U.S. patent application number 13/875430 was filed with the patent office on 2013-09-19 for piperidin-4-yl-azetidine diamides as monoacylglcerol lipase inhibitors.
This patent application is currently assigned to Janssen Pharmaceutica, NV. The applicant listed for this patent is JANSSEN PHARMACEUTICA, NV. Invention is credited to Haiyan Bian, Peter J. Connolly, Xun Li, Li Liu, Mark J. Macielag, Mark E. McDonnell.
Application Number | 20130244998 13/875430 |
Document ID | / |
Family ID | 48136455 |
Filed Date | 2013-09-19 |
United States Patent
Application |
20130244998 |
Kind Code |
A1 |
Connolly; Peter J. ; et
al. |
September 19, 2013 |
PIPERIDIN-4-YL-AZETIDINE DIAMIDES AS MONOACYLGLCEROL LIPASE
INHIBITORS
Abstract
Disclosed are compounds, compositions and methods for treating
various diseases, syndromes, conditions and disorders, including
pain. Such compounds, and enantiomers, diastereomers, and
pharmaceutically acceptable salts thereof, are represented by
Formula (I) as follows: ##STR00001## wherein Y, Z, and R are
defined herein.
Inventors: |
Connolly; Peter J.; (New
Providence, NJ) ; Bian; Haiyan; (Princeton, NJ)
; Li; Xun; (New Hope, NJ) ; Liu; Li;
(Germantown, MD) ; Macielag; Mark J.; (Gwynedd
Valley, PA) ; McDonnell; Mark E.; (Lansdale,
PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JANSSEN PHARMACEUTICA, NV |
Beerse |
|
BE |
|
|
Assignee: |
Janssen Pharmaceutica, NV
Beerse
BE
|
Family ID: |
48136455 |
Appl. No.: |
13/875430 |
Filed: |
May 2, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13277702 |
Oct 20, 2011 |
|
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13875430 |
|
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61405876 |
Oct 22, 2010 |
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Current U.S.
Class: |
514/210.18 ;
546/199; 546/201; 546/202; 546/209 |
Current CPC
Class: |
C07D 417/14 20130101;
A61P 25/00 20180101; A61P 25/06 20180101 |
Class at
Publication: |
514/210.18 ;
546/202; 546/209; 546/201; 546/199 |
International
Class: |
C07D 417/14 20060101
C07D417/14 |
Claims
1.-16. (canceled)
17. A compound of Formula (I) ##STR00051## selected from the group
consisting of wherein Y is thiazol-2-yl, Z is biphenyl-4-yl, and R
is H; Y is isothiazol-5-yl, Z is biphenyl-4-yl, and R is H; Y is
thiazol-2-yl, Z is 3-chloro-6-fluoro-benzothien-2-yl, and R is H; Y
is thiazol-4-yl, Z is 4-(3-trifluoromethylphenyl)-phenyl, and R is
H; Y is thiazol-4-yl, Z is 4-(5-trifluoromethylthien-2-yl)-phenyl,
and R is H; Y is thiazol-4-yl, Z is
4-(3-trifluoromethylphenylmethyl)-phenyl, and R is H; Y is
thiazol-4-yl, Z is 3-methyl-6-trifluoromethyl-benzothien-2-yl, and
R is H; Y is thiazol-2-yl, Z is 2-fluoro-4-phenyl-phenyl, and R is
H; Y is thiazol-2-yl, Z is 4-(3-trifluoromethylphenyl)-phenyl, and
R is H; Y is thiazol-2-yl, Z is 3-(3-fluorophenyl)-phenyl, and R is
H; Y is thiazol-2-yl, Z is 4-(5-trifluoromethylthien-2-yl)-phenyl,
and R is H; Y is thiazol-2-yl, Z is
4-(3-trifluoromethylphenylmethyl)-phenyl, and R is H; Y is
thiazol-2-yl, Z is 3-methyl-6-trifluoromethyl-benzothien-2-yl, and
R is H; Y is 1H-pyrrol-2-yl, Z is 2-fluoro-4-phenyl-phenyl, and R
is H; Y is 1H-pyrrol-2-yl, Z is 4-(3-trifluoromethylphenyl)-phenyl,
and R is H; Y is 1H-pyrrol-2-yl, Z is
4-(5-trifluoromethylthien-2-yl)-phenyl, and R is H; Y is
1H-pyrrol-2-yl, Z is 4-(3-trifluoromethylphenylmethyl)-phenyl, and
R is H; Y is 1H-pyrrol-2-yl, Z is
3-methyl-6-trifluoromethyl-benzothien-2-yl, and R is H; Y is
thiazol-2-yl, Z is 4-(4-trifluoromethylphenylmethyl)-phenyl, and R
is H; Y is thiazol-2-yl, Z is 2-phenyl-benzoxazol-6-yl, and R is H;
Y is thiazol-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl,
and R is H; Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-1H-indol-5-yl, and R is H; Y is thiazol-2-yl, Z
is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and R is H; Y is
thiazol-2-yl, Z is 1-(3,4-difluorophenyl)-1H-indol-5-yl, and R is
H; Y is thiazol-4-yl, Z is
4-(4-trifluoromethylphenylmethyl)-phenyl, and R is H; Y is
thiazol-4-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl, and
R is H; Y is thiazol-4-yl, Z is 1-(4-fluorophenyl)-1H-indol-5-yl,
and R is H; Y is thiazol-4-yl, Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and R is H; Y is
thiazol-4-yl, Z is 1-(3,4-difluorophenyl)-1H-indol-5-yl, and R is
H; Y is 1H-pyrrol-2-yl, Z is
4-(4-trifluoromethylphenylmethyl)-phenyl, and R is H; Y is
1H-pyrrol-2-yl, Z is 2-phenyl-benzoxazol-6-yl, and R is H; Y is
1H-pyrrol-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl,
and R is H; Y is 1H-pyrrol-2-yl, Z is
1-(4-fluorophenyl)-1H-indol-5-yl, and R is H; Y is 1H-pyrrol-2-yl,
Z is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and R is H; Y is
1H-pyrrol-2-yl, Z is 1-(3,4-difluorophenyl)-1H-indol-5-yl, and R is
H; Y is 2-fluoro-4-phenyl-phenyl, Z is thiazol-2-yl, and R is H; Y
is 1H-pyrrol-2-yl, Z is 2-fluoro-4-phenyl-phenyl, and R is H; Y is
4-(3-trifluoromethylphenyl)-phenyl, Z is thiazol-2-yl, and R is H;
Y is 4-(3-trifluoromethylphenyl)-phenyl, Z is thiazol-4-yl, and R
is H; Y is 4-(3-trifluoromethylphenyl)-phenyl, Z is 1H-pyrrol-2-yl,
and R is H; Y is 3-(3-fluorophenyl)-phenyl, Z is thiazol-2-yl, and
R is H; Y is 4-(5-trifluoromethyl-thien-2-yl)-phenyl, Z is
thiazol-2-yl, and R is H; Y is
4-(5-trifluoromethyl-thien-2-yl)-phenyl, Z is thiazol-4-yl, and R
is H; Y is 4-(5-trifluoromethyl-thien-2-yl)-phenyl, Z is
1H-pyrrol-2-yl, and R is H; Y is
4-(3-trifluoromethylphenylmethyl)-phenyl, Z is thiazol-2-yl, and R
is H; Y is 4-(3-trifluoromethylphenylmethyl)-phenyl, Z is
thiazol-4-yl, and R is H; Y is
4-(3-trifluoromethylphenylmethyl)-phenyl, Z is 1H-pyrrol-2-yl, and
R is H; Y is 3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is
thiazol-2-yl, and R is H; Y is
3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is 1H-pyrrol-2-yl,
and R is H; Y is 4-(4-trifluoromethylphenylmethyl)-phenyl, Z is
thiazol-2-yl, and R is H; Y is
4-(4-trifluoromethylphenylmethyl)-phenyl, Z is thiazol-4-yl, and R
is H; Y is 4-(4-trifluoromethylphenylmethyl)-phenyl, Z is
1H-pyrrol-2-yl, and R is H; Y is 2-phenyl-benzoxazol-6-yl, Z is
thiazol-2-yl, and R is H; Y is
3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is thiazol-2-yl, and
R is H; Y is 3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is
thiazol-4-yl, and R is H; Y is
3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is 1H-pyrrol-2-yl,
and R is H; Y is 1-(4-fluorophenyl)-1H-indol-5-yl, Z is
thiazol-2-yl, and R is H; the compound wherein Y is
1-(4-fluorophenyl)-1H-indol-5-yl, Z is thiazol-4-yl, and R is H; Y
is 1-(4-fluorophenyl)-1H-indol-5-yl, Z is 1H-pyrrol-2-yl, and R is
H; Y is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl, Z is
thiazol-2-yl, and R is H; Y is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, Z is thiazol-4-yl, and R
is H; Y is 1-(4-trifluoromethylphenyl)-1H-indol-5-yl, Z is
1H-pyrrol-2-yl, and R is H; Y is
1-(3,4-difluorophenyl)-1H-indol-5-yl, Z is thiazol-2-yl, and R is
H; Y is 1-(3,4-difluorophenyl)-1H-indol-5-yl, Z is thiazol-4-yl,
and R is H; Y is 1-(3,4-difluorophenyl)-1H-indol-5-yl, Z is
1H-pyrrol-2-yl, and R is H; Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-1H-benzimidazol-5-yl, and R is H; Y is
thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-1H-benzimidazol-5-yl, and R is H; Y is
thiazol-2-yl, Z is 1-phenyl-2-methyl-1H-benzimidazol-5-yl, and R is
H; Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-2-methyl-1H-benzimidazol-5-yl, and R is H; Y is
thiazol-2-yl, Z is
1-(3,4-difluorophenyl)-2-methyl-1H-benzimidazol-5-yl, and R is H; Y
is thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-2-methyl-1H-benzimidazol-5-yl, and R is
H; Y is thiazol-2-yl, Z is 1-(5-chloropyridin-2-yl)-1H-indol-5-yl,
and R is H; Y is thiazol-2-yl, Z is
6-trifluoromethyl-benzothien-2-yl, and R is OH; Y is thiazol-2-yl,
Z is 1-(2-methylpyridin-4-yl)-1H-indol-5-yl, and R is H; Y is
thiazol-2-yl, Z is
1-(3,4-difluorophenyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl, and R
is H; Y is thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl,
and R is H; and pharmaceutically acceptable salt forms thereof
18. A pharmaceutical composition comprising a compound of claim 17
and at least one of a pharmaceutically acceptable carrier, a
pharmaceutically acceptable excipient and a pharmaceutically
acceptable diluent.
19. The pharmaceutical composition of claim 18, wherein the
composition is a solid oral dosage form.
20. The pharmaceutical composition of claim 18, wherein the
composition is a syrup, an elixir or a suspension.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] The research and development of the invention described
below was not federally sponsored.
BACKGROUND OF THE INVENTION
[0003] Cannabis sativa has been used for the treatment of pain for
many years. .DELTA..sup.9-tetrahydrocannabinol is a major active
ingredient from Cannabis sativa and an agonist of cannabinoid
receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215). Two
cannabinoid G protein-coupled receptors have been cloned,
cannabinoid receptor type 1 (CB.sub.1 Matsuda et al., Nature, 1990,
346, 561-4) and cannabinoid receptor type 2 (CB.sub.2 Munro et al.,
Nature, 1993, 365, 61-5). CB.sub.1 is expressed centrally in brain
areas, such as the hypothalamus and nucleus accumbens as well as
peripherally in the liver, gastrointestinal tract, pancreas,
adipose tissue, and skeletal muscle (Di Marzo et al., Curr Opin
Lipidol, 2007, 18, 129-140). CB.sub.2 is predominantly expressed in
immune cells, such as monocytes (Pacher et al., Amer J Physiol,
2008, 294, H1133-H1134), and under certain conditions, also in the
brain (Benito et al., Brit J Pharmacol, 2008, 153, 277-285) and in
skeletal (Cavuoto et al., Biochem Biophys Res Commun, 2007, 364,
105-110) and cardiac (Hajrasouliha et al., Eur J Pharmacol, 2008,
579, 246-252) muscle. An abundance of pharmacological, anatomical
and electrophysiological data, using synthetic agonists, indicate
that increased cannabinoid signaling through CB.sub.1/CB.sub.2
promotes analgesia in tests of acute nociception and suppresses
hyperalgesia in models of chronic neuropathic and inflammatory pain
(Cravatt et al., J Neurobiol, 2004, 61, 149-60; Guindon et al.,
Brit J Pharmacol, 2008, 153, 319-334).
[0004] Efficacy of synthetic cannabinoid receptor agonists is well
documented. Moreover, studies using cannabinoid receptor
antagonists and knockout mice have also implicated the
endocannabinoid system as an important modulator of nociception.
Anandamide (AEA) (Devane et al., Science, 1992, 258, 1946-9) and
2-arachidinoylglycerol (2-AG) (Mechoulam et al., Biochem Pharmacol,
1995, 50, 83-90; Sugiura et al., Biochem Biophys Res Commun, 1995,
215, 89-97) are two major endocannabinoids. AEA is hydrolyzed by
fatty acid amide hydrolase (FAAH) and 2-AG is hydrolyzed by
monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4,
873-884). Genetic ablation of FAAH elevates endogenous AEA and
results in a CB.sub.1-dependent analgesia in models of acute and
inflammatory pain (Lichtman et al., Pain, 2004, 109, 319-27),
suggesting that the endocannabinoid system functions naturally to
inhibit pain (Cravatt et al., J Neurobiol, 2004, 61, 149-60).
Unlike the constitutive increase in endocannabinoid levels using
FAAH knockout mice, use of specific FAAH inhibitors transiently
elevates AEA levels and results in antinociception in vivo
(Kathuria et al., Nat Med, 2003, 9, 76-81). Further evidence for an
endocannabinoid-mediated antinociceptive tone is demonstrated by
the formation of AEA in the periaqueductal grey following noxious
stimulation in the periphery (Walker et al., Proc Natl Acad Sci
USA, 1999, 96, 12198-203) and, conversely, by the induction of
hyperalgesia following antisense RNA-mediated inhibition of
CB.sub.1 in the spinal cord (Dogrul et al., Pain, 2002, 100,
203-9).
[0005] With respect to 2-AG, intravenous delivery of 2-AG produces
analgesia in the tail flick (Mechoulam et al., Biochem Pharmacol,
1995, 50, 83-90) and hot plate (Lichtman et al., J Pharmacol Exp
Ther, 2002, 302, 73-9) assays. In contrast, it was demonstrated
that 2-AG given alone is not analgesic in the hot plate assay, but
when combined with other 2-monoacylglycerols (i.e., 2-linoleoyl
glycerol and 2-palmitoyl glycerol), significant analgesia is
attained, a phenomenon termed the "entourage effect" (Ben-Shabat et
al., Eur J Pharmacol, 1998, 353, 23-31). These "entourage"
2-monoacylglycerols are endogenous lipids that are co-released with
2-AG and potentiate endocannabinoid signaling, in part, by
inhibiting 2-AG breakdown, most likely by competition for the
active site on MGL. This suggests that synthetic MGL inhibitors
will have a similar effect. Indeed, URB602, a relatively weak
synthetic MGL inhibitor, showed an antinociceptive effect in a
murine model of acute inflammation (Comelli et al., Brit J
Pharmacol, 2007, 152, 787-794).
[0006] Although the use of synthetic cannabinoid agonists has
conclusively demonstrated that increased cannabinoid signaling
produces analgesic and anti-inflammatory effects, it has been
difficult to separate these beneficial effects from the unwanted
side effects of these compounds. An alternative approach is to
enhance the signaling of the endocannabinoid system by elevating
the level of 2-AG, the endocannabinoid of highest abundance in the
central nervous system (CNS) and gastrointestinal tract, which may
be achieved by inhibition of MGL. Therefore, MGL inhibitors are
potentially useful for the treatment of pain, inflammation, and CNS
disorders (Di Marzo et al., Curr Pharm Des, 2000, 6, 1361-80;
Shaveri et al., Brit J Pharmacol, 2007, 152, 624-632; McCarberg
Bill et al., Amer J Ther, 2007, 14, 475-83), as well as glaucoma
and disease states arising from elevated intraocular pressure
(Njie, Ya Fatou; He, Fang; Qiao, Zhuanhong; Song, Zhao-Hui, Exp.
Eye Res., 2008, 87(2):106-14).
SUMMARY OF THE INVENTION
[0007] The present invention is directed to a compound of Formula
(I)
##STR00002##
[0008] wherein [0009] Y and Z are independently selected from Group
a) or Group b) such that one of Y and Z is Group a) and the other
is Group b);
Group a) is
[0009] [0010] i) C.sub.6-10 aryl is unsubstituted or substituted
with a substituent selected from the group consisting of fluoro,
chloro, C.sub.1-4 alkyl, C.sub.1-4alkoxy, cyano, and
trifluoromethyl; or [0011] ii) an unsubstituted heteroaryl selected
from the group consisting of thiazolyl, isothiazolyl, and
1H-pyrrolyl;
Group b) is
[0011] [0012] i) C.sub.6-10 aryl; [0013] ii) a heteroaryl selected
from the group consisting of benzoxazolyl, benzothiazolyl,
benzimidazolyl, benzothienyl, indazolyl, and indolyl; [0014] iii)
phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is
unsubstituted or substituted with trifluoromethyl or fluoro; or
[0015] iv) 1,3-dihydro-3H-benzimidazol-2-on-yl; [0016] wherein
Group b) other than phenylmethyl-phenyl is unsubstituted or
substituted with one or two substitutents each of which is
independently selected from the group consisting of bromo, chloro,
fluoro, iodo, C.sub.1-4alkyl, C.sub.1-4alkoxy, and R.sub.b;
provided that no more than one substituent is R.sub.b; and [0017]
R.sub.b is selected from the group consisting of trifluoromethyl,
2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,
4,4-difluorocyclohexyl, thienyl, pyridinyl, and phenyl; wherein
said thienyl, pyridinyl, and phenyl of R.sub.b are unsubstituted or
substituted with one or two substitutents each of which is
independently selected from the group consisting of
trifluoromethyl, methyl, chloro, cyano, and fluoro; R is hydrogen
or hydroxy; and enantiomers, diastereomers, solvates and
pharmaceutically acceptable salts thereof.
[0018] The present invention also provides, inter alia, a
pharmaceutical composition comprising, consisting of and/or
consisting essentially of a pharmaceutically acceptable carrier, a
pharmaceutically acceptable excipient, and/or a pharmaceutically
acceptable diluent, and a compound of Formula (I) or a
pharmaceutically acceptable salt form thereof.
[0019] Also provided are processes for making a pharmaceutical
composition comprising, consisting of, and/or consisting
essentially of admixing a compound of Formula (I) or a
pharmaceutically acceptable salt form thereof, and a
pharmaceutically acceptable carrier, a pharmaceutically acceptable
excipient, and/or a pharmaceutically acceptable diluent.
[0020] The present invention further provides, inter alia, methods
for treating or ameliorating a MGL-modulated disorder in a subject,
including a human or other mammal in which the disease, syndrome,
or condition is affected by the modulation of the MGL enzyme, such
as pain and the diseases that lead to such pain, inflammation and
CNS disorders, using a compound of Formula (I) or a
pharmaceutically acceptable salt form thereof.
[0021] The present invention also provides, inter alia, methods for
producing the instant compounds and pharmaceutical compositions and
medicaments thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0022] With reference to substituents, the term "independently"
refers to the situation where when more than one substituent is
possible, the substituents may be the same or different from each
other.
