R.sub.8, R.sub.8a, R.sub.9 and R.sub.9a are each individually
hydrogen; lower alkyl; --NHR.sub.15; aryl optionally substituted by
one or more hydroxy, halogen, --NH(R.sub.6a),
--SO.sub.2--NH(R.sub.6a), lower alkyl, carboxy, alkoxycarbonyl,
lower alkoxy, hydroxy-alkylene-, aryloxy or arylalkoxy;
C.sub.3-C.sub.12 cycloalkyl optionally substituted by one or more
hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl,
lower alkoxy, hydroxy-alkylene-, aryloxy, arylalkoxy, or lower
alkylene; or heterocyclyl optionally substituted by one or more
hydroxy, halogen, amino, lower alkyl, carboxy, alkoxycarbonyl,
lower alkoxy, hydroxy-alkylene-, aryloxy or arylalkoxy; [0030]
R.sub.10 is hydrogen, C.sub.1-C.sub.10 alkoxycarbonyl optionally
substituted at one or more positions by hydroxy, halogen or aryl;
--C(O)CF.sub.3; --SO.sub.2--NR.sub.14R.sub.14a; --C(O)-heterocyclyl
optionally substituted at one or more positions by hydroxy, halogen
or aryl; --C(O)NR.sub.14R.sub.14a; --SO.sub.2-aryl;
--SO.sub.2R.sub.14; or SO.sub.2NR.sub.14R.sub.14a; [0031] R.sub.11,
R.sub.11a, R.sub.12, R.sub.13, R.sub.14 and R.sub.14a and R.sub.15
are each individually hydrogen; C.sub.1-C.sub.10 alkyl;
heterocyclyl; C.sub.3-C.sub.12 cycloalkyl; or aryl optionally
substituted by lower alkyl, hydroxy, alkoxy, halogen
--SO.sub.2--N(R.sub.6a).sub.2, heterocyclyl or aryl-lower
alkylene-; [0032] Z.sub.1 is absent; --NH--; or is lower alkylene
optionally substituted at one or more positions by halogen,
hydroxy, lower alkoxy, carboxy or lower alkoxycarbonyl; [0033]
Z.sub.2 is absent; or is lower alkylene optionally substituted at
one or more positions by aryl, cycloalkyl, halogen, hydroxy, lower
alkyl, lower alkoxy, carboxy, alkoxycarbonyl or aryl; or a
pharmaceutically acceptable salt, isomer, prodrug, metabolite or
polymorph thereof.
[0034] An example of the present invention is a compound of formula
(I) wherein X.sub.1 is absent, or is lower alkylene, and R.sub.1 is
C.sub.3-C.sub.12 cycloalkyl; or aryl optionally substituted at one
or more positions by lower alkyl, lower alkoxy or halogen.
[0035] An example of the present invention is a compound of formula
(I) wherein the dashed line between positions 7 and X.sub.4R.sub.4
is absent; X.sub.4 is absent, or is lower alkylene; and, R.sub.4 is
hydrogen; hydroxy; lower alkyl; lower alkoxy; halogen; aryl
optionally substituted at one or more positions by lower alkoxy or
halogen; heterocyclyl optionally substituted at one or more
positions by halogen; or C.sub.3-C.sub.8 cycloalkyl.
[0036] An example of the present invention is a compound of formula
(I) wherein the dashed line between positions 7 and X.sub.4R.sub.4
is absent; X.sub.4 is absent; and, R.sub.4 is hydrogen.
[0037] An example of the present invention is a compound of formula
(I) wherein R.sub.3 is --R.sub.6C(O)NHZ.sub.2R.sub.9; R.sub.6 is
absent; Z.sub.2 is absent; or is lower alkylene optionally
substituted by lower alkyl, lower alkoxy, carboxy, lower
alkoxycarbonyl, hydroxy or halogen; and, R.sub.9 is aryl optionally
substituted by one or more hydroxy, halogen, --NH(R.sub.6a),
--SO.sub.2--NH(R.sub.6a), lower alkyl, lower alkoxy or arylalkoxy;
C.sub.5-C.sub.12 cycloalkyl optionally substituted at one or more
positions by lower alkyl, lower alkoxy, hydroxy, amino, halogen or
lower alkoxycarbonyl; or heterocyclyl.
[0038] An example of the present invention is a compound of formula
(I) wherein R.sub.3 is --R.sub.6C(O)Z.sub.1R.sub.7; R.sub.6 is
absent; and, R.sub.7 is lower alkoxy; aryl optionally substituted
by one or more hydroxy, lower alkoxy, --NH(R.sub.6a) or arylalkoxy;
C.sub.3-C.sub.12 cycloalkyl optionally substituted by one or more
lower alkyl, lower alkyl-aminocarbonyl, carboxy, alkoxycarbonyl,
lower alkoxy-lower alkylene-, hydroxy-alkylene-, arylalkoxy-lower
alkylene- optionally substituted on aryl by one or more halogen; or
heterocyclyl optionally substituted by one or more lower alkyl,
alkoxycarbonyl or lower alkoxy-lower alkylene-.
[0039] An example of the present invention is a compound of formula
(I) wherein X.sub.3 is lower alkylidene; R.sub.3 is
--SO.sub.2NHR.sub.8; and, R.sub.8 is aryl or C.sub.5-C.sub.12
cycloalkyl.
[0040] An example of the present invention is a compound of formula
(I) wherein X.sub.2 is absent, or is lower alkylene; and, R.sub.2
is C.sub.3-C.sub.12 cycloalkyl; or aryl optionally substituted at
one or more positions by lower alkyl, lower alkoxy or halogen.
[0041] An example of the present invention is a compound of formula
(I) wherein the dashed line between positions 7 and X.sub.4R.sub.4
is present, X.sub.4 is absent; and, R.sub.4 is CH-aryl wherein aryl
is optionally substituted at one or more positions by hydroxy,
lower alkyl, lower alkoxy or halogen; or CH-heterocyclyl wherein
heterocyclyl is optionally substituted at one or more positions by
hydroxy, lower alkyl, lower alkoxy or halogen.
[0042] An example of the present invention is a compound of formula
(I) wherein the dashed line between positions 7 and X.sub.4R.sub.4
is present, X.sub.4 is absent; and, R.sub.4 is CH-aryl wherein aryl
is optionally substituted at one or more positions by lower alkyl,
lower alkoxy or halogen; or CH-heterocyclyl, wherein heterocyclyl
is optionally substituted at one or more positions by lower alkyl,
lower alkoxy or halogen.
[0043] An example of the present invention is a compound of formula
(I) wherein the dashed line between positions 7 and X.sub.4R.sub.4
is present, X.sub.4 is absent; and, R.sub.4 is CH-phenyl,
CH-thienyl or CH-furyl, wherein phenyl, thienyl or furyl is each
optionally substituted at one or more positions by lower alkyl,
lower alkoxy or halogen.
[0044] An example of the present invention is a compound of formula
(I) wherein X.sub.5 is absent; and, R.sub.5 is hydrogen; hydroxy;
lower alkyl: hydroxy-lower alkylene-; carboxy; lower
alkoxycarbonyl; aryl-alkoxycarbonyl; NHR.sub.10;
--C(O)NR.sub.11R.sub.11a; --O--C(O)--R.sub.12; or oxo.
[0045] An example of the present invention is a compound of formula
(I) wherein R.sub.10 is hydrogen; C.sub.1-C.sub.10 alkoxycarbonyl;
--C(O)CF.sub.3; --C(O)-heterocyclyl; --C(O)NR.sub.14R.sub.14a; or
--SO.sub.2NR.sub.14R.sub.14a; and wherein R.sub.11, R.sub.11a,
R.sub.12, R.sub.14 and R.sub.14a are each individually hydrogen;
C.sub.1-C.sub.10 alkyl; or aryl optionally substituted by lower
alkyl, heterocyclyl or aryl-lower alkylene-.
[0046] An example of the present invention is a compound of formula
(Ia)
##STR00006##
wherein X.sub.1R.sub.1, X.sub.3R.sub.3, X.sub.4R.sub.4 and
X.sub.5R.sub.5 are dependently selected from
TABLE-US-00001 Cpd X.sub.1R.sub.1 X.sub.3R.sub.3 X.sub.5R.sub.5
X.sub.4R.sub.4 1 phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H yl 2
(4-OCH.sub.3)- C(O)NHN[(CH.sub.2CH.sub.3)(2-OCH.sub.3-phenyl)] H H
phenyl 3 (4-OCH.sub.3)-
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(3-OCH.sub.2- H H phenyl
phenyl)phenyl 5 (4-OCH.sub.3)-
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OH)phenyl H H phenyl 7
(4-OCH.sub.3)- C(O)NH(CH.sub.2).sub.2-(4-NH.sub.2)phenyl H H phenyl
9 (4-OCH.sub.3)-
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H phenyl yl
10 (4-F)phenyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
H H yl 11 (4-CH.sub.3)-
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H phenyl yl
12 (4-Cl)-phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H yl 13
(4-F)phenyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
CH.sub.3 yl 14 (4-F)phenyl
C(O)NHCH.sub.2-6,6-(CH.sub.3).sub.2-bicyclo[3.1.1]hept- H H 2-yl 15
(4-F)phenyl C(O)NH-cyclooctyl H H 16 (2-F)phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H yl 17
(2-F)phenyl C(O)NHCH.sub.2-6,6-(CH.sub.3).sub.2-bicyclo[3.1.1]hept-
H H 2-yl 18 (3-F)phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H yl 19
(3-F)phenyl C(O)NHCH.sub.2-6,6-(CH.sub.3).sub.2-bicyclo[3.1.1]hept-
H H 2-yl 20 (4-F)phenyl C(O)NH-bicyclo[2.2.1]hept-2-yl H H 21
(4-F)phenyl C(O)NH-1,7,7-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H
yl 22 (4-F)phenyl C(O)NHCH(CH.sub.3)-adamantan-2-yl H H 23
(4-F)phenyl C(O)NH-3-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept- H
H 2-yl 24 (4-F)phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H cyclohexyl yl
25 cyclohexyl C(O)NH-1,7,7-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
H yl 26 cyclohexyl C(O)NHCH(CH.sub.3)-adamantan-1-yl H H 27
cycloheptyl C(O)NH--(2R)-1,3,3-(CH.sub.3).sub.3- H H
bicyclo[2.2.1]hept-2-yl 28 cyclohexyl
C(O)NH-2-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept- H H 3-yl 29
CH.sub.2-phenyl C(O)NHNH(cyclohexyl) H H 30 (4-F)phenyl
C(O)NHNH(cyclohexyl) H H 31 cyclohexyl C(O)NHNH(cyclohexyl) H H 32
cyclohexyl C(O)NHCH.sub.2-adamantan-1-yl H H 33 (4-F)phenyl
C(O)NH--(1S,2R)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl H H 34
(4-F)phenyl C(O)NH--(1R,2R)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl H
H 35 (4-F)phenyl C(O)NH-azepan-1-yl H H 36 cyclohexyl
C(O)NH--(1S,2R)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl H H 37
cyclohexyl C(O)NH-azepan-1-yl H H 38 CH.sub.2-phenyl
C(O)NH--(1S*,2R*)-2-CO.sub.2CH.sub.2CH.sub.3- H H cyclohexyl 39
CH.sub.2-phenyl C(O)NHCH(CH.sub.3)-adamantan-1-yl H H 40 cyclohexyl
C(O)NH-2-CH.sub.2OH-bicyclo[2.2.1]hept-3-yl H H 41 CH.sub.2-phenyl
C(O)NH-azepan-1-yl H H 43 CH.sub.2-phenyl
C(O)NH-2-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept- H H 3-yl 44
cyclohexyl C(O)NH-adamantan-1-yl H H 45 cyclohexyl
C(O)NH-adamantan-2-yl H H 46 cyclohexyl
C(O)NH-8-CH.sub.3-8-aza-bicyclo[3.2.1]oct-3-yl H H 47 cyclohexyl
C(O)NH-2-CH.sub.2OH-bicyclo[2.2.1]hept-3-yl H H 48 cyclohexyl
C(O)NH-(1R*,2S*)-2-CH.sub.2OH-cyclohexyl H H 49 cyclohexyl
C(O)NH-(1R*,2S*)-2-CH.sub.2OH-cyclohexyl H H 50 cyclohexyl
(CH.sub.2).sub.2C(O)NH-1,3,3-(CH.sub.3).sub.3- H H
bicyclo[2.2.1]hept-2-yl 51 cyclohexyl
(CH.sub.2).sub.2C(O)NH--(1R*,2R*)-2-CH.sub.2OH- H H cyclohexyl 52
cyclohexyl (CH.sub.2).sub.2C(O)NH--(2S,3R)-2-CH.sub.2OH- H H
bicyclo[2.2.1]hept-3-yl 53 cyclohexyl
(CH.sub.2).sub.2C(O)NHCH(CH.sub.3)-adamantan-1-yl H H 54 cyclohexyl
(CH.sub.2).sub.2C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-3-yl 55 cyclohexyl
C(O)NH-3-CO.sub.2CH.sub.2CH.sub.3-5,6,7,8-tetrahydro- H H
4H-cyclohepta(b)thien-2-yl 56 cyclohexyl
C(O)NH-3-CO.sub.2CH.sub.2CH.sub.3-5,6-dihydro-4H- H H
cyclopenta(b)thien-2-yl 57 cyclohexyl
C(O)NH-2-CO.sub.2CH.sub.2CH.sub.3-cyclopent-1-en-1-yl H H 58
cyclohexyl C(O)NH--(1R,2S)-2-CO.sub.2CH.sub.2CH.sub.3- H H
cyclopentyl 59 cyclohexyl
C(O)NH--(1S,2S)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl H H 60
cyclohexyl C(O)NH--(1S*,2R*)-2-CH.sub.2OH-cyclohexyl H Cl 61
cyclohexyl C(O)NH--(1S*,2R*)-2-CO.sub.2CH.sub.2CH.sub.3- H Cl
cyclopentyl 62 cyclohexyl C(O)NH-adamantan-2-yl H Cl 63 cyclohexyl
C(O)NH--(2S*,3R*)-2-CO.sub.2CH.sub.2CH.sub.3- H Cl
bicyclo[2.2.1]hept-3-yl 64 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl H Cl 65 cyclohexyl
CH.sub.2C(CH.sub.3).sub.2C(O)NHCH(CH.sub.3)-adamantan- H H 1-yl 66
cyclohexyl CH.sub.2C(CH.sub.3).sub.2C(O)NH-adamantan-2-yl H H 67
cyclohexyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-CO.sub.2--CH.sub.2CH.sub.3 H yl 68 cyclohexyl
C(O)NH-adamantan-2-yl 6-CO.sub.2--CH.sub.2CH.sub.3 H 69 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 6-CO.sub.2--CH.sub.2CH.sub.3 H 70
cyclohexyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
6-CO.sub.2--CH.sub.2CH.sub.3 H yl 71 cyclohexyl
C(O)NH-adamantan-2-yl 4-CO.sub.2--CH.sub.2CH.sub.3 H 72 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 4-CO.sub.2--CH.sub.2CH.sub.3 H 73
cyclohexyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
4-CO.sub.2--CH.sub.2CH.sub.3 H yl 74 cycloheptyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H yl 75
CH.sub.2-phenyl C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OH)phenyl H H
76 CH.sub.2-phenyl C(O)NHCH(CO.sub.2H)CH.sub.2-(4-OCH.sub.2- H H
phenyl)phenyl 77 cyclohexyl
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OH)phenyl H H 78 cyclohexyl
C(O)NHCH(CO.sub.2H)CH.sub.2-(4-OCH.sub.2- H H phenyl)phenyl 79
cyclohexyl C(O)NH-adamantan-2-yl 5-CO.sub.2CH.sub.2- H phenyl 80
CH.sub.2-phenyl C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OCH.sub.2- H
H phenyl)phenyl 81 cyclohexyl
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OCH.sub.2- H H phenyl)phenyl
82 CH.sub.2-phenyl
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(3,4-(OH).sub.2- H H phenyl) 83
CH.sub.2-phenyl C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-1H-indol-3-yl H
H 85 cyclohexyl C(O)NH-adamantan-2-yl
5-NHCO.sub.2--C(CH.sub.3).sub.3 H 86 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-NHCO.sub.2--C(CH.sub.3).sub.3 H yl 87 cyclohexyl
C(O)NH-adamantan-2-yl 5-NHC(O)--CF.sub.3 H 88 cyclohexyl
C(O)NH-adamantan-2-yl 5-NH--CO.sub.2CH.sub.3 H 89 cyclohexyl
C(O)NH-adamantan-2-yl 5-NHC(O)--N(CH.sub.3).sub.2 H 90 cyclohexyl
C(O)NH-adamantan-2-yl 5-NHC(O)- H morpholin- 4-yl 92 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- 5-NH.sub.2 H yl
93 cyclohexyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-OH H yl 94 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-OC(O)--CH.sub.3 H yl 95 cyclohexyl C(O)NH-adamantan-2-yl
5-C(O)NH- H [1,2,4]- triazol-4-yl 96 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- 5-oxo H yl 97
cyclohexyl C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-oxo H 98 cyclohexyl
C(O)NH-adamantan-2-yl 5-C(CH.sub.3).sub.3 H 99 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-C(CH.sub.3).sub.3 H yl 100 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-C(CH.sub.3).sub.3 H 101
cyclohexyl C(O)NH-octahydro-2,5-methano-pentalen-
5-C(CH.sub.3).sub.3 H 3a-yl 102 cyclohexyl
C(O)NHCH.sub.2-adamantan-1-yl 5-C(CH.sub.3).sub.3 H 103 cyclohexyl
C(O)NH-adamantan-2-yl 5-NHC(O)--N[(CH.sub.3)- H phenyl] 104
cyclohexyl C(O)NH-adamantan-2-yl 5-NH--SO.sub.2CH.sub.3 H 105
cyclohexyl C(O)NH-adamantan-2-yl 5-NHSO.sub.2- H (4-CH.sub.3)-
phenyl 106 cyclohexyl C(O)NH-adamantan-2-yl
5-NHSO.sub.2--N(CH.sub.3).sub.2 H 107 cyclohexyl
C(O)NH--(2S,3R)-2-CH.sub.2OCH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-3-yl 108 cyclohexyl
C(O)NH--(2S,3R)-2-CH.sub.2OCH.sub.2-(2-Br- H H
phenyl)-bicyclo[2.2.1]hept-3-yl 109 phenyl C(O)NH-adamantan-2-yl
5-C(CH.sub.3).sub.3 H 110 phenyl C(O)NHCH(CH.sub.3)-adamantan-1-yl
5-C(CH.sub.3).sub.3 H 111 phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-C(CH.sub.3).sub.3 H yl 112 phenyl C(O)NHCH.sub.2-adamantan-1-yl
5-C(CH.sub.3).sub.3 H 113 phenyl C(O)NH-adamantan-1-yl
5-C(CH.sub.3).sub.3 H 114 phenyl
C(O)NHCH(CH.sub.3)--(1R)-cyclohexyl 5-C(CH.sub.3).sub.3 H 115
phenyl C(O)NH-adamantan-2-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H 116
phenyl C(O)NHCH(CH.sub.3)-adamantan-1-yl
5-CO.sub.2--CH.sub.2CH.sub.3 H 117 phenyl
C(O)NHCH.sub.2-adamantan-1-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H 118
phenyl C(O)NH-adamantan-1-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H 119
CH.sub.2-phenyl
C(O)NH-6-CO.sub.2CH.sub.2CH.sub.3-cyclohex-3-en-1-yl H H 120
cyclohexyl C(O)NH-6-CO.sub.2CH.sub.2CH.sub.3-cyclohex-3-en-1-yl H
OCH.sub.3 122 CH.sub.2- C(O)NH-adamantan-2-yl H H cyclohexyl 123
CH.sub.2- C(O)NHCH(CH.sub.3)-adamantan-1-yl H H cyclohexyl 124
CH.sub.2- C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H H
cyclohexyl bicyclo[2.2.1]hept-3-yl 125 CH.sub.2-(4-CH.sub.3)-
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H phenyl yl
126 CH.sub.2-(4-CH.sub.3)-
C(O)NH-2-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept- H H phenyl
3-yl 127 CH.sub.2-phenyl C(O)NH-cyclooctyl H H 128 cyclohexyl
C(O)NH-cyclooctyl H H 129 (2,4-Cl.sub.2)-
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H phenyl yl
130 (2,4-Cl.sub.2)- C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H H
phenyl bicyclo[2.2.1]hept-3-yl 131 (2,4-Cl.sub.2)-
C(O)NH-adamantan-2-yl H H phenyl 132 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H
133 cyclohexyl C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-CO.sub.2H H 134
(2,4-Cl.sub.2)- C(O)NH-azepan-1-yl H H phenyl 135 CH.sub.2-phenyl
C(O)NHCH.sub.2-adamantan-1-yl H H 136 CH.sub.2-phenyl
C(O)NH-adamantan-2-yl H H 137 cyclohexyl
C(O)NH-3-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept-
5-CO.sub.2--CH.sub.2CH.sub.3 H 2-yl 138 cyclohexyl
C(O)NH-3-CH.sub.2OH-bicyclo[2.2.1]hept-2-yl 5-CO.sub.2H H 139
(2,4-Cl.sub.2)- C(O)NH-adamantan-1-yl H H phenyl 141
(2,4-Cl.sub.2)- C(O)NHCH.sub.2-adamantan-1-yl H H phenyl 143
cyclohexyl C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-CH.sub.2OH H 144
(4-F)phenyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
phenyl yl 145 (4-F)phenyl C(O)NHCH.sub.2-adamantan-1-yl H phenyl
146 (4-F)phenyl C(O)NHCH(CH.sub.3)-adamantan-1-yl H phenyl 147
(4-F)phenyl C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H phenyl
bicyclo[2.2.1]hept-3-yl 148 CH.sub.2-phenyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H
149 CH.sub.2-phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-CO.sub.2--CH.sub.2CH.sub.3 H yl 150 (4-F)phenyl
C(O)NH-adamantan-1-yl H (CH.sub.2).sub.2-
phenyl 151 (4-F)phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
(CH.sub.2).sub.2- yl phenyl 152 (4-F)phenyl
C(O)NHCH.sub.2-adamantan-1-yl H (CH.sub.2).sub.2- phenyl 153
(4-F)phenyl C(O)NHCH(CH.sub.3)-adamantan-1-yl H (CH.sub.2).sub.2-
phenyl 154 (4-F)phenyl C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3-
H (CH.sub.2).sub.2- bicyclo[2.2.1]hept-3-yl phenyl 155
CH.sub.2-phenyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-CO.sub.2H H yl 156 CH.sub.2-phenyl C(O)NHCH.sub.2-adamantan-1-yl
6-CO.sub.2--CH.sub.2CH.sub.3 H 157 CH.sub.2-phenyl
C(O)NH-octahydro-2,5-methano-pentalen- 6-CO.sub.2--CH.sub.2CH.sub.3
H 3a-yl 158 CH.sub.2-phenyl C(O)NH-adamantan-2-yl
4-CO.sub.2--CH.sub.2CH.sub.3 H 159 CH.sub.2-phenyl
C(O)NHCH.sub.2-adamantan-1-yl 4-CO.sub.2--CH.sub.2CH.sub.3 H 160
pyridin-2-yl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
H yl 161 cyclohexyl C(O)NHCH(CH.sub.3)-adamantan-1-yl H OCH.sub.3
162 cyclohexyl C(O)NH-adamantan-2-yl H OCH.sub.3 163 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl H OH 164 cyclohexyl
C(O)NH--(2S*,3R*)-2-CO.sub.2CH.sub.2CH.sub.3- H OH
bicyclo[2.2.1]hept-3-yl 165 (4-F)phenyl C(O)NH-adamantan-1-yl H
