U.S. patent application number 14/671030 was filed with the patent office on 2015-09-24 for inhibitors of the 11-beta-hydroxysteroid dehydrogenase type 1 enzyme.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to R. Scott Bitner, Kaitlin E. Browman, Michael E. Brune, Jurgen Dinges, Steven Fung, Peer B. Jacobson, Ravi Kurukulasuriya, James T. Link, Jyoti R. Patel, Jeffrey J. Rohde, Lynne E. Rueter, Qi Shuai, Bryan K. Sorensen, Marina I. Strakhova, Jiahong Wang, Vince S. Yeh, Hong Yong.
Application Number | 20150265613 14/671030 |
Document ID | / |
Family ID | 40845075 |
Filed Date | 2015-09-24 |
United States Patent
Application |
20150265613 |
Kind Code |
A1 |
Bitner; R. Scott ; et
al. |
September 24, 2015 |
INHIBITORS OF THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE 1
ENZYME
Abstract
The present invention relates to inhibitors of the
11-beta-hydroxysteroid dehydrogenase Type 1 enzyme and their use in
treatment of non-insulin dependent type 2 diabetes, insulin
resistance, obesity, lipid disorders, metabolic syndrome, central
nervous system disorders, and diseases and conditions that are
related to excessive glucocorticoids.
Inventors: |
Bitner; R. Scott; (Pleasant
Prairie, WI) ; Browman; Kaitlin E.; (Deerfield,
IL) ; Brune; Michael E.; (Mundelein, IL) ;
Fung; Steven; (Mount Prospect, IL) ; Jacobson; Peer
B.; (Libertyville, IL) ; Rueter; Lynne E.;
(Round Lake Beach, IL) ; Strakhova; Marina I.;
(Vernon Hills, IL) ; Wang; Jiahong; (Lake Bluff,
IL) ; Rohde; Jeffrey J.; (Evanston, IL) ;
Shuai; Qi; (Dekalb, IL) ; Link; James T.;
(Stanford, CA) ; Patel; Jyoti R.; (Libertyville,
IL) ; Dinges; Jurgen; (Wadsworth, IL) ;
Sorensen; Bryan K.; (Antioch, IL) ; Yong; Hong;
(Libertyville, IL) ; Yeh; Vince S.; (San Diego,
CA) ; Kurukulasuriya; Ravi; (East Lyme, CT) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
40845075 |
Appl. No.: |
14/671030 |
Filed: |
March 27, 2015 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
13469021 |
May 10, 2012 |
8993632 |
|
|
14671030 |
|
|
|
|
12390286 |
Feb 20, 2009 |
8198331 |
|
|
13469021 |
|
|
|
|
11733636 |
Apr 10, 2007 |
7528282 |
|
|
12390286 |
|
|
|
|
11326277 |
Jan 5, 2006 |
7217838 |
|
|
11733636 |
|
|
|
|
12195937 |
Aug 21, 2008 |
|
|
|
12390286 |
|
|
|
|
60641496 |
Jan 5, 2005 |
|
|
|
60957082 |
Aug 21, 2007 |
|
|
|
Current U.S.
Class: |
514/249 ;
514/325; 514/357; 514/406; 514/423; 514/438; 514/563; 514/616;
514/617 |
Current CPC
Class: |
A61K 31/44 20130101;
C07C 2601/02 20170501; A61P 25/18 20180101; A61P 25/24 20180101;
C07C 233/11 20130101; C07C 2603/74 20170501; A61K 31/195 20130101;
A61P 25/00 20180101; A61K 31/4409 20130101; A61K 31/45 20130101;
A61P 9/12 20180101; C07D 207/277 20130101; C07D 333/24 20130101;
C07C 233/63 20130101; C07C 233/52 20130101; C07D 231/12 20130101;
A61K 31/415 20130101; C07C 233/58 20130101; A61P 3/04 20180101;
A61P 25/22 20180101; A61K 31/381 20130101; A61K 31/4015 20130101;
A61K 31/5377 20130101; A61K 31/451 20130101; C07C 237/24 20130101;
A61P 3/10 20180101; C07D 261/08 20130101; A61P 25/28 20180101; A61K
31/165 20130101; C07C 2601/04 20170501; A61P 5/46 20180101; A61P
3/00 20180101; A61K 31/196 20130101; C07C 311/46 20130101; C07C
2601/14 20170501; C07D 211/78 20130101; A61K 31/498 20130101; C07D
213/56 20130101; C07C 2601/08 20170501 |
International
Class: |
A61K 31/498 20060101
A61K031/498; A61K 31/165 20060101 A61K031/165; A61K 31/4409
20060101 A61K031/4409; A61K 31/415 20060101 A61K031/415; A61K 31/44
20060101 A61K031/44; A61K 31/451 20060101 A61K031/451; A61K 31/4015
20060101 A61K031/4015; A61K 31/196 20060101 A61K031/196; A61K
31/381 20060101 A61K031/381 |
Claims
1. A method for treating a patient suffering from a disorder
selected from the group consisting of neuropathy, neuronal
dysfunction, neurodegeneration, dementia, decline in cognitive
function in Alzheimer's disease and associated dementias, senile
dementia, AIDS dementia, attention deficit disorder in general,
attention deficit hyperactivity disorder (ADHD), mild cognitive
impairment, steroid-induced acute psychosis, schizophrenia, and
combinations thereof, comprising administering to the patient an
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a
combination thereof, ##STR00022## wherein one of A.sup.1, A.sup.2,
A.sup.3 and A.sup.4 is selected from the group consisting of
alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl.sup.1, arylalkyl,
aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl,
heterocyclealkyl, heterocycleoxyalkyl,
--S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)].sub.p--C(O)--R.sup.13, --OR.sup.14a,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17, --C(O)--N
(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22,
--C(R.sup.23R.sup.24)--N(R.sup.25, R.sup.26), and heterocycle, with
the exception that 5 membered heterocycles may not contain two
oxygen atoms, and the remaining members of the group consisting of
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are each individually
selected from the group consisting of hydrogen, alkyl,
alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,
aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl,
--S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)].sub.p--C(O)--R.sup.13, --OR.sup.14b,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22, and
--C(R.sup.23R.sup.24)--N(R.sup.25R.sup.26); n is 0 or 1; p is 0 or
1; D is selected from the group consisting of a bond,
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; E is selected from
the group consisting of a cycloalkyl, alkyl, aryl, heteroaryl and
heterocycle, wherein the heteroaryl and the heterocycle are
appended to the parent molecular moiety through an available carbon
atom, or R.sup.4 and E together with the atoms to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; X is selected from the group consisting
of a bond, --N(R.sup.31)--, --O--, --S--, --S(O)-- and
--S(O).sub.2--; R.sup.1 is selected from the group consisting of
hydrogen and alkyl; R.sup.2 is selected from the group consisting
of hydrogen, alkyl and cycloalkyl; R.sup.3 and R.sup.4 are each
independently selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl,
aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle and
heterocyclealkyl, or R.sup.3 and R.sup.4 together with the atom to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle; R.sup.5 and R.sup.6 are
each independently selected from the group consisting of hydrogen,
alkoxy, alkyl, alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl,
aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy,
aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl,
heteroarylsulfonyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,
heterocycleoxy, heterocyclesulfonyl and hydroxy, or R.sup.5 and
R.sup.6 together with the atom to which they are attached form a
heterocycle; R.sup.7 is selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl,
heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl
and heterocycleoxyalkyl; R.sup.8 and R.sup.9 are each independently
selected from the group consisting of hydrogen and alkyl, or
R.sup.8 and R.sup.9 taken together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; R.sup.10 is selected from the group
consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy,
alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy,
heterocycleoxyalkyl and --N(R.sup.32R.sup.33); R.sup.11 and
R.sup.12 are each independently selected from the group consisting
of hydrogen and alkyl or R.sup.11 and R.sup.12 taken together with
the atom to which they are attached form a ring selected from the
group consisting of cycloalkyl and heterocycle; R.sup.13 is
selected from the group consisting of hydroxy and
--N(R.sup.34R.sup.35); R.sup.14a is selected from the group
consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl; R.sup.14b is selected from the group
consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,
heterocyclealkyl and heterocycleoxyalkyl; R.sup.15 and R.sup.16 are
each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl,
aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl,
heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl,
heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl,
heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,
heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl,
alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl, or R.sup.15 and
R.sup.16 together with the atom to which they are attached form a
heterocycle; R.sup.17 is selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl; R.sup.18 and R.sup.19 are each independently
selected from the group consisting of hydrogen, alkoxy, alkyl,
alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
heterocyclesulfonyl and hydroxy, or R.sup.18 and R.sup.19 together
with the atom to which they are attached form a heterocycle;
R.sup.20, R.sup.21 and R.sup.22 are each independently selected
from the group consisting of hydrogen, alkyl, aryl, arylalkyl,
carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl,
heteroarylalkyl, heterocycle and heterocyclealkyl; R.sup.23 and
R.sup.24 are each independently selected from the group consisting
of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,
arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl,
cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl,
heteroarylcarbonyl, heteroarylsulfonyl, heterocycle,
heterocyclecarbonyl and heterocyclesulfonyl; R.sup.25 and R.sup.26
are each independently selected from the group consisting of
hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,
arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy,
cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy,
heteroarylsulfonyl, heterocycle, heterocyclecarbonyl,
heterocycleoxy, heterocyclesulfonyl and hydroxy, or R.sup.25 and
R.sup.26 together with the nitrogen to which they are attached form
a ring selected from the group consisting of heteroaryl and
heterocycle; R.sup.27 and R.sup.28 are each independently selected
from the group consisting of hydrogen, alkyl, aryl, cycloalkyl,
heteroaryl and heterocycle or R.sup.27 and R.sup.28 together with
the atom to which they are attached form a ring selected from the
group consisting of cycloalkyl and heterocycle, or R.sup.27 and
R.sup.29 together with the atoms to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle, or R.sup.28 and R.sup.4 together with the atoms to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle; R.sup.29 and R.sup.30 are
each independently selected from the group consisting of hydrogen,
alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy,
heteroaryl, heterocycle, and --N(R.sup.36R.sup.37), or R.sup.29 and
R.sup.30 together with the atom to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle, or R.sup.29 and R.sup.4 together with the atoms to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle, or R.sup.29 and E
together with the atoms to which they are attached form a ring
selected from the group consisting of cycloalkyl and heterocycle;
R.sup.31 is selected from the group consisting of hydrogen, alkyl,
aryl, cycloalkyl, heterocycle and heteroaryl, or R.sup.31 and E
together with the atom to which they are attached form a ring
selected from the group consisting of heteroaryl and heterocycle,
or R.sup.31 and R.sup.4 together with the atoms to which they are
attached form a heterocycle; R.sup.32 and R.sup.33 are each
independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,
carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,
heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl,
and heterocyclesulfonyl, or R.sup.32 and R.sup.33 together with the
atom to which they are attached form a heterocycle; R.sup.34 and
R.sup.35 are each independently selected from the group consisting
of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl,
cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl,
heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl,
arylsulfonyl, and heterocyclesulfonyl, or R.sup.34 and R.sup.35
together with the atom to which they are attached form a
heterocycle; and R.sup.36 and R.sup.37 are each independently
selected from the group consisting of hydrogen, alkyl and aryl.
2. The method according to claim 1, wherein the inhibitor is a
therapeutically suitable metabolite of a compound of formula
(I).
3. The method according to claim 1, wherein the inhibitor is a
compound selected from the group consisting of:
E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carbox-
ylic acid;
E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carbox-
ylic acid;
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic
acid;
E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1--
carboxylic acid amide;
E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic
acid amide;
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid
amide;
E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxami-
de;
E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carbo-
xamide;
E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-c-
arboxamide;
E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide-
;
E-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamide;
E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxam-
ide;
E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamanta-
ne-1-carboxamide;
E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxam-
ide;
E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carb-
oxamide;
E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide-
;
E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-car-
boxamide;
E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane--
1-carboxamide;
E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxam-
ide;
E-4-{[2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]amino}adamantane-1-c-
arboxamide;
E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide;
E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamide;
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamant-
ane-1-carboxamide;
E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2
yl]phenyl}propanoyl)amino]adamantane-1-carboxamide;
E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxa-
mide;
E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxa-
mide;
E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-ox-
opiperidine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-car-
boxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-o-
xopyrrolidine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrroli-
dine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrroli-
dine-3-carboxamide;
E-4-({2-methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propanoyl}amino)adam-
antane-1-carboxamide;
E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;
E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2-methylpropanoyl}amino)ada-
mantane-1-carboxamide;
E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-1-carbo-
xamide;
4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}ca-
rbonyl)amino]methyl}benzoic acid;
E-4-({2-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1--
carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-ox-
opyrrolidine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyr-
rolidine-3-carboxamide;
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyr-
rolidine-3-carboxamide;
E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxami-
de;
E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-
-3-carboxamide;
E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamid-
e;
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-ca-
rboxamide;
E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1--
carboxamide;
E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantane-1-carboxam-
ide;
E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-c-
arboxamide;
E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide;
(E)-4-[(2-methyl-2-pyrazin-2-ylpropanoyl)amino]adamantane-1-carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(2-pyridin-2-yleth-
yl) pyrrolidine-3-carboxamide;
methyl(E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxylate;
(E)-4-({2-methyl-2-[3-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)ada-
mantane-1-carboxamide;
(E)-4-({2-methyl-2-[6-(methylamino)pyridin-3-yl]propanoyl}amino)adamantan-
e-1-carboxamide;
(E)-4-({2-methyl-2-[3-(morpholin-4-ylmethyl)phenyl]propanoyl}amino)adaman-
tane-1-carboxamide;
(E)-4-({2-methyl-2-[4-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adama-
ntane-1-carboxamide;
(E)-4-[(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-2-methylpropanoyl)amino]-
adamantane-1-carboxamide;
methyl(E)-4-{[(1-phenylcyclopropyl)carbonyl]amino}adamantane-1-carboxylat-
e;
(E)-4-{[2-(6-fluoropyridin-3-yl)-2-methylpropanoyl]amino}adamantane-1-c-
arboxamide;
(E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adam-
antane-1-carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopi-
peridine-3-carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-4-ylmethy-
l) pyrrolidine-3-carboxamide;
(E)-4-[2-methyl-2-(4-phenoxyphenyl)propanoyl]aminol
adamantane-1-carboxylic acid;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-phenylcyclopropanecarboxamide;
(E)-4-({3-[(5-cyanopyridin-2-yl)oxy]-2,2-dimethylpropanoyl}amino)adamanta-
ne-1-carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(1-pyridin-2-yleth-
yl)pyrrolidine-3-carboxamide;
(E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-1-carboxamide;
(E)-4-[2-methyl-2-(6-morpholin-4-ylpyridin-3-yl)propanoyl]amino)adamantan-
e-1-carboxamide;
methyl(E)-4-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-1-c-
arboxy late;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-3-ylmethy-
l)pyrrolidine-3-carboxamide;
(E)-4-[(2-methyl-2-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl}propanoy-
l)amino]adamantane-1-carboxamide;
(E)-4-[(2-methyl-2-{4-[(E)-2-pyridin-4-ylvinyl]phenyl}propanoyl)amino]ada-
mantane-1-carboxamide;
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanam-
ide;
(E)-4-({2-methyl-2-[3-(2-morpholin-4-ylethoxy)phenyl]propanoyl}amino)-
adamantane-1-carboxamide;
(E)-4-{[2-(3-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carb-
oxamide;
(E)-4-({2-methyl-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]propan-
oyl}amino) adamantane-1-carboxamide;
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-2-ylmethy-
l) pyrrolidine-3-carboxamide;
(E)-N[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adama-
ntane-1-carboxamide;
(E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-1-carb-
oxylic acid;
(E)-4-({2-methyl-2-[4-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)ada-
mantane-1-carboxylic acid;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(1,3-thiazol-5-ylmethyl)adama-
ntane-1-carboxamide;
(E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carb-
oxylic acid;
(E)-4-{[2-(5-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carb-
oxamide;
(E)-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-c-
arboxylic acid;
4-[({[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino-
)-1-adamantyl]carbonyl}amino)methyl]benzoic acid;
4-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amin-
o]methyl}benzoic acid;
3-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amin-
o]methyl}benzoic acid;
(E)-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carbox-
ylic acid;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-Nyridin-4-ylmethyl)ad-
amantane-1-carboxamide;
(E)-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-ca-
rboxylic acid;
(E)-N-(2-furylmethyl)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-c-
arboxamide;
3-[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-1-
-adamantyl]-1H-pyrazole-5-carboxamide;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-Nyridin-3-ylmethyl)adamantane-1-
-carboxamide;
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-Nyridin-2-ylmethyl)adamantane-1-
-carboxamide;
(E)-4-({2-[4-(cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantan-
e-1-carboxylic acid;
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}propanoyl)a-
mino]adamantine-1-carboxylic acid; and
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopy-
rrolidine-3-carboxamide; or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof.
4. The method of claim 1, wherein the patient is a mammal.
5. The method of claim 4, wherein the disorder is mediated by
excessive glucocorticoid action in the mammal.
6. The method of claim 4, wherein the disorder is decline in
cognitive function in Alzheimer's disease.
7. The method of claim 4, wherein the disorder is
neurodegeneration.
8. The method of claim 4, wherein the disorder is dementia, senile
dementia or AIDS dementia.
9. The method of claim 4, wherein the disorder is attention deficit
disorder in general, attention deficit hyperactivity disorder
(ADHD), or mild cognitive impairment.
10. The method of claim 4, wherein the disorder is
schizophrenia.
11. A method for treating a patient suffering from a disorder
selected from the group consisting of non insulin dependent type 2
diabetes, insulin resistance, obesity, metabolic syndrome,
hypertension, anxiety, major depressive disorder, psychotic
depression, treatment resistant depression, panic disorder, post
traumatic stress disorder, depression in Cushing's syndrome,
cognitive deficits associated with diabetes and cognitive deficits
associated with aging, and combinations thereof, comprising
administering to the patient an effective amount of a selective
inhibitor of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
activity, wherein said inhibitor is a compound of formula (I), or a
pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a
combination thereof, ##STR00023## wherein one of A.sup.1, A.sup.2,
A.sup.3 and A.sup.4 is selected from the group consisting of
alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl.sup.1, arylalkyl,
aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, haloalkyl,
heterocyclealkyl, heterocycleoxyalkyl,
--S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)].sub.p--C(O)--R.sup.13, --OR.sup.14a,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22, and
--C(R.sup.23R.sup.24)--N(R.sup.25R.sup.26); and heterocycle, with
the exception that 5 membered heterocycles may not contain two
oxygen atoms, and the remaining members of the group consisting of
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are each individually
selected from the group consisting of hydrogen, alkyl,
alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,
aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl,
--S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)].sub.p--C(O)--R.sup.13, --OR.sup.14b,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22, and
--C(R.sup.23R.sup.24)--N(R.sup.25R.sup.26); n is 0 or 1; p is 0 or
1; D is selected from the group consisting of a bond,
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; E is selected from
the group consisting of a heteroaryl and heterocycle, wherein the
heteroaryl and the heterocycle are appended to the parent molecular
moiety through an available carbon atom, or R.sup.4 and E together
with the atoms to which they are attached form a heterocycle ring;
X is selected from the group consisting of a bond, N(R.sup.31)--,
--O--, --S--, --S(O)-- and --S(O).sub.2--; R.sup.1 is selected from
the group consisting of hydrogen and alkyl; R.sup.2 is selected
from the group consisting of hydrogen, alkyl and cycloalkyl;
R.sup.3 and R.sup.4 are each independently selected from the group
consisting of hydrogen, alkyl, carboxyalkyl, carboxycycloalkyl,
cycloalkyl, haloalkyl, aryl, arylalkyl, heteroaryl,
heteroarylalkyl, heterocycle and heterocyclealkyl, or R.sup.3 and
R.sup.4 together with the atom to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle; R.sup.5 and R.sup.6 are each independently selected
from the group consisting of hydrogen, alkoxy, alkyl,
alkylcarbonyl, alkylsufonyl, carboxy, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, cycloalkyloxy, cycloalkylsulfonyl,
aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxy,
aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroarylalkylcarbonyl, heteroarylcarbonyl, heteroaryloxyalkyl,
heteroarylsulfonyl, heterocycle, heterocyclealkyl,
heterocyclealkylcarbonyl, heterocyclecarbonyl, heterocycleoxyalkyl,
heterocycleoxy, heterocyclesulfonyl and hydroxy, or R.sup.5 and
R.sup.6 together with the atom to which they are attached form a
heterocycle; R.sup.7 is selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl,
heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl
and heterocycleoxyalkyl; R.sup.8 and R.sup.9 are each independently
selected from the group consisting of hydrogen and alkyl, or
R.sup.8 and R.sup.9 taken together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; R.sup.10 is selected from the group
consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl, hydroxy,
alkoxy, cycloalkyloxy, heteroaryl, heteroarylalkyl, heteroaryloxy,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxy,
heterocycleoxyalkyl and --N(R.sup.32R.sup.33); R.sup.11 and
R.sup.12 are each independently selected from the group consisting
of hydrogen and alkyl or R.sup.11 and R.sup.12 taken together with
the atom to which they are attached form a ring selected from the
group consisting of cycloalkyl and heterocycle; R.sup.13 is
selected from the group consisting of hydroxy and
--N(R.sup.34R.sup.35); R.sup.14a is selected from the group
consisting of carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl; R.sup.14b is selected from the group
consisting of hydrogen, alkyl, carboxyalkyl, cycloalkyl,
carboxycycloalkyl, aryl, arylalkyl, aryloxyalkyl, haloalkyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,
heterocyclealkyl and heterocycleoxyalkyl; R.sup.15 and R.sup.16 are
each independently selected from the group consisting of hydrogen,
alkyl, alkylcarbonyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl,
aryl, arylalkyl, arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl,
heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl,
heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl,
heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,
heterocyclecarbonyl, heterocycleoxyalkyl, heterocyclesulfonyl,
alkylsufonyl, cycloalkylsulfonyl and arylsulfonyl, or R.sup.15 and
R.sup.16 together with the atom to which they are attached form a
heterocycle; R.sup.17 is selected from the group consisting of
hydrogen, alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl; R.sup.18 and R.sup.19 are each independently
selected from the group consisting of hydrogen, alkoxy, alkyl,
alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
heterocyclesulfonyl and hydroxy, or R.sup.18 and R.sup.19 together
with the atom to which they are attached form a heterocycle;
R.sup.20, R.sup.21 and R.sup.22 are each independently selected
from the group consisting of hydrogen, alkyl, aryl, arylalkyl,
carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl, heteroaryl,
heteroarylalkyl, heterocycle and heterocyclealkyl; R.sup.23 and
R.sup.24 are each independently selected from the group consisting
of hydrogen, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,
arylcarbonyl, arylsulfonyl, carboxyalkyl, carboxycycloalkyl,
cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl, heteroaryl,
heteroarylcarbonyl, heteroarylsulfonyl, heterocycle,
heterocyclecarbonyl and heterocyclesulfonyl; R.sup.25 and R.sup.26
are each independently selected from the group consisting of
hydrogen, alkoxy, alkyl, alkylcarbonyl, alkylsulfonyl, aryl,
arylcarbonyl, aryloxy, arylsulfonyl, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl, cycloalkyloxy,
cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl, heteroaryloxy,
heteroarylsulfonyl, heterocycle, heterocyclecarbonyl,
heterocycleoxy, heterocyclesulfonyl and hydroxy, or R.sup.25 and
R.sup.26 together with the nitrogen to which they are attached form
a ring selected from the group consisting of heteroaryl and
heterocycle; R.sup.27 and R.sup.28 are each independently selected
from the group consisting of hydrogen, alkyl, aryl, cycloalkyl,
heteroaryl and heterocycle or R.sup.27 and R.sup.28 together with
the atom to which they are attached form a ring selected from the
group consisting of cycloalkyl and heterocycle, or R.sup.27 and
R.sup.29 together with the atoms to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle, or R.sup.28 and R.sup.4 together with the atoms to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle; R.sup.29 and R.sup.30 are
each independently selected from the group consisting of hydrogen,
alkyl, alkoxy, aryl, aryloxy, cycloalkyl, cycloalkyloxy,
heteroaryl, heterocycle, and --N(R.sup.36R.sup.37), or R.sup.29 and
R.sup.30 together with the atom to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle, or R.sup.29 and R.sup.4 together with the atoms to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle, or R.sup.29 and E
together with the atoms to which they are attached form a ring
selected from the group consisting of cycloalkyl and heterocycle;
R.sup.31 is selected from the group consisting of hydrogen, alkyl,
aryl, cycloalkyl, heterocycle and heteroaryl, or R.sup.31 and E
together with the atom to which they are attached form a ring
selected from the group consisting of heteroaryl and heterocycle,
or R.sup.31 and R.sup.4 together with the atoms to which they are
attached form a heterocycle; R.sup.32 and R.sup.33 are each
independently selected from the group consisting of hydrogen,
alkyl, carboxy, carboxyalkyl, cycloalkyl, cycloalkyloxy,
carboxycycloalkyl, aryl, arylalkyl, aryloxy, aryloxyalkyl,
heterocycle, heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl, arylsulfonyl,
and heterocyclesulfonyl, or R.sup.32 and R.sup.33 together with the
atom to which they are attached form a heterocycle; R.sup.34 and
R.sup.35 are each independently selected from the group consisting
of hydrogen, alkyl, carboxy, carboxyalkyl, cycloalkyl,
cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, heterocycle, heterocyclealkyl, heterocycleoxyalkyl,
heterocycleoxy, hydroxy, alkoxy, alkylsufonyl, cycloalkylsulfonyl,
arylsulfonyl, and heterocyclesulfonyl, or R.sup.34 and R.sup.35
together with the atom to which they are attached form a
heterocycle; and R.sup.36 and R.sup.37 are each independently
selected from the group consisting of hydrogen, alkyl and aryl.
12. The method according to claim 11, wherein the inhibitor is a
compound selected from the group consisting of:
E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide;
E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamide;
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamant-
ane-1-carboxamide;
4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)-
amino]methyl}benzoic acid;
E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxami-
de;
E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantane-1-carbo-
xamide;
E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane--
1-carboxamide; and
E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide;
or a pharmaceutically acceptable salt, prodrug, salt of a prodrug,
or a combination thereof.
13. The method of claim 11, wherein the patient is a mammal.
14. The method of claim 13, wherein the disorder is mediated by
excessive glucocorticoid action in a mammal.
15. The method of claim 13, wherein the disorder is selected from
the group consisting of non insulin dependent type 2 diabetes,
insulin resistance, obesity, metabolic syndrome, and
hypertension.
16. The method of claim 13, wherein the disorder is cognitive
deficits associated with aging.
17. The method of claim 13, wherein the disorder is depression.
18. The method of claim 17, wherein the depression is major
depressive disorder, psychotic depression, depression in Cushing's
syndrome, or treatment resistant depression.
19. The method of claim 13, wherein the disorder is anxiety, panic
disorder, or post traumatic stress disorder.
20. The method of claim 13, wherein the disorder is cognitive
deficits associated with diabetes.
Description
[0001] This application is a divisional of U.S. Non-provisional
patent application Ser. No. 12/390,286, filed Feb. 20, 2009, which
is a continuation-in-part application of U.S. Non-provisional
patent application Ser. No. 11/733,636, filed Apr. 10, 2007, which
is a continuation of U.S. Non-provisional patent application Ser.
No. 11/326,277, filed May 15, 2007, which claims priority from U.S.
Provisional Patent Application Ser. No. 60/641,496, filed Jan. 5,
2005, which are incorporated herein by reference. Also, U.S.
Non-provisional patent application Ser. No. 12/390,286 filed Feb.
20, 2009 is a continuation-in-part of U.S. Non-provisional patent
application Ser. No. 12/195,937, filed Aug. 21, 2008, which claims
priority from U.S. Provisional Patent Application Ser. No.
60/957,082, filed Aug. 21, 2007, which are hereby incorporated by
reference.
FIELD OF INVENTION
[0002] The present invention relates to compounds that are
inhibitors of the 11-beta-hydroxysteroid dehydrogenase Type 1
enzyme. The present invention further relates to the use of
inhibitors of 11-beta-hydroxysteroid dehydrogenase Type 1 enzyme
for the treatment of non-insulin dependent type 2 diabetes, insulin
resistance, obesity, lipid disorders, metabolic syndrome, disorders
and deficits of the central nervous system associated with
diabetes, associated with aging and neurodegeneration, comprising
attention deficit disorder in general, attention deficit
hyperactivity disorder (ADHD), Alzheimer's disease (AD), mild
cognitive impairment, senile dementia, AIDS dementia,
neurodegeneration, depression, and schizophrenia, and other
diseases and conditions that are mediated by excessive
glucocorticoid action.
BACKGROUND OF THE INVENTION
[0003] Insulin is a hormone that modulates glucose and lipid
metabolism. Impaired action of insulin (i.e., insulin resistance)
results in reduced insulin-induced glucose uptake, oxidation and
storage, reduced insulin-dependent suppression of fatty acid
release from adipose tissue (i.e., lipolysis) and reduced
insulin-mediated suppression of hepatic glucose production and
secretion. Insulin resistance frequently occurs in diseases that
lead to increased and premature morbidity and mortality.
[0004] Diabetes mellitus is characterized by an elevation of plasma
glucose levels (hyperglycemia) in the fasting state or after
administration of glucose during a glucose tolerance test. While
this disease may be caused by several underlying factors, it is
generally grouped into two categories, Type 1 and Type 2 diabetes.
Type 1 diabetes, also referred to as Insulin Dependent Diabetes
Mellitus ("IDDM"), is caused by a reduction of production and
secretion of insulin. In type 2 diabetes, also referred to as
non-insulin dependent diabetes mellitus, or NIDDM, insulin
resistance is a significant pathogenic factor in the development of
hyperglycemia. Typically, the insulin levels in type 2 diabetes
patients arc elevated (i.e., hyperinsulinemia), but this
compensatory increase is not sufficient to overcome the insulin
resistance. Persistent or uncontrolled hyperglycemia in both type 1
and type 2 diabetes mellitus is associated with increased incidence
of macrovascular and/or microvascular complications including
atherosclerosis, coronary heart disease, peripheral vascular
disease, stroke, nephropathy, neuropathy and retinopathy.
[0005] Insulin resistance, even in the absence of profound
hyperglycemia, is a component of the metabolic syndrome. Recently,
diagnostic criteria for metabolic syndrome have been established.
To qualify a patient as having metabolic syndrome, three out of the
five following criteria must be met: elevated blood pressure above
130/85 mmHg, fasting blood glucose above 110 mg/dl, abdominal
obesity above 40'' (men) or 35'' (women) waist circumference and
blood lipid changes as defined by an increase in triglycerides
above 150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men)
or 50 mg/dl (women). It is currently estimated that 50 million
adults, in the US alone, fulfill these criteria. That population,
whether or not they develop overt diabetes mellitus, are at
increased risk of developing the macrovascular and microvascular
complications of type 2 diabetes listed above.
[0006] Available treatments for type 2 diabetes have recognized
limitations. Diet and physical exercise can have profound
beneficial effects in type 2 diabetes patients, but compliance is
poor. Even in patients having good compliance, other forms of
therapy may be required to further improve glucose and lipid
metabolism.
[0007] One therapeutic strategy is to increase insulin levels to
overcome insulin resistance. This may be achieved through direct
injection of insulin or through stimulation of the endogenous
insulin secretion in pancreatic beta cells. Sulfonylureas (e.g.,
tolbutamide and glipizide) or meglitinide are examples of drugs
that stimulate insulin secretion (i.e., insulin secretagogues)
thereby increasing circulating insulin concentrations high enough
to stimulate insulin-resistant tissue. However, insulin and insulin
secretagogues may lead to dangerously low glucose concentrations
(i.e., hypoglycemia). In addition, insulin secretagogues frequently
lose therapeutic potency over time.
[0008] Two biguanides, metformin and phenformin, may improve
insulin sensitivity and glucose metabolism in diabetic patients.
However, the mechanism of action is not well understood. Both
compounds may lead to lactic acidosis and gastrointestinal side
effects (e.g., nausea or diarrhea).
[0009] Alpha-glucosidase inhibitors (e.g., acarbose) may delay
carbohydrate absorption from the gut after meals, which may in turn
lower blood glucose levels, particularly in the postprandial
period. Like biguanides, these compounds may also cause
gastrointestinal side effects.
[0010] Glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a
newer class of compounds used in the treatment of type 2 diabetes.
These agents may reduce insulin resistance in multiple tissues,
thus lowering blood glucose. The risk of hypoglycemia may also be
avoided. Glitazones modify the activity of the Peroxisome
Proliferator Activated Receptor ("PPAR") gamma subtype. PPAR is
currently believed to be the primary therapeutic target for the
main mechanism of action for the beneficial effects of these
compounds. Other modulators of the PPAR family of proteins are
currently in development for the treatment of type 2 diabetes
and/or dyslipidemia. Marketed glitazones suffer from side effects
including bodyweight gain and peripheral edema.
[0011] Additional treatments to normalize blood glucose levels in
patients with diabetes mellitus arc needed. Other therapeutic
strategies are being explored. For example, research is being
conducted concerning Glucagon-Like Peptide 1 ("GLP-1") analogues
and inhibitors of Dipeptidyl Peptidase IV ("DPP-IV") that increase
insulin secretion. Other examples include. Inhibitors of key
enzymes involved in the hepatic glucose production and secretion
(e.g., fructose-1,6-bisphosphatase inhibitors) and direct
modulation of enzymes involved in insulin signaling (e.g., Protein
Tyrosine Phosphatase-1B, or "PTP-1B").
[0012] Another method of treating or prophylactically treating
diabetes mellitus includes using inhibitors of
11-.beta.-hydroxysteroid dehydrogenase Type 1 (11.beta.-HSD1). Such
methods are discussed in J. R. Seckl et al., Endocrinology,
142:1371-1376, 2001 and references cited therein. Glucocorticoids
are steroid hormones that are potent regulators of glucose and
lipid metabolism. Excessive glucocorticoid action may lead to
insulin resistance, type 2 diabetes, dyslipidemia, increased
abdominal obesity and hypertension. Glucocorticoids circulate in
the blood in an active form (i.e., cortisol in humans) and an
inactive form (i.e., cortisone in humans). 11.beta.-HSD1, which is
highly expressed in liver and adipose tissue, converts cortisone to
cortisol leading to higher local concentration of cortisol.
Inhibition of 11.beta.-HSD1 prevents or decreases the tissue
specific amplification of glucocorticoid action thus imparting
beneficial effects on blood pressure and glucose- and
lipid-metabolism.
[0013] 11.beta.-HSD-1 is a low affinity enzyme with K.sub.m for
cortisone in the micromolar range that prefers NADPH/NADP.sup.+
(nicotinamide adenine dinucleotide phosphate) as cofactors.
11.beta.-HSD-1 is widely expressed and particularly high expression
levels are found in liver, brain, lung, adipose tissue, and
vascular smooth muscle cells. In vitro studies indicate that
11.beta.-HSD-1 is capable of acting both as a reductase and a
dehydrogenase. However, many studies have shown that it functions
primarily as a reductase in vivo and in intact cells. It converts
inactive 11-ketoglucocorticoids (i.e., cortisone or
dehydrocorticosterone) to active 11-hydroxyglucocorticoids (i.e.,
cortisol or corticosterone), and thereby amplifies glucocorticoid
action in a tissue-specific manner.