[0023] The term "alkyl" whether used alone or as part of a
substituent group, refers to straight and branched carbon chains
having 1 to 8 carbon atoms. Therefore, designated numbers of carbon
atoms (e.g., C.sub.1-8) refer independently to the number of carbon
atoms in an alkyl moiety or to the alkyl portion of a larger
alkyl-containing substituent. In substituent groups with multiple
alkyl groups such as, (C.sub.1-6alkyl).sub.2-amino-, the
C.sub.1-6alkyl groups of the dialkylamino may be the same or
different.
[0024] The term "alkoxy" refers to an --O-alkyl group, wherein the
term "alkyl" is as defined above.
[0025] The terms "alkenyl" and "alkynyl" refer to straight and
branched carbon chains having 2 to 8 carbon atoms, wherein an
alkenyl chain contains at least one double bond and an alkynyl
chain contains at least one triple bond.
[0026] The term "cycloalkyl" refers to saturated or partially
saturated, monocyclic or polycyclic hydrocarbon rings of 3 to 14
carbon atoms. Examples of such rings include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and
adamantyl.
[0027] The term "benzo-fused cycloalkyl" refers to a 5- to
8-membered monocyclic cycloalkyl ring fused to a benzene ring. The
carbon atom ring members that form the cycloalkyl ring may be fully
saturated or partially saturated.
[0028] The term "heterocyclyl" refers to a nonaromatic monocyclic
or bicyclic ring system having 3 to 10 ring members that include at
least 1 carbon atom and from 1 to 4 heteroatoms independently
selected from N, O, and S. Included within the term heterocyclyl is
a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members
are N, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1
or 2 members are N and up to 2 members are O or S and at least one
member must be either N, O, or S; wherein, optionally, the ring
contains 0 to 1 unsaturated bonds, and, optionally, when the ring
is of 6 or 7 members, it contains up to 2 unsaturated bonds. The
carbon atom ring members that form a heterocycle ring may be fully
saturated or partially saturated. The term "heterocyclyl" also
includes two 5 membered monocyclic heterocycloalkyl groups bridged
to form a bicyclic ring. Such groups are not considered to be fully
aromatic and are not referred to as heteroaryl groups. When a
heterocycle is bicyclic, both rings of the heterocycle are
non-aromatic and at least one of the rings contains a heteroatom
ring member. Examples of heterocycle groups include, and are not
limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or
3-pyrrolinyl), pyrrolidinyl, imidazolinyl, imidazolidinyl,
pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, and piperazinyl. Unless otherwise noted, the
heterocycle is attached to its pendant group at any heteroatom or
carbon atom that results in a stable structure.
[0029] The term "benzo-fused heterocyclyl" refers to a 5 to 7
membered monocyclic heterocycle ring fused to a benzene ring. The
heterocycle ring contains carbon atoms and from 1 to 4 heteroatoms
independently selected from N, O, and S. The carbon atom ring
members that form the heterocycle ring may be fully saturated or
partially saturated. Unless otherwise noted, benzo-fused
heterocycle ring is attached to its pendant group at a carbon atom
of the benzene ring.
[0030] The term "aryl" refers to an unsaturated, aromatic
monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of
aryl rings include phenyl and naphthalenyl.
[0031] The term "heteroaryl" refers to an aromatic monocyclic or
bicyclic aromatic ring system having 5 to 10 ring members and which
contains carbon atoms and from 1 to 4 heteroatoms independently
selected from the group consisting of N, O, and S.
[0032] Included within the term heteroaryl are aromatic rings of 5
or 6 members wherein the ring consists of carbon atoms and has at
least one heteroatom member. Suitable heteroatoms include nitrogen,
oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl
ring preferably contains one member of nitrogen, oxygen or sulfur
and, in addition, up to 3 additional nitrogens. In the case of 6
membered rings, the heteroaryl ring preferably contains from 1 to 3
nitrogen atoms. For the case wherein the 6 membered ring has 3
nitrogens, at most 2 nitrogen atoms are adjacent. Examples of
heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl,
thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl,
oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl,
benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, benzisoxazolyl, benzothiadiazolyl, benzotriazolyl,
quinolinyl, isoquinolinyl and quinazolinyl. Unless otherwise noted,
the heteroaryl is attached to its pendant group at any heteroatom
or carbon atom that results in a stable structure.
[0033] The term "halogen" or "halo" refers to fluorine, chlorine,
bromine and iodine atoms.
[0034] The term "formyl" refers to the group --C(.dbd.O)H.
[0035] The term "oxo" refers to the group (.dbd.O).
[0036] Whenever the term "alkyl" or "aryl" or either of their
prefix roots appear in a name of a substituent (e.g., arylalkyl,
alkylamino) the name is to be interpreted as including those
limitations given above for "alkyl" and "aryl." Designated numbers
of carbon atoms (e.g., C.sub.1-C.sub.6) refer independently to the
number of carbon atoms in an alkyl moiety, an aryl moiety, or in
the alkyl portion of a larger substituent in which alkyl appears as
its prefix root. For alkyl and alkoxy substituents, the designated
number of carbon atoms includes all of the independent members
included within a given range specified. For example C.sub.1-6
alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl
individually as well as sub-combinations thereof (e.g., C.sub.1-2,
C.sub.1-3, C.sub.1-4, C.sub.1-5, C.sub.2-6, C.sub.3-6, C.sub.4-6,
C.sub.5-6, C.sub.2-5, etc.).
[0037] In general, under standard nomenclature rules used
throughout this disclosure, the terminal portion of the designated
side chain is described first followed by the adjacent
functionality toward the point of attachment. Thus, for example, a
"C.sub.1-C.sub.6 alkylcarbonyl" substituent refers to a group of
the formula:
##STR00003##
[0038] The term "R" at a stereocenter designates that the
stereocenter is purely of the R-configuration as defined in the
art; likewise, the term "S" means that the stereocenter is purely
of the S-configuration. As used herein, the terms "*R" or "*S" at a
stereocenter are used to designate that the stereocenter is of pure
but unknown configuration. As used herein, the term "RS" refers to
a stereocenter that exists as a mixture of the R- and
S-configurations. Similarly, the terms "*RS" or "*SR" refer to a
stereocenter that exists as a mixture of the R- and
S-configurations and is of unknown configuration relative to
another stereocenter within the molecule.
[0039] Compounds containing one stereocenter drawn without a stereo
bond designation are a mixture of 2 enantiomers. Compounds
containing 2 stereocenters both drawn without stereo bond
designations are a mixture of 4 diastereomers. Compounds with 2
stereocenters both labeled "RS" and drawn with stereo bond
designations are a 2-component mixture with relative
stereochemistry as drawn. Compounds with 2 stereocenters both
labeled "*RS" and drawn with stereo bond designations are a
2-component mixture with relative stereochemistry unknown.
Unlabeled stereocenters drawn without stereo bond designations are
a mixture of the R- and S-configurations. For unlabeled
stereocenters drawn with stereo bond designations, the absolute
stereochemistry is as depicted.
[0040] Unless otherwise noted, it is intended that the definition
of any substituent or variable at a particular location in a
molecule be independent of its definitions elsewhere in that
molecule. It is understood that substituents and substitution
patterns on the compounds of Formula (I) can be selected by one of
ordinary skill in the art to provide compounds that are chemically
stable and that can be readily synthesized by techniques known in
the art as well as those methods set forth herein.
[0041] The term "subject" refers to an animal, preferably a mammal,
most preferably a human, who has been the object of treatment,
observation or experiment.
[0042] The term "therapeutically effective amount" refers to an
amount of an active compound or pharmaceutical agent, including a
compound of the present invention, which 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 or partial alleviation of the
symptoms of the disease, syndrome, condition, or disorder being
treated.
[0043] The term "composition" refers to a product that includes the
specified ingredients in therapeutically effective amounts, as well
as any product that results, directly, or indirectly, from
combinations of the specified ingredients in the specified
amounts.
[0044] The term "MGL inhibitor" is intended to encompass a compound
that interacts with MGL to substantially reduce or eliminate its
catalytic activity, thereby increasing the concentrations of its
substrate(s). The term "MGL-modulated" is used to refer to the
condition of being affected by the modulation of the MGL enzyme
including the condition of being affected by the inhibition of the
MGL enzyme such as pain, and the diseases that lead to such pain,
inflammation and CNS disorders.
[0045] As used herein, unless otherwise noted, the term "affect" or
"affected" (when referring to a disease, syndrome, condition or
disorder that is affected by inhibition of MGL) includes a
reduction in the frequency and/or severity of one or more symptoms
or manifestations of said disease, syndrome, condition or disorder;
and/or include the prevention of the development of one or more
symptoms or manifestations of said disease, syndrome, condition or
disorder or the development of the disease, condition, syndrome or
disorder.
[0046] The compounds of Formula (I) are useful in methods for
treating, ameliorating and/or preventing a disease, a syndrome, a
condition or a disorder that is affected by the inhibition of MGL.
Such methods comprise, consist of and/or consist essentially of
administering to a subject, including an animal, a mammal, and a
human in need of such treatment, amelioration and/or prevention, a
therapeutically effective amount of a compound of Formula (I), or
an enantiomer, diastereomer, solvate or pharmaceutically acceptable
salt thereof. In particular, the compounds of Formula (I), or an
enantiomer, diastereomer, solvate or pharmaceutically acceptable
salt thereof are useful for treating, ameliorating and/or
preventing pain; diseases, syndromes, conditions, or disorders
causing such pain; inflammation and/or CNS disorders. More
particularly, the compounds of Formula (I), or an enantiomer,
diastereomer, solvate or pharmaceutically acceptable salt thereof
are useful for treating, ameliorating and/or preventing
inflammatory pain, inflammatory hypersensitivity conditions and/or
neuropathic pain, comprising administering to a subject in need
thereof a therapeutically effective amount of a compound of Formula
(I), or an enantiomer, diastereomer, solvate or pharmaceutically
acceptable salt thereof as herein defined.
[0047] Examples of inflammatory pain include pain due to a disease,
condition, syndrome, disorder, or a pain state including
inflammatory bowel disease, visceral pain, migraine, post operative
pain, osteoarthritis, rheumatoid arthritis, back pain, lower back
pain, joint pain, abdominal pain, chest pain, labor,
musculoskeletal diseases, skin diseases, toothache, pyresis, burn,
sunburn, snake bite, venomous snake bite, spider bite, insect
sting, neurogenic bladder, interstitial cystitis, urinary tract
infection, rhinitis, contact dermatitis/hypersensitivity, itch,
eczema, pharyngitis, mucositis, enteritis, irritable bowel
syndrome, cholecystitis, pancreatitis, postmastectomy pain
syndrome, menstrual pain, endometriosis, pain due to physical
trauma, headache, sinus headache, tension headache, or
arachnoiditis.
[0048] One type of inflammatory pain is inflammatory
hyperalgesia/hypersensitivity. Examples of inflammatory
hyperalgesia include a disease, syndrome, condition, disorder, or
pain state including inflammation, osteoarthritis, rheumatoid
arthritis, back pain, joint pain, abdominal pain, musculoskeletal
diseases, skin diseases, post operative pain, headaches, toothache,
burn, sunburn, insect sting, neurogenic bladder, urinary
incontinence, interstitial cystitis, urinary tract infection,
cough, asthma, chronic obstructive pulmonary disease, rhinitis,
contact dermatitis/hypersensitivity and/or dermal allergy, itch,
eczema, pharyngitis, enteritis, irritable bowel syndrome,
inflammatory bowel diseases including Crohn's Disease, ulcerative
colitis, benign prostatic hypertrophy, and nasal
hypersensitivity.
[0049] In an embodiment, the present invention is directed to a
method for treating, ameliorating and/or preventing inflammatory
visceral hyperalgesia in which a enhanced visceral irritability
exists, comprising, consisting of, and/or consisting essentially of
the step of administering to a subject in need of such treatment a
therapeutically effective amount of a compound, salt or solvate of
Formula (I). In a further embodiment, the present invention is
directed to a method for treating inflammatory somatic hyperalgesia
in which a hypersensitivity to thermal, mechanical and/or chemical
stimuli exists, comprising administering to a mammal in need of
such treatment a therapeutically effective amount of a compound of
Formula (I) or an enantiomer, diastereomer, solvate or
pharmaceutically acceptable salt thereof.
[0050] A further embodiment of the present invention is directed to
a method for treating, ameliorating and/or preventing neuropathic
pain. Examples of a neuropathic pain include pain due to a disease,
syndrome, condition, disorder, or pain state including cancer,
neurological disorders, spine and peripheral nerve surgery, brain
tumor, traumatic brain injury (TBI), spinal cord trauma, chronic
pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus,
sarcoidosis, peripheral neuropathy, bilateral peripheral
neuropathy, diabetic neuropathy, central pain, neuropathies
associated with spinal cord injury, stroke, amyotrophic lateral
sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic
neuritis, mandibular joint neuralgia, peripheral neuritis,
polyneuritis, stump pain, phantom limb pain, bony fractures, oral
neuropathic pain, Charcot's pain, complex regional pain syndrome I
and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome,
meralgia paresthetica, burning-mouth syndrome, optic neuritis,
postfebrile neuritis, migrating neuritis, segmental neuritis,
Gombault's neuritis, neuronitis, cervicobrachial neuralgia, cranial
neuralgia, geniculate neuralgia, glossopharyngeal neuralgia,
migrainous neuralgia, idiopathic neuralgia, intercostals neuralgia,
mammary neuralgia, Morton's neuralgia, nasociliary neuralgia,
occipital neuralgia, postherpetic neuralgia, causalgia, red
neuralgia, Sluder's neuralgia, splenopalatine neuralgia,
supraorbital neuralgia, trigeminal neuralgia, vulvodynia, or vidian
neuralgia.
[0051] One type of neuropathic pain is neuropathic cold allodynia,
which can be characterized by the presence of a
neuropathy-associated allodynic state in which a hypersensitivity
to cooling stimuli exists. Examples of neuropathic cold allodynia
include allodynia due to a disease, condition, syndrome, disorder
or pain state including neuropathic pain (neuralgia), pain arising
from spine and peripheral nerve surgery or trauma, traumatic brain
injury (TBI), trigeminal neuralgia, postherpetic neuralgia,
causalgia, peripheral neuropathy, diabetic neuropathy, central
pain, stroke, peripheral neuritis, polyneuritis, complex regional
pain syndrome I and II (CRPS I/II) and radiculopathy.
[0052] In a further embodiment, the present invention is directed
to a method for treating, ameliorating and/or preventing
neuropathic cold allodynia in which a hypersensitivity to a cooling
stimuli exists, comprising, consisting of, and/or consisting
essentially of the step of administering to a subject in need of
such treatment a therapeutically effective amount of a compound of
Formula (I) or an enantiomer, diastereomer, solvate or
pharmaceutically acceptable salt thereof.
[0053] In a further embodiment, the present invention is directed
to a method for treating, ameliorating and/or preventing CNS
disorders. Examples of CNS disorders include anxieties such as,
social anxiety, post-traumatic stress disorder, phobias, social
phobia, special phobias, panic disorder, obsessive-compulsive
disorder, acute stress disorder, separation anxiety disorder, and
generalized anxiety disorder, as well as depression such as, major
depression, bipolar disorder, seasonal affective disorder, post
natal depression, manic depression, and bipolar depression.
[0054] Embodiments of the present invention include a compound of
Formula (I)
##STR00004##
[0055] wherein [0056] Y and Z are independently selected from Group
a) or Group b) such that one of Y and Z is Group a) and the other
is Group b); and [0057] a) Group a) is unsubstituted phenyl or an
unsubstituted heteroaryl selected from the group consisting of
thiazolyl, isothiazolyl, and 1H-pyrrolyl; [0058] b) Group a) is
unsubstituted phenyl or an unsubstituted heteroaryl selected from
the group consisting of thiazol-2-yl, thiazol-4-yl, thiazol-5-yl,
isothiazolyl, 1H-pyrrol-2-yl, and 1H-pyrrol-3-yl; [0059] c) Group
b) is [0060] i) phenyl; [0061] ii) a heteroaryl selected from the
group consisting of benzoxazolyl, benzimidazolyl, benzothienyl, and
indolyl; [0062] iii) phenylmethyl-phenyl wherein the phenyl group
of phenylmethyl is unsubstituted or substituted with
trifluoromethyl or fluoro; or [0063] iv)
1,3-dihydro-3H-benzimidazol-2-on-yl; [0064] wherein Group b) other
than phenylmethyl-phenyl is unsubstituted or substituted with one
or two substitutents each of which is independently selected from
the group consisting of chloro, fluoro, methyl, and R.sub.b;
provided that no more than one substituent is R.sub.b; and [0065]
R.sub.b is selected from the group consisting of trifluoromethyl,
2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,
4,4-difluorocyclohexyl, thienyl, pyridinyl, and phenyl; wherein
said thienyl, pyridinyl, and phenyl of R.sub.b are unsubstituted or
substituted with one or two substituents each of which is
independently selected from the group consisting of
trifluoromethyl, methyl, chloro, and fluoro; [0066] d) Group b) is
[0067] i) phenyl; [0068] ii) a heteroaryl selected from the group
consisting of benzoxazolyl, benzimidazolyl, benzothienyl, and
indolyl; [0069] iii) phenylmethyl-phenyl wherein the phenyl group
of phenylmethyl is unsubstituted or substituted with
trifluoromethyl; or [0070] iv) 1,3-dihydro-3H-benzimidazol-2-on-yl;
[0071] wherein Group b) other than phenylmethyl-phenyl is
unsubstituted or substituted with one or two substitutents
independently selected from the group consisting of chloro, fluoro,
methyl, and R.sub.b; provided that no more than one substituent is
R.sub.b; and [0072] R.sub.b is selected from the group consisting
of trifluoromethyl, thienyl, pyridinyl, and phenyl; wherein said
thienyl, pyridinyl, and phenyl of R.sub.b are optionally
independently substituted with one to two trifluoromethyl, methyl,
chloro, or fluoro substituents; [0073] e) R is hydrogen;
[0074] and any combination of embodiments a) through e) above,
provided that it is understood that combinations in which different
embodiments of the same substituent would be combined are
excluded;
and enantiomers, diastereomers, solvates and pharmaceutically
acceptable salts thereof.
[0075] An embodiment of the present invention includes a compound
of Formula (I)
##STR00005##
wherein
[0076] Y and Z are independently selected from Group a) or Group b)
such that one of Y and Z is Group a) and the other is Group b);
[0077] Group a) is an unsubstituted phenyl or an unsubstituted
heteroaryl selected from the group consisting of thiazolyl,
isothiazolyl, and 1H-pyrrolyl;
[0078] Group b) is [0079] i) phenyl; [0080] ii) a heteroaryl
selected from the group consisting of benzoxazolyl, benzimidazolyl,
benzothienyl, and indolyl; [0081] iii) phenylmethyl-phenyl wherein
the phenyl group of phenylmethyl is unsubstituted or substituted
with trifluoromethyl or fluoro; or [0082] iv)
1,3-dihydro-3H-benzimidazol-2-on-yl; [0083] wherein Group b) other
than phenylmethyl-phenyl is unsubstituted or substituted with one
or two substitutents independently selected from the group
consisting of chloro, fluoro, methyl, and R.sub.b; provided that no
more than one substituent is R.sub.b; and [0084] R.sub.b is
selected from the group consisting of trifluoromethyl,
2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl,
4,4-difluorocyclohexyl, thienyl, pyridinyl, and phenyl; wherein
said thienyl, pyridinyl, and phenyl of R.sub.b are unsubstituted or
substituted with one or two substituents independently selected
from the group consisting of trifluoromethyl, methyl, chloro, and
fluoro;
[0085] R is hydrogen;
and enantiomers, diastereomers, solvates and pharmaceutically
acceptable salts thereof.