phenyl 166 CH.sub.2-phenyl C(O)NHCH(CH.sub.3)-adamantan-1-yl
5-CO.sub.2H H 167 CH.sub.2-phenyl
C(O)NH--(2R*,3S*)-2-C(O)NHCH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-3-yl 168 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- 5-CO.sub.2H H
yl 169 cycloheptyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-CO.sub.2CH.sub.3 H yl 170 cyclohexyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-C(O)--NH.sub.2 H yl 171 CH.sub.2-phenyl
C(O)NH-1-CO.sub.2CH.sub.2CH.sub.3-piperidin-4-yl H H 172
(4-F)phenyl C(O)NH-1-CO.sub.2H-cyclohexyl H H 173 cyclohexyl
C(O)NHCH.sub.2-pyridin-3-yl H H 174 CH.sub.2-phenyl
C(O)NH(CH.sub.2).sub.2-morpholin-4-yl H H 175 CH.sub.2-phenyl
C(O)NH(CH.sub.2).sub.2-morpholin-4-ium H H 176 cyclohexyl
C(O)NHCH.sub.2C(O)-(4-OCH.sub.3)phenyl H H 177 cyclohexyl
C(O)NHCH.sub.2C(O)-(4-Br)phenyl H H 178 cyclohexyl
NHC(O)naphthalen-2-yl H H 179 cyclohexyl NHC(O)adamantan-1-yl H H
180 cyclohexyl NHC(O)cyclohexyl H H 181 cyclohexyl
NHC(O)naphthalen-1-yl H H 182 cyclohexyl NHC(O)NH-adamantan-1-yl H
H 183 cyclohexyl C(O)NH-1,2,3,4-tetrahydro-naphthalen-1-yl H H 184
cyclohexyl C(O)NHCH(CH.sub.3)-cyclohexyl H H 185 cyclohexyl
C(O)NHCH.sub.2CH(OH)-cyclohexyl H H 186 cyclohexyl NHC(O)phenyl H H
187 cyclohexyl C(O)NHCH.sub.2C(O)-cyclohexyl H H 188 cyclohexyl
C(O)NHCH.sub.2C(O)-phenyl H H 189 CH.sub.2-phenyl
C(O)NHCH.sub.2-cyclohexyl H H 191 (4-F)phenyl
C(O)NH--(2S*,3R*)-2-CO.sub.2CH.sub.2CH.sub.3- H CH.sub.2CH.sub.3
bicyclo[2.2.1]hept-3-yl 192 (4-F)phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
CH.sub.2CH.sub.3 yl 193 cyclohexyl C(O)NHCH(CH.sub.3)-cyclopentyl H
H 194 CH.sub.2-phenyl
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H H yl 195
cyclohexyl C(O)NHCH--(R--CH.sub.3)-cyclohexyl H H 196 cyclohexyl
C(O)NHCH--(S--CH.sub.3)-phenyl H H 197 cyclohexyl
C(O)NHCH--(R--CH.sub.3)-phenyl H H 198 CH.sub.2-phenyl
C(O)NHCH--(R--CH.sub.3)-cyclohexyl H H 199 CH.sub.2-phenyl
C(O)NHCH--(R--CH.sub.3)-phenyl H H 200 CH.sub.2-phenyl
C(O)NHCH--(S--CH.sub.3)-phenyl H H 201 CH.sub.2-phenyl
C(O)NHCH--(S--CH.sub.3)-cyclohexyl H H 202 (4-F)phenyl
C(O)NH--(2S)-1,3,3-(CH.sub.3).sub.3- H H bicyclo[2.2.1]hept-2-yl
203 cyclohexyl C(O)N[(CH.sub.2CH.sub.3)[CH(R--CH.sub.3)cyclohexyl]]
H H 204 cyclohexyl C(O)NHCH--(R--CH.sub.2CH.sub.3)-phenyl H H 205
cyclohexyl NHC(O)NH-1,3,3-(CH.sub.3).sub.3- H H
bicyclo[2.2.1]hept-2-yl 206 CH.sub.2-phenyl
C(O)NH--(2R*,3S*)-2-CO.sub.2CH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-5-en-3-yl 207 cyclohexyl
C(O)NH--(2S*)-1,3,3-(CH.sub.3).sub.3- H H bicyclo[2.2.1]hept-2-yl
208 cyclohexyl C(O)NH-adamantan-2-yl
5S*--CO.sub.2--CH.sub.2CH.sub.3 H 209 cyclohexyl
C(O)NH-adamantan-2-yl 5R*--CO.sub.2--CH.sub.2CH.sub.3 H 210
CH.sub.2-phenyl C(O)NH-adamantan-2-yl
5S*--CO.sub.2--CH.sub.2CH.sub.3 H 211 CH.sub.2-phenyl
C(O)NH-adamantan-2-yl 5R*--CO.sub.2--CH.sub.2CH.sub.3 H 212
cyclohexyl C(O)NHCH--(R*--CH.sub.3)-adamantan-1-yl H H 213
cyclohexyl C(O)NHCH--(S*--CH.sub.3)-adamantan-1-yl H H 214
cyclohexyl C(O)NHCH(CH.sub.3)-adamantan-1-yl
5R*--CO.sub.2--CH.sub.2CH.sub.3 H 215 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 5S*--CO.sub.2--CH.sub.2CH.sub.3 H
216 cyclohexyl C(O)NH--(2S*,3S*)-2-CH.sub.3-6,6-(CH.sub.3).sub.2- H
H bicyclo[3.1.1]hept-3-yl 217 CH.sub.2-phenyl
C(O)NH--(2R*)-1,3,3-(CH.sub.3).sub.3- H H bicyclo[2.2.1]hept-2-yl
218 cyclohexyl C(O)NH-adamantan-2-yl 5S*--CO.sub.2--CH.sub.3 H 219
cyclohexyl C(O)NH-adamantan-2-yl 5R*--CO.sub.2--CH.sub.3 H 220
phenyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5R*--CO.sub.2--CH.sub.2CH.sub.3 H yl 222 cyclohexyl
C(O)NH-adamantan-2-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H 223 cyclohexyl
C(O)NH-adamantan-2-yl 5-CO.sub.2H H 224 cyclohexyl
C(O)NHCH(CH.sub.3)-adamantan-1-yl 5-C(O)NH.sub.2 H 225 cyclohexyl
C(O)NH-1-aza-bicyclo[2.2.2]oct-3-yl H H 226 CH.sub.2-phenyl
C(O)NH-adamantan-2-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H 228 cyclohexyl
C(O)NH-adamantan-2-yl
5-C(O)NH--C(CH.sub.3).sub.2--CH.sub.2--C(CH.sub.3).sub.3 H 229
cyclohexyl C(O)NH-piperidin-1-yl 5-CO.sub.2--CH.sub.2CH.sub.3 H 230
CH.sub.2-phenyl C(O)NH-adamantan-2-yl 6-CO.sub.2--CH.sub.2CH.sub.3
H 231 cyclohexyl C(O)NH-adamantan-2-yl 5-CO.sub.2CH.sub.3 H 232
cyclohexyl C(O)NH-adamantan-2-yl 5-CO.sub.2--CH(CH.sub.3).sub.2 H
233 cyclohexyl C(O)NH-adamantan-2-yl 5-CO.sub.2--C(CH.sub.3).sub.3
H 234 cyclohexyl C(O)NHCH(CH.sub.2CH.sub.3)-cyclohexyl H H 235
cyclohexyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
5-C(O)--N(CH.sub.3).sub.2 H yl 236 cyclohexyl
C(O)NH(CH.sub.2).sub.2-(2-OCH.sub.3)phenyl H H 237 CH.sub.2-phenyl
C(O)NH(CH.sub.2).sub.2-(2-OCH.sub.3)phenyl H H 238 phenyl
C(O)NH(CH.sub.2).sub.2-(2-OCH.sub.3)phenyl H H 239 CH.sub.2-phenyl
C(O)NH-adamantan-2-yl 5-CO.sub.2H H 240 cyclohexyl
C(O)NHCH.sub.2CH(OH)-(4-Br)phenyl H H 241 cyclohexyl
C(O)NHCH.sub.2CH(OH)-(4-OCH.sub.3)phenyl H H 242 CH(CH.sub.3)-
C(O)NHCH.sub.2-cyclohexyl H H phenyl 243 CH(CH.sub.3)-
C(O)NH-adamantan-2-yl H H phenyl 244 CH(CH.sub.3)-
C(O)NH-adamantan-1-yl H H phenyl 245 cyclohexyl
C(O)NH-2-CH.sub.3-cyclohexyl H H 246 cyclohexyl
C(O)NHCH(CH.sub.3)-cycloheptyl H H 247 cyclohexyl
C(O)NHCH(CH.sub.3)-cyclobutyl H H 248 cyclohexyl
C(O)NHCH(CH.sub.3)--(1R,4R)-4-CH.sub.3- H H cyclohexyl 249
CH(CH.sub.3)- C(O)NHCH(CH.sub.3)-cyclohexyl H H phenyl 250
CH(CH.sub.3)- C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2- H
H phenyl yl 251 cyclohexyl C(O)NH--(R*--CH)(CH.sub.3)-cyclohexyl
5-CO.sub.2--CH.sub.2CH.sub.3 H 252 cyclohexyl
C(O)NH--(2R*,3R*)-2-CH.sub.3-6,6-(CH.sub.3).sub.2- H H
bicyclo[3.1.1]hept-3-yl 253 CH.sub.2-phenyl
C(O)NHCH(CH.sub.3)-phenyl H phenyl 254 CH.sub.2-phenyl
C(O)NH-3-CH.sub.2OCH.sub.3-pyrrolidin-1-yl H phenyl 255
CH.sub.2-phenyl C(O)NH-phenyl H phenyl 256 CH.sub.2-phenyl
C(O)NH--CH(CH.sub.3)-phenyl 5-CO.sub.2--CH.sub.2CH.sub.3 H 257
cyclohexyl C(O)NH--CH(CH.sub.3)-phenyl 5-CO.sub.2--CH.sub.2CH.sub.3
H 258 (4-F)phenyl (CH).sub.2--SO.sub.2NH--CH(CH.sub.3)-phenyl H
(CH.sub.2).sub.2- phenyl 259 (4-F)phenyl
(CH).sub.2--SO.sub.2NH--CH(CH.sub.3)-cyclohexyl H (CH.sub.2).sub.2-
phenyl 260 CH.sub.2-phenyl
(CH).sub.2--SO.sub.2NH--CH(R--CH.sub.3)-phenyl H H 261
CH.sub.2-phenyl (CH).sub.2--SO.sub.2NH--CH(S--CH.sub.3)-phenyl H H
262 CH.sub.2-phenyl
(CH).sub.2--SO.sub.2NH--CH(R--CH.sub.3)-cyclohexyl H H 263
CH.sub.2-phenyl (CH).sub.2--SO.sub.2NH--CH(S--CH.sub.3)-cyclohexyl
H H 264 CH.sub.2-phenyl
C(O)NH-1-CO.sub.2C(CH.sub.3).sub.3-piperidin-4-yl H H 265
CH.sub.2-phenyl C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-
H phenyl yl 266 CH.sub.2-phenyl C(O)NH-piperidin-1-yl H phenyl 267
CH.sub.2-phenyl C(O)NHCH(CH.sub.3)-cyclohexyl H phenyl 268
CH.sub.2-phenyl C(O)NH-azepan-1-yl H phenyl 269 cyclohexyl
C(O)NH--(1R,2R)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl H H 272
CH.sub.2-phenyl
C(O)NH--(2R--CO.sub.2CH.sub.2CH.sub.3)-(R)-cyclohexyl H H 274
CH.sub.2-phenyl C(O)NH--(2R*,3S*)-2-CO.sub.2CH.sub.2CH.sub.3-
bicyclo[2.2.1]hept-3-yl 276 CH.sub.2-phenyl
C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-5-en-3-yl 278 cyclohexyl
C(O)NH--(2R,3S)-2-CO.sub.2CH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-3-yl 279 cyclohexyl
C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-5-en-3-yl 280 cyclohexyl
C(O)NH--(2R,3S)-2-CO.sub.2CH.sub.2CH.sub.3- H H
bicyclo[2.2.1]hept-5-en-3-yl 281 cyclohexyl
CH.sub.2C(CH.sub.3).sub.2C(O)NH--(2S,3R)-2- H H
CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept-3-yl 282 cyclohexyl
C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3- H OCH.sub.3
bicyclo[2.2.1]hept-3-yl 283 (2,4-Cl.sub.2)-
C(O)NHCH(CH.sub.3)-adamantan-1-yl H H phenyl 284 cyclohexyl
C(O)NH--(R*--CH)(CH.sub.3)-cyclohexyl 6-CO.sub.2--CH.sub.2CH.sub.3
H 285 cyclohexyl C(O)NH--(R*--CH)(CH.sub.3)-cyclohexyl
4-CO.sub.2--CH.sub.2CH.sub.3 H 286 cyclohexyl
C(O)NH--(R*--CH)(CH.sub.3)-cyclohexyl
5-NHCO.sub.2--C(CH.sub.3).sub.3 H 287 (2,4-Cl.sub.2)-
C(O)NH-piperidin-1-yl H H phenyl 288 cyclohexyl
C(O)NHCH--(R--CH.sub.3)-phenyl 5-CO.sub.2--CH.sub.2CH.sub.3 H 289
CH.sub.2-phenyl C(O)NH--(R--CH)(CH.sub.3)-cyclohexyl
5-CO.sub.2--CH.sub.2CH.sub.3 H 299 (4-F)phenyl C(O)NHNH(cyclooctyl)
H H 300 cyclohexyl C(O)NHNH(cyclooctyl) H H 301 cyclohexyl
C(O)NH-6-CO.sub.2CH.sub.2CH.sub.3-cyclohex-3-en-1-yl H H 302
cyclohexyl C(O)NH--(2S*,3R*)-2-CH.sub.2OH- H H
bicyclo[2.2.1]hept-3-yl 303 cyclohexyl C(O)NHCH.sub.2-pyridin-4-yl
H H 304 cyclohexyl C(O)NHCH.sub.2-cyclohexyl H H 305
CH.sub.2-phenyl (CH).sub.2--C(O)NH--CH(S--CH.sub.3)-phenyl H H 306
CH.sub.2-phenyl (CH).sub.2--C(O)NH--CH(R--CH.sub.3)-phenyl H H 312
(2,4-Cl.sub.2)- C(O)NHCH(R--CH.sub.3)-phenyl H (3-OCH.sub.3)-
phenyl phenyl 313 (2,4-Cl.sub.2)- C(O)NHCH(S--CH.sub.2OH)-phenyl H
(3-OCH.sub.3)- phenyl phenyl 314 (2,4-Cl.sub.2)-
C(O)NHCH(R--CH.sub.2OH)-phenyl H (3-OCH.sub.3)- phenyl phenyl 315
(2,4-Cl.sub.2)- C(O)NHCH(R--CH.sub.2Cl)-phenyl H (3-OCH.sub.3)-
phenyl phenyl 316 (2,4-Cl.sub.2)- C(O)NHCH(S--CH.sub.2Cl)-phenyl H
(3-OCH.sub.3)- phenyl phenyl 317 (2,4-F.sub.2)-
C(O)NHCH(R--CH.sub.3)-phenyl H (3-OCH.sub.3)- phenyl phenyl 318
(2,4-F.sub.2)- C(O)NHCH(R--CH.sub.2OH)-phenyl H (3-OCH.sub.3)-
phenyl phenyl 326 cyclohexyl C(O)NH-adamantan-2-yl
5-C(O)--N(CH.sub.2- H phenyl).sub.2 327 cyclohexyl
C(O)NH-adamantan-2-yl 5-C(O)NH--(CH.sub.2).sub.2CH.sub.3 H 328
cyclohexyl C(O)N(CH.sub.3)CH(R--CH.sub.3)cyclohexyl H H 329
cyclohexyl C(O)N[CH(CH.sub.3).sub.2]CH(R--CH.sub.3)-cyclohexyl H H
330 cyclohexyl C(O)NHCH(CH.sub.3)CH.sub.2-cyclohexyl H H 331
cyclohexyl C(O)NHCH(phenyl)-cyclohexyl H H 332 cyclohexyl
CH.sub.2CH(CO.sub.2CH.sub.2CH.sub.3)-(2-OCH.sub.3)-phenyl H H 333
cyclohexyl CH.sub.2CH(2-OCH.sub.3-phenyl)-C(O)NH-1,3,3- H H
(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-yl 334 cyclohexyl
NHC(O)NH--CH(CH.sub.3)-cyclohexyl H H 335 CH.sub.2-phenyl
C(O)N(CH.sub.3)(phenyl) H phenyl 336 cyclohexyl
NHSO.sub.2-(4-CH.sub.3)phenyl H H 337 CH.sub.2-phenyl
NHC(O)NH-adamantan-1-yl H H 338 CH.sub.2-phenyl
NHC(O)NH-1,3,3-(CH.sub.3).sub.3- H H bicyclo[2.2.1]hept-2-yl
and pharmaceutically acceptable forms thereof.
[0047] An example of the present invention is a compound of formula
(Ib)
##STR00007##
wherein X.sub.2R.sub.2, X.sub.3R.sub.3 and X.sub.5R.sub.5 are
dependently selected from
TABLE-US-00002 Cpd X.sub.2R.sub.2 X.sub.5R.sub.5 X.sub.3R.sub.3 4
(4-OCH.sub.3)- H
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OCH.sub.2-phenyl)phenyl
phenyl 6 (4-OCH.sub.3)- H
C(O)NHCH(CO.sub.2CH.sub.3)CH.sub.2-(4-OH)phenyl phenyl 8
(4-OCH.sub.3)- H C(O)NH(CH.sub.2).sub.2-(4-NH.sub.2)phenyl phenyl
42 CH.sub.2-phenyl H
C(O)NH-(2-CO.sub.2CH.sub.2CH.sub.3)-bicyclo[2.2.1]hept-3-yl 84
cyclohexyl 5-NHCO.sub.2C(CH.sub.3).sub.3 C(O)NH-adamantan-2-yl 91
phenyl 5-CO.sub.2CH.sub.2CH.sub.3 C(O)NH-adamantan-1-yl 121
(4-OCH.sub.3)- H C(O)N--(CH.sub.2CH.sub.3)-(2-OCH.sub.3)phenyl
phenyl 140 (2,4-Cl.sub.2)-phenyl H C(O)NH-adamantan-1-yl 142
(2,4-Cl.sub.2)-phenyl H C(O)NHCH.sub.2-adamantan-1-yl 190
cyclohexyl 5-CO.sub.2CH.sub.2CH.sub.3
C(O)NHCH(CH.sub.3)-adamantan-1-yl 221 cyclohexyl
5-CO.sub.2CH.sub.2CH.sub.3 C(O)NH-adamantan-2-yl 227
CH.sub.2-phenyl 5-CO.sub.2CH.sub.2CH.sub.3
C(O)NH-octahydro-2,5-methano-pentalen-3a-yl 270 CH.sub.2-phenyl H
C(O)NH--(1S*,2R*)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl 271
CH.sub.2-phenyl H
C(O)NH--(1S,2S)-2-CO.sub.2CH.sub.2CH.sub.3-cyclohexyl 273
CH.sub.2-phenyl H
C(O)NH--(2R,3S)-2-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept-3- yl
275 CH.sub.2-phenyl H
C(O)NH--(2S,3R)-2-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept-5-
en-3-yl 277 CH.sub.2-phenyl H
C(O)NH--(2R,3S)-2-CO.sub.2CH.sub.2CH.sub.3-bicyclo[2.2.1]hept-5-
en-3-yl 322 phenyl 5-CO.sub.2CH.sub.2CH.sub.3
C(O)NH-1,3,3-(CH.sub.3).sub.3-bicyclo[2.2.1]hept-2-yl 323 phenyl
5-CO.sub.2CH.sub.2CH.sub.3 C(O)NHCH.sub.2-adamantan-1-yl 324 phenyl
5-CO.sub.2CH.sub.2CH.sub.3 C(O)NH-adamantan-2-yl 325 phenyl
5-CO.sub.2CH.sub.2CH.sub.3 C(O)NHCH(CH.sub.3)-adamantan-1-yl
and pharmaceutically acceptable forms thereof.
[0048] An example of the present invention is a compound of Formula
(Ic)
##STR00008##
wherein X.sub.1R.sub.1, X.sub.3R.sub.3 and R.sub.4 are dependently
selected from
TABLE-US-00003 Cpd X.sub.1R.sub.1 R.sub.4 X.sub.3R.sub.3 290
(2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl C(O)NH-piperidin-1-yl 291
(2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl C(O)NH-morpholin-4-yl 292
(2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl
C(O)NH--(1S,2R,4R)-1-CH.sub.3-3,3-(CH.sub.3).sub.2-
bicyclo[2.2.1]hept-2-yl 293 (2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl
C(O)NH--(R--CH)(CH.sub.3)-cyclohexyl 294 (2,4-Cl.sub.2)phenyl
CH-(4-Cl)phenyl C(O)NH--(S--CH)(CH.sub.3)-phenyl 295
(2,4-Cl.sub.2)phenyl CH-(4-F)phenyl
C(O)NH--(R--CH)(CH.sub.3)-cyclohexyl 296 (2,4-Cl.sub.2)phenyl
CH-(4-F)phenyl C(O)NH--(R--CH)(CH.sub.3)-phenyl 297
(2,4-Cl.sub.2)phenyl CH-(4-F)phenyl C(O)NH-piperidin-1-yl 298
(2,4-Cl.sub.2)phenyl CH-(4-F)phenyl C(O)NH-morpholin-4-yl 307
(2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl
C(O)NH--(R--CH)(CH.sub.3)-phenyl 308 (2,4-Cl.sub.2)phenyl
CH-(4-F)phenyl C(O)NH--(S--CH)(CH.sub.3)-phenyl 309
(2,4-Cl.sub.2)phenyl CH-(4-F)phenyl
C(O)NH--(S--CH)(CH.sub.3)-cyclohexyl 310 (2,4-Cl.sub.2)phenyl
CH-(4-Cl)phenyl C(O)NHNH-(4-SO.sub.2NH.sub.2)phenyl 311
(2,4-Cl.sub.2)phenyl CH-(4-F)phenyl C(O)NHNH-pyridin-4-yl 319
(2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl C(O)NHCH.sub.2-pyridin-2-yl
320 (2,4-Cl.sub.2)phenyl CH-(4-Cl)phenyl
C(O)NHCH(CH.sub.3)-pyridin-2-yl 321 (2,4-Cl.sub.2)phenyl
CH-(4-Cl)phenyl C(O)NH--(S--CH)(CH.sub.3)-cyclohexyl 339
(2,4-Cl.sub.2)phenyl CH-(4-F)phenyl C(O)NH-azepan-1-yl 340
(2,4-Cl.sub.2)phenyl CH-thien-2-yl C(O)NH--CH(R--CH.sub.3)-phenyl
341 (2,4-Cl.sub.2)phenyl CH-thien-2-yl
C(O)NH--CH(R--CH.sub.3)-cyclohexyl 342 (2,4-Cl.sub.2)phenyl
CH-thien-2-yl C(O)NH-piperidin-1-yl 343 (2,4-Cl.sub.2)phenyl
CH-thien-2-yl C(O)NH-azepan-1-yl 344 (2,4-Cl.sub.2)phenyl
CH-thien-2-yl C(O)NH-2,6-(CH.sub.3).sub.2-piperidin-1-yl 345
(2,4-Cl.sub.2)phenyl CH-thien-2-yl C(O)NH-pyrrolidin-1-yl 346
(2,4-Cl.sub.2)phenyl CH-thien-2-yl
C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 347 (2,4-Cl.sub.2)phenyl
CH-thien-3-yl C(O)NH-piperidin-1-yl 348 (2,4-Cl.sub.2)phenyl
CH-thien-3-yl C(O)NH-azepan-1-yl 349 (2,4-Cl.sub.2)phenyl
CH-thien-3-yl C(O)NH-2,6-(CH.sub.3).sub.2-piperidin-1-yl 350
(2,4-Cl.sub.2)phenyl CH-thien-3-yl
C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 351 (2,4-Cl.sub.2)phenyl
CH-thien-3-yl C(O)NH--CH(R--CH.sub.3)-cyclohexyl 352
(2,4-Cl.sub.2)phenyl CH-thien-3-yl
C(O)NH--CH(S--CH.sub.3)-cyclohexyl 353 (2,4-Cl.sub.2)phenyl
CH-thien-3-yl C(O)NH--CH(R--CH.sub.3)-phenyl 354
(2,4-Cl.sub.2)phenyl CH-thien-3-yl C(O)NH--CH(S--CH.sub.3)-phenyl
355 (2,4-Cl.sub.2)phenyl CH-thien-3-yl
C(O)NH--(R--CH)(CH.sub.2OH)-phenyl 356 (2,4-Cl.sub.2)phenyl
CH-thien-3-yl C(O)NH--(S--CH)(CH.sub.2OH)-phenyl 357
(2,4-Cl.sub.2)phenyl CH-thien-3-yl C(O)NH-pyrrolidin-1-yl 358
(2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH--CH(R--CH.sub.3)-phenyl 359
(2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH--CH(S--CH.sub.3)-phenyl 360
(2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH--CH(R--CH.sub.3)-cyclohexyl
361 (2,4-Cl.sub.2)phenyl CH-fur-3-yl
C(O)NH--CH(S--CH.sub.3)-cyclohexyl 362 (2,4-Cl.sub.2)phenyl
CH-fur-3-yl C(O)NH-2,6-(CH.sub.3).sub.2-piperidin-1-yl 363
(2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH-azepan-1-yl 364
(2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH-piperidin-1-yl 365
(2,4-Cl.sub.2)phenyl CH-fur-3-yl
C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 366 (2,4-Cl.sub.2)phenyl
CH-fur-3-yl C(O)NH--(R--CH)(CH.sub.2OH)-phenyl 367
(2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH--(S--CH)(CH.sub.2OH)-phenyl
368 (2,4-Cl.sub.2)phenyl CH-fur-3-yl C(O)NH-pyrrolidin-1-yl 369
(2,4-Cl.sub.2)phenyl CH-fur-2-yl C(O)NH--CH(R--CH.sub.3)-cyclohexyl
370 (2,4-Cl.sub.2)phenyl CH-fur-2-yl
C(O)NH--CH(S--CH.sub.3)-cyclohexyl 371 (2,4-Cl.sub.2)phenyl
CH-fur-2-yl C(O)NH--CH(R--CH.sub.3)-phenyl 372 (2,4-Cl.sub.2)phenyl
CH-fur-2-yl C(O)NH--CH(S--CH.sub.3)-phenyl 373 (2,4-Cl.sub.2)phenyl
CH-fur-2-yl C(O)NH-azepan-1-yl 374 (2,4-Cl.sub.2)phenyl CH-fur-2-yl
C(O)NH-piperidin-1-yl 375 (2,4-Cl.sub.2)phenyl CH-fur-2-yl
C(O)NH-2,6-(CH.sub.3).sub.2-piperidin-1-yl 376 (2,4-Cl.sub.2)phenyl
CH-fur-2-yl C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 377
(2,4-Cl.sub.2)phenyl CH-fur-2-yl C(O)NH-pyrrolidin-1-yl 378
(2,4-Cl.sub.2)phenyl CH-fur-2-yl C(O)NH--(R--CH)(CH.sub.2OH)-phenyl
379 (2,4-Cl.sub.2)phenyl CH-fur-2-yl
C(O)NH--(S--CH)(CH.sub.2OH)-phenyl 380 (2,4-Cl.sub.2)phenyl
CH-(4-Br)phenyl C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 381
(2,4-Cl.sub.2)phenyl CH-(4-Br)phenyl
C(O)NH--(R--CH)(CH.sub.3)-pyridin-2-yl 382 (2,4-Cl.sub.2)phenyl
CH-(4-Br)phenyl C(O)NH--(R--CH)(CH.sub.3)-cyclohexyl 383
(2,4-Cl.sub.2)phenyl CH-(4-Br)phenyl
C(O)NH--(R--CH)(CH.sub.3)-phenyl 384 (2,4-Cl.sub.2)phenyl
CH-(4-Br)phenyl C(O)NH-piperidin-1-yl 385 (2,4-Cl.sub.2)phenyl
CH-(5-Cl)thien-2-yl C(O)NH--CH(R--CH.sub.3)-cyclohexyl 386
(2,4-Cl.sub.2)phenyl CH-(5-Cl)thien-2-yl
C(O)NH--CH(R--CH.sub.3)-phenyl 387 (2,4-Cl.sub.2)phenyl
CH-(5-Cl)thien-2-yl C(O)NH-piperidin-1-yl 388 (2,4-Cl.sub.2)phenyl
CH-(5-Cl)thien-2-yl C(O)NH-azepan-1-yl 389 (2,4-Cl.sub.2)phenyl
CH-(5-Cl)thien-2-yl C(O)NH-2,6(CH.sub.3).sub.2-piperidin-1-yl 390
(2,4-Cl.sub.2)phenyl CH-(5-Cl)thien-2-yl
C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 391 (2,4-Cl.sub.2)phenyl
CH-(5-Cl)thien-2-yl C(O)NH--CH(S--CH.sub.3)-cyclohexyl 392
(2,4-Cl.sub.2)phenyl CH-(5-Cl)thien-2-yl
C(O)NH--CH(S--(CH.sub.3)-phenyl 393 (2,4-Cl.sub.2)phenyl
CH-(5-Cl)thien-2-yl C(O)NH-pyrrolidin-1-yl 394 (2,4-Cl.sub.2)phenyl
CH-(5-Br)thien-2-yl C(O)NH-piperidin-1-yl 395 (2,4-Cl.sub.2)phenyl
CH-(5-Br)thien-2-yl C(O)NH-azepan-1-yl 396 (2,4-Cl.sub.2)phenyl
CH-(5-Br)fur-2-yl C(O)NH-hexahydro-cyclopenta[c]pyrrol-2-yl 397
(2,4-Cl.sub.2)phenyl CH-(5-Br)fur-2-yl
C(O)NH--CH(R--CH.sub.3)-phenyl 398 (2,4-Cl.sub.2)phenyl
CH-(5-Br)fur-2-yl C(O)NH--CH(R--CH.sub.3)-cyclohexyl 399
(2,4-Cl.sub.2)phenyl CH-(3-Br)thien-2-yl
C(O)NH-2,6-(CH.sub.3).sub.2-piperidin-1-yl 400 (2,4-Cl.sub.2)phenyl
CH-(4-Br)thien-3-yl C(O)NH-piperidin-1-yl
and pharmaceutically acceptable forms thereof.