[0014] 11.beta.-HSD-1 is expressed in mammalian brain, and
published data indicates that elevated levels of glucocorticoids
may cause neuronal degeneration and dysfunction, particularly in
the aged (de Quervain et al., Hum Mol Genet., 13, 47-52 (2004);
Belanoff et al. J. Psychiatr Res., 35, 127-35, (2001)). Evidence in
rodents and humans suggests that prolonged elevation of plasma
glucocorticoid levels impairs cognitive function that becomes more
profound with aging. (A. M. Issa et al., J. Neurosci., 10,
3247-3254 (1990); S. J. Lupien et. al., Nat. Neurosci., 1, 69-73
(1998); J. L. Yau et al., Neuroscience, 66, 571-581 (1995)).
Chronic excessive cortisol levels in the brain may result in
neuronal loss and neuronal dysfunction. (D. S. Kerr et al.,
Psychobiology, 22, 123-133 (1994); C. Woolley, Brain Res., 531,
225-231, (1990); P. W. Landfield, Science, 272, 1249-1251 (1996)).
Furthermore, glucocorticoid-induced acute psychosis exemplifies a
more pharmacological induction of this response, and is of major
concern to physicians when treating patients with these steroidal
agents (Wolkowitz et al.; Ann NY Acad Sci., 1032, 191-194 (2004)).
It has been recently shown that 11.beta.-HSD-1 mRNA is expressed in
human hippocampus, frontal cortex and cerebellum, and that
treatment of elderly diabetic individuals with the non-selective
11.beta.-HSD-1 and 11.beta.-HSD-2 inhibitor carbenoxolone improved
verbal fluency and memory (Thekkapat et al., Proc Natl Acad Sci
USA, 101, 6743-6749 (2004)). Excessive glucocorticoid levels also
affects psychopathology, as shown in animal models, it leads to
increased anxiety and aggression. Chronic elevation of cortisol has
been also associated with depression in Cushing's disease (McEwen,
Metab. Clin. & Exp., 54, 20-23 (2005)). A number of animal and
clinical studies have provided evidence for the correlation between
increases in glucocorticoid levels and neuropsychiatric disorders
such as major depressive disorder, psychotic depression, anxiety,
panic disorder, post traumatic stress disorder, and depression in
Cushing's syndrome (Budziszewska, Polish J. of Pharmacol., 54,
343-349, (2002); Strohle et al., Pharmacopsychiatry Vol. 36,
S207-S214, 2003; DeBattista et al., TRENDS in Endocr. Metab., 17,
117-120 (2006); Norman et al., Expert Rev. Neurotherapeutics, Vol.
7, pages 203-213 (2007)).
[0015] Thus, inhibiting 11.beta.-HSD1 benefits patients suffering
from non-insulin dependent type 2 diabetes, insulin resistance,
obesity, lipid disorders, metabolic syndrome, central nervous
system disorders, age-related or glucocorticoid-related declines in
cognitive function such as those seen in Alzheimer's and associated
dementias, major depressive disorder, psychotic depression,
anxiety, panic disorder, post traumatic stress disorder, depression
in Cushing's syndrome, and treatment resistant depression, and
other diseases and conditions mediated by excessive glucocorticoid
action.
SUMMARY OF THE INVENTION
[0016] All patents, patent applications and literature references
cited in the specification are herein incorporated by reference in
their entirety.
[0017] One aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof
##STR00001##
[0018] wherein
[0019] one of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 is selected
from the group consisting of alkyl-NH-alkyl, alkylcarbonyl,
alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl,
aryl carbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl,
aryl.sup.1, arylalkyl, aryloxyalkyl, carboxyalkyl,
carboxycycloalkyl, haloalkyl, heterocyclealkyl,
heterocycleoxyalkyl, --S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)].sub.p--C(O)--R.sup.13, --OR.sup.14a,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22,
--C(R.sup.23R.sup.24)--N(R.sup.25R.sup.26), and heterocycle, with
the exception that 5 membered heterocycles may not contain two
oxygen atoms, and the remaining members of the group consisting of
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are each individually
selected from the group consisting of hydrogen, alkyl,
alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,
aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl,
--S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)]).sub.p--C(O)--R.sup.13, --OR.sup.14b,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22, and
--C(R.sup.23R.sup.24)--. N(R.sup.25R.sup.26);
[0020] n is 0 or 1;
[0021] p is 0 or 1;
[0022] D is selected from the group consisting of a bond,
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--;
[0023] E is selected from the group consisting of a cycloalkyl,
alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and
the heterocycle are appended to the parent molecular moiety through
an available carbon atom, or R.sup.4 and E together with the atoms
to which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle; X is selected from the
group consisting of a bond, N(R.sup.31)--, --O--, --S--, --S(O)--
and --S(O).sub.2--;
[0024] R.sup.1 is selected from the group consisting of hydrogen
and alkyl;
[0025] R.sup.2 is selected from the group consisting of hydrogen,
alkyl and cycloalkyl;
[0026] R.sup.3 and R.sup.4 are each independently selected from the
group consisting of hydrogen, alkyl, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle;
[0027] R.sup.5 and R.sup.6 are each independently selected from the
group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl,
alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl,
arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl,
arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl,
heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl,
heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,
heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy,
heterocyclesulfonyl and hydroxy, or R.sup.5 and R.sup.6 together
with the atom to which they are attached form a heterocycle;
[0028] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl,
heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl
and heterocycleoxyalkyl;
[0029] R.sup.8 and R.sup.9 are each independently selected from the
group consisting of hydrogen and alkyl, or R.sup.8 and R.sup.9
taken together with the atom to which they are attached form a ring
selected from the group consisting of cycloalkyl and
heterocycle;
[0030] R.sup.10 is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy,
heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl,
heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl
and --N(R.sup.32R.sup.33);
[0031] R.sup.11 and R.sup.12 are each independently selected from
the group consisting of hydrogen and alkyl or R.sup.11 and R.sup.12
taken together with the atom to which they are attached form a ring
selected from the group consisting of cycloalkyl and
heterocycle;
[0032] R.sup.13 is selected from the group consisting of hydroxy
and --N(R.sup.34R.sup.35);
[0033] R.sup.14a is selected from the group consisting of
carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,
aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl;
[0034] R.sup.14b is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl;
[0035] R.sup.15 and R.sup.16 arc each independently selected from
the group consisting of hydrogen, alkyl, alkylcarbonyl,
carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,
arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl,
heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl,
heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,
heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufonyl,
cycloalkylsulfonyl and arylsulfonyl, or R.sup.15 and R.sup.16
together with the atom to which they are attached form a
heterocycle;
[0036] R.sup.17 is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl;
[0037] R.sup.18 and R.sup.19 are each independently selected from
the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl,
carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
heterocyclesulfonyl and hydroxy, or R.sup.18 and R.sup.19 together
with the atom to which they are attached form a heterocycle;
[0038] R.sup.20, R.sup.21 and R.sup.22 are each independently
selected from the group consisting of hydrogen, alkyl, aryl,
arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl,
heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
[0039] R.sup.23 and R.sup.24 are each independently selected from
the group consisting of hydrogen, alkyl, alkylcarbonyl,
alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,
heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and
heterocyclesulfonyl;
[0040] R.sup.25 and R.sup.26 are each independently selected from
the group consisting of hydrogen, alkoxy, alkyl, alkyl carbonyl,
alkylsulfonyl, aryl, arylcarbonyl, aryloxy, aryl sulfonyl,
carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,
heteroaryloxy, heteroarylsulfonyl, heterocycle,
heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and
hydroxy, or R.sup.25 and R.sup.26 together with the nitrogen to
which they are attached form a ring selected from the group
consisting of heteroaryl and heterocycle;
[0041] R.sup.27 and R.sup.28 are each independently selected from
the group consisting of hydrogen, alkyl, aryl, cycloalkyl,
heteroaryl and heterocycle or R.sup.27 and R.sup.28 together with
the atom to which they are attached form a ring selected from the
group consisting of cycloalkyl and heterocycle, or R.sup.27 and
R.sup.29 together with the atoms to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle, or R.sup.28 and R.sup.4 together with the atoms to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle;
[0042] R.sup.29 and R.sup.36 are each independently selected from
the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy,
cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and
N(R.sup.36R.sup.37), or R.sup.29 and R.sup.30 together with the
atom to which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle, or R.sup.29 and R.sup.4
together with the atoms to which they are attached form a ring
selected from the group consisting of cycloalkyl and heterocycle,
or R.sup.29 and E together with the atoms to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle;
[0043] R.sup.31 is selected from the group consisting of hydrogen,
alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R.sup.31
and E together with the atom to which they are attached form a ring
selected from the group consisting of heteroaryl and heterocycle,
or R.sup.31 and R.sup.4 together with the atoms to which they are
attached form a heterocycle;
[0044] R.sup.32 and R.sup.33 are each independently selected from
the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl,
heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl,
cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or
R.sup.32 and R.sup.33 together with the atom to which they are
attached form a heterocycle;
[0045] R.sup.34 and R.sup.35 are each independently selected from
the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl,
heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl,
cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or
R.sup.34 and R.sup.35 together with the atom to which they are
attached form a heterocycle; and
[0046] R.sup.36 and R.sup.3' are each independently selected from
the group consisting of hydrogen, alkyl and aryl.
[0047] A further aspect of the present invention encompasses the
use of the compounds of formula (I) for the treatment of disorders
that are mediated by 11-beta-hydroxysteroid dehydrogenase Type 1
enzyme, such as non-insulin dependent type 2 diabetes, insulin
resistance, obesity, lipid disorders, metabolic syndrome and other
diseases and conditions that are mediated by excessive
glucocorticoid action, comprising administering a therapeutically
effective amount of a compound of formula (I).
[0048] According to still another aspect, the present invention is
directed to a pharmaceutical composition comprising a
therapeutically effective amount of a compound of formula 0) in
combination with a pharmaceutically suitable carrier.
BRIEF DESCRIPTION OF THE FIGURES
[0049] FIG. 1 shows the results of memory consolidation in treated
and untreated mice measured as Mean Transfer Latency.
[0050] FIG. 2 depicts amount of phosphorylation of CREB in treated
and untreated mice.
[0051] FIG. 3 shows the results of memory consolidation in treated
and untreated mice measured as Mean Transfer Latency.
[0052] FIG. 4 shows the results of short memory retention in
treated and untreated mice measured as Mean Transfer Latency.
[0053] FIGS. 5a-5c show REM episodes, time and latency to first
episode, respectively, on rat treated with an exemplary
11.beta.-HSD-1 inhibitor.
[0054] FIGS. 6a, 6b and 6c show the effects of an exemplary
11.beta.-HSD-1 inhibitor on cortical and hippocampal Ach
release.
[0055] FIGS. 7a and 7b show the effects of an exemplary
11.beta.-HSD-1 inhibitor on cortical and hippocampal 5-HT
release.
DETAILED DESCRIPTION OF THE INVENTION
[0056] One aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof
##STR00002##
[0057] wherein
[0058] one of A.sup.1, A.sup.2, A.sup.3 and A.sup.4 is selected
from the group consisting of alkyl-NH-alkyl, alkylcarbonyl,
alkylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylsulfonyl,
arylcarbonyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocyclecarbonyl, heterocyclesulfonyl,
aryl.sup.1, arylalkyl, aryloxyalkyl, carboxyalkyl,
carboxycycloalkyl, haloalkyl, heterocyclealkyl,
heterocycleoxyalkyl, --S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)]).sub.p--C(O)--R.sup.13, --OR.sup.14a,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22, and
--C(R.sup.23R.sup.24)--N(R.sup.25R.sup.26), and heterocycle, with
the exception that 5 membered heterocycles may not contain two
oxygen atoms, and the remaining members of the group consisting of
A.sup.1, A.sup.2, A.sup.3 and A.sup.4 are each individually
selected from the group consisting of hydrogen, alkyl,
alkyl-NH-alkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
cycloalkylcarbonyl, cycloalkylsulfonyl, arylcarbonyl, arylsulfonyl,
heterocyclecarbonyl, heterocyclesulfonyl, aryl, arylalkyl,
aryloxyalkyl, carboxyalkyl, carboxycycloalkyl, halogen, haloalkyl,
heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl,
--S(O).sub.2--N(R.sup.5R.sup.6),
--NR.sup.7--[C(R.sup.8R.sup.9)].sub.n--C(O)--R.sup.10,
--O--[C(R.sup.11R.sup.12)]).sub.p--C(O)--R.sup.13, --OR.sup.14b,
--N(R.sup.15R.sup.16), --CO.sub.2R.sup.17,
--C(O)--N(R.sup.18R.sup.19), --C(R.sup.20R.sup.21)--OR.sup.22, and
--C(R.sup.23R.sup.24)--. N(R.sup.25R.sup.26);
[0059] n is 0 or 1;
[0060] p is 0 or 1;
[0061] D is selected from the group consisting of a bond,
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--;
[0062] E is selected from the group consisting of a cycloalkyl,
alkyl, aryl, heteroaryl and heterocycle, wherein the heteroaryl and
the heterocycle are appended to the parent molecular moiety through
an available carbon atom, or R.sup.4 and E together with the atoms
to which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle;
[0063] X is selected from the group consisting of a bond,
N(R.sup.31)--, --O--, --S--, --S(O)-- and --S(O).sub.2--;
[0064] R.sup.1 is selected from the group consisting of hydrogen
and alkyl;
[0065] R.sup.2 is selected from the group consisting of hydrogen,
alkyl and cycloalkyl;
[0066] R.sup.3 and R.sup.4 are each independently selected from the
group consisting of hydrogen, alkyl, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, haloalkyl, aryl, arylalkyl,
heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl, or
R.sup.3 and R.sup.4 together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle;
[0067] R.sup.5 and R.sup.6 are each independently selected from the
group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl,
alkylsufonyl, carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl,
arylalkylcarbonyl, arylcarbonyl, aryloxy, aryloxyalkyl,
arylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylalkylcarbonyl,
heteroarylcarbonyl, heteroaryloxyalkyl, heteroarylsulfonyl,
heterocycle, heterocyclealkyl, heterocyclealkylcarbonyl,
heterocyclecarbonyl, heterocycleoxyalkyl, heterocycleoxy,
heterocyclesulfonyl and hydroxy, or R.sup.5 and R.sup.6 together
with the atom to which they are attached form a heterocycle;
[0068] R.sup.7 is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, hydroxy, alkoxy, heteroaryl,
heteroarylalkyl, heteroaryloxyalkyl, heterocycle, heterocyclealkyl
and heterocycleoxyalkyl;
[0069] R.sup.8 and R.sup.9 are each independently selected from the
group consisting of hydrogen and alkyl, or R.sup.8 and R.sup.9
taken together with the atom to which they are attached form a ring
selected from the group consisting of cycloalkyl and
heterocycle;
[0070] R.sup.19 is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxy, aryloxyalkyl, hydroxy, alkoxy, cycloalkyloxy,
heteroaryl, heteroarylalkyl, heteroaryloxy, heteroaryloxyalkyl,
heterocycle, heterocyclealkyl, heterocycleoxy, heterocycleoxyalkyl
and --N(R.sup.32R.sup.33);
[0071] R.sup.11 and R.sup.12 are each independently selected from
the group consisting of hydrogen and alkyl or R.sup.11 and R.sup.12
taken together with the atom to which they are attached form a ring
selected from the group consisting of cycloalkyl and
heterocycle;
[0072] R.sup.13 is selected from the group consisting of hydroxy
and --N(R.sup.34R.sup.35);
[0073] R.sup.14a is selected from the group consisting of
carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,
aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl;
[0074] R.sup.14b is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, haloalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl;
[0075] R.sup.15 and R.sup.16 are each independently selected from
the group consisting of hydrogen, alkyl, alkylcarbonyl,
carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl, arylalkyl,
arylalkylcarbonyl, arylcarbonyl, aryloxyalkyl, heteroaryl,
heteroarylalkyl, heteroarylalkylcarbonyl, heteroarylcarbonyl,
heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,
heterocyclealkyl, heterocyclealkylcarbonyl, heterocyclecarbonyl,
heterocycleoxyalkyl, heterocyclesulfonyl, alkylsufonyl,
cycloalkylsulfonyl and arylsulfonyl, or R.sup.15 and R.sup.16
together with the atom to which they are attached form a
heterocycle;
[0076] R.sup.17 is selected from the group consisting of hydrogen,
alkyl, carboxyalkyl, cycloalkyl, carboxycycloalkyl, aryl,
arylalkyl, aryloxyalkyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heterocycle, heterocyclealkyl and
heterocycleoxyalkyl;
[0077] R.sup.13 and R.sup.19 are each independently selected from
the group consisting of hydrogen, alkoxy, alkyl, alkylsufonyl,
carboxy, carboxyalkyl, carboxycycloalkyl, cycloalkyl,
cycloalkyloxy, cycloalkylsulfonyl, aryl, arylalkyl, aryloxy,
aryloxyalkyl, arylsulfonyl, heteroaryl, heteroarylalkyl,
heteroaryloxyalkyl, heteroarylsulfonyl, heterocycle,
heterocyclealkyl, heterocycleoxyalkyl, heterocycleoxy,
heterocyclesulfonyl and hydroxy, or R.sup.18 and R.sup.19 together
with the atom to which they are attached form a heterocycle;
[0078] R.sup.20, R.sup.21 and R.sup.22 are each independently
selected from the group consisting of hydrogen, alkyl, aryl,
arylalkyl, carboxyalkyl, carboxycycloalkyl, cycloalkyl, haloalkyl,
heteroaryl, heteroarylalkyl, heterocycle and heterocyclealkyl;
[0079] R.sup.23 and R.sup.24 are each independently selected from
the group consisting of hydrogen, alkyl, alkylcarbonyl,
alkylsulfonyl, aryl, arylcarbonyl, arylsulfonyl, carboxyalkyl,
carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,
heteroarylsulfonyl, heterocycle, heterocyclecarbonyl and
heterocyclesulfonyl;
[0080] R.sup.25 and R.sup.26 are each independently selected from
the group consisting of hydrogen, alkoxy, alkyl, alkylcarbonyl,
alkylsulfonyl, aryl, arylcarbonyl, aryloxy, arylsulfonyl,
carboxyalkyl, carboxycycloalkyl, cycloalkyl, cycloalkylcarbonyl,
cycloalkyloxy, cycloalkylsulfonyl, heteroaryl, heteroarylcarbonyl,
heteroaryloxy, heteroarylsulfonyl, heterocycle,
heterocyclecarbonyl, heterocycleoxy, heterocyclesulfonyl and
hydroxy, or R.sup.25 and R.sup.26 together with the nitrogen to
which they are attached form a ring selected from the group
consisting of heteroaryl and heterocycle;
[0081] R.sup.27 and R.sup.28 are each independently selected from
the group consisting of hydrogen, alkyl, aryl, cycloalkyl,
heteroaryl and heterocycle or R.sup.27 and R.sup.28 together with
the atom to which they are attached form a ring selected from the
group consisting of cycloalkyl and heterocycle, or R.sup.27 and
R.sup.29 together with the atoms to which they are attached form a
ring selected from the group consisting of cycloalkyl and
heterocycle, or R.sup.28 and R.sup.4 together with the atoms to
which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle;
[0082] R.sup.29 and R.sup.30 are each independently selected from
the group consisting of hydrogen, alkyl, alkoxy, aryl, aryloxy,
cycloalkyl, cycloalkyloxy, heteroaryl, heterocycle, and
--N(R.sup.36R.sup.37), or R.sup.29 and R.sup.30 together with the
atom to which they are attached form a ring selected from the group
consisting of cycloalkyl and heterocycle, or R.sup.29 and R.sup.4
together with the atoms to which they are attached form a ring
selected from the group consisting of cycloalkyl and heterocycle,
or R.sup.29 and E together with the atoms to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle;
[0083] R.sup.31 is selected from the group consisting of hydrogen,
alkyl, aryl, cycloalkyl, heterocycle and heteroaryl, or R.sup.31
and E together with the atom to which they are attached form a ring
selected from the group consisting of heteroaryl and heterocycle,
or R.sup.31 and R.sup.4 together with the atoms to which they are
attached form a heterocycle;
[0084] R.sup.32 and R.sup.33 are each independently selected from
the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl,
heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl,
cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or
R.sup.32 and R.sup.33 together with the atom to which they are
attached form a heterocycle;
[0085] R.sup.34 and R.sup.35 are each independently selected from
the group consisting of hydrogen, alkyl, carboxy, carboxyalkyl,
cycloalkyl, cycloalkyloxy, carboxycycloalkyl, aryl, arylalkyl,
aryloxy, aryloxyalkyl, heterocycle, heterocyclealkyl,
heterocycleoxyalkyl, heterocycleoxy, hydroxy, alkoxy, alkylsufonyl,
cycloalkylsulfonyl, arylsulfonyl, and heterocyclesulfonyl, or
R.sup.34 and R.sup.35 together with the atom to which they are
attached form a heterocycle; and
[0086] R.sup.36 and R.sup.37 are each independently selected from
the group consisting of hydrogen, alkyl and aryl.
[0087] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0088] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0089] R.sup.1 and R.sup.2 are hydrogen; and A.sup.1, R.sup.3,
R.sup.4, D and E are as described in the summary of the
invention.
[0090] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0091] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0092] R.sup.1 and R.sup.2 arc hydrogen;
[0093] D is a bond; and A.sup.1, R.sup.3, R.sup.4 and E are as
described in the summary of the invention.
[0094] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0095] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0096] R.sup.1 and R.sup.2 are hydrogen;
[0097] D is a bond;
[0098] E is selected from the group consisting of alkyl, aryl, and
heteroaryl; and
[0099] A.sup.1, R.sup.3, and R.sup.4 arc as described in the
summary of the invention.
[0100] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0101] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0102] R.sup.1 and R.sup.2 are hydrogen;
[0103] D is a bond;
[0104] E is selected from the group consisting of alkyl, aryl and
heteroaryl;
[0105] R.sup.3 and R.sup.4 are hydrogen; and
[0106] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6, R'7,
R.sup.18 and R.sup.19 are as described in the summary of the
invention.
[0107] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0108] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0109] R.sup.1 and R.sup.2 are hydrogen;
[0110] D is a bond;
[0111] E is selected from the group consisting of alkyl, aryl and
heteroaryl;
[0112] R.sup.3 is hydrogen;
[0113] R.sup.4 is alkyl; and
[0114] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0115] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof; wherein
[0116] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0117] R.sup.1 and R.sup.2 are hydrogen;
[0118] D is a bond;
[0119] E is selected from the group consisting of alkyl, aryl and
heteroaryl;
[0120] R.sup.3 and R.sup.4 are alkyl; and
[0121] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0122] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0123] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0124] R.sup.1 and R.sup.2 are hydrogen;
[0125] D is a bond;
[0126] E is selected from the group consisting of alkyl, aryl and
heteroaryl;
[0127] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; and A.sup.1 is as described in the
summary of the invention.
[0128] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0129] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0130] R.sup.1 and R.sup.2 are hydrogen;
[0131] D is a bond;
[0132] E is selected from the group consisting of alkyl, aryl and
heteroaryl;
[0133] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a cycloalkyl ring; and
[0134] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 arc as described in the summary of
the invention.
[0135] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0136] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0137] R.sup.1 and R.sup.2 are hydrogen;
[0138] D is a bond;
[0139] E is selected from the group consisting of alkyl, aryl and
heteroaryl;
[0140] R.sup.3 and R.sup.4 together with the atom to which they are
attached, form a heterocycle ring; and
[0141] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein. R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0142] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0143] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0144] R.sup.1 and R.sup.2 are hydrogen;
[0145] D is a bond;
[0146] R.sup.4 and E together with the atoms to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; and
[0147] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.3, R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0148] Another aspect of the present invention is directed toward a
compound of formula (II), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof,
##STR00003##
[0149] wherein
[0150] t is 1 or 2;
[0151] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0152] R.sup.1 and R.sup.2 are hydrogen;
[0153] R.sup.3 is alkyl;
[0154] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention; and
[0155] R.sup.38 is selected from the group consisting of arylalkyl
and heteroarylalkyl wherein the aryl of the arylalkyl and the
heteroaryl of the heteroarylalkyl are each independently
unsubstituted or substituted with 1, 2 or 3 substituents selected
from the group consisting of alkyl, halogen and haloalkyl.
[0156] Another aspect of the present invention is directed toward a
compound of formula (III), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof,
##STR00004##
[0157] wherein
[0158] t is 1 or 2;
[0159] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0160] R.sup.1 and R.sup.2 are hydrogen;
[0161] R.sup.3 is alkyl;
[0162] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention; and
[0163] R.sup.38 is selected from the group consisting of arylalkyl
and heteroarylalkyl wherein the aryl of the arylalkyl and the
heteroaryl of the heteroarylalkyl are each independently
unsubstituted or substituted with 1, 2 or 3 substituents selected
from the group consisting of alkyl, halogen and haloalkyl.
[0164] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0165] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0166] R.sup.1 and R.sup.2 are hydrogen;
[0167] D is selected from the group consisting of
--C(R.sup.27R.sup.24)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; and R.sup.27,
R.sup.28, R.sup.29, R.sup.30, X, A.sup.1, R.sup.3, R.sup.4 and E
are as described in the summary of the invention.
[0168] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0169] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0170] R.sup.1 and R.sup.2 are hydrogen;
[0171] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, R.sup.30, and X are as described in the summary
of the invention;
[0172] E is selected from the group consisting of aryl and
heteroaryl; and A.sup.1, R.sup.3, and R.sup.4 are as described in
the summary of the invention.
[0173] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0174] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0175] R.sup.1 and R.sup.2 are hydrogen;
[0176] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are as described in the summary of
the invention;
[0177] E is selected from the group consisting of aryl and
heteroaryl;
[0178] X is a bond; and A.sup.1, R.sup.3, and R.sup.4 are as
described in the summary of the invention.
[0179] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0180] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0181] R.sup.1 and R.sup.2 are hydrogen;
[0182] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.39 are each independently selected
from the group consisting of hydrogen and alkyl;
[0183] E is selected from the group consisting of aryl and
heteroaryl;
[0184] X is a bond;
[0185] R.sup.3 and R.sup.4 are hydrogen; and
[0186] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.7, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0187] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0188] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0189] R.sup.1 and R.sup.2 are hydrogen;
[0190] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0191] E is selected from the group consisting of aryl and
heteroaryl;
[0192] X is a bond;
[0193] R.sup.3 is hydrogen;
[0194] R.sup.4 is alkyl; and
[0195] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0196] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0197] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0198] R.sup.1 and R.sup.2 are hydrogen;
[0199] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0200] E is selected from the group consisting of aryl and
heteroaryl;
[0201] X is a bond;
[0202] R.sup.3 and R.sup.4 are alkyl; and
[0203] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0204] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0205] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0206] R.sup.1 and R.sup.2 arc hydrogen;
[0207] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)
[0208] X--; wherein R.sup.27, R.sup.28, R.sup.29, and R.sup.30 are
as described in the summary of the invention;
[0209] E is selected from the group consisting of aryl and
heteroaryl;
[0210] X is a bond;
[0211] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; and A.sup.1 is as described in the
summary of the invention.
[0212] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0213] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0214] R.sup.1 and R.sup.2 are hydrogen;
[0215] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0216] E is selected from the group consisting of aryl and
heteroaryl;
[0217] X is a bond;
[0218] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a cycloalkyl ring; and
[0219] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0220] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0221] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0222] R.sup.1 and R.sup.2 are hydrogen;
[0223] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.39 are each independently selected
from the group consisting of hydrogen and alkyl;
[0224] E is selected from the group consisting of aryl and
heteroaryl;
[0225] X is a bond;
[0226] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a heterocycle ring; and
[0227] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0228] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0229] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0230] R.sup.1 and R.sup.2 are hydrogen;
[0231] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.39 are as described in the summary of
the invention; E is selected from the group consisting of aryl and
heteroaryl;
[0232] X is selected from the group consisting of --N(R.sup.31)--
and --O--; and A.sup.1, R.sup.3, and R.sup.4 are as described in
the summary of the invention.
[0233] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0234] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0235] R.sup.1 and R.sup.2 are hydrogen;
[0236] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.39 are each independently selected
from the group consisting of hydrogen and alkyl;
[0237] E is selected from the group consisting of aryl and
heteroaryl;
[0238] X is selected from the group consisting of --N(R.sup.31)--
and --O--;
[0239] R.sup.3 and R.sup.4 are hydrogen; and
[0240] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0241] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0242] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0243] R.sup.1 and R.sup.2 are hydrogen;
[0244] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0245] E is selected from the group consisting of aryl and
heteroaryl;
[0246] X is selected from the group consisting of --N(R.sup.31)--
and --O--;
[0247] R.sup.3 is hydrogen;
[0248] R.sup.4 is alkyl; and
[0249] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6, R.sup.18
and R.sup.19 are as described in the summary of the invention.
[0250] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0251] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0252] R.sup.1 and R.sup.2 are hydrogen;
[0253] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0254] E is selected from the group consisting of aryl and
heteroaryl;
[0255] X is selected from the group consisting of --N(R.sup.31)--
and --O--;
[0256] R.sup.3 and R.sup.4 are alkyl; and
[0257] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0258] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0259] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0260] R.sup.1 and R.sup.2 are hydrogen;
[0261] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0262] E is selected from the group consisting of aryl and
heteroaryl;
[0263] X is selected from the group consisting of --N(R.sup.31)--
and --O--;
[0264] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a ring selected from the group consisting of
cycloalkyl and heterocycle; and
[0265] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0266] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0267] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0268] R.sup.1 and R.sup.2 are hydrogen;
[0269] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0270] E is selected from the group consisting of aryl and
heteroaryl;
[0271] X is selected from the group consisting of --N(R.sup.31)--
and --O--;
[0272] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a cycloalkyl ring; and
[0273] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0274] Another aspect of the present invention is directed toward a
compound of formula (I), or a pharmaceutically acceptable salt,
prodrug, salt of a prodrug, or a combination thereof, wherein
[0275] A.sup.2, A.sup.3 and A.sup.4 are hydrogen;
[0276] R.sup.1 and R.sup.2 are hydrogen;
[0277] D is selected from the group consisting of
--C(R.sup.27R.sup.28)--X-- and --C(R.sup.27R.sup.28)--X-- and
--C(R.sup.27R.sup.28)--C(R.sup.29R.sup.30)--X--; wherein R.sup.27,
R.sup.28, R.sup.29, and R.sup.30 are each independently selected
from the group consisting of hydrogen and alkyl;
[0278] E is selected from the group consisting of aryl and
heteroaryl;
[0279] X is selected from the group consisting of --N(R.sup.31)--
and --O--;
[0280] R.sup.3 and R.sup.4 together with the atom to which they are
attached form a heterocycle ring; and
[0281] A.sup.1 is selected from the group consisting of heteroaryl,
--CO.sub.2R.sup.17, --C(O)--N(R.sup.18R.sup.19), alkylsulfonyl, and
--S(O).sub.2--N(R.sup.5R.sup.6); wherein R.sup.5, R.sup.6,
R.sup.17, R.sup.18 and R.sup.19 are as described in the summary of
the invention.