[0086] An embodiment of the present invention includes a compound
of Formula (I)
##STR00006##
wherein
[0087] Y and Z are independently selected from Group a) or Group b)
such that one of Y and Z is Group a) and the other is Group b);
[0088] Group a) is an unsubstituted phenyl or an unsubstituted
heteroaryl selected from the group consisting of thiazolyl,
isothiazolyl, and 1H-pyrrolyl;
[0089] Group b) is [0090] i) phenyl; [0091] ii) a heteroaryl
selected from the group consisting of benzoxazolyl, benzimidazolyl,
benzothienyl, and indolyl; [0092] iii) phenylmethyl-phenyl wherein
the phenyl group of phenylmethyl is unsubstituted or substituted
with trifluoromethyl; or [0093] iv)
1,3-dihydro-3H-benzimidazol-2-on-yl; [0094] wherein Group b) other
than phenylmethyl-phenyl is unsubstituted or substituted with one
or two substitutents independently selected from the group
consisting of chloro, fluoro, methyl, and R.sub.b; provided that no
more than one substituent is R.sub.b; and [0095] R.sub.b is
selected from the group consisting of trifluoromethyl, thienyl,
pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl
of R.sub.b are unsubstituted or substituted with one or two
substitutents independently selected from the group consisting of
trifluoromethyl, methyl, chloro, and fluoro;
[0096] R is hydrogen or hydroxy;
and enantiomers, diastereomers, solvates and pharmaceutically
acceptable salts thereof.
[0097] An embodiment of the present invention includes a compound
of Formula (I)
##STR00007##
wherein
[0098] Y and Z are independently selected from Group a) or Group b)
such that one of Y and Z is Group a) and the other is Group b);
[0099] Group a) is unsubstituted phenyl or an unsubstituted
heteroaryl selected from the group consisting of thiazol-2-yl,
thiazol-4-yl, thiazol-5-yl, isothiazolyl, 1H-pyrrol-2-yl, and
1H-pyrrol-3-yl;
[0100] Group b) is [0101] i) phenyl; [0102] ii) a heteroaryl
selected from the group consisting of benzoxazolyl, benzimidazolyl,
benzothienyl, and indolyl; [0103] iii) phenylmethyl-phenyl wherein
the phenyl group of phenylmethyl is unsubstituted or substituted
with trifluoromethyl; or [0104] iv)
1,3-dihydro-3H-benzimidazol-2-on-yl; [0105] wherein Group b) other
than phenylmethyl-phenyl is unsubstituted or substituted with one
or two substitutents independently selected from the group
consisting of chloro, fluoro, methyl, and R.sub.b; provided that no
more than one substituent is R.sub.b; and [0106] R.sub.b is
selected from the group consisting of trifluoromethyl, thienyl,
pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl
of R.sub.b are unsubstituted or substituted with one or two
substituents independently selected from the group consisting of
trifluoromethyl, methyl, chloro, and fluoro;
[0107] R is hydrogen or hydroxy;
and enantiomers, diastereomers, solvates and pharmaceutically
acceptable salts thereof.
[0108] An embodiment of the present invention includes a compound
of Formula (I)
##STR00008##
selected from the group consisting of [0109] the compound wherein Y
is thiazol-4-yl, Z is biphenyl-4-yl, and R is H; [0110] the
compound wherein Y is thiazol-2-yl, Z is biphenyl-4-yl, and R is H;
[0111] the compound wherein Y is isothiazol-5-yl, Z is
biphenyl-4-yl, and R is H; [0112] the compound wherein Y is
1H-pyrrol-3-yl, Z is biphenyl-4-yl, and R is H; [0113] the compound
wherein Y is thiazol-5-yl, Z is biphenyl-4-yl, and R is H; [0114]
the compound wherein Y is phenyl, Z is
5-trifluoromethyl-benzothien-2-yl, and R is OH; [0115] the compound
wherein Y is thiazol-4-yl, Z is 3-chloro-6-fluoro-benzothien-2-yl,
and R is H; [0116] the compound wherein Y is thiazol-2-yl, Z is
3-chloro-6-fluoro-benzothien-2-yl, and R is H; [0117] the compound
wherein Y is thiazol-4-yl, Z is 2-fluoro-4-phenyl-phenyl, and R is
H; [0118] the compound wherein Y is thiazol-4-yl, Z is
4-(3-trifluoromethylphenyl)-phenyl, and R is H; [0119] the compound
wherein Y is thiazol-4-yl, Z is 3-(3-fluorophenyl)-phenyl, and R is
H; [0120] the compound wherein Y is thiazol-4-yl, Z is
4-(5-trifluoromethylthien-2-yl)-phenyl, and R is H; [0121] the
compound wherein Y is thiazol-4-yl, Z is
4-(3-trifluoromethylphenylmethyl)-phenyl, and R is H; [0122] the
compound wherein Y is thiazol-4-yl, Z is
3-methyl-6-trifluoromethyl-benzothien-2-yl, and R is H; [0123] the
compound wherein Y is thiazol-2-yl, Z is 2-fluoro-4-phenyl-phenyl,
and R is H; [0124] the compound wherein Y is thiazol-2-yl, Z is
4-(3-trifluoromethylphenyl)-phenyl, and R is H; [0125] the compound
wherein Y is thiazol-2-yl, Z is 3-(3-fluorophenyl)-phenyl, and R is
H; [0126] the compound wherein Y is thiazol-2-yl, Z is
4-(5-trifluoromethylthien-2-yl)-phenyl, and R is H; [0127] the
compound wherein Y is thiazol-2-yl, Z is
4-(3-trifluoromethylphenylmethyl)-phenyl, and R is H; [0128] the
compound wherein Y is thiazol-2-yl, Z is
3-methyl-6-trifluoromethyl-benzothien-2-yl, and R is H; [0129] the
compound wherein Y is 1H-pyrrol-2-yl, Z is
2-fluoro-4-phenyl-phenyl, and R is H; [0130] the compound wherein Y
is 1H-pyrrol-2-yl, Z is 4-(3-trifluoromethylphenyl)-phenyl, and R
is H; [0131] the compound wherein Y is 1H-pyrrol-2-yl, Z is
3-(3-fluorophenyl)-phenyl, and R is H; [0132] the compound wherein
Y is 1H-pyrrol-2-yl, Z is 4-(5-trifluoromethylthien-2-yl)-phenyl,
and R is H; [0133] the compound wherein Y is 1H-pyrrol-2-yl, Z is
4-(3-trifluoromethylphenylmethyl)-phenyl, and R is H; [0134] the
compound wherein Y is 1H-pyrrol-2-yl, Z is
3-methyl-6-trifluoromethyl-benzothien-2-yl, and R is H; [0135] the
compound wherein Y is thiazol-2-yl, Z is
4-(4-trifluoromethylphenylmethyl)-phenyl, and R is H; [0136] the
compound wherein Y is thiazol-2-yl, Z is 2-phenyl-benzoxazol-6-yl,
and R is H; [0137] the compound wherein Y is thiazol-2-yl, Z is
3-chloro-6-trifluoromethyl-benzothien-2-yl, and R is H; [0138] the
compound wherein Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-1H-indol-5-yl, and R is H; [0139] the compound
wherein Y is thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and R is H; [0140] the
compound wherein Y is thiazol-2-yl, Z is
1-(3,4-difluorophenyl)-1H-indol-5-yl, and R is H; [0141] the
compound wherein Y is thiazol-4-yl, Z is
4-(4-trifluoromethylphenylmethyl)-phenyl, and R is H; [0142] the
compound wherein Y is thiazol-4-yl, Z is 2-phenyl-benzoxazol-6-yl,
and R is H; [0143] the compound wherein Y is thiazol-4-yl, Z is
3-chloro-6-trifluoromethyl-benzothien-2-yl, and R is H; [0144] the
compound wherein Y is thiazol-4-yl, Z is
1-(4-fluorophenyl)-1H-indol-5-yl, and R is H; [0145] the compound
wherein Y is thiazol-4-yl, Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and R is H; [0146] the
compound wherein Y is thiazol-4-yl, Z is
1-(3,4-difluorophenyl)-1H-indol-5-yl, and R is H; [0147] the
compound wherein Y is 1H-pyrrol-2-yl, Z is
4-(4-trifluoromethylphenylmethyl)-phenyl, and R is H; [0148] the
compound wherein Y is 1H-pyrrol-2-yl, Z is
2-phenyl-benzoxazol-6-yl, and R is H; [0149] the compound wherein Y
is 1H-pyrrol-2-yl, Z is 3-chloro-6-trifluoromethyl-benzothien-2-yl,
and R is H; [0150] the compound wherein Y is 1H-pyrrol-2-yl, Z is
1-(4-fluorophenyl)-1H-indol-5-yl, and R is H; [0151] the compound
wherein Y is 1H-pyrrol-2-yl, Z is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, and R is H; [0152] the
compound wherein Y is 1H-pyrrol-2-yl, Z is
1-(3,4-difluorophenyl)-1H-indol-5-yl, and R is H; [0153] the
compound wherein Y is 2-fluoro-4-phenyl-phenyl, Z is thiazol-2-yl,
and R is H; [0154] the compound wherein Y is
2-fluoro-4-phenyl-phenyl, Z is thiazol-4-yl, and R is H; [0155] the
compound wherein Y is 1H-pyrrol-2-yl, Z is
2-fluoro-4-phenyl-phenyl, and R is H; [0156] the compound wherein Y
is 4-(3-trifluoromethylphenyl)-phenyl, Z is thiazol-2-yl, and R is
H; [0157] the compound wherein Y is
4-(3-trifluoromethylphenyl)-phenyl, Z is thiazol-4-yl, and R is H;
[0158] the compound wherein Y is
4-(3-trifluoromethylphenyl)-phenyl, Z is 1H-pyrrol-2-yl, and R is
H; [0159] the compound wherein Y is 3-(3-fluorophenyl)-phenyl, Z is
thiazol-2-yl, and R is H; [0160] the compound wherein Y is
3-(3-fluorophenyl)-phenyl, Z is thiazol-4-yl, and R is H; [0161]
the compound wherein Y is 3-(3-fluorophenyl)-phenyl, Z is
1H-pyrrol-2-yl, and R is H; [0162] the compound wherein Y is
4-(5-trifluoromethyl-thien-2-yl)-phenyl, Z is thiazol-2-yl, and R
is H; [0163] the compound wherein Y is
4-(5-trifluoromethyl-thien-2-yl)-phenyl, Z is thiazol-4-yl, and R
is H; [0164] the compound wherein Y is
4-(5-trifluoromethyl-thien-2-yl)-phenyl, Z is 1H-pyrrol-2-yl, and R
is H; [0165] the compound wherein Y is
4-(3-trifluoromethylphenylmethyl)-phenyl, Z is thiazol-2-yl, and R
is H; [0166] the compound wherein Y is
4-(3-trifluoromethylphenylmethyl)-phenyl, Z is thiazol-4-yl, and R
is H; [0167] the compound wherein Y is
4-(3-trifluoromethylphenylmethyl)-phenyl, Z is 1H-pyrrol-2-yl, and
R is H; [0168] the compound wherein Y is
3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is thiazol-2-yl, and
R is H; [0169] the compound wherein Y is
3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is thiazol-4-yl, and
R is H; [0170] the compound wherein Y is
3-methyl-6-trifluoromethyl-benzothien-2-yl, Z is 1H-pyrrol-2-yl,
and R is H; [0171] the compound wherein Y is
4-(4-trifluoromethylphenylmethyl)-phenyl, Z is thiazol-2-yl, and R
is H; [0172] the compound wherein Y is
4-(4-trifluoromethylphenylmethyl)-phenyl, Z is thiazol-4-yl, and R
is H; [0173] the compound wherein Y is
4-(4-trifluoromethylphenylmethyl)-phenyl, Z is 1H-pyrrol-2-yl, and
R is H; [0174] the compound wherein Y is 2-phenyl-benzoxazol-6-yl,
Z is thiazol-2-yl, and R is H; [0175] the compound wherein Y is
2-phenyl-benzoxazol-6-yl, Z is thiazol-4-yl, and R is H; [0176] the
compound wherein Y is 2-phenyl-benzoxazol-6-yl, Z is
1H-pyrrol-2-yl, and R is H; [0177] the compound wherein Y is
3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is thiazol-2-yl, and
R is H; [0178] the compound wherein Y is
3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is thiazol-4-yl, and
R is H; [0179] the compound wherein Y is
3-chloro-6-trifluoromethyl-benzothien-2-yl, Z is 1H-pyrrol-2-yl,
and R is H; [0180] the compound wherein Y is
1-(4-fluorophenyl)-1H-indol-5-yl, Z is thiazol-2-yl, and R is H;
[0181] the compound wherein Y is 1-(4-fluorophenyl)-1H-indol-5-yl,
Z is thiazol-4-yl, and R is H; [0182] the compound wherein Y is
1-(4-fluorophenyl)-1H-indol-5-yl, Z is 1H-pyrrol-2-yl, and R is H;
[0183] the compound wherein Y is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, Z is thiazol-2-yl, and R
is H; [0184] the compound wherein Y is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, Z is thiazol-4-yl, and R
is H; [0185] the compound wherein Y is
1-(4-trifluoromethylphenyl)-1H-indol-5-yl, Z is 1H-pyrrol-2-yl, and
R is H; [0186] the compound wherein Y is
1-(3,4-difluorophenyl)-1H-indol-5-yl, Z is thiazol-2-yl, and R is
H; [0187] the compound wherein Y is
1-(3,4-difluorophenyl)-1H-indol-5-yl, Z is thiazol-4-yl, and R is
H; [0188] the compound wherein Y is
1-(3,4-difluorophenyl)-1H-indol-5-yl, Z is 1H-pyrrol-2-yl, and R is
H; [0189] the compound wherein Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-1H-benzimidazol-5-yl, and R is H; [0190] the
compound wherein Y is thiazol-2-yl, Z is
1-(3,4-difluorophenyl)-1H-benzimidazol-5-yl, and R is H; [0191] the
compound wherein Y is thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-1H-benzimidazol-5-yl, and R is H;
[0192] the compound wherein Y is thiazol-2-yl, Z is
1-(2,2,2-trifluoroethyl)-1H-benzimidazol-5-yl, and R is H; [0193]
the compound wherein Y is thiazol-2-yl, Z is
1-(3,3,3-trifluoropropyl)-1H-benzimidazol-5-yl, and R is H; [0194]
the compound wherein Y is thiazol-2-yl, Z is
1-phenyl-2-methyl-1H-benzimidazol-5-yl, and R is H; [0195] the
compound wherein Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-2-methyl-1H-benzimidazol-5-yl, and R is H;
[0196] the compound wherein Y is thiazol-2-yl, Z is
1-(3,4-difluorophenyl)-2-methyl-1H-benzimidazol-5-yl, and R is H;
[0197] the compound wherein Y is thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-2-methyl-1H-benzimidazol-5-yl, and R is
H; [0198] the compound wherein Y is thiazol-2-yl, Z is
1-(2,2,2-trifluoroethyl)-2-methyl-1H-benzimidazol-5-yl, and R is H;
[0199] the compound wherein Y is thiazol-2-yl, Z is
1-(3,3,3-trifluoropropyl)-2-methyl-1H-benzimidazol-5-yl, and R is
H; [0200] the compound wherein Y is thiazol-2-yl, Z is
1-(4,4-difluorocyclohexyl)-2-methyl-1H-benzimidazol-5-yl, and R is
H; [0201] the compound wherein Y is thiazol-2-yl, Z is
1-(5-chloropyridin-2-yl)-1H-indol-5-yl, and R is H; [0202] the
compound wherein Y is thiazol-2-yl, Z is
6-trifluoromethyl-benzothien-2-yl, and R is OH; [0203] the compound
wherein Y is thiazol-2-yl, Z is
1-(2-methylpyridin-4-yl)-1H-indol-5-yl, and R is H; [0204] the
compound wherein Y is thiazol-2-yl, Z is
1-phenyl-1,3-dihydro-3H-benzimidazol-2-on-5-yl, and R is H; [0205]
the compound wherein Y is thiazol-2-yl, Z is
1-(4-fluorophenyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl, and R is
H; [0206] the compound wherein Y is thiazol-2-yl, Z is
1-(3,4-difluorophenyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl, and R
is H; [0207] the compound wherein Y is thiazol-2-yl, Z is
1-(4-trifluoromethylphenyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl,
and R is H; [0208] the compound wherein Y is thiazol-2-yl, Z is
1-(3,3,3-trifluoropropyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl,
and R is H; [0209] the compound wherein Y is thiazol-2-yl, Z is
1-(4,4-difluorocyclohexyl)-1,3-dihydro-3H-benzimidazol-2-on-5-yl,
and R is H; and pharmaceutically acceptable salt forms thereof.
[0210] For use in medicine, salts of compounds of Formula (I) refer
to non-toxic "pharmaceutically acceptable salts." Other salts may,
however, be useful in the preparation of compounds of Formula (I)
or of their pharmaceutically acceptable salt forms thereof.
Suitable pharmaceutically acceptable salts of compounds of Formula
(I) include acid addition salts that can, for example, be formed by
mixing a solution of the compound with a solution of a
pharmaceutically acceptable acid such as, hydrochloric acid,
sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic
acid, benzoic acid, citric acid, tartaric acid, carbonic acid or
phosphoric acid. Furthermore, where the compounds of Formula (I)
carry an acidic moiety, suitable pharmaceutically acceptable salts
thereof may include alkali metal salts such as, sodium or potassium
salts; alkaline earth metal salts such as, calcium or magnesium
salts; and salts formed with suitable organic ligands such as,
quaternary ammonium salts. Thus, representative pharmaceutically
acceptable salts include acetate, benzenesulfonate, benzoate,
bicarbonate, bisulfate, bitartrate, borate, bromide, calcium
edetate, camsylate, carbonate, chloride, clavulanate, citrate,
dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,
gluceptate, gluconate, glutamate, glycollylarsanilate,
hexylresorcinate, hydrabamine, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isothionate, lactate, lactobionate,
laurate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate,
N-methylglucamine ammonium salt, oleate, pamoate (embonate),
palmitate, pantothenate, phosphate/diphosphate, polygalacturonate,
salicylate, stearate, sulfate, subacetate, succinate, tannate,
tartrate, teoclate, tosylate, triethiodide, and valerate.
[0211] Representative acids and bases that may be used in the
preparation of pharmaceutically acceptable salts include acids
including acetic acid, 2,2-dichloroacetic acid, acylated amino
acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid,
benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid,
(+)-camphoric acid, camphorsulfonic acid,
(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid,
caprylic acid, cinnamic acid, citric acid, cyclamic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid,
galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic
acid, D-glucoronic acid, L-glutamic acid, .alpha.-oxo-glutaric
acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric
acid, (+)-L-lactic acid, (.+-.)-DL-lactic acid, lactobionic acid,
maleic acid, (-)-L-malic acid, malonic acid, (.+-.)-DL-mandelic
acid, methanesulfonic acid, naphthalene-2-sulfonic acid,
naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid,
nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid,
palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid,
salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid,
succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid,
thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and
bases including ammonia, L-arginine, benethamine, benzathine,
calcium hydroxide, choline, deanol, diethanolamine, diethylamine,
2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,
N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesium
hydroxide, 4-(2-hydroxyethyl)-morpholin, piperazine, potassium
hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide,
triethanolamine, tromethamine, and zinc hydroxide.
[0212] Embodiments of the present invention include prodrugs of
compounds of Formula (I). In general, such prodrugs will be
functional derivatives of the compounds that are readily
convertible in vivo into the required compound. Thus, in the
methods of treating or preventing embodiments of the present
invention, the term "administering" encompasses the treatment or
prevention of the various diseases, conditions, syndromes and
disorders described with the compound specifically disclosed or
with a compound that may not be specifically disclosed, but which
converts to the specified compound in vivo after administration to
a patient. Conventional procedures for the selection and
preparation of suitable prodrug derivatives are described, for
example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier,
1985.