[0049] An example of the present invention is a compound selected
from:
##STR00009## ##STR00010## ##STR00011## ##STR00012## ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017## ##STR00018##
##STR00019## ##STR00020## ##STR00021## ##STR00022## ##STR00023##
##STR00024## ##STR00025## ##STR00026## ##STR00027## ##STR00028##
##STR00029## ##STR00030## ##STR00031## ##STR00032## ##STR00033##
##STR00034## ##STR00035## ##STR00036## ##STR00037## ##STR00038##
##STR00039## ##STR00040## ##STR00041## ##STR00042## ##STR00043##
##STR00044## ##STR00045## ##STR00046## ##STR00047## ##STR00048##
##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053##
##STR00054## ##STR00055## ##STR00056## ##STR00057## ##STR00058##
##STR00059## ##STR00060## ##STR00061## ##STR00062## ##STR00063##
##STR00064## ##STR00065## ##STR00066## ##STR00067## ##STR00068##
##STR00069## ##STR00070## ##STR00071## ##STR00072## ##STR00073##
##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078##
##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083##
##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##
##STR00089## ##STR00090## ##STR00091## ##STR00092## ##STR00093##
##STR00094## ##STR00095## ##STR00096## ##STR00097## ##STR00098##
##STR00099## ##STR00100## ##STR00101## ##STR00102## ##STR00103##
##STR00104## ##STR00105## ##STR00106## ##STR00107## ##STR00108##
##STR00109## ##STR00110## ##STR00111## ##STR00112## ##STR00113##
##STR00114## ##STR00115## ##STR00116## ##STR00117## ##STR00118##
##STR00119## ##STR00120## ##STR00121## ##STR00122## ##STR00123##
##STR00124## ##STR00125## ##STR00126## ##STR00127## ##STR00128##
##STR00129## ##STR00130## ##STR00131## ##STR00132## ##STR00133##
##STR00134## ##STR00135## ##STR00136## ##STR00137## ##STR00138##
##STR00139## ##STR00140## ##STR00141##
and pharmaceutically acceptable forms thereof.
[0050] Another example of the present invention is a compound
selected from:
##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146##
##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151##
##STR00152## ##STR00153## ##STR00154## ##STR00155## ##STR00156##
##STR00157##
and pharmaceutically acceptable forms thereof.
[0051] Another example of the present invention is a compound
selected from:
##STR00158## ##STR00159## ##STR00160## ##STR00161## ##STR00162##
##STR00163## ##STR00164## ##STR00165## ##STR00166## ##STR00167##
##STR00168##
and pharmaceutically acceptable forms thereof.
[0052] Another example of the present invention is a compound
selected from:
##STR00169## ##STR00170## ##STR00171## ##STR00172## ##STR00173##
##STR00174## ##STR00175##
and pharmaceutically acceptable forms thereof.
DEFINITIONS
[0053] As used herein, the following terms have the following
meanings:
[0054] The term "alkyl" means a saturated branched or straight
chain monovalent hydrocarbon radical of up to 10 carbon atoms.
Alkyl typically includes, but is not limited to, methyl, ethyl,
propyl, isopropyl, n-butyl, t-butyl, pentyl, hexyl, heptyl and the
like.
[0055] The term "lower alkyl" means an alkyl radical of up to 4
carbon atoms. The point of attachment may be on any alkyl or lower
alkyl carbon atom and, when further substituted, substituent
variables may be placed on any carbon atom.
[0056] The term "alkylene" means a saturated branched or straight
chain monovalent hydrocarbon linking group of up to 10 carbon
atoms, whereby the linking group is derived by the removal of one
hydrogen atom each from two carbon atoms. Alkylene typically
includes, but is not limited to, methylene, ethylene, propylene,
isopropylene, n-butylene, t-butylene, pentylene, hexylene,
heptylene and the like. The term "lower alkylene" means an alkylene
linking group of up to 4 carbon atoms. The point of attachment may
be on any alkylene or lower alkylene carbon atom and, when further
substituted, substituent variables may be placed on any carbon
atom.
[0057] The term "alkylidene" means an alkylene linking group of
from 1 to 10 carbon atoms having at least one double bond formed
between two adjacent carbon atoms, wherein the double bond is
derived by the removal of one hydrogen atom each from the two
carbon atoms. Atoms may be oriented about the double bond in either
the cis (E) or trans (Z) conformation. Alkylidene typically
includes, but is not limited to, methylidene, vinylidene,
propylidene, iso-propylidene, methallylene, allylidene
(2-propenylidene), crotylene (2-butenylene), prenylene
(3-methyl-2-butenylene) and the like. The term "lower alkylidene"
means a radical or linking group of from 1 to 4 carbon atoms. The
point of attachment may be on any alkylidene or lower alkylidene
carbon atom and, when further substituted, substituent variables
may be placed on any carbon atom.
[0058] The term "alkoxy" means an alkyl, alkylene or alkylidene
radical of up to 10 carbon atoms attached via an oxygen atom,
whereby the point of attachment is formed by the removal of the
hydrogen atom from a hydroxide substituent on a parent radical. The
term "lower alkoxy" means an alkyl, alkylene or alkylidene radical
of up to 4 carbon atoms. Lower alkoxy typically includes, but is
not limited to, methoxy, ethoxy, propoxy, butoxy and the like. When
further substituted, substituent variables may be placed on any
alkoxy carbon atom.
[0059] The term "cycloalkyl" means a saturated or partially
unsaturated monocyclic, polycyclic or bridged hydrocarbon ring
system radical or linking group. A ring of 3 to 20 carbon atoms may
be designated by C.sub.3-20 cycloalkyl; a ring of 3 to 12 carbon
atoms may be designated by C.sub.3-12 cycloalkyl, a ring of 3 to 8
carbon atoms may be designated by C.sub.3-8 cycloalkyl and the
like.
[0060] Cycloalkyl typically includes, but is not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,
cycloheptyl, cyclooctyl, indanyl, indenyl,
1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro-naphthalenyl,
6,7,8,9-tetrahydro-5H-benzocycloheptenyl,
5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl,
bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl,
bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl,
bicyclo[3.2.1]octenyl, adamantanyl,
octahydro-4,7-methano-1H-indenyl, octahydro-2,5-methano-pentalenyl
and the like. When further substituted, substituent variables may
be placed on any ring carbon atom.
[0061] The term "heterocyclyl" means a saturated, partially
unsaturated or unsaturated monocyclic, polycyclic or bridged
hydrocarbon ring system radical or linking group, wherein at least
one ring carbon atom has been replaced with one or more heteroatoms
independently selected from N, O or S. A heterocyclyl ring system
further includes a ring system having up to 4 nitrogen atom ring
members or a ring system having from 0 to 3 nitrogen atom ring
members and 1 oxygen or sulfur atom ring member. When allowed by
available valences, up to two adjacent ring members may be a
heteroatom, wherein one heteroatom is nitrogen and the other is
selected from N, O or S. A heterocyclyl radical is derived by the
removal of one hydrogen atom from a single carbon or nitrogen ring
atom. A heterocyclyl linking group is derived by the removal of two
hydrogen atoms each from either carbon or nitrogen ring atoms.
[0062] Heterocyclyl typically includes, but is not limited to,
furyl, thienyl, 2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl,
pyrrolidinyl, pyrrolyl, 1,3-dioxolanyl, oxazolyl, thiazolyl,
imidazolyl, 2-imidazolinyl (also referred to as
4,5-dihydro-1H-imidazolyl), imidazolidinyl, 2-pyrazolinyl,
pyrazolidinyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,
triazolyl, thiadiazolyl, tetrazolyl, 2H-pyran, 4H-pyran, pyridinyl,
piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,
thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,
azepanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl,
benzo[b]furyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl,
benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl,
cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl,
1,8-naphthyridinyl, pteridinyl, quinuclidinyl,
hexahydro-1,4-diazepinyl, 1,3-benzodioxolyl (also known as
1,3-methylenedioxyphenyl), 2,3-dihydro-1,4-benzodioxinyl (also
known as 1,4-ethylenedioxyphenyl), benzo-dihydro-furyl,
benzo-tetrahydro-pyranyl, benzo-dihydro-thienyl,
5,6,7,8-tetrahydro-4H-cyclohepta(b)thienyl,
5,6,7-trihydro-4H-cyclohexa(b)thienyl,
5,6-dihydro-4H-cyclopenta(b)thienyl, 2-aza-bicyclo[2.2.1]heptyl,
1-aza-bicyclo[2.2.2]octyl, 8-aza-bicyclo[3.2.1]octyl,
7-oxa-bicyclo[2.2.1]heptyl and the like.
[0063] The term "aryl" means an unsaturated, conjugated .pi.
electron monocyclic or polycyclic hydrocarbon ring system radical
or linking group of 6, 9, 10 or 14 carbon atoms. An aryl radical is
derived by the removal of one hydrogen atom from a single carbon
ring atom. An arylene linking group is derived by the removal of
two hydrogen atoms each of two carbon ring atoms. Aryl typically
includes, but is not limited to, phenyl, naphthalenyl, azulenyl,
anthracenyl and the like.
[0064] The term "carbonyl" means a linking group of the formula
--C(O)-- or --C(.dbd.O)--.
[0065] The term "alkoxycarbonyl" means a radical of the formula
--C(O)O-alkyl.
[0066] The term "carboxy" means a radical of the formula --COOH or
--CO.sub.2H.
[0067] The term "aryloxy" means a radical of the formula
--O-aryl.
[0068] The term "aryloxycarbonyl" means a radical of the formula
--C(O)O-aryl.
[0069] The term "arylalkoxycarbonyl" means a radical of the formula
--C(O)O-alkyl-aryl.
[0070] The term "halo" or "halogen" means fluoro, chloro, bromo or
iodo.
[0071] The term "substituted" means one or more hydrogen atoms on a
core molecule have been replaced with one or more radicals or
linking groups, wherein the linking group, by definition is also
further substituted.
[0072] The term "dependency selected" means one or more substituent
variables are present in a specified combination (e.g. groups of
substituents commonly appearing in a tabular list).
[0073] The substituent nomenclature used in the disclosure of the
present invention was derived using nomenclature rules well known
to those skilled in the art (e.g., IUPAC).
Pharmaceutical Preparations and Methods of Use
[0074] The compounds of the present invention may also be present
in the form of pharmaceutically acceptable salts. For use in
medicines, the salts of the compounds of this invention refer to
non-toxic "pharmaceutically acceptable salts." FDA approved
pharmaceutically acceptable salt forms (Ref. International J.
Pharm. 1986, 33, 201-217; J. Pharm. Sci, 1977, January, 66 (1), p
1) include pharmaceutically acceptable acidic/anionic or
basic/cationic salts.
[0075] Pharmaceutically acceptable acidic/anionic salts include,
and are not limited to acetate, benzenesulfonate, benzoate,
bicarbonate, bitartrate, bromide, calcium edetate, camsylate,
carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, glyceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamoate,
pantothenate, phosphate/diphosphate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulfate, tannate, tartrate,
teoclate, tosylate and triethiodide. Organic or inorganic acids
also include, and are not limited to, hydroiodic, perchloric,
sulfuric, phosphoric, propionic, glycolic, methanesulfonic,
hydroxyethanesulfonic, oxalic, 2-naphthalenesulfonic,
p-toluenesulfonic, cyclohexanesulfamic, saccharinic or
trifluoroacetic acid.
[0076] Pharmaceutically acceptable basic/cationic salts include,
and are not limited to aluminum,
2-amino-2-hydroxymethyl-propane-1,3-diol (also known as
tris(hydroxymethyl)aminomethane, tromethane or "TRIS"), ammonia,
benzathine, t-butylamine, calcium, calcium gluconate, calcium
hydroxide, chloroprocaine, choline, choline bicarbonate, choline
chloride, cyclohexylamine, diethanolamine, ethylenediamine,
lithium, LiOMe, L-lysine, magnesium, meglumine, NH.sub.3,
NH.sub.4OH, N-methyl-D-glucamine, piperidine, potassium,
potassium-t-butoxide, potassium hydroxide (aqueous), procaine,
quinine, sodium, sodium carbonate, sodium-2-ethylhexanoate (SEH),
sodium hydroxide, triethanolamine (TEA) or zinc.
[0077] The present invention includes within its scope prodrugs and
metabolites of the compounds of this invention. In general, such
prodrugs and metabolites will be functional derivatives of the
compounds that are readily convertible in vivo into an active
compound.
[0078] Thus, in the methods of treatment of the present invention,
the term "administering" shall encompass the means for treating,
ameliorating or preventing a syndrome, disorder or disease
described herein with a compound specifically disclosed or a
compound, or prodrug or metabolite thereof, which would obviously
be included within the scope of the invention albeit not
specifically disclosed for certain of the instant compounds.
[0079] The term "prodrug" means a pharmaceutically acceptable form
of a functional derivative of a compound of the invention (or a
salt thereof), wherein the prodrug may be: 1) a relatively active
precursor which converts in vivo to an active prodrug component; 2)
a relatively inactive precursor which converts in vivo to an active
prodrug component; or 3) a relatively less active component of the
compound that contributes to therapeutic biological activity after
becoming available in vivo (i.e., as a metabolite). Conventional
procedures for the selection and preparation of suitable prodrug
derivatives are described in, for example, "Design of Prodrugs",
ed. H. Bundgaard, Elsevier, 1985.
[0080] The term "metabolite" means a pharmaceutically acceptable
form of a metabolic derivative of a compound of the invention (or a
salt thereof), wherein the derivative is a relatively less active
component of the compound that contributes to therapeutic
biological activity after becoming available in vivo.
[0081] The present invention contemplates compounds of various
isomers and mixtures thereof. The term "isomer" refers to compounds
that have the same composition and molecular weight but differ in
physical and/or chemical properties. Such substances have the same
number and kind of atoms but differ in structure. The structural
difference may be in constitution (geometric isomers) or in an
ability to rotate the plane of polarized light (stereoisomers).
[0082] The term: "stereoisomer" refers to isomers of identical
constitution that differ in the arrangement of their atoms in
space. Enantiomers and diastereomers are stereoisomers wherein an
asymmetrically substituted carbon atom acts as a chiral center. The
term "chiral" refers to a molecule that is not superposable on its
mirror image, implying the absence of an axis and a plane or center
of symmetry. The term "enantiomer" refers to one of a pair of
molecular species that are mirror images of each other and are not
superposable. The term "diastereomer" refers to stereoisomers that
are not related as mirror images. The symbols "R" and "S" represent
the configuration of substituents around a chiral carbon atom(s).
The symbols "R*" and "S*" denote the relative configurations of
substituents around a chiral carbon atom(s).
[0083] The term "racemate" or "racemic mixture" refers to a
compound of equimolar quantities of two enantiomeric species,
wherein the compound is devoid of optical activity. The term
"optical activity" refers to the degree to which a chiral molecule
or nonracemic mixture of chiral molecules rotates the plane of
polarized light.
[0084] The term "geometric isomer" refers to isomers that differ in
the orientation of substituent atoms in relationship to a
carbon-carbon double bond, to a cycloalkyl ring or to a bridged
bicyclic system. Substituent atoms (other than H) on each side of a
carbon-carbon double bond may be in an E or Z configuration. In the
"E" (opposite sided) or "chair" configuration, the substituents are
on opposite sides in relationship to the carbon-carbon double bond;
in the "Z" (same sided) or "boat" configuration, the substituents
are oriented on the same side in relationship to the carbon-carbon
double bond. Substituent atoms (other than H) attached to a
carbocyclic ring may be in a cis or trans configuration. In the
"cis" configuration, the substituents are on the same side in
relationship to the plane of the ring; in the "trans"
configuration, the substituents are on opposite sides in
relationship to the plane of the ring. Compounds having a mixture
of "cis" and "trans" species are designated "cis/trans".
Substituent atoms (other than H) attached to a bridged bicyclic
system may be in an "endo" or "exo" configuration. In the "endo"
configuration, the substituents attached to a bridge (not a
bridgehead) point toward the larger of the two remaining bridges;
in the "exo" configuration, the substituents attached to a bridge
point toward the smaller of the two remaining bridges.
[0085] It is to be understood that the various substituent
stereoisomers, geometric isomers and mixtures thereof used to
prepare compounds of the present invention are either commercially
available, can be prepared synthetically from commercially
available starting materials or can be prepared as isomeric
mixtures and then obtained as resolved isomers using techniques
well-known to those of ordinary skill in the art.
[0086] The isomeric descriptors "R," "S," "S*," "R*," "E," "Z,"
"cis," "trans," "exo" and "endo" are used as described herein for
indicating atom configuration(s) relative to a core molecule and
are intended to be used as defined in the literature (IUPAC
Recommendations for Fundamental Stereochemistry (Section E), Pure
Appl. Chem., 1976, 45:13-30).
[0087] The compounds of the present invention may be prepared as
individual isomers by either isomer-specific synthesis or resolved
from an isomeric mixture. Conventional resolution techniques
include forming the free base of each isomer of an isomeric pair
using an optically active salt (followed by fractional
crystallization and regeneration of the free base), forming an
ester or amide of each of the isomers of an isomeric pair (followed
by chromatographic separation and removal of the chiral auxiliary)
or resolving an isomeric mixture of either a starting material or a
final product using preparative TLC (thin layer chromatography) or
a chiral HPLC column.
[0088] Furthermore, compounds of the present invention may have one
or more polymorph or amorphous crystalline forms and as such are
intended to be included in the scope of the invention. In addition,
some of the compounds may form solvates with water (i.e., hydrates)
or common organic solvents, and such are also intended to be
encompassed within the scope of this invention.
[0089] During any of the processes for preparation of the compounds
of the present invention, it may be necessary and or desirable to
protect sensitive or reactive groups on any of the molecules
concerned. This may be achieved by means of conventional protecting
groups, such as those described in Protective Groups in Organic
Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.
Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis,
John Wiley & Sons, 1991. The protecting groups may be removed
at a convenient subsequent stage using methods known in the
art.
[0090] Therapeutic Use
[0091] CB1 and CB2 cannabinoid receptors belong to the
G-protein-coupled receptor (GCPR) family, a receptor super-family
with a distinctive pattern of seven transmembrane domains, which
inhibits N-type calcium channels and/or adenylate cyclase to
inhibit Q-type calcium channels. CB1 receptors are present in the
CNS, predominately expressed in brain regions associated with
memory and movement such as the hippocampus (memory storage),
cerebellum (coordination of motor function, posture and balance),
basal ganglia (movement control), hypothalamus (thermal regulation,
neuroendocrine release, appetite), spinal cord (nociception),
cerebral cortex (emesis) and periphery regions such as lymphoid
organs (cell mediated and innate immunity), vascular smooth muscle
cells (blood pressure), gastrointestinal tract (duodenum, ileum and
myenteric plexus for emesis control), lung smooth muscle cells
(bronchodilation), eye ciliary body (intraocular pressure). CB2
receptors appear to be primarily expressed peripherally in lymphoid
tissue (cell mediated and innate immunity), peripheral nerve
terminals (peripheral nervous system), spleen immune cells (immune
system modulation) and retina (intraocular pressure) and in the CNS
in cerebellar granule cell mRNA (coordination of motor function).
Pharmacological and physiological evidence also suggests that there
may be other cannabinoid receptor subtypes that have yet to be
cloned and characterized.
[0092] Where activation or inhibition of a CB receptor appears to
mediate various syndromes, disorders or diseases, potential areas
of clinical application include, but are not limited to,
controlling appetite, regulating metabolism, diabetes, reducing
glaucoma-associated intraocular pressure, treating social and mood
disorders, treating seizure-related disorders, treating substance
abuse disorders, enhancing learning, cognition and memory,
controlling organ contraction and muscle spasm, treating
respiratory disorders, treating locomotor activity or movement
disorders, treating immune and inflammation disorders, regulating
cell growth, use in pain management, use as a neuroprotective agent
and the like.
[0093] Thus, cannabinoid receptor modulators, including the
compounds of the formula (I), (Ia), (Ib) or (Ic) of the present
invention, are useful for treating, ameliorating or preventing a
cannabinoid receptor mediated syndrome, disorder or disease
including, but not limited to, controlling appetite, regulating
metabolism, diabetes, glaucoma-associated intraocular pressure,
pain, social and mood disorders, seizure-related disorders,
substance abase disorders, learning, cognition and/or memory
disorders, respiratory disorders, locomotor activity disorders,
movement disorders, immune disorders or inflammation disorders,
controlling organ contraction and muscle spasm, enhancing learning,
cognition and/or memory, regulating cell growth, providing
neuroprotection and the like.
[0094] The present invention is directed to a method for treating,
ameliorating or preventing a cannabinoid receptor mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a compound of formula (I).
[0095] The present invention is directed to a method for treating,
ameliorating or preventing a cannabinoid receptor mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a compound of formulae (Ia), (Ib) or (Ic) or prodrug,
metabolite, or composition thereof.
[0096] The present invention is directed to a method for treating,
ameliorating or preventing a cannabinoid receptor mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject a combination
product and/or therapy comprising an effective amount of a compound
of formula (I) and a therapeutic agent.
[0097] The present invention is directed to a method for treating,
ameliorating or preventing a cannabinoid receptor mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject a combination
product and/or therapy comprising an effective amount of a compound
of formulae (Ia), (Ib), or (Ic) and a therapeutic agent.
[0098] Therapeutic agents contemplated for use in a combination
product and/or therapies of the present invention include an
anticonvulsant or a contraceptive agent. The anticonvulsant agents
include, and are not limited to, topiramate, analogs of topiramate,
carbamazepine, valproic acid, lamotrigine, gabapentin, phenyloin
and the like and mixtures or pharmaceutically acceptable salts
thereof. The contraceptive agents include, and are not limited to,
such as progestin-only contraceptives and contraceptives that
include both a progestin component and an estrogen component. The
invention further includes a pharmaceutical composition wherein the
contraceptive is an oral contraceptive, and wherein the
contraceptive optionally includes a folic acid component.
[0099] The invention also includes a method of contraception in a
subject comprising the step of administering to the subject a
composition, wherein the composition comprises a contraceptive and
a CB1 receptor inverse-agonist or antagonist compound of formulae
(I), (Ia), (Ib) or (Ic), wherein the composition reduces the urge
to smoke in the subject and/or assists the subject in losing
weight.
[0100] The present invention includes cannabinoid receptor
modulators useful for treating, ameliorating or preventing a CB
receptor mediated syndrome, disorder or disease. The usefulness of
a compound of the present invention or composition thereof as a CB
modulator can be determined according to the methods disclosed
herein. The scope of such use includes treating, ameliorating or
preventing a plurality of CB receptor mediated syndromes, disorders
or diseases.
[0101] The present invention is also directed to a method for
treating, ameliorating or preventing a CB receptor mediated
syndrome, disorder or disease in a subject in need thereof wherein
the syndrome, disorder or disease is related to appetite,
metabolism, diabetes, glaucoma-associated intraocular pressure,
social and mood disorders, seizures, substance abuse, learning,
cognition or memory, organ contraction or muscle spasm, respiratory
disorders, locomotor activity or movement disorders, immune and
inflammation disorders, unregulated cell growth, pain management,
neuroprotection and the like.
[0102] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator includes a compound having a mean inhibition
constant (IC.sub.50) for CB receptor binding activity of between
about 5 .mu.M to about 0.01 nM; between about 1 .mu.M to about 0.01
nM; between about 800 nM to about 0.01 nM; between about 200 nM to
about 0.01 nM; between about 100 nM to about 0.01 nM; between about
80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;
between about 10 nM to about 0.1 nM; or about 1 nM.
[0103] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator of the invention includes a compound having a
CB1 agonist IC.sub.50 for CB1 agonist binding activity of between
about 5 .mu.M to about 0.01 nM; between about 1 .mu.M to about 0.01
nM; between about 800 nM to about 0.01 nM; between about 200 nM to
about 0.01 nM; between about 100 nM to about 0.01 nM; between about
80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;
between about 10 nM to about 0.1 nM; or about 1 nM.
[0104] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator of the invention includes a compound having a
CB1 antagonist IC.sub.50 for CB1 antagonist binding activity of
between about 5 .mu.M to about 0.01 nM; between about 1 .mu.M to
about 0.01 nM; between about 800 nM to about 0.01 nM; between about
200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM;
between about 80 nM to about 0.01 nM; between about 20 nM to about
0.01 nM; between about 10 nM to about 0.1 nM; or about 1 nM.
[0105] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator of the invention includes a compound having a
CB1 inverse-agonist IC.sub.50 for CB3 inverse-agonist binding
activity of between about 5 .mu.M to about 0.01 nM; between about 1
.mu.M to about 0.01 nM; between about 800 nM to about 0.01 nM;
between about 200 nM to about 0.01 nM; between about 100 nM to
about 0.01 nM; between about 80 nM to about 0.01 nM; between about
20 nM to about 0.01 nM; between about 10 nM to about 0.1 nM; or
about 1 nM.
[0106] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator of the invention includes a compound having a
CB2 agonist IC.sub.50 for CB2 agonist binding activity of between
about 5 .mu.M to about 0.01 nM; between about 1 .mu.M to about 0.01
nM; between about 800 nM to about 0.01 nM; between about 200 nM to
about 0.01 nM; between about 300 nM to about 0.01 nM; between about
80 nM to about 0.03 nM; between about 20 nM to about 0.01 nM;
between about 10 nM to about 0.1 nM; or about 1 nM.