[0282] Exemplary compounds of the present invention having formula
(I) include, but are not limited to, [0283]
E-4-([1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino)-adamantane-1-carbox-
ylic acid; [0284]
E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic
acid; [0285]
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic
acid; [0286]
E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carbox-
ylic acid amide; [0287]
E-4-[(1-Phenyl-cyclopropanecarbonyl)-amino]-adamantane-1-carboxylic
acid amide; [0288]
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid
amide; [0289]
E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxami-
de; [0290]
E-4-([1-(4-chlorophenyl)cyclopropyl]carbonyl)amino)adamantane-1-
-carboxamide; [0291]
E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxam-
ide; [0292]
E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide-
; [0293]
E-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamid-
e; [0294]
E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-
-carboxamide; [0295]
E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-
-carboxamide; [0296]
E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxam-
ide; [0297]
E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxam-
ide; [0298]
E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide;
[0299]
E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carb-
oxamide; [0300]
E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxa-
mide; [0301]
E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxam-
ide; [0302]
E-4-{[2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]amino}adamantane-1-carbo-
xamide; [0303]
E-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide;
[0304]
E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamid-
e; [0305]
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amin-
o)adamantane-1-carboxamide; [0306]
E-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2yl]phenyl}propanoyl)amin-
o]adamantane-1-carboxamide; [0307]
E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxa-
mide; [0308]
E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;
[0309]
E-4-[5-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2--
oxopiperidine-3-carboxamide; [0310]
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-car-
boxamide; [0311]
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrroli-
dine-3-carboxamide; [0312]
E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrroli-
dine-3-carboxamide; [0313]
E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrroli-
dine-3-carboxamide; [0314]
E-4-({2-methyl-2-[4-(1-methyl-1-pyrazol-4-yl)phenyl]propanoyl}amino)adama-
ntane-1-carboxamide; [0315]
E-4-{[2-(3-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide;
[0316]
E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2-methylpropanoyl}am-
ino)adamantane-1-carboxamide; [0317]
E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-1-carbo-
xamide; [0318]
4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)-
amino]methyl}benzoic acid; [0319]
E-4-({2-methyl-2-[4-(1H-pyrazol-4-yl)phenyl]propanoyl}amino)adamantane-1--
carboxamide; [0320]
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-ox-
opyrrolidine-3-carboxamide; [0321]
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyr-
rolidine-3-carboxamide; [0322]
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyr-
rolidine-3-carboxamide; [0323]
E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxami-
de; [0324]
E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpip-
eridine-3-carboxamide; [0325]
E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamid-
e; [0326]
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidi-
ne-3-carboxamide; [0327]
E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamid-
e; [0328]
E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantane-1-
-carboxamide; [0329]
E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carbo-
xamide; [0330]
E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide;
[0331]
(E)-4-[(2-methyl-2-pyrazin-2-ylpropanoyl)amino]adamantane-1-carbox-
amide; [0332]
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(2-pyridin-2-yleth-
yl)pyrrolidine-3-carboxamide; [0333]
methyl(E)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-carboxylate;
[0334]
(E)-4-({2-methyl-2-[3-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}am-
ino)adamantane-1-carboxamide; [0335]
(E)-4-({2-methyl-2-[6-(methylamino)pyridin-3-yl]propanoyl}amino)adamantan-
e-1-carboxamide; [0336]
(E)-4-({2-methyl-2-[3-(morpholin-4-ylmethyl)phenyl]propanoyl}amino)adaman-
tane-1-carboxamide; [0337]
(E)-4-({2-methyl-2-[4-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adama-
ntane-1-carboxamide; [0338]
(E)-4-[(2-{3-[2-(1H-imidazol-1-yl)ethoxy]phenyl}-2-methylpropanoyl)amino]-
adamantane-1-carboxamide; [0339]
methyl(E)-4-{[(1-phenylcyclopropyl)carbonyl]amino}adamantane-1-carboxylat-
e; [0340]
(E)-4-[{2-(6-fluoropyridin-3-yl)-2-methylpropanoyl]amino}adamant-
ane-1-carboxamide; [0341]
(E)-N-[3-(aminocarbonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adam-
antane-1-carboxamide; [0342]
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopi-
peridine-3-carboxamide; [0343]
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-4-ylmethy-
l)pyrrolidine-3-carboxamide; [0344]
(E)-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxyl-
ic acid; [0345]
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-phenylcyclopropanecarboxamide;
[0346]
(E)-4-({3-[(5-cyanopyridin-2-yl)oxy]-2,2-dimethylpropanoyl}amino)a-
damantane-1-carboxamide; [0347]
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(1-pyridin-2-yleth-
yl)pyrrolidine-3-carboxamide; [0348]
(E)-4-[(2-methyl-3-phenylpropanoyl)amino]adamantane-1-carboxamide;
[0349]
(E)-4-([2-methyl-2-(6-morpholin-4-ylpyridin-3-yl)propanoyl]aminol
adamantane-1-carboxamide; [0350]
methyl(E)-4-({[1-(4-chlorophenyl)cyclobutyl]carbonyl}amino)adamantane-1-c-
arboxylate; [0351]
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-3-ylmethy-
l)pyrrolidine-3-carboxamide; [0352]
(E)-4-[(2-methyl-2-{6-[(2-morpholin-4-ylethyl)amino]pyridin-3-yl}propanoy-
l)amino]adamantane-1-carboxamide; [0353]
(E)-4-[(2-methyl-2-{4-[(E)-2-pyridin-4-ylvinyl]phenyl}propanoyl)amino]ada-
mantane-1-carboxamide; [0354]
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-2-(4-chlorophenyl)-2-methylpropanam-
ide; [0355]
(E)-4-({2-methyl-2-[3-(2-morpholin-4-ylethoxy)phenyl]propanoyl}amino)adam-
antane-1-carboxamide; [0356]
(E)-4-{[2-(3-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carb-
oxamide; [0357]
(E)-4-({2-methyl-2-[6-(4-methylpiperazin-1-yl)pyridin-3-yl]propanoyl}amin-
o)adamantane-1-carboxamide; [0358]
N-[(E)-5-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-(pyridin-2-ylmethy-
l)pyrrolidine-3-carboxamide; [0359]
(E)-N-[4-(aminosulfonyl)benzyl]-4-[(2-methyl-2-phenylpropanoyl)amino]adam-
antane-1-carboxamide; [0360]
(E)-4-({2-methyl-2-[4-(pentyloxy)phenyl]propanoyl}amino)adamantane-1-carb-
oxylic acid; [0361]
(E)-4-({2-methyl-2-[4-(1,3-thiazol-4-ylmethoxy)phenyl]propanoyl}amino)ada-
mantane-1-carboxylic acid; [0362]
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-N-(1,3-thiazol-5-ylmethyl)adama-
ntane-1-carboxamide; [0363]
(E)-4-({2-[4-(benzyloxy)phenyl]-2-methylpropanoyl}amino)adamantane-1-carb-
oxylic acid; [0364]
(E)-4-{[2-(5-cyanopyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carb-
oxamide; [0365] (E)-4-[2-(4-chlorophenyl)-2-methylpropanoyl]amino)
adamantane-1-carboxylic acid; [0366]
4-[({[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino-
)-1-adamantyl]carbonyl}amino)methyl]benzoic acid; [0367]
4-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amin-
o]methyl}benzoic acid; [0368]
3-{[({(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-1-adamantyl}carbonyl)amin-
o]methyl}benzoic acid; [0369]
(E)-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carbox-
ylic acid; [0370]
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-Nyridin-4-ylmethyl)adamantane-1-
-carboxamide; [0371]
(E)-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-ca-
rboxylic acid; [0372]
(E)-N-(2-furylmethyl)-4-[(2-methyl-2-phenylpropanoyl)amino]adamantane-1-c-
arboxamide; [0373]
3-[(E)-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)-1-
-adamantyl]-1H-pyrazole-5-carboxamide; [0374]
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-Nyridin-3-ylmethyl)adamantane-1-
-carboxamide; [0375]
(E)-4-[(2-methyl-2-phenylpropanoyl)amino]-Nyridin-2-ylmethyl)adamantane-1-
-carboxamide; [0376]
(E)-4-({2-[4-(cyclohexylmethoxy)phenyl]-2-methylpropanoyl}amino)adamantan-
e-1-carboxylic acid; [0377]
(E)-4-[(2-methyl-2-{4-[5-(trifluoromethyl)pyridin-2-yl]phenyl}propanoyl)a-
mino]adamantane-1-carboxylic acid; and [0378]
N-[(E)-5-(aminosulfonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopy-
rrolidine-3-carboxamide.
[0379] Another embodiment of the present invention discloses a
method of inhibiting 11-beta-hydroxysteroid dehydrogenase Type I
enzyme, comprising administering to a mammal, a therapeutically
effective amount of the compound of formula (I).
[0380] Another embodiment of the present invention discloses a
method of treating disorders in a mammal by inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising
administering to a mammal, a therapeutically effective amount of
the compound of formula (I).
[0381] Another embodiment of the present invention discloses a
method of treating non-insulin dependent type 2 diabetes in a
mammal by inhibiting 11-beta-hydroxysteroid dehydrogenase Type I
enzyme comprising administering to a mammal, a therapeutically
effective amount of the compound of formula (I).
[0382] Another embodiment of the present invention discloses a
method of treating insulin resistance in a mammal by inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising
administering to a mammal, a therapeutically effective amount of
the compound of formula (I).
[0383] Another embodiment of the present invention discloses a
method of treating obesity in a mammal by inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising
administering to a mammal, a therapeutically effective amount of
the compound of formula (I).
[0384] Another embodiment of the present invention discloses a
method of treating lipid disorders in a mammal by inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising
administering to a mammal, a therapeutically effective amount of
the compound of formula (I).
[0385] Another embodiment of the present invention discloses a
method of treating metabolic syndrome in a mammal by inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising
administering to a mammal, a therapeutically effective amount of
the compound of formula (I).
[0386] Another embodiment of the present invention discloses a
method of treating diseases and conditions that are mediated by
excessive glucocorticoid action in a mammal by inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme comprising
administering to a mammal, a therapeutically effective amount of
the compound of formula (I).
[0387] Another embodiment of the present invention discloses a
pharmaceutical composition comprising a therapeutically effective
amount of the compound of formula (I) in combination with a
pharmaceutically suitable carrier.
DEFINITION OF TERMS
[0388] The term "alkenyl" as used herein, refers to a straight or
branched chain hydrocarbon containing from 2 to 10 carbons and
containing at least one carbon-carbon double bond formed by the
removal of two hydrogens. Representative examples of alkenyl
include, but are not limited to, ethenyl, 2-propenyl,
2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl,
2-methyl-1-heptenyl, and 3-decenyl.
[0389] The term "alkoxy" as used herein, refers to an alkyl group,
as defined herein, appended to the parent molecular moiety through
an oxygen atom. Representative examples of alkoxy include, but are
not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,
tert-butoxy, pentyloxy and hexyloxy.
[0390] The term "alkoxyalkyl" as used herein, refers to an alkoxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of alkoxyalkyl include, but are not limited to, tert-butoxymethyl,
2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.
[0391] The term "alkoxycarbonyl" as used herein, refers to an
alkoxy group, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein. Representative
examples of alkoxycarbonyl include, but are not limited to,
methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl.
[0392] The term "alkyl" as used herein, refers to a straight or
branched chain hydrocarbon containing from 1 to 10 carbon atoms.
Representative examples of alkyl include, but are not limited to,
methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,
2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl
and n-decyl.
[0393] The term "alkylcarbonyl," as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of alkylcarbonyl include, but are not limited to, acetyl,
1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and
1-oxopentyl.
[0394] The term "alkylsulfonyl" as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of alkylsulfonyl include, but are not limited to,
methylsulfonyl and ethylsulfonyl.
[0395] The term "alkyl-NH" as used herein, refers to an alkyl
group, as defined herein, appended to the parent molecular moiety
through a nitrogen atom.
[0396] The term "alkyl-NH-alkyl" as used herein, refers to an
alkyl-NH group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0397] The term "aryl" as used herein, means a phenyl group, or a
bicyclic or a tricyclic fused ring system. Bicyclic fused ring
systems are exemplified by a phenyl group appended to the parent
molecular moiety and fused to a monocyclic cycloalkyl group, as
defined herein, a phenyl group, a monocyclic heteroaryl group, as
defined herein, or a monocyclic heterocycle, as defined herein.
Tricyclic fused ring systems are exemplified by an aryl bicyclic
fused ring system, as defined herein and fused to a monocyclic
cycloalkyl group, as defined herein, a phenyl group, a monocyclic
heteroaryl group, as defined herein, or a monocyclic heterocycle,
as defined herein. Representative examples of aryl include, but are
not limited to, anthracenyl, azulenyl, fluorenyl, indanyl, indenyl,
naphthyl, phenyl and tetrahydronaphthyl.
[0398] The aryl groups of this invention may be optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl,
aryl, arylalkenyl, arylalkyl, arylalkoxy, arylcarbonyl, aryloxy,
arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,
cycloalkylalkoxy, ethylenedioxy, formyl, haloalkoxy, haloalkyl,
halogen, heteroaryl, heteroarylalkenyl, heteroarylalkyl,
heteroarylalkoxy, heteroarylcarbonyl, heterocycle,
heterocyclealkyl, heterocyclealkoxy, heterocyclecarbonyl,
heterocycleoxy, hydroxy, hydroxyalkyl, nitro, R.sub.fR.sub.gN--,
R.sub.fR.sub.gNalkyl, R.sub.fR.sub.gNcarbonyl and
R.sub.fR.sub.gNsulfonyl, wherein R.sub.f and R.sub.g are
independently selected from the group consisting of hydrogen,
alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl,
heterocyclealkyl and cycloalkylalkyl and wherein the cycloalkyl,
the heterocycle of heterocyclealkyl and the cycloalkyl of
cycloalkylalkyl as represented by R.sub.f and R.sub.g are each
independently unsubstituted or substituted with 1, 2 or 3
substituent selected from the group consisting of alkyl, haloalkyl
and halogen. The substituent aryl, the aryl of arylalkyl, the aryl
of arylalkenyl, the aryl of arylalkoxy, the aryl of arylcarbonyl,
the aryl of aryloxy, the aryl of arylsulfonyl, the cycloalkyl of
cycloalkylalkoxy, the substituent heteroaryl, the heteroaryl of
heteroarylalkyl, the heteroaryl of heteroarylalkenyl, the
heteroaryl of heteroarylalkoxy, the heteroaryl of
heteroarylcarbonyl, the substituent heterocycle, the heterocycle of
heterocyclealkyl, the heterocycle of heterocyclealkoxy, the
heterocycle of heterocyclecarbonyl, the heterocycle of
heterocycleoxy, the heterocycle of heterocyclesulfonyl may be
optionally substituted with 1, 2 or 3 substituents independently
selected from the group consisting of alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy,
carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl,
nitro, R.sub.fR.sub.eN--, R.sub.fR.sub.gNalkyl,
R.sub.fR.sub.gNcarbonyl and R.sub.fR.sub.gNsulfonyl.
[0399] The term "aryl.sup.1 " as used herein, refers to a
substituted phenyl group wherein the substituent is a member
selected from the group consisting of alkenyl, alkoxy,
alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl,
alkyl, alkylcarbonyl, alkynyl, aryl, aryl carbonyl, aryloxy,
arylsulfonyl, carboxy, carboxyalkyl, cyano, cyanoalkyl,
ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl,
heteroaryl alkyl, heteroarylcarbonyl, heterocycle,
heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl and
nitro, or a bicyclic or a tricyclic fused ring system. Bicyclic
fused ring systems are exemplified by a phenyl group appended to
the parent molecular moiety, which is fused to a cycloalkyl group,
as defined herein, a phenyl group, a heteroaryl, as defined herein,
or a heterocycle as defined herein. Tricyclic fused ring systems
are exemplified by an aryl bicyclic fused ring system fused to a
cycloalkyl group, as defined herein, a phenyl group, a heteroaryl,
as defined herein, or a heterocycle as defined herein. Bicyclic and
tricyclic fused ring systems of this invention may be optionally
substituted with 1, 2, 3, 4 or 5 substituents independently
selected from alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl,
alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl,
aryl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy, carboxyalkyl,
cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy, haloalkyl,
halogen, heteroaryl, heteroarylalkyl, heteroarylcarbonyl,
heterocycle, heterocyclecarbonyl, heterocycleoxy, hydroxy,
hydroxyalkyl, nitro, R.sub.fR.sub.gN--, R.sub.fR.sub.gNalkyl,
R.sub.fR.sub.gNcarbonyl and R.sub.fR.sub.gNsulfonyl, wherein
R.sub.f and R.sub.g are as described herein. Representative
examples of aryl' include, but are not limited to, anisole,
aniline, anthracenyl, azulenyl, fluorenyl, naphthyl, and
tetrahydronaphthyl.
[0400] The term "arylalkenyl" as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkenyl group, as defined herein.
[0401] The term "arylalkyl" as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of arylalkyl include, but are not limited to, benzyl,
2-phenylethyl, 3-phenylpropyl and 2-naphth-2-ylethyl.
[0402] The term "arylalkoxy" as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through an alkoxy group, as defined herein.
[0403] The term "arylcarbonyl" as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through a carbonyl group, as defined herein. Representative
examples of arylcarbonyl include, but are not limited to, benzoyl
and naphthoyl.
[0404] The term "aryl-NH--" as used herein, refers to an aryl
group, as defined herein. appended to the parent molecular moiety
through a nitrogen atom.
[0405] The term "aryl-NH-alkyl" as used herein, refers to an
aryl-NH-group, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0406] The term "aryloxy," as used herein, refers to an aryl group,
as defined herein, appended to the parent molecular moiety through
an oxy moiety, as defined herein. Representative examples of
aryloxy include, but are not limited to phenoxy, naphthyloxy,
3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and
3,5-dimethoxyphenoxy.
[0407] The term "aryloxyalkyl" as used herein, refers to an aryloxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein.
[0408] The term "arylsulfonyl" as used herein, refers to an aryl
group, as defined herein, appended to the parent molecular moiety
through a sulfonyl group, as defined herein. Representative
examples of arylsulfonyl include, but are not limited to,
phenylsulfonyl, 4-bromophenylsulfonyl, and naphthylsulfonyl.
[0409] The term "carbonyl" as used herein refers to a --C(O)--
group.
[0410] The term "carboxy" as used herein refers to a --C(O)--OH
group.
[0411] The term "carboxyalkyl" as used herein refers to a carboxy
group as defined herein, appended to the parent molecular moiety
through an alkyl group as defined herein.
[0412] The term "carboxycycloalkyl" as used herein refers to a
carboxy group as defined herein, appended to the parent molecular
moiety through an cycloalkyl group as defined herein.
[0413] The term "cycloalkyl" as used herein, refers to a
monocyclic, bicyclic, or tricyclic ring system. Monocyclic ring
systems are exemplified by a saturated cyclic hydrocarbon group
containing from 3 to 8 carbon atoms. Examples of monocyclic ring
systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl. Bicyclic fused ring systems are
exemplified by a cycloalkyl group appended to the parent molecular
moiety, which is fused to an additional cycloalkyl group, as
defined herein, a phenyl group, a heteroaryl, as defined herein, or
a heterocycle as defined herein. Tricyclic fused ring systems are
exemplified by a cycloalkyl bicyclic fused ring system fused to an
additional cycloalkyl group, as defined herein, a phenyl group, a
heteroaryl, as defined herein, or a heterocycle as defined herein.
Bicyclic ring systems are also exemplified by a bridged monocyclic
ring system in which two non-adjacent carbon atoms of the
monocyclic ring are linked by an alkylene bridge of between one and
three additional carbon atoms. Representative examples of bicyclic
ring systems include, but are not limited to,
bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane,
bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and
bicyclo[4.2.1]nonane. Tricyclic ring systems arc also exemplified
by a bicyclic ring system in which two non-adjacent carbon atoms of
the bicyclic ring are linked by a bond or an alkylene bridge of
between one and three carbon atoms. Representative examples of
tricyclic-ring systems include, but are not limited to,
tricyclo[3.3.1.0.sup.3,7]nonane and tricyclo[3.3.1.1.sup.3,7]decane
(adamantane).
[0414] The cycloalkyl groups of this invention may be substituted
with 1, 2, 3, 4 or 5 substituents independently selected from
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl,
arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy,
carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, ethylenedioxy, formyl,
haloalkoxy, haloalkyl, halogen, heteroaryl, heteroarylalkyl,
heteroarylcarbonyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro,
R.sub.fR.sub.gN--, R.sub.fR.sub.gNalkyl, R.sub.fR.sub.gNcarbonyl
and R.sub.fR.sub.gNsulfonyl, wherein R.sub.f and R.sub.g are
independently selected from the group consisting of hydrogen,
alkyl, alkoxyalkyl, alkylcarbonyl, alkylsulfonyl, cycloalkyl and
cycloalkylalkyl. The substituent aryl, the aryl of arylalkyl, the
aryl of arylcarbonyl, the aryl of aryloxy, the aryl of
arylsulfonyl, the substituent heteroaryl, the heteroaryl of
heteroarylalkyl, the heteroaryl of heteroarylcarbonyl, the
substituent heterocycle, the heterocycle of heterocyclealkyl, the
heterocycle of heterocyclecarbonyl, the heterocycle of
heterocycleoxy, the heterocycle of heterocyclesulfonyl may be
optionally substituted with 0, 1, 2 or 3 substituents independently
selected from the group consisting of alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy,
carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl,
nitro, R.sub.fR.sub.gN--, R.sub.fR.sub.gNalkyl,
R.sub.fR.sub.gNcarbonyl and R.sub.fR.sub.gNsulfonyl.
[0415] The term "cycloalkylalkyl" as used herein, refers to a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
Representative examples of cycloalkylalkyl include, but are not
limited to, cyclopropylmethyl, 2-cyclobutylethyl,
cyclopentylmethyl, cyclohexylmethyl and 4-cycloheptylbutyl.
[0416] The term "cycloalkylalkoxy" as used herein, refers to a
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an alkoxy group, as defined herein.
[0417] The term "cycloalkylcarbonyl" as used herein, refers to
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
Representative examples of cycloalkylcarbonyl include, but are not
limited to, cyclopropylcarbonyl, 2-cyclobutylcarbonyl and
cyclohexylcarbonyl.
[0418] The term "cycloalkyloxy," as used herein, refers to
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through an oxy group, as defined herein.
[0419] The term "cycloalkylsulfonyl," as used herein, refers to
cycloalkyl group, as defined herein, appended to the parent
molecular moiety through a sulfonyl group, as defined herein.
Representative examples of cycloalkylsulfonyl include, but are not
limited to, cyclohexylsulfonyl and cyclobutylsulfonyl.
[0420] The term "halo" or "halogen," as used herein, refers to
--Cl, --Br, --I or --F.
[0421] The term "haloalkyl," as used herein, refers to at least one
halogen, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of haloalkyl include, but are not limited to, chloromethyl,
2-fluoroethyl, trifluoromethyl, pentafluoroethyl and
2-chloro-3-fluoropentyl.
[0422] The term "heteroaryl," as used herein, refers to an aromatic
monocyclic ring or an aromatic bicyclic ring system. The aromatic
monocyclic rings are five or six membered rings containing at least
one heteroatom independently selected from the group consisting of
N, O and S. The five membered aromatic monocyclic rings have two
double bonds and the six membered aromatic monocyclic rings have
three double bonds. The bicyclic heteroaryl groups are exemplified
by a monocyclic heteroaryl ring appended to the parent molecular
moiety and fused to a monocyclic cycloalkyl group, as defined
herein, a monocyclic aryl group, as defined herein, a monocyclic
heteroaryl group, as defined herein, or a monocyclic heterocycle,
as defined herein. Representative examples of heteroaryl include,
but are not limited to, benzimidazolyl, benzofuranyl,
benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl,
indazolyl, indolyl, indolizinyl, isobenzofuranyl, isoindolyl,
isoxazolyl, isoquinolinyl, isothiazolyl, naphthyridinyl,
oxadiazolyl, oxazolyl, phthalazinyl, pyridinyl, pyridazinyl,
pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, quinolinyl,
quinolizinyl, quinoxalinyl, quinazolinyl, tetrazolyl, thiadiazolyl,
thiazolyl, thienyl, triazolyl and triazinyl.
[0423] The heteroaryls of this invention may be optionally
substituted with 1, 2 or 3 substituents independently selected from
alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl,
arylalkenyl, arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl,
carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl,
ethylenedioxy, formyl, haloalkoxy, haloalkyl, halogen, heteroaryl,
heteroarylalkenyl, heteroarylalkyl, heterocycle, heterocyclealkyl,
heterocyclecarbonyl, heterocycleoxy, hydroxy, hydroxyalkyl, nitro,
R.sub.fR.sub.gN--, R.sub.fR.sub.gNalkyl, R.sub.fR.sub.gNcarbonyl
and R.sub.fR.sub.gNsulfonyl, wherein R.sub.f and R.sub.g are as
described herein. The substituent aryl, the aryl of arylalkyl, the
aryl of arylalkenyl, the aryl of arylcarbonyl, the aryl of aryloxy,
the aryl of arylsulfonyl, the substituent heteroaryl, the
heteroaryl of heteroarylalkyl, the heteroaryl of heteroarylalkenyl,
the substituent heterocycle, the heterocycle of heterocyclealkyl,
the heterocycle of heterocyclecarbonyl, the heterocycle of
heterocycleoxy, may be optionally substituted with 1, 2 or 3
substituents independently selected from the group consisting of
alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl,
carboxy, carboxyalkyl, cyano, haloalkyl, halogen, hydroxy,
hydroxyalkyl, nitro, R.sub.rR.sub.gN--, R.sub.fR.sub.gNalkyl,
R.sub.fR.sub.gNcarbonyl and R.sub.fR.sub.gNsulfonyl.
[0424] The term "heteroarylalkenyl" as used herein, refers to a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkenyl group, as defined herein.
[0425] The term "heteroarylalkyl" as used herein, refers to a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0426] The term "heteroarylalkoxy" as used herein, refers to a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein.
[0427] The term "heteroaryloxy" as used herein, refers to a
heteroaryl, as defined herein, appended to the parent molecular
moiety through an oxy group, as defined herein.
[0428] The term "heteroaryloxyalkyl" as used herein, refers to a
heteroaryloxy, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0429] The term "heterocycle" as used herein, refers to a
non-aromatic monocyclic ring or a non-aromatic bicyclic ring. The
non-aromatic monocyclic ring is a three, four, five, six, seven, or
eight membered ring containing at least one heteroatom,
independently selected from the group consisting of N, O and S.
Representative examples of monocyclic ring systems include, but are
not limited to, azetidinyl, aziridinyl, diazepinyl, dithianyl,
imidazolinyl, imidazolidinyl, isothiazolinyl, isoxazolinyl,
isoxazolidinyl, morpholinyl, oxazolinyl, oxazolidinyl, piperazinyl,
piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,
pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl,
tetrahydro-2H-pyran-2-yl, tetrahydro-2H-pyran-4-yl,
tetrahydrothienyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,
1,1-dioxidothiomorpholinyl (thiomorpholine sulfone) and
thiopyranyl. The bicyclic heterocycles are exemplified by a
monocyclic heterocycle appended to the parent molecular moiety and
fused to a monocyclic cycloalkyl group, as defined herein, a
monocyclic aryl group, a monocyclic heteroaryl group, as defined
herein, or a monocyclic heterocycle, as defined herein. Bicyclic
ring systems are also exemplified by a bridged monocyclic ring
system in which two non-adjacent atoms of the monocyclic ring are
linked by a bridge of between one and three atoms selected from the
group consisting of carbon, nitrogen and oxygen. Representative
examples of bicyclic ring systems include but are not limited to,
for example, benzopyranyl, benzothiopyranyl, benzodioxinyl,
1,3-benzodioxolyl, cinnolinyl, 1,5-diazocanyl,
3,9-diaza-bicyclo[4.2.1]non-9-yl, 3,7-diazabicyclo[3.3.1]nonane,
octahydro-pyrrolo[3,4-c]pyrrole, indolinyl, isoindolinyl,
2,3,4,5-tetrahydro-1H-benzo[c]azepine,
2,3,4,5-tetrahydro-1H-benzo[b]azepine,
2,3,4,5-tetrahydro-1H-benzo[d]azepine, tetrahydroisoquinolinyl and
tetrahydroquinolinyl.
[0430] The heterocycles of this invention may be optionally
substituted with 1, 2 or 3 substituents independently selected from
oxo, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,
alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkynyl, aryl,
arylalkyl, arylcarbonyl, aryloxy, arylsulfonyl, carboxy,
carboxyalkyl, cyano, cyanoalkyl, ethylenedioxy, formyl, haloalkoxy,
haloalkyl, halogen, heteroaryl, heteroarylalkyl, heterocycle,
heterocyclealkyl, heterocyclecarbonyl, heterocycleoxy, hydroxy,
hydroxyalkyl, nitro, R.sub.fR.sub.gN--, R.sub.fR.sub.gNalkyl,
R.sub.fR.sub.gNcarbonyl and R.sub.fR.sub.gNsulfonyl, wherein
R.sub.f and R.sub.g are as described herein.
[0431] The substituent aryl, the aryl of arylalkyl, the aryl of
arylcarbonyl, the aryl of aryloxy, the aryl of arylsulfonyl, the
heteroaryl, the heteroaryl of heteroarylalkyl, the substituent
heterocycle, the heterocycle of heterocyclealkyl, the heterocycle
of heterocyclecarbonyl, the heterocycle of heterocycleoxy, may be
optionally substituted with 1, 2 or 3 substituents independently
selected from the group consisting of alkoxy, alkoxyalkyl,
alkoxycarbonyl, alkyl, alkylcarbonyl, alkynyl, carboxy,
carboxyalkyl, cyano, haloalkyl, halogen, hydroxy, hydroxyalkyl,
nitro, R.sub.fR.sub.gN--, R.sub.fR.sub.gNalkyl,
R.sub.fR.sub.gNcarbonyl and R.sub.fR.sub.gNsulfonyl.
[0432] The term "heterocyclealkyl" as used herein, refers to a
heterocycle, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein. Representative
examples of heterocyclealkyl include, but are not limited to,
pyridin-3-ylmethyl and 2-pyrimidin-2-ylpropyl.
[0433] The term "heterocyclealkylcarbonyl" as used herein, refers
to a heterocyclealkyl, as defined herein, appended to the parent
molecular moiety through a carbonyl group, as defined herein.
[0434] The term "heterocyclealkoxy" as used herein, refers to a
heterocycle, as defined herein, appended to the parent molecular
moiety through an alkoxy group, as defined herein.
[0435] The term "heterocycleoxy" as used herein, refers to a
heterocycle, as defined herein, appended to the parent molecular
moiety through an oxy group, as defined herein.
[0436] The term "heterocycleoxyalkyl" as used herein, refers to a
heterocycleoxy, as defined herein, appended to the parent molecular
moiety through an alkyl group, as defined herein.
[0437] The term "heterocycle-NH-" as used herein, refers to a
heterocycle, as defined herein, appended to the parent molecular
moiety through a nitrogen atom.
[0438] The term "heterocycle-NH-alkyl" as used herein, refers to a
heterocycle-NH--, as defined herein, appended to the parent
molecular moiety through an alkyl group, as defined herein.
[0439] The term "heterocyclecarbonyl" as used herein, refers to a
heterocycle, as defined herein, appended to the parent molecular
moiety through a carbonyl group, as defined herein. Representative
examples of heterocyclecarbonyl include, but are not limited to,
1-piperidinylcarbonyl, 4-morpholinylcarbonyl, pyridin-3-ylcarbonyl
and quinolin-3-ylcarbonyl.
[0440] The term "heterocyclesulfonyl" as used herein, refers to a
heterocycle, as defined herein, appended to the parent molecular
moiety through a sulfonyl group, as defined herein. Representative
examples of heterocyclesulfonyl include, but are not limited to,
1-piperidinylsulfonyl, 4-morpholinylsulfonyl, pyridin-3-ylsulfonyl
and quinolin-3-ylsulfonyl.
[0441] The term "hydroxy" as used herein, refers to an --OH
group.
[0442] The term "hydroxyalkyl" as used herein, refers to a hydroxy
group, as defined herein, appended to the parent molecular moiety
through an alkyl group, as defined herein. Representative examples
of hydroxyalkyl include, but arc not limited to, hydroxymethyl,
2-hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.
[0443] The term "oxo" as used herein, refers to a .dbd.O group.
[0444] The term "oxy" as used herein, refers to a --O-- group.
[0445] The term "sulfonyl" as used herein, refers to a
--S(O).sub.2-- group.
[0446] The present compounds may exist as therapeutically suitable
salts. The term "therapeutically suitable salt," refers to salts or
zwitterions of the compounds which are water or oil-soluble or
dispersible, suitable for treatment of disorders without undue
toxicity, irritation and allergic response, commensurate with a
reasonable benefit/risk ratio and effective for their intended use.
The salts may be prepared during the final isolation and
purification of the compounds or separately by reacting an amino
group of the compounds with a suitable acid. For example, a
compound may be dissolved in a suitable solvent, such as but not
limited to methanol and water and treated with at least one
equivalent of an acid, like hydrochloric acid. The resulting salt
may precipitate out and be isolated by filtration and dried under
reduced pressure. Alternatively, the solvent and excess acid may be
removed under reduced pressure to provide the salt. Representative
salts include acetate, adipate, alginate, citrate, aspartate,
benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,
camphorsulfonate, digluconate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, form ate, isethionate, fumarate, lactate,
maleate, methanesulfonate, naphthylenesulfonate, nicotinate,
oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate,
picrate, oxalate, maleate, pivalate, propionate, succinate,
tartrate, trichloroacetate, trifluoroacetate, glutamate,
para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic,
sulfuric, phosphoric and the like. The amino groups of the
compounds may also be quaternized with alkyl chlorides, bromides
and iodides such as methyl, ethyl, propyl, isopropyl, butyl,
lauryl, myristyl, stearyl and the like.
[0447] Basic addition salts may be prepared during the final
isolation and purification of the present compounds by reaction of
a carboxyl group with a suitable base such as the hydroxide,
carbonate, or bicarbonate of a metal cation such as lithium,
sodium, potassium, calcium, magnesium, or aluminum, or an organic
primary, secondary, or tertiary amine. Quaternary amine salts
derived from methylamine, dimethylamine, trimethylamine,
triethylamine, diethylamine, ethylamine, tributylamine, pyridine,
N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,
dicyclohexylamine, procaine, dibenzylamine,
N,N-dibenzylphenethylamine, 1-ephenamine and
N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine,
diethanolamine, piperidine, piperazine and the like, are
contemplated as being within the scope of the present
invention.
[0448] The present compounds may also exist as therapeutically
suitable prodrugs. The term "therapeutically suitable prodrug,"
refers to those prodrugs or zwitterions which are suitable for use
in contact with the tissues of patients without undue toxicity,
irritation and allergic response, are commensurate with a
reasonable benefit/risk ratio and are effective for their intended
use. The term "prodrug," refers to compounds that are rapidly
transformed in vivo to the parent compounds of formula (I-IXc) for
example, by hydrolysis in blood. The term "prodrug," refers to
compounds that contain, but are not limited to, substituents known
as "therapeutically suitable esters." The term "therapeutically
suitable ester," refers to alkoxycarbonyl groups appended to the
parent molecule on an available carbon atom. More specifically, a
"therapeutically suitable ester," refers to alkoxycarbonyl groups
appended to the parent molecule on one or more available aryl,
cycloalkyl and/or heterocycle groups as defined herein. Compounds
containing therapeutically suitable esters are an example, but are
not intended to limit the scope of compounds considered to be
prodrugs. Examples of prodrug ester groups include
pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl and
methoxymethyl, as well as other such groups known in the art. Other
examples of prodrug ester groups are found in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S.
Symposium Series and in Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and
Pergamon Press, 1987, both of which are incorporated herein by
reference.
[0449] Asymmetric centers may exist in the present compounds.
Individual stereoisomers of the compounds arc prepared by synthesis
from chiral starting materials or by preparation of racemic
mixtures and separation by conversion to a mixture of diastereomers
followed by separation or recrystallization, chromatographic
techniques, or direct separation of the enantiomers on chiral
chromatographic columns. Starting materials of particular
stereochemistry are either commercially available or are made by
the methods described hereinbelow and resolved by techniques well
known in the art.
[0450] Geometric isomers may exist in the present compounds. The
invention contemplates the various geometric isomers and mixtures
thereof resulting from the disposal of substituents around a
carbon-carbon double bond, a cycloalkyl group, or a
heterocycloalkyl group. Substituents around a carbon-carbon double
bond are designated as being of Z or E configuration and
substituents around a cycloalkyl or heterocycloalkyl are designated
as being of cis or trans configuration. Furthermore, the invention
contemplates the various isomers and mixtures thereof resulting
from the disposal of substituents around an adamantane ring system.
Two substituents around a single ring within an adamantane ring
system are designated as being of Z or E relative configuration.
For examples, see C. D. Jones, M. Kaselj, R. N. Salvatore, W. J. le
Noble J. Org. Chem. 63: 2758-2760, 1998.
Preparation of Compounds of the Invention
[0451] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes and Experimentals that illustrate a means by which the
compounds of the invention can be prepared.
[0452] The compounds of this invention can be prepared by a variety
of procedures and synthetic routes. Representative procedures and
synthetic routes are shown in, but are not limited to, Schemes
1-17.
[0453] Abbreviations which have been used in the descriptions of
the Schemes and the Examples that follow are: AcCl for acetyl
chloride; DCM for dichloromethane; AIBN for
2,2'-azobis(2-methylpropionitrile); DMA for N,N-dimethylacetamide;
DIEA or Hunig's base for N,N-diisopropylethylamine; DMAP for
dimethylaminopyridine; DMF for N,N-dimethylformamide; DMSO for
dimethylsulfoxide; DMPU for
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone; EDCI or EDAC
for (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;
EtOAc for ethyl acetate; EtOH for ethanol; Et.sub.2O for diethyl
ether; HATU for O---(7-azabenzotriazol-1-yl)-N, N,
N',N'-tetramethyluronium hexafluoro-phosphate; HOBt for
hydroxybenzotriazole hydrate; KOTMS for potassium
trimethylsilanolate; MeOH for methanol; MeCN for acetonitrile; MTBE
for methyl t-butyl ether; NMO for N-methylmorpholine N-oxide; TBTU
for O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate; THF for tetrahydrofuran; and, triflate for
trifluoromethane sulfonyl
##STR00005##
[0454] Substituted adamantanes of general formula (3), wherein
A.sup.1, A.sup.2, A.sup.3, A.sup.4, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, D and E are as defined in formula I, may be prepared as in
Scheme 1. Substituted adamantamines of general formula (1),
purchased, prepared as described herein, or prepared using
methodology known to those in the art, may be treated with an
acylating agents of general formula (2), wherein Y is chloro,
bromo, or fluoro and R.sup.3, R.sup.4, D and E are defined as in
formula I, in the presence of a base such as diisopropylethylamine
to provide amides of general formula (3). Alternatively, acids of
general formula (2) wherein Y.dbd.OH can be coupled to substituted
adamantamines of general formula (1) with reagents such as EDCT and
HOBt to provide amides of general formula (3). In some examples,
A.sup.1, A.sup.2, A.sup.3 and/or A.sup.4 in amines of formula (1)
and D and E in the reagents of formula (2) may exist as or contain
a group further substituted with a protecting group such as a
carboxylic acid protected as the methyl ester. Examples containing
a protected functional group may be required due to the synthetic
schemes and the reactivity of said groups and could be later
removed to provide the desired compound. Such protecting groups can
be removed using methodology known to those skilled in the art or
as described in T. W. Greene, P. G. M. Wuts "Protective Groups in
Organic Synthesis" 3.sup.rd ed. 1999, Wiley & Sons, Inc.
