U.S. patent application number 14/072239 was filed with the patent office on 2014-08-07 for heteroaryl substituted urea modulators of fatty acid amide hydrolase.
This patent application is currently assigned to JANSSEN PHARMACEUTICA NV. The applicant listed for this patent is JANSSEN PHARMACEUTICA NV. Invention is credited to J. Guy Breitenbucher, Alison L. Chambers, Natalie A. Hawryluk, William M. Jones, John M. Keith, Jeffrey E. Merit, Mark J. Selerstad, Mark S. Tichenor, Amy K. Timmons.
Application Number | 20140221322 14/072239 |
Document ID | / |
Family ID | 41600655 |
Filed Date | 2014-08-07 |
United States Patent
Application |
20140221322 |
Kind Code |
A1 |
Breitenbucher; J. Guy ; et
al. |
August 7, 2014 |
HETEROARYL SUBSTITUTED UREA MODULATORS OF FATTY ACID AMIDE
HYDROLASE
Abstract
Certain heteroaryl-substituted piperidinyl and piperazinyl urea
compounds are described, which are useful as FAAH inhibitors. Such
compounds may be used in pharmaceutical compositions and methods
for the treatment of disease states, disorders, and conditions
mediated by fatty acid amide hydrolase (FAAH) activity, such as
anxiety, pain, inflammation, sleep disorders, eating disorders,
insulin resistance, diabetes, osteoporosis, and movement disorders
(e.g., multiple sclerosis).
Inventors: |
Breitenbucher; J. Guy;
(Escondido, CA) ; Keith; John M.; (San Diego,
CA) ; Tichenor; Mark S.; (San Diego, CA) ;
Chambers; Alison L.; (San Diego, CA) ; Jones; William
M.; (San Diego, CA) ; Hawryluk; Natalie A.;
(San Diego, CA) ; Timmons; Amy K.; (Renton,
WA) ; Merit; Jeffrey E.; (Stanford, CA) ;
Selerstad; Mark J.; (Escondido, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JANSSEN PHARMACEUTICA NV |
BEERSE |
|
BE |
|
|
Assignee: |
JANSSEN PHARMACEUTICA NV
BEERSE
BE
|
Family ID: |
41600655 |
Appl. No.: |
14/072239 |
Filed: |
November 5, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13131061 |
May 25, 2011 |
8598356 |
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PCT/US2009/065752 |
Nov 24, 2009 |
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14072239 |
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61117880 |
Nov 25, 2008 |
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Current U.S.
Class: |
514/161 ;
514/248; 514/256; 514/300; 514/302; 514/314; 514/318; 514/321;
514/326; 544/236; 544/329; 546/113; 546/115; 546/121; 546/175;
546/194; 546/198; 546/209 |
Current CPC
Class: |
A61K 31/506 20130101;
A61P 25/22 20180101; A61P 25/08 20180101; A61K 31/454 20130101;
A61K 31/5025 20130101; A61P 15/00 20180101; A61P 9/10 20180101;
A61P 29/00 20180101; C07D 413/12 20130101; C07D 498/04 20130101;
C07D 487/04 20130101; A61P 1/08 20180101; A61K 31/437 20130101;
A61K 45/06 20130101; A61P 25/24 20180101; C07D 401/14 20130101;
A61P 25/30 20180101; A61P 37/06 20180101; C07D 471/04 20130101;
C07D 401/12 20130101; C07D 405/14 20130101; A61K 31/4709 20130101;
A61P 25/04 20180101; A61K 31/4545 20130101; A61P 19/02
20180101 |
Class at
Publication: |
514/161 ;
514/248; 514/256; 514/300; 514/302; 514/314; 514/318; 514/321;
514/326; 544/236; 544/329; 546/113; 546/115; 546/121; 546/175;
546/194; 546/198; 546/209 |
International
Class: |
C07D 498/04 20060101
C07D498/04; A61K 31/506 20060101 A61K031/506; A61K 31/437 20060101
A61K031/437; A61K 31/4709 20060101 A61K031/4709; A61K 31/4545
20060101 A61K031/4545; A61K 45/06 20060101 A61K045/06; C07D 487/04
20060101 C07D487/04; C07D 401/12 20060101 C07D401/12; C07D 471/04
20060101 C07D471/04; C07D 401/14 20060101 C07D401/14; C07D 405/14
20060101 C07D405/14; C07D 413/12 20060101 C07D413/12; A61K 31/5025
20060101 A61K031/5025; A61K 31/454 20060101 A61K031/454 |
Claims
1. A chemical entity selected from compounds of Formula (I):
##STR00066## wherein: Ar.sup.1 is mono- or fused bicyclic
heteroaryl group consisting of 5-10 ring atoms and having one
heteroatom selected from the group consisting of N, O and S, with a
carbon atom as point of ring attachment, and optionally having up
to four additional carbon ring atoms replaced with nitrogen, said
heteroaryl group having not more than five heteroatoms, each
heteroaryl group independently unsubstituted or substituted with
halo, --C.sub.1-4alkyl, --OC.sub.1-4alkyl, --OCF.sub.3, --CN, or
--CF.sub.3; Ar.sup.2 is (i) phenyl unsubstituted or substituted
with one or two R.sup.a moieties; where each R.sup.a moiety is
independently --C.sub.1-8alkyl, --OC.sub.1-8alkyl, halo,
--CF.sub.3, --OCF.sub.3, --OCH.sub.2CF.sub.3,
--S(O).sub.0-2C.sub.1-8alkyl, --S(O).sub.0-2CF.sub.3, --CO.sub.2H,
--N(R.sup.b)R.sup.c, --SO.sub.2NR.sup.bR.sup.c,
--NR.sup.bSO.sub.2R.sup.c, --C(O)NR.sup.bR.sup.c, or --NO.sub.2; or
two adjacent R.sup.a moieties taken together form
--O(CH.sub.2).sub.1-2O-- or --OCF.sub.2O--; where R.sup.b and
R.sup.c are each independently --H or --C.sub.1-8alkyl, or
optionally R.sup.b and R.sup.c taken together with the atoms of
attachment form a 4-8 membered ring; (ii) phenyl substituted at the
3- or 4-position with -L-Ar.sup.3, unsubstituted or substituted
with one or two R.sup.a moieties, wherein: L is a linker selected
from the group consisting of --(CH.sub.2).sub.1-6--, --CH.dbd.CH--,
--O--, --C.sub.1-6alkyl-O--C.sub.1-6alkyl-,
--C.sub.1-6alkyl-N(C.sub.1-6alkyl)-C.sub.1-6alkyl-,
--C.sub.1-6alkyl-S(O).sub.0-2C.sub.1-6alkyl-, --C.ident.C--,
--C(O)--, or a covalent bond; Ar.sup.3 is: (a) phenyl unsubstituted
or substituted with one or two R.sup.a moieties; (b) a monocyclic
heteroaryl group unsubstituted or substituted with one or two
R.sup.a moieties; or (c) a 9- or 10-membered fused bicyclic
heteroaryl group unsubstituted or substituted with one or two
R.sup.a moieties; or (iii) a 9- or 10-membered fused bicyclic
heteroaryl having one heteroatom selected from the group consisting
of N, O, and S, and optionally having up to four additional carbon
ring atoms replaced with nitrogen, said fused bicyclic heteroaryl
having not more than five heteroatoms, and unsubstituted or
substituted with one, two or three R.sup.a moieties; and
pharmaceutically acceptable salts of compounds of Formula (I),
pharmaceutically acceptable prodrugs of compounds of Formula (I),
and pharmaceutically active metabolites of compounds of Formula
(I).
2. A chemical entity as in claim 1, wherein Ar.sup.1 is
isoxazolo[5,4-c]pyridin-3-yl, isoxazolo[4,5-c]pyridin-3-yl,
isoxazolo[4,5-b]pyridin-3-yl, isoxazolo[5,4-b]pyridin-3-yl,
imidazo[1,2-a]pyridin-8-yl, imidazo[1,2-a]pyridin-7-yl,
imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl,
imidazo[1,2-b]pyridazin-3-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-7-yl,
imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-c]pyrimidin-7-yl,
benzooxazol-6-yl, 1H-indazol-7-yl, quinolin-8-yl, isoquinolin-5-yl,
isoquinolin-4-yl, 1,1-dioxo-1H-1A.sup.6-benzo[d]isothiazol-3-yl,
1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl,
1H-pyrrolo[3,2-b]pyridin-6-yl, 2-methyl-benzothiazol-6-yl,
1-isopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl,
2-methyl-benzooxazol-5-yl, 1H-indazol-7-yl,
1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl,
2-methyl-2H-indazol-4-yl, benzooxazole-2-yl group,
6-[1,2,3]triazol-1-yl-pyridin-3-yl,
6-[1,2,4]triazol-4-yl-pyridin-3-yl,
6-[1,2,4]triazol-1-yl-pyridin-3-yl,
6-[1,2,3]triazol-2-yl-pyridin-3-yl, 4-[1,2,3]triazol-2-yl-phenyl,
4-[1,2,3]triazol-1-yl-phenyl, 5-methyl-[1,3,4]oxadiazol-2-yl,
2-phenyl-pyrimidin-5-yl, 3-pyridyl, benzisoxazol-3-yl,
pyrimidin-4-yl, isoxazol-3-yl, 6-fluorobenzo[d]isoxazol-3-yl,
3-phenyl-[1,2,4]thiadiazol-5-yl, 1H-tetrazol-5-yl,
benzo[1,2,5]thiadiazol-4-yl, benzo[1,2,5]oxadiazol-4-yl,
thiophen-2-yl, thiophen-3-yl, 6-chloro-pyridazin-3-yl,
pyrazin-2-yl, 1H-benzotriazol-5-yl, [1,5]naphthyridin-2-yl,
benzothiazol-6-yl, or 1H-pyrazol-3-yl.
3. A chemical entity as in claim 1, wherein Ar.sup.1 is pyrimidine,
isoxazole, benzisoxazole, or pyridine, each group optionally
substituted with one or two R.sup.a.
4. A chemical entity as in claim 1, wherein Ar.sup.2 is phenyl
substituted with one or two R.sup.a moieties.
5. A chemical entity as in claim 4, wherein each R.sup.a moiety is
independently selected from the group consisting of: chloro, cyano,
isobutyl, methylsulfanyl, methanesulfonyl, trifluoromethyl,
trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, methyl, methoxy,
tert-butyl, bromo, methoxycarbonyl, cyanomethyl,
methoxycarbonylmethyl, trifluoromethanesulfonyl,
trifluoromethanesulfanyl, and butyl; or two adjacent R.sup.a
moieties taken together form --OCH.sub.2O-- or --OCF.sub.2O--.
6. A chemical entity as in claim 4, wherein each R.sup.a moiety is
independently selected from the group consisting of: F, Cl, Br,
CF.sub.3, or two adjacent R.sup.a moieties taken together form
--OCF.sub.2O--.
7. A chemical entity as in claim 1, wherein Ar.sup.2 is phenyl
substituted at the 3- or 4-position with -L-Ar.sup.3, unsubstituted
or substituted with one or two R.sup.a moieties.
8. A chemical entity as in claim 7, wherein L is
--CH.sub.2CH.sub.2--, --O--, --OCH.sub.2--, or --C.delta.C--.
9. A chemical entity as in claim 7, wherein L is --O--.
10. A chemical entity as in claim 7, wherein Ar.sup.3 is phenyl,
unsubstituted or substituted with one or two R.sup.a moieties.
11. A chemical entity as in claim 10, wherein each R.sup.a moiety
is independently selected from the group consisting of: chloro,
cyano, isobutyl, methylsulfanyl, methanesulfonyl, trifluoromethyl,
trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, methyl, methoxy,
tert-butyl, bromo, methoxycarbonyl, cyanomethyl,
methoxycarbonylmethyl, trifluoromethanesulfonyl,
trifluoromethanesulfanyl, and butyl; or two adjacent R.sup.a
moieties taken together form --OCH.sub.2O-- or --OCF.sub.2O--.
12. A chemical entity as in claim 10, wherein each R.sup.a moiety
is independently fluoro.
13. A chemical entity selected from the group consisting of:
3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide;
N-pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carbox-
amide;
N-pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1--
carboxamide;
3-[(4-fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}piperidine-
-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}piperidine-
-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamid-
e;
N-isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carbo-
xamide;
N-isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1--
carboxamide;
3-[3-(4-fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-chloro-pyridin-3-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-b]pyridazin-3-ylamide;
(+)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide;
(-)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-[3-(4-trifluoromethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridine-3-ylamide;
3-quinolin-3-ylmethyl-piperidine-1-carboxylic acid
pyridin-3-ylamide; 3-(3,4-dichloro-benzyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide;
3-(3-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-(4-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(1H-pyrrolo[2,3-b]pyridin-4-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[4,5-c]pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[5,4-c]pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-8-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-5-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-5-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-c]pyrimidin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-cyano-pyridin-3-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
quinolin-8-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoquinolin-5-ylamide;
3-[3-(4-trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridin-3-ylamide;
3-(4-chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide; and pharmaceutically acceptable salts
thereof.
14. A pharmaceutical composition for treating a disease, disorder,
or medical condition mediated by FAAH activity, comprising: (a) an
effective amount of at least one chemical entity selected from
compounds of Formula (I): ##STR00067## wherein: Ar.sup.1 is mono-
or fused bicyclic heteroaryl group consisting of 5-10 ring atoms
and having one heteroatom selected from the group consisting of N,
O and S, with a carbon atom as point of ring attachment, and
optionally having up to four additional carbon ring atoms replaced
with nitrogen, said heteroaryl group having not more than five
heteroatoms, each heteroaryl group independently unsubstituted or
substituted with halo, --C.sub.1-4alkyl, --OC.sub.1-4alkyl,
--OCF.sub.3, --CN, or --CF.sub.3; Ar.sup.2 is (i) phenyl
unsubstituted or substituted with one or two R.sup.a moieties;
where each R.sup.a moiety is independently --C.sub.1-8alkyl,
--OC.sub.1-8alkyl, halo, --CF.sub.3, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --S(O).sub.0-2C.sub.1-8alkyl,
--S(O).sub.0-2CF.sub.3, --CO.sub.2H, --N(R.sup.b)R.sup.c,
--SO.sub.2NR.sup.bR.sup.c, --NR.sup.bSO.sub.2R.sup.c,
--C(O)NR.sup.bR.sup.c, or --NO.sub.2; or two adjacent R.sup.a
moieties taken together form --O(CH.sub.2).sub.1-2O-- or
--OCF.sub.2O--; where R.sup.b and R.sup.c are each independently
--H or --C.sub.1-8alkyl, or optionally R.sup.b and R.sup.c taken
together with the atoms of attachment form a 4-8 membered ring;
(ii) phenyl substituted at the 3- or 4-position with -L-Ar.sup.3,
unsubstituted or substituted with one or two R.sup.a moieties,
wherein: L is a linker selected from the group consisting of
--(CH.sub.2).sub.1-6--, --CH.dbd.CH--, --O--,
--C.sub.1-6alkyl-O--C.sub.1-6alkyl-,
--C.sub.1-6alkyl-N(C.sub.1-6alkyl)-C.sub.1-6alkyl-,
--C.sub.1-6alkyl-S(O).sub.0-2C.sub.1-6alkyl-, --C.ident.C--,
--C(O)--, or a covalent bond; Ar.sup.3 is: (a) phenyl unsubstituted
or substituted with one or two R.sup.a moieties; (b) a monocyclic
heteroaryl group unsubstituted or substituted with one or two
R.sup.a moieties; or (c) a 9- or 10-membered fused bicyclic
heteroaryl group unsubstituted or substituted with one or two
R.sup.a moieties; or (iii) a 9- or 10-membered fused bicyclic
heteroaryl having one heteroatom selected from the group consisting
of N, O, and S, and optionally having up to four additional carbon
ring atoms replaced with nitrogen, said fused bicyclic heteroaryl
having not more than five heteroatoms, and unsubstituted or
substituted with one, two or three R.sup.a moieties; and
pharmaceutically acceptable salts of compounds of Formula (I),
pharmaceutically acceptable prodrugs of compounds of Formula (I),
and pharmaceutically active metabolites of compounds of Formula
(I); and (b) a pharmaceutically acceptable excipient.