[0107] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator of the invention includes a compound having a
CB2 antagonist IC.sub.50 for CB2 antagonist binding activity of
between about 5 .mu.M to about 0.01 nM; between about 1 .mu.M to
about 0.01 nM; between about 800 nM to about 0.01 nM; between about
200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM;
between about 80 nM to about 0.01 nM; between about 20 nM to about
0.01 nM; between about 10 nM to about 0.1 nM; or about 1 nM.
[0108] A compound of formulae (I), (Ia), (Ib) or (Ic) for use as a
CB receptor modulator of the invention includes a compound having a
CB2 inverse-agonist IC.sub.50 for CB2 inverse-agonist binding
activity of between about 5 .mu.M to about 0.01 nM; between about 1
.mu.M to about 0.01 nM; between about 800 nM to about 0.01 nM;
between about 200 nM to about 0.01 nM; between about 100 nM to
about 0.01 nM; between about 80 nM to about 0.01 nM; between about
20 nM to about 0.01 nM; between about 10 nM to about 0.1 nM; or
about 1 nM.
[0109] The term "cannabinoid receptor" refers to any one of the
known or heretofore unknown subtypes of the class of cannabinoid
receptors that may be bound by a cannabinoid modulator compound of
the present invention; in particular, a cannabinoid receptor
selected from the group consisting of a CB1 receptor and a CB2
receptor. The term "modulator" further refers to the use of a
compound of the invention as a CB receptor agonist, antagonist or
inverse-agonist.
[0110] The present invention includes a method for treating,
ameliorating or preventing a CB receptor mediated syndrome,
disorder or disease in a subject in need thereof comprising the
step of administering to the subject an effective amount of a
compound of the present invention or composition thereof, wherein
the cannabinoid receptor is a CB1 or CB2 receptor; and, the
compound is an agonist, antagonist or inverse-agonist of the
receptor.
[0111] The present invention includes a method for treating,
ameliorating or preventing a CB receptor mediated syndrome,
disorder or disease in a subject in need thereof comprising the
step of administering to the subject an effective amount of a
compound of the present invention in a combination product and/or
therapy with a therapeutic agent such as an anticonvulsant or
contraceptive agent or composition thereof, wherein the cannabinoid
receptor is a CB1 or CB2 receptor; and, the compound is an agonist,
antagonist or inverse-agonist of the receptor.
[0112] It should be understood that contraceptive agents suitable
for use in a combination product and/or therapy are not limited to
oral contraceptives, but also include other commonly available
contraceptives such as those that are administered transdermally,
by injection or via implant.
[0113] Except as further specified, "combination product and/or
therapy" means a pharmaceutical composition comprising a compound
of formulae (I), (Ia), (Ib) or (Ic) in combination with one or more
therapeutic agents. The dosages of the compound of formula (I) and
the one or more therapeutic agents are adjusted when combined to
achieve an effective amount.
[0114] The term "subject" as used herein, refers to a patient,
which may be an animal, preferably a mammal, most preferably a
human, which has been the object of treatment, observation or
experiment and is at risk of (or susceptible to) developing a CB
receptor mediated syndrome, disorder or disease.
[0115] The term "administering" is to be interpreted in accordance
with the methods of the present invention. Such methods include
therapeutically or prophylactically administering an effective
amount of a composition or medicament of the present invention at
different times during the course of a therapy or concurrently as a
product in a combination form.
[0116] Prophylactic administration can occur prior to the
manifestation of symptoms characteristic of a CB receptor mediated
syndrome, disorder or disease such that the syndrome, disorder or
disease is treated, ameliorated, prevented or otherwise delayed in
its progression. The methods of the present invention are further
to be understood as embracing all therapeutic or prophylactic
treatment regimens used by those skilled in the art.
[0117] The term "effective amount" refers to that amount of active
compound or pharmaceutical agent that elicits the biological or
medicinal response in a tissue system, animal or human, that is
being sought by a researcher, veterinarian, medical doctor, or
other clinician, which includes alleviation of the symptoms of the
syndrome, disorder or disease being treated. The effective amount
of a compound of the invention is from about 0.001 mg/kg/day to
about 300 mg/kg/day.
[0118] Wherein the present invention is directed to the
administration of a combination of a compound of formula (I) and an
anticonvulsant or contraceptive agent, the term "effective amount"
means that amount of the combination of agents taken together so
that the combined effect elicits the desired biological or
medicinal response.
[0119] As those skilled in the art will appreciate, the effective
amounts of the components comprising the combination product may be
independently optimized and combined to achieve a synergistic
result whereby the pathology is reduced more than it would be if
the components of the combination product were used alone.
[0120] For example, the effective amount of a combination product
and/or therapy comprising administration of a compound of formula
(I) and topiramate would be the amount of the compound of formula
(I) and the amount of topiramate that when taken together or
sequentially have a combined effect that is effective. Further, it
will be recognized by one skilled in the art that in the ease of
combination product and/or therapy with an effective amount, as in
the example above, the amount of the compound of formula (I) and/or
the amount of the anticonvulsant (e.g., topiramate) individually
may or may not be effective.
[0121] Wherein the present invention is directed to the
administration of a combination product and/or therapy, the instant
compound and the anticonvulsant or contraceptive agent may be
co-administered by any suitable means, simultaneously, sequentially
or in a single pharmaceutical composition. Where the instant
compound(s) and the anticonvulsant or contraceptive agent
components are administered separately, the number of dosages of
each compound(s) given per day, may not necessarily be the same,
e.g. where one compound may have a greater duration of activity,
and will therefore, be administered less frequently.
[0122] The compound(s) of formula (I) and the anticonvulsant(s) or
contraceptive agent(s) may be administered via the same or
different routes of administration. The compound(s) of formula (I)
and the anticonvulsant(s) or contraceptive agent(s) may be
administered via the same or different routes of
administration.
[0123] Suitable examples of methods of administration are orally,
intravenous (iv), intramuscular (im), and subcutaneous (sc).
Compounds may also be administrated directly to the nervous system
including, but not limited to the intracerebral, intraventricular,
intracerebroventricular, intrathecal, intracisternal, intraspinal
and/or peri-spinal routes of administration by delivery via
intracranial or intravertebral needles and/or catheters with or
without pump devices.
[0124] The compound(s) of formula (I) and the anticonvulsant(s) or
contraceptive agent(s) may be administered according to
simultaneous or alternating regimens, at the same or different
times during the course of the therapy, concurrently in divided or
single forms.
[0125] Optimal dosages to be administered may be readily determined
by those skilled in the art, and will vary with the particular
compound used, the mode of administration, the strength of the
preparation and the advancement of the disease condition. In
addition, factors associated with the particular patient being
treated, including patient's sex, age, weight, diet, time of
administration and concomitant diseases, will result in the need to
adjust dosages.
[0126] The term "CB receptor mediated syndrome, disorder, or
disease" refers to syndromes, disorders or diseases associated with
a biological response mediated by a CB receptor such that there is
discomfort or decreased life expectancy to the organism.
[0127] CB receptor mediated syndromes, disorders or diseases can
occur in both animals and humans and include appetite, metabolism,
diabetes, obesity, glaucoma-associated intraocular pressure,
social, mood, seizure, substance abuse, learning, cognition,
memory, organ contraction, muscle spasm, respiratory, locomotor
activity, movement, immune, inflammation, cell growth, pain or
neurodegenerative related syndromes, disorders or diseases.
[0128] Appetite related syndromes, disorders or diseases include
obesity, overweight condition, anorexia, bulimia, cachexia,
dysregulated appetite and the like.
[0129] Obesity related syndromes, disorders or diseases include
obesity as a result of genetics, diet, food intake volume,
metabolic syndrome, disorder or disease, hypothalmic disorder or
disease, age, reduced activity, abnormal adipose mass distribution,
abnormal adipose compartment distribution and the like.
[0130] Metabolism related syndromes, disorders or diseases include
metabolic syndrome, dyslipidemia, elevated blood pressure,
diabetes, insulin sensitivity or resistance, hyperinsulinemia,
hypercholesterolemia, hyperlipidemias, hypertriglyceridemias,
atherosclerosis, hepatomegaly, steatosis, abnormal alanine
aminotransferase levels, inflammation, atherosclerosis and the
like.
[0131] Diabetes related syndromes, disorders or diseases include
glucose dysregulation, insulin resistance, glucose intolerance,
hyperinsulinemia, dyslipidemia, hypertension, obesity and the
like.
[0132] Type II diabetes mellitus (non-insulin-dependent diabetes
mellitus) is a metabolic disorder (i.e., a metabolism related
syndrome, disorder or disease) in which glucose dysregulation and
insulin resistance results in chronic, long-term medical
complications for both adolescents and adults affecting the eyes,
kidneys, nerves and blood vessels and can lead to blindness,
end-stage renal disease, myocardial infarction or limb amputation
and the like. Glucose dysregulation includes the inability to make
sufficient insulin (abnormal insulin secretion) and the inability
to effectively use insulin (resistance to insulin action in target
organs and tissues). Individuals suffering from Type II diabetes
mellitus have a relative insulin deficiency. That is, in such
individuals, plasma insulin levels are normal to high in absolute
terms, although they are lower than predicted for the level of
plasma glucose that is present.
[0133] Type II diabetes mellitus is characterized by the following
clinical signs or symptoms: persistently elevated plasma glucose
concentration or hyperglycemia; polyuria; polydipsia and/or
polyphagia; chronic microvascular complications such as
retinopathy, nephropathy and neuropathy; and macrovascular
complications such as hyperlipidemia and hypertension. These micro-
and macro-vascular complications can lead to blindness, end-stage
renal disease, limb amputation and myocardial infarction.
[0134] Insulin Resistance Syndrome (IRS) (also referred to as
Syndrome X, Metabolic Syndrome or Metabolic Syndrome X) is a
disorder that presents risk factors for the development of Type II
diabetes and cardiovascular disease including glucose intolerance,
hyperinsulinemia, insulin resistance, dyslipidemia (e.g. high
triglycerides, low HDL-cholesterol and the like), hypertension and
obesity.
[0135] Social or mood related syndromes, disorders or diseases
include depression, anxiety, psychosis, social affective disorders
or cognitive disorders and the like.
[0136] Substance abuse related syndromes, disorders or diseases
include drug abuse, drug withdrawal, alcohol abuse, alcohol
withdrawal, nicotine withdrawal, cocaine abuse, cocaine withdrawal,
heroin abuse, heroin withdrawal and the like.
[0137] Learning, cognition or memory related syndromes, disorders
or diseases include memory loss or impairment as a result of age,
disease, side effects of medications (adverse events) and the
like.
[0138] Muscle spasm syndromes, disorders or diseases include
multiple sclerosis, cerebral palsy and the like.
[0139] Locomotor activity and movement syndromes, disorders or
diseases include stroke, Parkinson's disease, multiple sclerosis,
epilepsy and the like.
[0140] Respiratory related syndromes, disorders or diseases include
chronic pulmonary obstructive disorder, emphysema, asthma,
bronchitis and the like.
[0141] Immune or inflammation related syndromes, disorders or
diseases include allergy, rheumatoid arthritis, dermatitis,
autoimmune disease, immunodeficiency, chronic neuropathic pain and
the like.
[0142] Cell growth related syndromes, disorders or diseases include
dysregulated mammalian cell proliferation, breast cancer cell
proliferation, prostrate cancer cell proliferation and the
like.
[0143] Pain related syndromes, disorders or diseases include
central and peripheral pathway mediated pain, bone and joint pain,
migraine headache associated pain, cancer pain, menstrual cramps,
labor pain and the like.
[0144] Neurodegenerative related syndromes, disorders or diseases
include Parkinson's Disease, multiple sclerosis, epilepsy, ischemia
or secondary biochemical injury collateral to traumatic head or
brain injury, brain inflammation, eye injury or stroke and the
like.
[0145] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid agonist compound of the present invention
or composition thereof.
[0146] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid agonist compound of the present invention
in a combination product and/or therapy with an anticonvulsant or
composition thereof.
[0147] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor inverse-agonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid inverse-agonist compound of the present
invention or composition thereof.
[0148] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor inverse-agonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid inverse-agonist compound of the present
invention in a combination product and/or therapy with an
anticonvulsant or composition thereof.
[0149] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor inverse-agonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid inverse-agonist compound of the present
invention in a combination product and/or therapy with one or more
contraceptives or composition thereof.
[0150] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor antagonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid antagonist compound of the present
invention or composition thereof.
[0151] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor antagonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a cannabinoid antagonist compound of the present
invention in a combination product and/or therapy with an
anticonvulsant or composition thereof.
[0152] The present invention includes a method for treating,
ameliorating or preventing a cannabinoid receptor antagonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject a
therapeutically or prophylactically effective amount of a
cannabinoid antagonist compound of the present invention in a
combination product and/or therapy with one or more contraceptives
or composition thereof.
[0153] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 agonist compound of the present invention or
composition thereof.
[0154] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 agonist compound of the present invention in a
combination product and/or therapy with an anticonvulsant or
composition thereof.
[0155] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 inverse-agonist compound of the present invention
or composition thereof.
[0156] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 inverse-agonist compound of the present invention
in a combination product and/or therapy with an anticonvulsant or
composition thereof.
[0157] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 inverse-agonist compound of the present invention
in a combination product and/or therapy with one or more
contraceptives or composition thereof.
[0158] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
appetite related obesity related or metabolism related syndrome,
disorder or disease in a subject in need thereof comprising the
step of administering to the subject an effective amount of a CB1
inverse-agonist compound of the present invention or composition
thereof.
[0159] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
appetite related obesity related or metabolism related syndrome,
disorder or disease in a subject in need thereof comprising the
step of administering to the subject an effective amount of a CB1
inverse-agonist compound of the present invention in a combination
product and/or therapy with an anticonvulsant or composition
thereof.
[0160] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor inverse-agonist mediated
appetite related obesity related or metabolism related syndrome,
disorder or disease in a subject in need thereof comprising the
step of administering to the subject an effective amount of a CB1
inverse-agonist compound of the present invention in a combination
product and/or therapy with one or more contraceptives or
composition thereof.
[0161] Appetite related syndromes, disorders or diseases include
obesity, overweight condition, anorexia, bulimia, cachexia,
dysregulated appetite and the like.
[0162] Obesity related syndromes, disorders or diseases include
obesity as a result of genetics, diet, food intake volume,
metabolic syndrome, disorder or disease, hypothalmic disorder or
disease, age, reduced activity, abnormal adipose mass distribution,
abnormal adipose compartment distribution and the like.
[0163] Metabolism related syndromes, disorders or diseases include
metabolic syndrome, dyslipidemia, elevated blood pressure,
diabetes, insulin sensitivity or resistance, hyperinsulinemia,
hypercholesterolemia, hyperlipidemias, hypertriglyceridemias,
atherosclerosis, hepatomegaly, steatosis, abnormal alanine
aminotransferase levels, inflammation, atherosclerosis and the
like.
[0164] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor antagonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 antagonist compound of the present invention or
composition thereof.
[0165] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor antagonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 antagonist compound of the present invention in a
combination product and/or therapy with an anticonvulsant or
composition thereof.
[0166] The present invention includes a method for treating,
ameliorating or preventing a CB1 receptor antagonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB1 antagonist compound of the present invention in a
combination product and/or therapy with one or more contraceptives
or composition thereof.
[0167] The present invention includes a method for treating,
ameliorating or preventing a CB2 receptor agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB2 agonist compound of the present invention or
composition thereof.
[0168] The present invention includes a method for treating,
ameliorating or preventing a CB2 receptor agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB2 agonist compound of the present invention in a
combination product and/or therapy with an anticonvulsant or
composition thereof.
[0169] The present invention includes include a method for
treating, ameliorating or preventing a CB2 receptor inverse-agonist
mediated syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB2 inverse-agonist compound of the present invention
or composition thereof.
[0170] The present invention includes a method for treating,
ameliorating or preventing a CB2 receptor inverse-agonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB2 inverse-agonist compound of the present invention
in a combination product and/or therapy with an anticonvulsant or
composition thereof.
[0171] The present invention includes a method for treating,
ameliorating or preventing a CB2 receptor antagonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB2 antagonist compound of the present invention or
composition thereof.
[0172] The present invention includes a method for treating,
ameliorating or preventing a CB2 receptor antagonist mediated
syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a CB2 antagonist compound of the present invention in a
combination product and/or therapy with an anticonvulsant or
composition thereof.
[0173] The present invention includes a method for treating,
ameliorating or preventing a metabolism related syndrome, disorder
or disease, an appetite related syndrome, disorder or disease, a
diabetes related syndrome, disorder or disease, an obesity related
syndrome, disorder or disease or a learning, cognition or memory
related syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a compound of the present invention or composition
thereof.
[0174] The present invention includes a method for treating,
ameliorating or preventing a metabolism related syndrome, disorder
or disease, an appetite related syndrome, disorder or disease, a
diabetes related syndrome, disorder or disease, an obesity related
syndrome, disorder or disease or a learning, cognition or memory
related syndrome, disorder or disease in a subject in need thereof
comprising the step of administering to the subject an effective
amount of a compound of the present invention in a combination
product and/or therapy with an anticonvulsant or composition
thereof.
[0175] The present invention includes a pharmaceutical composition
or medicament comprising an admixture of a compound of the present
invention and an optional pharmaceutically acceptable carrier.
[0176] The present invention includes a pharmaceutical composition
or medicament comprising an admixture of two or more compounds of
the present invention and an optional pharmaceutically acceptable
carrier.
[0177] The present invention also includes a pharmaceutical
composition or medicament comprising an admixture of a compound of
formula (I), an anticonvulsant and an optional pharmaceutically
acceptable carrier.
[0178] Such pharmaceutical compositions are particularly useful for
treating a subject suffering from a metabolism related syndrome,
disorder or disease, an appetite related syndrome, disorder or
disease, a diabetes related syndrome, disorder or disease, an
obesity related syndrome, disorder or disease, or a learning,
cognition or memory related syndrome, disorder or disease.
[0179] Anticonvulsants useful in the methods and compositions of
the present invention in combination with a compound of formula
(I), (Ia), (Ib) or (Ic) include, but are not limited to,
topiramate, analogs of topiramate, carbamazepine, valproic acid,
lamotrigine, gabapentin, phenyloin and the like and mixtures or
pharmaceutically acceptable salts thereof.
[0180] Topiramate,
2,3:4,5-bis-O-(1-methylethylidene)-.beta.-D-fructopyranose
sulfamate, is currently marketed for the treatment of seizures in
patients with simple and complex partial epilepsy and seizures in
patients with primary or secondary generalized seizures in the
United States, Europe and most other markets throughout the world.
Topiramate is currently available for oral administration in round
tablets containing 25 mg, 100 mg or 200 mg of active agent, and as
15 mg and 25 mg sprinkle capsules for oral administration as whole
capsules or opened and sprinkled onto soft food. U.S. Pat. No.
4,513,006, incorporated herein by reference, discloses topiramate
and analogs of topiramate, their manufacture and use for treating
epilepsy. Additionally, topiramate may also be made by the process
disclosed in U.S. Pat. Nos. 5,242,942 and 5,384,327, which are
incorporated by reference herein. The term "analogs of topiramate",
as used herein, refers to the sulfamate compounds of formula (I),
which are disclosed in U.S. Pat. No. 4,513,006 (see, e.g., column
1, lines 36-65 of U.S. Pat. No. 4,513,006).
[0181] For use in the methods of the present invention in
combination with a compound of the formula (I), (Ia), (Ib) or (Ic),
topiramate (or an analog of topiramate) can be administered in the
range of about 10 to about 1000 mg daily, preferably in the range
of about 10 to about 650 mg daily, more preferably in the range of
about 15 to about 325 mg once or twice daily.
[0182] Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide, is an
anticonvulsant and specific analgesic for trigeminal neuralgia,
available for oral administration as chewable tablets of 100 mg,
tablets of 200 mg, XR (extended release) tablets of 100, 200, and
400 mg, and as a suspension of 100 mg/5 mL (teaspoon); U.S. Pat.
No. 2,948,718, herein incorporated by reference in its entirety,
discloses carbamazepine and its methods of use.
[0183] For use in the methods of the present invention in
combination with a compound of the formula (I), (Ia), (Ib) or (Ic),
carbamazepine can be administered in the range of about 200 to
about 1200 mg/day; preferably, about 400 mg/day.
[0184] Valproic acid, 2-propylpentanoic acid or dipropylacetic
acid, is an antiepileptic agent commercially available as soft
elastic capsules containing 250 mg valproic acid, and as syrup
containing the equivalent of 250 mg valproic acid per 5 mL as the
sodium salt. Valproic acid and various pharmaceutically acceptable
salts are disclosed in U.S. Pat. No. 4,699,927, which is
incorporated by reference herein in its entirety.
[0185] For use in the methods of the present invention in
combination with a compound of the formula (I), (Ia), (Ib) or (Ic),
valproic acid can be administered in the range of about 250 to
about 2500 mg/day; preferably, about 1000 mg/day.
[0186] Lamotrigine,
3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is an
antiepileptic drug commercially available for oral administration
as tablets containing 25 mg, 100 mg, 150 mg, and 200 mg of
lamotrigine, and as chewable dispersible tablets containing 2 mg, 5
mg, or 25 mg of lamotrigine. Lamotrigine and its uses are disclosed
in U.S. Pat. No. 4,486,354, incorporated by reference herein in its
entirety.
[0187] For use in the methods of the present invention in
combination with a compound of the formula (I), (Ia), (Ib) or (Ic),
lamotrigine can be administered in the range of about 50 to about
600 mg/day in one to two doses; preferably, about 200 to about 400
mg/day; most preferably, about 200 mg/day.
[0188] Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid, is
commercially available for the adjunctive treatment of epilepsy and
for postherpetic neuralgia in adults as capsules containing 100 mg,
300 mg, and 400 mg of gabapentin, film-coated tablets containing
600 mg and 800 mg of gabapentin, and an oral solution containing
250 mg/5 mL of gabapentin. Gabapentin and its methods of use are
described in U.S. Pat. Nos. 4,024,175 and 4,087,544, herein
incorporated by reference in their entirety.
[0189] For use in the methods of the present invention in
combination with a compound of the formula (I), (Ia), (Ib) or (Ic),
gabapentin can be administered in the range of about 300 to about
3600 mg/day in two to three divided doses; preferably, about 300 to
about 1800 mg/day; most preferably, about 900 mg/day.
[0190] Phenyloin sodium, 5,5-diphenylhydantoin sodium salt, is an
anticonvulsant, which is commercially available for oral
administration as capsules containing 100 mg, 200 mg or 300 mg of
phenyloin sodium.
[0191] For use in the methods of the present invention in
combination with a compound of the formula (I), (Ia), (Ib) or (Ic),
phenyloin sodium can be administered in the range of about 100 to
about 500 mg/day; preferably, about 300 to about 400 mg/day; most
preferably, about 300 mg/day.
[0192] The present invention also includes a pharmaceutical
composition or medicament comprising an admixture of a compound of
formula (I), (Ia), (Ib) or (Ic), one or more contraceptives and an
optional pharmaceutically acceptable carrier.
[0193] Contraceptives suitable for use in a combination product
and/or therapy include, for example, ORTHO CYCLEN.RTM., ORTHO
TRI-CYCLEN.RTM., ORTHO TRI-CYCLEN LO.RTM., and ORTHO EVRA.RTM., all
available from Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J. It
should also be understood that contraceptives suitable for use in
the invention encompass those contraceptives that include a folic
acid component.
[0194] Smoking and/or obesity have been identified as risk factors
in women taking oral contraceptives. CB1 receptor antagonists and
inverse agonists have been found to be useful therapeutic agents
for reducing the urge to smoke and for assisting patients with
eating disorders to lose weight.
[0195] Accordingly, the invention further includes a method of
reducing the risk factors associated with smoking and/or obesity
for women taking contraceptives by co-administering with a
contraceptive at least one of a CB1 receptor antagonist and/or CB1
receptor inverse-agonist compound of formula (I), (Ia), (Ib) or
(Ic).
[0196] The use of such compounds or a pharmaceutical composition or
medicament thereof is to reduce the desire to smoke and/or to
assist in weight loss for patients taking contraceptives.
[0197] The term "composition" refers to a product comprising the
specified ingredients in the specified amounts, as well as any
product that results, directly or indirectly, from combinations of
the specified ingredients in the specified amounts. The invention
further comprises mixing one or more of the compounds of the
invention and a pharmaceutically acceptable carrier; and, includes
those compositions resulting from such a process. Contemplated
processes include both traditional and modern pharmaceutical
techniques.
[0198] Pharmaceutical compositions of the invention may,
alternatively or in addition to a compound of formula (I), (Ia),
(Ib) or (Ic), comprise a pharmaceutically acceptable salt of a
compound of formula (I), (Ia), (Ib) or (Ic) or a prodrug or
pharmaceutically active metabolite of such a compound or salt in
admixture with a pharmaceutically acceptable carrier.
[0199] The term "medicament" refers to a product for use in
treating, ameliorating or preventing a cannabinoid receptor
mediated syndrome, disorder or disease.
[0200] "Pharmaceutically acceptable carrier" means molecular
entities and compositions that are of sufficient purity and quality
for use in the formulation of a composition of the invention and
that, when appropriately administered to an animal or a human, do
not produce an adverse, allergic, or other untoward reaction.
[0201] Since both clinical and veterinary uses are equally included
within the scope of the present invention, a pharmaceutically
acceptable formulation would include a composition or medicament
formulation for either clinical or veterinary use.
[0202] The present invention includes a process for making the
composition or medicament comprising mixing any of the instant
compounds and a pharmaceutically acceptable carrier and include
those compositions or medicaments resulting from such a process.
Contemplated processes include both conventional and unconventional
pharmaceutical techniques. Other examples include a composition or
medicament comprising a mixture of at least two of the instant
compounds in association with a pharmaceutically acceptable
carrier.
[0203] The composition or medicament may be administered in a wide
variety of dosage unit forms depending on the method of
administration; wherein such methods include (without limitation)
oral, sublingual, nasal (inhaled or insufflated), transdermal,
rectal, vaginal, topical (with or without occlusion), intravenous
(bolus or infusion) or for injection (intraperitoneally,
subcutaneously, intramuscularly, intratumorally or parenterally)
using a suitable dosage form well known to those of ordinary skill
in the area of pharmaceutical administration. Accordingly, the term
"dosage unit" or "dosage form" is alternatively used to refer to
(without limitation) a tablet, pill, capsule, solution, syrup,
elixir, emulsion, suspension, suppository, powder, granule or
sterile solution, emulsion or suspension (for injection from an
ampoule or using a device such as an auto-injector or for use as an
aerosol, spray or drop). Furthermore, the composition may be
provided in a form suitable for weekly or monthly administration
(e.g. as an insoluble salt of the active compound (such as the
decanoate salt) adapted to provide a depot preparation for
intramuscular injection).