##STR00006##
[0455] Substituted adamantane amines of general formula (5),
wherein A.sup.1, A.sup.2, A.sup.3, A.sup.4 and R.sup.2 are as
defined in formula I, may be prepared as in Scheme 2. Substituted
adamantane ketones of general formula (4) can be purchased,
prepared as described herein, or prepared using methodology known
to those skilled in the art. Ketones of general formula (4) can be
treated with ammonia or primary amines (R.sup.2NH.sub.2) followed
by reduction with reagents such as sodium borohydride or H.sub.2
over Pd/C in a solvent like methanol to provide amines of general
formula (5). In some examples, A.sup.1, A.sup.2, A.sup.3 and/or
A.sup.4 in ketones of formula (4) may be a substituent with a
functional group containing a protecting group such as a carboxylic
acid protected as the methyl ester. Such esters can be hydrolyzed
and other protecting groups removed here to provide compounds of
general formula (5) or in compounds subsequently prepared from (5)
using methodology known to those skilled in the art.
##STR00007##
[0456] Substituted adamantanes of general formula (7), wherein
A.sup.2, A.sup.3 and A.sup.4 are as defined in formula I and G is
alkyl, cycloalkyl, arylalkyl, or aryl, as defined in the definition
of terms, or G is hydrogen or an acid protecting group, may be
prepared as in Scheme 3. Substituted adamantanes of general formula
(6) can be purchased or prepared using methodology known to those
in the art. Tertiary alcohols of general formula (6) can be treated
with oleum and formic acid followed by water or an alcohol GOH to
provide polycycles of general formula (7). In some examples, G in
formula (7) may be a protecting group such as methyl. Such ester
protecting groups can be removed from polycycles of general formula
(7) or from compounds subsequently prepared from (7).
##STR00008##
[0457] Substituted adamantanes of general formula (10), wherein
A.sup.2, A.sup.3, A.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4, D,
E, R.sup.18 and R.sup.19 are as defined in formula I, may be
prepared as in Scheme 4. Adamantane acids of general formula (8)
may be prepared as described herein or using methodology known to
those in the art. The acids of general formula (8) may be coupled
with amines of general formula (9) (wherein R.sup.18 and R.sup.19
are defined as in formula I) with reagents such as
O-(benzotrialzol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate
(TBTU) to provide amides of general formula (10). In some examples,
R.sup.18 and/or R.sup.19 in amides of formula (10) may be a
substituent with a functional group containing a protecting group,
such as a carboxylic acid protected as the methyl ester. Such
esters can be hydrolyzed and other protecting groups removed using
methodology known to those skilled in the art.
##STR00009##
[0458] Acids of general formula (12), wherein R.sup.101 is
hydrogen, and R.sup.3, R.sup.4, D and E are as defined in formula
(I) can be prepared as shown in Scheme 5.
[0459] Esters of general formula (11) wherein P is an acid
protecting group such as, but not limited to, C.sub.1-C.sub.6
alkyl, unsubstituted or substituted aryl (for example, phenyl) or
unsubstituted or substituted arylalkyl (for example, benzyl),
R.sup.3 and R.sup.4 are hydrogen, or one of R.sup.3 and R.sup.4 is
hydrogen and the other is as defined in formula (I), can be
purchased, prepared as described herein, or prepared using
methodologies known to those skilled in the art. Esters of general
formula (11) can be mono-alkylated or bis-alkylated to provide
esters of general formula (12) wherein R.sup.101 is the acid
protecting group, P, as described above. The bis-alkylation can be
conducted either sequentially or in a one pot reaction.
[0460] Mono or bis-alkylation of esters of general formula (11) can
be achieved in the presence of a base such as, but not limited to,
sodium hydride, and an alkylating agent such as, but not limited
to, alkyl halides (for example, methyl iodide, allyl bromide and
the like). The reaction is generally performed in a solvent such
as, but not limited to, anhydrous N,N-dimethylformamide, at a
temperature from about 0.degree. C. to about 23.degree. C.
[0461] Removal of the protecting group P can be achieved using
methodologies known to those skilled in the art or as described in
T. W. Greene, P. G. M. Wuts "Protective Groups in Organic
Synthesis" 3.sup.rd ed. 1999, Wiley & Sons, Inc., to provide
compounds of formula (12) wherein R.sup.101 is hydrogen. Typically,
such transformation can be achieved by stirring with an acid (for
example, hydrochloric acid and the like) or a base (for example,
lithium hydroxide, sodium hydroxide and the like) in a solvent such
as, but not limited to, dioxane, tetrahydrofuran, ethanol, and
mixtures thereof, at ambient temperature or at elevated temperature
(typically at about 50.degree. C. to about 70.degree. C.). In cases
where P is unsubstituted or substituted arylalkyl (for example,
benzyl), hydrogenation can be employed to cleave the acid
protecting group.
##STR00010##
[0462] Synthesis of acids of general formula (15), wherein
R.sup.101 is hydrogen, R.sup.3, R.sup.4, and D are as defined in
formula (I), and G.sup.1 and Z are independently aryl or
heteroaryl, is outlined in Scheme 6.
[0463] Esters of formula (13), wherein P is C.sub.1-C.sub.6 alkyl,
unsubstituted or substituted aryl (for example, phenyl) or
unsubstituted or substituted arylalkyl (for example, benzyl); and Y
is Cl, Br, I, or triflate can be purchased, prepared as described
herein, or prepared using methodologies known to those skilled in
the art. Esters of formula (13) can be converted to boronic esters
of formula (14) when treated with a boron source like
bis(pinacolato)diboron, a catalyst such as
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II), and a
base like potassium acetate. The conversion is facilitated in a
solvent such as, but not limited to, dimethyl sulfoxide,
N,N-dimethylformamide or toluene, at a temperature of about
80.degree. C. to about 100.degree. C. Boronic esters of general
formula (14) may be coupled with reagents of formula Z-Y, wherein Z
is aryl or heteroaryl and Y is Cl, Br, I, or triflate, a catalyst
such as 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II),
and a base like sodium carbonate, to provide compounds of formula
(15) wherein R.sup.101 is an acid protecting group, P. The reaction
can be performed in a solvent system like N,N-dimethylformamide and
water at a temperature of about 80.degree. C. to 90.degree. C.
[0464] Alternatively, compounds of formula (13) wherein Y is Cl,
Br, I, or triflate can be treated with a boronic acid or ester of
formula (13A) or Z--B(OR.sup.102).sub.2, wherein R.sup.102 is
hydrogen or alkyl, in the presence of a catalyst, such as but not
limited to, bis(triphenylphospine)palladium (II) chloride or
dichlorobis(tri-o-tolylphosphine)palladium (II), and a base such as
triethylamine or sodium carbonate, to provide compounds of formula
(15) wherein R.sup.101 is an acid protecting group, P. The reaction
can be effected by heating at a temperature from about 50.degree.
C. to about 180.degree. C. in solvents such as isopropanol,
ethanol, dimethoxyethane, water or dioxane.
[0465] Conversion of compounds of formula (15) wherein R.sup.101 is
an acid protecting group, P, to compounds of formula (15) wherein
R.sup.101 is hydrogen can be prepared using reaction conditions as
described in Scheme 5.
##STR00011##
[0466] Acids of general formula (19), wherein R.sup.101 is
hydrogen, R.sup.3 is as defined in formula (I) and A is a
substituent of heterocycle as defined in the definition of terms,
can be prepared from malonic acid di-ester of formula (16) wherein
P is C.sub.1-C.sub.6 alkyl or benzyl as shown in Scheme 7.
[0467] Malonic acid di-esters of general formula (16) wherein P is
an acid protecting group such as C.sub.1-C.sub.6 alkyl,
unsubstituted or substituted aryl (for example, phenyl) or
unsubstituted or substituted arylalkyl (for example, benzyl), can
be purchased or prepared using methodologies known to those skilled
in the art. Malonic acid di-esters of general formula (16) can be
treated with one molar equivalent of allyl bromide or
4-bromo-1-butene, using mono alkylation conditions for the
conversion of (11) to (12) in Scheme 5, to provide compounds of
formula (17). Ozonolysis of the terminal olefin of di-ester (17)
may be achieved in a solvent system like dichloromethane and
methanol at a low temperature of about 78.degree. C., by bubbling
ozone through the solution, followed by purging the solution with
nitrogen gas, and reduction of the intermediate ozonide with
dimethyl sulfide to provide aldehyde di-esters of the general
formula (18). Treatment of aldehyde di-ester (18) with a primary
amine of formula A-NH.sub.2, wherein A is a substituent of
heterocycle as defined in the definition of terms, a reducing agent
like resin bound MP-triacetoxy borohydride, and in a solvent like
tetrahydrofuran at a temperature around 23.degree. C., provides
esters of general formula (19) wherein R.sup.101 is an acid
protecting group, P. Removal of P using reaction conditions as
outlined in Scheme 5 converts (19) wherein R.sup.101 is an acid
protecting group, P, to compounds of formula (19) wherein R.sup.101
is hydrogen.
##STR00012##
[0468] Scheme 8 outlines the synthesis of esters of general formula
(23), wherein P.sup.1 is an acid protecting group such as, but not
limited to, C.sub.1-C.sub.6 alkyl, and X.sup.1 and X.sup.2 are
substituents of heteoraryl as defined in the definition of terms,
from thiazoles of formula (20).
[0469] Thiazoles of formula (20) can be purchased or prepared using
methodologies known to those skilled in the art. Thiazoles of
formula (20) may be alkylated by in situ activation with a
chloroformate such as, but not limited to, ethyl chloroformate,
followed by treatment of a nucleophile such as lithio
diethylmalonate (prepared from a malonic acid di-ester in a
solution such as tetrahydrofuran with a base such as lithium
bis(trimethylsilyl)amide), to afford compounds of formula (21)
wherein P.sup.1 and P.sup.2 are C.sub.1-C.sub.6 alkyl. The former
can be conducted in a solvent such as, but not limited to,
tetrahydrofuran, at a temperature around 0.degree. C. Treatment
with the nucleophile can be effected in a solvent such as
tetrahydrofuran and at a temperature around 23.degree. C. The
lithio diethylmalonate may be formed in a solvent such as
tetrahydrofuran. The N-protected malonic acid di-ester adduct of
general formula (21) may be oxidized with an agent such as
tetrachloro-1,2-benzoquinone in a solvent such as dichloromethane
at a temperature around 0.degree. C. to afford the di-ester of
general formula (22). Mono-decarboxylation of di-ester (22) may be
achieved by heating in a solvent system such as water and dimethyl
sulfoxide with a salt such as sodium chloride at a temperature near
180.degree. C. to provide esters of general formula (23).
##STR00013##
[0470] Acids of formula (27) wherein R.sup.101 is hydrogen, P.sup.3
is --C(O)OCH.sub.2C.sub.6H.sub.5, and R.sup.3 is as defined in
formula (1) can be prepared from compounds of formula (24) where P
is an acid protecting group such as, C.sub.1-C.sub.6 alkyl,
unsubstituted or substituted aryl (for example, phenyl) or
unsubstituted or substituted arylalkyl (for example, benzyl), as
shown in Scheme 9.
[0471] Compounds of formula (24) can be purchased or prepared using
methodologies known to those skilled in the art. Treatment of
compounds of formula (24) with benzyl chloroformate and a base such
as, but not limited to, sodium bicarbonate in water, provides
compounds of formula (25) wherein P.sup.3 is
--C(O)OCH.sub.2C.sub.6H.sub.5. Mono alkylation of compounds of
formula (25) with halides of formula R.sup.3--X.sup.3 wherein
X.sup.3 is Cl, Br or I, using reaction conditions as described in
Scheme 5 provides compounds of formula (26).
[0472] Conversion of compounds of formula (26) to compounds of
formula (27) wherein R.sup.101 is hydrogen can be achieved using
reaction conditions as described in Scheme 5 for removal of a
protecting group, P.
##STR00014##
[0473] Compounds of general formula (29), wherein R.sup.3, R.sup.4,
R.sup.27, R.sup.28, R.sup.29, R.sup.30, and R.sup.31 are as defined
in formula I; G.sup.2 is --N(R.sup.31)--, --O-- or --S--; Z.sup.1
is aryl or heteroaryl; R.sup.101 is hydrogen or is an acid
protecting group, P, such as, but not limited to, C.sub.1-C.sub.6
alkyl, unsubstituted or unsubstituted aryl (for example, phenyl) or
unsubstituted or substituted arylalkyl (for example benzyl), can be
prepared as shown in Scheme 10.
[0474] Compounds of formula (28) can be purchased, prepared as
described herein, or prepared using methodologies known to those
skilled in the art. Compounds of formula (28) wherein P is an acid
protecting group can be reacted with compounds of formula
Z.sup.1-Y, wherein Y is Cl, Br, I, or triflate such as
6-chloronicotinonitrile, with a base such as sodium hydride, and in
an anhydrous solvent system such as tetrahydrofuran and
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) at a
temperature ranging from 0.degree. C. to 23.degree. C. to provide
esters of general formula (29), wherein R.sup.101 is a protecting
group, P.
[0475] Conversion of compounds of formula (29) wherein R.sup.101 is
P to compounds of formula (29) wherein R.sup.101 is hydrogen can be
achieved using reaction conditions as described in Scheme 5 for
removal of a protecting group, P.
##STR00015##
[0476] Compounds of general formula (31), wherein R.sup.3 and
R.sup.4 arc as defined in formula (I), G.sup.3 is aryl or
heteroaryl, and R.sup.103 is hydrogen, potassium, sodium, lithium,
or C.sub.1-C.sub.6 alkyl, can be prepared as shown in Scheme
11.
[0477] Compounds of formula G.sup.3-Y wherein G.sup.3 is aryl or
heteroaryl and Y is CI, Br, 1 or triflate can be purchased or
prepared using methodologies known to those skilled in the art, as
well as, alkyl trimethylsilyl ketene acetals of formula (30)
wherein R.sup.103 is C.sub.1-C.sub.6 alkyl. Compounds of formula
G.sup.3-Y such as, but not limited to,
2-chloro-5-(trifluoro-methyl)pyridine can be reacted with an alkyl
trimethylsilyl ketene acetal of formula (30) wherein R.sup.103 is
C.sub.1-C.sub.6 alkyl such as, but not limited to, methyl or ethyl;
a salt such as zinc fluoride; a catalyst such as
tris(dibenzylideneacetone)dipalladium (0); a ligand such as
tri-t-butylphosphinc; and, in a solvent such as
N,N-dimethylformamide at a temperature of about 90.degree. C. to
provide esters of general formula (31) wherein R.sup.103 is
C.sub.1-C.sub.6 alkyl.
[0478] Numerous methodologies for the conversion of compounds of
formula (31) wherein R.sup.103 is C.sub.1-C.sub.6 alkyl to
compounds of formula (31) wherein R.sup.103 is hydrogen are
described in "Protective Groups in Organic Synthesis" 3.sup.rd
edition, 1999, Wiley & Sons, Inc. Additionally, one can obtain
a salt of compounds of formula (31) where R.sup.101 is potassium,
sodium, or lithium by stirring compounds of formula (31) wherein
R.sup.103 is C.sub.1-C.sub.6 alkyl with a base such as, but not
limited to, potassium trimethylsilanolate in a solvent such as, but
not limited to, tetrahydrofuran, at ambient temperature.
##STR00016##
[0479] Compounds of formula (32) wherein Y is Cl, Br, I or
triflate, G.sup.4 is aryl or heteroaryl as defined in the
definition of terms, and A.sup.1, A.sup.2, A.sup.3, A.sup.4,
R.sup.1, R.sup.2, R.sup.3, R.sup.4 and D are as defined in formula
(I) can be prepared as described herein or prepared using
methodologies known to those skilled in the art. Conversion of
compounds of formula (32) to compounds of formula (33), depicted in
Scheme 12, wherein Z.sup.2 is aryl or heteroaryl can be achieved
using the series of reaction conditions as described in Scheme 6
for the transformation of (13) to (15).
##STR00017##
[0480] Adamantanes of general formula (36), wherein A.sup.1,
A.sup.2, A.sup.3, A.sup.4, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and D
are as defined in formula (I), and G.sup.5 and Z.sup.3 are
independently either aryl or heteroaryl as defined in the
definition of terms, can be prepared as shown in Scheme 13.
[0481] Adamantanes of general formula (34) wherein Y is Cl, Br or
I, can be prepared as described herein or prepared using
methodologies known to those skilled in the art. Olefins of general
formula (35) wherein Z.sup.3 is either aryl or heteroaryl can be
purchased or prepared using methodologies known to those skilled in
the art. Adamantanes of general formula (34) can be reacted with
olefins of general formula (35), such as, but not limited to,
4-vinylpyridine; a catalyst such as, but not limited to,
bis(triphenylphosphine)palladium (II) dichloride; a base such as,
but not limited to, triethylamine; and, in a solvent system such as
N,N-dimethylformamide at a temperature of near 150.degree. C. to
provide adamantanes of general formula (36).
##STR00018##
[0482] Substituted adamantanes of general formula (38), wherein
A.sup.1, A.sup.2, A.sup.3, A.sup.4, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and D are as defined in formula (I); G.sup.6 is aryl or
heteroaryl; and, Q is alkyl, arylalkyl, heteroarylalkyl,
heterocycle alkyl, or cycloalkylalkyl, can be prepared as shown in
Scheme 14.
[0483] Substituted adamantanes of general formula (37) can be
prepared as described herein or prepared using methodologies known
to those skilled in the art. Substituted adamantanes of general
formula (37) can be alkylated with alkylating agents Q-Y, wherein Q
is alkyl, arylalkyl, heteroarylalkyl, heterocycle alkyl, or
cycloalkylalkyl and Y is a leaving group like I, Br, Cl, or
triflate, in the presence of a base like potassium carbonate and in
a solvent like N,N-dimethylformamide to yield substituted
adamantanes of general formula (38).
##STR00019##
[0484] Substituted adamantanes of general formula (40), wherein
A.sup.1, A.sup.2, A.sup.3, A.sup.4, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and D are as defined in formula I; G.sup.7 is aryl or
heteroaryl; and, R.sup.k and R.sup.m are independently hydrogen,
alkyl, or heterocyclealkyl, or R.sup.k and R.sup.m together with
the nitrogen to which they are attached form a heterocycle ring,
can be prepared as shown in Scheme 15.
[0485] Substituted adamantanes of general formula (39), wherein Y
is F, Cl, Br, or I, can be prepared as described herein or prepared
using methodologies known to those skilled in the art. Substituted
adamantanes of general formula (39) can be condensed with amines of
general formula R.sup.kR.sup.mNH, to provide compounds of formula
(40). The reaction can be conducted neat in a microwave synthesizer
at a temperature near 150.degree. C. for a period of about 40
minutes.
##STR00020##
[0486] Substituted adamantanes of general formula (43), wherein
A.sup.1, A.sup.2, A.sup.3, A.sup.4, R.sup.1, R.sup.2, R.sup.3,
R.sup.4, and D arc as defined in formula I; G.sup.8 is aryl or
heteroaryl as defined in the definition of terms; Q.sup.1 is
C.sub.1-C.sub.3 alkyl; and, R.sup.q and R.sup.r are independently
hydrogen, alkyl, or heterocyclealkyl, or R.sup.q and R.sup.r
together with the nitrogen to which they are attached form a
heterocycle ring, can be prepared as shown in Scheme 16.
[0487] Substituted adamantanes of general formula (41) can be
prepared as described herein or prepared using methodologies known
to those skilled in the art. Substituted adamantanes of general
formula (41) can be halogenated with a reagent like
N-halosuccinimide (for example, N-chlorosuccinimide and the like)
in the presence of a radical initiator like AIBN and in a solvent
like carbon tetrachloride at a temperature near 80.degree. C. to
yield substituted adamantanes of general formula (42), wherein Y is
Cl, Br, or I. Substituted adamantanes of general formula (42) when
treated with amines of general formula R.sup.qR'NH in a solvent
like dichloromethane at a temperature between 23.degree. C. and
40.degree. C. provide substituted adamantanes of general formula
(43).
##STR00021##
[0488] Substituted adamantanes of general formula (50), wherein
A.sup.2, A.sup.3, A.sup.4, R.sup.2, R.sup.5 and R.sup.6 are as
defined in formula I, can be prepared as shown in Scheme 17.
[0489] Substituted adamantanes of general formula (6) can be
purchased or prepared using methodology known to those in the art.
Substituted adamantanes of general formula (6) can be brominated
with a reagent like hydrobromic acid in a solvent like water to
provide bromides of general formula (44). Adamantanes of general
formula (44) when treated with ethylene glycol and a catalytic
amount of an acid like p-toluenesulfonic acid in a solvent like
benzene provide adamantanes of general formula (45). Bromides of
general formula (45) can be (a) treated with Rieke zinc in a
solvent like tetrahydrofuran; and (b) followed by treatment with
reagent (46) (prepared as described in Han, Z.; Krishnamurthy, D.;
Grover, P.; Fang, Q. K.; Senanayake, C. H. J. Am. Chem. Soc. 2002,
124, 7880-7881) in a solvent like tetrahydrofuran to provide
adamantanes of general formula (47). Adamantanes of general formula
(47) may be treated with lithium amide of formula
LiNHR.sup.5R.sup.6 (prepared in situ by reacting ammonia with
lithium or amines of formula R.sup.5R.sup.6NH wherein R.sup.5 and
R.sup.6 are other than hydrogen, with t-butyl lithium) in a solvent
like tetrahydrofuran. The resulting sulfinamides can be oxidized
with a reagent like osmium tetroxide with a catalyst oxidant like
NMO in a solvent like tetrahydrofuran to provide sulfonamides of
general formula (48). Adamantanes of general formula (48) can be
deketalized with reagents like hydrochloric acid in a solvent
mixture like water and tetrahydrofuran to provide ketones of
formula (49). Ketones of formula (49) can be treated with amines of
formula R.sup.2NH.sub.2 followed by reduction with reducing
reagents such as, but not limited to, sodium borohydride or
hydrogen over Pd/C in a solvent like methanol to provide amines of
general formula (50). In some examples, A.sup.2, A.sup.3, A.sup.4,
R.sup.2, R.sup.5 and R.sup.6 in amines of formula (50) may be a
substituent with a functional group containing a protecting group
such as a carboxylic acid protected as the methyl ester. Such
esters can be hydrolyzed and other protecting groups removed here
or in compounds subsequently prepared from (50) using methodology
known to those skilled in the art.
[0490] It is understood that the schemes described herein are for
illustrative purposes and that routine experimentation, including
appropriate manipulation of the sequence of the synthetic route,
protection of any chemical functionality that are not compatible
with the reaction conditions and deprotection are included in the
scope of the invention. Protection and Deprotection of carboxylic
acids and amines are known to one skilled in the art and references
can be found in "Protective Groups in Organic Synthesis", T. W.
Greene, P. G. M. Wuts, 3rd edition, 1999, Wiley & Sons,
Inc.
[0491] The compounds and processes of the present invention will be
better understood by reference to the following Examples, which are
intended as an illustration of and not a limitation upon the scope
of the invention. Further, all citations herein arc incorporated by
reference.
[0492] Compounds of the invention were named by ACD/ChemSketch
version 5.01 (developed by Advanced Chemistry Development, Inc.,
Toronto, ON, Canada) or were given names consistent with ACD
nomenclature. Adamantane ring system isomers were named according
to common conventions. Two substituents around a single ring within
an adamantane ring system are designated as being of Z or E
relative configuration (for examples see C. D. Jones, M. Kaselj, R.
N. Salvatore, W. J. le Noble J. Org. Chem. 63: 2758-2760,
1998).
Example 1
E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxy-
lic acid
Example 1A
4-oxo-adamantane-1-carboxylic acid
[0493] A 5 L 4-neck flask equipped with N.sub.2 inlet/bubbler with
H.sub.2O trap, overhead stirring, and an addition funnel was
charged with 30% oleum (.about.10.5 volumes, 2.2 L, 8.times.500 g
bottles+100 mL), and heated to 50.degree. C. under a slight N.sub.2
flow. 5-Hydroxy-2-adamantanone (220 g, 81 wt % purity, 1.07 mol)
was dissolved in 5 volumes HCO.sub.2H (.about.98%, 1.10 L) and
added drop-wise to the warm oleum solution over 5 hours. The
addition rate was adjusted to maintain the internal temperature
between 70-90.degree. C. After stirring an additional 2 hours at
70.degree. C. The reaction solution was cooled to 10.degree. C. in
an ice bath. 20 volumes of 10% NaCl aq (4 L) were cooled to
<10.degree. C., the crude reaction mixture was quenched into the
brine solution in batches, maintaining an internal temperature
<70.degree. C. The quenched reaction solution was combined with
a second identical reaction mixture for isolation. The combined
product solutions were extracted 3.times.5 volumes with
CH.sub.2Cl.sub.2 (3.times.2.2 L) and the combined CH.sub.2Cl.sub.2
layers were then washed 1.times.2 volumes with 10% NaCl (1 L). The
CH.sub.2Cl.sub.2 solution was then extracted 3.times.5 volumes with
10% Na.sub.2CO.sub.3 (3.times.2.2 L). The combined Na.sub.2CO.sub.3
extracts were washed with 1.times.2 volumes with CH.sub.2Cl.sub.2
(1 L). The Na.sub.2CO.sub.3 layer was then adjusted to pH 1-2 with
concentrated HCl (.about.2 volumes, product precipitates out of
solution). The acidic solution was then extracted 3.times.5 volumes
with CH.sub.2Cl.sub.2 (3.times.2.2 L), and the organic layer was
washed 1.times.2 volumes with 10% NaCl. The organic solution was
then dried over Na.sub.2SO.sub.4, filtered, concentrated to
.about.1/4 volume, then chase distilled with 2 volumes EtOAc (1 L).
Nucleation occurred during this distillation. The suspension was
then chase distilled 2.times.5 volumes (2.times.2 L) with heptane
and cooled to room temperature. The suspension was then filtered,
and the liquors were recirculated 2.times. to wash the wet cake.
The resultant material was dried overnight at 50.degree. C., 20 mm
Hg to afford the title compound.
Example 1B
E- and Z-4-amino-adamantane-1-carboxylic acid
[0494] To 1.0 g (10 wt %) of 5% Pd/C is added 10.0 g of the product
from Example 1A followed by 200 mL (20 volumes) of 7M NH.sub.3 in
MeOH. The reaction mixture is stirred under an atmosphere of
H.sub.2 at RT for 16-24 hours. 200 mL of water is added and the
catalyst is removed by filtration. The catalyst is washed with
MeOH. Solvent is removed by distillation at a bath temperature of
35.degree. C. until solvent stops coming over. Approximately 150 mL
of a slurry remains. 300 ml, of MeCN is added to the slurry, which
is then stirred for three hours at RT. The slurry is filtered and
washed once with 100 mL MeCN. The wet cake is dried at 50.degree.
C. and 20 mm Hg under N.sub.2 to afford the title compound with a
13.1:1.0 E:Z ratio by .sup.1H-NMR (D.sub.2O).
Example 1C
E-4-amino-adamantane-1-carboxylic acid methyl ester
hydrochloride
[0495] Methanol (10 volumes, 85 mL) was cooled to 0.degree. C. AcCl
was added dropwise (5.0 equiv., 15.5 mL), and the solution was
warmed to ambient temperature for 15-20 minutes. The product from
Example 1B (8.53 g, 43.7 mmol, 1.0 equiv.) was added and the
reaction solution was heated to 45.degree. C. for 16 hours
(overnight). Consumption of the starting aminoacid was monitored by
LC/MS (APCI). The reaction solution was then cooled to room
temperature, 10 volumes McCN (85 mL) was added, distilled to 1/4
volume (heterogeneous), and chase distilled 2.times.10 volumes with
MeCN (2.times.85 mL). The resulting suspension was cooled to room
temperature, filtered, and the filtrate was recirculated twice to
wash the wet cake. The product was dried at 50.degree. C., 20 mm Hg
overnight to afford the title compound.
Example 1D
E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxy-
lic acid
Step A
[0496] A solution of the product from Example 1C (50 mg, 0.20
mmol), 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid (39 mg, 0.19
mmol), and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) (65 mg, 0.20 mmol) in
N,N-dimethylacetamide (DMA) (2 mL) and DIEA (80 .mu.L, 0.46 mmol)
was stirred for 16 hours at 23.degree. C. The reaction mixture was
analyzed by LC/MS and determined to be near completion. The
reaction mixture was concentrated under reduced pressure. The
residue was taken up in methylene chloride and washed with 1 N HCl
(2.times.), saturated NaHCO.sub.3 (2.times.), water, and brine
before drying over Na.sub.2SO.sub.4, filtering, and concentrating
under reduced pressure. The resultant solid was triturated with
ethyl acetate, dried under reduced pressure to provide the methyl
ester of the titled compound.
Step B
[0497] The methyl ester of the titled compound obtained from step A
(50 mg, 0.12 mmol) was dissolved in 3 N HCl (1 mL), dioxane (0.25
mL), and 4 N HCl (1 mL). The homogenous acid solution was heated to
60.degree. C. for 24 hours, was cooled to 23.degree. C., and was
then concentrated under reduced pressure to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.02 (s,
1H), 7.40 (m, 4H), 6.87 (d, J=6.6 Hz, 1H), 3.68 (m, 1H), 2.71 (m,
2H), 2.36 (m, 2H), 1.75 (m, 13H), 1.34 (m, 2H); MS (ESI+) m/z 389
(M+H).sup.+.
Example 2
E-4-1(1-Phenyl-cyclopropanecarbonyl)-aminol-adamantane-1-carboxylic
acid
Step A
[0498] The methyl ester of the titled compound was prepared
according to the method of step A of Example ID substituting
1-phenyl-1-cyclopropanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and the crude
methyl ester was purified by chromatography on flash silica gel
with an eluant gradient of 20-40% ethyl acetate/hexanes.
Step B
[0499] The methyl ester obtained from step A (47 mg, 0.13 mmol) was
dissolved in 3 N HCl (1 mL), dioxane (0.25 mL), and 4 N HCl (1 mL),
heated to 60.degree. C. for 24 hours, was cooled to 23.degree. C.,
and was then concentrated under reduced pressure to provide the
title compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.05
(s, 1H), 7.43 (m, 4H), 7.36 (m, 1H), 5.80 (d, J=7.8 Hz, 1H), 3.72
(m, 1H), 1.79 (m, 6H), 1.71 (m, 3H), 1.40 (m, 1H), 1.35 (m, 3H),
1.20 (m, 2H), 1.02 (m, 2H); MS (ESI+) m/z 341 (M+H).sup.1.
Example 3
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic
acid
Step A
[0500] The methyl ester of the titled compound was prepared
according to the method of step A of Example 1D substituting
2-methyl-2-phenyl propionic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and the crude
methyl ester was purified by chromatography on flash silica gel
with an eluant gradient of 20-40% ethyl acetate/hexanes.
Step B
[0501] The methyl ester obtained from step A (49 mg, 0.14 mmol) was
dissolved in 3 N HCl (1 mL) and dioxane (0.25 mL), heated to
60.degree. C. for 24 hours, was cooled to 23.degree. C., and was
then concentrated under reduced pressure to provide the title
compound. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 12.04 (s,
1H), 7.34 (m, 4H), 7.24 (m, 1H), 6.26 (d, J=6.9 Hz, 1H), 3.74 (m,
1H), 1.87 (m, 2H), 1.81 (m, 4H), 1.74 (m, 3H), 1.55 (m, 2H), 1.49
(s, 6H), 1.35 (m, 2H); MS (ESI+) m/z 343 (M+H).sup.+.
Example 4
E-4-{[1-(4-Chloro-phenyl)-cyclobutanecarbonyl]-amino}-adamantane-1-carboxy-
lic acid amide
[0502] A solution of the product from step B of Example 1D (24 mg,
0.062 mmol) in DCM (2 mL) was treated with HOBt (12 mg, 0.090 mmol)
and EDCI (20 mg, 0.10 mmol) and stirred at room temperature for 1
hour. Excess of aqueous (35%) ammonia (1 mL) was added and the
reaction was stirred for 16 hours. The layers were separated and
the aqueous extracted twice more with methylene chloride (2.times.2
mL). The combined organic extracts were dried over
Na.sub.2SO.sub.4, filtered, and concentrated under reduced
pressure. The residue was dissolved in DMSO/MeOH (1:1, 1.5 mL) and
purified by preparative HPLC on a Waters Symmetry C8 column (25
mm.times.100 mm, 7 um particle size) using a gradient of 10% to
100% acetonitrile:aqueous ammonium acetate (10 mM) over 8 minutes
(10 minute run time) at a flow rate of 40 mL/minute on reverse
phase HPLC to afford the title compound upon concentration under
reduced pressure. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.40
(m, 4H), 6.94 (s, 1H), 6.84 (d, J=6.6 Hz, 1H), 6.68 (s, 1H), 3.69
(m, 1H), 2.71 (m, 2H), 2.35 (m, 2H), 1.76 (m, 13H), 1.32 (m, 2H);
MS (ESI+) m/z 388 (M+H).sup.+.
Example 5
E-4-f
(1-Phenyl-cyclopropanecarbonyl)-aminol-adamantane-1-carboxylic acid
amide
[0503] The title compound was prepared according to the method of
Example 4 substituting the product from step B of Example 2 for the
product from step B of Example 1D. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.42 (m, 4H), 7.36 (m, 1H), 6.94 (s, 1H),
6.68 (s, 1H), 6.78 (d, J=7.8 Hz, 1H), 3.73 (m, 1H), 1.75 (m, 7H),
1.65 (m, 2H), 1.35 (m, 4H), 1.18 (m, 2H), 1.02 (m, 2H); MS (ESI+)
m/z 340 (M+H).sup.+.
Example 6
E-4-(2-Methyl-2-phenyl-propionylamino)-adamantane-1-carboxylic acid
amide
[0504] The title compound was prepared according to the method of
Example 4 substituting the product from step B of Example 3 for the
product from step B of Example 1D. .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 7.35 (m, 4H), 7.25 (m, 1H), 6.96 (s, 1H),
6.69 (s, 1H), 6.23 (d, J=7.2 Hz, 1H), 3.74 (m, 1H), 1.85 (m, 2H),
1.75 (m, 5H), 1.69 (m, 2H), 1.53 (m, 2H), 1.49 (s, 6H), 1.32 (m,
2H); MS (ESI+) m/z 342 (M+H).sup.+.
Example 7
N-2-adamantyl-2-methyl-2-phenylpronanamide
[0505] A solution of 2-adamantanamine hydrochloride (38 mg, 0.20
mmol), 2-phenylisobutyric acid (30 mg, 0.19 mmol), and
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(TBTU) (65 mg, 0.20 mmol) in N,N-dimethylacetamide (DMA) (2 mL) and
DIEA (80 .mu.L, 0.46 mmol) was stirred for 16 hours at 23.degree.