15. A pharmaceutical composition according to claim 14, wherein
said at least one chemical entity is selected from the group
consisting of:
3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide;
N-pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carbox-
amide;
N-pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1--
carboxamide;
3-[(4-fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}piperidine-
-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}piperidine-
-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamid-
e;
N-isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carbo-
xamide;
N-isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1--
carboxamide;
3-[3-(4-fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-chloro-pyridin-3-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-b]pyridazin-3-ylamide;
(+)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide;
(-)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-[3-(4-trifluoromethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridine-3-ylamide;
3-quinolin-3-ylmethyl-piperidine-1-carboxylic acid
pyridin-3-ylamide; 3-(3,4-dichloro-benzyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide;
3-(3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-(4-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(1H-pyrrolo[2,3-b]pyridin-4-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[4,5-c]pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[5,4-c]pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-8-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-5-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-5-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-c]pyrimidin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-cyano-pyridin-3-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
quinolin-8-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoquinolin-5-ylamide;
3-[3-(4-trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridin-3-ylamide;
3-(4-chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide; and pharmaceutically acceptable salts
thereof.
16. A pharmaceutical composition according to claim 14, further
comprising: an analgesic selected from the group consisting of
opioids and non-steroidal anti-inflammatory drugs.
17. A pharmaceutical composition according to claim 14, further
comprising: an additional active ingredient selected from the group
consisting of aspirin, acetaminophen, opioids, ibuprofen, naproxen,
COX-2 inhibitors, gabapentin, pregabalin, and tramadol.
18. A method of treating a subject suffering from or diagnosed with
a disease, disorder, or medical condition mediated by FAAH
activity, comprising administering to the subject in need of such
treatment an effective amount of at least one chemical entity
selected from compounds of Formula (I): ##STR00068## wherein:
Ar.sup.1 is mono- or fused bicyclic heteroaryl group consisting of
5-10 ring atoms and having one heteroatom selected from the group
consisting of N, O and S, with a carbon atom as point of ring
attachment, and optionally having up to four additional carbon ring
atoms replaced with nitrogen, said heteroaryl group having not more
than five heteroatoms, each heteroaryl group independently
unsubstituted or substituted with halo, --C.sub.1-4alkyl,
--OC.sub.1-4alkyl, --OCF.sub.3, --CN, or --CF.sub.3; Ar.sup.2 is
(i) phenyl unsubstituted or substituted with one or two R.sup.a
moieties; where each R.sup.a moiety is independently
--C.sub.1-8alkyl, --OC.sub.1-8alkyl, halo, --CF.sub.3, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --S(O).sub.0-2C.sub.1-8alkyl,
--S(O).sub.0-2CF.sub.3, --CO.sub.2H, --N(R.sup.b)R.sup.c,
--SO.sub.2NR.sup.bR.sup.c, --NR.sup.bSO.sub.2R.sup.c,
--C(O)NR.sup.bR.sup.c, or --NO.sub.2; or two adjacent R.sup.a
moieties taken together form --O(CH.sub.2).sub.1-2O-- or
--OCF.sub.2O--; where R.sup.b and R.sup.c are each independently
--H or --C.sub.1-8alkyl, or optionally R.sup.b and R.sup.c taken
together with the atoms of attachment form a 4-8 membered ring;
(ii) phenyl substituted at the 3- or 4-position with -L-Ar.sup.3,
unsubstituted or substituted with one or two R.sup.a moieties,
wherein: L is a linker selected from the group consisting of
--(CH.sub.2).sub.1-6--, --CH.dbd.CH--, --O--,
--C.sub.1-6alkyl-O--C.sub.1-6alkyl-,
--C.sub.1-6alkyl-N(C.sub.1-6alkyl)-C.sub.1-6alkyl-,
--C.sub.1-6alkyl-S(O).sub.0-2C.sub.1-6alkyl-, --C.ident.C--,
--C(O)--, or a covalent bond; Ar.sup.3 is: (a) phenyl unsubstituted
or substituted with one or two R.sup.a moieties; (b) a monocyclic
heteroaryl group unsubstituted or substituted with one or two
R.sup.a moieties; or (c) a 9- or 10-membered fused bicyclic
heteroaryl group unsubstituted or substituted with one or two
R.sup.a moieties; or (iii) a 9- or 10-membered fused bicyclic
heteroaryl having one heteroatom selected from the group consisting
of N, O, and S, and optionally having up to four additional carbon
ring atoms replaced with nitrogen, said fused bicyclic heteroaryl
having not more than five heteroatoms, and unsubstituted or
substituted with one, two or three R.sup.a moieties; and
pharmaceutically acceptable salts of compounds of Formula (I),
pharmaceutically acceptable prodrugs of compounds of Formula (I),
and pharmaceutically active metabolites of compounds of Formula
(I).
19. A method according to claim 18, wherein said at least one
chemical entity is selected from the group consisting of:
3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide;
N-pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carbox-
amide;
N-pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1--
carboxamide;
3-[(4-fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}-piperidin-
e-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}-piperidin-
e-1-carboxamide;
N-1,2-benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamid-
e;
N-isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carbo-
xamide;
N-isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1--
carboxamide;
3-[3-(4-fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-chloro-pyridin-3-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-b]pyridazin-3-ylamide;
(+)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide;
(-)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-[3-(4-trifluoromethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridine-3-ylamide;
3-quinolin-3-ylmethyl-piperidine-1-carboxylic acid
pyridin-3-ylamide; 3-(3,4-dichloro-benzyl)piperidine-1-carboxylic
acid pyridin-3-ylamide;
3-(3-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-(4-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid
pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(1H-pyrrolo[2,3-b]pyridin-4-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[4,5-c]pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[5,4-c]pyridin-3-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-8-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-5-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-5-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-c]pyrimidin-7-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-cyano-pyridin-3-yl)-amide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
quinolin-8-ylamide;
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoquinolin-5-ylamide;
3-[3-(4-trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridin-3-ylamide;
3-(4-chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide; and pharmaceutically acceptable salts
thereof.
20. A method according to claim 18, wherein the disease, disorder,
or medical condition is selected from the group consisting of:
anxiety, depression, pain, sleep disorders, eating disorders,
inflammation, movement disorders, HIV wasting syndrome, closed head
injury, stroke, learning and memory disorders, Alzheimer's disease,
epilepsy, Tourette's syndrome, Niemann-Pick disease, Parkinson's
disease, Huntington's chorea, optic neuritis, autoimmune uveitis,
drug withdrawal, nausea, emesis, sexual dysfunction, post-traumatic
stress disorder, cerebral vasospasm, glaucoma, irritable bowel
syndrome, inflammatory bowel disease, immunosuppression,
gastroesophageal reflux disease, paralytic ileus, secretory
diarrhea, gastric ulcer, rheumatoid arthritis, unwanted pregnancy,
hypertension, cancer, hepatitis, allergic airway disease,
autoimmune diabetes, intractable pruritis, and
neuroinflammation.
21. A method according to claim 18, wherein the disease, disorder,
or medical condition is pain or inflammation.
22. A method according to claim 18, wherein the disease, disorder,
or medical condition is anxiety, a sleep disorder, an eating
disorder, or a movement disorder.
23. A method according to claim 18, wherein the disease, disorder,
or medical condition is multiple sclerosis.
24. A method according to claim 18, wherein the disease, disorder,
or medical condition is energy metabolism or bone homeostasis.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to certain
heteroaryl-substituted piperidinyl and piperazinyl urea compounds,
pharmaceutical compositions containing them, and methods of using
them for the treatment of disease states, disorders, and conditions
mediated by fatty acid amide hydrolase (FAAH) activity.
BACKGROUND OF THE INVENTION
[0002] Medicinal benefits have been attributed to the cannabis
plant for centuries.
[0003] The primary bioactive constituent of cannabis is
.DELTA..sup.9-tetrahydro-cannabinol (THC). The discovery of THC
eventually led to the identification of two endogenous cannabinoid
receptors responsible for its pharmacological actions, namely
CB.sub.1 and CB.sub.2 (Goya, Exp. Opin. Ther. Patents 2000, 10,
1529). These discoveries not only established the site of action of
THC, but also inspired inquiries into the endogenous agonists of
these receptors, or "endocannabinoids". The first endocannabinoid
identified was the fatty acid amide anandamide (AEA). AEA itself
elicits many of the pharmacological effects of exogenous
cannabinoids (Piomelli, Nat. Rev. Neurosci. 2003, 4(11), 873).
[0004] The catabolism of AEA is primarily attributable to the
integral membrane bound protein fatty acid amide hydrolase (FAAH),
which hydrolyzes AEA to arachidonic acid. FAAH was characterized in
1996 by Cravatt and co-workers (Cravatt, Nature 1996, 384, 83). It
was subsequently determined that FAAH is additionally responsible
for the catabolism of a large number of important lipid signaling
fatty acid amides including: another major endocannabinoid,
2-arachidonoylglycerol (2-AG) (Science 1992, 258, 1946-1949); the
sleep-inducing substance, oleamide (OEA) (Science 1995, 268, 1506);
the appetite-suppressing agent, N-oleoylethanolamine (Rodriguez de
Fonesca, Nature 2001, 414, 209); and the anti-inflammatory agent,
palmitoylethanolamide (PEA) (Lambert, Curr. Med. Chem. 2002, 9(6),
663).
[0005] Small-molecule inhibitors of FAAH should elevate the
concentrations of these endogenous signaling lipids and thereby
produce their associated beneficial pharmacological effects. There
have been some reports of the effects of various FAAH inhibitors in
pre-clinical models.
[0006] In particular, two carbamate-based inhibitors of FAAH were
reported to have analgesic properties in animal models. In rats,
BMS-1 (see WO 02/087569), which has the structure shown below, was
reported to have an analgesic effect in the Chung spinal nerve
ligation model of neuropathic pain, and the Hargraves test of acute
thermal nociception. URB-597 was reported to have efficacy in the
zero plus maze model of anxiety in rats, as well as analgesic
efficacy in the rat hot plate and formalin tests (Kathuria, Nat.
Med. 2003, 9(1), 76). The sulfonylfluoride AM374 was also shown to
significantly reduce spasticity in chronic relapsing experimental
autoimmune encephalomyelitis (CREAE) mice, an animal model of
multiple sclerosis (Baker, FASEB J. 2001, 15(2), 300).
##STR00001##
[0007] In addition, the oxazolopyridine ketone OL-135 is reported
to be a potent inhibitor of FAAH, and has been reported to have
analgesic activity in both the hot plate and tail emersion tests of
thermal nociception in rats (WO 04/033652).
##STR00002##
[0008] Results of research on the effects of certain exogenous
cannabinoids has elucidated that a FAAH inhibitor may be useful for
treating various conditions, diseases, disorders, or symptoms.
These include pain, nausea/emesis, anorexia, spasticity, movement
disorders, epilepsy and glaucoma. To date, approved therapeutic
uses for cannabinoids include the relief of chemotherapy-induced
nausea and emesis among patients with cancer and appetite
enhancement in patients with HIV/AIDs who experience anorexia as a
result of wasting syndrome. Two products are commercially available
in some countries for these indications, namely, dronabinol
(Marinol.RTM.) and nabilone.
[0009] Apart from the approved indications, a therapeutic field
that has received much attention for cannabinoid use is analgesia,
i.e., the treatment of pain. Five small randomized controlled
trials showed that THC is superior to placebo, producing
dose-related analgesia (Robson, Br. J. Psychiatry 2001, 178,
107-115). Atlantic Pharmaceuticals is reported to be developing a
synthetic cannabinoid, CT-3, a 1,1-dimethyl heptyl derivative of
the carboxylic metabolite of tetrahydrocannabinol, as an orally
active analgesic and anti-inflammatory agent. A pilot phase II
trial in chronic neuropathic pain with CT-3 was reportedly
initiated in Germany in May 2002.
[0010] A number of individuals with locomotor activity-related
diseases, such as multiple sclerosis have claimed a benefit from
cannabis for both disease-related pain and spasticity, with support
from small controlled trials (Croxford et el., J. Neuroimmunol,
2008, 193, 120-9; Svendsen, Br. Med. J. 2004, 329, 253). Likewise,
various victims of spinal cord injuries, such as paraplegia, have
reported that their painful spasms are alleviated after smoking
marijuana. A report showing that cannabinoids appear to control
spasticity and tremor in the CREAE model of multiple sclerosis
demonstrated that these effects are mediated by CB.sub.1 and
CB.sub.2 receptors (Baker, Nature 2000, 404, 84-87). Phase 3
clinical trials have been undertaken in multiple sclerosis and
spinal cord injury patients with a narrow ratio mixture of
tetrahydrocannabinol/cannabidiol (THC/CBD). It has been reported
that FAAH knockout mice consistently recover to a better clinical
score than wild type controls, and this improvement is not a result
of anti-inflammatory activity, but erather may reflect some
neuroprotection or remyelination promoting effect of lack of the
enzyme (Webb et al, Neurosci Lett., 2008, vol. 439, 106-110).
[0011] Reports of small-scale controlled trials to investigate
other potential commercial uses of cannabinoids have been made.
Trials in volunteers have been reported to have confirmed that
oral, injected, and smoked cannabinoids produced dose-related
reductions in intraocular pressure (IOP) and therefore may relieve
glaucoma symptoms. Ophthalmologists have prescribed cannabis for
patients with glaucoma in whom other drugs have failed to
adequately control intraocular pressure (Robson, 2001, supra).
[0012] Inhibition of FAAH using a small-molecule inhibitor may be
advantageous compared to treatment with a direct-acting CB.sub.1
agonist. Administration of exogenous CB.sub.1 agonists may produce
a range of responses, including reduced nociception, catalepsy,
hypothermia, and increased feeding behavior. These four in
particular are termed the "cannabinoid tetrad." Experiments with
FAAH -/- mice show reduced responses in tests of nociception, but
did not show catalepsy, hypothermia, or increased feeding behavior
(Cravatt, Proc. Natl. Acad. Sci. USA 2001, 98(16), 9371). Fasting
caused levels of AEA to increase in rat limbic forebrain, but not
in other brain areas, providing evidence that stimulation of AEA
biosynthesis may be anatomically regionalized to targeted CNS
pathways (Kirkham, Br. J. Pharmacol. 2002, 136, 550). The finding
that AEA increases are localized within the brain, rather than
systemic, suggests that FAAH inhibition with a small molecule could
enhance the actions of AEA and other fatty acid amides in tissue
regions where synthesis and release of these signaling molecules is
occurring in a given pathophysiological condition (Piomelli, 2003,
supra).