[0213] Where the compounds according to embodiments of this
invention have at least one chiral center, they may accordingly
exist as enantiomers. Where the compounds possess two or more
chiral centers, they may additionally exist as diastereomers. It is
to be understood that all such isomers and mixtures thereof are
encompassed within the scope of the present invention. Furthermore,
some of the crystalline forms for the compounds may exist as
polymorphs and as such are intended to be included in the present
invention. In addition, some of the compounds may form solvates
with water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention. The skilled artisan will understand that the term
compound as used herein, is meant to include solvated compounds of
Formula (I).
[0214] Where the processes for the preparation of the compounds
according to certain embodiments of the invention give rise to
mixture of stereoisomers, these isomers may be separated by
conventional techniques such as, preparative chromatography. The
compounds may be prepared in racemic form, or individual
enantiomers may be prepared either by enantiospecific synthesis or
by resolution. The compounds may, for example, be resolved into
their component enantiomers by standard techniques such as, the
formation of diastereomeric pairs by salt formation with an
optically active acid such as, (-)-di-p-toluoyl-d-tartaric acid
and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional
crystallization and regeneration of the free base. The compounds
may also be resolved by formation of diastereomeric esters or
amides, followed by chromatographic separation and removal of the
chiral auxiliary. Alternatively, the compounds may be resolved
using a chiral HPLC column.
[0215] One embodiment of the present invention is directed to a
composition, including a pharmaceutical composition, comprising,
consisting of, and/or consisting essentially of the (+)-enantiomer
of a compound of Formula (I) wherein said composition is
substantially free from the (-)-isomer of said compound. In the
present context, substantially free means less than about 25%,
preferably less than about 10%, more preferably less than about 5%,
even more preferably less than about 2% and even more preferably
less than about 1% of the (-)-isomer calculated as
% ( + ) - enantiomer = ( mass ( + ) - enantiomer ) ( mass ( + ) -
enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.
##EQU00001##
[0216] Another embodiment of the present invention is a
composition, including a pharmaceutical composition, comprising,
consisting of, and consisting essentially of the (-)-enantiomer of
a compound of Formula (I) wherein said composition is substantially
free from the (+)-isomer of said compound. In the present context,
substantially free from means less than about 25%, preferably less
than about 10%, more preferably less than about 5%, even more
preferably less than about 2% and even more preferably less than
about 1% of the (+)-isomer calculated as
% ( + ) - enantiomer = ( mass ( + ) - enantiomer ) ( mass ( + ) -
enantiomer ) + ( mass ( - ) - enantiomer ) .times. 100.
##EQU00002##
[0217] During any of the processes for preparation of the compounds
of the various embodiments 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, Second Edition, J. F. W.
McOmie, Plenum Press, 1973; T. W. Greene & P. G. M. Wuts,
Protective Groups in Organic Synthesis, John Wiley & Sons,
1991; and T. W. Greene & P. G. M. Wuts, Protective Groups in
Organic Synthesis, Third Edition, John Wiley & Sons, 1999. The
protecting groups may be removed at a convenient subsequent stage
using methods known from the art.
[0218] Even though the compounds of embodiments of the present
invention (including their pharmaceutically acceptable salts and
pharmaceutically acceptable solvates) can be administered alone,
they will generally be administered in admixture with a
pharmaceutically acceptable carrier, a pharmaceutically acceptable
excipient and/or a pharmaceutically acceptable diluent selected
with regard to the intended route of administration and standard
pharmaceutical or veterinary practice. Thus, particular embodiments
of the present invention are directed to pharmaceutical and
veterinary compositions comprising compounds of Formula (I) and at
least one pharmaceutically acceptable carrier, pharmaceutically
acceptable excipient, and/or pharmaceutically acceptable
diluent.
[0219] By way of example, in the pharmaceutical compositions of
embodiments of the present invention, the compounds of Formula (I)
may be admixed with any suitable binder(s), lubricant(s),
suspending agent(s), coating agent(s), solubilizing agent(s), and
combinations thereof.
[0220] Solid oral dosage forms such as, tablets or capsules,
containing the compounds of the present invention may be
administered in at least one dosage form at a time, as appropriate.
It is also possible to administer the compounds in sustained
release formulations.
[0221] Additional oral forms in which the present inventive
compounds may be administered include elixirs, solutions, syrups,
and suspensions; each optionally containing flavoring agents and
coloring agents.
[0222] Alternatively, compounds of Formula (I) can be administered
by inhalation (intratracheal or intranasal) or in the form of a
suppository or pessary, or they may be applied topically in the
form of a lotion, solution, cream, ointment or dusting powder. For
example, they can be incorporated into a cream comprising,
consisting of, and/or consisting essentially of an aqueous emulsion
of polyethylene glycols or liquid paraffin. They can also be
incorporated, at a concentration of between about 1% and about 10%
by weight of the cream, into an ointment comprising, consisting of,
and/or consisting essentially of a wax or soft paraffin base
together with any stabilizers and preservatives as may be required.
An alternative means of administration includes transdermal
administration by using a skin or transdermal patch.
[0223] The pharmaceutical compositions of the present invention (as
well as the compounds of the present invention alone) can also be
injected parenterally, for example, intracavernosally,
intravenously, intramuscularly, subcutaneously, intradermally, or
intrathecally. In this case, the compositions will also include at
least one of a suitable carrier, a suitable excipient, and a
suitable diluent.
[0224] For parenteral administration, the pharmaceutical
compositions of the present invention are best used in the form of
a sterile aqueous solution that may contain other substances, for
example, enough salts and monosaccharides to make the solution
isotonic with blood.
[0225] For buccal or sublingual administration, the pharmaceutical
compositions of the present invention may be administered in the
form of tablets or lozenges, which can be formulated in a
conventional manner.
[0226] By way of further example, pharmaceutical compositions
containing at least one of the compounds of Formula (I) as the
active ingredient can be prepared by mixing the compound(s) with a
pharmaceutically acceptable carrier, a pharmaceutically acceptable
diluent, and/or a pharmaceutically acceptable excipient according
to conventional pharmaceutical compounding techniques. The carrier,
excipient, and diluent may take a wide variety of forms depending
upon the desired route of administration (e.g., oral, parenteral,
etc.). Thus, for liquid oral preparations such as, suspensions,
syrups, elixirs and solutions, suitable carriers, excipients and
diluents include water, glycols, oils, alcohols, flavoring agents,
preservatives, stabilizers, coloring agents and the like; for solid
oral preparations such as, powders, capsules, and tablets, suitable
carriers, excipients and diluents include starches, sugars,
diluents, granulating agents, lubricants, binders, disintegrating
agents and the like. Solid oral preparations also may be optionally
coated with substances such as, sugars, or be enterically coated so
as to modulate the major site of absorption and disintegration. For
parenteral administration, the carrier, excipient and diluent will
usually include sterile water, and other ingredients may be added
to increase solubility and preservation of the composition.
Injectable suspensions or solutions may also be prepared utilizing
aqueous carriers along with appropriate additives such as,
solubilizers and preservatives.
[0227] A therapeutically effective amount of a compound of Formula
(I) or a pharmaceutical composition thereof includes a dose range
from about 0.1 mg to about 3000 mg, or any particular amount or
range therein, in particular from about 1 mg to about 1000 mg, or
any particular amount or range therein, or, more particularly, from
about 10 mg to about 500 mg, or any particular amount or range
therein, of active ingredient in a regimen of about 1 to about 4
times per day for an average (70 kg) human; although, it is
apparent to one skilled in the art that the therapeutically
effective amount for a compound of Formula (I) will vary as will
the diseases, syndromes, conditions, and disorders being
treated.
[0228] For oral administration, a pharmaceutical composition is
preferably provided in the form of tablets containing about 1.0,
about 10, about 50, about 100, about 150, about 200, about 250, and
about 500 milligrams of a compound of Formula (I).
[0229] Advantageously, a compound of Formula (I) may be
administered in a single daily dose, or the total daily dosage may
be administered in divided doses of two, three and four times
daily.
[0230] Optimal dosages of a compound of Formula (I) to be
administered may be readily determined and will vary with the
particular compound used, the mode of administration, the strength
of the preparation and the advancement of the disease, syndrome,
condition or disorder. In addition, factors associated with the
particular subject being treated, including subject gender, age,
weight, diet and time of administration, will result in the need to
adjust the dose to achieve an appropriate therapeutic level and
desired therapeutic effect. The above dosages are thus exemplary of
the average case. There can be, of course, individual instances
wherein higher or lower dosage ranges are merited, and such are
within the scope of this invention.
[0231] Compounds of Formula (I) may be administered in any of the
foregoing compositions and dosage regimens or by means of those
compositions and dosage regimens established in the art whenever
use of a compound of Formula (I) is required for a subject in need
thereof.
[0232] As MGL Inhibitors, the compounds of Formula (I) are useful
in methods for treating and preventing a disease, a syndrome, a
condition or a disorder in a subject, including an animal, a mammal
and a human in which the disease, the syndrome, the condition or
the disorder is affected by the modulation, including inhibition,
of the MGL enzyme. Such methods comprise, consist of and/or consist
essentially of administering to a subject, including an animal, a
mammal, and a human in need of such treatment or prevention a
therapeutically effective amount of a compound, salt or solvate of
Formula (I).
General Synthetic Methods
[0233] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and illustrated in the schemes and examples that
follow. Since the schemes are an illustration, the invention should
not be construed as being limited by the chemical reactions and
conditions described in the schemes. The various starting materials
used in the schemes and examples are commercially available or may
be prepared by methods well within the skill of persons versed in
the art. The variables are as defined herein.
[0234] Abbreviations used in the instant specification,
particularly the schemes and examples, are as follows: [0235] AcCl
acetyl chloride [0236] AcOH glacial acetic acid [0237] aq. aqueous
[0238] Bn or Bzl benzyl [0239] Boc tert-butyloxycarbonyl [0240]
conc. concentrated [0241] DBE 1,2-dibromoethane [0242] DCC
N,N'-dicyclohexyl-carbodiimide [0243] DCE 1,2-dichloroethane [0244]
DCM dichloromethane [0245] DIPEA diisopropylethylamine [0246] DMAP
4-(N,N-dimethylamino)pyridine [0247] DMA N,N-dimethylacetamide
[0248] DMF N,N-dimethylformamide [0249] DMSO dimethylsulfoxide
[0250] DPPA diphenylphosphoryl azide [0251] EDC
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride [0252]
ESI electrospray ionization [0253] EtOAc ethyl acetate [0254] EtOH
ethanol [0255] h hour(s) [0256] HATU
O-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0257] HBTU
O-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate [0258] HEK human embryonic kidney [0259] HEPES
(4-(2-hydroxyethyl)-1-piperazineethane sulfonic acid [0260] HMPA
hexamethylphosphoramide [0261] HPLC high performance liquid
chromatography [0262] mCPBA meta-chloroperoxybenzoic acid [0263]
MeCN acetonitrile [0264] MeOH methanol [0265] MeOTf methyl triflate
[0266] MHz megahertz [0267] min minutes [0268] MS mass spectrometry
[0269] NMR nuclear magnetic resonance [0270] PIPES
piperazine-N,N'-bis(2-ethanesulfonic acid) [0271] PyBrOP
bromo-tris-pyrrolidinophosphonium hexafluorophosphate [0272] RP
reverse-phase [0273] R.sub.t retention time [0274] TEA or Et.sub.3N
triethylamine [0275] TFA trifluoroacetic acid [0276] THF
tetrahydrofuran [0277] TLC thin layer chromatography [0278] TMS
tetramethylsilane
[0279] Scheme A illustrates a route for the synthesis of
intermediates that are useful for the preparation of compounds of
Formula (I) wherein R is hydrogen.
##STR00009##
A compound of formula A1 (wherein P is a conventional amino
protecting group) is either commercially available or may be
prepared by known methods described in the scientific literature. A
compound of formula A1 may be treated with zinc metal in the
presence of TMS-Cl, in an aprotic solvent, followed by addition of
a compound of formula A2, in the presence of palladium catalyst to
afford a compound of formula A3. Treatment with benzyl bromide
affords the pyridinium bromide of formula A4. A compound of formula
A4 may be reduced to a compound of formula A5 in the presence of a
hydride source such as, sodium borohydride, in an organic alcoholic
solvent such as, ethanol. Removal of the benzyl group and reduction
of the double bond may be achieved by palladium catalyzed
hydrogenation to afford the desired intermediate of formula A6.
[0280] Scheme B illustrates a route for the preparation of
compounds of Formula (I)-B wherein Y and Z are as defined herein
and R of Formula (I) is hydrogen.
##STR00010##
The amino protecting group (P) of a compound of formula A3 may be
removed by conventional synthetic methods to afford a secondary
amine of formula B1. The amino group may be coupled with a
carboxylic acid of formula B2 (wherein Q is hydroxy) in the
presence of an appropriate coupling agent such as HATU, DCC, EDC,
HBTU, PyBrOP, and the like, optionally in the presence of a base
such as DIPEA, to afford an amide of formula B3. Similarly, an acid
chloride of formula B2 (wherein Q is chloro) may be used to effect
the acylation of a compound of formula B1. In such case a
non-nucleophilic base such as pyridine may be added to afford an
amide of formula B3. Reduction of the pyridine ring of a compound
of formula B3 may be achieved by palladium catalyzed hydrogenation
to afford a compound of formula B4. A second acylation with an
appropriately Y-substituted carboxylic acid or acid chloride of
formula B5 affords a compound of Formula (I)-B wherein R of Formula
(I) is hydrogen.
[0281] Scheme C illustrates an alternate route for the preparation
of compounds of Formula (I)-B wherein Y and Z are as defined herein
and R of Formula (I) is hydrogen.
##STR00011##
The compound of formula A6 may be acylated according to the
synthetic methods described under Scheme B to afford the acylated
compound of formula C1. Conventional amino deprotection affords the
amine of formula C2, which may undergo a second acylation as
previously described to afford a compound of Formula (I)-B.
[0282] Scheme D illustrates a route for the preparation of
compounds of Formula (I)-D wherein Y and Z are as defined herein
and R of Formula (I) is hydroxy.
##STR00012##
Compounds of formulae D1 and D2 are either commercially available
or may be prepared by known methods described in the scientific
literature. A compound of formula D1 may be treated with samarium
iodide in the presence of HMPA, in an aprotic solvent, followed by
the addition of a ketone of formula D2 to afford the condensed
product of formula D3. Removal of the benzhydryl group may be
effected by palladium catalyzed hydrogenation to afford the free
amine of formula D4. The amine of formula D4 may be acylated with a
Z-substituted compound of formula B2 by the methods previously
described herein to afford a compound of Formula (I)-D.
[0283] Scheme E illustrates an alternate route for the preparation
of compounds of Formula (I)-D wherein Y and Z are as defined herein
and R of Formula (I) is hydroxy.
##STR00013##
A compound of formula D1 may be condensed with a compound of
formula E1 in the presence of samarium iodide and HMPA to afford a
compound of formula E2. Removal of the amino protecting group (P)
using conventional synthetic methods affords a compound of formula
E3. Acylation with a compound of formula B5 affords a compound of
formula E4, which, upon benzhydryl removal, affords a free amine of
formula E5. A second acylation with an appropriately substituted
Z-substituted carboxylic acid or acid chloride of formula B2
affords a compound of Formula (I)-D.
Example 1
##STR00014##
[0284] A. tert-Butyl 3-(pyridin-4-yl)azetidine-1-carboxylate,
1c
[0285] A 1-liter 3-neck round bottom flask equipped with a
thermocouple, magnetic stirrer, condenser, heating mantle, and
N.sub.2 inlet adapter was charged with anhydrous dimethylacetamide
(DMA, 100 mL) and zinc (42.94 g, 650.2 mmol). The mixture was
stirred at 20.degree. C. while a mixture of 1,2-dibromoethane (DBE,
5.38 mL, 62.34 mmol) and trimethylsilyl chloride (TMS-Cl, 7.54 mL,
59.28 mmol) was added at a rate to maintain the temperature below
65.degree. C. over 30 min. The resulting slurry was aged for 15
min. A solution of tert-butyl 3-iodoazetidine-1-carboxylate 1a
(122.78 g, 420.69 mmol) in DMA (201 mL) was added dropwise over 1 h
at a rate to maintain the temperature below 65.degree. C. and the
milky suspension was stirred for 30 min while slowly cooling to
20.degree. C.
[0286] Another 3-liter 4-neck round bottom flask equipped a
thermocouple, mechanical stirrer, condenser, heating mantle, and
N.sub.2 inlet adapter was charged with
[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
dichloromethane complex (4.73 g, 5.74 mmol), cuprous iodide (2.19
g, 11.47 mmol), and 4-iodopyridine 1b (80.0 g, 382.44 mmol) in DMA
(255 mL) under N.sub.2. The resulting mixture was degassed with
alternate vacuum/N.sub.2 purges. The above prepared zinc iodide
reagent of compound 1a in DMA was added as a suspension. The
mixture was degassed with vacuum/N.sub.2 twice and then heated to
80.degree. C. (Note: The reaction was exothermic.) The progress of
the reaction was monitored by HPLC and LC-MS and was complete after
2 h. The reaction mixture was cooled to 40.degree. C.; EtOAc (1.6
L) was added and the mixture was stirred for 10 min. The insoluble
material (excess Zn and Cu complexes/salts) was removed by passing
through a diatomaceous earth pad, which was washed with EtOAc (200
mL.times.2). The combined filtrate was stirred with 1 N aqueous
NH.sub.4Cl (0.8 L) at 20.degree. C. for 30 min and the aqueous
layer (pH=5-6) was adjusted to pH=9-10 using 3 N aqueous NaOH
solution (.about.480 mL) while a significant amount of brown
precipitate was formed. The precipitate was removed by paper
filtration and was washed with deionized water (100 mL). The
separated aqueous phase was extracted with EtOAc (1 L), and the
combined organic phases were treated with saturated aqueous
NH.sub.4Cl (0.8 L.times.2) and stirred for 15 min (repeated again),
washed with 5% aqueous NaHSO.sub.3 (500 mL) and brine (1 L), and
dried over MgSO.sub.4. The organic solvent was concentrated at
66.degree. C. under house vacuum (.about.120 mmHg) and then
high-vacuum (12 mmHg) to afford 80.1 g (89% isolated yield) of
crude compound 1c as an oil (88% purity at 254 nm and 86% purity at
230 nm; HPLC area %. Retention time=2.39 min), which was used in
the next step without further purification.
B. 1-Benzyl-4-(1-(tert-butoxycarbonyl)azetidin-3-yl)pyridin-1-ium
bromide, 1e
[0287] A 2-liter 4-neck round bottom flask equipped a thermocouple,
mechanical stirrer, condenser, and N.sub.2 inlet adapter was
charged with crude compound 1c (78.22 g, 290.5 mmol) and
acetonitrile (503 mL). The mixture was stirred at 20.degree. C. and
benzyl bromide 1d (36.41 mL, 299.2 mmol) was added. The mixture was
warmed to 80.degree. C. and stirred for 1 h. The reaction was
cooled to 20.degree. C. and the solvent was concentrated at
60.degree. C. under house-/high-vacuum. The resulting material was
chased with MeOH (100 mL) once to afford 128.9 g (109% isolated
yield; 80-84% purity; HPLC area %. HPLC retention time=3.61 min) of
crude 1e as a syrup, which was used in next step without further
purification.