[0204] In preparing a dosage form, the principal active ingredient
(such as a compound of the present invention or a pharmaceutically
acceptable salt, racemate, enantiomer, or diastereomer thereof) is
optionally mixed with one or more pharmaceutical carriers (such as
a starch, sugar, diluent, granulating agent, lubricant, glidant,
binder, disintegrating agent and the like), one or more inert
pharmaceutical excipients (such as water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, syrup and the
like), one or more conventional tableting ingredient (such as corn
starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium
stearate, dicalcium phosphate, any of a variety of gums and the
like) and a diluent (such as water and the like) to form a
homogeneous composition (whereby the active ingredient is dispersed
or suspended evenly throughout the mixture) which may be readily
subdivided into dosage units containing equal amounts of a compound
of the present invention.
[0205] Binders include, without limitation, starch, gelatin,
natural sugars (such as glucose, beta-lactose and the like), corn
sweeteners and natural and synthetic gums (such as acacia,
tragacanth, sodium oleate, sodium stearate, magnesium stearate,
sodium benzoate, sodium acetate, sodium chloride and the like).
Disintegrating agents include, without limitation, starch, methyl
cellulose, agar, bentonite, xanthan gum and the like.
[0206] Because of the ease of administration, tablets and capsules
represent an advantageous oral dosage unit form, wherein solid
pharmaceutical carriers are employed. If desired, tablets may be
sugar or film coated or enteric-coated by standard techniques.
Tablets may also be coated or otherwise compounded to provide a
prolonged therapeutic effect. For example, the dosage form may
comprise an inner dosage and an outer dosage component, whereby the
outer component is in the form of an envelope over the inner
component. The two components may further be separated by a layer,
which resists disintegration in the stomach (such as an enteric
layer) and permits the inner component to pass intact into the
duodenum or a layer which delays or sustains release. A variety of
enteric and nonenteric layer or coating materials may be used (such
as polymeric acids, shellacs, acetyl alcohol, cellulose acetate and
the like) or combinations thereof.
[0207] The liquid forms in which a compound of the present
invention may be incorporated for oral administration include
(without limitation), aqueous solutions, suitably flavored syrups,
aqueous or oil suspensions (using a suitable synthetic or natural
gum dispersing or suspending agent such as tragacanth, acacia,
alginate, dextran, sodium carboxymethylcellulose, methylcellulose,
polyvinylpyrrolidone, gelatin and the like), flavored emulsions
(using a suitable edible oil such as cottonseed oil, sesame oil,
coconut oil, peanut oil and the like), elixirs and other similar
liquid forms with a variety of pharmaceutically acceptable
vehicles.
[0208] As is also known in the art, the compounds may alternatively
be administered parenterally via injection. For parenteral
administration, sterile solutions or injectable suspensions may be
parenteral vehicles wherein appropriate liquid carriers, suspending
agents and the like are employed. Sterile solutions are a preferred
parenteral vehicle. Isotonic preparations that generally contain
suitable preservatives are employed when intravenous administration
is desired. A parenteral formulation may consist of the active
ingredient dissolved in or mixed with an appropriate inert liquid
carrier. Acceptable liquid carriers comprise aqueous solvents and
the like and other optional ingredients for aiding solubility or
preservation. Such aqueous solvents include sterile water, Ringer's
solution or an isotonic aqueous saline solution. Alternatively, a
sterile non-volatile oil may be employed as a solvent agent. Other
optional ingredients include vegetable oils (such as peanut oil,
cottonseed oil, sesame oil and the like), organic solvents (such as
solketal, glycerol, formyl and the like), preservatives,
isotonizers, solubilizers, stabilizers, pain-soothing agents and
the like. A parenteral formulation is prepared by dissolving or
suspending the active ingredient in the liquid carrier whereby the
final dosage unit contains from 0.005 to 10% by weight of the
active ingredient.
[0209] Compounds of the present invention may be administered
intranasally using a suitable intranasal vehicle. Compounds of the
present invention may be administered topically using a suitable
topical transdermal vehicle or a transdermal patch. Administration
via a transdermal delivery system requires a continuous rather than
intermittent dosage regimen.
[0210] Compounds of the present invention may also be administered
via a rapid dissolving or a slow release composition, wherein the
composition includes a biodegradable rapid dissolving or slow
release carrier (such as a polymer carrier and the like) and a
compound of the invention. Rapid dissolving or slow release
carriers are well known in the art and are used to form complexes
that capture therein an active compound(s) and either rapidly or
slowly degrade/dissolve in a suitable environment (e.g., aqueous,
acidic, basic, etc). Such particles are useful because they
degrade/dissolve in body fluids and release the active compound(s)
therein. The particle size of a compound of the present invention,
carrier or any excipient used in such a composition may be
optimally adjusted using techniques known to those of ordinary
skill in the art.
[0211] The present invention includes a composition of an instant
compound or prodrug thereof present in a prophylactically or
therapeutically effective amount necessary for symptomatic relief
to a subject in need thereof. A prophylactically or therapeutically
effective amount of an instant compound or prodrug thereof may
range from about 0.01 ng to about 1 g and may be constituted into
any form suitable for the administration method and regimen
selected for the subject.
[0212] Depending on the subject and disease to be treated, the
prophylactically or therapeutically effective amount for a person
of average body weight of about 70 kg per day may range from about
0.01 .mu.g/kg to about 300 mg/kg; from about 0.1 .mu.g/kg to about
200 mg/kg; from about 0.5 .mu.g/kg to about 100 mg/kg; or, from
about 1 .mu.g/kg to about 50 mg/kg.
[0213] An optimal prophylactically or therapeutically effective
amount and administration method and regimen may be readily
determined by those skilled in the art, and will vary depending on
factors associated with the particular patient being treated (age,
weight, diet and time of administration), the severity of the
condition being treated, the compound and dosage unit being
employed, the mode of administration and the strength of the
preparation.
[0214] Dosage unit(s) may be administered to achieve the
therapeutically or prophylactically effective amount in a regimen
of from about once per day to about 5 times per day. The preferred
dosage unit for oral administration is a tablet containing 0.01,
0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150,
200, 250 or 500 mg of the active ingredient.
Synthetic Methods
[0215] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic schemes
described below and are illustrated more particularly in the
specific synthetic examples that follow. The general schemes and
specific examples are offered by way of illustration; the invention
should not be construed as being limited by the chemical reactions
and conditions expressed. The methods for preparing the various
starting materials used in the schemes and examples are well within
the skill of persons versed in the art. No attempt has been made to
optimize the yields obtained in any of the example reactions. One
skilled in the art would know how to increase such yields through
routine variations in reaction times, temperatures, solvents and/or
reagents.
[0216] The terms used in describing the invention are commonly used
and known to those skilled in the art. When used herein, the
following abbreviations have the indicated meanings:
Boc tert-butoxy carbonyl Cpd compound DMF N,N-dimethyl formamide
EtOAc ethyl acetate Et.sub.2O anhydrous ether KOH potassium
hydroxide LHMDS lithium hexamethyl disilane LiOH lithium hydroxide
min/hr(s)/d(s)/mp minute/hour(s)/day(s)/melting point N.sub.2
nitrogen RT/rt/r.t. room temperature TEA or Et.sub.3N triethylamine
TFA trifluoroacetic acid THF tetrahydrofuran
[0217] Except where indicated, all reagents, solvents and starting
materials are commercially available and were used without further
purification. Where a particular component or piece of equipment
was used, such are also commercially available.
##STR00176##
[0218] An optionally substituted cyclohexanone Compound A1 in
solution (with one or more of Et.sub.2O, THF and the like) is
rapidly added to a reagent solution (containing a mixture of LHMDS
and the like in one or more of Et.sub.2O or THF and the like) at a
temperature of about -78.degree. C. under an inert atmosphere
(using nitrogen and the like) and stirred at about -78.degree. C.
for about 40 mins. An optionally substituted oxalic acid di-ethyl
ester Compound A2 in solution (with Et.sub.2O and the like) is then
added to the Compound A1 mixture.
[0219] The reaction mixture is stirred at about -78.degree. C. for
about 1 hr, then allowed to warm to r.t. over an additional 2 hr
period of time. The reaction is quenched (using saturated
NH.sub.4Cl, 1N HCl and the like) and the organic layer is extracted
(with one or more of EtOAc, Et.sub.2O and the like) and washed
(with brine and the like), then separated and dried (with anhydrous
sodium sulfate and the like). The extract is filtered and
concentrated in vacuo to yield an optionally substituted
oxo-(2-oxo-cyclohexyl)-acetic acid alkyl ester Compound A3 as a
crude product used without further purification in the next
step.
##STR00177##
[0220] A substituted hydrazine hydrochloride Compound A4 and
K.sub.2CO.sub.3 (potassium carbonate) are added to Compound A3 in
solution (with one or more of MeOH, EtOH, CH.sub.2Cl.sub.2 and the
like) at room temperature under an inert atmosphere. The reaction
mixture is stirred overnight, then concentrated and diluted (with
one or more of water, EtOAc (ethyl acetate) and the like). The
organic layer is washed, separated and dried, then filtered and
concentrated in vacuo to yield a crude product Compound A5 as a
mixture of isomers, wherein a mixture of X.sub.1R.sub.1 and
X.sub.2R.sub.2 isomers are present. The X.sub.aR.sub.a substituent
moiety on Compound A4 represents the possibility that, after
separation, the substituted amine group may be found either on the
N.sup.1 position as X.sub.1R.sub.1 or on the N.sup.2 position as
X.sub.2R.sub.2.
[0221] The hydrazine hydrochloride or dihydrochloride Compound A4
may be converted to the free base by methods known to those skilled
in the art. In the examples of the present invention, the free base
is prepared either in situ (as shown for illustrative purposes in
this Scheme) or separately (then added to the reaction mixture) by
reaction with K.sub.2CO.sub.3.
[0222] As illustrated in this Scheme, Compound A4 may also be
further substituted with a variety of X.sub.aR.sub.a substituents
(as previously defined herein). In many instances, the substituted
hydrazine Compound A4 is commercially available. When not
commercially available, a particularly substituted Compound A4 may
be prepared by methods known to those skilled in the art. More
specifically, a halogenated X.sub.aR.sub.a substituent moiety is
reacted with a hydrazine hydrate solution at reflux and used
without further purification as Compound A4 (as described more
completely in Example 3).
##STR00178##
[0223] The Compound A5 isomeric mixture is separated via flash
chromatography (eluted with a suitable solvent mixture such as 20%
or 30% EtOAc:hexane and the like) to provide a purified major
isomer Compound A6 and a minor isomer Compound A7. The major isomer
Compound A6 is substituted on the N.sup.1 position with
X.sub.1R.sub.1 (X.sub.2R.sub.2 is necessarily absent). The minor
isomer Compound A7 is substituted on the N.sup.2 position with
X.sub.2R.sub.2 (wherein X.sub.1R.sub.1 is absent).
##STR00179##
[0224] The separated major isomer Compound A6 is treated with a
reagent solution (such as a mixture of NaOH in a solvent such as
THF or water and the like) and stirred overnight. The reaction is
quenched and extracted with a solvent (such as CH.sub.2Cl.sub.2,
EtOAc and the like). The organic layer is dried, filtered and
concentrated in vacuo to yield Compound A8.
##STR00180##
[0225] A reagent (such as SOCl.sub.2 (thionyl chloride) and the
like) in a solvent (such as CH.sub.2Cl.sub.2 and the like) is added
to Compound A8 at ambient temperature under an inert nitrogen
atmosphere. The reaction mixture is stirred at reflux temperature
for about 15 min, then concentrated in vacuo to afford the
corresponding acid chloride intermediate Compound A9.
##STR00181##
[0226] Compound A9 (optionally in solution with TEA (triethylamine)
and the like) is added to a solution of a substituted amine
Compound A10 (in a solvent such as CH.sub.2Cl.sub.2 and the like)
at ambient temperature under an inert nitrogen atmosphere.
[0227] In general, Compound A10 is a commercially available
substituted amine. When not commercially available, a particularly
substituted amine Compound A10 may be prepared by methods known to
those skilled in the art.
[0228] The Compound A9/A10 mixture is stirred at about r.t. for a
period of time, then diluted (with a mixture of water and
CH.sub.2Cl.sub.2 and the like). The organic layer is separated and
dried, then filtered and concentrated in vacuo to yield a crude
product. The product is purified via flash chromatography (eluted
with a solvent mixture such as 20% or 30% EtOAc in hexane) to
provide a target Compound A11.
[0229] For purposes of illustration in this Scheme, the Compound
A11 X.sub.3R.sub.3 substituent moiety incorporates the C(O) portion
of the C.sup.3 substituent from Compound A9 and the --NH-- portion
from Compound A10, wherein X.sub.3 is absent and R.sub.3 is either
--(R.sub.6)C(O)Z.sub.1R.sub.7 or
--(R.sub.6)C(O)N(R.sub.9a)Z.sub.2R.sub.9, and wherein R.sub.6 is
absent.
##STR00182##
[0230] A catalytic amount of tetrabutylammonium bromide
((n-Bu).sub.4NBr) is added to a solution of Compound A9 (in a
solvent such as DCE (dichloroethane) and the like) at 0.degree. C.
A saturated solution of NaN.sub.3 (sodium azide) (in water) is
added dropwise at 0.degree. C. The reaction mixture is stirred for
about 0.5 hrs, then diluted (with one or more of cold water,
CH.sub.2Cl.sub.2 and the like). The organic layer is washed (with
one or more of water, brine and the like) and dried (using sodium
sulfate), then filtered and concentrated to give an azide Compound
B1.
##STR00183##
[0231] t-BuOH (tert-butanol) is added to a solution of Compound B1
(in a solvent such as CH.sub.2Cl.sub.2 and the like) and the
mixture is refluxed for about 48 hrs. The reaction product is
concentrated and purified via silica gel column (eluted with a
solvent mixture such as 10% EtOAc in hexane) to give a
Boc-protected amine Compound B2.
##STR00184##
[0232] TFA is added to a solution of Compound B2 (in a solvent such
as CH.sub.2Cl.sub.2 and the like) and the mixture is stirred
overnight. The reaction product is concentrated and the residue is
dissolved (in a solvent such as CH.sub.2Cl.sub.2 and the like) and
washed (with one or more of 1N NaOH, water and the like) and dried
(using sodium sulfate), then filtered and concentrated to give an
amine Compound B3.
##STR00185##
[0233] Compound B3 (optionally in solution with TEA and the like)
is added to a solution of a substituted amine Compound B4 (in a
solvent such as CH.sub.2Cl.sub.2 and the like) at ambient
temperature under an inert nitrogen atmosphere. The mixture is
stirred at r.t. for about 4 hrs, then concentrated and purified via
silica gel column (eluted with a solvent mixture such as 15%, 20%
or 30% EtOAc in hexane) to provide the target Compound A11.
[0234] For purposes of illustration in this Scheme, the Compound
A11 X.sub.3R.sub.3 substituent moiety incorporates the NH portion
of the C.sup.3 substituent from Compound B3 and the R.sub.YC(O)--
portion from Compound B4, wherein X.sub.3 is a --NH-- and R.sub.3
is either --(R.sub.6)C(O)Z.sub.1R.sub.7,
--SO.sub.2N(R.sub.8)R.sub.8a, or
--(R.sub.6)C(O)N(R.sub.9a)Z.sub.2R.sub.9, and wherein R.sub.6 is
absent.
[0235] The synthetic examples that follow herein describe more
completely the preparation of particular compounds included within
the scope of the present invention.
Example 1
(5S)-3-(adamantan-2-ylcarbamoyl)-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazo-
le-5-carboxylic acid ethyl ester
Cpd 208
(5R)-3-(adamantan-2-ylcarbamoyl)-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazo-
le-5-carboxylic acid ethyl ester
Cpd 209
##STR00186##
[0237] 4-oxo-cyclohexanecarboxylic acid ethyl ester Compound 1a
(3.4 g, 0.02 mol) was added to LHMDS (20 mL, 1M in THF, 0.02 mol)
in THF (15 ml) at about -78.degree. C. under N.sub.2 and stirred at
-78.degree. C. for 40 min. Then oxalic acid di-tert-butyl ester
Compound 1b (4.04 g, 0.02 mol) in THF (15 mL) was transferred into
the mixture via cannula. The mixture was stirred for 1 hr at
-78.degree. C. and 2 hrs at r.t. The reaction was quenched with
saturated NH.sub.4Cl and the product was concentrated in vacuo,
then extracted using EtOAc (30 mL). The EtOAc was evaporated to
provide a crude 3-tert-butoxyoxalyl-4-oxo-cyclohexanecarboxylic
acid ethyl ester Compound 1c (5.0 g) which was used in the next
step without further purification.
##STR00187##
[0238] The crude Compound 1c (2.98 g) was stirred with cyclohexyl
hydrazine hydrochloride Compound 1d (1.51 g, 0.01 mol) and
K.sub.2CO.sub.3 (0.69 g, 0.005 mol) in CH.sub.2Cl.sub.2 (30 mL)
under N.sub.2 at r.t. overnight and then washed with water. The
crude product was chromatographically purified (eluted with 30%
EtOAc in hexane) to afford a mixture of a major isomer Compound 1e
(2.5 g, 66.5% yield from Compound 1a) and a minor isomer Compound
1f (0.3 g, 8.0% yield from Compound 1a).
[0239] Compound 1e: MS m/z 377 (M+H).sup.+; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 4.18 (2H, q, J=7.1 Hz), 3.95 (1H,
m), 3.14 (1H, m), 2.82 (2H, m), 2.63 (2H, m), 2.21 (1H, m), 3.89
(6H, m), 1.66 (1H, m), 1.58 (9H, s), 1.29 (4H, m), 1.28 (3H, t,
J=7.1 Hz).
[0240] Compound 1f: MS m/z 377 (M+H).sup.+; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 5.02 (1H, m), 4.16 (2H, q, J=7.2
Hz), 3.09 (1H, m), 2.82 (2H, m), 2.62 (2H, m), 2.21 (1H, m), 1.91
(6H, m), 1.69 (1H, m), 1.58 (9H, s), 1.25-1.45 (4H, m), 1.26 (3H,
t, J=7.2 Hz).
##STR00188##
[0241] The separated major isomer Compound 1e (4.2 g, 11.16 mMol)
was treated with a 50% TFA/CH.sub.2Cl.sub.2 solution (20 mL) over
about an 8 hr period (overnight). The solvent was evaporated and
the residue was washed with CH.sub.2Cl.sub.2 to give
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3,5-dicarboxylic acid
5-ethyl ester Compound 1g (3.6 g, 100% yield) as a solid.
[0242] Compound 1g: MS m/z 321 (M+H).sup.+, 343 (M+Na).sup.+;
.sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.: 4.23 (2H, q, J=7.1 Hz),
4.13 (1H, m), 3.19 (1H, m), 2.85 (4H, m), 2.3 (1H, m), 1.92 (6H,
m), 1.72 (1H, m), 1.32 (7H, m).
##STR00189##
[0243] Compound 1g (3.6 g, 11.2 mMol) was reacted with thionyl
chloride (14 mL, 190 mMol) and refluxed for about 15 min to form an
acid chloride intermediate. The intermediate was further reacted
with a 2-adamantanamine hydrochloride Compound 1h (2.09 gms, 11.16
mMol) in CH.sub.2Cl.sub.2. The crude product afforded was
chromatographically purified (eluted with 30% EtOAc in hexane) to
provide a
3-(adamantan-2-ylcarbamoyl)-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-5-
-carboxylic acid ethyl ester Compound 1i (3.2 g, 63% yield) as a
white solid racemate.
##STR00190##
[0244] The racemic Compound 1i was enantiomerically separated via
chiral column chromatography (eluted with 90% hexane in IPA) to
provide an (S)-enantiomer Compound 208 and an (R)-enantiomer
Compound 209.
[0245] MS m/z 454 (M+H).sup.+, 476 (M+Na).sup.+; IR (KBr): 3419,
2908, 1732, 1668 cm.sup.-1; .sup.1H NMR (CDCl.sub.3, 300 MHz)
.delta.: 7.25 (1H, d, J=8.3 Hz), 4.22 (1H, m), 4.14 (2H, q, J=7.1
Hz), 3.91 (1H, m), 3.32 (1H, dd, J=16.4, 5.3 Hz), 2.83 (2H, m),
2.63 (2H, m), 2.20 (1H, m), 1.88 (23H, m), 1.32 (2H, m), 1.25 (3H,
t, J=7.1 Hz); .sup.13C NMR (CDCl.sub.3, 75 MHz) .delta.: 175.5,
162.8, 141.5, 138.3, 116.6, 60.8, 58.7, 52.9, 40.4, 38.0, 37.6,
33.0, 32.9, 32.54, 32.51, 32.47, 27.7, 27.6, 25.9, 25.5, 25.3,
24.9, 21.1, 14.6; Anal. Calcd for C.sub.27H.sub.39N.sub.3O.sub.3:
C, 71.49; H, 8.67; N, 9.26. Found: C, 71.32; H, 8.77; N, 9.07.
Example 2
1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide
Cpd 194
##STR00191##
[0247] Cyclohexanone Compound 2a (20.54 g, 0.25 mol) in Et.sub.2O
(100 mL) was added to a solution of LHMDS (250 mL, 0.25 mol) in
Et.sub.2O (400 mL) at -78.degree. C. under a N.sub.2 atmosphere.
The mixture was maintained at -78.degree. C. and stirred for 60
min. A diethyloxylate Compound 2b (36.53 g, 0.25 mMol) in Et.sub.2O
(100 mL) was added to the mixture, which was stirred at -78.degree.
C. for 1 hr. The reaction mixture was allowed to warm to r.t. over
3 hrs and the reaction was quenched with 1N HCl (150 mL), The
organic layer was extracted with Et.sub.2O (200 mL), washed with
brine and separated, then dried with anhydrous sodium sulfate,
filtered and concentrated in vacuo to yield 48.50 g, 95% of
oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester Compound 2c as a
yellow oil. Compound 2c was used in the next step without further
purification.
##STR00192##
[0248] Benzylhydrazine dihydrochloride Compound 2d (1.75 g, 9.0
mMol) and K.sub.2CO.sub.3 (2.77 g, 19.5 mMol) were added to a
solution of Compound 2c (1.88 g, 8.85 mMol) in MeOH (50 mL) at
ambient temperature under a N.sub.2 atmosphere. The resultant
heterogeneous mixture was stirred overnight. The reaction mixture
was concentrated to dryness and diluted with H.sub.2O (100 mL) and
EtOAc (500 mL). The organic layer was washed with brine, separated,
dried with anhydrous sodium sulfate, filtered and concentrated in
vacuo to yield a product as a crude oil. Purification by flash
chromatography (eluted with 20% EtOAc in hexane) afforded a major
isomer 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
ethyl ester Compound 2e (1.51 g, 60%) and a minor isomer
2-benzyl-4,5,6,7-tetrahydro-2H-indazole-3-carboxylic acid ethyl
ester Compound 2f as a colorless oil.
##STR00193##
[0249] 1N NaOH (10 mL) was added to Compound 2e (0.30 g, 1.05 mMol)
in THF (10 mL). The mixture was stirred for 30 hours, acidified to
pH 2 with 1N HCl and extracted with EtOAc (100 mL). The organic
layer was washed with brine, dried over sodium sulfate, then
filtered and concentrated in vacuo to yield
1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid Compound
2g (0.190 g, 70%) as a white solid. Thionyl chloride (0.17 g, 0.39
mMol) was added to a solution of the carboxylic acid Compound 2g
(0.15 g, 0.55 mMol) in CH.sub.2Cl.sub.2 (10 mL) at ambient
temperature under a N.sub.2 atmosphere. The reaction was stirred
for 3 hrs and concentrated in vacuo to afford the corresponding
acid chloride Compound 2h in quantitative yield.
##STR00194##
[0250] NEt.sub.3 (triethylamine) (0.10 g, 0.98 mMol) and acid
chloride Compound 2h (0.17 g, 0.39 mMol) were added to a solution
of 1,3,3-trimethylbicyclo[2.2.1]hept-2-ylamine hydrochloride
Compound 2i (0.071 g, 0.39 mMol) (prepared from commercially
available L(-)-fenchone as described in Suchocki J A; May E L;
Martin T J; Clifford G; Martin, B R, J. Med. Chem., 1991, 34, 1003)
in CH.sub.2Cl.sub.2 (10 mL) at ambient temperature under a N.sub.2
atmosphere.
[0251] The reaction was stirred at r.t. for 3 hrs, then diluted
with water (10 mL) and CH.sub.2Cl.sub.2 (50 mL). The organic layer
was separated, dried with anhydrous sodium sulfate, filtered and
concentrated in vacuo to yield a crude oil. Purification by flash
chromatography (eluted with 20% EtOAc in hexane) afforded Compound
194 (0.09 g, 41%), as a white solid.
[0252] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.37-7.27 (m, 3H),
7.14-7.09 (m, 2H), 7.03-6.99 (d, J=12 Hz, 2H), 5.23 (s, 2H),
3.76-3.72 (m, 1H), 2.85-2.80 (m, 1H), 2.44-2.40 (m, 1H), 1.80-1.70
(m, 7H), 1.55-1.42 (m, 2H), 1.24-1.28 (m, 1H), 1.17 (s, 3H), 1.12
(s, 3H), 0.86 (s, 3H). MS m/z 392 (M.sup.+).
Example 3
1-(1-phenyl-ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
[(1S)-1-cyclohexyl-ethyl]-amide
Cpd 249
##STR00195##
[0254] 1-bromoethylbenzene Compound 3a (8.0 mL, 58.0 mMol) was
added to a solution of hydrazine hydrate Compound 3b (20 mL) in THF
(80 mL) which was then heated to reflux for 8 hrs. The solvent was
removed in vacuo and Et.sub.2O (100 mL) was added. The organic
layer was washed with brine, separated and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo to yield
(1-phenyl-ethyl)-hydrazine Compound 3c as a pale yellow oil (5.8
g), used in the next step without purification. MS m/z 137 (M+H,
70%), 105 (M-NHNH.sub.2, 100%).
##STR00196##
[0255] Oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester Compound 2c
(3.97 g, 20.0 mMol) was added to a solution containing crude
Compound 3c (5.8 g, 29.0 mMol) and K.sub.2CO.sub.3 (0.2 g) in MeOH
(40 mL). The suspension was stirred at r.t. for 48 hrs. The solvent
was removed in vacuo and the residue was extracted with
CH.sub.2Cl.sub.2. The organic layer was washed with water and
brine, then separated and dried over Na.sub.2SO.sub.4 to provide
Compound 3d as a red oil (4.6 g), used in the next step without
further purification. MS m/z 321 (M+Na, 100%).