[0013] In addition to the effects of a FAAH inhibitor on AEA and
other endocannabinoids, inhibitors of FAAH's catabolism of other
lipid mediators may be used in treating certain other therapeutic
indications. For example, PEA has demonstrated biological effects
in animal models of inflammation (Holt, et al. Br. J. Pharmacol.
2005, 146, 467-476), immunosuppression, analgesia, and
neuroprotection (Ueda, J. Biol. Chem. 2001, 276(38), 35552).
Oleamide, another substrate of FAAH, induces sleep (Boger, Proc.
Natl. Acad. Sci. USA 2000, 97(10), 5044; Mendelson,
Neuropsychopharmacology 2001, 25, S36). Inhibition of FAAH has also
been implicated in cognition (Varvel et al., J. Pharmacol. Exp.
Ther. 2006, 317(1), 251-257) and depression (Gobbi et al., Proc.
Natl. Acad. Sci. USA 2005, 102(51), 18620-18625).
[0014] Two additional indications for FAAH are supported by recent
data indicating that FAAH substrate activated receptors are
important in energy metabolism, and in bone homeostasis (Overton et
al., Br. J. Pharmacol. 2008, in press; and Plutzky, Diab. Vasc.
Dis. Res. 2007, 4 Suppl 3, S12-4). It has been shown that the
previously mentioned lipid signaling fatty acid amides catabolized
by FAAH, oleoylethanolamide (OEA), is one of the most active
agonists of the recently de-orphanised GPCR 119 (GPR119) (also
termed glucose dependent insulinotropic receptor). This receptor is
expressed predominantly in the pancreas in humans and activation
improves glucose homeostasis via glucose-dependent insulin release
in pancreatic beta-cells. GPR119 agonists can suppress glucose
excursions when administered during oral glucose tolerance tests,
and OEA has also been shown independently to regulate food intake
and body weight gain when administered to rodents, indicating a
probable benefit in energy metabolism disorders, such as insulin
resistance and diabetes. The FAAH substrate palmitoylethanolamide
(PEA) is an agonist at the PPARa receptor. Evidence from surrogate
markers in human studies with the PPARa agonist fenofibrate is
supportive of the concept that PPARa agonism offers the potential
for inducing a coordinated PPARa response that may improve
dyslipidaemia, repress inflammation and limit atherosclerosis in
patients with the metabolic syndrome or type 2 diabetes. The FAAH
substrate anandamide (AEA) is an agonist at the PPARy receptor.
Anandamide treatment induces 3T3-L1 differentiation into
adipocytes, as well as triglyceride droplet accumulation and
expression of adiponectin (Bouaboula et al., E. J. Pharmacol. 2005,
517, 174-181). Low dose cannabinoid therapy has been shown to
reduce atherosclerosis in mice, further suggesting a therapeutic
benefit of FAAH inhibition in dyslipidemia, liver steatosis,
steatohepatitis, obesity, and metabolic syndrome (Steffens et al.,
Nature, 2005, 434, 782-6).
[0015] Osteoporosis is one of the most common degenerative
diseases. It is characterized by reduced bone mineral density (BMD)
with an increased risk for bone fractures. CB.sub.2-deficient mice
have a markedly accelerated age-related trabecular bone loss and
cortical expansion. A CB.sub.2-selective agonism enhances
endocortical osteoblast number and activity and restrains
trabecular osteoclastogenesis and attenuates ovariectomy-induced
bone loss (Ofek et al., Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
696-701). There is a substantial genetic contribution to BMD,
although the genetic factors involved in the pathogenesis of human
osteoporosis are largely unknown. The applicability to human BMD is
suggested by genetic studies in which a significant association of
single polymorphisms and haplotypes was found encompassing the CNR2
gene on human chromosome 1p36, demonstrating a role for the
peripherally expressed CB.sub.2 receptor in the etiology of
osteoporosis (Karsak et al., Hum. Mol. Genet, 2005, 14,
3389-96).
[0016] Thus, small-molecule FAAH inhibitors should be useful in
treating pain of various etiologies, anxiety, multiple sclerosis
and other movement disorders, nausea/emesis, eating disorders,
epilepsy, glaucoma, inflammation, immunosuppression,
neuroprotection, depression, cognition enhancement, and sleep
disorders, and potentially with fewer side effects than treatment
with an exogenous cannabinoid.
[0017] A number of heteroaryl-substituted ureas have been reported
in various publications. Certain substituted thiophene ureas are
described in U.S. Pat. No. 6,881,741. Certain ureido-pyrazoles are
described in U.S. Pat. No. 6,387,900. Certain benzothiazole amide
derivatives are described in US Patent Publication US 2003/149036.
Certain ureas are reported as prenyltransferase inhibitors in WO
2003/047569. Piperidinyl ureas are described as histamine H.sub.3
receptor antagonists in U.S. Pat. No. 6,100,279. piperazinyl ureas
are disclosed as calcitonin mimetics in U.S. Pat. Nos. 6,124,299
and 6,395,740. Various ureas are reported as small-molecule FAAH
modulators in US Patent Publication Nos. US 2006/173184 and US
2007/0004741, in Intl. Patent Appl. Nos. WO 2008/023720, WO
2008/047229, and WO 2008/024139, and by Cravatt et al.
(Biochemistry 2007, 46(45), 13019. Ureas are described as
modulators of other targets in U.S. Pat. Appl. Publ. US
2007/270433, and in Intl. Pat. Appl. Publ. Nos. WO 2007/096251 and
WO 2006/085108. Certain piperidinyl ureas and piperazinyl ureas
have been previously described as FAAH modulators in U.S. Pat.
Appl. No. 60/931,920, filed May 25, 2007. However, there remains a
desire for potent FAAH modulators with suitable pharmaceutical
properties.
SUMMARY OF THE INVENTION
[0018] Certain heteroaryl-substituted piperidinyl urea derivatives
have been found to have FAAH-modulating activity. Thus, the
invention is directed to the general and preferred embodiments
defined, respectively, by the independent and dependent claims
appended hereto, which are incorporated by reference herein.
[0019] In one general aspect, the invention is directed to a
chemical entity of Formula (I):
##STR00003## [0020] Ar.sup.1 is mono- or fused bicyclic heteroaryl
group consisting of 5-10 ring atoms and having one heteroatom
selected from the group consisting of N, O and S, with a carbon
atom as point of ring attachment, and optionally having up to four
additional carbon ring atoms replaced with nitrogen, said
heteroaryl group having not more than five heteroatoms, each
heteroaryl group independently unsubstituted or substituted with
halo, --C.sub.1-4alkyl, --OC.sub.1-4alkyl, --OCF.sub.3, --CN, or
--CF.sub.3; [0021] Ar.sup.2 is [0022] (i) phenyl unsubstituted or
substituted with one or two R.sup.a moieties; [0023] where each
R.sup.a moiety is independently --C.sub.1-8alkyl,
--OC.sub.1-8alkyl, halo, --CF.sub.3, --OCF.sub.3,
--OCH.sub.2CF.sub.3, --S(O).sub.0-2C.sub.1-8alkyl,
--S(O).sub.0-2CF.sub.3, --CO.sub.2H, --N(R.sup.b)R.sup.c,
--SO.sub.2NR.sup.bR.sup.c, --NR.sup.bSO.sub.2R.sup.c,
--C(O)NR.sup.bR.sup.c, or --NO.sub.2; [0024] or two adjacent
R.sup.a moieties taken together form --O(CH.sub.2).sub.1-2O-- or
--OCF.sub.2O--; [0025] where R.sup.b and R.sup.c are each
independently --H or --C.sub.1-8alkyl, or optionally R.sup.b and
R.sup.c taken together with the atoms of attachment form a 4-8
membered ring; [0026] (ii) phenyl substituted at the 3- or
4-position with -L-Ar.sup.3, unsubstituted or substituted with one
or two R.sup.a moieties, wherein: [0027] L is a linker selected
from the group consisting of --(CH.sub.2).sub.1-6--, --CH.dbd.CH--,
--O--, --C.sub.1-6alkyl-O--C.sub.1-6alkyl-,
--C.sub.1-6alkyl-N(C.sub.1-6alkyl)-C.sub.1-6alkyl-,
--C.sub.1-6alkyl-S(O).sub.0-2C.sub.1-6alkyl-, --C.ident.C--,
--C(O)--, or a covalent bond; [0028] Ar.sup.3 is: [0029] (a) phenyl
unsubstituted or substituted with one or two R.sup.a moieties;
[0030] (b) a monocyclic heteroaryl group unsubstituted or
substituted with one or two R.sup.a moieties; or [0031] (c) a 9- or
10-membered fused bicyclic heteroaryl group unsubstituted or
substituted with one or two R.sup.a moieties; or [0032] (iii) a 9-
or 10-membered fused bicyclic heteroaryl having one heteroatom
selected from the group consisting of N, O, and S, and optionally
having up to four additional carbon ring atoms replaced with
nitrogen, said fused bicyclic heteroaryl having not more than five
heteroatoms, and unsubstituted or substituted with one, two or
three R.sup.a moieties; and pharmaceutically acceptable salts,
pharmaceutically acceptable prodrugs, and pharmaceutically active
metabolites of such compounds. In especially preferred embodiments,
the invention is directed to compounds described or exemplified in
the detailed description below and their pharmaceutically
acceptable salts.
[0033] In a further general aspect, the invention relates to
pharmaceutical compositions each comprising an effective amount of
at least one chemical entity selected from compounds of Formula
(I), pharmaceutically acceptable salts of compounds of Formula (I),
pharmaceutically acceptable prodrugs of compounds of Formula (I),
and pharmaceutically active metabolites of compounds of Formula
(I); and (b) a pharmaceutically acceptable excipient.
[0034] In another general aspect, the invention is directed to a
method of treating a subject suffering from or diagnosed with a
disease, disorder, or medical condition mediated by FAAH activity,
comprising administering to the subject in need of such treatment
an effective amount of at least one chemical entity selected from
compounds of Formula (I) and their pharmaceutically acceptable
salts, pharmaceutically active prodrugs, and pharmaceutically
active metabolites. In preferred embodiments of the inventive
method, the disease, disorder, or medical condition is selected
from: anxiety, depression, pain, sleep disorders, eating disorders,
inflammation, multiple sclerosis and other movement disorders, HIV
wasting syndrome, closed head injury, stroke, learning and memory
disorders, Alzheimer's disease, epilepsy, Tourette's syndrome,
Niemann-Pick disease, Parkinson's disease, Huntington's chorea,
optic neuritis, autoimmune uveitis, symptoms of drug withdrawal,
nausea, emesis, sexual dysfunction, post-traumatic stress disorder,
cerebral vasospasm, glaucoma, irritable bowel syndrome,
inflammatory bowel disease, immunosuppression, gastroesophageal
reflux disease, paralytic ileus, secretory diarrhea, gastric ulcer,
rheumatoid arthritis, unwanted pregnancy, hypertension, cancer,
hepatitis, allergic airway disease, auto-immune diabetes,
intractable pruritis, and neuroinflammation.
[0035] Additional embodiments, features, and advantages of the
invention will be apparent from the following detailed description
and through practice of the invention.
DETAILED DESCRIPTION OF INVENTION AND ITS PREFERRED EMBODIMENTS
[0036] The invention may be more fully appreciated by reference to
the following detailed description, including the following
glossary of terms and the concluding examples. For the sake of
brevity, the disclosures of the publications, including patents,
cited in this specification are herein incorporated by
reference.
[0037] As used herein, the terms "including", "containing" and
"comprising" are used in their open, non-limiting sense.
[0038] The term "alkyl" refers to a straight- or branched-chain
alkyl group having from 1 to 12 carbon atoms in the chain. Examples
of alkyl groups include methyl (Me, which also may be structurally
depicted by/symbol), ethyl (Et), n-propyl, isopropyl, butyl,
isobutyl, sec-butyl, tert-butyl (tBu), pentyl, isopentyl,
tert-pentyl, hexyl, isohexyl, and so on.
[0039] The term "alkenyl" refers to a straight- or branched-chain
alkenyl group having from 2 to 12 carbon atoms in the chain. (The
double bond of the alkenyl group is formed by two sp.sup.2
hybridized carbon atoms.) Illustrative alkenyl groups include
prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl,
hex-2-enyl, and so on.
[0040] The term "cycloalkyl" refers to a saturated or partially
saturated, monocyclic, fused polycyclic, or spiro polycyclic
carbocycle having from 3 to 12 ring atoms per carbocycle.
Illustrative examples of cycloalkyl groups include the following
entities, in the form of properly bonded moieties:
##STR00004##
[0041] A "heterocycloalkyl" refers to a monocyclic, or fused,
bridged, or spiro polycyclic ring structure that is saturated or
partially saturated and has from 3 to 12 ring atoms per ring
structure selected from carbon atoms and up to three heteroatoms
selected from nitrogen, oxygen, and sulfur. The ring structure may
optionally contain up to two oxo groups on carbon or sulfur ring
members. Illustrative examples of heterocycloalkyl groups include
the following entities, in the form of properly bonded
moieties:
##STR00005##
[0042] The term "heteroaryl" refers to a monocyclic, fused
bicyclic, or fused polycyclic aromatic heterocycle (ring structure
having ring atoms selected from carbon atoms and up to four
heteroatoms selected from nitrogen, oxygen, and sulfur) having from
3 to 12 ring atoms per heterocycle. Illustrative examples of
heteroaryl groups include the following entities, in the form of
properly bonded moieties:
##STR00006##
[0043] The term "halogen" represents chlorine, fluorine, bromine or
iodine. The term "halo" represents chloro, fluoro, bromo or
iodo.
[0044] The term "substituted" means that the specified group or
moiety bears one or more substituents. The term "unsubstituted"
means that the specified group bears no substituents. The term
"optionally substituted" means that the specified group is
unsubstituted or substituted by one or more substituents. Where the
term "substituted" is used to describe a structural system, the
substitution is meant to occur at any valency-allowed position on
the system. In cases where a specified moiety or group is not
expressly noted as being optionally substituted or substituted with
any specified substituent, it is understood that such a moiety or
group is intended to be unsubstituted.
[0045] A structural formula given herein is intended to represent
compounds having structures depicted by the formula as well as
equivalent variations or forms. For example, compounds encompassed
by Formula (I) may have asymmetric centers and therefore exist in
different enantiomeric forms. All optical isomers and stereoisomers
of the compounds of the general formula, and mixtures thereof, are
considered within the scope of the formula. Thus, a general formula
given herein is intended to represent a racemate, one or more
enantiomeric forms, one or more diastereomeric forms, one or more
atropisomeric forms, and mixtures thereof. Furthermore, certain
structures may exist as geometric isomers (i.e., cis and trans
isomers), as tautomers (e.g. pyrazole, benzimidazole, tetrazole, or
benzotriazole tautomers), or as atropisomers, which are intended to
be represented by the structural formula. Additionally, a formula
given herein is intended to embrace hydrates, solvates, and
polymorphs of such compounds, and mixtures thereof.