C. tert-Butyl
3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)azetidine-1-carboxylate,
1f
[0288] A 3-liter 4-neck round bottom flask equipped a thermocouple,
mechanical stirrer, condenser, and N.sub.2 inlet adapter was
charged with crude compound 1e (117.73 g, 232.4 mmol) and EtOH
(1.04 L). The solution was cooled to 0.degree. C. with stirring;
sodium tetrahydroborate (17.8 g, 464.7 mmol) was added and the
mixture was stirred at 0.degree. C. for 10 min, then gradually
warmed to 20.degree. C. and stirred for 1 h. The mixture was cooled
to 0.degree. C. and quenched with half-saturated NaHCO.sub.3 (100
mL, prepared by adding 50 mL of deionized water to 50 mL of
saturated NaHCO.sub.3). The organic solvent was concentrated at
60.degree. C. under house vacuum to a wet solid, which was
dissolved in EtOAc (1.5 L) and stirred for 10 min with half
saturated NaHCO.sub.3 (1 L). After phase separation, the milky
aqueous layer (pH=6-7) was adjusted to pH=10-11 using 3 N aqueous
NaOH solution and extracted with EtOAc (500 mL). The combined
organic phases were washed with brine (500 mL) and then
concentrated at 60.degree. C. under house-/high-vacuum to afford
98.7 g of crude if as a syrup, which was purified using flash
column chromatography (silica gel, EtOAc/heptane/MeOH
20/80/0-50/50/3) to afford 67.11 g (91% isolated yield, 95% purity
at 210 nm; HPLC area %) of compound 1f as a yellow syrup.
D. tert-Butyl 3-(piperidin-4-yl)azetidine-1-carboxylate, 1g
[0289] A 500-mL Parr pressure bottle was charged with compound 1f
(18.4 g, 54.3 mmol), EtOH (152 mL), and Pd(OH).sub.2 (1.91 g). The
mixture was purged twice with N.sub.2 and then shaken under a 50
psi H.sub.2 atmosphere at 20.degree. C. After 40 h, the H.sub.2 was
removed and additional Pd(OH).sub.2 (1.9 g) was added to the
mixture of 1f, dihydro-1f, and 1g, which was purged twice with
N.sub.2 and shaken under a 50 psi H.sub.2 atmosphere at 20.degree.
C. for an additional 56 h. The catalyst was removed by filtration
though a diatomaceous earth pad, which was washed with MeOH (50
mL.times.3). Concentration of the filtrate at 50.degree. C. under
high-vacuum (.about.10 mmHg) afforded 13.4 g (103% isolated yield,
97% pure at 210 nm, HPLC area %) of pure compound 1g as a slight
yellowish, thick oil, which contained a trace amount of EtOH
residue by .sup.1H-NMR analysis.
E. tert-Butyl
3-(1-(thiazole-2-carbonyl)piperidin-4-yl)azetidine-1-carboxylate,
1i
[0290] To a stirring solution of compound 1g (14.3 mmol, 3.44 g)
and thiazole-2-carboxylic acid 1 h (15.7 mmol, 2.03 g) in 50 mL of
CH.sub.2Cl.sub.2 was added Et.sub.3N (42.9 mmol, 5.98 mL). After 20
min at 20.degree. C., HATU (17.2 mmol, 6.53 g) was added and the
mixture was stirred at 20.degree. C. for 5 h. Water was added to
the mixture and the organic layer was separated, dried over
MgSO.sub.4, and concentrated. The residue was purified using flash
column chromatography (silica gel, 30-70% EtOAc/heptane) to give
3.8 g (75% yield) of compound 1i. MS m/z 374.2 (M+Na.sup.+), 296.1
(M+H-C.sub.4H.sub.8), 252.1 (M+H-C.sub.5H.sub.8O.sub.2).
F. (4-(Azetidin-3-yl)piperidin-1-yl)(thiazol-2-yl)methanone, 1j
[0291] A portion of TFA (20 mL) was added to a solution of compound
1i (10.8 mmol, 3.8 g) in 100 mL of CH.sub.2Cl.sub.2. The solution
was stirred at 20.degree. C. for 5 h. The solvent was removed under
vacuum and the residue was partitioned between CH.sub.2Cl.sub.2 and
1N aqueous NaOH. The organic layer was dried over MgSO.sub.4 and
concentrated to give 2.6 g (85% yield) of compound 1j, which was
used in the next reaction without purification. MS m/z 252.1
(M+H.sup.+).
G.
4-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azeti-
din-3-yl)-1-(1,3-thiazol-2-ylcarbonyl)piperidine, Cpd 29
[0292] To a stirring solution of compound 1j (1.59 mmol, 0.40 g)
and 3-chloro-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid
1k (1.75 mmol, 0.49 g) in 10 mL of CH.sub.2Cl.sub.2 was added
Et.sub.3N (6.37 mmol, 0.89 mL). After 20 min at 20.degree. C., HATU
(1.91 mmol, 0.73 g) was added and the mixture was stirred at
20.degree. C. for 20 h. The solvent was removed and the crude
residue was purified by preparative reverse-phase chromatography to
give 210 mg (26% yield) of Cpd 29. .sup.1H NMR (CD.sub.3OD, 400
MHz): .delta.=8.40 (s, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.93 (br. s.,
1H), 7.75-7.85 (m, 2H), 5.31 (t, J=10.8 Hz, 1H), 4.63 (t, J=11.0
Hz, 1H), 4.37 (t, J=8.2 Hz, 1H), 4.28 (t, J=9.3 Hz, 1H), 4.10 (br.
s., 1H), 4.00 (br. s., 1H), 3.15-3.29 (m, 1H), 2.82-3.00 (m, 1H),
2.47-2.63 (m, 1H), 1.67-2.02 (m, 3H), 1.05-1.34 (m, 2H). MS m/z
514.0 (M+H.sup.+).
[0293] Following the procedure described above for Example 1 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00001 Cpd Name and data 35
4-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}azetidin-3-yl)-1-(1,3-thiazol-4-ylcarbonyl)piperidine.
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. = 9.04 (br. s., 1H),
8.39 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 8.01 (s, 1H), 7.81 (d, J =
8.6 Hz, 1H), 4.56-4.73 (m, 1H), 3.87-4.44 (m, 5H), 3.05-3.24 (m,
1H), 2.76-2.97 (m, 1H), 2.47-2.64 (m, 1H), 1.57-1.94 (m, 3H),
1.06-1.30 (m, 2H). MS m/z 514.0 (M + H.sup.+). 41
4-(1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}azetidin-3-yl)-1-(1H-pyrrol-2-ylcarbonyl)piperidine.
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta. = 8.41 (s, 1H), 8.10 (d,
J = 8.6 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 6.90 (dd, J = 2.4, 1.2
Hz, 1H), 6.54 (dd, J = 3.7, 1.2 Hz, 1H), 6.13-6.21 (m, 1H), 4.57
(t, J = 13.2 Hz, 2H), 4.33-4.42 (m, 1H), 4.29 (t, J = 9.4 Hz, 1H),
4.10 (dd, J = 9.4, 6.2 Hz, 1H), 3.94-4.04 (m, 1H), 3.05 (br. s.,
2H), 2.49-2.63 (m, 1H), 1.70-1.98 (m, 3H), 1.06-1.25 (m, 2H). MS
m/z 496.2 (M + H.sup.+). 69
1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-
4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-yl]piperidine. MS m/z
514.0 (M + H.sup.+). 70
1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-
4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-yl]piperidine. MS m/z
514.0 (M + H.sup.+). 71
1-{[3-Chloro-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}-
4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 496.0
(M + H.sup.+).
Example 2
##STR00015##
[0294] A. 3-Chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride,
2b
[0295] Thionyl chloride (73.7 mmol, 5.36 mL) was added to a mixture
of 4-fluorocinnamic acid 2a (21.1 mmol, 3.5 g) and pyridine (2.53
mmol, 0.2 mL). The mixture was heated at 135.degree. C. for 30 min
and then cooled to room temperature. The crude mixture was
triturated with hot hexanes to remove the solid pyridinium
hydrochloride by-product. Compound 2b was isolated from the
combined hexanes solutions.
B.
4-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-3-yl}-1-
-(1,3-thiazol-2-ylcarbonyl)piperidine, Cpd 8)
[0296] A solution of compound 2b (0.45 mmol, 112 mg) in 4 mL of
CH.sub.2Cl.sub.2 was added to a solution of compound 1j mono-TFA
salt (0.41 mmol, 150 mg) in Et.sub.3N (2.46 mmol, 0.34 mL) at
0.degree. C. The reaction mixture was stirred at 0.degree. C. for 3
h. The crude product was purified by preparative reverse-phase
chromatography to afford 18 mg (9% yield) of Cpd 8. .sup.1H NMR
(CD.sub.3OD, 400 MHz): .delta.=7.88-7.97 (m, 2H), 7.81 (d, J=2.9
Hz, 1H), 7.76 (dd, J=8.8, 2.2 Hz, 1H), 7.36 (td, J=9.0, 2.3 Hz,
1H), 5.22-5.37 (m, 1H), 4.55-4.70 (m, 1H), 4.32-4.44 (m, 1H),
4.23-4.32 (m, 1H), 4.11 (br. s., 1H), 3.91-4.05 (m, 1H), 3.15-3.28
(m, 1H), 2.84-3.00 (m, 1H), 2.48-2.62 (m, 1H), 1.70-2.02 (m, 3H),
1.10-1.29 (m, 2H). MS m/z 464.1 (M+H.sup.+).
[0297] Following the procedure described above for Example 2 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compound of the present invention was prepared:
TABLE-US-00002 Cpd Name and data 7
4-{1-[(3-Chloro-6-fluoro-1-benzothiophen-2-yl)carbonyl]azetidin-
3-yl}-1-(1,3-thiazol-4-ylcarbonyl)piperidine. MS m/z 464.1 (M +
H.sup.+).
Example 3
##STR00016##
[0298] A.
3-Methyl-6-(trifluoromethyl)benzo[b]thiophene-2-carboxylate, 3c
[0299] Methyl thioglycolate 3b (30.3 mmol, 2.76 mL) was added
dropwise to a suspension of NaH (60% oil dispersion, 75.8 mmol,
3.03 g) in 10 mL of THF and 50 mL of DMSO at 20.degree. C. The
mixture was stirred for 15 min and a solution of
1-(2-fluoro-4-(trifluoromethyl)phenyl)ethanone 3a (24.3 mmol, 5.0
g) in 10 mL of DMSO was added. The reaction mixture was stirred at
20.degree. C. for 4 h and water was added. The mixture was
extracted with EtOAc. The organic layer was dried over MgSO.sub.4
and concentrated to give compound 3c as a white solid.
B.
4-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-yl]carbonyl}azeti-
din-3-yl)-1-(1,3-thiazol-2-ylcarbonyl)piperidine, Cpd 20
[0300] To a stirring solution of compound 1j mono-TFA salt (0.27
mmol, 100 mg) and compound 3c (0.30 mmol, 78 mg) in 4 mL of
CH.sub.2Cl.sub.2 was added Et.sub.3N (1.09 mmol, 0.15 mL). After 20
min at 20.degree. C., HATU (0.33 mmol, 125 mg) was added and the
mixture was stirred at 20.degree. C. for 20 h. The solvent was
removed and the crude residue was purified by preparative
reverse-phase chromatography to give 34 mg (25% yield) of Cpd 20.
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.=8.29 (s, 1H), 8.04 (d,
J=8.6 Hz, 1H), 7.93 (br. s., 1H), 7.81 (d, J=3.2 Hz, 1H), 7.71 (d,
J=8.3 Hz, 1H), 5.31 (br. s., 1H), 4.56-4.69 (m, 1H), 4.32-4.42 (m,
1H), 4.26 (t, J=9.2 Hz, 1H), 4.09 (br. s., 1H), 3.98 (br. s., 1H),
3.23 (br. s., 1H), 2.92 (br. s., 1H), 2.61 (s, 3H), 2.47-2.59 (m,
1H), 1.70-2.00 (m, 3H), 1.03-1.35 (m, J=9.3 Hz, 2H). MS m/z 494.1
(M+H.sup.+).
[0301] Following the procedure described above for Example 3, and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00003 Cpd Name and data 14
4-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}azetidin-3-yl)-1-(1,3-thiazol-4-ylcarbonyl)piperidine.
MS m/z 494.1 (M + H.sup.+). 26
4-(1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}azetidin-3-yl)-1-(1H-pyrrol-2-ylcarbonyl)piperidine. MS
m/z 476.2 (M + H.sup.+). 60
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-
yl]piperidine. MS m/z 494.1 (M + H.sup.+). 61
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-
yl]piperidine. MS m/z 494.1 (M + H.sup.+). 62
1-{[3-Methyl-6-(trifluoromethyl)-1-benzothiophen-2-
yl]carbonyl}-4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-
yl]piperidine. MS m/z 476.2 (M + H.sup.+).
Example 4
##STR00017##
[0302] A. 3'-(Trifluoromethyl)-[1,1'-biphenyl]-4-carboxylic acid,
4c
[0303] A portion of Pd(dppf)Cl.sub.2 (1.49 mmol, 1.09 g) was added
to a suspension of 4-bromobenzoic acid 4a (14.9 mmol, 3.0 g),
3-trifluoromethylboronic acid 4b (17.9 mmol, 3.4 g), and
Cs.sub.2CO.sub.3 (37.3 mmol, 12.2 g) in 30 mL of dioxane and 7.5 mL
of EtOH. The mixture was stirred at 80.degree. C. for 2 h. After
cooling, the solid was collected by filtration and washed with
MeOH. The filtrate was concentrated and partitioned between EtOAc
and 1N aqueous HCl. The organic layer was washed with brine, dried
over MgSO.sub.4, and concentrated. CH.sub.2Cl.sub.2 was added to
the residue and the resulting solid was collected by filtration,
washed with CH.sub.2Cl.sub.2, and dried to give 3.58 g (86% yield)
of compound 4c, which was used in the next step without further
purification.
B.
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[3'-(trifluoromethyl)biphenyl-4-yl]c-
arbonyl}azetidin-3-yl)piperidine, Cpd 16
[0304] To a stirring solution of compound 1j mono-TFA salt (0.27
mmol, 100 mg) and compound 4c (0.30 mmol, 80 mg) in 4 mL of
CH.sub.2Cl.sub.2 was added Et.sub.3N (1.09 mmol, 0.15 mL). After 20
min at 20.degree. C., HATU (0.33 mmol, 125 mg) was added and the
mixture was stirred at 20.degree. C. for 20 h. The solvent was
removed and the crude residue was purified by preparative
reverse-phase chromatography to give 57 mg (42% yield) of Cpd 16.
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.=7.93 (br. s., 3H),
7.73-7.83 (m, 5H), 7.63-7.73 (m, 2H), 5.24-5.38 (m, 1H), 4.64 (t,
J=10.8 Hz, 1H), 4.46 (t, J=8.2 Hz, 1H), 4.13-4.31 (m, 2H),
3.90-4.01 (m, 1H), 3.15-3.29 (m, 1H), 2.84-2.99 (m, 1H), 2.44-2.60
(m, 1H), 1.73-2.00 (m, 3H), 1.08-1.32 (m, 2H). MS m/z 500.3
(M+H.sup.+).
[0305] Following the procedure described above for Example 4 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00018## ##STR00019## ##STR00020## ##STR00021##
##STR00022##
[0306] Following the procedure described above for Example 4, and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00004 Cpd Name and data 9
4-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-1-(1,3-
thiazol-4-ylcarbonyl)piperidine. MS m/z 450.1 (M + H.sup.+). 10
1-(1,3-Thiazol-4-ylcarbonyl)-4-(1-{[3'-
(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperidine.
MS m/z 500.3 (M + H.sup.+). 11
4-{1-[(3'-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-1-
(1,3-thiazol-4-ylcarbonyl)piperidine. MS m/z 450.2 (M + H.sup.+).
12 1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[5-
(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-
yl]piperidine. MS m/z 506.1 (M + H.sup.+). 15
4-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-1-(1,3-
thiazol-2-ylcarbonyl)piperidine. MS m/z 450.1 (M + H.sup.+). 17
4-{1-[(3'-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-1-
(1,3-thiazol-2-ylcarbonyl)piperidine. MS m/z 450.1 (M + H.sup.+).
18 1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[5-
(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-
yl]piperidine. MS m/z 506.1 (M + H.sup.+). 21
4-{1-[(3-Fluorobiphenyl-4-yl)carbonyl]azetidin-3-yl}-1-(1H-
pyrrol-2-ylcarbonyl)piperidine. MS m/z 432.1 (M + H.sup.+). 22
1-(1H-Pyrrol-2-ylcarbonyl)-4-(1-{[3'-
(trifluoromethyl)biphenyl-4-yl]carbonyl}azetidin-3- yl)piperidine.
MS m/z 482.2 (M + H.sup.+). 23
4-{1-[(3'-Fluorobiphenyl-3-yl)carbonyl]azetidin-3-yl}-1-
(1H-pyrrol-2-ylcarbonyl)piperidine. MS m/z 432.1 (M + H.sup.+). 24
1-(1H-Pyrrol-2-ylcarbonyl)-4-[1-({4-[5-
(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)azetidin-3-
yl]piperidine. MS m/z 488.3 (M + H.sup.+). 45
1-[(3-Fluorobiphenyl-4-yl)carbonyl]-4-[1-(1,3-thiazol-2-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 450.1 (M + H.sup.+). 46
1-[(3-Fluorobiphenyl-4-yl)carbonyl]-4-[1-(1,3-thiazol-4-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 450.1 (M + H.sup.+). 47
1-[(3-Fluorobiphenyl-4-yl)carbonyl]-4-[1-(1H-pyrrol-2-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 432.1 (M + H.sup.+). 48
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-1-{[3'-
(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidine. MS m/z 500.3 (M
+ H.sup.+). 49
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-1-{[3'-
(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidine. MS m/z 500.1 (M
+ H.sup.+). 50 4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-1-{[3'-
(trifluoromethyl)biphenyl-4-yl]carbonyl}piperidine. MS m/z 482.2 (M
+ H.sup.+). 51
1-[(3'-Fluorobiphenyl-3-yl)carbonyl]-4-[1-(1,3-thiazol-2-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 450.1 (M + H.sup.+). 52
1-[(3'-Fluorobiphenyl-3-yl)carbonyl]-4-[1-(1,3-thiazol-4-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 450.1 (M + H.sup.+). 53
1-[(3'-Fluorobiphenyl-3-yl)carbonyl]-4-[1-(1H-pyrrol-2-
ylcarbonyl)azetidin-3-yl]piperidine. MS m/z 432.1 (M + H.sup.+). 54
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-1-({4-[5-
(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperidine. MS m/z
506.1 (M + H.sup.+). 55
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-1-({4-[5-
(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperidine. MS m/z
506.1 (M + H.sup.+). 56
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-1-({4-[5-
(trifluoromethyl)thiophen-2-yl]phenyl}carbonyl)piperidine. MS m/z
488.3 (M + H.sup.+).
Example 5
##STR00023##
[0307] A. Methyl 4-(3-(trifluoromethyl)benzyl)benzoate, 5b
[0308] A portion of Pd(dppf)Cl.sub.2 (0.87 mmol, 0.64 g) was added
to a suspension of methyl 4-(bromomethyl)benzoate 5a (8.73 mmol,
2.0 g), 3-trifluoromethylboronic acid 4b (10.5 mmol, 1.99 g), and
Na.sub.2CO.sub.3 (17.5 mmol, 1.85 g) in 20 mL of dioxane and 5 mL
of water. The mixture was stirred at 80.degree. C. for 3 h. After
cooling, the solid was collected by filtration and washed with
EtOAc. The filtrate was washed with 1N aqueous HCl and brine, dried
over MgSO.sub.4, and concentrated. The crude product was purified
by flash column chromatography (silica gel, 0-10% EtOAc:heptane) to
give 2.2 g (85% yield) of compound 5b. MS m/z 295.2
(M+H.sup.+).