C. The reaction mixture was analyzed by LC/MS and determined to be
near completion. The reaction mixture was concentrated under
reduced pressure. The residue was dissolved in DMSO/MeOH (1:1, 1.5
mL) and purified by preparative HPLC on a Waters Symmetry C8 column
(25 mm.times.100 mm, 7 urn particle size) using a gradient of 10%
to 100% acetonitrile:aqueous ammonium acetate (10 mM) over 8
minutes (10 minute run time) at a flow rate of 40 mL/minute on
reverse phase HPLC to afford the title compound upon concentration
under reduced pressure. .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
7.35 (m, 4H), 7.24 (m, 1H), 6.16 (d, J=6.9 Hz, 1H), 3.78 (m, 1H),
1.74 (m, 7H), 1.64 (m, 3H), 1.55 (m, 2H), 1.48 (s, 6H), 1.41 (m,
2H); MS (DCI+) m/z 298 (M+H).sup.+.
Example 8
N-2-adamantyl-1-phenylcyclopropanecarboxamide
[0506] The titled compound was prepared according to the method of
Example 7 substituting 1-phenyl cyclopropanecarboxylic acid for
2-phenylisobutyric acid. .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 7.43 (m, 4H), 7.37 (m, 1H), 5.77 (d, J=7.8 Hz, 1H), 3.76
(m, 1H), 1.68 (m, 10H), 1.42 (m, 2H), 1.35 (m, 2H), 1.21 (m, 2H),
1.01 (m, 2H); MS (DCI+) m/z 296 (M+H).sup.+.
Example 9
E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamid-
e
Example 9A
E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxylic
acid
Step A
[0507] The methyl ester of the title compound was prepared
according to the method as described in step A of Example ID,
substituting 1-(4-chlorophenyl)-1-cyclohexanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 um particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0508] The methyl ester obtained from step A (47 mg, 0.11 mmol) was
dissolved in 5 N aqueous HO (1 mL) and 4 N HCl in dioxane (2 mL),
heated to 60.degree. C. for 24 hours, was cooled to 23.degree. C.,
and was then concentrated under reduced pressure to provide the
title compound.
Example 9B
E-4-({[1-(4-chlorophenyl)cyclohexyl]carbonyl}amino)adamantane-1-carboxamid-
e
[0509] The title compound was prepared according to the method as
described in Example 4 substituting the product of step B of
Example 9A for the product of step B of Example ID, and with the
exception that the crude title compound was purified by normal
phase flash chromatography with. MeOH/DCM (5:95) as eluant. .sup.1H
NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.36-7.42 (m, 4H),
6.95-6.96 (bs, 1H), 6.69-6.70 (bs, 1H), 6.57 (d, J=6.56 Hz, 1H),
3.72-3.76 (m, 1H), 2.36-2.44 (m, 2H), 1.84-1.86 (m, 2H), 1.73-1.82
(m, 5H), 1.64-1.73 (m, 6H), 1.49-1.56 (m, 3H), 1.36-1.51 (m, 2H),
1.32-1.36 (m, 2H), 1.23-1.30 (m, 1H); MS (ESI+) m/z 415
(M+H).sup.+.
Example 10
E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxami-
de
Example 10A
E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxyli-
c acid
Step A
[0510] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(4-chlorophenyl)-1-cyclopropanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0511] The methyl ester obtained from step A (51 mg, 0.13 mmol) was
dissolved in 5 N aqueous MCI (1 mL) and 4 N HCl in dioxane (2 mL),
heated to 60.degree. C. for 24 hours, was cooled to 23.degree. C.,
and was then concentrated under reduced pressure to provide the
title compound.
Example 10B
E-4-({[1-(4-chlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxami-
de
[0512] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 10A for the product of step B of Example 1D and with the
exception that title compound was purified by normal phase flash
chromatography with MeOH/DCM (5:95) as eluant. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 7.43-7.48 (m, 4H), 6.95-6.97 (bs,
11-1), 6.69-6.70 (bs, 1H), 5.98 (d, J=7.30 Hz, 1H), 3.71-3.76 (m,
1H), 1.79-1.82 (m, 2H), 1.73-1.78 (m, 5H), 1.67-1.69 (m, 2H),
1.29-1.41 (m, 6H), 0.99-1.03 (m, 2H); MS (ESI+) m/z 373
(M+H).sup.+.
Example 1.1
E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
Example 11A
E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxyli-
c acid
Step A
[0513] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(4-chlorophenyl)-1-cyclopentanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0514] The methyl ester obtained from step A (30 mg, 0.072 mmol)
was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 11B
E-4-({[1-(4-chlorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
[0515] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 11A for the product of step B of Example 1D, and with the
exception that title compound was purified by normal phase flash
chromatography with MeOH/DCM (5:95) as eluant. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 7.35-7.41 (m, 4H), 6.94-6.96 (bs,
1H), 6.68-6.70 (bs, 1H), 6.58 (d, J=6.59 Hz, 1H), 3.66-3.70 (m,
1H), 2.51-2.60 (m, 2H), 1.77-1.86 (m, 5H), 1.73-1.77 (m, 4H),
1.68-1.69 (m, 2H), 1.58-1.66 (m, 6H), 1.30-1.34 (m, 2H); MS (ESI+)
m/z 401 (M+H)'.
Example 12
E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide
Example 12A
E-4-{[2-(4-chlorophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxylic
acid
Step A
[0516] The methyl ester of the title compound was prepared
according to the method as described in step A of Example ID,
substituting 2-methyl-2-(4-chlorophenyl) propionic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 um particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0517] The methyl ester obtained from step A (50 mg, 0.13 mmol) was
dissolved in 5 N aqueous HCl (1 mL) and 4 N HCl in dioxane (2 mL),
heated to 60.degree. C. for 24 hours, was cooled to 23.degree. C.,
and was then concentrated under reduced pressure to provide the
title compound.
Example 12B
E-4-{[2-(4-chlorophenyl)-2-methylpronanoyl]amino}adamantane-1-carboxamide
[0518] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 12A for the product of step B of Example 1D, and with the
exception that title compound was purified by normal phase flash
chromatography with MeOH/DCM (5:95) as eluant. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 7.34-7.40 (m, 4H), 6.95-6.97 (bs,
1H), 6.69-6.71 (bs, 1H), 6.44 (d, J=6.72 Hz, 1H), 3.73-3.77 (m,
1H), 1.86-1.89 (m, 2H), 1.69-1.81 (m, 5H), 1.67-1.73 (m, 2H),
1.61-1.66 (m, 2H), 1.47 (s, 6H), 1.32-1.36 (m, 2H); MS (EST+) m/z
375 (M+H).sup.+.
Example 13
E-4-{[1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamide
Example 13A
E-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxylic
acid
Step A
[0519] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-phenyl-1-cyclopentanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 um particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0520] The methyl ester obtained from step A (20 mg, 0.052 mmol)
was dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 13B
E-4-{[(1-phenylcyclopentyl)carbonyl]amino}adamantane-1-carboxamide
[0521] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 13A for the product of step B of Example 1D, and with the
exception that title compound was purified by normal phase flash
chromatography with MeOH/DCM (5:95) as eluant. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 7.38-7.40 (m, 2H), 7.30-7.34 (m,
2H), 7.20-7.24 (m, 1H), 6.93-6.95 (bs, 1H), 6.68-6.69 (bs, 1H),
6.38 (d, J=6.80 Hz, 1H), 3.65-3.69 (m, 1H), 2.51-2.58 (m, 2H),
1.78-1.90 (m, 4H), 1.71-1.78 (m, 5H), 1.65-1.69 (m, 2H), 1.60-1.64
(m, 4H), 1.51-1.56 (m, 2H), 1.28-1.32 (m, 2H); MS (ESI+) m/z 367
(M+H).sup.+.
Example 14
E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
Example 14A
E-4-({[1-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxyli-
c acid
Step A
[0522] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(3-fluorophenyl)-1-cyclopentanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0523] The methyl ester obtained from step A (41 mg, 0.10 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 14B
E-4-({[-(3-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxamid-
e
[0524] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 14A for the product of step B of Example ID. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.31-7.40 (m, 1H), 7.18-7.24
(m, 2H), 7.01-7.09 (m, 1H), 6.93-6.96 (bs, 1H), 6.68-6.70 (bs, 1H),
6.60 (d, J=6.55 Hz, 1H), 3.64-3.71 (m, 1H), 2.48-2.66 (m, 2H),
1.71-1.88 (m, 9H), 1.58-1.71 (m, 8H), 1.29-1.35 (m, 2H); MS (ESI+)
m/z 385 (M+H).sup.+.
Example 15
E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1--
carboxamide
Example 15A
E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1--
carboxylic acid
Step A
[0525] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(2-chloro-4-fluorophenyl)-1-cyclopentanecarboxylic
acid for 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with
the exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0526] The methyl ester obtained from step A (66 mg, 0.15 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 15B
E-4-({[1-(2-chloro-4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1--
carboxamide
[0527] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 15A for the product of step B of Example 1D. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.61 (dd, J=8.86, 6.18 Hz, 1H),
7.43 (dd, J=8.66, 2.77 Hz, 1H), 7.24 (ddd, J=8.81, 8.11, 2.80 Hz,
1H), 6.94-6.96 (m, 1H), 6.68-6.71 (bs, 1H), 5.84 (d, J=6.96 Hz,
1H), 3.69-3.77 (m, 1H), 2.35-2.51 (m, 2H), 1.92-2.08 (m, 2H),
1.53-1.89 (m, 13H), 1.28-1.45 (m, 4H); MS (ESI+) m/z 419
(M+H).sup.+.
Example 16
E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
Example 16A
E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxyli-
c acid
Step A
[0528] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(4-fluorophenyl)-1-cyclopentanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 um particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0529] The methyl ester obtained from step A (58 mg, 0.15 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 16B
E-4-({[1-(4-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
[0530] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 16A for the product of step B of Example 1D. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.37-7.45 (m, 2H), 7.10-7.17
(m, 2H), 6.93-6.96 (bs, 1H), 6.67-6.70 (bs, 1H), 6.50 (d, J=6.65
Hz, 1H), 3.64-3.70 (m, 1H), 2.51-2.61 (m, 2H), 1.54-1.86 (m, 17H),
1.27-1.37 (m, 2H); MS (ESI+) m/z 385 (M+H).sup.+.
Example 17
E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
Example 17A
E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxyli-
c acid
Step A
[0531] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(2-fluorophenyl)-1-cyclopentanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 um particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0532] The methyl ester obtained from step A (56 mg, 0.14 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 17B
E-4-({[1-(2-fluorophenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxami-
de
[0533] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 17A for the product of step B of Example 1D. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.49 (td, J=7.94, 1.80 Hz, 1H),
7.29-7.37 (m, 1H), 7.11-7.24 (m, 2H), 6.94-6.96 (bs, 1H), 6.68-6.70
(bs, 1H), 6.02 (d, J=6.93 Hz, 1H), 3.67-3.74 (m, 1H), 2.34-2.53 (m,
2H), 1.85-2.01 (m, 2H), 1.57-1.86 (m, 13H), 1.28-1.43 (m, 4H); MS
(ESI+) m/z 385 (M+H).sup.+.
Example 18
E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide
Example 18A
E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxylic
acid
Step A
[0534] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-methyl-1-cyclohexanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid, and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 um particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0535] The methyl ester obtained from step A (33 mg, 0.10 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 18B
E-4-{[(1-methylcyclohexyl)carbonyl]amino}adamantane-1-carboxamide
[0536] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 18A for the product of step B of Example 1 D. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 6.96-6.99 (bs, 1H), 6.66-6.72
(m, 2H), 3.74-3.80 (m, 1H), 1.82-2.08 (m, 7H), 1.79-1.82 (m, 4H),
1.72-1.75 (m, 2H), 1.12-1.55 (m, 10H), 1.07 (s, 3H); MS (ESI+) m/z
319 (M+H).sup.+.
Example 19
E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carbo-
xamide
Example 19A
E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carbo-
xylic acid
Step A
[0537] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(2,4-dichlorophenyl)-1-cyclopropanecarboxylic acid
for 1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0538] The methyl ester obtained from step A (47 mg, 0.11 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (2
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 19B
E-4-({[1-(2,4-dichlorophenyl)cyclopropyl]carbonyl}amino)adamantane-1-carbo-
xamide
[0539] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 19A for the product of step B of Example 1D. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.73 (d, J=2.10 Hz, 1H), 7.56
(d, J=8.25 Hz, 1H), 7.49 (dd, J=8.27, 2.12 Hz, 1H), 6.94-6.97 (bs,
1H), 6.68-6.71 (bs, 1H), 5.66 (d, J=7.12 Hz, 1H), 3.70-3.77 (m,
1H), 1.80-1.84 (m, 2H), 1.71-1.78 (m, 5H), 1.68 (d, J=3.09 Hz, 2H),
1.43-1.53 (m, 2H), 1.27-1.42 (m, 4H), 1.02-1.12 (m, 2H); MS (ESI+)
m/z 407 (M+H).sup.+.
Example 20
E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxam-
ide
Example 20A
E-4-({[1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxyl-
ic acid
Step A
[0540] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(4-methoxyphenyl)-1-cyclopropanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0541] The methyl ester obtained from step A (43 mg, 0.11 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 20B
E-4-{[(1-(4-methoxyphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxam-
ide
[0542] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 20A for the product of step B of Example 1D. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.34-7.38 (m, 2H), 6.95-7.00
(m, 3H), 6.68-6.71 (bs, 1H), 5.78 (d, 0.1=7.66 Hz, 1H), 3.76 (s,
3H), 3.69-3.75 (m, 1H), 1.72-1.77 (m, 7H), 1.66-1.69 (m, 2H),
1.27-1.43 (m, 4H), 1.17-1.24 (m, 2H), 0.93-1.03 (m, 2H); MS (ESI+)
m/z 369 (M+H).sup.+.
Example 21
E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxami-
de
Example 21A
E-4-{[(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxylic
acid
Step A
[0543] The methyl ester of the title compound was prepared
according to the method as described in step A of Example 1D,
substituting 1-(4-methylphenyl)-1-cyclopropanecarboxylic acid for
1-(4-chlorophenyl)-1-cyclobutanecarboxylic acid and with the
exceptions that the methyl ester was purified by reverse phase
chromatography. Upon work up, the residue was dissolved in
DMSO/MeOH (1:1, 1.5 mL) and purified by preparative HPLC on a
Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size)
using a gradient of 10% to 100% acetonitrile:aqueous ammonium
acetate (10 mM) over 8 min (10 min run time) at a flow rate of 40
mL/min.
Step B
[0544] The methyl ester obtained from step A (39 mg, 0.11 mmol) was
dissolved in 5 N aqueous HCl (0.5 mL) and 4 N HCl in dioxane (1
mL), heated to 60.degree. C. for 24 hours, was cooled to 23.degree.
C., and was then concentrated under reduced pressure to provide the
title compound.
Example 21B
E-4-({[1-(4-methylphenyl)cyclopropyl]carbonyl}amino)adamantane-1-carboxami-
de
[0545] The title compound was prepared according to the method as
described in Example 4, substituting the product of step B of
Example 21A for the product of step B of Example ID. .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. ppm 7.30-7.34 (m, 2H), 7.20-7.25
(m, 2H), 6.94-6.97 (bs, 1H), 6.68-6.70 (bs, 1H), 5.80 (d, J=7.62
Hz, 1H), 3.69-3.76 (m, 1H), 2.31 (s, 3H), 1.71-1.81 (m, 7H),
1.66-1.68 (m, 2H), 1.31-1.39 (m, 4H), 1.17-1.23 (m, 2H), 0.96-0.99
(m, 2H); MS (ESI+) m/z 353 (M+H).sup.+.
Example 22
E-4-{[2-methyl-2-(4-pyridin-4-ylphenyl)propanoyl]amino}adamantane-1-carbox-
amide
Example 22A
Ethyl 2-(4-bromophenyl)-2-methylpropanoate
[0546] A 60% suspension of sodium hydride in mineral oil (3.3 g,
82.3 mmoles) was added to N,N-dimethylformamide (60.0 ml) under a
nitrogen atmosphere and the mixture was cooled to about -10.degree.
C. Iodomethane (5.1 ml, 82.3 mmoles) and subsequently ethyl
4-bromophenylacetate (5.0 g, 20.6 mmoles) were added over a period
of about 30 min and the reaction mixture was then stirred for about
16 hours while being allowed to warm to room temperature. This
suspension was then poured onto a mixture of ice and 2N
hydrochloric acid (30.0 ml) and was extracted four times with ethyl
acetate. The combined organic extracts were washed with water and
brine, dried over MgSO.sub.4 and filtered. The filtrate was
concentrated under reduced pressure and the crude product was
purified by flash column chromatography on silica gel using
hexanes/ethyl acetate (2:1) as the mobile phase to provide the
title compound.
Example 22B
2-(4-bromophenyl)-2-methylpropanoic Acid
[0547] To a solution of the product of Example 22A (3.7 g, 13.6
mmoles) in tetrahydrofuran (110.0 ml) and methanol (37.0 ml) was
added 2 N sodium hydroxide (19.0 ml) and the solution was stirred
at ambient temperature for about 16 hours. The reaction mixture was
concentrated in vacuum down to the water layer, was cooled with an
ice bath, and was acidified by addition of 2N hydrochloric acid.
The precipitate was filtered off and was dried in vacuum to provide
the title compound.
Example 22C
E-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-1-carboxylic
acid methyl ester
[0548] A solution of the product of Example 22B (3.3 g, 13.5
mmoles), the product of Example 1C (3.3 g, 13.5 mmoles),
O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium tetrafluoroborate
(8.6 g, 26.9 mmoles) and N,N-diisopropylethylamine (9.4 ml, 53.8
mmoles) in N,N-dimethylformamide (150.0 ml) was stirred at room
temperature for about 16 hours under a nitrogen atmosphere. The
solvent was evaporated in vacuum and the residue was purified by
flash column chromatography on silica gel using hexanes/ethyl
acetate (2:1) as the mobile phase to provide the title
compound.
Example 22D
E-4-[2-Methyl-2-(4-pyridin-4-yl-phenyl)-propionylamino]-adamantane-1-carbo-
xylic acid methyl ester
[0549] To a solution of the product of Example 22C (300 mg, 0.7
mmoles) in 1,2-dimethoxyethane (6.0 ml) was added a solution of
pyridine-4-boronic acid (127 mg, 1.0 mmoles) in ethanol (1.0 ml),
dichlorobis(tri-o-tolylphosphine)palladium(II) (28 mg, 0.04 mmoles)
and a 2M aqueous solution of sodium carbonate (1.7 ml, 3.5 mmoles)
and the mixture was stirred under nitrogen in a heavy walled
process vial in a microwave synthesizer (Personal Chemistry Smith
Synthesizer) at about 140.degree. C. for about 10 min. The reaction
mixture was concentrated in vacuum and the crude product was
purified by flash column chromatography on silica gel using
hexanes/ethyl acetate (2:1) as the mobile phase to provide the
title compound.
Example 22E
E-4-[2-Methyl-2-(4-pyridin-4-yl-phenyl)-propionylamino]-adamantane-1-carbo-
xylic acid
[0550] To a solution of the product of Example 22D (125 mg, 0.29
mmoles) in dioxane (4.0 ml) was added 2N aqueous hydrochloric acid
(4.0 ml) and the mixture was heated to about 60.degree. C. for
about 18 hours. The mixture was cooled, concentrated to dryness and
the residue was purified by preparative HPLC on a Waters Symmetry
C8 column (25 mm.times.100 mm, 7 .mu.m particle size) using a
gradient of 10% to 100% acetonitrile: 0.1% aqueous TFA over 8 min
(10 min run time) at a flow rate of 40 ml/min to provide the title
compound.
Example 22F
E-4-[2-Methyl-2-(4-pyridin-4-yl-phenyl)-propionylamino]-adamantane-1-carbo-
xylic acid amide
[0551] A solution of the product of Example 22E (60 mg, 0.14
mmoles), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (110 mg, 0.57 mmoles) and 1-hydroxybenzotriazole
hydrate (44 mg, 0.32 mmoles) in dichloromethane (4.0 ml) was
stirred at ambient temperature under a nitrogen atmosphere for
about 1 hour. A 0.5 M solution of ammonia in dioxane (2.9 ml, 1.43
mmoles) was added and stirring was continued for about 16 hours.
The mixture was evaporated to dryness and the residue was purified
by preparative HPLC on a Waters Symmetry C8 column (25 mm.times.100
mm, 7 .mu.m particle size) using a gradient of 10% to 100%
acetonitrile: 0.1% aqueous TFA over 8 min (10 min run time) at a
flow rate of 40 ml/min to provide the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 8.84-8.86 (m, 2H), 8.17-8.19 (m, 2H), 7.94-7.97 (m,
2H), 7.54-7.56 (m, 2H), 6.96-6.98 (bs, 1H), 6.70-6.72 (bs, 1H),
6.57 (d, J=6.64 Hz, 1H), 3.76-3.80 (m, 1H), 1.90-1.92 (m, 2H),
1.75-1.84 (m, 5H), 1.64-1.75 (m, 4H), 1.55 (s, 6H), 1.33-1.37 (m,
2H); MS(ESI+) m/z 418 (M+H).sup.4-.
Example 23
E-4-[2-methyl-2-thien-2-ylpropanoyl)amino]adamantane-1-carboxamide
Example 23A
Ethyl 2-methyl-2-(thiophen-2-yl)propanoate
[0552] The title compound was prepared according to the method of
Example 22A, substituting ethyl 2-(thiophen-2-yl)acetate for ethyl
4-bromophenylacetate.
Example 23B
2-Methyl-2-(thiophen-2-yl)propanoic acid
[0553] The title compound was prepared according to the method of
Example 22B, substituting the product of Example 23A for the
product of Example 22A.
Example 23C
E-4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carboxylic
acid methyl ester
[0554] The title compound was prepared according to the method of
Example 22C, substituting the product of Example 23B for the
product of Example 22B.
Example 23D
E-4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carboxylic
acid
[0555] To a solution of the product of Example 23C (250 mg, 0.69
mmoles) in dioxane (9.0 ml) was added 2N hydrochloric acid (9.0 ml)
and the mixture was heated to about 60.degree. C. for about 18
hours. The mixture was cooled, concentrated down to the water
layer, the precipitate was filtered off and was dried in vacuum to
give the title compound.
Example 23E
E-4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carboxylic
acid amide
[0556] The title compound was prepared according to the method of
Example 22F, substituting the product of Example 23D for the
product of Example 22E. .sup.1H NMR (500 MHz, DMSO-d.sub.6) 5 ppm
7.46 (dd, J=5.10, 1.20 Hz, 1H), 7.10 (dd, J=3.52, 1.21 Hz, 1H),
7.02 (dd, J=5.09, 3.52 Hz, 1H), 6.95-6.97 (bs, 1H), 6.69-6.71 (bs,
1H), 6.24 (d, J=7.11 Hz, 1H), 3.68-3.72 (m, 1H), 1.82-1.84 (m, 2H),
1.72-1.81 (m, 5H), 1.66-1.72 (m, 2H), 1.56 (s, 6H), 1.48-1.52 (m,
2H), 1.34-1.38 (m, 2H); MS(ESI+) m/z 347 (M+H).sup.+.
Example 24
E-4-[(2-methyl-2-thien-3-ylpropanoyl)amino]adamantane-1-carboxamide
Example 24A
Ethyl 2-methyl-2-(thiophen-3-yl)propionate
[0557] The title compound was prepared according to the method of
Example 22A substituting ethyl 2-(thiophen-3-yl)acetate for
4-bromophenylacetate.
Example 24B
2-Methyl-2-(thiophen-3-yl)propanoic acid
[0558] The title compound was prepared according to the method of
Example 22B, substituting the product of Example 24A for the
product of Example 22A.
Example 24C
E-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-1-carboxylic
acid methyl ester
[0559] The title compound was prepared according to the method of
Example 22C, substituting the product of Example 24B for the
product of Example 22B.
Example 24D
E-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-1-carboxylic
acid
[0560] The title compound was prepared according to the method of
Example 23D, substituting the product of Example 24C for the
product of Example 23C.
Example 24E
E-4-(2-Methyl-2-thiophen-3-yl-propionylamino)-adamantane-1-carboxylic
acid amide
[0561] The title compound was prepared according to the method of
Example 22F, substituting the product of Example 24D for the
product of Example 22E. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
ppm 7.54 (dd, J=5.03, 2.90 Hz, 1H), 7.41 (dd, J=2.89, 1.44 Hz, 1H),
7.12 (dd, J=5.00, 1.40 Hz, 1H), 6.95-6.97 (bs, 1H), 6.69-6.70 (bs,
1H), 6.01-6.07 (m, 1H), 3.68-3.72 (m, 1H), 1.76-1.82 (m, 7H), 1.69
(d, J=3.14 Hz, 2H), 1.51 (s, 6H), 1.43-1.48 (m, 2H), 1.33-1.37 (m,
2H); MS(ESI+) m/z 347 (M+H).sup.+.
Example 25
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamanta-
ne-1-carboxamide
Example 25A
Potassium;
2-methyl-2-(5-trifluoromethyl-pyridin-2-yl)-propionate
[0562] A solution of 2-chloro-5-(trifluoro-methyl)pyridine (328 mg,
1.8 mmol), methyl trimethylsilyl dimethylketene acetal (0.378 mg,
2.17 mmol), zinc fluoride (112 mg, 1.08 mmol),
tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) and
tri-t-butylphosphine-10 wt % in hexane (172 mg, 0.084 mmol) in
Argon degassed DMF (1.5 mL) was stirred at 90.degree. C. for 12
hours. The reaction was taken up in EtOAc (25 mL) and washed with
water (15 mL) followed by brine (15 mL). The organic layer was
dried with MgSO4, filtered, and evaporated in vacuo. The crude
product was purified by flash chromatography (hexane/EtOAc 100:0 to
80:20) to give the methyl ester of the title compound. A solution
of the methyl ester of the title compound (180 mg, 0.73 mmol),
potassium trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol) in THF (2
mL) was stirred for 12 hours at 23.degree. C. Methyl t-butyl ether
(MTBE) 8 mL was added to the solution and the title compound was
isolated by filtration.
Example 25B
E-4-[2-Methyl-2-(5-trifluoromethyl-pyridin-2-yl)-propionylamino]-adamantan-
e-1-carboxylic acid methyl ester
[0563] A solution of the product of Example 25A (50 mg, 0.184
mmol), the product of Example IC (54 mg, 0.22 mmol), TBTU (94 mg,
0.294 mmol) and DIEA (58 mg, 0.46 mmol) in DMF (1.2 mL) was stirred
for 3 hrs at 23.degree. C. The reaction was diluted with EtOAc (10
mL) and washed twice with water (6 mL) and brine (6 mL). The
organic layer was dried with MgSO.sub.4, filtered and evaporated in
vacuo to afford the title compound. The product was carried to the
next step without further purification.
Example 25C
E-4-({2-methyl-2-[5-(trifluoromethyl)pyridin-2-yl]propanoyl}amino)adamanta-
ne-1-carboxamide
[0564] A solution of Example 25B (30 mg, 0.071 mmol), KOTMS (14 mg,
0.11 mmol) in THF (1 mL) was stirred for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo to collect a solid. To the
solid was added TBTU (40 mg, 0.12 mmol), DIEA (22 mg, 0.17 mmol)
and DMF (0.5 mL) and stirred for 2 hours at 23.degree. C. Ammonium
hydroxide--30% by weight (2 mL) was added and stirred at 23.degree.
C. for a further 30 minutes. The reaction was partitioned between
EtOAc (8 mL) and water (3 mL). The organic layer was washed with
water (3 mL), dried with MgSO.sub.4, filtered, and evaporated in
vacuo. The crude reaction mixture was purified by preparative
reverse phase HPLC on a Waters Symmetry C8 column (25 mm.times.100
mm, 7 urn particle size) using a gradient of 20% to 100%
acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40
mL/min. to provide the title compound as the trifluoroacetic acid
salt. .sup.1H NMR (500 MHz, Chloroform-d.sub.1) .delta. ppm
8.86-8.87 (m, 1H), 7.94 (dd, J=8.38, 2.40 Hz, 1H), 7.59 (d, J=8.33
Hz, 1H), 7.41 (d, J=7.48 Hz, 1H), 6.13-6.18 (bs, 1H), 5.80-5.84
(bs, 1H), 3.93-3.97 (m, 1H), 1.99-2.03 (m, 3H), 1.93-1.99 (m, 4H),
1.87-1.89 (m, 2H), 1.69 (s, 6H), 1.63-1.68 (m, 2H), 1.56-1.60 (m,
2H); MS(APCI+) m/z 410 (M+H).sup.+.
Example 26
E-4-[(2-methyl-2-{4-[5-(trifluoro methyl)pyridin-2
yl]phenyl}propanoyl)amino]adamantane-1-carboxamide
Example 26A
Ethyl
2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pr-
opanoate
[0565] A mixture of the product of Example 22A (500 mg, 1.84
mmoles), bis(pinacolato)diboron (735 mg, 2.90 mmoles),
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (90 mg,
0.11 mmoles) and potassium acetate (903 mg, 9.20 mmoles) in
dimethyl sulfoxide (11.0 ml) was heated to about 80.degree. C.
under a nitrogen atmosphere for about two days. The mixture was
cooled, diluted with benzene (28.0 ml) and was washed three times
with water (18.0 ml each). The organic layer was dried over
MgSO.sub.4 and filtered. The filtrate was concentrated under
reduced pressure and the crude product was purified by flash column
chromatography on silica gel using hexanes/ethyl acetate (2:1) as
the mobile phase to provide the title compound.
Example 26B
Ethyl
2-methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)propanoate
[0566] To a solution of the product of Example 26A (370 mg, 1.16
mmoles) and 2-bromo-5-(trifluoromethyl)pyridine (341 mg, 1.51
mmoles) in N,N-dimethylformamide (10.0 ml) were added
1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28 mg,
0.04 mmoles) and a 2M aqueous solution of sodium carbonate (1.7 ml,
3.48 mmoles) and the reaction mixture was heated under a nitrogen
atmosphere to about 80.degree. C. for about 1 hour. Another portion
of 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II) (28
mg, 0.04 mmoles) was added and the mixture was heated to about
90.degree. C. for about 2 hours. The solvent was evaporated in high
vacuum, the residue was taken up in water (20.0 ml) and diethyl
ether (20.0 ml), and was filtered through Celite. The layers were
separated and the aqueous layer was extracted with diethyl ether.
The combined organic extracts were dried over MgSO.sub.4 and
filtered. The filtrate was concentrated under reduced pressure and
the crude product was purified by flash column chromatography on
silica gel using hexanes/ethyl acetate (2:1) as the mobile phase to
provide the title compound.
Example 26C
2-Methyl-2-(4-(5-(trifluoromethyl)pyridin-2-yl)phenyl)propanoic
acid
[0567] The title compound was prepared according to the method of
Example 22B, substituting the product of Example 26B for the
product of Example 22A.
Example 26D
E-4-{2-Methyl-2-(4-(5-trifluoromethyl-pyridin-2-yl)-phenyl)-propionylamino-
}-adamantane-1-carboxylic acid methyl ester
[0568] The title compound was prepared according to the method of
Example 22C substituting the product of Example 26C for the product
of Example 22B.
Example 26E
E-4-{2-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-propionylamino-
}-adamantane-1-carboxylic acid
[0569] The title compound was prepared according to the method of
Example 22E substituting the product of Example 26D for the product
of Example 22D.
Example 26F
E-4-{2-Methyl-2-[4-(5-trifluoromethyl-pyridin-2-yl)-phenyl]-propionylamino-
}-adamantane-1-carboxylic acid amide
[0570] The trifluoroacetic acid salt of the title compound was
prepared according to the method of Example 22F substituting the
product of Example 26E for the product of Example 22E. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 9.03-9.05 (m, 1H), 8.27 (dd,
J=8.46, 2.42 Hz, 1H), 8.20 (d, J=8.38 Hz, 1H), 8.13-8.16 (m, 2H),
7.50-7.53 (m, 2H), 6.96-6.98 (bs, 1H), 6.69-6.71 (bs, 1H), 6.48 (d,
J=6.75 Hz, 1H), 3.76-3.81 (m, 1H), 1.88-1.91 (m, 2H), 1.74-1.84 (m,
5H), 1.60-1.74 (m, 4H), 1.54 (s, 6H), 1.32-1.36 (m, 2H); MS(ESI+)
m/z 486 (M+H).sup.+.
Example 27
E-4-({[1-(4-methoxyphenyl)cyclopentyl]carbonyl}amino)adamantane-1-carboxam-
ide
Example 27A
E-4-{[1-(4-Methoxy-phenyl)-cyclopentanecarbonyl]-amino}-adamantane-1-carbo-
xylic acid methyl etser
[0571] A solution of the product of Example 1C (110 mg, 0.45 mmol),
1-(4-methoxyphenyl)-1-cyclopentanecarboxylic acid (100 mg, 0.45
mmol), and O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
tetrafluoroborate (TBTU) (219 mg, 0.68 mmol) in
N,N-dimethylformamide (DMF) (2 mL) was stirred ten minutes at room
temperature, and then, diisopropylethylamine (240 .mu.L, 1.4 mmol)
was added. Reaction stirred for 16 hours at room temperature. The
reaction was diluted with ethyl acetate and washed successively
with water, saturated sodium bicarbonate, 1N phosphoric acid, and
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated
under reduced pressure. The residue was purified by flash
chromatography on silica gel eluting with 20-30% ethyl
acetate/hexane to provide the title compound.
Example 27B
E-4-{[1-(4-Methoxy-phenyl)-cyclopentanecarbonyl]-amino}-adamantane-1-carbo-
xylic acid
[0572] A solution of the product of Example 27A (160 mg, 0.39 mmol)
in THF (3 mL) was treated with aqueous 4N sodium hydroxide (1.00
mL, 3.9 mmol) and methanol (1 mL), and reaction stirred 16 hours at
room temperature. The reaction mixture was concentrated under
reduced pressure, and the residue was taken up in water. The
solution was acidified to pH 3 by the addition of aqueous 1N
phosphoric acid, and the product was extracted with chloroform
(3.times.). The combined extracts were dried (Na.sub.2SO.sub.4),
filtered, and concentrated under reduced pressure to provide the
title compound.
Example 27C
E-4-{[1-(4-Methoxy-phenyl)-cyclopentanecarbonyl]-amino}-adamantane-1-carbo-
xylic acid amide
[0573] A solution of the product of Example 27B (130 mg, 0.330
mmol), 1-hydroxybenzotriazole (54 mg, 0.40 mmol), and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC)
(76 mg, 0.40 mmol) in dimethylformamide (5 mL) was stirred two
hours at room temperature. The reaction was treated with
concentrated ammonium hydroxide (1 mL) and stirred 16 hours at room
temperature. Reaction diluted with ethyl acetate and washed
successively with water, saturated sodium bicarbonate, 1N
phosphoric acid, and brine before drying over Na.sub.2SO.sub.4,
filtering, and concentrating under reduced pressure. Residue
purified by flash chromatography on silica gel eluting with 5%
methanol/ethyl acetate to provide the title compound. .sup.1H NMR
(500 MHz, DMSO-d.sub.6) .delta. ppm 7.29-7.31 (m, 2H), 6.94-6.95
(bs, 1H), 6.86-6.89 (m, 2H), 6.68-6.69 (bs, 1H), 6.32 (d, J=6.82
Hz, 1H), 3.73 (s, 3H), 3.64-3.70 (m, 1H), 2.46-2.51 (m, 2H),
1.74-1.85 (m, 9H), 1.68 (d, J=3.12 Hz, 2H), 1.53-1.62 (m, 6H),
1.30-1.34 (m, 2H); MS (ESI+) m/z 397 (M+H).sup.+.