[0046] A structural formula given herein is also intended to
represent unlabeled forms as well as isotopically labeled forms of
the compounds. Isotopically labeled compounds have structures
depicted by the formulas given herein except that one or more atoms
are replaced by an atom having a selected atomic mass or mass
number. Examples of isotopes that can be incorporated into
compounds of the invention include isotopes of hydrogen, carbon,
nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as
.sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18O,
.sup.17O, .sup.32P, .sup.33P, .sup.35S, .sup.18F, .sup.36Cl, and
.sup.125I, respectively. Such isotopically labeled compounds are
useful in metabolic studies (preferably with .sup.14C), reaction
kinetic studies (with, for example .sup.2H or .sup.3H), detection
or imaging techniques [such as positron emission tomography (PET)
or single-photon emission computed tomography (SPECT)], including
drug or substrate tissue distribution assays, or in radioactive
treatment of patients. In particular, an .sup.18F- or
.sup.11C-labeled compound may be preferred for PET or SPECT
studies. Further, substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements. Isotopically
labeled compounds of this invention and prodrugs thereof can
generally be prepared by carrying out the procedures disclosed in
the schemes or in the examples and preparations described below by
substituting a readily available isotopically labeled reagent for a
non-isotopically labeled reagent.
[0047] When referring to any formula given herein, the selection of
a particular moiety from a list of possible species for a specified
variable is not intended to define the moiety for the variable
appearing elsewhere. In other words, where a formula variable
appears more than once, the choice of the species from a specified
list is independent of the choice of the species for the same
variable elsewhere in the formula.
[0048] In certain embodiments, Ar.sup.1 is
isoxazolo[5,4-c]pyridin-3-yl, isoxazolo[4,5-c]pyridin-3-yl,
isoxazolo[4,5-b]pyridin-3-yl, isoxazolo[5,4-b]pyridin-3-yl,
imidazo[1,2-a]pyridin-8-yl, imidazo[1,2-a]pyridin-7-yl,
imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl,
imidazo[1,2-b]pyridazin-3-yl, imidazo[1,2-a]pyridin-3-yl,
imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-7-yl,
imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-c]pyrimidin-7-yl,
benzooxazol-6-yl, 1H-indazol-7-yl, quinolin-8-yl, isoquinolin-5-yl,
isoquinolin-4-yl, 1,1-dioxo-1H-1A.sup.6-benzo[d]isothiazol-3-yl,
1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl,
1H-pyrrolo[3,2-b]pyridin-6-yl, 2-methyl-benzothiazol-6-yl,
1-isopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl,
2-methyl-benzooxazol-5-yl, 1H-indazol-7-yl,
1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl,
2-methyl-2H-indazol-4-yl, benzooxazole-2-yl group,
6-[1,2,3]triazol-1-yl-pyridin-3-yl,
6-[1,2,4]triazol-4-yl-pyridin-3-yl,
6-[1,2,4]triazol-1-yl-pyridin-3-yl,
6-[1,2,3]triazol-2-yl-pyridin-3-yl, 4-[1,2,3]triazol-2-yl-phenyl,
4-[1,2,3]triazol-1-yl-phenyl, 5-methyl-[1,3,4]oxadiazol-2-yl,
2-phenyl-pyrimidin-5-yl, 3-pyridyl, benzisoxazol-3-yl,
pyrimidin-4-yl, isoxazol-3-yl, 6-fluorobenzo[d]isoxazol-3-yl,
3-phenyl-[1,2,4]thiadiazol-5-yl, 1H-tetrazol-5-yl,
benzo[1,2,5]thiadiazol-4-yl, benzo[1,2,5]oxadiazol-4-yl,
thiophen-2-yl, thiophen-3-yl, 6-chloro-pyridazin-3-yl,
pyrazin-2-yl, 1H-benzotri azol-5-yl, [1,5]naphthyridin-2-yl,
benzothiazol-6-yl, or 1H-pyrazol-3-yl. In certain embodiments,
Ar.sup.1 is pyrimidine, isoxazole, benzisoxazole,
imidazo[1,2-b]pyridazine, or pyridine, wherein each group is
optionally substituted with one or two R.sup.a moieties.
[0049] In certain embodiments, Ar.sup.2 is phenyl substituted with
one or two R.sup.a moieties. In certain embodiments, Ar.sup.2 is
phenyl, substituted with one or two R.sup.a moieties wherein each
wherein each R.sup.a moiety is independently selected from the
group consisting of: chloro, cyano, isobutyl, methylsulfanyl,
methanesulfonyl, trifluoromethyl, trifluoromethoxy,
2,2,2-trifluoroethoxy, fluoro, methyl, methoxy, tert-butyl, bromo,
methoxycarbonyl, cyanomethyl, methoxycarbonylmethyl,
trifluoromethanesulfonyl, trifluoromethanesulfanyl, and butyl; or
two adjacent R.sup.a moieties taken together form --OCH.sub.2O-- or
--OCF.sub.2O--. In further embodiments, each R.sup.a moiety is
independently selected from the group consisting of: F, Cl, Br,
CF.sub.3, or two adjacent R.sup.a moieties taken together form
--OCF.sub.2O--.
[0050] In certain embodiments, Ar.sup.2 is phenyl substituted at
the 3- or 4-position with -L-Ar.sup.3, unsubstituted or substituted
with one or two R.sup.a moieties. In further embodiments, Ar.sup.2
is phenyl substituted at the 3- or 4-position with -L-Ar.sup.3,
unsubstituted or substituted with one or two R.sup.a moieties and
wherein L is --CH.sub.2CH.sub.2--, --O--, --OCH.sub.2--, or
--C.ident.C--. In further embodiments, L is --O--. In further
embodiments, L is phenyl, unsubstituted or substituted with one or
two R.sup.a moieties and each R.sup.a moiety is independently
selected from the group consisting of: chloro, cyano, isobutyl,
methylsulfanyl, methanesulfonyl, trifluoromethyl, trifluoromethoxy,
2,2,2-trifluoroethoxy, fluoro, methyl, methoxy, tert-butyl, bromo,
methoxycarbonyl, cyanomethyl, methoxycarbonylmethyl,
trifluoromethanesulfonyl, trifluoromethanesulfanyl, and butyl; or
two adjacent R.sup.a moieties taken together form --OCH.sub.2O-- or
--OCF.sub.2O--. In certain preferred embodiments, each R.sup.a
moiety is independently fluoro.
[0051] In a further embodiment, Ar.sup.2 is a 9- or 10-membered
fused bicyclic heteroaryl having one heteroatom selected from the
group consisting of N, O, and S, and optionally having up to four
additional carbon ring atoms replaced with nitrogen, said fused
bicyclic heteroaryl having not more than five heteroatoms, and
unsubstituted or substituted with one, two or three R.sup.a
moieties. In one embodiment, Ar.sup.2 is a 9- or 10-membered fused
bicyclic heteroaryl having one heteroatom selected from the group
consisting of N, O, and S, with a carbon atom as point of ring
attachment, and optionally having up to four additional carbon ring
atoms replaced with nitrogen, said fused bicyclic heteroaryl having
not more than five heteroatoms, and unsubstituted or substituted
with one, two or three R.sup.a moieties. In still further preferred
embodiments, Ar.sup.2 is a benzimidazolyl, indazolyl,
benzothiophenyl, quinolinyl, indolyl, or benzofuranyl group. In a
further embodiment Ar.sup.2 is quinolinyl.
[0052] The invention also relates to pharmaceutically acceptable
salts of the free acids or bases represented by compounds in Table
1, preferably of the preferred embodiments described above and of
the specific compounds exemplified herein. The therapeutic
compositions and methods of the invention may employ
pharmaceutically acceptable salts of the free acids or bases
represented by compounds in Table 1, preferably of the preferred
embodiments described above and of the specific compounds
exemplified herein. A "pharmaceutically acceptable salt" is
intended to mean a salt of a free acid or base of a compound
represented by Formula (I) that is non-toxic, biologically
tolerable, or otherwise biologically suitable for administration to
the subject. See, generally, S. M. Berge, et al., "Pharmaceutical
Salts", J. Pharm. Sci., 1977, 66:1-19, and Handbook of
Pharmaceutical Salts, Properties, Selection, and Use, Stahl and
Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002.
[0053] Preferred pharmaceutically acceptable salts are those that
are pharmacologically effective and suitable for contact with the
tissues of patients without undue toxicity, irritation, or allergic
response. A compound from Table 1 may possess a sufficiently acidic
group, a sufficiently basic group, or both types of functional
groups, and accordingly react with a number of inorganic or organic
bases, and inorganic and organic acids, to form a pharmaceutically
acceptable salt. Examples of pharmaceutically acceptable salts
include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrogen-phosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, propionates, decanoates, caprylates, acrylates, formates,
isobutyrates, caproates, heptanoates, propiolates, oxalates,
malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates,
methyl benzoates, dinitrobenzoates, hydroxybenzoates,
methoxybenzoates, phthalates, sulfonates, xylenesulfonates,
phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, .gamma.-hydroxybutyrates, glycolates, tartrates,
methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,
naphthalene-2-sulfonates, and mandelates.
[0054] If the compound in Table 1 contains a basic nitrogen, the
desired pharmaceutically acceptable salt may be prepared by any
suitable method available in the art, for example, by treatment of
the free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric
acid, phosphoric acid, and the like; or with an organic acid, such
as acetic acid, phenylacetic acid, propionic acid, stearic acid,
lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid,
isethionic acid, succinic acid, valeric acid, fumaric acid, malonic
acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,
oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such
as mandelic acid, citric acid, or tartaric acid; an amino acid,
such as aspartic acid or glutamic acid; an aromatic acid, such as
benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic
acid; a sulfonic acid, such as laurylsulfonic acid,
p-toluenesulfonic acid, methanesulfonic acid, or ethanesulfonic
acid; or any compatible mixture of acids such as those given as
examples herein.
[0055] If the compound in Table 1 is an acid such as a carboxylic
acid or sulfonic acid, the desired pharmaceutically acceptable salt
may be prepared by any suitable method, for example, by treatment
of the free acid with an inorganic or organic base, such as an
amine (primary, secondary or tertiary), an alkali metal hydroxide,
alkaline earth metal hydroxide, or any compatible mixture of bases
such as those given as examples herein. Illustrative examples of
suitable salts include organic salts derived from amino acids, such
as glycine and arginine, ammonia, carbonates, bicarbonates,
primary, secondary, and tertiary amines, and cyclic amines, such as
benzylamines, pyrrolidines, piperidine, morpholine, and piperazine,
and inorganic salts derived from sodium, calcium, potassium,
magnesium, manganese, iron, copper, zinc, aluminum, and
lithium.
[0056] The invention also relates to pharmaceutically acceptable
prodrugs of the compounds of Table 1. The term "prodrug" means a
precursor of a designated compound that, following administration
to a subject, yields the compound in vivo via a chemical or
physiological process such as solvolysis or enzymatic cleavage, or
under physiological conditions (e.g., a prodrug on being brought to
physiological pH is converted to the compound of Table 1). A
"pharmaceutically acceptable prodrug" is a prodrug that is
non-toxic, biologically tolerable, and otherwise biologically
suitable for administration to the subject. Illustrative procedures
for the selection and preparation of suitable prodrug derivatives
are described, for example, in "Design of Prodrugs", ed. H.
Bundgaard, Elsevier, 1985.
[0057] Examples of prodrugs include compounds having an amino acid
residue, or a polypeptide chain of two or more (e.g., two, three or
four) amino acid residues, covalently joined through an amide or
ester bond to a free amino, hydroxy, or carboxylic acid group of a
compound of Formula (I). Examples of amino acid residues include
the twenty naturally occurring amino acids, commonly designated by
three letter symbols, as well as 4-hydroxyproline, hydroxylysine,
demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,
gamma-aminobutyric acid, citrulline homocysteine, homoserine,
ornithine and methionine sulfone.
[0058] Additional types of prodrugs may be produced, for instance,
by derivatizing free carboxyl groups of structures of compounds of
Table 1 as amides or alkyl esters. Examples of amides include those
derived from ammonia, primary C.sub.1-6alkyl amines and secondary
di(C.sub.1-6alkyl) amines. Secondary amines include 5- or
6-membered heterocycloalkyl or heteroaryl ring moieties. Examples
of amides include those that are derived from ammonia,
C.sub.1-3alkyl primary amines, and di(C.sub.1-2alkyl)amines.
Examples of esters of the invention include C.sub.1-7alkyl,
C.sub.5-7cycloalkyl, phenyl, and phenyl(C.sub.1-6alkyl) esters.
Preferred esters include methyl esters. Prodrugs may also be
prepared by derivatizing free hydroxy groups using groups including
hemisuccinates, phosphate esters, dimethylaminoacetates, and
phosphoryloxymethyloxycarbonyls, following procedures such as those
outlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19,
115-130. Carbamate derivatives of hydroxy and amino groups may also
yield prodrugs. Carbonate derivatives, sulfonate esters, and
sulfate esters of hydroxy groups may also provide prodrugs.
Derivatization of hydroxy groups as (acyloxy)methyl and
(acyloxy)ethyl ethers, wherein the acyl group may be an alkyl
ester, optionally substituted with one or more ether, amine, or
carboxylic acid functionalities, or where the acyl group is an
amino acid ester as described above, is also useful to yield
prodrugs. Prodrugs of this type may be prepared as described in
Robinson et al., J. Med. Chem. 1996, 39, 10-18. Free amines can
also be derivatized as amides, sulfonamides or phosphonamides. All
of these prodrug moieties may incorporate groups including ether,
amine, and carboxylic acid functionalities.
[0059] The present invention also relates to pharmaceutically
active metabolites of compounds of Table 1. A "pharmaceutically
active metabolite" means a pharmacologically active product of
metabolism in the body of a compound of Table 1 or salt thereof.
Prodrugs and active metabolites of a compound may be determined
using routine techniques known or available in the art. See, e.g.,
Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al.,
J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe, Drug Dev. Res.
1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13, 255-331;
Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen,
Design and Application of Prodrugs, Drug Design and Development
(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers,
1991).
[0060] The compounds of Table 1, and their pharmaceutically
acceptable salts, pharmaceutically acceptable prodrugs, and
pharmaceutically active metabolites (collectively, "active agents")
of the present invention are useful as FAAH inhibitors in the
methods of the invention. The active agents may be used in the
inventive methods for the treatment of medical conditions,
diseases, or disorders mediated through inhibition or modulation of
FAAH, such as those described herein. Active agents according to
the invention may therefore be used as an analgesic,
anti-depressant, cognition enhancer, neuroprotectant, sedative,
appetite stimulant, or contraceptive.
[0061] Exemplary medical conditions, diseases, and disorders
mediated by FAAH activity include anxiety, depression, pain, sleep
disorders, eating disorders, inflammation, multiple sclerosis and
other movement disorders, HIV wasting syndrome, closed head injury,
stroke, learning and memory disorders, Alzheimer's disease,
epilepsy, Tourette's syndrome, epilepsy, Niemann-Pick disease,
Parkinson's disease, Huntington's chorea, optic neuritis,
autoimmune uveitis, symptoms of drug withdrawal, nausea, emesis,
sexual dysfunction, post-traumatic stress disorder, cerebral
vasospasm, diabetes, metabolic syndrome and osteoporosis.