B. 4-(3-(Trifluoromethyl)benzyl)benzoic acid, 5c
[0309] 1N aqueous NaOH (12.9 mmol, 12.9 mL) was added to a
suspension of compound 5b (6.46 mmol, 1.9 g) in 75 mL of EtOH. The
mixture was stirred at 20.degree. C. for 20 h. The reaction mixture
was concentrated and the residue was acidified with 1N aqueous HCl.
The resulting solid was collected by filtration and dried to afford
1.6 g (87%) of compound 5c, which was used in the next reaction
without further purification. MS m/z 281.1 (M+H.sup.+).
C.
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[3-(trifluoromethyl)benzyl]phenyl-
}carbonyl)azetidin-3-yl]piperidine, Cpd 19
[0310] To a stirring solution of compound 1j mono-TFA salt (0.27
mmol, 100 mg) and compound 5c (0.30 mmol, 84 mg) in 4 mL of
CH.sub.2Cl.sub.2 was added Et.sub.3N (1.09 mmol, 0.15 mL). After 20
min at 20.degree. C., HATU (0.33 mmol, 125 mg) was added and the
mixture was stirred at 20.degree. C. for 20 h. The solvent was
removed and the crude residue was purified by preparative
reverse-phase chromatography to give 46 mg (33% yield) of Cpd 19.
.sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.=7.92 (br. s., 1H), 7.79
(d, J=3.2 Hz, 1H), 7.57-7.64 (m, J=8.1 Hz, 2H), 7.43-7.53 (m, 4H),
7.28-7.36 (m, J=8.1 Hz, 2H), 5.29 (t, J=10.0 Hz, 1H), 4.61 (t,
J=10.9 Hz, 1H), 4.38 (t, J=8.6 Hz, 1H), 4.20 (t, J=9.3 Hz, 1H),
4.10 (s, 2H), 4.07-4.15 (m, 1H), 3.85-3.96 (m, 1H), 3.10-3.27 (m,
1H), 2.78-2.96 (m, 1H), 2.36-2.53 (m, 1H), 1.66-1.93 (m, 3H),
1.03-1.29 (m, 2H). MS m/z 514.2 (M+H.sup.+).
[0311] Following the procedure described above for Example 5 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compound was prepared:
##STR00024##
[0312] Following the procedure described above for Example 5, and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00005 Cpd Name and data 13
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[3-
(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperidine.
MS m/z 514.2 (M + H.sup.+). 25
1-(1H-Pyrrol-2-ylcarbonyl)-4-[1-({4-[3-
(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperidine
MS m/z 497.2 (M + H.sup.+). 27
1-(1,3-Thiazol-2-ylcarbonyl)-4-[1-({4-[4-
(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperidine
MS m/z 514.2 (M + H.sup.+). 33
1-(1,3-Thiazol-4-ylcarbonyl)-4-[1-({4-[4-
(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperidine
MS m/z 514.2 (M + H.sup.+). 39
1-(1H-Pyrrol-2-ylcarbonyl)-4-[1-({4-[4-
(trifluoromethyl)benzyl]phenyl}carbonyl)azetidin-3- yl]piperidine
MS m/z 496.2 (M + H.sup.+). 57
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-1-({4-[3-
(trifluoromethyl)benzyl]phenyl}carbonyl)piperidine MS m/z 514.2 (M
+ H.sup.+). 58
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-1-({4-[3-
(trifluoromethyl)benzyl]phenyl}carbonyl)piperidine MS m/z 514.2 (M
+ H.sup.+). 59
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-1-({4-[3-
(trifluoromethyl)benzyl]phenyl}carbonyl)piperidine MS m/z 496.2 (M
+ H.sup.+). 63
4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]-1-({4-[4-
(trifluoromethyl)benzyl]phenyl}carbonyl)piperidine MS m/z 514.2 (M
+ H.sup.+). 64
4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]-1-({4-[4-
(trifluoromethyl)benzyl]phenyl}carbonyl)piperidine MS m/z 514.2 (M
+ H.sup.+). 65
4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]-1-({4-[4-
(trifluoromethyl)benzyl]phenyl}carbonyl)piperidine MS m/z 496.2 (M
+ H.sup.+).
Example 6
##STR00025##
[0313] A. 2-Phenylbenzo[d]oxazole-6-carboxylic acid, 6c
[0314] A solution of methyl 4-amino-3-hydroxybenzoate 6a (29.9
mmol, 5.0 g) and benzaldehyde 6b (29.9 mmol, 3.02 mL) in 150 mL of
MeOH was stirred at 20.degree. C. for 3 h. The solvent was removed
under vacuum and the residue was mixed with 150 mL of acetonitrile.
Lead (IV) acetate (29.9 mmol, 13.3 g) was added in one portion and
the mixture was refluxed for 20 min. After cooling, the precipitate
was removed by filtration and washed with acetonitrile. The
filtrate and wash solutions were stirred with 3N aqueous NaOH (120
mmol, 40 mL) at 50.degree. C. for 20 h. After cooling, the reaction
mixture was acidified and filtered to give 6.0 g (79%) of compound
6c. MS m/z 240.0 (M+H.sup.+).
B.
2-Phenyl-6-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-y-
l}carbonyl)-1,3-benzoxazole, Cpd 28
[0315] To a stirring solution of compound 1j (0.40 mmol, 100 mg)
and compound 6c (0.44 mmol, 100 mg) in 4 mL of CH.sub.2Cl.sub.2 was
added Et.sub.3N (1.59 mmol, 0.22 mL). After 20 min at 20.degree.
C., HATU (0.48 mmol, 180 mg) was added and the mixture was stirred
at 20.degree. C. for 20 h. The solvent was removed and the crude
residue was purified by preparative reverse-phase chromatography to
give 75 mg (39% yield) of Cpd 28. .sup.1H NMR (CD.sub.3OD, 400
MHz): .delta.=8.23-8.32 (m, 2H), 8.01 (s, 1H), 7.89-7.97 (m, 1H),
7.77-7.85 (m, 2H), 7.73 (dd, J=8.3, 1.2 Hz, 1H), 7.54-7.68 (m, 3H),
5.30 (t, J=11.0 Hz, 1H), 4.64 (t, J=12.0 Hz, 1H), 4.43-4.54 (m,
1H), 4.18-4.34 (m, 2H), 3.92-4.05 (m, 1H), 3.16-3.29 (m, 1H),
2.84-2.99 (m, 1H), 2.47-2.60 (m, 1H), 1.72-2.02 (m, 3H), 1.10-1.34
(m, 2H). MS m/z 473.1 (M+H.sup.+).
[0316] Following the procedure described above for Example 6, and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00006 Cpd Name and data 34
2-Phenyl-6-({3-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole. MS m/z 473.1 (M +
H.sup.+). 40 2-Phenyl-6-({3-[1-(1H-pyrrol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1,3-benzoxazole. MS m/z 455.3 (M +
H.sup.+). 66
2-Phenyl-6-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-
yl]piperidin-1-yl}carbonyl)-1,3-benzoxazole. MS m/z 473.1 (M +
H.sup.+). 67
2-Phenyl-6-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-
yl]piperidin-1-yl}carbonyl)-1,3-benzoxazole. MS m/z 473.1 (M +
H.sup.+). 68 2-Phenyl-6-({4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-
yl]piperidin-1-yl}carbonyl)-1,3-benzoxazole. MS m/z 455.3 (M +
H.sup.+).
Example 7
##STR00026##
[0317] A. Methyl 1-(4-fluorophenyl)-indole-5-carboxylate, 7c
[0318] A mixture of methyl indole-5-carboxylate 7a (0.5 g, 2.85
mmol), 1-bromo-4-fluoro-benzene 7b (2 mL, 18.21 mmol), CuI (0.544
g, 2.85 mmol), and K.sub.2CO.sub.3 (0.591 g, 4.28 mmol) was heated
in a microwave reactor at 220.degree. C. for 2.5 h. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 and filtered. The
solution was concentrated and the residue was purified by flash
column chromatography (silica gel, 15% EtOAc/heptane) to give 0.58
g of compound 7c. MS m/z 270.1 (M+H.sup.+).
B. 1-(4-Fluorophenyl)-indole-5-carboxylic acid, 7d
[0319] A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate
7c (0.58 g, 2.15 mmol) and LiOH H.sub.2O (0.36 g, 8.6 mmol) in THF
(15 mL) and H.sub.2O (10 mL) was stirred at room temperature for 5
days. Aqueous 10% HCl solution was added to the reaction mixture to
adjust pH=3.about.4. The resulting mixture was extracted with EtOAc
(2.times.). The organic solution was washed with aq. NaCl, dried
over Na.sub.2SO.sub.4 and concentrated to give 0.5 g of compound
7d. MS m/z 256.2 (M+H.sup.+).
C.
1-(4-Fluorophenyl)-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]az-
etidin-1-yl}carbonyl)-1H-indole, Cpd 30
[0320] To a stirring solution of compound 1j (0.40 mmol, 100 mg)
and compound 7d (0.44 mmol, 110 mg) in 4 mL of CH.sub.2Cl.sub.2 was
added Et.sub.3N (1.59 mmol, 0.22 mL). After 20 min at 20.degree.
C., HATU (0.48 mmol, 180 mg) was added and the mixture was stirred
at 20.degree. C. for 20 h. The solvent was removed and the crude
residue was purified by preparative reverse-phase chromatography to
give 165 mg (85% yield) of Cpd 30. .sup.1H NMR (CD.sub.3OD, 400
MHz): .delta.=7.99 (s, 1H), 7.92 (br. s., 1H), 7.79 (d, J=3.2 Hz,
1H), 7.44-7.58 (m, 5H), 7.30 (t, J=8.7 Hz, 2H), 6.77 (d, J=3.4 Hz,
1H), 5.28 (br. s., 1H), 4.53-4.69 (m, 1H), 4.39-4.51 (m, 1H),
4.10-4.29 (m, 2H), 3.95 (br. s., 1H), 3.10-3.27 (m, 1H), 2.89 (t,
J=10.5 Hz, 1H), 2.33-2.56 (m, 1H), 1.65-1.98 (m, J=10.8 Hz, 3H),
1.19 (br. s., 2H). MS m/z 489.1 (M+H.sup.+).
[0321] Following the procedure described above for Example 7, and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00027## ##STR00028##
[0322] Following the procedure described above for Example 7, and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the invention were prepared:
TABLE-US-00007 Cpd Name and data 31
5-({3-[1-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole. MS m/z 539.1
(M + H.sup.+). 36
1-(4-Fluorophenyl)-5-({3-[1-(1,3-thiazol-4-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1H-indole. MS m/z 489.1 (M + H.sup.+).
37 5-({3-[1-(1,3-Thiazol-4-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole. MS m/z 539.2
(M + H.sup.+). 42
1-(4-Fluorophenyl)-5-({3-[1-(1H-pyrrol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1H-indole. MS m/z 472.2 (M + H.sup.+).
43 5-({3-[1-(1H-Pyrrol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole. MS m/z 521.3
(M + H.sup.+). 72
1-(4-Fluorophenyl)-5-({4-[1-(1,3-thiazol-2-ylcarbonyl)azetidin-3-
yl]piperidin-1-yl}carbonyl)-1H-indole. MS m/z 489.1 (M + H.sup.+).
73
1-(4-Fluorophenyl)-5-({4-[1-(1,3-thiazol-4-ylcarbonyl)azetidin-3-
yl]piperidin-1-yl}carbonyl)-1H-indole. MS m/z 489.1 (M + H.sup.+).
74 1-(4-Fluorophenyl)-5-({4-[1-(1H-pyrrol-2-ylcarbonyl)azetidin-3-
yl]piperidin-1-yl}carbonyl)-1H-indole. MS m/z 471.3 (M + H.sup.+).
75 5-({4-[1-(1,3-Thiazol-2-ylcarbonyl)azetidin-3-yl]piperidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole. MS m/z 539.2
(M + H.sup.+). 76
5-({4-[1-(1,3-Thiazol-4-ylcarbonyl)azetidin-3-yl]piperidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole. MS m/z 539.2
(M + H.sup.+). 77
5-({4-[1-(1H-Pyrrol-2-ylcarbonyl)azetidin-3-yl]piperidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-indole. MS m/z 521.3
(M + H.sup.+). 93 1-(5-Chloropyridin-2-yl)-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H-indole.
.sup.1H NMR (CDCl.sub.3) .delta. = 8.51 (d, J = 2.5 Hz, 1H), 8.23
(d, J = 8.8 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.87 (br. s., 1H),
7.81 (dd, J = 8.7, 2.6 Hz, 1H), 7.70 (d, J = 3.5 Hz, 1H), 7.59 (dd,
J = 8.7, 1.5 Hz, 1H), 7.53 (d, J = 3.2 Hz, 1H), 7.45 (d, J = 8.7
Hz, 1H), 6.77 (dd, J = 2.9, 0.6 Hz, 1H), 5.40-5.54 (m, 1H), 4.73
(t, J = 9.8 Hz, 1H), 4.37-4.49 (m, 1H), 4.21-4.32 (m, 1H),
4.03-4.12 (m, 1H), 3.93-4.03 (m, 1H), 3.57-3.72 (m, 1H), 3.06-3.22
(m, 1H), 2.36-2.51 (m, 1H), 1.67-1.94 (m, 3H), 1.10-1.32 (m, 2H).
MS m/z 506 (M + H.sup.+).
Example 8
##STR00029##
[0323] A. Methyl 1-(3,4-difluorophenyl)-indole-5-carboxylate,
8b
[0324] A mixture of methyl indole-5-carboxylate 7a (2 g, 11.4
mmol), 1-iodo-3,4-difluoro-benzene 8a (1.5 mL, 12.5 mmol), CuI
(0.22 g, 1.14 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine
(0.54 mL, 3.43 mmol), and K.sub.3PO.sub.4 (6.06 g, 28.5 mmol) in
toluene (12 mL) was heated at 110.degree. C. for 7 h. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 and filtered. The
solution was concentrated and the residue was purified by flash
column chromatography (silica gel, 20% EtOAc/heptane) to give 3.0 g
of compound 8b. MS m/z 288.1 (M+H.sup.+).
B. 1-(3,4-Difluorophenyl)-indole-5-carboxylic acid, 8c
[0325] A mixture of methyl
1-(3,4-difluorophenyl)-indole-5-carboxylate 8b (3.0 g, 10.4 mmol)
and LiOH (1.0 g, 41.8 mmol) in THF (120 mL) and H.sub.2O (60 mL)
was stirred at room temperature for 5 days. Aqueous 10% HCl
solution was added to the reaction mixture to adjust pH=3.about.4.
The resulting mixture was extracted with EtOAc (2.times.). The
organic solution was washed with brine, dried over Na.sub.2SO.sub.4
and concentrated to give 2.85 g of compound 8c. MS m/z 274.2
(M+H.sup.+).
C.
1-(3,4-Difluorophenyl)-5-({3-[4-(1,3-thiazol-2-ylcarbonyl)piperazin-1-y-
l]azetidin-1-yl}carbonyl)-1H-indole, Cpd 32
[0326] To a stirring solution of compound 1j (0.40 mmol, 100 mg)
and compound 8c (0.44 mmol, 120 mg) in 4 mL of CH.sub.2Cl.sub.2 was
added Et.sub.3N (1.59 mmol, 0.22 mL). After 20 min at 20.degree.
C., HATU (0.48 mmol, 180 mg) was added and the mixture was stirred
at 20.degree. C. for 20 h. The solvent was removed and the crude
residue was purified by preparative reverse-phase chromatography to
give 118 mg (58% yield) of Cpd 32. .sup.1H NMR (CD.sub.3OD, 400
MHz): .delta.=8.00 (s, 1H), 7.93 (br. s., 1H), 7.81 (d, J=2.9 Hz,
1H), 7.51-7.60 (m, 4H), 7.44-7.52 (m, 1H), 7.33-7.42 (m, 1H), 6.79
(d, J=3.2 Hz, 1H), 5.22-5.38 (m, 1H), 4.55-4.71 (m, 1H), 4.48 (t,
J=8.8 Hz, 1H), 4.14-4.33 (m, 2H), 3.89-4.04 (m, 1H), 3.14-3.28 (m,
1H), 2.83-2.99 (m, 1H), 2.43-2.58 (m, 1H), 1.70-2.00 (m, 3H),
1.09-1.32 (m, 2H). MS m/z 507.1 (M+H.sup.+).
[0327] Following the procedure described above for Example 8, and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00030## ##STR00031## ##STR00032## ##STR00033## ##STR00034##
##STR00035## ##STR00036## ##STR00037##
[0328] Following the procedure described above for Example 8, and
substituting the appropriate reagents, starting materials, and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00008 Cpd Name and data 38
1-(3,4-Difluorophenyl)-5-({3-[1-(1,3-thiazol-4-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H- indole). MS
m/z 507.1 (M + H.sup.+). 44
1-(3,4-Difluorophenyl)-5-({3-[1-(1H-pyrrol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H- indole). MS
m/z 489.3 (M + H.sup.+). 78
1-(3,4-Difluorophenyl)-5-({4-[1-(1,3-thiazol-2-
ylcarbonyl)azetidin-3-yl]piperidin-1-yl}carbonyl)-1H-indole. MS m/z
507.1 (M + H.sup.+). 79
1-(3,4-Difluorophenyl)-5-({4-[1-(1,3-thiazol-4-
ylcarbonyl)azetidin-3-yl]piperidin-1-yl}carbonyl)-1H-indole. MS m/z
507.1 (M + H.sup.+). 80
1-(3,4-Difluorophenyl)-5-({4-[1-(1H-pyrrol-2-
ylcarbonyl)azetidin-3-yl]piperidin-1-yl}carbonyl)-1H-indole. MS m/z
489.2 (M + H.sup.+). 95
1-(2-Methylpyridin-4-yl)-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H-indole.
.sup.1H NMR (CDCl.sub.3) .delta. = 8.63 (d, J = 5.4 Hz, 1H), 8.00
(s, 1H), 7.87 (br. s., 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.61 (dd, J =
8.7, 1.4 Hz, 1H), 7.53 (d, J = 3.1 Hz, 1H), 7.44 (d, J = 3.4 Hz,
1H), 7.24-7.36 (m, 2H), 6.79 (d, J = 3.3 Hz, 1H), 5.50 (d, J = 12.5
Hz, 1H), 4.64-4.84 (m, 1H), 4.37-4.53 (m, 1H), 4.21-4.37 (m, 1H),
3.91-4.14 (m, 2H), 3.06-3.25 (m, 1H), 2.73-2.89 (m, 1H), 2.67 (s,
3H), 2.46 (d, J = 8.1 Hz, 1H), 1.65-1.94 (m, 3H), 1.09-1.35 (m,
2H).
Example 9
##STR00038## ##STR00039##
[0329] A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 9c
[0330] A mixture of methyl 4-fluoro-3-nitrobenzoate 9a (1 g, 5.02
mmol), 4-fluoroaniline 9b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL,
6.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 h.
Water was added to the mixture, the resulting solid was collected
by filtration, washed with water, and dried. The crude compound 9c
was used in the next reaction without further purification.
B. Methyl 3-amino-4-((4-fluorophenyl)amino)benzoate, 9d
[0331] A mixture of compound 9c (1.4 g, 4.8 mmol) and
SnCl.sub.2.2H.sub.2O (4.9 g, 21.7 mmol) in EtOH (50 mL) was stirred
at 80.degree. C. After 4 h, the mixture was cooled to room
temperature and was slowly added to saturated aqueous NaHCO.sub.3.
The solid was collected by filtration and washed with H.sub.2O. The
solid was triturated with EtOAc and the filtrate was concentrated.