Example 28
E-4-{[2-(4-bromophenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide
Example 28A
E-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-1-carboxylic
acid
[0574] The title compound was prepared according to the method of
Example 23D substituting the product of Example 22C for the product
of Example 23C.
Example 28B
E-4-[2-(4-Bromo-phenyl)-2-methyl-propionylamino]-adamantane-1-carboxylic
acid amide
[0575] The title compound was prepared according to the method of
Example 22F substituting the product of Example 28A for the product
of Example 22E. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.50-7.53 (m, 2H), 7.27-7.30 (m, 2H), 6.93-6.95 (bs, 1H), 6.65-6.68
(bs, 1H), 6.43 (d, 0.1=6.73 Hz, 1H), 3.72-3.76 (m, 1H), 1.86-1.89
(m, 2H), 1.77-1.79 (m, 5H), 1.61-1.73 (m, 4H), 1.47 (s, 6H),
1.32-1.37 (m, 2H); MS(DCI) m/z 419, 421 (M+H).sup.+.
Example 30
E-4-[5-(amino
carbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopineridine-3-carb-
oxamide
Example 30A
2-But-3-enyl-2-methyl-malonic acid dimethyl ester
[0576] A stirred solution of NaH-60% by weight (0.517 gm, 12.94
mmol) in DMF (5 mL) was cooled to 0.degree. C. and dimethyl methyl
malonate (1.26 gm, 8.63 mmol) in 3 mL of DMF was added dropwise.
The reaction was warmed to ambient and stirred for 15 minutes. A
solution of 4-bromo-1-butene (1.28 gm, 9.49 mmol) in 1.5 mL of DMF
was added to the reaction mixture and stirred for 12 hours at
23.degree. C. The reaction was partitioned between 10% NH.sub.4Cl
(20 mL) and 30 mL of EtOAc. The organic layer was washed with water
(20 mL), brine (20 mL), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The crude product was purified by flash
chromatography (hexane/EtOAc 100:0 to 85:15) to provide Example 30A
as an oil.
Example 30B
2-Methyl-2-(3-oxo-propyl)-malonic acid dimethyl ester
[0577] A solution of the product of Example 30A (0.1.0 gm, 5 mmol)
was dissolved in CH.sub.2Cl.sub.2/MeOH 10:1 (15 mL) and cooled to
78.degree. C. To the solution was bubbled 0.sub.3 over 20 minutes.
The reaction solution was purged with N.sub.2 for a further 10
minutes and dimethyl sulfide (DMS) (3.1 gm, 50 mmol) was added and
the reaction warmed to ambient temperature and stirred for a
further 2 hours. The solvent was evaporated in vacuo and product
purified by flash column chromatography (hexane/EtOAc 100:0 to
70:30) to collect Example 30B as an oil.
Example 30C
[0578] Potassium;
3-Methyl-1-(2-methyl-benzyl)-2-oxo-piperidine-3-carboxylate A
solution of the product of Example 30B (0.075 gm, 0.37 mmol),
2-methyl-benzylamine (53 mg, 0.44 mmol) and MP-triacetoxy
borohydride (420 mg, 0.92 mmol) in THF (2 mL) was stirred for 12
hours at 23.degree. C. The solution was filtered and evaporated in
vacuo. The resulting oil was taken up in THF (1.2 mL) and stirred
with KOTMS (71 mg, 0.55 mmol) at 23.degree. C. for 12 hours. The
solvent was evaporated in vacuo to provide the title compound as a
white solid.
Example 30D
E-[4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopiperid-
ine-3-carboxamide
[0579] A solution of the product of Example 30 C (50 mg, 0.167
mmol), the product of Example 1C (49 mg, 0.2 mmol), TBTU (85 mg,
0.26 mmol) and DIEA (53 mg, 0.42 mmol in DMF (1.2 mL) was stirred
for 2 hours at 23.degree. C. The reaction was partitioned between
EtOAc (8 ml) and water (4 ml). The organic layer was separated and
washed twice with water (4 mL each), dried with MgSO.sub.4,
filtered and evaporated in vacuo. The resulting oil was taken in
THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23.degree.
C. for 12 hours. The solvent was evaporated in vacuo. The resulting
solid was taken in DMF (1 mL) and stirred with TBTU (96 mg, 0.3
mmol) and DIEA (53 mg, 0.42 mmol) for 2 hours at 23.degree. C.
Ammonium hydroxide--30% by weight (2 mL) was added and stirred for
a further 30 minutes at 23.degree. C. The reaction was partitioned
between EtOAc (8 mL) and water (3 mL). The organic layer was washed
with water (3 mL), dried with MgSO.sub.4 and evaporated in vacuo.
The crude reaction mixture was purified by preparative reverse
phase HPLC on a Waters Symmetry C8. column (25 mm.times.100 mm, 7
um particle size) using a gradient of 20% to 100%
acetonitrile:water (0.1% TFA) over 18 min at a flow rate of 40
mL/min. to provide the title compound. .sup.1HNMR (500 MHz,
CDCl.sub.3) .delta. ppm 8.25 (d, J=8.1 Hz, 1H), 7.19 (m, 2H), 7.13
(m, 1H), 7.02 (d, J=7.5 Hz, 1H), 6.6 (bs, 1H), 5.82 (bs, 1H), 4.93
(d, J=15.3, 1H), 4.38 (d, J=15.3, 1H), 4.01 (m, 1H), 3.22 (m, 2H),
2.67 (m, 1H), 2.28 (s, 3H), 2.1 (m, 1H), 1.99 (m, 6H), 1.81 (m,
5H), 1.57 (m, 2H), 1.56 (s, 3H); MS(APCI) m/z 438 (M+H)
Example 31
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-carb-
oxamide
Example 31A
2-Allyl-2-methyl-malonic acid dimethyl ester
[0580] A stirred solution of NaH-60% by weight (0.493 gm, 12.34
mmol) in DMF (5 mL) was cooled to 0.degree. C. and dimethyl methyl
malonate (1.2 gm, 8.23 mmol) in 3 mL of DMF was added dropwise. The
reaction was warmed to ambient temperature and stirred for 15
minutes. A solution of allyl bromide (1.18 gm, 9.86 mmol) in 1.5 mL
of DMF was added to the reaction mixture and stirred for 12 hours
at 23.degree. C. The reaction was partitioned between 10%
NH.sub.4CI (20 mL) and 30 mL of EtOAc. The organic layer was washed
with water (20 mL), brine (20 mL), dried with MgSO.sub.4, filtered
and evaporated in vacuo. The crude product was purified by flash
chromatography (hexane/EtOAC 100:0 to 85:15) to provide the title
compound as an oil.
Example 31B
2-Methyl-2-(2-oxo-ethyl)-malonic acid dimethyl ester
[0581] A solution of the product of Example 31A (1.1 gm, 5.9 mmol)
was dissolved in CH.sub.2Cl.sub.2/MeOH 10:1 (15 mL) and cooled to
78.degree. C. To the solution was bubbled 0.sub.3 over 20 minutes.
The reaction solution was purged with N.sub.2 for a further 10
minutes and dimethyl sulfide (DMS) (3.6 gm, 59 mmol) was added and
the reaction warmed to ambient temperature and stirred for a
further 2 hours. The solvent was evaporated in vacuo and product
purified by flash column chromatography (hexane/EtOAc 100:0 to
70:30) to collect Example 31B as an oil.
Example 31C
Potassium; 1-benzyl-3-methyl-2-oxo-pyrrolidine-3-carboxylate
[0582] A solution of the product of Example 31B (0.075 gm, 0.4
mmol), benzylamine (51 mg, 0.47 mmol) and MP-triacetoxy borohydride
(431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours at
23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in THF (1.2 mL) and stirred with
KOTMS (77 mg, 0.6 mmol) for 12 hours at 23.degree. C. The solvent
was evaporated in vacuo to provide Example 31C.
Example 31 D
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopyrrolidine-3-carb-
oxamide
[0583] A solution of the product of Example 31C (50 mg, 0.18 mmol),
the product of Example 1C (54 mg, 0.22 mmol), TBTU (92 mg, 0.29
mmol) and DIEA (57 mg, 0.45 mmol in DMF (1.2 mL) was stirred for 2
hours at 23.degree. C. The reaction was partitioned between EtOAc
(8 ml) and water (4 ml). The organic layer was separated and washed
twice with water (4 mL each), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The resulting oil was taken in THF (1 mL) and
stirred with KOTMS (34 mg, 0.27 mmol) for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo. The resulting solid was taken
in DMF (1 mL) and stirred with TBTU (104 mg, 0.32 mmol) and DIEA
(57 mg, 0.45 mmol) for 2 hours at 23.degree. C. Ammonium
hydroxide--30% by weight (2 mL) was added and stirred for a further
30 minutes. The reaction was partitioned between EtOAc (8 mL) and
water (3 mL). The organic layer was washed with water (3 mL), dried
with MgSO.sub.4 and evaporated in vacuo. The crude reaction mixture
was purified by preparative reverse phase HPLC on a Waters Symmetry
C8 column (25 mm.times.100 mm, 7 urn particle size) using a
gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min
at a flow rate of 40 mL/min. to provide the title compound. .sup.1H
NMR (400 MHz, Chloroform-d.sub.1) .delta. ppm 8.18-8.23 (m, 1H),
7.29-7.35 (m, 3H), 7.19-7.21 (m, 2H), 5.48-5.70 (m, 2H), 4.51 (d,
J=14.73 Hz, 1H), 4.43 (d, J=14.58 Hz, 1H), 3.99-4.05 (m, 1H),
3.14-3.21 (m, 2H), 2.60-2.68 (m, 1H), 2.09-2.15 (m, 1H), 2.01-2.09
(m, 2H), 1.87-2.00 (m, 8H), 1.84-1.86 (m, 1H), 1.57-1.66 (m, 2H),
1.48 (s, 3H); MS(APCI) m/z 410 (M+H)
Example 32
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrrolid-
ine-3-carboxamide
Example 32A
Potassium;
3-methyl-1-(2-methyl-benzyl)-2-oxo-pyrrolidine-3-carboxylate
[0584] A solution of the product of Example 31B (0.075 gm, 0.4
mmol), 2-methyl-benzylamine (58 mg, 0.47 mmol) and MP-triacetoxy
borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours
at 23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in THF (1.2 mL) and stirred with
KOTMS (77 mg, 0.6 mmol) for 12 hours at 23.degree. C. The solvent
was evaporated in vacuo to provide Example 32A.
Example 32B
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(2-methylbenzyl)-2-oxopyrrolid-
ine-3-carboxamide
[0585] A solution of Example 32A (50 mg, 0.17 mmol), the product of
Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27 mmol) and DIEA (54
mg, 0.42 mmol) in DMF (1.2 mL) was stirred for 2 hours at
23.degree. C. The reaction was partitioned between EtOAc (8 ml) and
water (4 ml). The organic layer was separated and washed twice with
water (4 mL each), dried with MgSO.sub.4, filtered and evaporated
in vacuo. The resulting oil was taken in THF (1 mL) and stirred
with KOTMS (33 mg, 0.25 mmol) for 12 hours at 23.degree. C. The
solvent was evaporated in vacuo. The resulting solid was taken in
DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol) and DIEA (54
mg, 0.42 mmol) for 2 hours. Ammonium hydroxide--30% by weight (2
mL) was added and stirred for a further 30 minutes at 23.degree. C.
The reaction was partitioned between EtOAc (8 mL) and water (3 mL).
The organic layer was washed with water (3 mL), dried with
MgSO.sub.4 and evaporated in vacuo. The crude reaction mixture was
purified by preparative reverse phase HPLC on a Waters Symmetry C8
column (25 mm.times.100 mm, 7 um particle size) using a gradient of
20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow
rate of 40 mL/min. to provide the title compound. .sup.1H NMR (400
MHz, Chloroform-d.sub.1) .delta. ppm 8.17-8.22 (m, 1H), 7.12-7.24
(m, 3H), 7.08-7.11 (m, 1H), 5.56-5.66 (m, 1H), 5.34-5.43 (m, 1H),
4.50-4.51 (m, 2H), 3.99-4.05 (m, 1H), 3.07-3.17 (m, 2H), 2.65 (ddd,
J=13.33, 8.70, 7.16 Hz, 1H), 2.28 (s, 3H), 2.08-2.15 (m, 1H),
1.81-2.07 (m, 11H), 1.53-1.68 (m, 2H), 1.49 (s, 3H); MS(APCI) m/z
424 (M+H)
Example 33
E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolid-
ine-3-carboxamide
Example 33A
Potassium;
1-(2-chloro-benzyl)-methyl-2-oxo-pyrrolidine-3-carboxylate
[0586] A solution of the product of 31B (0.075 gm, 0.4 mmol),
2-chloro-benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy
borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours
at 23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in THF (1.2 mL) and stirred with
KOTMS (77 mg, 0.6 mmol) for 12 hours at 23.degree. C. The solvent
was evaporated in vacuo to provide Example 33A.
Example 33B
E-4-(aminocarbonyl)-2-adamantyl]-1-(2-chlorobenzyl)-3-methyl-2-oxopyrrolid-
ine-3-carboxamide
[0587] A solution of the product of Example 33A (50 mg, 0.16 mmol),
the product of Example IC (48 mg, 0.19 mmol), TBTU (82 mg, 0.25
mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2
hours at 23.degree. C. The reaction was partitioned between EtOAc
(8 ml) and water (4 ml). The organic layer was separated and washed
twice with water (4 mL each), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The resulting oil was taken in. THF (1 mL) and
stirred with KOTMS (31 mg, 0.24 mmol) for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo. The resulting solid was taken
in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) and DIEA (51
mg, 0.4 mmol) for 2 hours at 23.degree. C. Ammonium hydroxide--30%
by weight (2 mL) was added and stirred at 23.degree. C. for a
further 30 minutes. The reaction was partitioned between EtOAc (8
mL) and water (3 mL). The organic layer was washed with water (3
mL), dried with MgSO4 and evaporated in vacuo. The crude reaction
mixture was purified by preparative reverse phase HPLC on a Waters
Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size) using
a gradient of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min
at a flow rate of 40 mL/min. to provide the title compound. .sup.1H
NMR (400 MHz, Chloroform-d.sub.1) .delta. ppm 8.13-8.19 (m, 1H),
7.34-7.41 (m, 1H), 7.19-7.28 (m, 3H), 5.60-5.65 (bs, 1H), 5.54-5.60
(bs, 1H), 4.62-4.64 (m, 2H), 3.99-4.05 (m, 1H), 3.15-3.30 (m, 2H),
2.63-2.73 (m, 1H), 2.09-2.15 (m, 1H), 1.80-2.08 (m, 11H), 1.53-1.66
(m, 2H), 1.49 (s, 3H); MS (PCI) m/z 444 (M+H).
Example 34
E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrrolid-
ine-3-carboxamide
Example 34A
Potassium;
1-(3-chloro-benzyl)-3-methyl-2-oxo-pyrrolidine-3-carboxylate
[0588] A solution of the product of Example 31B (0.075 gm, 0.4
mmol), 3-chloro-benzylamine (68 mg, 0.47 mmol) and MP-triacetoxy
borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours
at 23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in THF (1.2 mL) and stirred with
KOTMS (77 mg, 0.6 mmol) at 23.degree. C. for 12 hours. The solvent
was evaporated in vacuo to provide Example 34A.
Example 34B
E-4-(aminocarbonyl)-2-adamantyl]-1-(3-chlorobenzyl)-3-methyl-2-oxopyrrolid-
ine-3-carboxamide
[0589] A solution of the product of Example 34A (50 mg, 0.16 mmol),
the product of Example 1C (48 mg, 0.19 mmol), TBTU (82 mg, 0.25
mmol) and DIEA (51 mg, 0.4 mmol in DMF (1.2 mL) was stirred for 2
hours at 23.degree. C. The reaction was partitioned between EtOAc
(8 ml) and water (4 ml). The organic layer was separated and washed
twice with water (4 mL each), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The resulting oil was taken in THF (1 mL) and
stirred with KOTMS (31 mg, 0.24 mmol) at 23.degree. C. for 12
hours. The solvent was evaporated in vacuo. The resulting solid was
taken in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) and
DIEA (51 mg, 0.4 mmol) for 2 hours at 23.degree. C. Ammonium
hydroxide--30% by weight (2 mL) was added and stirred at 23.degree.
C. for a further 30 minutes. The reaction was partitioned between.
EtOAc (8 mL) and water (3 mL). The organic layer was washed with
water (3 mL), dried with MgSO.sub.4 and evaporated in vacuo. The
crude reaction mixture was purified by preparative reverse phase
HPLC on a Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn
particle size) using a gradient of 20% to 100% acetonitrile:water
(0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the
title compound. .sup.1H NMR (400 MHz, Chloroform-d.sub.1) .delta.
ppm 8.11 (d, J=7.93 Hz, 1H), 7.26-7.29 (m, 2H), 7.18-7.20 (m, 1H),
7.07-7.10 (m, 1H), 5.64-5.79 (m, 2H), 4.44 (s, 2H), 3.99-4.04 (m,
1H), 3.18-3.23 (m, 2H), 2.68 (ddd, 0.1=15.66, 8.55, 7.17 Hz, 1H),
2.02-2.15 (m, 3H), 1.88-2.02 (m, 8H), 1.81-1.88 (m, 1H), 1.58-1.66
(m, 2H), 1.49 (s, 3H); MS (APCI) m/z 444.
Example 35
E-4-({2-methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]propanoyl}amino)adama-
ntane-1-carboxamide
Example 35A
E-4-{2-Methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-propionylamino}-adam-
antane-1-carboxylic acid methyl ester
[0590] The title compound was prepared according to the method of
Example 22D substituting
1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole
for pyridine-4-boronic acid.
Example 35B
E-4-{2-Methyl-2-[4-(1-methyl-1H-pyrazol-4-yl)-phenyl]-propionyl
amino}-adamantane-1-carboxylic acid
[0591] The title compound was prepared according to the method of
Example 23D, substituting the product of Example 35A for the
product of Example 23C.
Example 35C
E-4-{2-Methyl-2-[4-(1-methyl-1-pyrazol-4-yl)-phenyl]-propionylamino}-adama-
ntane-1-carboxylic acid amide
[0592] A solution of the product of Example 35B (240 mg, 0.55
mmoles), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (421 mg, 2.2 mmoles) and 1-hydroxybenzotriazole
hydrate (167 mg, 1.24 mmoles) in dichloromethane (19 ml) was
stirred at ambient temperature under a nitrogen atmosphere for
about 1 hour. A 0.5 M solution of ammonia in dioxane (11.0 ml, 5.50
mmoles) was added and stirring was continued for about 2 hours.
Ammonium hydroxide (9.5 ml) was added to the reaction mixture and
stirring was continued for about 2 hours. The mixture was diluted
with dichloromethane (60 ml), the layers were separated, the
organic layer was dried (MgSO.sub.4), filtered and the filtrate was
evaporated in vacuum. The residue was purified by flash column
chromatography on silica gel using dichloromethane/methanol (15:1)
as the mobile phase to provide the title compound. .sup.1H NMR (500
MHz, DMSO-d.sub.6) .delta. ppm 8.11 (s, 1H), 7.83 (s, 1H),
7.51-7.53 (m, 2H), 7.31-7.33 (m, 2H), 6.95-6.97 (bs, 1H), 6.69-6.71
(bs, 1H), 6.28 (d, J=6.87 Hz, 1H), 3.85 (s, 3H), 3.74-3.78 (m, 1H),
1.84-1.89 (m, 2H), 1.73-1.82 (m, 5H), 1.67-1.70 (m, 2H), 1.54-1.60
(m, 2H), 1.49 (s, 6H), 1.31-1.37 (m, 2H); MS(ESI+) m/z 421
(M+H).sup.+.
Example 36
E-4-{[2-(3-bromophenyl)-2-methylpronanoyl]amino}adamantane-1-carboxamide
Example 36A
(3-Bromophenyl)-acetic acid methyl ester
[0593] A solution of 3-bromophenylacetic acid (2.0 g, 9.3 mmol) and
4-dimethylamino pyridine (1.1 g, 9.3 mmol) in methanol (20 mL) was
treated with N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
hydrochloride (EDAC) (2.1 g, 11 mmol). Reaction stirred for 16
hours at room temperature. The reaction mixture was concentrated
under reduced pressure. The residue was taken up in ethyl acetate
and washed with water, saturated sodium bicarbonate, 1N phosphoric
acid, and brine before drying over Na.sub.2SO.sub.4, filtering, and
concentrating under reduced pressure to provide the title
compound.
Example 36B
2-(3-Bromophenyl)-2-methylpropionic acid methyl ester
[0594] A 0.degree. C. solution of the product of Example 36A (2.1
g, 9.3 mmol) in anhydrous dimethylformamide (20 mL) was treated
portion-wise with 60% sodium hydride (890 mg, 22 mmol) in mineral
oil. The reaction mixture was stirred for twenty minutes at
0.degree. C., and methyl iodide (1.4 mL, 22 mmol) was then added.
Ice bath was removed, and reaction mixture stirred 16 hours at room
temperature. Reaction mixture quenched with saturated ammonium
chloride, and product extracted with ethyl acetate (2.times.). The
combined extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. Residue purified by normal phase HPLC on silica gel
eluting with 10% ethyl acetate/hexane to provide the title
compound.
Example 36C
2-(3-Bromophenyl)-2-methylpropionic acid
[0595] The title compound was prepared according to the method as
described in Example 27B, substituting the product of Example 36B
for the product of Example 27A.
Example 36D
E-4-[2-(3-Bromophenyl)-2-methylpropionylamino]adamantane-1-carboxylic
acid methyl ester
[0596] The title compound was prepared according to the method as
described in Example 27A, substituting the product of Example 36C
for 1-(4-methoxyphenyl)-1-cyclopentanecarboxylic acid.
Example 36E
E-4-[2-(3-Bromophenyl)-2-methylpropionylamino]adamantane-1-carboxylic
acid
[0597] The title compound was prepared according to the method as
described in Example 27B, substituting the product of Example 36D
for the product of Example 27A.
Example 36F
E-4-[2-3-Bromophenyl)-2-methylpropionylamino]-adamantane-1-carboxylic
acid amide
[0598] The title compound was prepared according to the method as
described in Example 27C, substituting the product of Example 36E
for the product of Example 27B. .sup.1H NMR (400 MHz, DMSO-d.sub.6)
.delta. 7.48 (m, 1H), 7.42 (m, 1H), 7.20 (m, 2H), 6.95 (bs, 1H),
6.66 (bs, 1H), 6.32 (d, J=6 Hz, 1H), 3.77 (m, 1H), 1.95-1.60 (m,
11H), 1.47 (s, 6H), 1.33 (m, 2H); MS (ESI+) m/z 419
(M+H).sup.+.
Example 37
E-4-({2-[4-(3,5-dimethylisoxazol-4-yl)phenyl]-2-methylpropanoyl}amino)adam-
antane-1-carboxamide
Example 37A
E-4-{2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-2-methyl-propionylamino}-ad-
amantane-1-carboxylic acid methyl ester
[0599] The title compound was prepared according to the method of
Example 22D, substituting
3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)isoxazole
for pyridine-4-boronic acid.
Example 37B
E-4-{2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-2-methyl-propionylamino}-ad-
amantane-1-carboxylic acid
[0600] The title compound was prepared according to the method of
Example 23D, substituting the product of Example 37A for the
product of Example 23C.
Example 37C
E-4-{2-[4-(3,5-Dimethyl-isoxazol-4-yl)-phenyl]-2-methyl-propionylamino}-ad-
amantane-1-carboxylic acid amide
[0601] The title compound was prepared according to the method of
35C, substituting the product of Example 37B for the product of
Example 35B. The crude product was purified by preparative HPLC on
a Waters Symmetry C8 column (25 mm.times.100 mm, 7 gm particle
size) using a gradient of 10% to 100% acetonitrile: 0.1% aqueous
TFA over 8 min (10 min run time) at a flow rate of 40 ml/min.
.sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta. ppm 7.44-7.46 (m, 2H),
7.35-7.37 (m, 2H), 6.95-6.97 (bs, 1H), 6.69-6.71 (bs, 1H), 6.35 (d,
J=6.87 Hz, 1H), 3.74-3.78 (m, 1H), 2.38 (s, 3H), 2.21 (s, 3H),
1.87-1.89 (m, 2H), 1.73-1.83 (m, 5H), 1.67-1.73 (m, 2H), 1.56-1.60
(m, 2H), 1.53 (s, 6H), 1.32-1.36 (m, 2H); MS(ESI+) m/z 436
(M+1.1).sup.4.
Example 38
E-4-{[2-methyl-2-(4-pyridin-3-ylphenyl)propanoyl]amino}adamantane-1-carbox-
amide
Example 38A
E-4-[2-Methyl-2-(4-pyridin-3-yl-phenyl)-propionylamino]-adamantane-1-carbo-
xylic acid methyl ester
[0602] The title compound was prepared according to the method of
Example 22D, substituting pyridine-3-boronic acid for
pyridine-4-boronic acid.
Example 38B
E-4-[2-Methyl-2-(4-pyridin-3-yl-phenyl)-propionylamino]-adamantane-1-carbo-
xylic acid
[0603] The title compound was prepared according to the method of
Example 22E substituting the product of Example 38A for the product
of Example 22D.
Example 38C
E-4-[2-Methyl-2-(4-pyridin-3-yl-phenyl)-propionylamino]-adamantane-1-carbo-
xylic acid amide
[0604] The trifluoroacetic acid salt of the title compound was
prepared according to the method of Example 35C, substituting the
product of Example 38B for the product of Example 35B, and with the
exception that the crude product was purified by preparative HPLC
on a Waters Symmetry C8 column (25 mm.times.100 mm, 7 .mu.m
particle size) using a gradient of 10% to 100% acetonitrile: 0.1%
aqueous TFA over 8 min (10 min run time) at a flow rate of 40
ml/min. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm 9.07-9.08
(bs, 1H), 8.72 (d, J=5.06 Hz, 1H), 8.47 (d, J=8.03 Hz, 1H),
7.77-7.83 (m, 3H), 7.50-7.53 (m, 2H), 6.94-6.96 (bs, 1H), 6.66-6.69
(bs, 1H), 6.48 (d, J=6.68 Hz, 1H), 3.76-3.81 (m, 1H), 1.89-1.92 (m,
2H), 1.78-1.84 (m, 5H), 1.65-1.71 (m, 4H), 1.54 (s, 6H), 1.33-1.38
(m, 2H); MS(ESI+) m/z 418 (M+H).sup.+.
Example 39
4-{[({(E)-4-[(2-methyl-2-thien-2-ylpropanoyl)amino]-1-adamantyl}carbonyl)a-
mino]methyl}benzoic acid
Example 39A
E-4-({[4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carbonyl]--
amino}-methyl)-benzoic acid methyl ester
[0605] The title compound was prepared according to the method of
Example 22C, substituting the product of Example 23D for Example
22B and substituting methyl 4-(aminomethyl)-benzoate hydrochloride
for the product of Example IC.
Example 39B
E-4-({[4-(2-Methyl-2-thiophen-2-yl-propionylamino)-adamantane-1-carbonyl]--
amino}-methyl)-benzoic acid
[0606] The title compound was prepared according to the method of
Example 22B, substituting the product of Example 39A for the
product of Example 22A. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 12.70-12.94 (bs, 1H), 8.04-8.09 (m, 1H), 7.85-7.88 (m, 2H),
7.46 (dd, J=5.06, 1.22 Hz, 1H), 7.28-7.36 (m, 2H), 7.10 (dd,
J=3.52, 1.23 Hz, 1H), 7.02 (dd, J=5.08, 3.54 Hz, 1H), 6.25 (d,
J=7.10 Hz, 1H), 4.30 (d, J=5.87 Hz, 2H), 3.71-3.76 (m, 1H),
1.75-1.86 (m, 9H), 1.57 (s, 6H), 1.48-1.55 (m, 2H), 1.37-1.42 (m,
2H); MS(ESI+) m/z 481 (M+H).sup.4-.
Example 40
E-4-({2-methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]propanoyl}amino)adamantane-1--
carboxamide
Example 40A
E-4-{2-Methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1--
carboxylic acid methyl ester
[0607] The title compound was prepared according to the method of
Example 22D substituting
1-tert-butoxycarbonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyra-
zole for pyridine-4-boronic acid.
Example 40B
E-4-{2-Methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1--
carboxylic acid
[0608] The title compound was prepared according to the method of
Example 22E substituting the product of Example 40A for the product
of Example 22D.
Example 40C
E-4-{2-Methyl-2-[4-(1H-pyrazol-4-yl)-phenyl]-propionylamino}-adamantane-1--
carboxylic acid amide
[0609] The title compound was prepared according to the method of
Example 35C substituting the product of Example 40B for the product
of Example 35B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
8.03 (s, 2H), 7.55-7.58 (m, 2H), 7.31-7.34 (m, 2H), 6.92-6.96 (bs,
1H), 6.65-6.68 (bs, 1H), 6.25 (d, J=6.95 Hz, 1H), 5.15-5.94 (bs,
1H), 3.73-3.78 (m, 1H), 1.85-1.88 (m, 2H), 1.73-1.83 (m, 5H),
1.68-1.70 (m, 2H), 1.55-1.60 (m, 2H), 1.49 (s, 6H), 1.31-1.36 (m,
2H); MS(ESI+) m/z 407 (M+H).sup.+.
Example 41
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-oxo-
pyrrolidine-3-carboxamide
Example 41A
Potassium;
3-methyl-1-(1-methyl-1-phenyl-ethyl)-2-oxo-pyrrolidine-3-carbox-
ylate
[0610] A solution of the product of Example 31B (0.075 gm, 0.4
mmol), 1-methyl-1-phenylethylamine (65 mg, 0.47 mmol) and
MP-triacetoxy borohydride (431 mg, 1 mmol) in THF (2 mL) was
stirred for 12 hours at 23.degree. C. The solution was filtered and
evaporated in vacuo. The resulting oil was taken up in toluene (1.5
mL) and heated at 100.degree. C. for 5 hours. The solvent was
evaporated in vacuo and the residue taken in THF (1.2 mL) and
stirred with KOTMS (77 mg, 0.6 mmol) for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo to provide Example 41A.
Example 41B
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-1-(1-methyl-1-phenylethyl)-2-oxo-
pyrrolidine-3-carboxamide
[0611] A solution of the product of Example 41A (50 mg, 0.16 mmol),
the product of Example IC (48 mg, 0.19 mmol), TBTU (82 mg, 0.25
mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2
hours at 23.degree. C. The reaction was partitioned between EtOAc
(8 ml) and water (4 ml). The organic layer was separated and washed
twice with water (4 mL each), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The resulting oil was taken in THF (1 mL) and
stirred with KOTMS (31 mg, 0.24 mmol) for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo. The resulting solid was taken
in DMF (1 mL) and stirred with TBTU (92 mg, 0.29 mmol) and DIEA (51
mg, 0.4 mmol) for 2 hours at 23.degree. C. Ammonium hydroxide--30%
by weight (2 mL) was added and stirred for a further 30 minutes.
The reaction was partitioned between EtOAc (8 mL) and water (3 mL).
The organic layer was washed with water (3 mL), dried with
MgSO.sub.4 and evaporated in vacuo. The crude reaction mixture was
purified by preparative reverse phase HPLC on a Waters Symmetry C8
column (25 mm.times.100 mm, 7 um particle size) using a gradient of
20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow
rate of 40 mL/min. to provide the title compound. .sup.1H NMR (500
MHz, Chloroform-d.sub.1) 5 ppm 7.94 (d, J=7.78 Hz, 1H), 7.27-7.34
(m, 4H), 7.21-7.25 (m, 1H), 5.98-6.02 (bs, 1H), 5.69-5.73 (bs, 1H),
3.95-4.00 (m, 1H), 3.39-3.47 (m, 2H), 2.69 (ddd, J=13.17, 8.02,
6.58 Hz, 1H), 2.03-2.06 (m, 1H), 1.94-2.01 (m, 6H), 1.91 (ddd,
J=13.24, 7.44, 5.76 Hz, 1H), 1.86-1.88 (m, 2H), 1.76-1.81 (m, 1H),
1.75 (s, 3H), 1.72 (s, 3H), 1.64-1.69 (m, 1H), 1.47-1.56 (m, 2H),
1.43 (s, 3H); MS (APCI) m/z 438 (M+H).
Example 42
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-((1R)-1-phenylethyl)pyrr-
olidine-3-carboxamide
Example 42A
Potassium;
3-methyl-2-oxo-1-((1R)-1-phenylethyl)pyrrolidine-3-carboxylate
[0612] A solution of the product of Example 31B (0.075 gm, 0.4
mmol), (R)-1-phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy
borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours
at 23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in toluene (1.5 mL) and heated at
100.degree. C. for 5 hours. The solvent was evaporated in vacuo and
the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg,
0.6 mmol) for 12 hours at 23.degree. C. The solvent was evaporated
in vacuo to provide Example 42A as 1:1 mixture of
diastereomers.
Example 42B
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1R)-1-phenylethyl]pyrr-
olidine-3-carboxamide
[0613] A solution of the product of Example 42A (50 mg, 0.17 mmol),
the product of Example IC (52 mg, 0.21 mmol), TBTU (87 mg, 0.27
mmol) and DIEA (51 mg, 0.4 mmol) in DMF (1.2 mL) was stirred for 2
hours at 23.degree. C. The reaction was partitioned between EtOAc
(8 ml) and water (4 ml). The organic layer was separated and washed
twice with water (4 mL each), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The resulting oil was taken in THF (1 mL) and
stirred with KOTMS (32 mg, 0.25 mmol) for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo. The resulting solid was taken
in DMF (1 mL) and stirred with TBTU (98 mg, 0.31 mmol) and DIEA (51
mg, 0.4 mmol) for 2 hours at 23.degree. C. Ammonium hydroxide--30%
by weight (2 mL) was added and stirred for a further 30 minutes.
The reaction was partitioned between EtOAc (8 mL) and water (3 mL).
The organic layer was washed with water (3 mL), dried with
MgSO.sub.4, filtered and evaporated in vacuo. The crude reaction
mixture was purified by preparative reverse phase HPLC on a Waters
Symmetry C8 column (25 mm.times.100 mm, 7 urn particle size) using
a gradient of 20% to 100% acctonitrile:watcr (0.1% TFA) over 18 min
at a flow rate of 40 mL/min. to provide the title compound as a 1:1
mixture of diastereomers. .sup.1H NMR (500 MHz, Chloroform-d.sub.1)
.delta. ppm 8.3 (m, 2H), 7.38-7.22 (m, 10H), 6.34-6.18 (bs, 2H),
5.83-5.68 (bs, 2H), 5.52-5.41 (m, 2H), 4.06-3.95 (m, 2H), 3.31-3.18
(m, 2H), 3.01-2.78 (m, 2H), 2.62-2.44 (m, 4H), 2.1-1.87 (m, 24H),
1.56-1.53 (m, 6H), 1.47-1.43 (m, 6H); MS (APCI) m/z 424 (M+H).