##STR00197##
[0256] Compound 3d was dissolved in a solution of KOH (5.6 g, 100
mMol) in THF (40 mL) and water (60 mL). The resulting solution was
stirred at r.t. for 12 hrs, followed by removal of the THF in
vacuo. The aqueous solution was extracted with Et.sub.2O to remove
impurities. The aqueous layer was then acidified with 6 N HCl and
was extracted with Et.sub.2O (2.times.50 mL). The organic layer was
separated and dried over Na.sub.2SO.sub.4. The solvent was removed
in vacuo to yield
1-(1-phenyl-ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
Compound 3e as pale yellow solid. MS m/z (+ve mode) 293 (M+Na,
100%), MS m/z (-ve mode) 269 (M-H, 100%).
##STR00198##
[0257] Compound 3e (2.0 g, 7.4 mMol) was dissolved in
CH.sub.2Cl.sub.2 (15 mL) and treated with SOCl.sub.2 (8.0 g). The
resulting solution was heated to reflux for 3 hrs followed by
removal of the solvent in vacuo to provide
1-(1-phenyl-ethyl)-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl
chloride Compound 3f as a brownish yellow oil.
##STR00199##
[0258] A solution of Compound 3f (0.06 g, 0.2 mMol) in
CH.sub.2Cl.sub.2 (1 mL) was added to a solution of commercially
available (S)-1-cyclohexyl-ethylamine Compound 3g (0.03 mL, 0.18
mMol) in CH.sub.2Cl.sub.2 (2 mL) and triethylamine (0.1 mL, 0.8
mMol) at 0.degree. C. The resulting suspension was stirred for 2
hrs, then the reaction was quenched with wafer (5 mL) and the
mixture was extracted with Et.sub.2O. The organic layer was washed
with 10% NaOH and brine, then separated and dried over
Na.sub.2SO.sub.4. The solvent was removed in vacuo and the crude
product was purified by preparative TLC (1:1 hexane/EtOAc) to
provide Compound 249 as a mixture of diastereomers in a brown oil.
MS m/z 380 (M+H, 100%).
[0259] .sup.1H NMR (300 MHZ, CDCl.sub.3) .delta. 7.12-7.29 (m, 3H),
6.95-7.06 (m, 2H), 6.70 (br d, J=6.0 Hz, 1H), 5.27 (q, J=3.0 Hz,
1H), 3.84-4.01 (m, 1H), 2.72 (br t 2H), 2.30-2.45 (br m, 1H),
2.12-2.26 (br m, 1H), 1.82 (d, J=6.0 Hz, 3H), 1.48-1.86 (br m, 8H),
1.27-1.42 (m, 1H), 1.12 (d, J=6.0 Hz, 3H), 0.90-1.25 (br m,
6H).
Example 4
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
[2-hydroxy-2-(4-methoxy-phenyl)-ethyl]-amide
Cpd 241
##STR00200##
[0261] Compound 176 was prepared according to the procedure of
Example 2; replacing Compound 2d with cyclohexyl-hydrazine Compound
5a and using 2-amino-1-(4-methoxy-phenyl)-ethanone as Compound 2i).
NaBH.sub.4 (sodium borohydride) (0.05 g, 1.25 mMol) was added in
one portion to a solution of Compound 176 (0.08 g, 0.2 mMol) in
MeOH (2 mL) and THF (8 mL) at r.t. The mixture was stirred at r.t.
for 4 hrs and the solvent was removed in vacuo. The residue was
extracted with CH.sub.2Cl.sub.2 and the organic layer was washed
successively with water, saturated aqueous NaHCO.sub.3, and brine.
The organic layer was separated, then dried with anhydrous sodium
sulfate and filtered. The solvent was evaporated to provide a crude
product which was then purified by preparative TLC on silica gel
(3:2 hexane/EtOAc, Rf=0.35) to provide Compound 241 (29.8 mg, 75%)
as a sticky solid.
[0262] MS m/z 420 (M+Na, 30%), 380 (M-H.sub.2O, 100%); .sup.1H NMR
(300 MHZ, CDCl.sub.3) .delta. 7.25 (br s, 1H), 7.21 (d, J=6.0 Hz,
2H), 6.78 (d, J=6.0 Hz, 2H), 4.75-4.83 (m, 1H), 3.82-3.98 (m, 1H),
3.71 (s, 3H), 3.55-3.68 (m, 1H), 3.33-3.47 (m, 1H), 2.70 (br t,
2H), 2.48 (br t, 2H), 1.58-1.90 (m, 10H), 1.18-1.39 (m, 4H).
Example 5
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
cyclohexylmethylamide
Cpd 304
##STR00201##
[0264] For this example, Compound 2c was prepared as follows: LHMDS
(100 mL of 1.0 M solution in THF) was added to a 500 mL round
bottom flask and cooled to -78.degree. C. Cyclohexanone Compound 2a
(10.36 mL, 100 mMol) in 20 mL THF was added dropwise and the
mixture was stirred at -78.degree. C. for 1 hr. Diethyl oxalate
Compound 2b (13.6 mL, 100 mMol) was added slowly at -78.degree. C.
and the mixture was stirred at the same temperature for 1 hr. The
reaction mixture was stirred and allowed to warm to r.t. overnight.
The mixture was then concentrated and taken up in EtOAc (500 mL)
and washed with 1N HCl (2.times.200 mL) followed by water
(2.times.200 mL). The organic layer was separated, then dried with
anhydrous sodium sulfate and filtered. The organic layer was
separated, then dried with anhydrous sodium sulfate and filtered.
The solvent was evaporated to provide an ester Compound 2c (15 g,
75.7%) as an orange oil.
[0265] Compound 2c (1.98 g, 10 mMol) was taken up in EtOH (40 mL)
and anhydrous cyclohexyl hydrazine hydrochloride Compound 1d (1.5
g, 10 mMol) and K.sub.2CO.sub.3 (1.38 g, 10 mMol) were added. The
mixture was stirred at r.t. overnight, then filtered and washed
with EtOH (20 mL). The combined filtrate was concentrated and
purified on a silica gel column (eluted with 20% EtOAc in hexane)
to give of a mixture of a major isomer Compound 5b and a minor
isomer Compound 5c (2.3 g, 83%).
##STR00202##
[0266] The major isomer Compound 5b (0.81 g, 2.92 mMol) was
dissolved in a solution of MeOH (24 mL) and THF (8 mL) and aqueous
LiOH (0.52 g LiOH in 8 mL H.sub.2O) was added. The mixture was
stirred at r.t. for 4 hrs, then concentrated and diluted with water
(100 mL). The resulting aqueous solution was washed with EtOAc in
hexane (1:1 in 50 mL). The aqueous layer was acidified to pH 4
using 1N HCl and extracted with EtOAc (100 mL). The organic layer
was separated, then dried over magnesium sulfate and filtered. The
solvent was evaporated to provide an acid Compound 5d (0.7 g,
96%).
[0267] Compound 5d (0.4 g, 1.6 mMol) was dissolved in 10 mL
CH.sub.2Cl.sub.2 (methylene chloride) and was treated with
SOCl.sub.2 (thionyl chloride) (0.3 mL). The resulting solution was
heated to reflux for 3 hrs and the solvent was removed in vacuo to
provide 0.36 g (84%) of the acid chloride Compound 5e.
##STR00203##
[0268] The acid chloride Compound 5e (0.08 g, 0.3 mMol) was added
to a solution of cyclohexylmethylamine Compound 5f (0.08 mL, 0.6
mMol) in 2 mL of CH.sub.2Cl.sub.2 and triethylamine (0.125 mL, 0.9
mMol). The resulting suspension was stirred at r.t. for 2 hrs and
then diluted with 10 mL CH.sub.2Cl.sub.2. The resulting mixture was
washed with 1N HCl (2.times.10 mL) and water (2.times.10 mL). The
organic layer was dried over sodium sulfate, then concentrated and
purified on a silica gel column (eluted with 20% EtOAc in hexane)
to provide an amide Compound 304 (90 mg, 88%). MS m/z 344
(MH.sup.+).
Example 6
naphthalene-2-carboxylic acid
(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-amide
Cpd 178
##STR00204##
[0270] Tetrabutylammonium bromide ((n-Bu).sub.4NBr) (10 mg) in a
catalytic amount was added to a solution of
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl chloride
Compound 5e (0.134 g, 0.5 mMol) in DCE (dichloroethane) (5 mL) at
0.degree. C. NaN.sub.3 (sodium azide) (0.5 mL saturated solution in
water) was then added dropwise at 0.degree. C. The resulting
reaction mixture was stirred for 0.5 hrs before being diluted with
cold water and CH.sub.2Cl.sub.2. The organic layer was washed with
water (2.times.10 mL), brine (2.times.10 mL), dried over sodium
sulfate, filtered and concentrated to give an azide Compound 6a
(0.11 g, 80%).
##STR00205##
[0271] To a solution of azide Compound 6a (0.2 g, 0.73 mMol) in 5
mL CH.sub.2Cl.sub.2 was added t-BuOH (tert-butanol) (1 g, 13.5
mMol). The resulting mixture was refluxed for 48 hrs before being
concentrated. The crude product was purified on a silica gel column
(eluted with 10% EtOAc in hexane) to give a Boc-protected amine
Compound 6b (0.15 g, 64%).
##STR00206##
[0272] To a solution of Compound 6b (0.15 g, 0.47 mMol) in 8 mL
CH.sub.2Cl.sub.2 was added 2 mL TEA. The reaction mixture was
stirred overnight and then concentrated. The crude product was
dissolved in CH.sub.2Cl.sub.2 and washed with 1N NaOH (2.times.20
mL) and water (2.times.20 mL). The organic layer was dried over
sodium sulfate, filtered and concentrated to give Compound 6c
(0.127 g, 93%).
##STR00207##
[0273] Naphthalene-2-carbonyl chloride Compound 6d (5 mg, 0.026
mMol) and TEA (0.01 mL, 0.072 mMol) were added to a solution of
Compound 6c (5 mg, 0.023 mMol). The reaction mixture was stirred at
r.t. for 4 hrs, then concentrated and purified on a silica gel
column (eluted with 15% EtOAc in hexane) to give Compound 178 (5.1
mg, 60%). MS m/z 374 (MH.sup.+)
Example 7
3-(adamantan-2-ylcarbamoyl)-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-5--
carboxylic acid
Cpd 223
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3,5-dicarboxylic acid
3-adamantan-2-ylamide 5-[(1,1,3,3-tetramethyl-butyl)-amide]
Cpd 228
##STR00208##
[0275] The
3-(adamantan-2-ylcarbamoyl)-1-cyclohexyl-4,5,6,7-tetrahydro-1H--
indazole-5-carboxylic acid ethyl ester Compound 1i (100 mg, 0.22
mMol) was added to a solution of LiOH (lithium hydroxide)
monohydrate (46 mg) in a 3:1:1 ratio of THF:MeOH:water (10 mL). The
mixture was stirred overnight at r.t. and then concentrated in
vacuo. The residue was neutralized with 1N HCl to give Compound 223
(87 mg, 93%) as a white precipitate. MS m/z 426 (M+H).sup.+, 448
(M+Na).sup.+; .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta.: 7.26 (1H,
b), 4.21 (1H, m), 3.91 (1H, m), 3.31 (1H, m), 2.93 (1H, m), 2.75
(3H, m), 2.21 (1H, m), 1.88 (23H, m), 1.35 (2H, m).
##STR00209##
[0276] Thionyl chloride (1 mL) was added to Compound 223 (10 mg,
0.023 mMol) and the mixture was refluxed for 10 min. The excess
thionyl chloride was evaporated and the residue was washed with
CH.sub.2Cl.sub.2. 1,1,3,3-tetramethyl-butylamine Compound 7a (6 mg,
0.046 mMol) was added to the residue in CH.sub.2Cl.sub.2 and the
mixture was stirred for 70 min, washed with 1N HCl and brine, then
dried over sodium sulfate. The crude product was purified by
preparative TLC (50% EtOAc in hexane) to give Compound 228 (8 mg,
63.5%) as a white solid.
[0277] MS m/z 537 (M+H).sup.+, 559 (M+Na).sup.+; .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 7.26 (1H, b), 5.42 (1H, h), 4.19
(1H, m), 3.90 (1H, m), 3.21 (1H, m), 2.79 (2H, m), 2.56 (2H, m),
2.21 (1H, m), 1.7-2.1 (23H, m), 1.42 (4H, m), 1.19 (3H, s), 1.02
(9H, s), 0.97 (3H, s).
Example 8
[1-cyclohexyl-3-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-ylcarbamoyl)-4,5,6,7-
-tetrahydro-1H-indazol-5-yl]-carbamic acid tert-butyl ester
Cpd 86
5-amino-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide
Cpd 92
1-cyclohexyl-5-hydroxy-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide
Cpd 93
##STR00210##
[0279] According to the procedure of Example 2, a solution of
(4-oxo-cyclohexyl)-carbamic acid tert-butyl ester Compound 8a in
ether was used in place of cyclohexanone Compound 2a and carried
forward to produce
(5-tert-butoxycarbonylamino-2-oxo-cyclohexyl)-oxo-acetic acid ethyl
ester Compound 8b.
##STR00211##
[0280] Using the procedure of Example 2, Compound 8b was used in
place of oxo-(2-oxo-cyclohexyl)-acetic acid ethyl ester Compound 2c
and cyclohexyl-hydrazine Compound 1d was used in place of
benzylhydrazine dihydrochloride Compound 2d to produce a major
isomer
5-tert-butoxycarbonylamino-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3--
carboxylic acid ethyl ester Compound 8c and a minor isomer
5-tert-butoxycarbonylamino-2-cyclohexyl-4,5,6,7-tetrahydro-2H-indazole-3--
carboxylic acid ethyl ester Compound 8d.
##STR00212##
[0281] Using the procedure of Example 2, Compound 8c was used in
place of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
ethyl ester Compound 2e to produce
5-tert-butoxycarbonylamino-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3--
carboxylic acid Compound 8e.
##STR00213##
[0282] Using the procedure of Example 24, Compound 8e was used in
place of
1-cyclohexyl-7-hydroxy-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid Compound 24a and 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-ylamine
hydrochloride Compound 2i was used in place of
(2S,3R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester
Compound 24b to produce Compound 86.
##STR00214##
[0283] Ester Compound 86 (0.1 g, 0.2 mMol) was added to a solution
of 50% TFA in CH.sub.2Cl.sub.2 (2 mL). The mixture was stirred for
3 hrs and the solvent was evaporated to give Compound 92 (0.1 g,
yield 98%) as a TFA salt.
[0284] MS m/z 399 (M+H).sup.+, 421 (M+Na).sup.+. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 7.05 (1H, b), 6.03 (3H, b), 3.86
(1H, m), 3.64 (1H, m), 3.42 (1H, m), 2.89 (2H, m), 2.69 (1H, m),
2.36 (1H, m), 1.65-1.95 (11H, m), 1.18-1.41 (8H, m), 1.05 (3H, s),
1.02 (3H, s), 0.82 (3H, s).
##STR00215##
[0285] Compound 92 (0.1 g, 0.2 mMol) was added to a solution of
NaNO.sub.2 (27 mg, 0.4 mMol) in acetic acid (3 mL) at 0.degree. C.
The mixture was stirred for 2 hrs and the product was am on prep
TLC (30% EtOAc in hexane) to give Compound 93 (22 mg, yield
28%).
[0286] MS m/z 400 (M+H).sup.+, 422 (M+Na).sup.+. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 7.02 (1H, b), 4.19 (1H, m), 3.90
(1H, m), 3.72 (1H, m), 3.19 (1H, m), 2.81 (3H, m), 2.61 (1H, m),
1.89 (7H, m), 1.70 (4H, m), 1.34 (4H, m), 1.21 (3H, m), 1.13 (3H,
s), 1.09 (3H, s), 0.82 (3H, s).
Example 9
1-cyclohexyl-5-(3,3-dimethyl-ureido)-4,5,6,7-tetrahydro-1H-indazole-3-carb-
oxylic acid adamantan-2-ylamide
Cpd 89
##STR00216##
[0288] Dimethylcarbamyl chloride Compound 9b (0.56 ml, 6 mMol) was
added dropwise to a solution of Compound 9a (0.8 g, 2 mMol)
(prepared similarly to Compound 92 using the procedure of Example
8) and TEA (0.3 g, 3 mMol) in CH.sub.2Cl.sub.2 (10 mL). The mixture
was stirred for 2 hrs and the reaction was quenched with 1N NaOH.
The organic layer was dried over Na.sub.2SO.sub.4 and the
CH.sub.2Cl.sub.2 was evaporated. The crude product was purified via
column chromatography (using EtOAc as the eluent) to give Compound
89 (0.8 g, yield 86%) as a white solid.
[0289] MS m/z 468 (M+H).sup.+, 490 (M+Na).sup.+. .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 7.26 (1H, b), 4.32 (1H, d, J=6.6
Hz), 4.19 (1H, m), 4.07 (1H, m), 3.92 (1H, m), 3.21 (1H, dd,
J=16.0, 5.2 Hz), 2.88 (6H, s), 2.65 (2H, m), 2.15 (1H, m), 2.02
(2H, m), 1.90 (16H, m), 1.75 (6H, m), 1.32 (2H, m).
Example 10
1-(2,4-dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,5,6,7-tetrahydro-1H-ind-
azole-3-carboxylic acid piperidin-1-ylamide
Cpd 297
##STR00217##
[0291] An aqueous KOH (0.25 g in 4.4 mL water) solution was added
to p-fluorobenzaldehyde Compound 10a (1.04 mL, 10 mMol) and the
mixture was heated to 65.degree. C. Cyclohexanone Compound 2a (1.03
mL, 10 mMol) was added dropwise over 10 min and the reaction
mixture was refluxed for 5 hrs, then cooled to r.t. and stirred at
r.t. overnight. The reaction mixture was acidified with 1N HCl (26
mL) and diluted with EtOAc. The organic layer was separated and
washed with brine, then dried with anhydrous sodium sulfate and
filtered. The solvent was evaporated to provide a crude product
which was then purified by silica gel column (eluted with 6% EtOAc
in hexane) to give 2-(4-fluoro-benzylidene)-cyclohexanone Compound
10b (1.1 g, 54%).
##STR00218##
[0292] Cyclohexanone Compound 10b (1.1 g, 5.4 mMol) in THF (5 mL)
was added dropwise to a solution of lithium
bis(trimethylsilyl)amide (5.4 mL of 1.0M solution in THF) in THF
(10 mL) at -78.degree. C. The mixture was stirred at -78.degree. C.
for 1 hr, then diethyl oxalate Compound 2b (0.732 mL, 5.4 mMol) in
THF (5 mL) was added slowly at -78.degree. C. The mixture was
stirred at -78.degree. C. for 1 hr, then stirred and allowed to
warm to r.t. overnight. The mixture was concentrated, taken up in
EtOAc (100 mL) and washed with 1N HCl (2.times.50 mL) and water
(2.times.50 mL). The organic layer was separated, then dried with
anhydrous sodium sulfate and filtered. The solvent was evaporated
to provide a [3-(4-fluoro-benzylidene)-2-oxo-cyclohexyl]-oxo-acetic
acid ethyl ester Compound 10c (1.4 g, 85%) as an orange oil which
was used in the next step without further purification.
##STR00219##
[0293] Compound 10c (1.4 g, 4.62 mmol) was taken up in ethanol (30
mL), then anhydrous (2,4-dichloro-phenyl)-hydrazine hydrochloride
Compound 10d (0.99 g, 4.62 mMol) and K.sub.2CO.sub.3 (1.28 g, 9.24
mMol) were added. The reaction mixture was stirred at r.t.
overnight, then filtered and washed with ethanol (20 mL). The
combined filtrate was concentrated and purified on a silica gel
column (eluted with 20% EtOAc in hexane) to give
1-(2,4-Dichloro-phenyl)-7-(4-fluoro-benzylidene)-4,5,6,7-tetrahydro-1H-in-
dazole-3-carboxylic acid ethyl ester Compound 10e (0.8 g, 39%).
##STR00220##
[0294] Ethyl ester Compound 10e (0.8 g, 1.8 mMol) was dissolved in
THF (18 mL). Aqueous LiOH (lithium hydroxide) (0.26 g in 6 mL),
then ethanol (2 mL) were added and the mixture was stirred at r.t.
for 24 hrs, then concentrated, diluted with water (25 mL) and
acidified to pH 4 using 1N HCl. The aqueous suspension was
extracted with EtOAc (100 mL).
[0295] The organic layer was separated and washed with brine, then
dried over magnesium sulfate and filtered. The solvent was
evaporated to provide an acid Compound 10f (0.74 g, 98%).
##STR00221##
[0296] The acid Compound 10f (0.74 g, 1.77 mMol) was taken up in
CH.sub.2Cl.sub.2 (5 mL), then treated with thionyl chloride (1 mL,
14.1 mMol). The solution was heated to reflux for 3 hrs, the
solvent was removed in vacuo to obtain the acid chloride Compound
10g (0.76 g, 99%).
##STR00222##
[0297] Compound 10g (0.044 g, 0.1 mMol) was added to a solution of
commercially available 1-aminopiperidine Compound 10h (0.021 mL,
0.2 mMol) in CH.sub.2Cl.sub.2 (2 mL) and triethylamine (0.055 mL,
0.4 mMol). The suspension was stirred, men diluted and washed. The
organic layer was dried, concentrated and purified on a silica gel
column (eluted with 40% EtOAc in hexane) to provide Compound 297
(40 mg, 80.2%). MS m/z 499 (MH.sup.+); .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.57-7.41 (m, 4H), 7.07-6.92 (m, 4H), 5.89 (s, 1H),
3.09-3.00 (m, 2H), 2.87-2.79 (m, 4H), 2.71-2.54 (m, 2H), 1.93-1.68
(m, 6H), 1.45-1.36 (m, 2H).
[0298] Compound 297 (100 mg, 0.2 mMol) was dissolved in
CH.sub.2Cl.sub.2 (2 mL) and a solution of 1N HCl in ether (1 mL)
was added slowly. The mixture was stirred at r.t. for 1 hr, then
concentrated and washed with ether (3.times.). The remaining ether
was removed in vacuo to provide Compound 297 (95 mg, 89%) as a
hydrochloride salt.
[0299] MS m/z 499 (MH+); .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
9.33 (s, 1H), 7.57 (s, 1H), 7.46 (s, 2H), 7.06-6.93 (m, 4H), 5.93
(s, 1H), 4.20-3.61 (broad peak, 4H), 3.02-2.88 (m, 2H), 2.78-2.52
(m, 2H), 2.21-1.55 (m, 8H).
Example 11
2-(1-benzyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-ethenesulfonic acid
[(1R)-1-phenyl-ethyl]-amide
Cpd 260
##STR00223##
[0301] Cyclohexanone Compound 2a (1.37 g, 14.0 mMol) in THF (5 mL)
was added dropwise to a solution of LHMDS (16.0 mL, 16.0 mMol) in
anhydrous THF (25 mL) at -78.degree. C. under a N.sub.2 atmosphere.
The solution was stirred at -78.degree. C. for about 1 hr. Methyl
dimethoxyacetate Compound 11a (1.88 g, 14.0 mMol) in anhydrous THF
(5 mL) was then added dropwise. The reaction mixture was stirred
while warming to r.t. over a period of about 15 hrs, then the
reaction was quenched with water (5 mL). The organic layer was
diluted with EtOAc (100 mL) and washed with water and brine. The
organic layer was separated and dried with anhydrous sodium
sulfate, then filtered and concentrated in vacuo to yield a crude
product as an oil. The oil was purified by flash chromatography
(eluted with 10% EtOAc in hexane) to afford
2-(2,2-dimethoxy-acetyl)-cyclohexanone Compound 11b (1.82 g,
65%).
##STR00224##
[0302] Benzylhydrazine dihydrochloride Compound 11c (1.75 g, 9.00
mMol) and K.sub.2CO.sub.3 (1.51 g, 10.92 mMol) were added to a
solution of Compound 11b (1.80 g, 9.10 mMol) in MeOH (50 mL) at
0.degree. C. under a N.sub.2 atmosphere. The reaction mixture was
stirred overnight while warming to r.t., then the reaction was
quenched with water (20 mL). The organic layer was diluted with
EtOAc (200 mL) and washed with water and brine. The organic layer
was separated and dried with anhydrous sodium sulfate, then
filtered and concentrated in vacuo to yield a crude product as an
oil. The oil was purified by flash chromatography (eluted with 20%
EtOAc in hexane) to afford
1-benzyl-3-dimethoxymethyl-4,5,6,7-tetrahydro-1H-indazole Compound
11d (1.80 g, 70%) as a colorless oil.
##STR00225##
[0303] 3N HCl (8 mL) was added to a solution of Compound 11d (1.70
g, 5.9 mMol) in acetone (50 mL) at 0.degree. C. under a N.sub.2
atmosphere. The reaction mixture was stirred for 4 hrs while
warming to r.t., then the reaction was quenched with water (20 mL),
neutralized to pH 7 with K.sub.2CO.sub.3 and diluted with
CH.sub.2Cl.sub.2 (100 mL). The organic layer was washed with water
and brine, separated and dried with anhydrous sodium sulfate, then
filtered and concentrated in vacuo to afford a
1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carbaldehyde Compound 11e
(1.35 g, 95%) as a colorless oil.
##STR00226##
[0304] Methanesulfonyl chloride Compound 11f.sup.1 (2.0 g, 17 mMol)
and TEA (2.43 mL, 17.46 mMol) were added to a solution of
(1R)-1-phenyl-ethylamine Compound 11f.sup.2 (1.75 g, 17.5 mMol) in
CH.sub.2Cl.sub.2 (50 mL) at 0.degree. C. under a N.sub.2
atmosphere. The mixture was stirred for 3 hrs while warming to
r.t., then the reaction was quenched with water (5 mL). The organic
layer was diluted with CH.sub.2Cl.sub.2 (100 mL) and then washed
with water and brine. The organic layer was separated, dried with
anhydrous sodium sulfate, then filtered and concentrated in vacuo
to afford the corresponding N-(1-phenyl-ethyl)-methanesulfonamide
Compound 11f.sup.3 as an oil.