The crude compound 9d was used in the next reaction without further
purification. MS m/z 261.1 (M+H.sup.+).
C. Methyl 1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate,
9e
[0332] A mixture of compound 9d (0.18 g, 0.693 mmol) and trimethyl
orthoformate (0.7 mL, 6.39 mmol) in DMF (2 mL) was refluxed for 5 h
and then cooled to room temperature. Water was added to the
mixture. The resulting solid was collected by filtration, washed
with water, and dried. The crude compound 9e was used in the next
reaction without further purification. MS m/z 271.1
(M+H.sup.+).
D. 1-(4-Fluorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid,
9f
[0333] To a solution of compound 9e (0.18 g, 0.666 mmol) in EtOH
(10 mL) was added 1N aqueous NaOH (2.5 mL, 2.5 mmol). The mixture
was stirred at room temperature for 4 d. The solvent was evaporated
and 1N aqueous HCl was added, followed by extraction with EtOAc.
The organic layer was dried over MgSO.sub.4 and concentrated. The
crude compound 9f was purified by preparative reverse phase
chromatography. MS m/z 257.1 (M+H.sup.+).
E.
1-(4-Fluorophenyl)-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]az-
etidin-1-yl}carbonyl)-1H-benzimidazole, Cpd 81
[0334] To a solution of compound 1j (0.058 g, 0.178 mmol) and HATU
(0.081 g, 0.214 mmol) in 3 mL of CH.sub.2Cl.sub.2 was added
Et.sub.3N (0.099 mL, 0.713 mmol). The mixture was stirred at
20.degree. C. for 30 min, and then compound 9f (0.050 g, 0.196
mmol) was added. The reaction mixture was stirred at 20.degree. C.
for 20 h. Water (6 mL) was added and the mixture was extracted with
EtOAc. The organic layer was dried over MgSO.sub.4 and
concentrated. The crude product was purified by preparative reverse
phase chromatography to give 46 mg (47% yield) of Cpd 81. .sup.1H
NMR (CD.sub.3OD) .delta.=8.14 (s, 1H), 7.93 (br. s., 1H), 7.78-7.84
(m, 2H), 7.67-7.78 (m, 3H), 7.45 (t, J=8.7 Hz, 2H), 5.23-5.38 (m,
1H), 4.57-4.71 (m, 1H), 4.44-4.54 (m, 1H), 4.29 (t, J=9.7 Hz, 1H),
4.22 (br. s., 1H), 4.00 (br. s., 1H), 3.17-3.27 (m, 1H), 2.85-2.99
(m, 1H), 2.48-2.61 (m, 1H), 1.70-2.02 (m, 3H), 1.09-1.34 (m, 2H) MS
m/z 490.2 (M+H.sup.+).
[0335] Following the procedure described above for Example 9 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared.
##STR00040## ##STR00041##
[0336] Following the procedure described above for Example 9 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00009 Cpd Name and data 82
1-(3,4-Difluorophenyl)-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H-
benzimidazole. MS m/z 508.2 (M + H.sup.+). 83
5-({3-[1-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-benzimidazole. MS m/z
540.2 (M + H.sup.+). 84
5-({3-[1-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-benzimidazole. MS m/z
478.2 (M + H.sup.+). 85
5-({3-[1-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-benzimidazole. MS m/z
492.1 (M + H.sup.+).
Example 10
##STR00042##
[0337] A. Methyl
2-methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate,
10a
[0338] The title compound 10a was prepared using the method
described in Example 9, substituting trimethyl orthoacetate for
trimethyl orthoformate in Step C. The crude compound 10a was used
in the next reaction without further purification. MS m/z 285.1
(M+H.sup.+).
B. 2-Methyl-1-(4-fluorophenyl)-1H-benzo[d]imidazole-5-carboxylate,
10b
[0339] The title compound 10b was prepared using the method
described in Example 9, substituting compound 10a for compound 9e
in Step D. The crude product 10b was used in the next reaction
without further purification. MS m/z 271.2 (M+H.sup.+).
C.
1-(4-Fluorophenyl)-2-methyl-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidi-
n-4-yl]azetidin-1-yl}carbonyl)-1H-benzimidazole, Cpd 87
[0340] The title compound Cpd 87 was prepared using the method
described in Example 9, substituting compound 10b for compound 9f
in Step E. The crude product was purified by preparative reverse
phase chromatography to give 23 mg (50% yield) of Cpd 87. .sup.1H
NMR (CD.sub.3OD) .delta.=8.08 (s, 1H), 7.93 (br. s., 1H), 7.76-7.84
(m, 2H), 7.68 (dd, J=8.7, 4.5 Hz, 2H), 7.50 (t, J=8.6 Hz, 2H), 7.43
(d, J=8.8 Hz, 1H), 5.31 (br. s., 1H), 4.64 (t, J=13.0 Hz, 1H), 4.45
(t, J=8.4 Hz, 1H), 4.29 (t, J=9.7 Hz, 1H), 4.15-4.24 (m, 1H), 4.00
(br. s., 1H), 3.17-3.27 (m, 1H), 2.83-2.99 (m, 1H), 2.71 (s, 3H),
2.55 (q, J=7.7 Hz, 1H), 1.74-2.00 (m, 3H), 1.15-1.31 (m, 2H). MS
m/z 504.0 (M+H.sup.+).
[0341] Following the procedure described above for Example 10 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared:
##STR00043## ##STR00044##
[0342] Following the procedure described above for Example 10 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00010 Cpd Name and data 86
2-Methyl-1-phenyl-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1H-benzimidazole. MS m/z 486.1 (M +
H.sup.+). 88
1-(3,4-Difluorophenyl)-2-methyl-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H-
benzimidazole. MS m/z 522.0 (M + H.sup.+). 89
2-Methyl-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1H-
benzimidazole. MS m/z 554.1 (M + H.sup.+). 90
2-Methyl-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1-(2,2,2-trifluoroethyl)-1H-
benzimidazole. MS m/z 492.1 (M + H.sup.+). 91
2-Methyl-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1H-
benzimidazole. MS m/z 506.2 (M + H.sup.+). 92
1-(4,4-Difluorocyclohexyl)-2-methyl-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1H-
benzimidazole. MS m/z 528.3 (M + H.sup.+).
Example 11
##STR00045##
[0343] A. Methyl
1-(4-fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate,
11a
[0344] A mixture of compound 9d (0.20 g, 0.826 mmol) and
1,1'-carbonyldiimidazole (0.535 g, 3.3 mmol) in DMF (8 mL) was
heated at 90.degree. C. for 2 h. The solvent was removed and the
residue was triturated with water (15 mL). The resulting
precipitate was collected by filtration and washed several times
with water. The crude product 11a was used in the next reaction
without further purification. MS m/z 287.1 (M+H.sup.+).
B.
1-(4-Fluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxylate-
, 11b
[0345] The title compound 11b was prepared using the method
described in Example 9, substituting compound 11a for compound 9e
in Step D. The crude product 11b was used in the next reaction
without further purification. MS m/z 273.1 (M+H.sup.+).
C.
1-(4-Fluorophenyl)-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-yl]az-
etidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one, Cpd 97
[0346] The title compound Cpd 97 was prepared using the method
described in Example 9, substituting compound 11b for compound 9f
in Step E. The crude product was purified by preparative reverse
phase chromatography to give 51 mg (32% yield) of Cpd 97. .sup.1H
NMR (CD.sub.3OD) .delta.=7.93 (br. s., 1H), 7.81 (d, J=3.2 Hz, 1H),
7.51-7.59 (m, 2H), 7.45 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 1H), 7.33
(t, J=8.7 Hz, 2H), 7.04 (d, J=8.1 Hz, 1H), 5.30 (br. s., 1H),
4.56-4.69 (m, 1H), 4.40-4.51 (m, 1H), 4.21-4.29 (m, 1H), 4.18 (br.
s., 1H), 3.95 (br. s., 1H), 3.15-3.27 (m, 1H), 2.83-2.99 (m, 1H),
2.43-2.58 (m, 1H), 1.71-2.00 (m, 3H), 1.22 (br. s., 2H). MS m/z
506.1 (M+H.sup.+).
[0347] Following the procedure described above for Example 11 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following intermediate compounds were prepared.
##STR00046## ##STR00047##
[0348] Following the procedure described above for Example 11 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared.
TABLE-US-00011 Cpd Name and data 96
1-Phenyl-5-({3-[1-(1,3-thiazol-2-ylcarbonyl)piperidin-4-
yl]azetidin-1-yl}carbonyl)-1,3-dihydro-2H-benzimidazol-2-one. MS
m/z 488.1 (M + H.sup.+). 98
1-(3,4-Difluorophenyl)-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-
2H-benzimidazol-2-one. MS m/z 524.1 (M + H.sup.+). 99
5-({3-[1-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-[4-(trifluoromethyl)phenyl]-1,3-dihydro-2H-
benzimidazol-2-one. .sup.1H NMR (CD.sub.3OD) .delta. = 7.84-7.97
(m, 3H), 7.74-7.83 (m, 3H), 7.38-7.48 (m, 2H), 7.19 (d, J = 8.3 Hz,
1H), 5.22-5.36 (m, 1H), 4.56-4.69 (m, 1H), 4.39-4.53 (m, 1H),
4.11-4.30 (m, 2H), 3.90-4.01 (m, 1H), 2.83-3.00 (m, 1H), 2.43-2.59
(m, 1H), 1.68-2.01 (m,3H), 1.13-1.29 (m, 2H). 100
5-({3-[1-(1,3-Thiazol-2-ylcarbonyl)piperidin-4-yl]azetidin-1-
yl}carbonyl)-1-(3,3,3-trifluoropropyl)-1,3-dihydro-2H-
benzimidazol-2-one. MS m/z 508.2 (M + H.sup.+). 101
1-(4,4-Difluorocyclohexyl)-5-({3-[1-(1,3-thiazol-2-
ylcarbonyl)piperidin-4-yl]azetidin-1-yl}carbonyl)-1,3-dihydro-
2H-benzimidazol-2-one. MS m/z 530.2 (M + H.sup.+).
Example 12
##STR00048##
[0349] A. 3-(Pyridin-4-yl)azetidine, 12a
[0350] Compound 1c was dissolved in a mixture of 3N aqueous HCl and
THF and stirred until compound 1c was completely consumed. The
mixture was concentrated under reduced pressure and the aqueous
residue was lyophilized to give compound 12a as the
di-hydrochloride salt, which was used in the next step without
further purification.
B. [1,1'-Biphenyl]-4-yl-(3-(pyridin-4-yl)azetidin-1-yl)methanone,
12c
[0351] Compound 12a (4.5 mmol, 928 mg),
[1,1'-biphenyl]-4-carboxylic acid 12b (4.95 mmol, 980 mg), HBTU
(6.43 mmol, 2.44 g), and DIEA (20.2 mmol, 3.49 mL) were combined in
DMF and stirred at 20.degree. C. for 20 h. The crude reaction
mixture was purified by preparative reverse-phase HPLC to give
compound 12c. .sup.1H NMR (CD.sub.3OD, 400 MHz): .delta.=8.68 (d,
J=6.6 Hz, 2H), 7.92 (d, J=6.8 Hz, 2H), 7.68-7.77 (m, 2H), 7.60-7.68
(m, 2H), 7.57 (dd, J=8.3, 1.2 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H),
7.23-7.34 (m, 1H), 4.56-4.68 (m, 1H), 4.43-4.56 (m, 1H), 4.12-4.34
(m, 2H).
C. [1,1'-Biphenyl]-4-yl-(3-(piperidin-4-yl)azetidin-1-yl)methanone,
12d
[0352] Compound 12c and 10% palladium on carbon were combined in a
1:5 mixture of 1N aqueous HCl and ethanol in a Parr pressure
bottle. The mixture was purged with N.sub.2 and then shaken under a
55 psi H.sub.2 atmosphere at 20.degree. C. When the reaction was
complete, the catalyst was removed by filtration through a
diatomaceous earth pad. The filtrate was concentrated and
lyophilized to provide compound 12d in quantitative yield as the
hydrochloride salt.
D.
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-(1,3-thiazol-2-ylcarbonyl)-
piperidine, Cpd 2
[0353] A solution of compound 12d HCl salt (0.28 mmol, 98 mg),
thiazole-2-carboxylic acid 1 h (0.33 mmol, 43 mg), and HBTU (0.33
mmol, 126 mg) in 2.5 mL of DMF was stirred for 10 min. DIEA (1.1
mmol, 0.2 mL) was added and the mixture was stirred at 20.degree.
C. for 20 h. The crude reaction mixture was purified by preparative
reverse-phase HPLC to give Cpd 2. .sup.1H NMR (CD.sub.3OD, 400
MHz): .delta.=7.84 (br. s., 1H), 7.69-7.75 (m, 1H), 7.60-7.69 (m,
4H), 7.53-7.60 (m, 2H), 7.37 (t, J=7.5 Hz, 2H), 7.24-7.33 (m, 1H),
5.13-5.29 (m, 1H), 4.54 (t, J=11.6 Hz, 1H), 4.38 (t, J=8.7 Hz, 1H),
4.04-4.22 (m, 2H), 3.80-3.94 (m, 1H), 3.07-3.18 (m, 1H), 2.73-2.91
(m, 1H), 2.35-2.50 (m, 1H), 1.63-1.91 (m, 3H), 0.99-1.25 (m, 2H).
MS m/z 432.0 (M+H.sup.+).
[0354] Following the procedure described above for Example 12 and
substituting the appropriate reagents, starting materials and
purification methods known to those skilled in the art, the
following compounds of the present invention were prepared:
TABLE-US-00012 Cpd Name and data 1
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-(1,3-thiazol-4-
ylcarbonyl)piperidine. MS m/z 432.0 (M + H.sup.+). 3
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-(isothiazol-5-
ylcarbonyl)piperidine. MS m/z 432.0 (M + H.sup.+). 4
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-(1H-pyrrol-3-
ylcarbonyl)piperidine. MS m/z 414 (M + H.sup.+). 5
4-[1-(Biphenyl-4-ylcarbonyl)azetidin-3-yl]-1-(1,3-thiazol-5-
ylcarbonyl)piperidine. MS m/z 432.0 (M + H.sup.+).
Example 13
##STR00049##
[0355] A.
(4-(1-Benzhydrylazetidin-3-yl)-4-hydroxypiperidin-1-yl)(phenyl)m-
ethanone, 13c
[0356] A solution of 1-benzhydryl-3-iodoazetidine 13a (1.4 mmol,
490 mg) in 5 mL of THF was added to a stirring mixture of SmI.sub.2
(0.1 M THF solution, 3 mmol, 30 mL) and 1.7 mL of HMPA. After 5
min, a solution of 1-benzoylpiperidin-4-one 13b (3.1 mmol, 626 mg)
in 5 mL of THF was added. The reaction mixture was stirred for 2 h.
Saturated aqueous NH.sub.4Cl solution (20 mL) was added and the
suspension was filtered through a diatomaceous earth pad. The
solids were washed with chloroform and the combined organic layers
were washed with brine, dried, and concentrated. The crude residue
was purified by preparative reverse-phase chromatography to give
400 mg (55% yield) of compound 13c (mono-TFA salt) as a yellow oil.
MS m/z 401.2 (M+H.sup.+).
B. (4-(Azetidin-3-yl)-4-hydroxypiperidin-1-yl)(phenyl)methanone,
13d
[0357] Compound 13c mono-TFA salt (0.34 mmol, 180 mg) and 10%
palladium on carbon (40 mg) were combined in a 30 mL of ethanol in
a Parr pressure bottle. The mixture was purged with N.sub.2 and
then shaken under a 50 psi H.sub.2 atmosphere at 20.degree. C. for
20 h. The catalyst was removed by filtration through a diatomaceous
earth pad and the filtrate was concentrated. Water,
CH.sub.2Cl.sub.2, and aqueous HCl were added and the mixture was
frozen and lyophilized to give 82 mg (81% yield) of compound 13d
(mono-HCl salt). MS m/z 261.1 (M+H.sup.+).
C.
1-(Phenylcarbonyl)-4-(1-{[5-(trifluoromethyl)-1-benzothiophen-2-yl]carb-
onyl}azetidin-3-yl)piperidin-4-ol, Cpd 6
[0358] A solution of
5-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 13e (0.30
mmol, 75 mg), DIEA (0.83 mmol, 0.15 mL), and HBTU (0.33 mmol, 126
mg) in 2 mL of DMF was stirred for 10 min. The HCl salt of compound
13d (0.28 mmol, 82 mg) was added and the mixture was stirred at
20.degree. C. for 20 h. The reaction mixture was filtered through 3
g of silica gel carbonate and 3 g of aminopropyl silica gel using
CH.sub.3CN as eluant. The CH.sub.3CN was removed under reduced
pressure and the residue was purified by preparative reverse-phase
HPLC to give 45 mg (33% yield) of Cpd 6. .sup.1H NMR (CD.sub.3OD,
400 MHz): .delta.=8.13-8.24 (m, 1H), 8.04 (d, J=8.6 Hz, 1H),
7.82-7.90 (m, 1H), 7.60 (d, J=8.6 Hz, 1H), 7.27-7.42 (m, 5H),
4.44-4.59 (m, 2H), 4.25-4.39 (m, J=15.0, 2.8 Hz, 1H), 3.98-4.19 (m,
2H), 3.42-3.54 (m, 1H), 3.32-3.42 (m, 1H), 2.79 (quin, J=7.4 Hz,
1H), 1.57-1.69 (m, 1H), 1.31-1.56 (m, 3H). MS m/z 489.1
(M+H.sup.+).
Example 14
##STR00050##
[0359] A. (tert-Butyl
4-(1-benzhydrylazetidin-3-yl)-4-hydroxypiperidine-1-carboxylate,
14b
[0360] A solution of 1-benzhydryl-3-iodoazetidine 13a (4.75 mmol,
1.66 g) in 10 mL of THF was added to a stirring mixture of
SmI.sub.2 (0.1 M THF solution, 9.98 mmol, 99.8 mL) and 5.6 mL of
HMPA. After 15 min, a solution of tert-butyl
4-oxopiperidine-1-carboxylate 14a (4.75 mmol, 0.95 g) in 15 mL of
THF was added. The reaction mixture was stirred for 18 h. Saturated
aqueous NH.sub.4Cl solution (40 mL) was added and the suspension
was filtered through a diatomaceous earth pad. The solids were
washed with chloroform and the combined organic layers were washed
with brine, dried, and concentrated. The crude residue was purified
by preparative reverse-phase chromatography to give 1.0 g (45%
yield) of 90% pure compound 14b as a clear oil. MS m/z 423.3
(M+H.sup.+).
B. 4-(1-Benzhydrylazetidin-3-yl)piperidin-4-ol, 14c
[0361] Compound 14c was prepared according to the procedure
described in Example 1, Step F, substituting compound 14b for
compound 1i.
C.
(4-(1-Benzhydrylazetidin-3-yl)-4-hydroxypiperidin-1-yl)(thiazol-2-yl)me-
thanone, 14d
[0362] A solution of thiazole-2-carboxylic acid 1 h (1.79 mmol, 232
mg), DIEA (6.53 mmol, 1.12 mL), and HBTU (1.96 mmol, 742 mg) in 11
mL of DMF was stirred for 10 min. Compound 14c (1.63 mmol, 526 mg)
was added and the mixture was stirred at 20.degree. C. for 20 h.
The reaction mixture was purified by preparative reverse-phase HPLC
to give 298 mg (33% yield) of compound 14d as a buff powder. MS m/z
434.2 (M+H.sup.+).