[0062] Thus, the active agents may be used to treat subjects
diagnosed with or suffering from such a disease, disorder, or
condition. The term "treat" or "treating" as used herein is
intended to refer to administration of an agent or composition of
the invention to a subject for the purpose of effecting a
therapeutic benefit through modulation of FAAH activity. Treating
includes reversing, ameliorating, alleviating, inhibiting the
progress of, lessening the severity of, reducing the incidence of,
or preventing a disease, disorder, or condition, or one or more
symptoms of such disease, disorder or condition mediated through
modulation of FAAH activity. The term "subject" refers to a
mammalian patient in need of such treatment, such as a human.
"Modulators" include both inhibitors and activators, where
"inhibitors" refer to compounds that decrease, prevent, inactivate,
desensitize or down-regulate FAAH expression or activity, and
"activators" are compounds that increase, activate, facilitate,
sensitize, or up-regulate FAAH expression or activity.
[0063] Accordingly, the invention relates to methods of using the
active agents described herein to treat subjects diagnosed with or
suffering from a disease, disorder, or condition mediated through
FAAH activity, such as: anxiety, pain, sleep disorders, eating
disorders, inflammation, movement disorders (e.g., multiple
sclerosis), energy metabolism (e.g. insulin resistance, diabetes,
dyslipidemia, liver steatosis, steatohepatitis, obesity, and
metabolic syndrome) and bone homeostasis (e.g. osteoporosis).
[0064] Symptoms or disease states are intended to be included
within the scope of "medical conditions, disorders, or diseases."
For example, pain may be associated with various diseases,
disorders, or conditions, and may include various etiologies.
[0065] Illustrative types of pain treatable with a FAAH-modulating
agent, in one example herein a FAAH-inhibiting agent, according to
the invention include cancer pain, postoperative pain, GI tract
pain, spinal cord injury pain, visceral hyperalgesia, thalamic
pain, headache (including stress headache and migraine), low back
pain, neck pain, musculoskeletal pain, peripheral neuropathic pain,
central neuropathic pain, neurogenerative disorder related pain,
and menstrual pain. HIV wasting syndrome includes associated
symptoms such as appetite loss and nausea. Parkinson's disease
includes, for example, levodopa-induced dyskinesia. Treatment of
multiple sclerosis may include treatment of symptoms such as
spasticity, neurogenic pain, central pain, or bladder dysfunction.
Symptoms of drug withdrawal may be caused by, for example,
addiction to opiates or nicotine. Nausea or emesis may be due to
chemotherapy, postoperative, or opioid related causes. Treatment of
sexual dysfunction may include improving libido or delaying
ejaculation. Treatment of cancer may include treatment of glioma.
Sleep disorders include, for example, sleep apnea, insomnia, and
disorders calling for treatment with an agent having a sedative or
narcotic-type effect. Eating disorders include, for example,
anorexia or appetite loss associated with a disease such as cancer
or HIV infection/AIDS.
[0066] In treatment methods according to the invention, an
effective amount of at least one active agent according to the
invention is administered to a subject suffering from or diagnosed
as having such a disease, disorder, or condition. A
"therapeutically effective amount" or "effective amount" means an
amount or dose of a FAAH-modulating agent sufficient to generally
bring about a therapeutic benefit in patients in need of treatment
for a disease, disorder, or condition mediated by FAAH activity.
Effective amounts or doses of the active agents of the present
invention may be ascertained by routine methods such as modeling,
dose escalation studies or clinical trials, and by taking into
consideration routine factors, e.g., the mode or route of
administration or drug delivery, the pharmacokinetics of the agent,
the severity and course of the disease, disorder, or condition, the
subject's previous or ongoing therapy, the subject's health status
and response to drugs, and the judgment of the treating physician.
An exemplary dose is in the range of from about 0.0001 to about 200
mg of active agent per kg of subject's body weight per day,
preferably about 0.001 to 100 mg/kg/day, or about 0.01 to 35
mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divided
dosage units (e.g., BID, TID, QID). For a 70-kg human, an
illustrative range for a suitable dosage amount is from about 0.05
to about 7 g/day, or about 0.2 to about 5 g/day. Once improvement
of the patient's disease, disorder, or condition has occurred, the
dose may be adjusted for maintenance treatment. For example, the
dosage or the frequency of administration, or both, may be reduced
as a function of the symptoms, to a level at which the desired
therapeutic effect is maintained. Of course, if symptoms have been
alleviated to an appropriate level, treatment may cease. Patients
may, however, require intermittent treatment on a long-term basis
upon any recurrence of symptoms.
[0067] In addition, the active agents of the invention may be used
in combination with additional active ingredients in the treatment
of the above conditions. The additional active ingredients may be
coadministered separately with an active agent of compounds of
Table 1 or included with such an agent in a pharmaceutical
composition according to the invention. In an exemplary embodiment,
additional active ingredients are those that are known or
discovered to be effective in the treatment of conditions,
disorders, or diseases mediated by FAAH activity, such as another
FAAH modulator or a compound active against another target
associated with the particular condition, disorder, or disease. The
combination may serve to increase efficacy (e.g., by including in
the combination a compound potentiating the potency or
effectiveness of an active agent according to the invention),
decrease one or more side effects, or decrease the required dose of
the active agent according to the invention. In one illustrative
embodiment, a composition according to the invention may contain
one or more additional active ingredients selected from opioids,
NSAIDs (e.g., ibuprofen, cyclooxygenase-2 (COX-2) inhibitors, and
naproxen), gabapentin, pregabalin, tramadol, acetaminophen, and
aspirin.
[0068] The active agents of the invention are used, alone or in
combination with one or more additional active ingredients, to
formulate pharmaceutical compositions of the invention. A
pharmaceutical composition of the invention comprises: (a) an
effective amount of at least one active agent in accordance with
the invention; and (b) a pharmaceutically acceptable excipient.
[0069] A "pharmaceutically acceptable excipient" refers to a
substance that is non-toxic, biologically tolerable, and otherwise
biologically suitable for administration to a subject, such as an
inert substance, added to a pharmacological composition or
otherwise used as a vehicle, carrier, or diluent to facilitate
administration of a agent and that is compatible therewith.
Examples of excipients include calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils, and polyethylene glycols.
[0070] Delivery forms of the pharmaceutical compositions containing
one or more dosage units of the active agents may be prepared using
suitable pharmaceutical excipients and compounding techniques known
or that become available to those skilled in the art. The
compositions may be administered in the inventive methods by a
suitable route of delivery, e.g., oral, parenteral, rectal,
topical, or ocular routes, or by inhalation.
[0071] The preparation may be in the form of tablets, capsules,
sachets, dragees, powders, granules, lozenges, powders for
reconstitution, liquid preparations, or suppositories. Preferably,
the compositions are formulated for intravenous infusion, topical
administration, or oral administration.
[0072] For oral administration, the active agents of the invention
can be provided in the form of tablets or capsules, or as a
solution, emulsion, or suspension. To prepare the oral
compositions, the active agents may be formulated to yield a dosage
of, e.g., from about 5 mg to 5 g daily, or from about 50 mg to 5 g
daily, in single or divided doses. For example, a total daily
dosage of about 5 mg to 5 g daily may be accomplished by dosing
once, twice, three, or four times per day.
[0073] Oral tablets may include the active ingredient(s) mixed with
compatible pharmaceutically acceptable excipients such as diluents,
disintegrating agents, binding agents, lubricating agents,
sweetening agents, flavoring agents, coloring agents and
preservative agents. Suitable inert fillers include sodium and
calcium carbonate, sodium and calcium phosphate, lactose, starch,
sugar, glucose, methyl cellulose, magnesium stearate, mannitol,
sorbitol, and the like. Exemplary liquid oral excipients include
ethanol, glycerol, water, and the like. Starch,
polyvinyl-pyrrolidone (PVP), sodium starch glycolate,
microcrystalline cellulose, and alginic acid are exemplary
disintegrating agents. Binding agents may include starch and
gelatin. The lubricating agent, if present, may be magnesium
stearate, stearic acid or talc. If desired, the tablets may be
coated with a material such as glyceryl monostearate or glyceryl
distearate to delay absorption in the gastrointestinal tract, or
may be coated with an enteric coating.
[0074] Capsules for oral administration include hard and soft
gelatin capsules. To prepare hard gelatin capsules, active
ingredient(s) may be mixed with a solid, semi-solid, or liquid
diluent. Soft gelatin capsules may be prepared by mixing the active
ingredient with water, an oil such as peanut oil or olive oil,
liquid paraffin, a mixture of mono and di-glycerides of short chain
fatty acids, polyethylene glycol 400, or propylene glycol.
[0075] Liquids for oral administration may be in the form of
suspensions, solutions, emulsions or syrups or may be lyophilized
or presented as a dry product for reconstitution with water or
other suitable vehicle before use. Such liquid compositions may
optionally contain: pharmaceutically-acceptable excipients such as
suspending agents (for example, sorbitol, methyl cellulose, sodium
alginate, gelatin, hydroxyethylcellulose, carboxymethylcellulose,
aluminum stearate gel and the like); non-aqueous vehicles, e.g.,
oil (for example, almond oil or fractionated coconut oil),
propylene glycol, ethyl alcohol, or water; preservatives (for
example, methyl or propyl p-hydroxybenzoate or sorbic acid);
wetting agents such as lecithin; and, if desired, flavoring or
coloring agents.
[0076] The active agents of this invention may also be administered
by non-oral routes. For example, compositions may be formulated for
rectal administration as a suppository. For parenteral use,
including intravenous, intramuscular, intraperitoneal, or
subcutaneous routes, the agents of the invention may be provided in
sterile aqueous solutions or suspensions, buffered to an
appropriate pH and isotonicity or in parenterally acceptable oil.
Suitable aqueous vehicles include Ringer's solution and isotonic
sodium chloride. Such forms may be presented in unit-dose form such
as ampules or disposable injection devices, in multi-dose forms
such as vials from which the appropriate dose may be withdrawn, or
in a solid form or pre-concentrate that can be used to prepare an
injectable formulation. Illustrative infusion doses range from
about 1 to 1000 .mu.g/kg/minute of agent admixed with a
pharmaceutical carrier over a period ranging from several minutes
to several days.
[0077] For topical administration, the agents may be mixed with a
pharmaceutical carrier at a concentration of about 0.1% to about
10% of drug to vehicle. Another mode of administering the agents of
the invention may utilize a patch formulation to affect transdermal
delivery.
[0078] Active agents may alternatively be administered in methods
of this invention by inhalation, via the nasal or oral routes,
e.g., in a spray formulation also containing a suitable
carrier.
[0079] Exemplary active agents useful in methods of the invention
will now be described by reference to illustrative synthetic
schemes for their general preparation below and the specific
examples that follow. Artisans will recognize that, to obtain the
various compounds herein, starting materials may be suitably
selected so that the ultimately desired substituents will be
carried through the reaction scheme with or without protection as
appropriate to yield the desired product. Alternatively, it may be
necessary or desirable to employ, in the place of the ultimately
desired substituent, a suitable group that may be carried through
the reaction scheme and replaced as appropriate with the desired
substituent. Unless otherwise specified, the variables are as
defined above in reference to Formula (I).
##STR00007##
[0080] Referring to Scheme A, a carbamate of formula (IV) may be
obtained by reacting a compound of formula (II) with a compound of
formula (III), in which Q.sup.1 represents an aryl group, under
chloroformate condensation conditions. Preferably, Q.sup.1 is
substituted or unsubstituted phenyl, and the reaction occurs with
or without a base, in a solvent such as acetonitrile, at a
temperature from about 0.degree. C. to about 80.degree. C. More
preferably, Q.sup.1 is phenyl, and the reaction occurs in pyridine
at room temperature ("rt"), or in acetonitrile at 50.degree. C.
without added base.
##STR00008##
[0081] Referring to Scheme B, a compound of formula (VI) is
obtained by reacting a compound of formula (V) with a compound of
formula (IV) under aryl carbamate condensation conditions. The
reaction may preferably take place in a solvent at a temperature
from about rt to about 120.degree. C. Preferably, Q.sup.1 is
phenyl, and the reaction is performed in dimethylsulfoxide (DMSO)
in a microwave reactor at about 100.degree. C. or by conventional
heating from about rt to about 50.degree. C.
##STR00009##
[0082] Intermediate compounds of formula (IX) are prepared
according to Scheme C. Hydrometallation of an alkenyl compound
(VII) gives an activated species, which is subsequently reacted
with a suitable reagent Ar.sup.2-HAL (where HAL is chloride,
bromide, or iodide) to provide a compound (IX). Preferably,
hydrometallation is accomplished by hydroboration using a suitable
dialkylborane reagent such as 9-borabicyclo[3.3.1]nonane (9-BBN) or
diisopinocampheylborane, in a solvent such as THF. The resulting
boron adduct is preferably reacted with compounds of formula (VIII)
in the presence of a suitable palladium catalyst, a base such as
K.sub.2CO.sub.3 or Cs.sub.2CO.sub.3, in a solvent such as
N,N-dimethylformamide (DMF) or an aqueous mixture thereof. When
Q.sup.3 is a suitable protecting group, then compounds of formula
(IX) can be converted into compounds of formula (V) using suitable
deprotection conditions.
[0083] Compounds of Table 1 may be converted to their corresponding
salts by applying general techniques described in the art. For
example, a compound of Table 1 may be treated with trifluoroacetic
acid, HCl, or citric acid in a solvent such as Et.sub.20,
1,4-dioxane, dichloromethane (DCM), tetrahydrofuran (THF), or MeOH
to provide the corresponding salt forms.
[0084] Compounds prepared according to the schemes described above
may be obtained as single enantiomers, diastereomers, or
regioisomers, by enantio-, diastero-, or regio-specific synthesis,
or by resolution. Compounds prepared according to the schemes above
may alternatively be obtained as racemic (1:1) or non-racemic (not
1:1) mixtures or as mixtures of diastereomers or regioisomers.
Where racemic and non-racemic mixtures of enantiomers are obtained,
single enantiomers may be isolated using conventional separation
methods, such as chiral chromatography, recrystallization,
diastereomeric salt formation, derivatization into diastereomeric
adducts, biotransformation, or enzymatic transformation. Where
regioisomeric or diastereomeric mixtures are obtained, single
isomers may be separated using conventional methods such as
chromatography or crystallization.
[0085] The following specific examples are provided to further
illustrate the invention and various preferred embodiments.
EXAMPLES
Chemistry
[0086] In preparing the examples listed below, the following
general experimental and analytical methods were used.
[0087] Reaction mixtures were stirred under a nitrogen atmosphere
at rt unless otherwise noted. Where solutions or mixtures are
concentrated, they are typically concentrated under reduced
pressure using a rotary evaporator. Where solutions are dried, they
are typically dried over a drying agent such as MgSO.sub.4 or
Na.sub.2SO.sub.4, unless otherwise noted.
[0088] Microwave reactions were carried out in either a CEM
Discover.RTM. or a Biotage Initiator.TM. Microwave at specified
temperatures.
[0089] Normal phase flash column chromatography (FCC) was performed
on silica gel columns using ethyl acetate (EtOAc)/hexanes as
eluent, unless otherwise indicated.