##STR00227##
[0305] (Boc).sub.2O (di-tert-butyldicarbonate) (4.57 g, 21.0 mMol)
and DMAP (8 mg) were added to a solution of the methanesulfonamide
Compound 11f.sup.3 in CH.sub.2Cl.sub.2 (10 mL) at 0.degree. C.
under a N.sub.2 atmosphere. The mixture was stirred overnight while
warming to r.t., then the reaction was quenched with a saturated
solution of NaHCO.sub.3 (sodium bicarbonate) (10 mL). The organic
layer was diluted with CH.sub.2Cl.sub.2 (100 mL) and then washed
with water and brine. The organic layer was separated, dried with
anhydrous sodium sulfate, then filtered and concentrated in vacuo
to yield a crude Boc-protected methanesulfonamide product. The
product was purified by flash chromatography (eluted with 10% EtOAc
in hexane) to afford (methylsulfonyl)[(1R)-1-phenyl-ethyl]-carbamic
acid tert-butyl ester Compound 11f (3.89 g, 80%) as a colorless
oil.
##STR00228##
[0306] Adapting a published procedure (Tozer M J, Woolford A J A
and Linney I A, Synlett, 1998, 2, 186-188) to obtain the target
compound, a 1M solution of KOtBu (potassium tert-butoxide) in THF
(0.75 mL, 0.75 mMol) was added dropwise to a solution of the ester
Compound 11f (0.070 g, 0.250 mMol) in anhydrous THF (5 mL) at
-78.degree. C. under a N.sub.2 atmosphere. After 45 min. Compound
11e (0.060 g, 0.250 mMol) diluted in THF (3 mL) was added dropwise.
The solution was reacted over a 15 hr period while warming to
ambient temperature. The reaction was quenched with water (5 mL).
The organic layer was diluted with EtOAc (100 mL) and then washed
with water and brine. The organic layer was separated and dried
with anhydrous sodium sulfate, then filtered and concentrated in
vacuo to yield a crude product. The product was purified by flash
chromatography (eluted with 20% EtOAc in hexane) to give Compound
260 (0.079 g (75%), as a white solid.
[0307] MS m/z 422 (MH.sup.+); .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.56 (d, J=15.5 Hz, 1H), 7.35-7.19 (m, 8H), 7.11-7.09 (m,
2H), 6.42 (d, J=15.5 Hz, 1H), 5.21 (s, 2H), 4.61-4.11 (m, 2H),
2.45-2.41 (m, 2H), 2.36-2.33 (m, 2H), 1.75-1.67 (m, 4H), 1.55 (d,
J=6.5 Hz, 3H).
Example 12
3-(1-benzyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-N-[(1R)-1-phenyl-ethyl]-ac-
rylamide
Cpd 306
##STR00229##
[0309] Acetyl-(1-phenyl-ethyl)-carbamic acid tert-butyl ester
Compound 12a was synthesized using the procedure of Example 12,
replacing mesyl chloride Compound 11f.sup.1 with acetyl chloride
Compound 12a.sup.1.
##STR00230##
[0310] Acetyl(1-phenylethyl)carbamic acid tert-butyl ester Compound
11e was reacted with Compound 12a, using the procedure of Example
12, to afford Compound 306 (0.067 g, 70%) as a white solid.
[0311] MS m/z 386 (MH.sup.+) .sup.1H NMR (CDCl.sub.3, 400 MHz)
.delta. 7.56 (d, J=15.8 Hz, 1H), 7.35-7.23 (m, 8H), 7.11-7.09 (m,
2H), 6.42 (d, J=15.8 Hz, 1H), 5.77-5.11 (d, J=7.4 Hz, 1H),
5.30-5.23 (m, 1H), 5.21 (s, 2H), 2.59-2.56 (m, 2H), 2.44-2.42 (m,
2H), 1.74-1.71 (m, 4H), 1.54 (d, J=6.9 Hz, 3H).
Example 13
3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-2-(2-methoxy-phenyl)-p-
ropionic acid ethyl ester
Cpd 332
##STR00231##
[0313] Cyclohexylhydrazine hydrochloride Compound 1d (6.0 g, 46.5
mMol) and K.sub.2CO.sub.3 (9.0 g, 65.0 mMol) were added to a
solution of Compound 2c (10.10 g, 50.95 mMol) in EtOH (50 mL) at
ambient temperature under a N.sub.2 atmosphere. The mixture was
stirred overnight, concentrated to dryness, then diluted with water
(100 mL) and EtOAc (500 mL). The organic layer was washed with
brine, separated, dried with anhydrous sodium sulfate, then
filtered and concentrated in vacuo to yield a crude oil.
Purification by flash chromatography (eluted with 10% EtOAc in
hexane) afforded
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid ethyl
ester Compound 13a (12.2 g, 44.14 mMol, 95%) as a yellow oil.
##STR00232##
[0314] The scheme above, wherein Compound 13a is taken to Compound
332 using the conditions and reagents indicated, describes the use
of a published procedure (Murray W V, Hadden S K, Wachter M P, J.
Het. Chem., 1990, 27, 1933-40; U.S. Pat. No. 4,826,868; U.S. Pat.
No. 4,898,952; U.S. Pat. No. 5,051,518; U.S. Pat. No. 5,164,381 and
U.S. Pat. No. 5,242,940) to produce the target Compound 332. MS m/z
411 (MH.sup.+).
Example 14
3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-2-(2-methoxy-phenyl)-N-
-(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-propionamide
Cpd 333
##STR00233##
[0316] Using the procedure of Example 2, 1N NaOH (10 mL) was added
to a solution of ester Compound 336 (0.295 g, 0.72 mMol) in THF (10
mL). The mixture was stirred for 30 hrs, acidified to pH 2 with 1N
HCl and extracted with EtOAc (50 mL). The organic layer was washed
with brine, dried over sodium sulfate, then filtered and
concentrated in vacuo to yield a carboxylic acid Compound 14a
(0.150 g, 54%) as a white solid.
##STR00234##
[0317] Thionyl chloride (0.25 g, 2.16 mMol) was added to a solution
of Compound 14a (0.15 g, 0.39 mMol) in CH.sub.2Cl.sub.2 (10 mL) at
ambient temperature under a N.sub.2 atmosphere. The mixture was
stirred for 3 hrs and concentrated in vacuo to afford Compound
14b.
##STR00235##
[0318] Triethylamine (0.16 g, 1.58 mMol) and Compound 14b (0.075 g,
0.63 mMol) were added to a solution of Compound 2i (0.12 g, 0.63
mMol) in CH.sub.2Cl.sub.2 (10 mL) at ambient temperature under a
N.sub.2 atmosphere. The mixture was stirred at r.t. for 3 hrs, then
diluted with water (10 mL) and CH.sub.2Cl.sub.2 (50 mL). The
organic layer was separated, dried with anhydrous sodium sulfate,
then filtered and concentrated in vacuo to yield a crude oil.
Purification by flash chromatography (eluted with 20% EtOAc in
hexane) afforded Compound 333 (0.039 g, 33%) as a white solid. MS
m/z 518 (MH.sup.+).
Example 15
3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-N-(1,3,3-trimethyl-bic-
yclo[2.2.1]hept-2-yl)-propionamide
Cpd 50
##STR00236##
[0320] Carboxylic acid Compound 15a was derived using a published
procedure (as described in Murray W V, Wachter M P, Barton D and
Forero-Kelly Y, Synthesis, 1991, 01, 18-20) using cyclohexanone as
the starting material and carried forward using the procedure of
Example 2 to provide
3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)propionic acid
Compound 15b, MS m/z 277 (MH.sup.+).
##STR00237##
[0321] Thionyl chloride (1.94 g, 16.41 mMol) was added to a
solution of Compound 15b (1.51 g, 5.47 mMol) in CH.sub.2Cl.sub.2
(10 mL) at ambient temperature under a N.sub.2 atmosphere. The
mixture was stirred for 3 hrs and concentrated in vacuo to afford
the corresponding acid chloride Compound 15c.
##STR00238##
[0322] Triethylamine (0.16 g, 1.58 mMol) and acid chloride Compound
15c (0.15 g, 0.50 mMol) were added to a solution of Compound 2i
(0.08 g, 0.50 mMol) in CH.sub.2Cl.sub.2 (10 mL) at ambient
temperature under a N.sub.2 atmosphere. The mixture was stirred at
r.t. for 3 hrs, then diluted with water (10 mL) and
CH.sub.2Cl.sub.2 (50 mL). The organic layer was separated, dried
with anhydrous sodium sulfate, then filtered and concentrated in
vacuo to yield a crude oil. Purification by flash chromatography
(eluted with 20% EtOAc in hexane) afforded Compound 50 (0.05 g,
24%) as a white solid. MS m/z 412 (MH.sup.+).
Example 16
N-adamantan-2-yl-3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-2,2-d-
imethyl-propionamide
Cpd 66
##STR00239##
[0324]
3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-2,2-dimethyl-pr-
opionic acid Compound 16a was derived by the procedure described in
U.S. Pat. No. 5,051,518 whereby cyclohexanone Compound 2a was used
as the starting material and carried forward. MS m/z 305
(MH.sup.+). Thionyl chloride (0.28 g, 2.40 mMol) was added to a
solution of the acid Compound 16a (0.24 g, 0.80 mMol) in
CH.sub.2Cl.sub.2 (5 mL) at ambient temperature under a N.sub.2
atmosphere. The mixture was stirred for 3 hrs and concentrated in
vacuo to afford the corresponding acid chloride Compound 16b.
##STR00240##
[0325] Triethylamine (0.05 g, 0.50 mMol) and acid chloride Compound
16b (0.70 g, 0.60 mMol) were added to a solution of
2-adamantanamine Compound 1h (0.03 g, 0.20 mMol) in
CH.sub.2Cl.sub.2 (5 mL) at ambient temperature under a N.sub.2
atmosphere. The mixture was stirred at r.t. for 3 hrs, then diluted
with water (10 mL) and CH.sub.2Cl.sub.2 (50 mL). The organic layer
was separated, dried with anhydrous sodium sulfate, then filtered
and concentrated in vacuo to yield a erode oil. Purification by
flash chromatography (eluted with 20% EtOAc in hexane) afforded
Compound 66 (0.032 g, 37%) as a white solid. MS m/z 438
(MH.sup.+).
Example 17
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
[(1R)-1-cyclohexyl-ethyl]methylamide
Cpd 328
##STR00241##
[0327] Ethyl formate (1.2 mL, 15.0 mMol) was added to a round
bottom flask containing (1R)-1-cyclohexyl-ethylamine Compound 17a
(1.27 g, 10 mMol) at 0.degree. C. and the mixture was stirred at
r.t. for 15 hrs. Excess ethyl formate was removed in vacuo to
obtain N-[(1R)-1-cyclohexyl-ethyl]-formamide Compound 17b (1.55 g)
as a white solid, which was used in the next step without
purification. MS m/z 156 (MH.sup.+).
##STR00242##
[0328] A solution of LAH in THF (1.0 M, 15 mL, 15 mMol) was added
dropwise via syringe to a solution of Compound 17b (1.55 g, 10
mMol) in anhydrous THF at 0.degree. C. The mixture was heated to
reflux for 8 hrs and provided a grayish suspension. The suspension
was cooled to 0.degree. C. and the reaction was quenched carefully
by a sequential addition of water (0.6 mL), 2N NaOH (0.6 mL) and
water (2.0 mL). A white residue was produced, then filtered through
a sintered glass funnel and washed with Et.sub.2O (20 mL). The
solvent from the combined filtrate was removed in vacuo to provide
[(1R)-1-cyclohexyl-ethyl]-methylamine Compound 17c (1.1 g, 72%) as
a pale yellow oil, which was used in the next step without
purification. MS m/z 142 (MH.sup.+).
##STR00243##
[0329] The acid chloride Compound 5e (0.04 g, 0.15 mMol) was added
to a solution of the methylamine Compound 17c (0.05 g, 0.035 mMol)
in CH.sub.2Cl.sub.2 (2 mL) and triethylamime (0.06 mL, 0.5 mMol).
The resulting suspension was stirred at r.t. for 2 hrs, diluted
with CH.sub.2Cl.sub.2 (10 mL), then washed with 1N HCl (2.times.10
mL) and water (2.times.10 mL). The organic layer was dried over
sodium sulfate, then concentrated and purified on a silica gel
column (eluted with 20% EtOAc in hexane) to provide Compound 328
(44 mg, 80%). MS m/z 372 (MH.sup.+).
Example 18
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
(cyclohexyl-phenyl)methylamide
Cpd 331
##STR00244##
[0331] Hydroxylamine hydrochloride (0.48 g, 6.7 mMol) and sodium
acetate (1.4 g, 10.2 mMol) were added to a round bottom flask
containing cyclohexyl-phenyl-methanone Compound 18a (0.97 g, 5.1
mMol) in MeOH (30 mL) at r.t. Tire mixture was stirred at r.t. for
15 hrs. The solvent was removed in vacuo and the residue was
extracted with CH.sub.2Cl.sub.2. The organic layer was sequentially
washed with a saturated solution of NaHCO.sub.3, then brine. The
organic layer was dried over Na.sub.2SO.sub.4, decanted and the
solvent removed in vacuo to provide cyclohexyl-phenyl-methanone
oxime Compound 18b (1.0 g) as a white solid, which was used in the
next step without purification. MS m/z 204 (MH.sup.+).
##STR00245##
[0332] A solution of Compound 18b (0.45 g, 0.22 mMol) in anhydrous
THF (10 mL) added dropwise via syringe to a suspension of LAH (0.5
g, 1.3 mMol) in THF (20 mL) at 0.degree. C. The mixture was heated
to reflux for 8 hrs and provided a grayish suspension. The
suspension was cooled to 0.degree. C. and the reaction was quenched
carefully by sequential addition of water (0.5 mL), 2N NaOH (0.5
mL) and water (1.5 mL). A white residue was produced, then filtered
through a sintered glass funnel and washed with Et.sub.2O (20 mL).
The solvent from the combined filtrate was removed in vacuo to
provide C-cyclohexyl-C-phenyl-methylamine Compound 18c (0.38 g,
91%) as a pale yellow oil, which was used in the next step without
purification. MS m/z 190 (MH.sup.+).
##STR00246##
[0333] Using the procedure of Example 5, Compound 18c was reacted
with acid chloride Compound 5e to provide Compound 331.
Example 19
1-cyclohexyl-5-hydroxymethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid (1-adamantan-1-yl-ethyl)-amide
Cpd 143
##STR00247##
[0335] Compound 132 (prepared according to the procedure of Example
1, replacing Compound 1h with 1-adamantan-1-yl-ethylamine) (25.0
mg, 0.052 mMol), LiBH.sub.4 (lithium borohydride) (2.0 mg, 0.092
mMol) and methanol (0.01 mL) in ether (3.0 mL) were refluxed for
0.5 hr. The reaction was quenched with 1N HCl (2.0 mL). The organic
layer was concentrated, extracted with DCM (dichloromethane)
(2.times.5.0 mL) and dried over Na.sub.2SO.sub.4. The solvent was
evaporated to give Compound 143 (22.0 mg, 96%) as a white
solid.
[0336] MS m/z 440 (MH.sup.+), 462 (MNa.sup.+); .sup.1H NMR
(CDCl.sub.3, 300 MHz) .delta.: 6.71 (1H, d, J=10.1 Hz), 3.82 (2H,
m), 3.62 (1H, m), 3.41 (1H, m), 2.99 (1H, dd, J=16.4, 5.0 Hz), 2.65
(1H, m), 2.47 (1H, m), 2.24 (1H, m), 2.03 (1H, m), 1.83 (10H, m),
1.52 (14H; m), 1.25 (4H, m), 1.03 (3H, d, J=6.8 Hz).
Example 20
2-[1-(4-fluoro-phenyl)-7-phenethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl]-eth-
enesulfonic acid (1-phenyl-ethyl)-amide
Cpd 258
2-[1-(4-fluoro-phenyl)-7-phenethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl]ethe-
nesulfonic acid (1-cyclohexyl-ethyl)-amide
Cpd 259
##STR00248##
[0338] Cyclohexylamine Compound 20a (4.64 g, 46.50 mmol) was added
to a solution of cyclohexanone Compound 2a (4.0 g, 46.50 mmol) in
benzene (100 mL) at ambient temperature under a N.sub.2 atmosphere.
The mixture was refluxed at 80.degree. C. for 5 hours, using a Dean
Stark apparatus for the removal of water, and concentrated to
dryness. The crude product was purified by distillation at
aspirator pressure to afford cyclohexyl-cyclohexylidene-amine
Compound 20b (7.33 g, 88%) as a clear oil.
##STR00249##
[0339] s-BuLi (28.0 mL, 1.3 M) was added slowly to a solution of
Compound 20b (7.0 g) in THF (50 mL) at -78.degree. C. The mixture
stirred for 1 hr at -78.degree. C. and then
(2-chloro-ethyl)-benzene Compound 20c (5.11 g, 36.4 mmol) in THF
(10 mL) was added dropwise. The reaction mixture was stirred for 24
hrs while warming to r.t. The reaction was quenched with 1N HCl (5
mL), then diluted with water (100 mL) and EtOAc (500 mL). The
organic layer was washed with brine, separated and dried with
anhydrous sodium sulfate, then filtered and concentrated in vacuo
to yield a crude product. Purification by flash chromatography
(eluted with 10% EtOAc in Hexane) afforded
2-phenethyl-cyclohexanone Compound 20d (4.05 g, 20.0 mMol, 58%) as
a yellow oil.
##STR00250##
[0340] Compound 20d was carried forward in place of Compound 2a
using the procedure of Example 11 to provide
2-(2,2-dimethoxy-acetyl)-6-phenethyl-cyclohexanone Compound
20e.
##STR00251##
[0341] Using the procedure of Example 10, Compound 20e was used in
place of [3-(4-fluoro-benzylidene)-2-oxo-cyclohexyl]oxoacetic acid
ethyl ester Compound 10c and (4-fluoro-phenyl)-hydrazine Compound
20f was used in place of (2,4-dichloro-phenyl)-hydrazine Compound
10d to provide
1-[1-(4-fluoro-phenyl)-7-phenethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl]-2,-
2-dimethoxy-ethanone Compound 20g.
##STR00252##
[0342] Using the procedure of Example 11, Compound 20g was used in
place of [3-(4-fluoro-benzylidene)-2-oxo-cyclohexyl]-oxo-acetic
acid ethyl ester Compound 11d to provide
1-(4-fluoro-phenyl)-7-phenethyl-4,5,6,7-tetrahydro-1H-indazole-3-carbalde-
hyde Compound 20h.
##STR00253##
[0343] Using the procedure of Example 11, Compound 20h was used in
place of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carbaldehyde
Compound 11e and (methylsulfonyl)(1-phenyl-ethyl)carbamic acid
tert-butyl ester Compound 201 was used in place of
(methylsulfonyl)[(1R)-1-phenyl-ethyl]carbamic acid tert-butyl ester
Compound 11f to provide Compound 258.
##STR00254##
[0344] Using the procedure of Example 11, Compound 20h was used in
place of 1-benzyl-4,5,6,7-tetrahydro-1H-indazole-3-carbaldehyde
Compound 11e and (methylsulfonyl)(1-cyclohexyl-ethyl)-carbamic acid
tert-butyl ester Compound 20j was used in place of
(methylsulfonyl)[(1R)-1-phenyl-ethyl]-carbamic acid tert-butyl
ester Compound 11f to provide Compound 259.
Example 21
1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
N'-cyclooctyl-hydrazide
Cpd 300
##STR00255##
[0346] According to a published procedure, cyclooctanone Compound
21a was reacted with hydrazinecarboxylic acid tert-butyl ester to
produce an intermediate N'-cyclooctylidene-hydrazinecarboxylic acid
tert-butyl ester Compound 21b (as described in Ghali N K and Venton
D L, J. Org. Chem., 1981, 46, 5413). According to the published
procedure, Compound 21b was carried forward to provide
cyclooctyl-hydrazine hydrochloride Compound 21c.
##STR00256##
[0347] According to the procedure of Example 5, the acid chloride
Compound 5e was reacted with Compound 21c in a solution of
CH.sub.2Cl.sub.2 and triethylamine to provide an amide Compound
300. MS m/z 345.1 (MH.sup.+).
Example 22
1-cyclohexyl-5-oxo-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid
(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide
Cpd 96
##STR00257##
[0349] According to the procedure of Example 2, a solution of
1,4-dioxaspiro[4.5]decane-8-one Compound 22a in ether was added to
a solution of LHMDS in ether at -78.degree. C. The diethyloxalate
Compound 2b was added to the mixture and reacted to produce an
oxo(8-oxo-1,4-dioxa-spiro[4.5]dec-7-yl)acetic acid ethyl ester
Compound 22b.
##STR00258##
[0350] According to the procedure of Example 1, Compound 22b was
reacted with a solution of cyclohexyl hydrazine hydrochloride
Compound 1d and K.sub.2CO.sub.3 in CH.sub.2Cl.sub.2 to produce
(N-8-cyclohexyl-1,4-dioxa-spiro[4.6]-4,5,6,7-tetrahydro-1H-indazol-10-yl)
carboxylic acid ethyl ester Compound 22c.
##STR00259##
[0351] According to the procedure of Example 8, Compound 22c was
used in place of
5-tert-butoxycarbonylamino-1-cyclohexyl-4,5,6,7-tetrahydro-1H-in-
dazole-3-carboxylic acid ethyl ester Compound 8c and carried
forward to provide
(N-8-cyclohexyl-1,4-dioxa-spiro[4.6]-4,5,6,7-tetrahydro-1H-indazo-
l-10-yl)carboxylic acid
(1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide Compound 22d.
##STR00260##
[0352] 2N HCl (5 equiv.) was added to a solution of Compound 22d
(0.030 g 0.068 mMol) in THF (10 mL) at 0.degree. C. The mixture was
stirred for 1 hr while warming to ambient temperature. The reaction
was quenched with water (2 mL), neutralized to pH 7 with
K.sub.2CO.sub.3 and diluted with EtOAc (20 mL). The organic layer
was washed with water and brine, then separated, dried with
anhydrous sodium sulfate and filtered. The product was concentrated
in vacuo to afford Compound 96 (0.021 g, 79%) as a colorless oil.
MS m/z 398 (MH.sup.+).
Example 23
7-chloro-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid [(1S,2R)-2-hydroxymethyl-cyclohexyl]-amide
Cpd 60
##STR00261##
[0354]
1-cyclohexyl-7-methoxy-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid Compound 23a was prepared according to the procedure of
Example 2, wherein 2-methoxy-cyclohexanone was used in place of
Compound 2a as the starting material.
[0355] Thionyl chloride (0.20 g, 1.7 mmol) was added to a solution
of Compound 23a (0.15 g, 0.55 mmol) in CH.sub.2Cl.sub.2 (10 mL) at
ambient temperature under a N.sub.2 atmosphere. The mixture was
stirred for 3 hrs at 35.degree. C., cooled to ambient temperature,
then concentrated in vacuo to afford the corresponding
7-chloro-1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazole-3-carbonyl
chloride. Compound 23b.
##STR00262##
[0356] NEt.sub.3 (triethylamine) (0.10 g, 0.98 mMol) and Compound
23b (0.06, 0.20 mMol) were added to a solution of
(1R,2S)-(2-amino-cyclohexyl)-methanol hydrochloride Compound 23c
(0.064 g, 0.39 mMol) in CH.sub.2Cl.sub.2 (10 mL) at ambient
temperature under a N.sub.2 atmosphere. The mixture was stirred at
r.t. for 3 hrs, then diluted with water (10 mL) and
CH.sub.2Cl.sub.2 (50 mL). The organic layer was separated, dried
with anhydrous sodium sulfate, then filtered and concentrated in
vacuo to yield a crude product. Purification by flash
chromatography (eluted with 20% EtOAc in hexane) afforded Compound
60 (0.034 g, 45%) as a white solid. MS m/z 394 (MH.sup.+).
Example 24
(2S,3R)-3-[(1-cyclohexyl-7-hydroxy-4,5,6,7-tetrahydro-1H-indazole-3-carbon-
yl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester
Cpd 164
##STR00263##
[0358] 7-chloro-1-cyclohexyl-4,5,6,7-tetrahydro
1H-indazole-3-carbonyl chloride Compound 23b was hydrolyzed to
provide
1-cyclohexyl-7-hydroxy-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid Compound 24a.
##STR00264##
[0359] 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDCI) (0.15 g, 0.81 mmol), dimethylaminopyridine (DMAP) (8 mg) and
(2S,3R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester
Compound 24b (0.059 g, 0.27 mmol) were added to a solution of
1-cyclohexyl-7-hydroxy-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic
acid Compound 24a (0.071 g, 0.27 mmol) in 5 mL C.sub.2Cl.sub.2 at
0.degree. C. under a N.sub.2 atmosphere. The mixture was stirred
for 6 hrs while warming to r.t., then concentrated in vacuo and
purified by flash chromatography (eluted with 15% EtOAc in hexane)
to afford Compound 164 (0.075 g, 65%) as a white solid.
Example 25
1-(2,4-dichloro-phenyl)-7-(3-methoxy-phenyl)-4,5,6,7-tetrahydro-1H-indazol-
e-3-carboxylic acid [(1S)-2-hydroxy-1-phenyl-ethyl]-amide
Cpd 313
##STR00265##
[0361] According to the procedure of Example 2, a solution of
2-(3-methoxy-phenyl)-cyclohexanone Compound 25a (commercially
available) in ether was carried forward in place of Compound 2a to
produce
1-(2,4-dichloro-phenyl)-7-(3-methoxy-phenyl)-4,5,6,7-tetrahydro-1H-indazo-
le-3-carbonyl chloride Compound 25b.
##STR00266##
[0362] According to the procedure of Example 2, triethylamime and
Compound 25b were reacted with (1S)-2-amino-2-phenyl-ethanol
Compound 25c in CH.sub.2Cl.sub.2 to provide amide Compound 313.
Example 26
1-(2,4-dichloro-phenyl)-7-(3-methoxy-phenyl)-4,5,6,7-tetrahydro-1H-indazol-
e-3-carboxylic acid [(1S)-2-chloro-1-phenyl-ethyl]-amide
Cpd 316
##STR00267##
[0364] Thionyl chloride (0.01 g, 0.08 mmol) was added to a solution
of Compound 313 (0.02 g, 0.04 mmol) in 5 mL CH.sub.2CL at 0.degree.
C. under a N.sub.2 atmosphere. The mixture was stirred for 2 hrs
while warming to ambient temperature, then concentrated in vacuo to
afford the corresponding acid chloride. Purification by flash
chromatography (eluted with 20% EtOAc in hexane) afforded Compound
316 (0.036 g, 95%) as a white solid. MS m/z 554 (MH.sup.+).