D. 4
(4-(Azetidin-3-yl)-4-hydroxypiperidin-1-yl)(thiazol-2-yl)methanone,
14e
[0363] 1-Chloroethyl chloroformate (7.06 mmol, 0.76 mL) was added
dropwise to a solution of compound 14d in 20 mL of CH.sub.2Cl.sub.2
in an ice-water bath. After 30 min, the cooling bath was removed
and the reaction mixture was stirred for 2 h at 20.degree. C. The
CH.sub.2Cl.sub.2 was evaporated, 20 mL of MeOH was added, and the
resulting solution was refluxed for 2 h. The solvent was evaporated
and the residue was partitioned between CH.sub.2Cl.sub.2 and 0.2 N
aqueous HCl. The aqueous layer was lyophilized to give compound
14e, which was carried on to the next step without purification. MS
m/z 267.7 (M+H.sup.+).
E.
1-(1,3-Thiazol-2-ylcarbonyl)-4-(1-{[6-(trifluoromethyl)-1-benzothiophen-
-2-yl]carbonyl}azetidin-3-yl)piperidin-4-ol, Cpd 94
[0364] A solution of
6-(trifluoromethyl)benzo[b]thiophene-2-carboxylic acid 14f (0.30
mmol, 75 mg), DIEA (0.98 mmol, 0.17 mL), and HBTU (0.30 mmol, 112
mg) in 2 mL of DMF was stirred for 10 min. Compound 14e (0.25 mmol,
66 mg) was added and the mixture was stirred at 20.degree. C. for
20 h. The reaction mixture was purified by preparative
reverse-phase HPLC to give 77 mg (62% yield) of Cpd 94 as a white
powder. .sup.1H NMR (DMSO-d.sub.6): .delta.=8.39 (s, 1H), 8.29 (d,
J=8.6 Hz, 1H), 8.02-8.08 (m, 1H), 8.00 (s, 2H), 7.76 (dd, J=8.6,
1.5 Hz, 1H), 4.99 (d, J=12.7 Hz, 1H), 4.46-4.56 (m, 2H), 4.25 (d,
J=12.2 Hz, 1H), 4.06-4.15 (m, 1H), 3.97-4.06 (m, 1H), 3.17-3.27 (m,
2H), 2.74-2.86 (m, J=14.8, 7.3, 7.3 Hz, 1H), 1.36-1.66 (m, 4H). MS
m/z 496.1 (M+H.sup.+).
BIOLOGICAL EXAMPLES
In Vitro Methods
Example 1
MGL Enzyme Activity Assay
[0365] All rate-based assays were performed in black 384-well
polypropylene PCR microplates (Abgene) in a total volume of 30 pt.
Substrate 4-methylumbelliferyl butyrate (4MU-B; Sigma) and either
purified mutant MGL (mut-MGLL 11-313 L179S L186S) or purified wild
type MGL (wt-MGLL 6H-11-313) were diluted separately into 20 mM
PIPES buffer (pH=7.0), containing 150 mM NaCl and 0.001% Tween 20.
Compounds of Formula (I) were pre-dispensed (50 mL) into the assay
plate using a Cartesian Hummingbird prior to adding 4MU-B (25 .mu.l
of 1.2.times. solution to a final concentration of 10 .mu.M)
followed by enzyme (5 .mu.l of a 6.times. solution to a final
concentration of 5 nM) to initiate the reaction. Final compound
concentrations ranged from 17 to 0.0003 .mu.M. The fluorescence
change due to 4MU-B cleavage was monitored with excitation and
emission wavelengths of 335 and 440 nm, respectively, and a
bandwidth of 10 nm (Safire.sup.2, Tecan) at 37.degree. C. for 5
min.
[0366] The IC.sub.50 values for compounds of Formula (I) were
determined using Excel from a fit of the equation to the
concentration-response plot of the fractional activity as a
function of inhibitor concentration.
TABLE-US-00013 BIOLOGICAL DATA TABLE 1 MGL mutant MGL wild type Cpd
inh IC.sub.50 (.mu.M) inh IC.sub.50 (.mu.M) 1 0.079 0.258 2
<0.005 <0.005 3 0.0339 4 0.154 5 0.0876 6 0.918 7 0.0565 8
0.007 9 0.114 10 0.0155 11 0.498 12 0.01 13 <0.005 14 0.005 15
0.007 16 0.007 17 0.0173 18 0.0125 19 <0.005 20 <0.005 21
0.0124 22 0.008 23 0.368 24 0.0379 25 0.0120 26 <0.005 27
0.00900 28 0.0164 29 0.00600 30 <0.005 31 <0.005 32 <0.005
33 <0.005 34 0.0544 35 <0.005 36 <0.005 37 <0.005 38
0.005 39 <0.005 40 0.00900 41 <0.005 42 <0.005 43
<0.005 44 <0.005 45 <0.005 46 0.111 47 0.0379 48 <0.005
49 0.00600 50 <0.005 51 <0.005 52 0.0715 53 0.0466 54
<0.005 55 0.0130 56 <0.005 57 0.0170 58 <0.005 59 0.011 60
0.01 61 0.211 62 <0.005 63 <0.005 64 <0.005 65 <0.005
66 0.0192 67 0.0665 68 0.0621 69 <0.005 70 0.008 71 0.0120 72
0.0170 73 0.0120 74 0.0138 75 <0.005 76 0.0114 77 <0.005 78
<0.005 79 0.00900 80 <0.005 81 0.0232 82 0.0355 83 0.00916 84
0.175 85 0.280 86 0.0187 87 0.0316 88 0.00949 89 0.0341 90 0.173 91
0.237 92 0.163 93 <0.005 94 0.01 95 0.0140 96 0.0781 97 0.0340
98 0.0166 99 0.0173 100 0.101 101 0.104
Example 2
2-AG Accumulation Assay
[0367] To measure the accumulation of 2-AG due to inhibition of
MGL, one g rat brain was homogenized using a Polytron homogenizer
(Brinkmann, PT300) in 10 mL of 20 mM HEPES buffer (pH=7.4),
containing 125 mM NaCl, 1 mM EDTA, 5 mM KCl and 20 mM glucose.
Compounds of Formula (I) (10 .mu.M) were pre-incubated with rat
brain homogenate (50 mg). After a 15-min incubation time at
37.degree. C., CaCl.sub.2 (final concentration=10 mM) was added and
then incubated for 15 min at 37.degree. C. in a total volume of 5
mL. The reactions were stopped with 6 mL organic solvent extraction
solution of 2:1 chloroform/methanol. Accumulated 2-AG in the
organic phase was measured by a HPLC/MS method, according to the
following equation:
percent vehicle=(2-AG accumulation in the presence of compound/2-AG
accumulation in vehicle).times.100.
TABLE-US-00014 BIOLOGICAL DATA TABLE 2 Rat Brain 2AG % VehCntrl Cpd
(%) @1 .mu.M 1 109 2 329 3 135 7 185 8 523 10 194 12 134 13 335 14
231 15 281 16 493 17 184 18 457 19 559 20 728 21 287 22 470 24 298
25 540 26 303 27 634 28 777 29 800 30 443 31 779 32 1026 33 696 34
517 35 724 36 507 37 163 38 425 39 371 40 361 41 272 42 498 43 611
44 107 45 385 47 153 48 1022 49 908 50 561 51 266 52 193 53 225 54
736 55 733 56 285 57 869 58 370 59 346 60 508 62 422 63 435 64 383
65 241 66 889 67 590 68 453 69 539 70 561 71 552 72 657 73 875 74
788 75 1135 76 731 77 714 78 1046 79 946 80 860
Example 3
MGL ThermoFluor.RTM. Assay
Mutant
[0368] The ThermoFluor (TF) assay is a 384-well plate-based binding
assay that measures thermal stability of proteins.sup.1,2. The
experiments were carried out using instruments available from
Johnson & Johnson Pharmaceutical Research & Development,
LLC. TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47).
Final TF assay conditions used for MGL studies were 0.07 mg/ml of
mutant MGL, 100 .mu.M ANS, 200 mM NaCl, 0.001% Tween-20 in 50 mM
PIPES (pH=7.0).
[0369] Screening compound plates contained 100% DMSO compound
solutions at a single concentration. For follow-up
concentration-response studies, compounds were arranged in a
pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds
were serially diluted in 100% DMSO across 11 columns within a
series. Columns 12 and 24 were used as DMSO reference and contained
no compound. For both single and multiple compound
concentration-response experiments, the compound aliquots (46 mL)
were robotically predispensed directly into 384-well black assay
plates (Abgene: TF-0384/k) using the Hummingbird liquid handler.
Following compound dispension, protein and dye solutions were added
to achieve the final assay volume of 3 .mu.L. The assay solutions
were overlayed with 1 .mu.l of silicone oil (Fluka, type DC 200:
85411) to prevent evaporation.
[0370] Bar-coded assay plates were robotically loaded onto a
thermostatically controlled PCR-type thermal block and then heated
from 40 to 90.degree. C. degrees at a ramp-rate of 1.degree. C./min
for all experiments. Fluorescence was measured by continuous
illumination with UV light (Hamamatsu LC6), supplied via fiber
optics and filtered through a band-pass filter (380-400 nm; >6
OD cutoff). Fluorescence emission of the entire 384-well plate was
detected by measuring light intensity using a CCD camera (Sensys,
Roper Scientific) filtered to detect 500.+-.25 nm, resulting in
simultaneous and independent readings of all 384 wells. A single
image with 20-sec exposure time was collected at each temperature,
and the sum of the pixel intensity in a given area of the assay
plate was recorded vs temperature and fit to standard equations to
yield the T.sub.m.sup.1. [0371] 1. Pantoliano, M. W., Petrella, E.
C., Kwasnoski, J. D., Lobanov, V. S., Myslik, J., Graf, E., Carver,
T., Asel, E., Springer, B. A., Lane, P., and Salemme, F. R. (2001)
J Biomol Screen 6, 429-40. [0372] 2. Matulis, D., Kranz, J. K.,
Salemme, F. R., and Todd, M. J. (2005) Biochemistry 44,
5258-66.
[0373] The K.sub.d values for compounds of Formula (I) were
determined from a fit of the equation to the concentration-response
plot of the fractional activity as a function of T.sub.m. For some
experiments, quantitative NMR spectroscopy (qNMR) was used to
measure concentration of the initial 100% DMSO compound solutions
and, using the same fitting method, qK.sub.d values were
determined
TABLE-US-00015 BIOLOGICAL DATA TABLE 3 MGL mutant ThermoFluor qKd
MGL mutant (.mu.M) (using qNMR Cpd ThermoFluor Kd (.mu.M) conc.) 1
0.100 2 0.0089 3 0.0557 4 0.162 5 0.0641 6 0.258 7 0.0250 8 0.0040
9 0.100 10 0.0110 11 0.732 12 0.0220 13 0.0280 14 0.0050 15 0.0090
16 0.0020 17 0.0990 18 0.0030 19 0.0090 20 0.0010 0.0013 21 0.0286
22 0.0066 23 0.500 24 0.0199 25 0.0275 26 0.0036 27 0.0133 28
0.0111 29 0.0003 0.0012 30 0.0025 31 0.0026 32 0.0006 33 0.0626 34
0.198 35 0.0025 0.0057 36 0.0225 37 0.0160 38 0.0155 39 0.0489 40
0.0946 41 0.0041 0.0031 42 0.0245 43 0.0264 44 0.0213 45 0.0122 46
0.0200 47 0.0767 0.0333 48 0.0010 49 0.0010 50 0.0010 51 0.0180 52
0.0304 0.0322 53 0.0333 54 0.0018 55 0.0020 56 0.0055 0.0033 57
0.0059 58 0.0069 59 0.0202 0.0094 60 0.0008 0.0005 61 0.0006 0.0005
62 0.0013 0.0006 63 0.0174 64 0.0189 65 0.0404 66 0.0067 67 0.0066
68 0.0145 69 0.0012 70 0.0006 71 0.0012 72 0.0027 73 0.0048 74
0.0080 75 0.0039 76 0.0083 77 0.0050 78 0.0023 79 0.0033 80 0.0049
81 0.0148 82 0.0228 83 0.0136 84 0.0663 85 0.0645 86 0.0106 87
0.0075 88 0.0133 89 0.0077 90 0.0237 91 0.0325 92 0.0034 93 0.0055
94 0.0249 95 0.0386 96 0.0247 97 0.0221 98 0.0436 99 0.0167 100
0.0888 101 0.0039
In Vivo Methods
Example 4
CFA-Induced Paw Radiant Heat Hypersensitivity
[0374] Each rat was placed in a test chamber on a warm glass
surface and allowed to acclimate for approximately 10 min. A
radiant thermal stimulus (beam of light) was focused through the
glass onto the plantar surface of each hind paw in turn. The
thermal stimulus was automatically shut off by a photoelectric
relay when the paw was moved or when the cut-off time was reached
(20 sec for radiant heat at .about.5 amps). An initial (baseline)
response latency to the thermal stimulus was recorded for each
animal prior to the injection of complete Freund's adjuvant (CFA).
Twenty-four hours following intraplantar CFA injection, the
response latency of the animal to the thermal stimulus was
re-evaluated and compared to the animal's baseline response time.
Only rats that exhibited at least a 25% reduction in response
latency (i.e., are hyperalgesic) were included in further analysis.
Immediately following the post-CFA latency assessment, the
indicated test compound or vehicle was administered orally.
Post-compound treatment withdrawal latency was assessed at fixed
time intervals, typically 30, 60, 120, 180, and 300 min.
[0375] The percent reversal (% R) of hypersensitivity was
calculated in one of two different ways: 1) using group mean values
or 2) using individual animal values. More specifically:
[0376] Method 1. For all compounds, the % R of hypersensitivity was
calculated using the mean value for groups of animals at each time
point according to the following formula:
% reversal=[(group treatment response-group CFA response)/(group
baseline response-group CFA response)].times.100
Results are given for the maximum % reversal observed for each
compound at any time point tested.
[0377] Method 2. For some compounds, the % R of hypersensitivity
was calculated separately for each animal according to the
following formula:
% reversal=[(individual treatment response-individual CFA
response)/(individual baseline response-individual CFA
response)].times.100.
Results are given as a mean of the maximum % reversal values
calculated for each individual animal.
TABLE-US-00016 BIOLOGICAL DATA TABLE 4 last dose time Method 1:
Method 2: Cpd (mg/kg, no. of point peak % peak % No. p.o.) vehicle
animals (min) reversal reversal 20 30 20% HP.beta.CD 8 300 -6.7 Not
calculated 29 30 10% NMP/ 8 300 17.9 Not 20% solutol calculated
Example 5
CFA-Induced Paw Pressure Hypersensitivity
[0378] Prior to testing, rats may be acclimated to the handling
procedure twice a day for a period of two days. The test consists
of placing the left hindpaw on a polytetrafluoroethylene platform
and applying a linearly increasing mechanical force (constant rate
of 12.5 mmHg/s) in between the third and fourth metatarsal of the
dorsum of the rat's hindpaw, with a dome-tipped plinth (0.7 mm in
radius), using an analgesy-meter (Stoelting, Chicago, Ill.), also
known as a Randall-Selitto apparatus. The endpoint may be
automatically reached upon hindpaw withdrawal, and the terminal
force may be noted (in grams). An initial (baseline) response
threshold to the mechanical stimulus may be recorded for each
animal prior to the injection of complete Freund's adjuvant (CFA).
Forty hours following intraplantar CFA injection, the response
threshold of the animal to the mechanical stimulus may be
re-evaluated and compared to the animal's baseline response
threshold. A response may be defined as a withdrawal of the
hindpaw, a struggling to remove the hindpaw, or vocalization. Only
rats that exhibit at least a 25% reduction in response threshold
(i.e., hyperalgesia) may be included in further analysis.
Immediately following the post-CFA threshold assessment, rats may
be administered the indicated test compound or vehicle.
Post-treatment withdrawal thresholds may be assessed at 1 h. Paw
withdrawal thresholds may be converted to percent reversal of
hypersensitivity according to the following formula:
% reversal=[(post treatment response-predose response)/(baseline
response-predose response)].times.100.
Example 6
Chronic Constriction Injury (CCI)-Induced Model of Neuropathic
Pain
Cold Acetone-Hypersensitivity Test
[0379] Male Sprague-Dawley rats (225-450 g) may be used to evaluate
the ability of selected compounds to reverse CCI-induced cold
hypersensitivity. Four loose ligatures of 4-0 chromic gut may be
surgically placed around the left sciatic nerve under inhalation
anesthesia as described by Bennett et al. (Bennett G J, Xie Y K.
Pain 1988, 33(1): 87-107). Fourteen to 35 days following CCI
surgery, subjects may be placed in elevated observation chambers
containing wire mesh floors, and five applications of acetone (0.05
mL/application separated by approximately 5 minutes) may be
spritzed onto the plantar surface of the paw using a multidose
syringe. An abrupt withdrawal or lifting of the paw may be
considered a positive response. The number of positive responses
may be recorded for each rat over the five trials. Following
baseline withdrawal determinations, compounds may be administered
in the indicated vehicle, by the indicated route (see Table 6). The
number of withdrawals may be re-determined 1 to 4 hr after compound
administration. Results may be presented as a percent inhibition of
shakes, which may be calculated for each subject as [1-(test
compound withdrawals/pre-test withdrawals)].times.100 and then
averaged by treatment.
Example 7
Spinal Nerve Ligation (SNL) Model of Neuropathic Pain
Tactile Allodynia Test
[0380] For lumbar 5 (L.sub.5) spinal nerve ligation (SNL) studies,
anesthesia may be induced and maintained on isoflurane inhalation.
Fur may be clipped over the dorsal pelvic area, and a 2-cm skin
incision may be made just left of midline over the dorsal aspect of
the L.sub.4-S.sub.2 spinal segments, followed by separation of the
paraspinal muscles from spinous processes. The transverse process
of L.sub.6 may be carefully removed, and the L.sub.5 spinal nerve
may be identified. The left L.sub.5 spinal nerve may be ligated
tightly with 6-0 silk thread, the muscle may be sutured with 4-0
vicryl, and the skin may be closed with wound clips. Following
surgery, s.c. saline (5 mL) may be administered.
[0381] Behavioral testing may be performed four weeks
post-ligation. Following baseline von Frey determinations to verify
the presence of mechanical allodynia, L.sub.5 SNL rats may be
orally administered the indicated vehicle or drug. Tactile
allodynia may be quantified at 30, 60, 100, 180, and 300 min
post-dosing by recording the force at which the paw ipsilateral to
the nerve ligation is withdrawn from the application of a series of
calibrated von Frey filaments (0.4, 0.6, 1.0, 2.0, 4, 6, 8 and 15
g; Stoelting; Wood Dale, Ill.). Beginning at an intermediate
stiffness (2.0 g), filaments may be applied to the mid-plantar hind
paw for approximately 5 seconds to determine the response
threshold, a brisk paw withdrawal leads to the presentation of the
next lighter stimulus, whereas a lack of a withdrawal response
leads to the presentation of the next stronger stimulus. A total of
four responses after the first threshold detection may be
collected. The 50% withdrawal thresholds may be interpolated by the
method of Dixon as modified by Chaplan et. al., and when response
thresholds fall above or below the range of detection, respective
values of 15.0 or 0.25 g may be assigned. Threshold data from von
Frey filament testing may be reported as withdrawal threshold in
grams. Data may be normalized and results may be presented as % MPE
(maximum possible effect) of the drug calculated according to the
following formula:
% MPE = x g / force - baseline g / force 15 g / force - baseline g
/ force .times. 100 ##EQU00003##
[0382] While the foregoing specification teaches the principles of
the present invention, with examples provided for the purpose of
illustration, it will be understood that the practice of the
invention encompasses all of the usual variations, adaptations
and/or modifications as come within the scope of the following
claims and their equivalents.
* * * * *