Example 43
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyrr-
olidine-3-carboxamide
Example 43A
Potassium;
3-methyl-2-oxo-1-((1S)-1-phenylethyl)pyrrolidine-3-carboxylate
[0614] A solution of the product of Example 31B (0.075 gm, 0.4
mmol), (S)-1-phenylethylamine (58 mg, 0.47 mmol) and MP-triacetoxy
borohydride (431 mg, 1 mmol) in THF (2 mL) was stirred for 12 hours
at 23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in toluene (1.5 mL) and heated at
100.degree. C. for 5 hours. The solvent was evaporated in vacuo and
the residue taken in THF (1.2 mL) and stirred with KOTMS (77 mg,
0.6 mmol) at 23.degree. C. for 12 hours. The solvent was evaporated
in vacuo to provide Example 43A as a 1:1 mixture of
diastereomers.
Example 43B
E-4-(aminocarbonyl)-2-adamantyl]-3-methyl-2-oxo-1-[(1S)-1-phenylethyl]pyrr-
olidine-3-carboxamide
[0615] A solution of the product of Example 43A (50 mg, 0.17 mmol),
the product of Example 1C (52 mg, 0.21 mmol), TBTU (87 mg, 0.27
mmol) and DTEA (51 mg, 0.4 mmol in DMF (1.2 mL) was stirred at
23.degree. C. for 2 hours. The reaction was partitioned between
EtOAc (8 ml) and water (4 ml). The organic layer was separated and
washed twice with water (4 mL each), dried with MgSO.sub.4,
filtered and evaporated in vacuo. The resulting oil was taken in
THF (1 mL) and stirred with KOTMS (32 mg, 0.25 mmol) at 23.degree.
C. for 12 hours. The solvent was evaporated in vacuo. The resulting
solid was taken in DMF (1 mL) and stirred with TBTU (98 mg, 0.31
mmol) and DIEA (51 mg, 0.4 mmol) at 23.degree. C. for 2 hours.
Ammonium hydroxide--30% by weight (2 mL) was added and stirred for
a further 30 minutes. The reaction was partitioned between EtOAc (8
mL) and water (3 mL). The organic layer was washed with water (3
mL), dried with MgSO.sub.4, filtered, and evaporated in vacuo. The
crude reaction mixture was purified by preparative reverse phase
HPLC on a Waters Symmetry C8 column (25 mm.times.100 mm, 7 urn
particle size) using a gradient of 20% to 100% acetonitrile:water
(0.1% TFA) over 18 min at a flow rate of 40 mL/min. to provide the
title compound as a 1:1 mixture of diastereomers. .sup.1H NMR (500
MHz, Chloroform-d.sub.1) .delta. ppm 8.29 (m, 2H), 7.34-7.18 (m,
10H), 6.30-6.14 (bs, 2H), 5.79-5.66 (bs, 2H), 5.48-5.37 (m, 2H),
4.06-3.95 (m, 2H), 3.31-3.18 (m, 2H), 3.01-2.78 (m, 2H), 2.62-2.44
(m, 4H), 2.1-1.87 (m, 24H), 1.56-1.53 (m, 6H), 1.47-1.43 (m, 6H);
MS (APCI) m/z 424 (M+H).
Example 44
E-4-{[2-methyl-2-(1,3-thiazol-2-yl)propanoyl]amino}adamantane-1-carboxamid-
e
Example 44A
Diethyl 2-(3-(ethoxycarbonyl)-2,3-dihydrothiazol-2-yl)malonate
[0616] Ethyl chloroformate (6.46 ml, 67.8 mmoles) was added
dropwise to a stirred solution of thiazole (5.0 g, 58.7 mmoles) in
tetrahydrofuran (113.0 ml) at about 0.degree. C. under a nitrogen
atmosphere. After about 1 hour, a freshly prepared solution of
lithio diethylmalonate (To a solution of diethylmalonate (10.3 ml,
67.8 mmoles) in tetrahydrofuran (17.0 ml) was added dropwise a 1 M
solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran
(67.8 ml, 67.8 mmoles) and the mixture was stirred at 23.degree. C.
for about 10 min) was added via cannula and the mixture was stirred
at room temperature for about 18 hours. The mixture was diluted
with diethyl ether (60.0 ml), was washed with saturated aqueous
ammonium chloride (140.0 ml) and brine (120.0 ml). The organic
layer was dried over MgSO.sub.4, filtered, concentrated in vacuum
and the crude product was purified by flash column chromatography
on silica gel using hexanes/ethyl acetate (2:1) as the mobile phase
to provide the title compound.
Example 44B
Diethyl 2-(thiazol-2(3H)-ylidene)malonate
[0617] To a solution of the product of Example 44A (12.9 g, 40.7
mmoles) in dichloromethane (100.0 ml) was added
tetrachloro-1,2-benzoquinone (10.0 g, 40.7 mmoles) in portions at
about 0.degree. C., such that the mixture always had time to
decolorize to a yellow-orange color. The mixture was then stirred
for about 1 hour at 0.degree. C. and was then washed with saturated
aqueous sodium bicarbonate solution (200.0 ml) and brine (100.0
ml). The organic layer was dried over MgSO.sub.4, filtered,
concentrated in vacuum and the crude product was purified by flash
column chromatography on silica gel using hexanes/ethyl acetate
(2:1) as the mobile phase to provide the title compound.
Example 44C
Ethyl 2-(thiazol-2-yl)acetate
[0618] A solution of the product of Example 44B (2.8 g, 11.5
mmoles), sodium chloride (1.3 g, 22.9 mmoles) and water (0.4 ml,
22.9 mmoles) in dimethyl sulfoxide (48.0 ml) was stirred at about
180.degree. C. for about 30 min. The mixture was cooled, diluted
with water (100.0 ml) and was extracted twice with (1:1) ethyl
acetate/diethyl ether (80.0 ml each). The combined organic extracts
were washed with brine, dried over MgSO.sub.4, filtered and
concentrated in vacuum. The crude product was purified by flash
column chromatography on silica gel using hexanes/ethyl acetate
(2:1) as the mobile phase to provide the title compound.
Example 44D
Ethyl 2-methyl-2-(thiazol-2-yl)propanoate
[0619] The title compound was prepared according to the method of
Example 22A substituting the product of Example 44C for ethyl
4-bromophenylacetate.
Example 44E
2-Methyl-2-(thiazol-2-yl)propanoic acid
[0620] The title compound was prepared according to the method of
Example 22B substituting the product of Example 44D for the product
of Example 22A.
Example 44F
E-4-(2-Methyl-2-thiazol-2-yl-propionylamino)-adamantane-1-carboxylic
acid methyl ester
[0621] The title compound was prepared according to the method of
Example 22C substituting the product of Example 44E for the product
of Example 22B.
Example 44G
E-4-(2-Methyl-2-thiazol-2-yl-propionylamino)-adamantane-1-carboxylic
acid
[0622] The title compound was prepared according to the method of
Example 23D substituting the product of Example 44F for the product
of Example 23C.
Example 44H
E-4-(2-Methyl-2-thiazol-2-yl-propionylamino)-adamantane-1-carboxylic
acid amide
[0623] The title compound was prepared according to the method of
Example 35C substituting the product of Example 44G for the product
of Example 35B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.86 (d, J=3.30 Hz, 1H), 7.71 (d, J=3.29 Hz, 1H), 7.42 (d, J=7.26
Hz, 1H), 6.94-6.97 (bs, 1H), 6.67-6.69 (bs, 1H), 3.72-3.77 (m, 1H),
1.82-1.88 (m, 3H), 1.75-1.82 (m, 4H), 1.71-1.74 (m, 2H), 1.62 (s,
6H), 1.57-1.64 (m, 2H), 1.39-1.47 (m, 2H); MS(ESI+) m/z 348
(M+H).sup.+.
Example 45
E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-c-
arboxamide
Example 45A
Piperidine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester
[0624] To a room temperature solution of 4.05 g (25.8 mmoles) of
ethyl nipecotate and 4.33 g (51.5 mmoles) of NaHCO.sub.3 in water
(26 mL) was added benzyl chloroformate (4.1 mL, 28.3 mmol). The
reaction mixture was stirred at 23.degree. C. under an atmosphere
of N.sub.2 overnight. The crude products were diluted with water,
extracted with Et.sub.2O, washed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The crude
product was purified by silica gel chromatography employing a
solvent gradient (hexane.fwdarw.70:30 hexane:EtOAc) to yield the
title compound as a clear colorless oil.
Example 45B
3-Methyl-piperidine-1,3-dicarboxylic acid 1-benzyl ester
[0625] To a 78.degree. C. solution of the product of Example 45A
(6.0 g, 20.6 mmoles) in THF (50 mL) was added a solution of lithium
bis(trimethylsilyl)amide (1.0 M in THF, 22.7 mmoles). After 35 min,
iodomethane (1.4 mL, 22.7 mmoles) was added and the reaction was
slowly warmed to room temperature and stirred overnight. The
reaction was quenched with aqueous sat. ammonium chloride and
extracted with Et.sub.2O. The organic layer was then rinsed with
brine, dried over Na.sub.2SO.sub.4, filtered, and concentrated in
vacuo. The crude product was purified by silica gel chromatography
employing a solvent gradient (hexane.fwdarw.65:35 hexane:EtOAc).
The resulting ester was hydrolyzed overnight at room temperature in
THF (15 mL), H.sub.2O (10 mL), and EtOH (15 mL) with NaOH (2.5 g).
The solution was concentrated under vacuum; the residue was
dissolved in saturated ammonium chloride; and, the solution was
extracted with ethyl acetate (3.times.). The combined ethyl acetate
extracts were dried over sodium sulfate, filtered, and concentrated
under vacuum to yield the title compound as a white solid.
Example 45C
N-[E-4-(carbomethoxy)-2-adamantyl]-1-(4-benzyloxycarbonyl)-3-methylpiperid-
ine-3-carboxamide
[0626] The title compound was prepared according to the procedure
outlined in Example 7, substituting the product of Example 45B for
2-phenylisobutyric acid and substituting the product of Example 1C
for 2-adamantanamine hydrochloride.
Example 45D
N-[E-4-(carbomethoxy)-2-adamantyl-]-1-3-methylpiperidine-3-carboxamide
[0627] A solution of the product of Example 45C (0.62 g, 1.32
mmoles) and 10% palladium on carbon (60 mg) in EtOAc (20 mL) was
exposed to hydrogen (60 psi) at room temperature for 6 hours. The
reaction was incomplete so EtOH was added and the reaction
continued for an additional 8 h. The crude product was then
filtered away from the catalyst using methanol and isolated after
concentration in vacuo to provide the title compound.
Example 45E
E-4-(carbomethoxy)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-ca-
rboxamide
[0628] To a solution of the product of Example 45D (100 mg, 0.3
mmoles) and 4-chlorobenzaldehyde in dichloroethane (0.75 mL) and
acetic acid (0.07 mL, 1.2 mmoles) was added sodium
triacetoxyborohydride (127 mg, 0.6 mmoles). The resulting reaction
mixture was stirred at room temperature overnight. The reaction was
quenched with sat. aqueous NH.sub.4Cl and extracted with EtOAc. The
organic layer was then rinsed with brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo to provide a
crude sample of the title compound.
Example 45F
E-4-(aminocarbonyl)-2-adamantyl]-1-(4-chlorobenzyl)-3-methylpiperidine-3-c-
arboxamide
[0629] The crude product from Example 45E was hydrolyzed with an
excess of NaOH at room temperature in a solution of water, EtOH,
and tetrahydrofuran for 16 hours. The reaction was quenched with
sat. aqueous NH.sub.4C1 and extracted with EtOAc. The organic layer
was then rinsed with brine, dried over Na.sub.2SO.sub.4, filtered,
and concentrated in vacuo. The residue, EDCI (80 mg, 0.42 mmoles),
and 1-hydroxybenzotriazole hydrate (56.5 mg, 0.42 mmoles) were
dissolved in DMF (0.75 mL) and stirred for 30 min at room
temperature. Concentrated NH.sub.4OH (0.75 mL) was then added and
stirring was continued overnight. The reaction was quenched with
sat. aqueous NH.sub.4Cl and extracted with EtOAc. The organic layer
was then washed with water (2.times.), rinsed with brine, dried
over Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The
product was purified by reverse phase preparative HPLC
(acetonitrile: 10 mM NH.sub.4OAc in H.sub.2O on a YMC prep ODS-A
column) to provide the title compound. .sup.1H NMR (500 MHz,
Chloroform-d.sub.1) .delta. ppm 8.74-8.79 (m, 1H), 7.28-7.32 (m,
2H), 7.18-7.21 (m, 2H), 5.65-5.69 (bs, 1H), 5.55-5.59 (bs, 1H),
4.04-4.07 (m, 1H), 3.56 (d, J=12.82 Hz, 1H), 3.43 (d, J=12.82 Hz,
1H), 3.00-3.05 (m, 1H), 2.93-2.98 (m, 1H), 2.08-2.13 (m, 1H),
2.00-2.05 (m, 1H), 1.93-2.00 (m, 6H), 1.90-1.94 (m, 2H), 1.83-1.90
(m, 1H), 1.76-1.82 (m, 1H), 1.69-1.74 (m, 1H), 1.61-1.69 (m, 1H),
1.52-1.63 (m, 4H), 1.12 (s, 3H), 1.06-1.15 (m, 1H); MS (ESI+) m/z
444 (M+H).sup.+.
Example 46
E-4-{[2-(4-hydroxyphenyl)-2-methylpropanoyl]amino}adamantane-1-carboxamide
Example 46A
2-(4-Hydroxyphenyl)-proprionic acid methyl ester
[0630] The title compound was prepared according to the method as
described in Example 36A substituting
2-(4-hydroxyphenyl)-proprionic acid for 3-bromophenylacetic
acid.
Example 46B
2-(4-Allyloxyphenyl)-proprionic acid methyl ester
[0631] A solution of the product of Example 46A (2.6 g, 12 mmol) in
anhydrous dimethylformamide (20 mL) was treated with potassium
carbonate (3.3 g, 24 mmol) and allyl bromide (1.2 mL, 13 mmol), and
reaction heated for 16 hours at 80.degree. C. Reaction mixture
cooled and diluted with ethyl acetate. Mixture washed with water
and brine, dried (Na.sub.2SO.sub.4), filtered, and concentrated
under reduced pressure. Residue purified by normal phase HPLC on
silica gel eluting with 3% ethyl acetate/hexane to provide the
title compound.
Example 46C
2-(4-Allyloxyphenyl)-2-methylpropionic acid methyl ester
[0632] A 0.degree. C. solution of the product of Example 46B (1.9
g, 8.6 mmol) in anhydrous dimethylformamide (10 mL) was treated
portion-wise with 60% sodium hydride (410 mg, 10 mmol) in mineral
oil. The reaction mixture was stirred twenty minutes at 0.degree.
C., and methyl iodide (1.4 mL, 22 mmol) was then added. ice bath
was removed, and reaction mixture stirred 16 hours at room
temperature. Reaction mixture quenched with saturated ammonium
chloride, and product extracted with ethyl acetate (2.times.). The
combined extracts were washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. Residue purified by normal phase HPLC on silica gel
eluting with 3% ethyl acetate/hexane to provide the title
compound.
Example 46D
2-(4-Allyloxyphenyl)-2-methylpropionic acid
[0633] The title compound was prepared according to the method as
described in Example 27B, substituting the product of Example 46C
for the product of Example 27A.
Example 46E
E-4-[2-(4-Allyloxyphenyl)-2-methylpronionylamino]-adamantane-1-carboxylic
acid methyl ester
[0634] The title compound was prepared according to the method as
described in Example 27A, substituting the product of Example 46D
for 1-(4-methoxyphenyl)-1-cyclopentanecarboxylic acid.
Example 46F
E-4-[2-(4-Hydroxyphenyl)-2-methylpropionylamino]-adamantane-1-carboxylic
acid methyl ester
[0635] A 0.degree. C. solution of the product of Example 46E (1.4
g, 3.4 mmol) and tetrakis(triphenylphophine)palladium (390 mg, 0.34
mmol) in anhydrous methylene chloride (10 mL) was treated with
phenyl silane (0.84 mL, 6.8 mmol). Reaction stirred ten minutes at
0.degree. C. and two hours at room temperature. Reaction diluted
with methylene chloride, washed with brine, dried
(Na.sub.2SO.sub.4), filtered, and concentrated under reduced
pressure. Residue purified by normal phase HPLC on silica gel
eluting with 30-40% ethyl acetate/hexane to provide the title
compound.
Example 46G
E-4-[2-(4-Hydroxyphenyl)-2-methylpropionylamino]adamantine-1-carboxylic
acid
[0636] The title compound was prepared according to the method as
described in Example 27B substituting the product of Example 46F
for the product of Example 27A.
Example 46H
E-4-[2-(4-Hydroxyphenyl)-2-methylpropionylamino]adamantane-1-carboxylic
acid amide
[0637] The title compound was prepared according to the method as
described in Example 27C, substituting the product of Example 46G
for the product of Example 27B. .sup.1H NMR (500 MHz, DMSO-d.sub.6)
.delta. ppm 9.24-9.38 (bs, 1H), 7.15-7.17 (m, 2H), 6.95-6.97 (bs,
1H), 6.69-6.74 (m, 3H), 6.69-6.70 (m, 1H), 6.03 (d, J=7.16 Hz, 1H),
3.69-3.73 (m, 1H), 1.80-1.83 (m, 2H), 1.73-1.79 (m, 4H), 1.67-1.69
(m, 2H), 1.44-1.50 (m, 2H), 1.43 (s, 6H), 1.30-1.36 (m, 2H); MS
(ESI+) m/z 357 (M+H).sup.+.
Example 47
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-carbo-
xamide
Example 47A
Potassium; 1-benzyl-3-methyl-2-oxo-piperidine-3-carboxylate
[0638] A solution of the product of Example 30B (0.075 gm, 0.37
mmol), benzylamine (47 mg, 0.44 mmol) and MP-triacetoxy borohydride
(420 mg, 0.92 mmol) in THF (2 mL) was stirred for 12 hours at
23.degree. C. The solution was filtered and evaporated in vacuo.
The resulting oil was taken up in THF (1.2 mL) and stirred with
KOTMS (71 mg, 0.55 mmol) for 12 hours at 23.degree. C. The solvent
was evaporated in vacuo to provide Example 47A.
Example 47B
E-4-(aminocarbonyl)-2-adamantyl]-1-benzyl-3-methyl-2-oxopiperidine-3-carbo-
xamide
[0639] A solution of the product of Example 47A (50 mg, 0.17 mmol),
the product of Example 1C (49 mg, 0.2 mmol), TBTU (87 mg, 0.27
mmol) and DIEA (54 mg, 0.42 mmol in DMF (1.2 mL) was stirred for 2
hours at 23.degree. C. The reaction was partitioned between EtOAc
(8 ml) and water (4 ml). The organic layer was separated and washed
twice with water (4 ml, each), dried with MgSO.sub.4, filtered and
evaporated in vacuo. The resulting oil was taken in THF (1 mL) and
stirred with KOTMS (32 mg, 0.25 mmol) for 12 hours at 23.degree. C.
The solvent was evaporated in vacuo. The resulting solid was taken
in DMF (1 mL) and stirred with TBTU (96 mg, 0.3 mmol) and DIEA (53
mg, 0.42 mmol) at 23.degree. C. for 2 hours. Ammonium
hydroxide--30% by weight (2 mL) was added and stirred for a further
30 minutes. The reaction was partitioned between EtOAc (8 mL) and
water (3 mL). The organic layer was washed with water (3 mL), dried
with MgSO4 and evaporated in vacuo. The crude reaction mixture was
purified by preparative reverse phase HPLC on a Waters Symmetry C8
column (25 mm.times.100 mm, 7 urn particle size) using a gradient
of 20% to 100% acctonitrile:water (0.1% TFA) over 18 min at a flow
rate of 40 mL/min. to provide the title compound. .sup.1H NMR (500
MHz, Chloroform-d.sub.1) .delta. ppm 8.17 (d, J=7.93 Hz, 1H),
7.27-7.34 (m, 3H), 7.21-7.24 (m, 2H), 6.12-6.17 (bs, 1H), 5.68-5.83
(m, 1H), 4.95 (d, J=14.58 Hz, 1H), 4.29 (d, J=14.59 Hz, 1H),
3.97-4.02 (m, 1H), 3.24-3.35 (m, 2H), 2.65 (ddd, J=13.31, 5.72,
2.61 Hz, 1H), 2.09-2.11 (m, 1H), 1.96-2.05 (m, 6H), 1.85-1.90 (m,
3H), 1.64-1.83 (m, 4H), 1.55-1.63 (m, 2H), 1.54 (s, 3H); MS (APCI)
m/z 424 (M+H).
Example 48
E-4-{[2-methyl-2-(4-phenoxyphenyl)propanoyl]amino}adamantane-1-carboxamide
Example 48A
Methyl 2-(4-phenoxyphenyl)acetate
[0640] To a solution of 4-phenoxyphenylacetic acid (1.0 g, 4.38
mmoles) in methanol (5.0 ml) was added concentrated sulfuric acid
(0.05 ml, 0.88 mmoles) and the mixture was heated to reflux for
about 5 hours. The mixture was cooled and concentrated under
reduced pressure. To the residue was added a saturated aqueous
solution of sodium bicarbonate (20.0 ml) and the mixture was
extracted with ethyl acetate. The combined organic extracts were
washed with water and brine, dried over MgSO.sub.4, filtered and
evaporated to dryness to afford the title compound.
Example 48B
Methyl 2-methyl-2-(4-phenoxyphenyl)propanoate
[0641] The title compound was prepared according to the method of
Example 22A substituting the product of Example 48A for
ethyl-4-bromophenyl acetate.
Example 48C
2-Methyl-2-(4-phenoxyphenyl)propanoic acid
[0642] The title compound was prepared according to the method of
Example 22B, substituting the product of Example 48B for the
product of Example 22A.
Example 48D
E-4-[2-Methyl-2-(4-phenoxy-phenyl)-propionylamino]-adamantane-1-carboxylic
acid methyl ester
[0643] The title compound was prepared according to the method of
Example 22C, substituting the product of Example 48C for the
product of Example 22B.
Example 48E
E-4-[2-Methyl-2-(4-phenoxy-phenyl)-propionylamino]-adamantane-1-carboxylic
acid
[0644] The title compound was prepared according to the method of
Example 23D, substituting the product of Example 48D for the
product of Example 23C.
Example 48F
E-4-[2-Methyl-2-(4-phenoxy-phenyl)-propionylamino]-adamantane-1-carboxylic
acid amide
[0645] The title compound was prepared according to the method of
Example 35C, substituting the product of Example 48E for the
product of Example 35B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta.
ppm 7.34-7.41 (m, 4H), 7.10-7.15 (m, 1H), 6.93-7.01 (m, 5H),
6.66-6.68 (bs, 1H), 6.22 (d, J=6.94 Hz, 1H), 3.72-3.77 (m, 1H),
1.85-1.88 (m, 2H), 1.73-1.84 (m, 5H), 1.70-1.71 (m, 2H), 1.53-1.59
(m, 2H), 1.49 (s, 6H), 1.33-1.38 (m, 2H); MS(ESI+) m/z 433
(M+H).sup.+.
Example 49
E-4-{[2-(1-benzothien-3-yl)-2-methylpropanoyl]amino}adamantine-1-carboxami-
de
Example 49A
Methyl 2-(benzo[b]thiophen-3-yl)acetate
[0646] The title compound was prepared according to the method of
Example 48A substituting benzo[b]thiophene-3-acetic acid for
4-phenoxyphenylacetic acid.
Example 49B
Methyl 2-(benzo[b]thiophen-3-yl)-2-methylpropanoate
[0647] The title compound was prepared according to the method of
Example 22A substituting the product of Example 48A for
ethyl-4-bromophenylacetate.
Example 49C
2-(Benzo[b]thiophen-3-yl)-2-methylpropanoic acid
[0648] The title compound was prepared according to the method of
Example 22B substituting the product of Example 49B for the product
of Example 22A.
Example 49D
[0649]
4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylamino)-adamantane-1-ca-
rboxylic acid methyl ester
[0650] The title compound was prepared according to the method of
Example 22C, substituting the product of Example 49C for the
product of Example 22B.
Example 49E
[0651]
4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylamino)-adamantane-1-ca-
rboxylic acid
[0652] The title compound was prepared according to the method of
Example 23D substituting the product of Example 49D for the product
of Example 23C.
Example 49F
[0653]
4-(2-Benzo[b]thiophen-3-yl-2-methyl-propionylamino)-adamantane-1-ca-
rboxylic acid amide
[0654] The title compound was prepared according to the method of
Example 35C substituting the product of Example 49E for the product
of Example 35B. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. ppm
7.97 (s, 1H), 7.64-7.66 (m, 2H), 7.31-7.36 (m, 2H), 6.89-6.92 (bs,
1H), 6.63-6.66 (bs, 1H), 6.13 (d, J=7.21 Hz, 1H), 3.71-3.76 (m,
1H), 1.66-1.79 (m, 6H), 1.60 (s, 6H), 1.55-1.63 (m, 3H), 1.07-1.18
(m, 4H); MS(ESI+) m/z 397 (M+H).sup.+.
Example 50
E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carbox-
amide
Example 50A
Potassium; 2-(5-fluoro-pyridin-2-yl)-2-methyl-propionate
[0655] A solution of 2-bromo-5-fluoropyridine (315 mg, 1.8 mmol),
methyl trimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol),
zinc fluoride (112 mg, 1.08 mmol),
tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) and
tri-t-butylphosphine-10 wt % in hexane (172 mg, 0.084 mmol) in
Argon degassed DMF (1.5 mL) was stirred at 90.degree. C. for 12
hours. The reaction was taken up in EtOAc (25 mL) and washed with
water (15 mL) followed by brine (15 mL). The organic layer was
dried with MgSO.sub.4, filtered, and evaporated in vacuo. The crude
product was purified by flash chromatography (hexane/EtOAc 100:0 to
80:20) to give the methyl ester of Example 50A. A solution of the
corresponding methyl ester (144 mg, 0.73 mmol), potassium
trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol) in THF (2 mL) was
stirred for 12 hours at 23.degree. C. Methyl t-butyl ether (MTBE) 8
mL was added to the solution and Example 50A was isolated by
filtration.
Example 50B
E-4-{[2-(5-fluoropyridin-2-yl)-2-methylpropanoyl]amino}adamantane-1-carbox-
amide
[0656] A solution of the product of Example 50A (30 mg, 0.15 mmol),
the product of Example 1C (45 mg, 0.18 mmol), TBTU (77 mg, 0.24
mmol) and DIEA (47 mg, 0.37 mmol in DMF (1.2 mL) was stirred at
23.degree. C. for 3 hrs. The reaction was diluted with EtOAc (10
mL) and washed twice with water (6 mL) and brine (6 mL). The
organic layer was dried with MgSO.sub.4, filtered, and evaporated
in vacuo. The residue was taken in THF (1 mL) and stirred with
KOTMS (29 mg, 0.22 mmol) for 12 hours at 23.degree. C. The solvent
was evaporated in vacuo. The residue solid was taken in DMF (1 mL)
and added TBTU (86 mg, 0.27 mmol), DIEA (47 mg, 0.37 mmol) and
stirred at 23.degree. C. for 2 hours. Ammonium hydroxide--30% by
weight (2 mL) was added and stirred for a further 30 minutes. The
reaction was partitioned between EtOAc (8 mL) and water (3 mL). The
organic layer was washed with water (3 mL), dried with MgSO.sub.4,
filtered and evaporated in vacuo. The crude reaction mixture was
purified by preparative reverse phase HPLC on a Waters Symmetry C8
column (25 mm.times.100 mm, 7 um particle size) using a gradient of
20% to 100% acctonitrile:water (0.1% TFA) over 18 min at a flow
rate of 40 mL/min. to provide the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (500 MHz,
Chloroform-d.sub.1) .delta. ppm 8.51-8.55 (m, 1H), 7.58-7.64 (m,
1H), 7.50-7.55 (m, 2H), 7.42-7.48 (bs, 1H), 6.83-7.12 (bs, 1H),
6.00-6.07 (bs, 1H), 3.93-3.98 (m, 1H), 2.02-2.07 (m, 3H), 1.94-1.97
(m, 4H), 1.87-1.90 (m, 2H), 1.70 (s, 6H), 1.66-1.72 (m, 2H),
1.56-1.62 (m, 2H); MS (APCI) m/z 360 (M+H).
Example 51
E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide
Example 51A
Potassium; 2-methyl-2-quinoxalin-2-yl-propionate
[0657] A solution of 2-chloroquinoxaline (295 mg, 1.8 mmol), methyl
trimethylsilyl dimethylketene acetal (0.378 mg, 2.17 mmol), zinc
fluoride (112 mg, 1.08 mmol),
tris(dibenzylideneacetone)dipalladium(0) (20 mg, 0.021 mmol) and
tri-t-butylphosphine-10 wt % in hexane (172 mg, 0.084 mmol) in
Argon degassed DMF (1.5 mL) was stirred at 90.degree. C. for 12
hours. The reaction was taken up in EtOAc (25 mL) and washed with
water (15 mL) followed by brine (15 mL). The organic layer was
dried with MgSO.sub.4, filtered and evaporated in vacuo. The crude
product was purified by flash chromatography (hexane/EtOAc 100:0 to
80:20) to give the methyl ester of Example 51A. A solution of the
corresponding methyl ester (168 mg, 0.73 mmol), potassium
trimethylsilanolate (KOTMS) (140 mg, 1.1 mmol) in THF (2 mL) was
stirred at 23.degree. C. for 12 hours. Methyl t-butyl ether (MTBE)
8 mL was added to the solution and Example 51A was isolated by
filtration.
Example 51B
E-4-[(2-methyl-2-quinoxalin-2-ylpropanoyl)amino]adamantane-1-carboxamide
[0658] A solution of the product of Example 51A (30 mg, 0.12 mmol),
the product of Example 1 C (35 mg, 0.14 mmol), TBTU (61 mg, 0.19
mmol) and DIEA (38 mg, 0.3 mmol) in DMF (1.2 mL) was stirred at
23.degree. C. for 3 hrs. The reaction was diluted with EtOAc (10
mL) and washed twice with water (6 mL) and brine (6 mL). The
organic layer was dried with MgSO.sub.4, filtered and evaporated in
vacuo. The residue was taken in THF (1 mL) and stirred with KOTMS
(23 mg, 0.18 mmol) at 23.degree. C. for 12 hours. The solvent was
evaporated in vacuo. The residue solid was taken in DMF (1 mL) and
added TBTU (69 mg, 0.22 mmol), DIEA (38 mg, 0.3 mmol) and stirred
at 23.degree. C. for 2 hours. Ammonium hydroxide--30% by weight (2
mL) was added and stirred for a further 30 minutes. The reaction
was partitioned between EtOAc (8 mL) and water (3 mL). The organic
layer was washed with water (3 mL), dried with MgSO.sub.4,
filtered, and evaporated in vacuo. The crude reaction mixture was
purified by preparative reverse phase HPLC on a Waters Symmetry C8
column (25 mm.times.100 mm, 7 urn particle size) using a gradient
of 20% to 100% acetonitrile:water (0.1% TFA) over 18 min at a flow
rate of 40 mL/min. to provide the title compound as the
trifluoroacetic acid salt. .sup.1H NMR (400 MHz,
Chloroform-d.sub.1) .delta. ppm 9.03 (s, 1H), 8.12-8.16 (m, 1H),
8.04-8.08 (m, 1H), 7.76-7.85 (m, 2H), 7.33-7.38 (m, 1H), 6.28-6.41
(m, 1H), 5.69-5.82 (m, 1H), 3.91-4.05 (m, 1H), 1.96-2.04 (m, 4H),
1.89-1.97 (m, 4H), 1.84-1.88 (m, 2H), 1.83 (s, 6H), 1.62-1.69 (m,
2H), 1.52-1.59 (m, 2H); MS (APCI) m/z 393 (M+H).
Biological Data
Measurement of Inhibition Constants:
[0659] The ability of test compounds to inhibit human
11.beta.-HSD-1 enzymatic activity in vitro was evaluated in a
Scintillation Proximity Assay (SPA). Tritiated-cortisone substrate,
NADPH cofactor and titrated compound were incubated with truncated
human 11.beta.-HSD-1 enzyme (24-287AA) at room temperature to allow
the conversion to cortisol to occur. The reaction was stopped by
adding a non-specific 11.beta.-HSD inhibitor, 183-glycyrrhetinic
acid. The tritiated cortisol was captured by a mixture of an
anti-cortisol monoclonal antibody and SPA beads coated with
anti-mouse antibodies. The reaction plate was shaken at room
temperature and the radioactivity bound to SPA beads was then
measured on a .beta.-scintillation counter. The 11-.beta.HSD-1
assay was carried out in 96-well microtiter plates in a total
volume of 220 .mu.l. To start the assay, 188 .mu.l of master mix
which contained 17.5 nM .sup.3H-cortisone, 157.5 nM cortisone and
181 mM NADPH was added to the wells. In order to drive the reaction
in the forward direction, 1 mM G-6-P was also added. Solid compound
was dissolved in DMSO to make a 10 mM stock followed by a
subsequent 10-fold dilution with 3% DMSO in Tris/EDTA buffer (pH
7.4). 22 .mu.l of titrated compounds was then added in triplicate
to the substrate. Reactions were initiated by the addition of 10
.mu.l of 0.1 mg/ml E. coli lysates overexpressing 11.beta.-HSD-1
enzyme. After shaking and incubating plates for 30 minutes at room
temperature, reactions were stopped by adding 10 .mu.l of 1 mM
glycyrrhetinic acid. The product, tritiated cortisol, was captured
by adding 10 .mu.l of 1 .mu.M monoclonal anti-cortisol antibodies
and 100 .mu.l SPA beads coated with anti-mouse antibodies. After
shaking for 30 minutes, plates were read on a liquid scintillation
counter Topcount. Percent inhibition was calculated based on the
background and the maximal signal. Wells that contained substrate
without compound or enzyme were used as the background, while the
wells that contained substrate and enzyme without any compound were
considered as maximal signal. Percent of inhibition of each
compound was calculated relative to the maximal signal and
IC.sub.50 curves were generated. This assay was applied to
11.beta.-HSD-2 as well, whereby tritiated cortisol and NAD.sup.+
were used as substrate and cofactor, respectively.
[0660] Compounds of the present invention are active in the
11-.beta.HSD-1 assay described above and show selectivity for human
11-.beta.-HSD-1 over human 11-.beta.-HSD-2, as indicated in Table
1.