Example 27
1-adamantan-1-yl-3-(1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-urea
Cpd 182
##STR00268##
[0366] 1-isocyanato-adamantane Compound 27a (4.6 mg, 0.026 mMol)
and triethyl amine (0.01 mL, 0.072 mMol) were added to a solution
of 1-cyclohexyl-4,5,6,7-tetrahydro-1H-indazol-3-ylamine Compound 6c
(5 mg, 0.023 mMol) (Prepared using the procedure of Example 6). The
mixture was stirred at r.t. for 4 hrs. The mixture was then
concentrated and purified on a silica gel column (eluted with 15%
EtOAc/hexane) to give Compound 182 (5.5 mg, 60%). MS m/z 397
(MH.sup.+).
[0367] Additional compounds may be made according to the synthetic
methods of the present invention by one skilled in the art,
differing only in possible starting materials, reagents and
conditions used in the instant methods.
Biological Examples
[0368] The following examples illustrate that the compounds of the
present invention are CB receptor modulators useful for treating,
ameliorating or preventing a cannabinoid receptor mediated
syndrome, disorder or disease in a subject in need thereof.
Example 1
Binding Assay for CB1 or CB2 Agonists or Inverse Agonists
[0369] The human CB1 and CB2 receptors were stably expressed in
SK-N-MC cells transfected with pcDNA3 CB-1 (human) or pcDNA3 CB-2
(human). The cells were grown in T-180 cell culture flasks under
standard cell culture conditions at 37.degree. C. in a 5% CO.sub.2
atmosphere. The cells were harvested by trysinization and
homogenized in a homogenization buffer (10 mM Tris, 0.2 mM
MgCl.sub.2, 5 mM KCl, with protease inhibitors aprotinin,
leupeptin, pepstatin A and bacitracin) and centrifuged (2000 g).
The supernatant was then centrifuged in 2M sucrose (31,300 g) to
produce a semi-purified membrane pellet. The pellet was resuspended
in homogenization and store at -80.degree. C.
[0370] On the day of the assay, the pellet was thawed on ice and
diluted in assay buffer (50 mM Tris-HCl, 5 mM MgCl.sub.2, 2.5 mM
EDTA, 0.5 mg/mL fatty acid free bovine serum albumin, pH 7.5). The
diluted membrane was added with buffer, test compound or standard
and the radioligand [H].sup.3+-CP-55,940_(0.2 nM) to the wells of a
96-well polypropylene plate. Non-specific binding was measured in
wells containing 10 uM WIN 55,212. The plate was covered and
incubated for 90 minutes at 30.degree. C. The contents were then
aspirated onto a Packard Unifilter GF/C filter bottom plate prewet
with 0.5%) polyethyleneimine. The wells of the polypropylene plate
were rinsed and aspirated seven times with a 0.9% saline-0.5% Tween
20 solution. The Unifilter plate was dried, a scintillation
cocktail was added to each well and the counts representing binding
were quantitated in a TopCount scintillation counter.
CB1 and CB2 Receptor Binding Results
[0371] The IC.sub.50 binding values for compounds tested were
calculated by linear regression and were obtained from studies in
which varying compound concentrations were used.
TABLE-US-00004 TABLE 1a Cannabinoid CB1 Receptor Binding IC.sub.50
(.mu.M) Cpd IC.sub.50 Cpd IC.sub.50 Cpd IC.sub.50 Cpd IC.sub.50 1
0.3767 5 6.8 6 6.75 7 3.1 9 0.3383 10 0.045 11 0.2854 12 0.1485 13
0.1084 14 0.216 15 0.2413 16 0.1851 17 0.1682 18 0.0918 19 0.114 20
0.169 21 0.044 22 1.03 23 1.8 24 3.81 25 0.0753 26 0.7233 27 0.108
28 0.85 29 0.7897 30 7.885 31 1.694 32 0.02 33 0.058 34 0.1356 35
0.7 36 0.1053 37 0.0693 38 0.006 39 0.009 40 1.44 41 0.049 42 10.7
43 0.014 44 0.079 45 0.04 47 22.6 48 0.249 49 0.15 50 0.255 51 15.2
52 6.26 53 6.12 54 11.4 57 10.897 58 0.736 59 0.34 60 5.235 61
2.195 62 0.28 63 13.655 64 0.41 66 3.59 67 0.3 68 0.4633 69 0.22 70
0.125 71 0.53 72 8.4 73 0.76 74 0.015 75 0.0237 76 1.96 77 0.052 78
4.6 79 0.03 80 0.23 81 0.49 82 0.7 83 0.038 84 0.4 85 0.6 87 0.855
88 2.4 89 3.7 90 1.84 92 1.6 93 1.15 94 1.78 95 6.4 96 9.5 97 9.7
98 20.5 99 0.96 102 30.9 103 2 104 17.1 105 8.5 106 12.7 107 0.91
108 2.4 119 0.006 120 2.46 122 0.004 123 0.0075 124 0.007 125 0.026
126 0.597 127 0.0099 128 0.01 129 0.0057 130 0.4 131 0.03 132 2.9
133 12 134 0.4 135 0.67 136 0.0008 137 3.95 139 0.16 140 0.89 141
0.3 142 0.6 143 2.4 144 0.22 145 0.95 147 2.075 148 0.013 149 0.067
150 0.13 151 0.59 152 0.34 153 1.39 154 0.06 156 0.097 157 0.03 158
0.013 159 0.74 161 5.235 162 0.635 163 4.77 164 6.01 167 1.66 169
0.43 171 0.64 173 0.444 175 2.16 177 10.45 179 7.3 180 0.7 181 0.3
183 0.05 184 0.05 185 0.9 187 3.69 189 0.01 190 1.62 192 0.06 193
0.12 194 0.0001 195 0.1 196 0.125 197 0.98 198 0.1 199 0.019 200
0.008 201 0.0017 202 0.1147 203 0.59 204 0.8 205 1.58 206 0.097 207
0.0824 208 0.66 209 0.26 210 0.335 211 0.005 212 0.26 213 0.95 214
1.23 216 2.8 217 0.0026 218 0.4 219 0.1 221 3.29 222 0.28 223 169.9
224 1.5 226 0.0079 227 2.77 230 0.01 231 0.6375 232 2.4 233 1.6 234
0.23 235 3.6 236 25.35 237 0.89 238 25.1 241 3.4 242 0.3 243 0.13
244 0.3 245 0.02 246 2.27 247 0.26 248 0.16 249 0.05 250 0.07 252
0.04 253 0.025 256 0.26 265 0.096 267 0.15 269 0.191 270 3.1 271
6.2 272 0.086 273 1.59 274 0.0187 275 0.323 276 0.135 277 1.3 278
0.4025 279 3.8 280 3.6 281 19.66 282 11.805 283 0.1 284 0.35 285
2.9 287 2.5 289 0.88 290 0.025 291 0.18 292 0.033 293 0.006 294
0.11 295 0.003 296 0.005 297 0.013 298 0.064 301 0.024 304 0.16 305
9.8 308 0.019 309 0.047 320 0.014 321 0.23 328 5.1 329 1.7 330 1.9
331 3 332 3.9 333 5.7 334 12.5 336 45 338 1.35 339 0.008 340 0.016
341 0.02 342 0.041 343 0.037 344 0.053 345 0.07 346 0.033 347 0.018
348 0.011 349 0.04 350 0.017 351 0.012 353 0.016 356 0.077 357
0.021 358 0.013 360 0.012 362 0.038 363 0.013 364 0.016 365 0.016
368 0.039 369 0.042 371 0.039 373 0.02 374 0.019 376 0.016 377
0.043 380 0.032 381 0.015 382 0.005 383 0.01 384 0.021 385 0.007
386 0.011 387 0.033 388 0.015 389 0.014 390 0.02 393 0.043 394
0.077 395 0.071 396 0.052 397 0.059 398 0.048
TABLE-US-00005 TABLE 1b Cannabinoid CB2 Receptor Binding IC.sub.50
(.mu.M) Cpd IC.sub.50 Cpd IC.sub.50 Cpd IC.sub.50 Cpd IC.sub.50 1
0.0135 2 1.57 3 0.4285 4 3.69 5 0.2925 6 0.3665 7 3.575 8 21.22 9
0.0119 10 0.006 11 0.0406 12 0.0214 13 0.0065 14 0.0309 15 0.0538
16 0.0054 17 0.0045 18 0.0036 19 0.013 20 0.0352 21 0.011 22 0.143
23 0.1 24 6.82 25 0.0016 26 0.015 27 0.003 28 0.0075 29 0.1146 30
1.465 31 0.195 32 0.0069 33 0.008 34 0.0409 35 0.094 36 0.0128 37
0.112 38 0.0033 39 0.006 40 0.2147 41 0.0348 42 0.64 43 0.001 44
0.0024 45 0.0056 46 9.2 47 4.885 48 0.0553 49 0.0728 50 0.013 51
8.4177 52 4.9 53 0.23 54 6.05 55 7.9 56 20 57 2.2 58 0.1705 59 0.07
60 0.515 61 0.19 62 0.005 63 3.295 64 0.03 66 1.4 67 0.0155 68
0.057 69 0.0027 70 0.016 71 0.5 72 4.1 73 0.295 74 0.0014 75 0.0007
77 0.003 78 1.21 79 0.01 80 0.17 81 0.02 82 0.2 83 0.02 85 0.082 86
0.275 87 0.0266 88 0.087 89 0.0014 90 1.12 92 0.09 93 0.02 94 0.02
97 0.03 99 0.25 104 0.2 107 1.4 111 0.17 113 0.77 114 0.53 115 0.18
116 0.99 117 0.37 118 0.4 119 0.01 120 0.875 121 6.27 122 0.0015
123 0.0046 124 0.016 125 0.0022 126 0.593 127 0.0039 129 0.0017 130
0.005 131 0.01 132 0.0255 133 1.34 134 0.3 135 0.02 136 0.0005 137
1.55 138 11.8 139 0.3 140 3.4 141 0.14 142 0.4 143 1.26 144 0.04
145 1.1 147 1.79 148 0.03 149 0.008 150 0.04 151 0.03 152 0.2 153
0.06 154 0.37 156 0.002 157 0.002 158 0.009 159 0.13 160 3.5 161
0.775 162 0.11 163 0.21 164 0.49 165 0.8 166 1.7 167 0.028 169
0.017 170 0.3 171 0.3 173 0.526 174 16 175 1.56 176 4 177 2.4 178
2.9 179 0.7 180 1.7 181 1.6 182 0.028 183 0.0069 184 0.02 185 0.12
186 2.29 187 1.6 188 5.1 189 0.01 190 4.5 191 0.19 192 0.002 193
0.005 194 0.0002 195 0.02 196 0.12 197 0.8 198 0.0057 199 0.01 200
0.001 201 0.002 202 0.0045 203 0.24 204 0.01 205 0.07 206 0.0141
207 0.0016 208 0.014 209 0.2 210 0.008 211 0.0007 212 0.074 213 0.2
214 0.0153 215 0.2 216 0.07 217 0.0001 218 0.003 219 0.004 220 0.23
221 0.46 222 0.0049 223 2.9 224 1.2 225 0.65 226 0.0055 227 1.1535
228 0.25 229 1.3 230 0.001 232 0.03 233 0.88 234 0.01 235 1.4 236
0.94 237 0.1513 238 3.7225 239 0.3 240 1.7 241 0.5 242 1.6 243
0.004 244 0.079 245 0.002 246 0.09 247 0.047 248 0.02 250 0.0056
251 0.0028 252 0.048 253 0.3 256 0.3 265 0.041 267 0.27 269 0.0386
270 1.8 271 2.6 272 0.07 273 0.414 274 0.0016 275 1.3 276 0.25 277
3.3 278 0.0375 279 0.83 280 0.679 281 16.5 282 3.805 283 0.1 284
0.045 285 2.4 286 2.7 287 2.1 289 0.4 290 1 291 1.7 292 0.06 293
0.6 294 0.7 299 5.5167 301 0.033 302 9.41 304 0.02 305 7.2 306 1.8
321 0.6 328 1.6 329 0.02 330 0.03 331 0.098 332 1.9 333 2.9 334
0.98 336 2.7 337 0.08 338 0.027
Example 2
Functional Cell-Based Assay for CB1 or CB2 Agonist and Inverse
Agonist Effects on Intra-Cellular Adenylate Cyclase Activity
[0372] The CB1 and CB2 receptors are G-protein coupled receptors
(GPCR) which influence cell function via the Gi-protein. These
receptors modulate the activity of intracellular adenylate cyclase
which in turn produces the intracellular signal messenger
cyclic-AMP (cAMP).
[0373] At baseline, or during non-ligand bound conditions, these
receptors are constitutively active and tonically suppress
adenylate cyclase activity. The binding of an agonist causes
further receptor activation and produces additional suppression of
adenylate cyclase activity. The binding of an inverse agonist
inhibits the constitutive activity of the receptors and results in
an increase in adenylate cyclase activity.
[0374] By monitoring intracellular adenylate cyclase activity, the
ability of compounds to act as agonists or inverse agonists can be
determined.
Assay
[0375] Test compounds were evaluated in SK-N-MC cells which, using
standard transfection procedures, were stably transfected with
human cDNA for pcDNA3-CRE .beta.-gal and pcDNA3 CB1 receptor
(human) or pcDNA3 CB2 receptor (human). By expressing CRE
.beta.-gal, the cells produced .beta.-galactosidase in response to
CRE promoter activation by cAMP. Cells expressing CRE .beta.-gal
and either the human CB1 or CB2 receptor will produce less
.beta.-galactosidase when treated with a CB1/CB2 agonist and will
produce more .beta.-galactosidase when treated with a CB1/CB2
inverse agonist.
Cell Growth
[0376] The cells were grown in 96-well plates under standard cell
culture conditions at 37.degree. C. in a 5% CO.sub.2 atmosphere.
After 3 days, the media was removed and a test compound in media
(wherein the media was supplemented with 2 mM L-glutamine, 1M
sodium pyruvate, 0.1% low fatty acid FBS (fetal bovine serum) and
antibiotics) was added to the cell. The plates were incubated for
30 minutes at 37.degree. C. and the plate cells were then treated
with forskolin over a 4-6 hour period, then washed and lysed. The
.beta.-galactosidase activity was quantitated using commercially
available kit reagents (Promega Corp. Madison, Wis.) and a Vmax
Plate Reader (Molecular Devices, Inc).
CB1 Receptor Mediated Change in CRE .beta.-Gal Expression (Table 2a
& 2b)
[0377] For cells expressing CRE .beta.-gal and the CB1 receptor,
CB1 agonists reduced .beta.-galactosidase activity in a
dose-dependent manner and CB1 inverse agonists increased
.beta.-galactosidase activity in a dose-dependent manner.
[0378] The change in .beta.-galactosidase activity was determined
by setting a vehicle treated cell's activity value at 100% and
expressing the .beta.-galactosidase activity measured in a
corresponding compound treated cell as a percent of the vehicle
treated cell activity.
CB1 Receptor Results
[0379] The EC.sub.50 values for compounds tested were calculated by
linear regression and were obtained from studies in which varying
compound concentrations were used.
TABLE-US-00006 TABLE 2a CB1 Receptor Functional Inverse Agonist
EC.sub.50 (.mu.M) Cpd EC.sub.50 Cpd EC.sub.50 Cpd EC.sub.50 Cpd
EC.sub.50 2 1.51 7 3.876 9 2.755 28 2.03 43 0.2947 67 0.5242 70 1
73 1.742 91 3.371 144 0.1759 146 1.515 147 0.1525 151 0.8008 165
1.034 167 3.36 169 0.05 220 0.399 253 1.94 256 0.25 258 0.48 259
0.61 290 0.044 291 0.01 292 0.009 293 0.025 294 0.14 295 <0.03
296 0.013 297 0.005 298 0.004 305 0.63 307 0.1 309 0.081 312 0.036
316 0.046 319 0.05 320 0.001 321 0.133
TABLE-US-00007 TABLE 2b CB1 Receptor Functional Agonist EC.sub.50
(.mu.M) Cpd EC.sub.50 33 0.135 38 0.103 222 0.1945 226 0.52 338
0.0060
CB2 Receptor Mediated Change in CRE .beta.-Gal Expression (Table 2c
& 2d)
[0380] For cells expressing CRE .beta.-gal and the CB2 receptor,
CB2 agonists reduced .beta.-galactosidase activity in a
dose-dependent manner and CB2 inverse agonists increased
.beta.-galactosidase activity in a dose-dependent manner.
[0381] The change in .beta.-galactosidase activity was determined
by setting a vehicle treated cell's activity value at 100% and
expressing the .beta.-galactosidase activity measured in a
corresponding compound treated cell as a percent of the vehicle
treated cell activity.
CB2 Receptor Binding Results
[0382] The EC.sub.50 values for compounds tested were calculated by
linear regression and were obtained from studies in which varying
compound concentrations were used.
TABLE-US-00008 TABLE 2c CB2 Receptor Functional Inverse Agonist
EC.sub.50 (.mu.M) Cpd EC.sub.50 Cpd EC.sub.50 Cpd EC.sub.50 3 0.19
67 0.023 70 0.0459 116 0.5 149 0.0079 156 0.035 157 0.0015 208
0.0086 209 0.074 211 0.016 214 0.12 215 0.22 218 0.006 219 0.32 220
0.22 222 0.033 226 0.065 231 0.035 232 0.36 251 0.023 284 0.36
TABLE-US-00009 TABLE 2d CB2 Receptor Functional Agonist EC.sub.50
(.mu.M) Cpd EC.sub.50 Cpd EC.sub.50 Cpd EC.sub.50 1 0.015 10 0.0019
13 0.0041 18 0.0027 26 0.011 28 0.33 32 0.047 35 0.035 36 0.005 37
0.01 40 0.031 44 0.029 62 0.00057 75 0.0001 87 0.25 94 0.025 122
0.037 123 0.0075 154 0.009 184 0.1 195 0.0055 207 0.01 212 0.0037
217 0.000052 278 0.00078 338 0.00000082
Example 3
Effect of Sub-Chronic Treatment on Food Consumption and Body Weight
Gain in Sprague-Dawley Rats
[0383] The effect of daily administration of a compound of the
present invention was tested in male Sprague-Dawley rats. Animals
in each dose group (n=6/group) were orally administered a daily
dose of either a test compound (at a 3, 10 or 30 mg/Kg dose) or
vehicle (50% PEG-400 in distilled water) in a volume of 2 mL/Kg of
body weight immediately prior to the beginning of the dark phase
each day for a period of 7 days.
[0384] Food consumption was electronically monitored during the
dark and light phase that followed dosing (24 hrs total). The
effect on food intake was expressed as the percent change of total
food consumed in the 24 hr period after dosing to total food
consumed in the 24 hr period prior to dosing.
Effect on Total Food Consumption
[0385] Animals at all three test compound dose levels had a
relatively dose-dependent decrease in total food consumed compared
to animals dosed with vehicle at the end of the treatment
period.
Effect on Body Weight Gain
[0386] Animals at all three test compound dose levels had a
dose-dependent decrease in body weight gain compared to animals in
the vehicle chow group over the treatment period.
Example 4
Effect of Acute Treatment on Food Consumption in Sprague-Dawley
Rats
[0387] The effect of acute, single-dose administration of a
compound of the present invention was tested in male Sprague-Dawley
rats. Animals in each dose group (n=6/group) were orally
administered a single dose of either a test compound (at a 3, 10 or
30 mg/Kg dose) or vehicle (50% PEG-400 in distilled water) in a
volume of 2 mL/Kg of body weight immediately prior to the beginning
of the dark phase.
[0388] Food consumption was electronically monitored during the
dark and light phase prior to dosing and the dark and light phase
that followed dosing (48 hrs total). The effect on food intake was
expressed as the percent change of total food consumed in the 24 hr
period after dosing to total food consumed in the 24 hr period
prior to dosing.
Effect on Total Food Consumption
[0389] Animals administered a single dose of the test compound at
all three dose levels had a dose-dependent decrease in total food
consumed compared to animals administered a single vehicle dose (p
value <0.05 for 30 mg/Kg dose level).
Example 5
Effect of Chronic Treatment on Body and Epididymal Fat Pad Weight
in Sprague-Dawley Rats
[0390] The effect of daily administration of a compound of the
present invention was tested in male Sprague-Dawley rats. Animals
were fed chow (10% Kcal) containing either a test compound (test
chow) or vehicle (vehicle chow) over a 28 day treatment period. The
test chow was formulated based upon the estimated daily consumption
needed to achieve a 1, 3, 10 or 30 mg/kg dose level.
Effect on Body Weight Gain
[0391] Animals in the test chow groups had a dose-dependent
decrease in body weight gain compared to animals in the vehicle
chow group over the treatment period.
Effect on Epididymal Fat Pad Weight
[0392] Animals in the test chow groups had a relatively
dose-dependent decrease in epididymal fat pad weight compared to
animals in the vehicle chow group over the treatment period (p
value <0.01 for 30 mg/Kg dose level).
Example 6
Effect of Acute Treatment on Food Consumption and Meal Count in
Ob/Ob Mice
[0393] The effect of acute, single-dose administration of a
compound of the present invention was tested in hyperphagic obese
ob/ob mice. Animals in each dose group (n=8/group) were orally
administered a single dose of either a test compound (at a 3, 10 or
30 mg/Kg dose) or vehicle (50% PEG-400 in distilled water) in a
volume of 2 mL/Kg of body weight immediately prior to the beginning
of the dark phase.
[0394] Food consumption was electronically monitored during the
dark and light phase prior to dosing and the dark and light phase
that followed dosing (48 hrs total). The effect on food intake was
expressed as the percent change of total food consumed in the 24 hr
period after dosing to total food consumed in the 24 hr period
prior to dosing.
Effect on Total Food Consumption
[0395] Animals administered a single dose of the test compound at
all three dose levels had a relatively dose-dependent decrease in
total food consumed compared to animals administered a single
vehicle dose (one-way ANOVA p value <0.05) and a downward trend
in total meal count.
Example 7
Effect of Chronic Treatment on Body Weight Gain, Adipose
Distribution, Energy Expenditure and Locomotor Activity in Ob/Ob
Mice
[0396] The effect of daily administration of a compound of the
present invention was tested in ob/ob mice. The mice were fed chow
containing either a test compound (test chow) or vehicle (vehicle
chow) over a 26 day treatment period. The test chow was formulated
based upon the estimated daily consumption needed to achieve a 3,
10 or 30 mg/kg dose level.
Effect on Body Weight Gain
[0397] Animals in the 10 or 30 mg/kg test chow groups had a
dose-dependent decrease in body weight gain compared to animals in
the vehicle chow group over the treatment period.
Effect on Adipose Distribution
[0398] Adipose distribution was measured by quantitative
computerized tomography for mice in the 30 mg/kg test chow
group.
[0399] Animals in the test chow group had a lower total mass (as
measured by abdominal cross-section), a lower adipose mass and
reduced visceral adipose compartments compared to animals in the
vehicle chow group over the treatment period (one-way ANOVA p value
<0.05). Lean mass for test chow animals was relatively
unaffected.
Effect on Energy Expenditure and Locomotor Activity
[0400] Energy expenditure was measured by indirect calorimetry
measurements during both light and dark phases for mice in the 30
mg/kg test chow group.
[0401] Animals in the test chow group had a decreased respiratory
quotient (CO.sub.2/O.sub.2), suggesting a shift in the primary fuel
source from carbohydrates to fatty acids, an increased energy
metabolism (O.sub.2) and slightly increased spontaneous motor
activity (as determined by summation of movement along the X, Y and
Z axes) compared to animals in the vehicle chow group over the
treatment period (one-way ANOVA p value <0.05).
Example 8
Effect of Chronic Treatment on Body, Epididymal Fat Pad and Liver
Weight, Adipose Distribution, Energy Expenditure and Locomotor
Activity and Plasma Triglyceride and Cholesterol Levels in Mice
with Diet-Induced Obesity
[0402] The effect of daily administration of a compound of the
present invention was tested in mice with diet-induced obesity
(DIO), Obesity was induced by feeding "high-fat" (60% Kcal) chow to
non-leptin-deficient mice over a 4 month period. The mice with DIO
thus produced were then fed "high-fat" chow containing either a
test compound (test chow) or vehicle (vehicle chow) over a 28 day
treatment period. The test chow was formulated based upon the
estimated daily consumption needed to achieve a 1, 3, 10 or 30
mg/kg dose level.
Effect on Body Weight Gain
[0403] Animals in all four test chow groups had a dose-dependent
decrease in body weight gain compared to animals in the vehicle
chow group over the treatment period.
Effect on Epididymal Fat Pad Weight
[0404] Animals in all four test chow groups had either maintained
epididymal fat pad weight or lost weight compared to animals in the
vehicle chow group over the treatment period (one-way ANOVA p value
<0.05).
Effect on Liver Weight and Fat Content
[0405] Animals in all four test chow groups either maintained
relatively the same liver weight or lost weight compared to animals
in the vehicle chow group over the treatment period (one-way ANOVA
p value <0.05).
[0406] Animals in the 10 and 30 mg/kg test chow groups tested for
liver fat content also had a decrease in fat content (as a percent
of total liver area) compared to animals in the vehicle chow group
over the treatment period (one-way ANOVA p value <0.05).
Effect on Adipose Distribution
[0407] Adipose distribution was measured by quantitative
computerized tomography for mice in the 30 mg/kg test chow
group.
[0408] Animals in the test chow group had a lower total mass (as
measured by abdominal cross-section), a lower adipose mass and
reduced visceral adipose compartments compared to animals in the
vehicle chow group over the treatment period (one-way ANOVA p value
<0.05). Lean mass for test chow animals was relatively
unaffected.
Effect on Energy Expenditure and Locomotor Activity
[0409] Energy expenditure was measured by indirect calorimetry
measurements during both light and dark phases for mice in the 30
mg/kg test chow group.
[0410] Animals in the test chow group had a decreased respiratory
quotient (CO.sub.2/O.sub.2), suggesting a shift in the primary fuel
source from carbohydrates to fatty acids, an increased energy
metabolism (O.sub.2) and relatively no increase in spontaneous
motor activity (as determined by summation of movement along the X,
Y and Z axes) compared to animals in the vehicle chow group over
the treatment period (one-way ANOVA p value <0.05).
Effect on Plasma Triglyceride and Cholesterol Levels
[0411] Animals in all four test chow groups had a decreased plasma
triglyceride level compared to animals in the vehicle chow group
over the treatment period (one-way ANOVA p value <0.05) and a
downward trend in total cholesterol.
[0412] It is to be understood that the preceding description of the
invention and various examples thereof have emphasized certain
aspects. Numerous other equivalents not specifically elaborated on
or discussed may nevertheless fall within the spirit and scope of
the present invention or the following claims and are intended to
be included.
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