[0090] Reversed-Phase High Performance Liquid Chromatography (HPLC)
was performed using: Shimadzu instrument with a Phenomenex Gemini
column 5 .mu.m C18 (150.times.21.2 mm) or Waters Xterra RP18 OBD
column 5 .mu.m (100.times.30 mm), a gradient of 95:5 to 0:100 water
(0.05% TFA)/CH.sub.3CN (0.05% TFA), a flow rate of 80 mL/min, and
detection at 254 nM.
[0091] Mass spectra were obtained on an Agilent series 1100 MSD
using electrospray ionization (ESI) in positive mode unless
otherwise indicated.
[0092] NMR spectra were obtained on either a Bruker model DPX400
(400 MHz), DPX500 (500 MHz) or DRX600 (600 MHz) spectrometer. The
format of the .sup.1H NMR data below is: chemical shift in ppm down
field of the tetramethylsilane reference (multiplicity, coupling
constant J in Hz, integration).
[0093] Chemical names were generated using ChemDraw Ultra 6.0.2
(CambridgeSoft Corp., Cambridge, Mass.) or ACD/Name Version 9
(Advanced Chemistry Development, Toronto, Ontario, Canada).
Intermediate 1: Isoxazolo[5,4-c]pyridin-3-ylamine
##STR00010##
[0095] To a solution of 3-chloro-isonicotinitrile (1.13 g, 8.36
mmol) in DMF (6.0 mL) were added potassium carbonate (1.69 g, 12.2
mmol) and acetohydroxamic acid (0.91 g, 12.2 mmol). The reaction
mixture was stirred at rt overnight, diluted with EtOAc (200 mL)
and extracted with saturated aqueous NaHCO.sub.3 (200 mL) then
saturated aqueous NaCl (100 mL). The aqueous layers were back
extracted with EtOAc (200 mL) and the combined organic layers were
dried (MgSO.sub.4) and concentrated. The crude residue was purified
(FCC, 2 N NH.sub.3 in MeOH/DCM) to give
isoxazolo[5,4-c]pyridin-3-ylamine (0.447 g, 41%). MS (ESI.sup.+):
calcd for C.sub.6H.sub.5N.sub.3O m/z 135.04. found 136.2
(M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO): 8.93 (d, J=0.8, 1H), 8.45
(d, J=5.2, 1H), 7.88-7.86 (dd, J=5.2, 1.2, 1H), 6.72 (br s,
2H).
[0096] Intermediates 2 and 3 were prepared using methods analogous
to those described for intermediate 1 with the stated changes to
reagents described below.
Intermediate 2: Isoxazolo[4,5-c]pyridin-3-ylamine
##STR00011##
[0098] The title compound was prepared using methods analogous to
those described for intermediate 1 except 4-chloro-3-cyanopyridine
was the starting material. MS (ESI.sup.+): calcd for
C.sub.6H.sub.5N.sub.3O m/z 135.04. found 136.2 (M+H).sup.+. .sup.1H
NMR (d.sub.6-DMSO): 9.09 (d, J=1.0, 1H), 8.57 (d, J=5.9, 1H), 7.53
(dd, J=5.9, 1.0, 1H), 6.77 (br s, 2H).
Intermediate 3: Isoxazolo[4,5-b]pyridin-3-ylamine
##STR00012##
[0100] The title compound was prepared using methods analogous to
those described for intermediate 1 except 3-chloro-2-cyanopyridine
was the starting material. MS (ESI.sup.+): calcd for
C.sub.6H.sub.5N.sub.3O m/z 135.04, 136.2 (M+H).sup.+. .sup.1H NMR
(d.sub.6-DMSO): 8.58 (dd, J=4.5, 1.1, 1H), 7.98 (dd, J=8.5, 1.1,
1H), 7.57 (dd, J=8.5, 4.5, 1H), 6.55 (br s, 2H).
Intermediate 4: Imidazo[1,2-a]pyridin-8-ylamine
##STR00013##
[0102] To a solution of 50% aqueous chloroacetaldehyde (4.14 mL,
32.6 mmol) were added sodium bicarbonate (3.19 g, 40.0 mmol) and
2,3-diaminopyridine (3.56 g, 32.6 mmol). The reaction mixture was
stirred at rt overnight, then diluted with saturated aqueous NaCl
(100 mL) and extracted with n-butanol (3.times.200 mL). The organic
layers were combined, dried (MgSO.sub.4), and concentrated. The
crude residue was purified (FCC, 2 N NH.sub.3 in MeOH/DCM) to give
imidazo[1,2-a]pyridin-8-ylamine (2.18 g, 51%). MS (ESI.sup.+):
calcd for C.sub.7H.sub.7N.sub.3 m/z 133.06. found 134.1
(M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO): 7.79-7.75 (m, 2H), 7.40
(d, J=1.1, 1H), 6.60 (s, 1H), 6.21 (dd, J=7.3, 1.1, 1H), 5.53 (br
s, 2H).
Intermediate 5: Imidazo[1,2-a]pyridin-7-ylamine
##STR00014##
[0104] Intermediate 5 was prepared using methods analogous to those
described for intermediate 4 except 2,4-diaminopyridine was the
starting material. MS (ESI.sup.+): calcd for C.sub.7H.sub.7N.sub.3
m/z 133.06. found 134.1 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO):
8.13-8.10 (m, 1H), 7.48 (s, 1H), 7.15 (s, 1H), 6.36-6.33 (m, 2H),
5.52 (br s, 2H).
Intermediate 6: Imidazo[1,2-a]pyridin-5-ylamine
##STR00015##
[0106] To a solution of 2,6-diaminopyridine (5.00 g, 45.8 mmol) in
1:1 H.sub.2O:EtOH (10 mL) were added sodium bicarbonate (5.00 g,
59.5 mmol) and chloroacetaldehyde (4.31 g, 27.5 mmol). The reaction
mixture was heated to 70.degree. C. overnight, then cooled to rt,
diluted with saturated aqueous NaCl (100 mL), and extracted with
n-butanol (3.times.200 mL). The organic layers were combined, dried
(MgSO.sub.4), and concentrated. The crude residue was purified
(FCC, 2 N NH.sub.3 in MeOH/DCM) to give
imidazo[1,2-a]pyridin-5-ylamine (1.32 g, 22%). MS (ESI.sup.+):
calcd for C.sub.7H.sub.7N.sub.3 m/z 133.06. found 134.1
(M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO): 8.23-8.21 (m, 1H), 7.91
(d, J=1.3, 1H), 7.50 (dd, J=8.8, 7.4, 1H), 7.22 (d, J=8.8, 1H),
6.97 (br s, 2H), 6.37 (dd, J=7.4, 0.9, 1H).
[0107] Intermediates 7 to 9 were prepared using methods analogous
to those described for intermediate 6 with the stated changes to
reagents described below.
Intermediate 7: Imidazo[1,2-a]pyrimidin-7-ylamine
##STR00016##
[0109] Intermediate 7 was prepared using methods analogous to those
described for Intermediate 6 except 2,4-diaminopyrimidine was the
starting material. MS (ESI.sup.+): calcd for C.sub.6H.sub.6N.sub.4
m/z 134.06. found 135.1 (M-FH).sup.+. .sup.1H NMR
(d.sub.4-methanol): 8.27 (d, J=7.2, 1H), 7.31 (d, J=1.8, 1H), 7.18
(d, J=1.8, 1H), 6.35 (d, J=7.2, 1H).
Intermediate 8: Imidazo[1,2-a]pyrimidin-5-ylamine
##STR00017##
[0111] Intermediate 8 was prepared using methods analogous to those
described for intermediate 6 except 2,4-diaminopyrimidine was the
starting material. MS (ESI.sup.+): calcd for C.sub.6H.sub.6N.sub.4
m/z 134.06. found 135.1 (M+H).sup.+. .sup.1H NMR
(d.sub.4-methanol): 8.41 (d, J=5.4, 1H), 7.72 (d, J=1.8, 1H), 7.55
(d, J=1.8, 1H), 6.17 (d, J=5.4, 1H).
Intermediate 9: Imidazo[1,2-c]pyrimidin-7-ylamine
##STR00018##
[0113] Intermediate 9 was prepared using methods analogous to those
described for intermediate 6 except 4,6-diaminopyrimidine was the
starting material. MS (ESI.sup.+): calcd for C.sub.6H.sub.6N.sub.4
m/z 134.06. found 135.1 (M-FH).sup.+. .sup.1H NMR (d.sub.6-DMSO):
9.80 (s, 1H), 8.39 (s, 1H), 8.03 (s, 1H), 7.01 (s, 1H), 6.90 (s,
2H).
[0114] Intermediates 10 to 18 were prepared by treatment of the
appropriate aminoheterocycle intermediate with 1 equivalent of
phenylchloroformate in dry CH.sub.3CN and 1 equivalent of pyridine.
The reagents were stirred at rt for 4 h, diluted with EtOAc, washed
with NaHCO.sub.3, and dried over MgSO.sub.4. The material was
purified by FCC to provide pure phenyl carbamate intermediates.
Intermediate 10: Imidazo[1,2-a]pyridin-8-yl-carbamic acid phenyl
ester
##STR00019##
[0116] MS (ESI.sup.+): calcd for C.sub.14H.sub.11N.sub.3O.sub.2 m/z
253.09. found 254.1 (M+H).sup.+.
Intermediate 11: Imidazo[1,2-a]pyridin-3-yl-carbamic acid phenyl
ester
##STR00020##
[0118] MS (ESI.sup.+): calcd for C.sub.14H.sub.11N.sub.3O.sub.2 m/z
253.09. found 254.1 (M+H).sup.+.
Intermediate 12: Imidazo[1,2-a]pyridin-2-yl-carbamic acid phenyl
ester
##STR00021##
[0120] MS (ESI.sup.+): calcd for C.sub.14H.sub.11N.sub.3O.sub.2 m/z
253.09. found 254.1 (M+H).sup.+.
Intermediate 13: (1H-Indazol-7-yl)-carbamic acid phenyl ester
##STR00022##
[0122] MS (ESI.sup.+): calcd for C.sub.14H.sub.11N.sub.3O.sub.2 m/z
253.09. found 254.3 (M+H).sup.+.
Intermediate 14: Quinolin-8-yl-carbamic acid phenyl ester
##STR00023##
[0124] MS (ESI.sup.+): calcd for C.sub.16E1.sub.12N.sub.2O.sub.2
m/z 264.09. found 265.1 (M+1-1.sup.+).
Intermediate 15: Isoquinolin-5-yl-carbamic acid phenyl ester
##STR00024##
[0126] MS (ESI.sup.+): calcd for C.sub.16H.sub.12N.sub.2O.sub.2 m/z
264.09. found 265.1 (M-FH).sup.+.
Intermediate 16: Isoquinolin-4-yl-carbamic acid phenyl ester
##STR00025##
[0128] MS (ESI.sup.+): calcd for C.sub.16H.sub.12N.sub.2O.sub.2 m/z
264.09. found 265.1 (M-FH).sup.+.
Intermediate 17: (1H-Pyrrolo[2,3-b]pyridin-4-yl)-carbamic acid
phenyl ester
##STR00026##
[0130] MS (ESI.sup.+): calcd for C.sub.14H.sub.11N.sub.3O.sub.2 m/z
253.09. found 254.1 (M-FH).sup.+.
Intermediate 18: (1H-Pyrrolo[3,2-b]pyridin-6-yl)-carbamic acid
phenyl ester
##STR00027##
[0132] MS (ESI.sup.+): calcd for C.sub.14H.sub.11N.sub.3O.sub.2 m/z
253.09. found 254.1 (M-FH).sup.+.
Intermediate 19: Imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl
ester
##STR00028##
[0134] To a solution of imidazo[1,2-b]pyridazin-3-ylamine (209 mg,
1.56 mmol) in dry DMF (5.0 mL) was added pyridine (382 .mu.L, 4.68
mmol) and phenyl chloroformate (244 mg, 1.56 mmol). After 3 h at
rt, the mixture was diluted with EtOAc (100 mL) and washed with
saturated aqueous NaHCO.sub.3 (50 mL). The organic layer was dried
(MgSO.sub.4) and concentrated. The residue was purified (FCC) to
give imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl ester (285
mg, 72%). MS (ESI.sup.+): calcd for C.sub.13H.sub.10N.sub.4O.sub.2
m/z 254.08. found 255.3 (M-FH).sup.+.
Intermediate 20: Isoxazolo[5,4-c]pyridin-3-yl-carbamic acid phenyl
ester
##STR00029##
[0136] To a suspension of isoxazolo[5,4-c]pyridin-3-ylamine (1.49
g, 11.0 mmol) in CH.sub.3CN (50 mL) was added phenyl chloroformate
(0.696 mL, 5.50 mmol). The reaction mixture was heated at
70.degree. C. overnight, then cooled to rt, diluted with H.sub.2O
(100 mL) and saturated aqueous NaHCO.sub.3 (10 mL). The resulting
yellow precipitate was filtered and dried under vacuum to give
isoxazolo[5,4-c]pyridin-3-yl-carbamic acid phenyl ester (1.099 g,
39%). MS (ESI.sup.+): calcd for C.sub.13H.sub.9N.sub.3O.sub.3 m/z
255.06. found 256.1 (M+H).sup.+.
[0137] Intermediates 21 to 23 were prepared using methods analogous
to those described for Intermediate 20.
Intermediate 21: Isoxazolo[5,4-b]pyridin-3-yl-carbamic acid phenyl
ester
##STR00030##
[0139] MS (ESI.sup.+): calcd for C.sub.13H.sub.9N.sub.3O.sub.3 m/z
255.06. found 256.1 (M+H).sup.+.
Intermediate 22: Isoxazolo[4,5-c]pyridin-3-yl-carbamic acid phenyl
ester
##STR00031##
[0141] MS (ESI.sup.+): calcd for C.sub.13H.sub.9N.sub.3O.sub.3 m/z
255.06. found 256.1 (M+H).sup.+.
Intermediate 23: Isoxazolo[4,5-b]pyridin-3-yl-carbamic acid phenyl
ester
##STR00032##
[0143] MS (ESI.sup.+): calcd for C.sub.13H.sub.9N.sub.3O.sub.3 m/z
255.06. found 256.1 (M+H).sup.+.
Example 1
3-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide
##STR00033##
[0144] Step A:
3-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester
[0145] 1-Boc-3-methylene piperidine (842 mg, 4.27 mmol) was
degassed (neat) for 15 minutes and then treated with a THF solution
of 9-BBN (0.5 M in THF, 8.6 mL, 4.3 mmol). The reaction mixture was
refluxed for 2 h, then cooled to rt. The reaction mixture was then
added, via cannula, to a preformed solution of
5-bromo-2,2-difluoro-1,3-benzodioxole (1.00 g, 4.22 mmol),
Pd(dppf)Cl.sub.2--CH.sub.2Cl.sub.2 (94 mg, 0.128 mmol), and
potassium carbonate (746 mg, 5.40 mmol) in DMF/H.sub.2O (10 mL/1
mL). The resultant mixture was heated at 60.degree. C. for 18 h,
cooled to rt, poured into water, basified to pH 11 with 1 N NaOH,
and extracted with EtOAc (3.times.). The organic layers were
combined, dried (Na.sub.2SO.sub.4), and concentrated. The crude
residue was purified (FCC) to give
3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester (1.00 g, 67%).
Step B: 3-[(2,2-Difluoro-1,3-benzodioxol-5-yl)methyl]-piperidine
hydrochloride
[0146] To a solution of
3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid tert-butyl ester (1.0 g, 2.8 mmol) in CH.sub.2Cl.sub.2 (11 mL)
was added HCl (4 M in dioxane, 4.2 mL, 16.9 mmol). The reaction
mixture was stirred at r.t. overnight and then concentrated to give
3-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-piperidine as the
hydrochloride salt (791 mg, 96%). The crude product was used
without further purification.
Step C:
3-(2,2-Difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxyl-
ic acid pyridin-3-ylamide
[0147] To a solution of
3-[(2,2-difluoro-1,3-benzodioxol-5-yl)methyl]-piperidine
hydrochloride (100 mg, 0.34 mmol) in CH.sub.3CN (2 mL) was added
Et.sub.3N (0.07 mL, 0.52 mmol). To this reaction mixture,
pyridin-3-yl-carbamic acid phenyl ester (77.0 mg, 1.05 mmol) was
added and the reaction mixture was heated overnight at 35.degree.
C. The reaction mixture was then concentrated and the crude residue
was purified (FCC, 2 N NH.sub.3 in MeOH/DCM) to give
3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic
acid pyridin-3-ylamide (120 mg, 93%). MS (ESI.sup.+): calcd for
C.sub.19H.sub.19F.sub.2N.sub.3O.sub.3 m/z 375.14. found 376.2
(M+H).sup.+. .sup.1H NMR (d.sub.4-methanol): 8.54 (d, J=2.3, 1H),
8.17-8.13 (m, 1H), 7.86 (ddd, J=8.4, 2.6, 1.4, 1H), 7.34-7.30 (m,
1H), 7.10-7.06 (m, 2H), 6.99 (dd, J=8.2, 1.5, 1H), 4.05-3.95 (m,
2H), 3.04-2.98 (m, 1H), 2.74-2.64 (m, 2H), 2.58-2.53 (m, 1H),
1.86-1.74 (m, 3H), 1.56-1.47 (m, 1H), 1.30-1.22 (m, 1H).
[0148] The compounds in Examples 2 to 9 were prepared using methods
analogous to those described in Example 1.
Example 2
N-Pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxa-
mide
##STR00034##
[0150] .sup.1H NMR (d.sub.4-methanol): 8.76 (d, J=1.0, 1H), 8.53
(d, J=6.0, 1H), 8.00 (dd, J=1.5, 6.0, 1H), 7.57 (d, J=8.0, 2H),
7.37 (br s, 1H), 7.28 (d, J=8.0, 2H), 4.04 (d, J=12.5, 1H), 3.90
(d, J=12.5, 1H), 3.75-3.02 (m, 1H), 2.74-2.70 (m, 2H), 2.56 (dd,
J=8, 13.5, 1H), 1.96-1.75 (m, 3H), 1.57-1.47 (m, 1H), 1.30-1.18 (m,
1H).
Example 3
N-Pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxa-
mide
##STR00035##
[0152] MS (ESI.sup.+): calcd for C.sub.18H.sub.19F.sub.3N.sub.4O
m/z 364.15. found 365.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3): 8.76
(d, J=1.0, 1H), 8.53 (d, J=5.5, 1H), 8.00 (dd, J=1.5, 6.0, 1H),
7.50 (d, J=7.5, 1H), 7.43-7.42 (m, 2H), 7.38-7.35 (m, 2H), 4.04 (d,
J=12.5, 1H), 3.90 (d, J=12.5, 1H), 3.07-3.01 (m, 1H), 2.76-2.70 (m,
2H), 2.56 (dd, J=8.0, 13.5, 1H), 1.97-1.75 (m, 3H), 1.57-1.46 (m,
1H), 1.29-1.19 (m, 1H).
Example 4
3-[(4-Fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide
##STR00036##
[0154] .sup.1H NMR (CDCl.sub.3): 8.76 (d, J=1.0, 1H), 8.52 (d,
J=6.0, 1H), 8.00 (dd, J=1.0, 6.0, 1H), 7.40 (br s, 1H), 7.11-7.10
(m, 2H), 7.01-6.97 (m, 2H), 3.99 (d, J=12.5, 1H), 3.91 (d, J=12.5,
1H), 3.04-2.99 (m, 1H), 2.69-2.63 (m, 1H), 2.62 (dd, J=6.5, 14.0,
1H), 2.49 (dd, J=7.5, 14.0, 1H), 1.87-1.71 (m, 3H), 1.56-1.44 (m,
1H), 1.29-1.14 (m, 1H).
Example 5
N-1,2-Benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}-piperidine-
-1-carboxamide
##STR00037##
[0156] .sup.1H NMR (CDCl.sub.3): 9.04 (s, 1H), 8.05 (d, J=8.5, 1H),
7.58-7.54 (m, 3H), 7.45 (d, J=8.5, 1H), 7.33-7.28 (m, 3H),
4.21-4.14 (m, 2H), 3.09-3.05 (m, 1H), 2.84-2.75 (m, 2H), 2.56 (dd,
J=8.0, 13.5, 1H), 1.99-1.91 (m, 1H), 1.88-1.76 (m, 2H), 1.64-1.50
(m, 1H), 1.30-1.17 (m, 1H).
Example 6
N-1,2-Benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}-piperidine-
-1-carboxamide
##STR00038##
[0158] MS (ESI.sup.+): calcd for
C.sub.21H.sub.20F.sub.3N.sub.3O.sub.2 m/z 403.15. found 404.2
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3): 9.02 (s, 1H), 8.06 (d,
J=8.5, 1H), 7.57-7.54 (m, 1H), 7.48-7.45 (m, 3H), 7.41-7.36 (m,
2H), 7.31-7.28 (m, 1H), 4.20 (d, J=10.5, 1H), 4.15 (d, J=11.5, 1H),
3.10-3.05 (m, 1H), 2.83-2.79 (m, 2H), 2.55 (dd, J=8.5, 13.5, 1H),
1.99-1.90 (m, 1H), 1.87-1.77 (m, 2H), 1.64-1.51 (m, 1H), 1.29-1.17
(m, 1H).
Example 7
N-1,2-Benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamide
##STR00039##
[0160] MS (ESI.sup.+): calcd for C.sub.20H.sub.20FN.sub.3O.sub.2
m/z 353.15. found 354.2 (M+H).sup.+. .sup.1H NMR (CDCl.sub.3): 8.50
(s, 1H), 8.06 (d, J=8.0, 1H), 7.55-7.52 (m, 1H), 7.45 (d, J=8.5,
1H), 7.29-7.28 (m, 1H), 7.14-7.12 (m, 2H), 7.00-6.96 (m, 2H),
4.17-4.10 (m, 2H), 3.10-3.04 (m, 1H), 2.79-2.76 (m, 1H), 2.70 (dd,
J=6.5, 13.5, 1H), 1.94-1.75 (m, 3H), 1.68-1.52 (m, 1H), 1.28-1.15
(m, 1H).
Example 8
N-Isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxam-
ide
##STR00040##
[0162] .sup.1H NMR (CDCl.sub.3): 8.93 (s, 1H), 8.21 (d, J=2.0, 1H),
7.55 (d, J=8.0, 2H), 7.28 (d, J=8.0, 2H), 7.05 (d, J=2.0, 1H), 4.12
(d, J=12.0, 1H), 4.03 (d, J=13.0, 1H), 3.04-2.99 (m, 1H), 2.77-2.72
(m, 2H), 2.54 (dd, J=8.5, 13.5, 1H), 1.94 (br s, 1H), 1.86-1.73 (m,
2H), 1.59-1.45 (m, 1H), 1.29-1.15 (m, 1H).
Example 9
N-Isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxam-
ide
##STR00041##
[0164] MS (ESI.sup.+): calcd for
C.sub.17H.sub.18F.sub.3N.sub.3O.sub.3 m/z 353.14. found 354.2
(M+H).sup.+. .sup.1H NMR (CDCl.sub.3): 9.01 (s, 1H), 8.20 (d,
J=2.0, 1H), 7.48 (d, J=7.5, 1H), 7.44-7.39 (m, 2H), 7.34 (d, J=7.5,
1H), 7.03 (d, J=2.0, 1H), 4.14 (d, J=13.0, 1H), 4.05 (d, J=13.0,
1H), 3.04-2.99 (m, 1H), 2.78-2.70 (m, 2H), 2.55-2.50 (m, 1H),
1.90-1.86 (m, 1H), 1.82-1.75 (m, 2H), 1.61-1.43 (m, 1H), 1.28-1.16
(m, 1H).
Example 10
3-[3-(4-Fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide
##STR00042##
[0165] Step A: 3-(4-Fluoro-phenoxy)-bromobenzene
[0166] To a solution of 1-bromo-3-iodo-benzene (1.00 g, 3.55 mmol),
4-fluorophenol (462 mg, 3.59 mmol), N,N-dimethylglycine
hydrochloride (149 mg, 1.06 mmol), and cesium carbonate (2.28 g,
7.00 mmol) in DMA was added CuI (66.8 mg, 0.351 mmol). The reaction
mixture was heated at 90.degree. C. for 48 h, cooled to rt, and
then poured into water and extracted with EtOAc (3.times.). The
organic layers were combined, dried (Na.sub.2SO.sub.4), and
concentrated. The crude residue was purified (FCC) to give the
title compound as a colorless oil (319 mg, 32%).
Step B: 3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic
acid tert-butyl ester
[0167] The title compound was prepared using methods analogous to
those described in Example 1, Step A.
Step C: 3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine
hydrochloride
[0168] The title compound was prepared using methods analogous to
those described in Example 1, Step B.
Step D:
3-[3-(4-Fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxami-
de
[0169] The title compound was prepared using methods analogous to
those described in Example 1, Step C. MS (ESI.sup.+): calcd for
C.sub.24H.sub.24FN.sub.3O.sub.2 m/z 405.18. found 406.2
(M-FH).sup.+. .sup.1H NMR (d.sub.4-methanol): 8.54-8.53 (m, 1H),
8.15 (dd, J=4.8, 1.4, 1H), 7.87 (ddd, J=8.4, 2.6, 1.4, 1H),
7.34-7.31 (m, 1H), 7.25 (t, J=7.9, 1H), 7.08-7.03 (m, 2H),
7.00-6.94 (m, 3H), 6.83-6.81 (m, 1H), 6.79-6.77 (m, 1H), 4.05-4.01
(m, 1H), 4.00-3.95 (m, 1H), 3.03-2.95 (m, 1H), 2.69 (dd, J=13.2,
10.1, 1H), 2.64-2.60 (m, 1H), 2.53-2.48 (m, 1H), 1.85-1.71 (m, 3H),
1.55-1.46 (m, 1H), 1.29-1.21 (m, 1H).
[0170] The compounds in Examples 11 to 15 were prepared using
methods analogous to those described in Example 10.
Example 11
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-chloro-pyridin-3-yl)-amide
##STR00043##
[0172] MS (ESI.sup.+): calcd for C.sub.24H.sub.23ClFN.sub.3O.sub.2
m/z 439.14. found 440.2 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO):
8.58 (s, 1H), 8.34 (s, 1H), 8.28 (d, J=5.3, 1H), 7.56 (d, J=5.3,
1H), 7.29 (t, J=7.8, 1H), 7.22-7.14 (m, 2H), 7.07-7.01 (m, 2H),
6.97 (d, J=7.6, 1H), 6.86-6.82 (m, 1H), 6.82-6.76 (m, 1H), 3.93 (d,
J=13.2, 2H), 2.95-2.87 (m, 1H), 2.68-2.43 (m, 3H), 1.78-1.59 (m,
3H), 1.47-1.29 (m, 1H), 1.23-1.07 (m, 1H).
Example 12
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-b]pyridazin-3-ylamide
##STR00044##
[0174] MS (ESI.sup.+): calcd for C.sub.25H.sub.24FN.sub.5O.sub.2
m/z 445.19. found 446.2 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO):
8.80 (s, 1H), 8.64-8.61 (m, 1H), 8.16 (dd, J=9.2, 1.4, 1H), 7.78
(s, 1H), 7.34 (dd, J=9.2, 4.5, 1H), 7.29 (t, J=7.8, 1H), 7.21-7.14
(m, 2H), 7.07-7.01 (m, 2H), 6.98 (d, J=7.6, 1H), 6.87-6.83 (m, 1H),
6.82-6.77 (m, 1H), 3.97 (d, J=12.9, 2H), 2.91 (s, 1H), 2.70-2.44
(m, 3H), 1.81-1.59 (m, 3H), 1.41 (m, 1H), 1.24-1.12 (m, 1H).
[0175] Examples 13 and 14 were resolved using chiral column
chromatography: Jasco Preparative SFC System using a Phenomenex Lux
II column (5 .mu.m 250.times.21 mm, L.times.I.D.) @ 40.degree. C.,
150 bar, 8.3 mL/min ethanol with 0.2% triethylamine and 33.3 mL/min
CO.sub.2, detection at 220 nm. Retention times: Example 13,
(+)-enantiomer: 33-38 minutes; Example 14, (-)-enantiomer: 42-48
minutes.
Example 13
(+)-3-[3-(4-Chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00045##
[0177] MS (ESI.sup.+): calcd for C.sub.24H.sub.24ClN.sub.3O.sub.2
m/z 421.16. found 422.2 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO):
8.64-8.58 (m, 2H), 8.13 (dd, J=4.6, 1.5, 1H), 7.86-7.81 (m, 1H),
7.40 (d, J=9.0, 2H), 7.32 (t, J=7.8, 1H), 7.24 (dd, J=8.3, 4.7,
1H), 7.05-6.98 (m, 3H), 6.91-6.88 (m, 1H), 6.88-6.84 (m, 1H),
4.01-3.92 (m, 2H), 2.90-2.82 (m, 1H), 2.63-2.43 (m, 3H), 1.75-1.61
(m, 3H), 1.45-1.31 (m, 1H), 1.22-1.07 (m, 1H);
[.alpha.].sup.23.sub.D+22.4 (c 0.15, MeOH).
Example 14
(-)-3-[3-(4-Chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00046##
[0179] MS (ESI.sup.+): calcd for C.sub.24H.sub.24ClN.sub.3O.sub.2
m/z 421.16. found 422.2 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO):
8.64-8.58 (m, 2H), 8.13 (dd, J=4.6, 1.5, 1H), 7.86-7.81 (m, 1H),
7.40 (d, J=9.0, 2H), 7.32 (t, J=7.8, 1H), 7.24 (dd, J=8.3, 4.7,
1H), 7.05-6.98 (m, 3H), 6.91-6.88 (m, 1H), 6.88-6.84 (m, 1H),
4.01-3.92 (m, 2H), 2.90-2.82 (m, 1H), 2.63-2.43 (m, 3H), 1.75-1.61
(m, 3H), 1.45-1.31 (m, 1H), 1.22-1.07 (m, 1H);
[.alpha.].sup.23.sub.D-22.0 (c 0.15, MeOH).
Example 15
3-[3-(4-Trifluorormethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridine-3-ylamide
##STR00047##
[0181] MS (ESI.sup.+): calcd for
C.sub.25H.sub.24F.sub.3N.sub.3O.sub.3 m/z 471.18. found 472.2
(M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO): 8.35 (br s, 1H), 8.27 (br
s, 1H), 7.99-7.95 (m, 1H), 7.31-7.27 (m, 1H), 7.24-7.20 (m, 1H),
7.19-7.15 (m, 2H), 6.99 (d, J=9.1, 2H), 6.95 (d, J=7.5, 1H),
6.88-6.84 (m, 2H), 6.26 (s, 1H), 3.94-3.88 (m, 1H), 3.87-3.82 (m,
1H), 3.09-3.01 (m, 1H), 2.69 (dd, J=13.2, 9.8, 1H), 2.62 (dd,
J=13.8, 7.2, 1H), 2.54 (dd, J=13.8, 7.0, 1H), 1.92-1.83 (m, 2H),
1.81-1.74 (m, 1H), 1.59-1.50 (m, 1H), 1.29-1.20 (m, 1H).
[0182] The compounds in Examples 16 to 19 were prepared using
methods analogous to those described in Example 1.
Example 16
3-Quinolin-3-ylmethyl-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00048##
[0184] MS (ESI.sup.+): calcd for C.sub.21H.sub.22N.sub.4O m/z
346.18. found 347.2 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO): 8.77
(d, J=2.2, 1H), 8.36 (d, J=2.5, 1H), 8.26 (dd, J=4.7, 1.3, 1H),
8.09 (d, J=8.5, 1H), 7.96-7.91 (m, 2H), 7.76 (dd, J=8.2, 1.0, 1H),
7.71-7.66 (m, 1H), 7.56-7.51 (m, 1H), 7.21 (dd, J=8.3, 4.7, 1H),
6.33 (s, 1H), 4.08-4.01 (m, 1H), 3.89-3.81 (m, 1H), 3.11-3.02 (m,
1H), 2.87 (dd, J=13.9, 6.7, 1H), 2.81-2.67 (m, 2H), 2.06-1.95 (m,
1H), 1.92-1.84 (m, 1H), 1.84-1.75 (m, 1H), 1.61-1.49 (m, 1H),
1.35-1.24 (m, 1H).
Example 17
3-(3,4-Dichloro-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00049##
[0186] MS (ESI.sup.+): calcd for C.sub.18H.sub.19Cl.sub.2N.sub.3O
m/z 363.09. found 364.1 (M+H).sup.+. .sup.1H NMR (d.sub.6-DMSO):
8.39 (d, J=2.4, 1H), 8.27 (dd, J=4.7, 1.4, 1H), 7.95 (ddd, J=8.4,
2.6, 1.5, 1H), 7.36 (d, J=8.2, 1H), 7.27 (s, 1H), 7.22 (dd, J=8.3,
4.7, 1H), 7.01 (dd, J=8.2, 2.0, 1H), 6.28 (s, 1H), 4.00-3.93 (m,
1H), 3.87-3.80 (m, 1H), 3.08-3.00 (m, 1H), 2.67 (dd, J=13.2, 10.0,
1H), 2.64-2.57 (m, 1H), 2.48 (dd, J=13.8, 7.4, 1H), 1.90-1.73 (m,
3H), 1.60-1.48 (m, 1H), 1.27-1.16 (m, 1H).
Example 18
3-(3-Trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00050##
[0188] MS (ESI.sup.+): calcd for
C.sub.19H.sub.20F.sub.3N.sub.3O.sub.2 m/z 379.15. found 380.2
(M-FH).sup.+. .sup.1H NMR (d.sub.6-DMSO): 8.36 (d, J=2.5, 1H), 8.26
(dd, J=4.7, 1.3, 1H), 7.95 (ddd, J=8.3, 2.5, 1.4, 1H), 7.32 (t,
J=7.9, 1H), 7.22 (dd, J=8.3, 4.7, 1H), 7.12-7.07 (m, 2H), 7.02 (s,
1H), 6.34 (s, 1H), 3.98-3.92 (m, 1H), 3.91-3.84 (m, 1H), 3.06-2.98
(m, 1H), 2.72-2.64 (m, 2H), 2.54 (dd, J=13.7, 7.5, 1H), 1.92-1.81
(m, 2H), 1.80-1.74 (m, 1H), 1.59-1.49 (m, 1H), 1.28-1.18 (m,
1H).
Example 19
3-(4-Trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00051##
[0190] MS (ESI.sup.+): calcd for
C.sub.19H.sub.20F.sub.3N.sub.3O.sub.2 m/z 379.15. found 380.2
(M-FH).sup.+. .sup.1H NMR (d.sub.6-DMSO): 8.37 (d, J=2.4, 1H), 8.26
(dd, J=4.7, 1.4, 1H), 7.94 (ddd, J=8.4, 2.6, 1.5, 1H), 7.24-7.12
(m, 5H), 6.32 (s, 1H), 3.98-3.91 (m, 1H), 3.89-3.81 (m, 1H),
3.08-2.99 (m, 1H), 2.73-2.62 (m, 2H), 2.52 (dd, J=13.8, 7.3, 1H),
1.91-1.73 (m, 3H), 1.60-1.48 (m, 1H), 1.29-1.16 (m, 1H).
[0191] The compounds in Examples 20 to 23 can be synthesized using
the synthetic schemes given in Example 10.
Example 20
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(1H-Pyrrolo[2,3-b]pyridin-4-yl)-amide
##STR00052##
[0192] Example 21
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[4,5-c]pyridin-3-ylamide
##STR00053##
[0193] Example 22
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoxazolo[5,4-c]pyridin-3-ylamide
##STR00054##
[0194] Example 23
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-8-ylamide
##STR00055##
[0195] Example 24
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-7-ylamide
##STR00056##
[0197] To a solution consisting of 1 equivalent of
imidazo[1,2-a]pyridin-7-ylamine in CH.sub.2Cl.sub.2 is added 1
equivalent of N,N'-disuccinimidyl carbonate and 1 equivalent of
4-dimethylaminopyridine (DMAP). The reaction mixture is stirred at
rt for 6 h, then treated with 1 equivalent of
3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine hydrochloride and 2
equivalents of diisopropylethylamine and stirred for an additional
16 h at rt. The reaction mixture is diluted with EtOAc and
extracted with H.sub.2O then saturated aqueous NaCl. The organic
layer is dried (MgSO.sub.4) and concentrated. The crude residue is
purified (FCC, 2 N NH.sub.3 in MeOH/DCM) to give
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-7-ylamide.
[0198] The compounds in Examples 25 to 28 can be synthesized using
the synthetic scheme given in Example 24.
Example 25
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyridin-5-ylamide
##STR00057##
[0199] Example 26
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-7-ylamide
##STR00058##
[0200] Example 27
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-a]pyrimidin-5-ylamide
##STR00059##
[0201] Example 28
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
imidazo[1,2-c]pyrimidin-7-ylamide
##STR00060##
[0203] The compounds in Examples 29 to 32 can be synthesized using
the synthetic schemes given in Example 10.
Example 29
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
(4-cyano-pyridin-3-yl)-amide
##STR00061##
[0204] Example 30
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
quinolin-8-ylamide
##STR00062##
[0205] Example 31
3-[3-(4-Fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid
isoquinolin-5-ylamide
##STR00063##
[0206] Example 32
3-[3-(4-Trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic
acid pyridin-3-ylamide
##STR00064##
[0208] The compound in Example 33 can be synthesized using the
synthetic schemes given in Example 1.
Example 33
3-(4-Chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid
pyridin-3-ylamide
##STR00065##
[0209] Biological Testing:
[0210] Assay Method 1
[0211] A. Transfection of Cells with Human FAAH
[0212] A 10-cm tissue culture dish with a confluent monolayer of
SK-N-MC cells was split 2 days (d) prior to transfection. Using
sterile technique, the media was removed and the cells were
detached from the dish by the addition of trypsin. One fifth of the
cells were then placed onto a new 10-cm dish. Cells were grown in a
37.degree. C. incubator with 5% CO.sub.2 in Minimal Essential Media
Eagle with 10% Fetal Bovine Serum. After 2 d, cells were
approximately 80% confluent. These cells were removed from the dish
with trypsin and pelleted in a clinical centrifuge. The pellet was
re-suspended in 400 .mu.L complete media and transferred to an
electroporation cuvette with a 0.4 cm gap between the electrodes.
Supercoiled human FAAH cDNA (1 .mu.g) was added to the cells and
mixed. The voltage for the electroporation was set at 0.25 kV, and
the capacitance was set at 960 .mu.F. After electroporation, the
cells were diluted into complete media (10 mL) and plated onto four
10-cm dishes. Because of the variability in the efficiency of
electroporation, four different concentrations of cells were
plated. The ratios used were 1:20, 1:10, and 1:5, with the
remainder of the cells being added to the fourth dish. The cells
were allowed to recover for 24 h before adding the selection media
(complete media with 600 .mu.g/mL G418). After 10 d, dishes were
analyzed for surviving colonies of cells. Dishes with well-isolated
colonies were used. Cells from individual colonies were isolated
and tested. The clones that showed the most FAAH activity, as
measured by anandamide hydrolysis, were used for further study.
[0213] B. FAAH Assay
[0214] T84 frozen cell pellets or transfected SK-N-MC cells
(contents of 1.times.15 cm culture dishes) were homogenized in 50
mL of FAAH assay buffer (125 mM Tris, 1 mM EDTA, 0.2% Glycerol,
0.02% Triton X-100, 0.4 mM Hepes, pH 9). The assay mixture
consisted of 50 .mu.L of the cell homogenate, 10 .mu.L of the test
compound, and 40 .mu.L of anandamide [1-.sup.3H-ethanolamine]
(.sup.3H-AEA, Perkin-Elmer, 10.3 C.sub.i/mmol), which was added
last, for a final tracer concentration of 80 nM. The reaction
mixture was incubated at rt for 1 h. During the incubation, 96-well
Multiscreen filter plates (catalog number MAFCNOB50; Millipore,
Bedford, Mass., USA) were loaded with 254 of activated charcoal
(Multiscreen column loader, catalog number MACL09625, Millipore)
and washed once with 100 .mu.L of MeOH. Also during the incubation,
96-well DYNEX MicroLite plates (catalog number NL510410) were
loaded with 100 .mu.L of MicroScint40 (catalog number 6013641,
Packard Bioscience, Meriden, Conn., USA). After the 1 h incubation,
60 .mu.L of the reaction mixture were transferred to the charcoal
plates, which were then assembled on top of the DYNEX plates using
Centrifuge Alignment Frames (catalog number MACF09604, Millipore).
The unbound labeled ethanolamine was centrifuged through to the
bottom plate (5 min at 2000 rpm), which was preloaded with the
scintillant, as described above. The plates were sealed and left at
rt for 1 h before counting on a Hewlett Packard TopCount.
[0215] Assay Method 2
[0216] A. Transfection of Cells with Rat FAAH
[0217] A 10-cm tissue culture dish with a confluent monolayer of
SK-N-MC cells was split 2 days (d) prior to transfection. Using
sterile technique, the media was removed and the cells were
detached from the dish by the addition of trypsin. One fifth of the
cells were then placed onto a new 10-cm dish. Cells were grown in a
37.degree. C. incubator with 5% CO.sub.2 in Minimal Essential Media
Eagle with 10% Fetal Bovine Serum. After 2 d, cells were
approximately 80% confluent. These cells were removed from the dish
with trypsin and pelleted in a clinical centrifuge. The pellet was
re-suspended in 4004 complete media and transferred to an
electroporation cuvette with a 0.4 cm gap between the electrodes.
Supercoiled rat FAAH cDNA (1 .mu.g) was added to the cells and
mixed. The voltage for the electroporation was set at 0.25 kV, and
the capacitance was set at 960 .mu.F. After electroporation, the
cells were diluted into complete media (10 mL) and plated onto four
10-cm dishes. Because of the variability in the efficiency of
electroporation, four different concentrations of cells were
plated. The ratios used were 1:20, 1:10, and 1:5, with the
remainder of the cells being added to the fourth dish. The cells
were allowed to recover for 24 h before adding the selection media
(complete media with 600 .mu.g/mL G418). After 10 d, dishes were
analyzed for surviving colonies of cells. Dishes with well-isolated
colonies were used. Cells from individual colonies were isolated
and tested. The clones that showed the most FAAH activity, as
measured by anandamide hydrolysis, were used for further study.
[0218] B. FAAH Assay
[0219] T84 frozen cell pellets or transfected SK-N-MC cells
(contents of 1.times.15 cm culture dishes) were homogenized in 50
mL of FAAH assay buffer (125 mM Tris, 1 mM EDTA, 0.2% Glycerol,
0.02% Triton X-100, 0.4 mM Hepes, pH 9). The assay mixture
consisted of 50 .mu.L of the cell homogenate, 10 .mu.L of the test
compound, and 40 .mu.L of anandamide [1.sup.-3H-ethanolamine]
(.sup.3H-AEA, Perkin-Elmer, 10.3 C.sub.i/mmol), which was added
last, for a final tracer concentration of 80 nM. The reaction
mixture was incubated at rt for 1 h. During the incubation, 96-well
Multiscreen filter plates (catalog number MAFCNOB50; Millipore,
Bedford, Mass., USA) were loaded with 254 of activated charcoal
(Multiscreen column loader, catalog number MACL09625, Millipore)
and washed once with 1004 of MeOH. Also during the incubation,
96-well DYNEX MicroLite plates (catalog number NL510410) were
loaded with 100 .mu.L of MicroScint40 (catalog number 6013641,
Packard Bioscience, Meriden, Conn., USA). After the 1 h incubation,
60 .mu.L of the reaction mixture were transferred to the charcoal
plates, which were then assembled on top of the DYNEX plates using
Centrifuge Alignment Frames (catalog number MACF09604, Millipore).
The unbound labeled ethanolamine was centrifuged through to the
bottom plate (5 min at 2000 rpm), which was preloaded with the
scintillant, as described above. The plates were sealed and left at
rt for 1 h before counting on a Hewlett Packard TopCount.
[0220] Results for compounds tested in these assays are summarized
in Table 1, as an average of results obtained. Compounds were
tested in free base, hydrochloride salt, and/or trifluoroacetic
acid salt forms. Where activity is shown as greater than (>) a
particular value, the value is the solubility limit of the compound
in the assay medium or the highest concentration tested in the
assay.
TABLE-US-00001 TABLE 1 Assay 1 Assay 2 Ex. IC.sub.50 (.mu.M)
IC.sub.50 (.mu.M) 1 0.410 0.604 2 8.000 >10 3 8.000 10.000 4
10.000 >10 5 2.000 0.183 6 0.645 0.050 7 2.000 0.152 8 10.000
>10 9 7.000 8.999 10 0.018 0.019 11 0.087 0.008 12 0.056 0.007
13 0.019 0.031 14 0.073 0.027 15 0.011 0.017 16 1.000 >10 17
0.048 0.180 18 0.190 0.450 19 0.430 1.600
[0221] While the invention has been illustrated by reference to
exemplary and preferred embodiments, it will be understood that the
invention is intended not to be limited to the foregoing detailed
description, but to be defined by the appended claims as properly
construed under principles of patent law.
* * * * *