TABLE-US-00001 TABLE 1 11-.beta.-HSD-1 and 11-.beta.-HSD-2 activity
for representative compounds. Compound 11-.beta.-HSD-1 IC.sub.50
(nM) 11-.beta.-HSD-2 IC.sub.50 (nM) A (Example 1) 43 >10,000 B
(Example 2) 102 C (Example 3) 82 >10,000 D (Example 4) 24 G
(Example 9) 59 7,400 H (Example 10) 33 >30,000 I (Example 11) 35
12,000 J (Example 12) 33 30,000 K (Example 13) 43 16,000 L (Example
14) 25 16,000 M (Example 15) 30 >30,000 N (Example 16) 31
>30,000 O (Example 17) 38 16,000 P (Example 18) 38 >30,000 Q
(Example 19) 36 16,000 R (Example 20) 27 21,000 S (Example 21) 37
15,000 T (Example 22) 31 >30,000 U (Example 23) 16 12,000 V
(Example 24) 19 15,000 W (Example 25) 23 >30,000 X (Example 26)
104 >30,000 Y (Example 27) 18 13,000 Z (Example 28) 21 23,000 AA
(Example 30) 15 15,000 BB (Example 31) 26 30,000 CC (Example 32) 23
12,000 DD (Example 33) 23 6,300 EE (Example 34) 29 10,000 FF
(Example 35) 28 >100,000 GG (Example 36) 17 9,300 HH (Example
37) 44 40,000 II (Example 38) 62 44,000 JJ (Example 39) 95
60,000
[0661] The data in Table 1 demonstrates that compounds of formula
(I) are active in the human 11.beta.-HSD-1 enzymatic SPA assay
described above and the tested compounds show selectivity for
11.beta.-HSD-1 over 11.beta.-HSD-2. The 11.beta.-HSD-1 inhibitors
of this invention generally have an inhibition constant IC.sub.50
of less than 600 nM and preferably less than 50 nM. The compounds
preferably are selective, having an inhibition constant IC.sub.50
against 11.beta.-HSD-2 greater than 1000 nM and preferably greater
than 10,000 nM. Generally, the IC.sub.50 ratio for 11.beta.-HSD-2
to 11.beta.-HSD-1 of a compound is at least 10 or greater and
preferably 100 or greater.
Metabolic Stability
Incubation Conditions:
[0662] Metabolic stability screen: each substrate (10 .mu.M) was
incubated with microsomal protein (0.1-0.5 mg/ml) in 50 mM
potassium phosphate buffer (pH 7.4) in 48-Well plate. The enzyme
reaction was initiated by the addition of 1 mM NADPH, then
incubated at 37.degree. C. in a Forma Scientific incubator
(Marietta, Ohio, USA) with gentle shaking. The reactions were
quenched by the addition of 800 .mu.l of ACN/MeOH (1:1, v/v),
containing 0.5 .mu.M of internal standard (IS), after 30 min
incubation. Samples were then filtered by using Captiva 96-Well
Filtration (Varian, Lake Forest, Calif., USA) and analyzed by LC/MS
(mass spectrometry). Liver microsomal incubations were conducted in
duplicate.
LC/MS Analysis:
[0663] The parent remaining in the incubation mixture was
determined by LC/MS. The LC/MS system consisted of an Agilent 1100
series (Agilent Technologies, Waldbronn, Germany) and API 2000 (MDS
SCIEX, Ontario, Canada). A Luna C8(2) (50.times.2.0 mm, particle
size 3 um, Phenomenex, Torrance, Calif., USA) was used to quantify
each compound at ambient temperature. The mobile phase consisted of
(A): 10 mM NH.sub.4AC (pH 3.3) and (B): 100% ACN and was delivered
at a flow rate of 0.2 ml/min. Elution was achieved using a linear
gradient of 0-100% B over 3 min, then held 100% B for 4 min and
returned to 100% A in 1 min. The column was equilibrated for 7 min
before the next injection.
[0664] The peak area ratios (each substrate over IS) at each
incubation time were expressed as the percentage of the ratios
(each substrate over IS) of the control samples (0 min incubation).
The parent remaining in the incubation mixture was expressed as the
percentage of the values at 0 min incubation. The percentage
turnover is calculated using the following equation (%
turnover=100% turnover-% parent remaining) and is recorded as the
percentage turnover in the Table 2.
TABLE-US-00002 TABLE 2 Microsomal metabolic stability. Human Liver
Microsomal Mouse Liver Microsomal Compound Turnover (%) Turnover
(%) A 5 5 B 2 0 C 0 0 D 10 E 83 F 62
[0665] Compounds A, B, C and D contain a substituted adamantane,
whereas the adamantane ring of Compounds E and F is unsubstituted.
The microsomal, metabolic, stability data in Table 2 demonstrates
that substituted adamantane compounds of the present invention may
exhibit an increase in metabolic stability compared to
unsubstituted adamantane compounds which may lead to longer in vivo
half lives and pharmacokinetic advantages over unsubstituted
adamantanes.
Selective 11.beta.-HSD1 Inhibitors Enhance Memory Consolidation in
Mice after 2-Week Food-in-Diet Dosing
[0666] Episodic memory is a type of long-term memory that requires
one exposure for memory formation to occur. Patients with
Alzheimer's disease suffer from episodic memory dysfunction, among
other cognitive deficits. In addition, studies indicate that
patients with a genetic risk for Alzheimer's disease have early
deficits in episodic memory and executive function (Ringman, J.
Geriatr. Psychiatry Neurology, 2005, 18:228-233).
[0667] The 24-hour inhibitory avoidance task in mice is a measure
of one-trial learning and memory consolidation in response to a
discrete aversive event (foot-shock). Mice are first placed in an
illuminated compartment of a two-compartment apparatus. Mice will
naturally step through into an adjoining dark compartment, which
they prefer. When the mice enter the dark they receive a mild
foot-shock. To assess memory, mice are tested 24 hours later and
the length of time the animal refrains from entering the dark
compartment is recorded (higher latencies indicate improved memory
for the aversive event).
[0668] Male CD-1 mice were obtained from Charles River, Wilmington,
Mass. Mice were group-housed 10 per cage. The body weight upon
arrival was 20-25 g. Food and water were available ad libitum
except during experiments. Animals were acclimated to the animal
facilities for a period of at least one week prior to commencement
of experiments. Animals were tested in the light phase of a 12-hour
light: 12-hour dark schedule (lights on 0600 hours).
[0669] Compound KK
([2-(2-Chloro-4-fluorophenoxy)-2-methyl-N-[(E)-5-(methylsulfonyl)-2-adama-
ntyl]propanamide]) was synthesized at Abbott Laboratories. Compound
KK was administered via a drug-in-diet administration (100
mg/kg/day in Western diet) or (10 mg/kg/day in Western diet).
[0670] On the first day of testing (17 days after drug-in-diet was
presented) mice were removed from the colony room in their home
cage, brought to the testing room, and left undisturbed for 2 hours
prior to testing initiation. Following this habituation period,
drug-in-diet mice were tested. Upon testing initiation, mice were
placed one at a time into the light (safe) compartment of a
two-chambered apparatus (Gemini apparatus, San Diego Instruments,
San Diego, Calif.), during which time the retractable door was
closed. After 30 sec at the completion of the acclimation period
the door between the light and dark compartments was opened.
Measurement of the training latency commenced at this point. This
measure (training) provides some indication of general locomotor
activity. If a mouse has not crossed within 60 s the animal's data
is excluded from the analysis. After the mouse crossed into the
dark chamber the door was lowered and inescapable footshock (0.13
mA, 1 sec duration) was presented to the mouse after it completely
entered the chamber and the door closed. The mouse was immediately
removed from the chamber and returned to the home cage. 24-hours
later the mouse was tested using methods identical to those on the
training day, except without being dosed and without shock
presentation. The latency to enter the dark chamber was recorded
and was the dependent variable measured for assessing memory
retention (latency is defined as entry of the whole mouse; all 4
paws on the grids in the dark side, plus the tail in the chamber
for 5 see; 180 sec is maximum latency). Data were analyzed using
Mann Whitney U comparisons. P<0.05 was regarded as significant.
As illustrated in FIG. 1, there was a significant improvement in
memory retention following the administration of Compound KK at
both doses compared to the response of vehicle control mice.
A Selective 11.beta.-HSD1 Inhibitor Enhances Phosphorylated CREB, a
Biochemical Marker of Cognitive Enhancement, in Mice after 2-Week
Food-in-Diet Dosing
[0671] In vivo signaling studies were conducted to examine the
biochemical pathways that may be mechanistically involved in the
cognitive efficacy associated with Compound KK. An important
signaling process that serves as a biochemical correlate of
synaptic plasticity underlying learning and memory is the
phosphorylation of CREB (c-AMP-response element binding protein), a
transcription factor critical to long-term memory. To investigate
the effects of Compound KK on CREB phosphorylation, CD1 mice
treated and tested (data presented in FIG. 1) were given a 24-hour
rest after testing before immunohistochemical procedures
commenced.
[0672] Male CD-1 mice were obtained from Charles River, Wilmington,
Mass. Mice were group-housed 10 per cage. The body weight upon
arrival was 20-25 g. Food and water were available ad libitum
except during experiments. Animals were acclimated to the animal
facilities for a period of at least one week prior to commencement
of experiments. Animals were tested in the light phase of a 12-hour
light: 12-hour dark schedule (lights on 0600 hours).
[0673] Compound KK was administered via a drug-in-diet
administration (100 mg/kg/day in Western diet) or (10 mg/kg/day in
Western diet). 18-days after receiving Compound KK food-in-diet (10
and 100 mg/kg/day) rats were anesthetized and perfused through the
aorta with normal saline followed by 10% formalin. Following
perfusion, brains were removed and postfixed in 20% sucrose-PBS
(phosphate buffered saline) overnight and subsequently cut on a
cryostat (40 gm coronal sections) and collected as free-floating
sections in PBS. Sections were then immunostained for Fos protein
using a 3-step ABC-peroxidase technique beginning with a 30-min
incubation with blocking serum. Sections were next incubated with
anti-phsopho-CREB (rabbit IgG, 1:1000, Cell signaling) antibodies
for 48 hrs at 4 degrees C., washed with PBS and incubated for 1-hr
with either biotinylated secondary anti-sheep or anti-mouse
antibody (Ab) solution (1:200). Finally, sections were washed in
PBS, incubated with ABC reagent (Vector) and then developed in a
peroxidase substrate solution. The sections were mounted,
coverslipped and examined and photographed with a light microscope
(Leica, DMRB). Immuno-reactivity (IR) was quantified using an image
analysis system (Leica, Quantimet 500) that determined number
and/or area of peroxidase substrate-positive stained neurons from
digitized photomicrographs according to a pixel gray level
empirically determined prior to analysis. Overall statistical
significance was determined using a one-way ANOVA, with Dunnett's
post hoc analyses used to determine significance (p<0.05 was
considered significant). FIG. 2 shows the increase in
phosphorylated CREB following the administration of Compound KK
mg/kg/day.
Selective 11.beta.-HSD1 Inhibitors Enhance Memory Consolidation in
Mice after Subchronic Dosing
[0674] The 24-hour inhibitory avoidance model in mice was used to
evaluate the effects of
[0675] Compound KK and Compound LL
([N-{(E)-5-[(Z)-Amino(hydroxyimino)methyl]-2-adamantyl}-2-(4-chlorophenox-
y)-2-methylpropanamide]) following a subchronic (3 administration)
dosing regimen.
[0676] Male CD-1 mice were obtained from Charles River, Wilmington,
Mass. Mice were group-housed 10 per cage. The body weight upon
arrival was 20-25 g. Food and water were available ad libitum
except during experiments. Animals were acclimated to the animal
facilities for a period of at least one week prior to commencement
of experiments. Animals were tested in the light phase of a 12-hour
light: 12-hour dark schedule (lights on 0600 hours).
[0677] Compound KK and Compound LL were synthesized at Abbott
Laboratories. Compounds AA and BB were solubilized in a solution of
5% Tween80/water. Compound KK. was administered in a cloudy, fine
suspension, while Compound LL was administered in a solution.
[0678] Mice were weighed and dosed BID (.apprxeq.8 AM and 3 PM) PO
with Compound AA (30 mg/kg), or Compound LL (30 mg/kg) or vehicle
the day before training. On training day, mice were injected with
Compound KK, Compound LL or vehicle one-hour PO before training.
One hour following injection (start of training) mice were
subjected to a training session in which they were placed in a
lighted compartment of a two-compartment chamber (Gemini apparatus,
San Diego Instruments, San Diego, Calif.) with a manually operated
gate separating the compartments. Following a 30 second habituation
period in the lighted compartment, the door to the adjacent dark
compartment was opened. Once the mouse had completely transferred,
the door was closed and a 0.13 mA current was applied to the grid
floor for 1 s. The mouse was then immediately removed and returned
to the home cage. Twenty-four hours later mice were again tested in
the same apparatus, except without shock, and the transfer latency
from the lighted to the dark compartment recorded and used as an
index of memory for the punished response 24 hours earlier. The
electric shock parameters of this test were established such that
vehicle treated mice would only have minimal retention of the
conditioning trial, thus allowing a large window for improvement of
the memory following drug treatment. Data were analyzed using Mann
Whitney U comparisons. P<0.05 was regarded as significant.
[0679] As illustrated in FIG. 3, there was a significant
improvement in memory retention following the administration of
both Compounds AA and BB compared to the response of vehicle
control mice.
A Selective 11.beta.-HSD1 Inhibitor Enhances Short-Term Memory in
Rats after Subchronic Dosing
[0680] Social memory and social cognition are impaired in disorders
such as Alzheimer's disease and schizophrenia. One of the more
commonly used preclinical models of social recognition memory is
short-term social recognition in the rat, a model of short-term
memory based on the recognition of a juvenile rat by an adult rat.
When adult rats are allowed to interact with a juvenile rat for 5
min, the adult exhibits behaviors such as close following, grooming
or sniffing the juvenile for as much as 40-50% of the duration of a
5 min trial. The juvenile rat is then removed and reintroduced 120
min later, and interactive behavior of the adult rat is again
monitored. If memory has been lost over the interval between trials
1 and 2, the extent of interaction is equal (expressed as a ratio
of investigation time of T1/T2) and the ratio will be close to 1.
However, if the adult remembers the juvenile, the investigation
ratio declines. To test for non-specific effects, a novel juvenile
is introduced at 120 minutes instead of the familiar juvenile. If
the ratio is less than 1, this indicates the drug is having effects
that may not be specific to cognition.
[0681] Male Sprague Dawley rats from Charles Rivers (Portage,
Mich., USA) were used. Adults weighed 370-500 g, and juveniles
weighed 70-120 g at the time of testing. All animals were housed in
a quiet room under conditions of 12 h lights on/12 h lights off (on
at 06:00 am) in groups of four with food and water available ad
libitum. Studies were conducted between 08:00 h and 16:00 h, and
treatment groups were arranged for equal representation of time of
day. Compound MM
([N-[(E)-5-Hydroxy-2-adamantyl]-2-{4-[5-(trifluoromethyl)pyridin-2-yl]pip-
erazin-1-yl}acetamide], 30 mg/kg) was dissolved in PEG 400 using a
warm sonicator bath. Compound was administered in solution in a
volume of 1 mL/1 g body weight, p.o.
[0682] Rats were pre-dosed po at 24, 18 and 1 hour before first
juvenile rat exposure with vehicle, or Compound MM (30 mg/kg).
During testing, the adult rat was placed into the test cage. After
30 min, a juvenile rat was placed into the test cage with the adult
rat for 5 min. The time the adult spent exploring (sniffing,
grooming, close following) the juvenile during this test session
was recorded, and defined as the first investigation duration. The
juvenile was then removed from the test cage, and placed into its
home cage. Following a further 90 min, the adult was placed back
into the same test chamber, for a second 30-min habituation.
Following this second habituation the same juvenile (familiar) was
again placed into the test cage for a 5-min test session; the time
spent exploring the juvenile during this test session was defined
as the second investigation duration. Vehicle treated rats do not
remember the familiar juvenile following this two hr delay. Data
were analyzed using a one-way analysis of variance. If there was a
significant effect, subsequent post hoc significance was determined
using Dunnett's multiple comparison testing (p<0.05 was regarded
as significant).
[0683] As shown in FIG. 4, there was a significant improvement in
short-term memory retention following the administration of
Compound MM compared to the response of vehicle control rats.
Effects of 11.beta.HSD-1 Inhibitor on Rat Wake EEG Power Spektrum
and REM Sleep Parameter
[0684] EEG of Fisher rats (n=8/group) with chronically implanted
supracortical EEG-electrodes were analyzed for an 8 h period.
Intraindividual drug-induced changes of power spectra were
analyzed. For REM sleep the number of REM episodes, latency to
first REM, and total REM time was analyzed. Compound MM (30 mg/kg;
3 times at 24, 26, and 0.1 hours before measurement) significantly
reduced the number of REM sleep episodes by 16% (total sleep time
by 10%); the corresponding REM time was reduced by 23%. The latency
to first REM significantly increased by 62% (See FIGS. 5a, 5b and
5c, respectively).
[0685] The observed effects on REM were in line with the effects of
antidepressants like SSRIs and TCAs. These effects differ from the
procognitive effects induced by inhibitors of ACh-esteras like
donepezil and physostigmine.
Modulation of Cortical/Hippocampal Acetylcholine Serotonin Release
by 11.beta.-HSD1 Inhibition
[0686] Microdialysis studies (resting or challenging conditions) in
freely moving, male Sprague Dawley rats (Janvier, 295-315 g,
n=5-8/treatment group) were performed using stereotactically
instrumented microdialysis probes (CMA/12-14-2): mPFC, hippocampus.
Aliquots of the same microdialysate fractions (6 before, and 9-12
after compound administration) were analyzed either for
acetylcholine or for serotonin by HPLC and electrochemical
detection.
[0687] Microdialysate Acetylcholine Levels
[0688] Acute, single administration of Compound MM (30 mg/kg, p.o.)
did not change ACh release under resting conditions. Challeging
conditions as the transfer from home cage to novel cage, and back
to home cage resulted in stimulation of ACh release (see FIGS. 6a,
6b and 6c). Single administration of Compound MM did not induce any
further stimulation of ACh release, neither in the cortex nor in
the hippocampus.
[0689] Microdialysate Serotonin Levels
[0690] Single administration of Compound MM (30 mg/kg, p.o.)
resulted in a long-lasting increase of serotonin (5-HT) levels in
the medial prefrontal cortex and in the hippocampus. This is a
feature shared by marketed anti-depressive drugs and might indicate
the potential use for 11.beta.-HSD1 inhibitors as
antidepressants/anxiolytic drugs. These findings remain to be
confirmed by (i) investigating 11.beta.-HSD1 inhibitors from
different chemotype(s) in selected microdialysis studies and/or
(ii) in animal models of depression/anxiety. Additionally, these
results differentiate 11.beta.-HSD-1 inhibition from acetylcholine
esterase inhibition, the current therapeutic principle for
symptomatic treatment of Alzheimer's disease.
Effects of HSD-1 Inhibitors on Monkey Ex Vivo HSD1 Activity
[0691] Compound KK demonstrated potent ex vivo inhibition of monkey
brain, fat and liver 2.5 and 16 hours following a single oral 10
mg/kg dose. Harvested tissues (approximately 150 mg) were minced
into small, 2 mm pieces in the presence of 5.times. volume of
incubation buffer. Cortisone at final concentrations of 0, 3, 10 or
30 .mu.M was added to each well. Cell culture plates with tissues
were incubated at 37.degree. C. for three hours. Two-hundred .mu.L
of tissue culture supernatant was then removed and spun at 1000 rpm
in an Eppindorf tube, and then 100 .mu.L of resulting supernatant
was aliquotted into two tubes for LCMS analysis of cortisol.
Results are indicated as & vehicle control activity in the
table below:
TABLE-US-00003 TABLE 3 HSD-1 Ex Vivo Activity in Cynomolgus Monkeys
Following a Single 10 mg/kg Oral Dose of Compound KK N = 3/group
Mean % Veh Tissue Time Control Liver 2.5 hours 38% Mesenteric Fat
2.5 hours 90% Liver 16 hours 9% Mesenteric Fat 16 hours 50%
Cerebral Cortex 16 hours 30% Hippocampus 16 hours 42%
Biochemical Mechanism
[0692] Glucocorticoids arc steroid hormones that play an important
role in regulating multiple physiological processes in a wide range
of tissues and organs. For example, glucocorticoids arc potent
regulators of glucose and lipid metabolism. Excess glucocorticoid
action may lead to insulin resistance, type 2 diabetes,
dyslipidemia, visceral obesity and hypertension. Cortisol is the
major active and cortisone is the major inactive form of
glucocorticoids in humans, while corticosterone and
dehydrocorticosterone are the major active and inactive forms in
rodents.
[0693] Previously, the main determinants of glucocorticoid action
were thought to be the circulating hormone concentration and the
density of glucocorticoid receptors in the target tissues. In the
last decade, it was discovered that tissue glucocorticoid levels
may also be controlled by 11.beta.-hydroxysteroid dehydrogenases
enzymes (11.beta.-HSDs). There are two 11.beta.-HSD isozymes which
have different substrate affinities and cofactors. The
11.beta.-hydroxysteroid dehydrogenases type 1 enzyme
(11.beta.-HSD-1) is a low affinity enzyme with K.sub.m for
cortisone in the micromolar range that prefers NADPH/NADP.sup.+
(nicotinamide adenine dinucleotide) as cofactors. 11.beta.-HSD-1 is
widely expressed and particularly high expression levels are found
in liver, brain, lung, adipose tissue and vascular smooth muscle
cells. In vitro studies indicate that 11.beta.-HSD-1 is capable of
acting both as a reductase and a dehydrogenase. However, many
studies have shown that it is predominantly a reductase in vivo and
in intact cells. It converts inactive 11-ketoglucocorticoids (i.e.,
cortisone or dehydrocorticosterone) to active
11-hydroxyglucocorticoids (i.e., cortisol or corticosterone) and
therefore amplifies the glucocorticoid action in a tissue-specific
manner.
[0694] With only 20% homology to 11.beta.-HSD-1, the
11.beta.-hydroxysteroid dehydrogenases type 2 enzyme
(11.beta.-HSD-2) is a NAD.sup.+-dependent, high affinity
dehydrogenase with a K.sub.m for cortisol in the nanomolar range.
11.beta.-HSD-2 is found primarily in mineralocorticoid target
tissues, such as kidney, colon and placenta. Glucocorticoid action
is mediated by the binding of glucocorticoids to receptors, such as
mineralocorticoid receptors and glucocorticoid receptors. Through
binding to its receptor, the main mineralocorticoid aldosterone
controls the water and salts balance in the body. However, the
mineralocorticoid receptors have a high affinity for both cortisol
and aldosterone. 11.beta.-HSD-2 converts cortisol to inactive
cortisone, therefore preventing the non-selective mineralocorticoid
receptors from being exposed to high levels of cortisol. Mutations
in the gene encoding 11.beta.-HSD-2 cause Apparent
Mineralocorticoid Excess Syndrome (AME), which is a congenital
syndrome resulting in hypokaleamia and severe hypertension. AME
Patients have elevated cortisol levels in mineralocorticoid target
tissues due to reduced 11.beta.-HSD-2 activity. The AME symptoms
may also be induced by administration of 11.beta.-HSD-2 inhibitor,
glycyrrhetinic acid. The activity of 11.beta.-HSD-2 in placenta is
probably important for protecting the fetus from excess exposure to
maternal glucocorticoids, which may result in hypertension, glucose
intolerance and growth retardation. Due to the potential side
effects resulting from 11.beta.-HSD-2 inhibition, the present
invention describes selective 11.beta.-HSD-1 inhibitors.
[0695] Glucocorticoid levels and/or activity may contribute to
numerous disorders, including Type II diabetes, obesity,
dyslipidemia, insulin resistance and hypertension. Administration
of the compounds of the present invention decreases the level of
cortisol and other 11.beta.-hydroxysteroids in target tissues,
thereby reducing the effects of glucucocrticoid activity in key
target tissues. The present invention could be used for the
treatment, control, amelioration, prevention, delaying the onset of
or reducing the risk of developing the diseases and conditions that
are described herein.
[0696] Since glucocorticoids are potent regulators of glucose and
lipid metabolism, glucocorticoid action may contribute or lead to
insulin resistance, type 2 diabetes, dyslipidcmia, visceral obesity
and hypertension. For example, cortisol antagonizes the insulin
effect in liver resulting in reduced insulin sensitivity and
increased gluconeogenesis. Therefore, patients who already have
impaired glucose tolerance have a greater probability of developing
type 2 diabetes in the presence of abnormally high levels of
cortisol. Previous studies (B. R. Walker et al., J. of Clin.
Endocrinology and Met., 80: 3155-3159, 1995) have demonstrated that
administration of non-selective 11.beta.-HSD-1 inhibitor,
carbenoxolone, improves insulin sensitivity in humans. Therefore,
administration of a therapeutically effective amount of an
11.beta.-HSD-1 inhibitor may treat, control, ameliorate, delay, or
prevent the onset of type 2 diabetes.
[0697] Administration of glucocorticoids in vivo has been shown to
reduce insulin secretion in rats (B. Billaudel et al., Horm. Metab.
Res. 11: 555-560, 1979). It has also been reported that conversion
of dehydrocorticosterone to corticosterone by 11.beta.-HSD-1
inhibits insulin secretion from isolated murine pancreatic p cells.
(B. Davani et al., J. Biol. Chem., 275: 34841-34844, 2000), and
that incubation of isolated islets with an 11.beta.-HSD-1 inhibitor
improves glucose-stimulated insulin secretion (H Orstater et al.,
Diabetes Metab. Res. Rev. 21: 359-366, 2005). Therefore,
administration of a therapeutically effective amount of an
11.beta.-HSD-1 inhibitor may treat, control, ameliorate, delay, or
prevent the onset of type 2 diabetes by improving
glucose-stimulated insulin secretion in the pancreas.
[0698] Abdominal obesity is closely associated with glucose
intolerance (C. T. Montague et al., Diabetes, 49: 883-888, 2000),
hyperinsulinemia, hypertriglyceridemia and other factors of
metabolic syndrome (also known as syndrome X), such as high blood
pressure, elevated VLDL and reduced HDL. Animal data supporting the
role of 11.beta.-HSD-1 in the pathogenesis of the metabolic
syndrome is extensive (Masuzaki, et al. Science. 294: 2166-2170,
2001; Paterson, J. M., et al.; Proc Natl. Acad. Sci. USA. 101:
7088-93, 2004; Montague and O'Rahilly. Diabetes. 49: 883-888,
2000). Therefore, administration of a therapeutically effective
amount of an 11.beta.-HSD-1 inhibitor may treat, control,
ameliorate, delay, or prevent the onset of obesity. Long-term
treatment with an 11.beta.-HSD-1 inhibitor may also be useful in
delaying the onset of obesity, or perhaps preventing it entirely if
the patients use an 11.beta.-HSD-1 inhibitor in combination with
controlled diet, exercise, or in combination or sequence with other
pharmacological approaches.
[0699] By reducing insulin resistance and/or maintaining serum
glucose at normal concentrations and/or reducing obestity compounds
of the present invention also have utility in the treatment and
prevention of conditions that accompany Type 2 diabetes and insulin
resistance, including the metabolic syndrome or syndrome X,
obesity, reactive hypoglycemia, and diabetic dyslipidemia.
[0700] 11.beta.-HSD-1 is present in multiple tissues, including
vascular smooth muscle, where local glucocorticoid levels that are
thought to increase insulin resistance, leading to reductions in
nitric oxide production, and potentiation of the vasoconstrictive
effects of both catecholamines and angiotensin II (M. Pirpiris et
al., Hypertension, 19:567-574, 1992, C. Kornel et al., Steroids,
58: 580-587, 1993, B. R. Walker and B. C. Williams, Clin. Sci.
82:597-605, 1992; Hodge, G. et al Exp. Physiol 87:1-8, 2002). High
levels of cortisol in tissues where the mineralocorticoid receptor
is present may lead to hypertension, as observed in Cushing's
patients (See, D. N. Orth, N. Engl. J. Med. 332:791-803, 1995, M.
Boscaro, et al., Lancet, 357: 783-791, 2001, X. Bertagna, et al,
Cushing's Disease. In: Melmed. S., Ed. The Pituitary. 2.sup.nd ed.
Malden, M A: Blackwell; 592-612, 2002). Transgenic mice
overexpressing 11.beta.-HSD-1 in liver and fat are also
hypertensive, a phenotype believed to result from glucocorticoid
activation of the renin angiotensin system (Paterson, J. M. et al,
PNAS. 101: 7088-93, 2004; Masuzaki, H. et al, J. Clin. Invest. 112:
83-90, 2003). Therefore, administration of a therapeutically
effective dose of an 11.beta.-HSD-1 inhibitor may treat, control,
ameliorate, delay, or prevent the onset of hypertension.
[0701] Cushing's syndrome is a life-threatening metabolic disorder
characterized by sustained and elevated glucocorticoid levels
caused by the endogenous and excessive production of cortisol from
the adrenal glands. Typical Cushingoid characteristics include
central obesity, diabetes and/or insulin resistance, moon face,
buffalo hump, skin thinning, dyslipidemia, osteoporosis, reduced
cognitive capacity, dementia, hypertension, sleep deprivation, and
atherosclerosis among others (Principles and Practice of
Endocrinology and Metabolism. Edited by Kenneth Becker, Lippincott
Williams and Wilkins Pulishers, Philadelphia, 2001; pg 723-8). The
same characteristics can also arise from the exogenous
administration of high doses of exogenous glucocorticoids, such as
prednisone or dexamethasone, as part of an anti-inflammatory
treatment regimen. Endogenous Cushings typically evolves from
pituitary hyperplasia, some other ectopic source of ACTH, or from
an adrenal carcinoma or nodular hyperplasia. Administration of a
therapeutically effective dose of an 11.beta.-HSD-1 inhibitor may
reduce local glucocorticoid concentrations and therefore treat,
control, ameliorate, delay, or prevent the onset of Cushing's
disease and/or similar symptoms arising from glucocorticoid
treatment.
[0702] 11.beta.-HSD-1 is expressed in mammalian brain, and
published data indicates that glucocorticoids may cause neuronal
degeneration and dysfunction, particularly in the aged (de Quervain
et al.; Hunt Mol Genet. 13: 47-52, 2004; Belanoff et al. J.
Psychiatr Res. 35: 127-35, 2001). Evidence in rodents and humans
suggests that prolonged elevation of plasma glucocorticoid levels
impairs cognitive function that becomes more profound with aging.
(Issa, A. M. et al. J. Neurosci. 10: 3247-54, 1990; Lupien, S. J et
al. Nat. Neurosci. 1: 69-73, 1998; Yau, J. L. W. et al Proc Natl
Acad Sci USA. 98: 4716-47.12, 2001). Thekkapat et al has recently
shown that 11.beta.-HSD-1 mRNA is expressed in human hippocampus,
frontal cortex and cerebellum, and that treatment of elderly
diabetic individuals with the non-selective HSD1/2 inhibitor
carbenoxolone improved verbal fluency and memory (Prot Natl Acad
Sci USA. 101: 6743-9, 2004). Additional CNS effects of
glucocorticoids include glucocorticoid-induced acute psychosis
which is of major concern to physicians when treating patients with
these steroidal agents (Wolkowitz et al.; Ann NY Acad Sci.
1032:191-4, 2004). Conditional mutagenesis studies of the
glucocorticoid receptor in mice have also provided genetic evidence
that reduced glucocorticoid signaling in the brain results in
decreased anxiety (Tronche, F. et al. (1999) Nature Genetics 23:
99-103). Therefore, it is expected that potent, selective
11.beta.-HSD-1 inhibitors would treat, control, ameliorate, delay,
or prevent the onset of cognitive decline, dementia,
steroid-induced acute psychosis, depression, and/or anxiety.
[0703] In Cushing's patients, excess cortisol levels contributes to
the development of hypertension, dyslipidemia, insulin resistance,
and obesity, conditions characteristic of metabolic syndrome (Orth,
D. N. et al N. Engl. J. Med. 332:791-803, 1995; Boscaro, M. et al.,
Lancet, 357: 783-791, 2001, Bertagna, X. et al, Cushing's Disease.
In: Melmed S., Ed. The Pituitary. 2.sup.nd ed. Malden, M A:
Blackwell; 592-612, 2002). Hypertension and dyslipidemia are also
associated with development of atherosclerosis. 11.beta.-HSD-1
knockout mice are resistant to the dyslipidemic effects of a high
fat diet and have an improved lipid profile vs wild type controls
(Morton N. M. et al, JBC, 276: 41293-41300, 2001), and mice which
overexpress 11.beta.-HSD-1 in fat exhibit the dyslipidemic
phenotype characteristic of metabolic syndrome, including elevated
circulating free fatty acids, and triclylgerides (Masuzaki, H., et
al Science. 294: 2166-2170, 2001). Administration of a selective
11.beta.-HSD-1 inhibitor has also been shown to reduce elevated
plasma triglycerides and free fatty acids in mice on a high fat
diet, and significantly reduce aortic content of cholesterol
esters, and reduce progression of atherosclerotic plaques in mice
(Hermanowski-Vosatka, A. et al. J. Exp. Med. 202: 517-27, 2005).
The administration of a therapeutically effective amount of an
11.beta.-HSD-1 inhibitor would therefore be expected to treat,
control, ameliorate, delay, or prevent the onset of dyslipidemia
and/or atherosclerosis.
[0704] Glucocorticoids are known to cause a variety of skin related
side effects including skin thinning, and impairment of wound
healing (Anstead, G. Adv Wound Care. 11: 277-85, 1998; Beer, et
al.; Vitam Hortn. 59: 217-39, 2000). 11.beta.-HSD-1 is expressed in
human skin fibroblasts, and it has been shown that the topical
treatment with the non-selective HSD1/2 inhibitor glycerrhetinic
acid increases the potency of topically applied hydrocortisone in a
skin vasoconstrictor assay (Hammami, M M, and Siiteri, P K. J.
Clin. Endocrinol. Metab. 73: 326-34, 1991). Advantageous effects of
selective 11.beta.-HSD-1 inhibitors such as BVT.2733 on wound
healing have also been reported (WO 2004/11310). High levels of
glucocorticoids inhibit blood flow and formation of new blood
vessels to healing tissues. In vitro and in vivo models of
angiogenesis have shown that systemic antagonism with the
glucocorticoid receptor RU-486 enchances angiogenesis in
subcutaneous sponges as well as in mouse myocardium following
coronary artery ligation (Walker, et al, PNAS, 102:12165-70, 2005).
11.beta.-HSD-1 knockout mice also showed enhanced angiogenesis in
vitro and in vivo within sponges, wounds, and infarcted myocardium.
It is therefore expected that potent, selective 11.beta.-HSD-1
inhibitors would treat, control, ameliorate, delay, or prevent the
onset of skin thinning and/or promote wound healing and/or
angiogenesis.
[0705] Although cortisol is an important and well-recognized
anti-inflammatory agent (J. Baxer, Pharmac. Ther., 2:605-659,
1976), if present in large amount it also has detrimental effects.
In certain disease states, such as tuberculosis, psoriasis and
stress in general, high glucocorticoid activity shifts the immune
response to a humoral response, when in fact a cell based response
may be more beneficial to patients. Inhibition of 11.beta.-HSD-1
activity may reduce glucocorticoid levels, thereby shifting the
immuno response to a cell based response. (D. Mason, Immunology
Today, 12: 57-60, 1991, G. A. W. Rook, Baillier's Clin. Endocrinol.
Metab. 13: 576-581, 1999). Therefore, administration of
11.beta.-HSD-1 specific inhibitors could treat, control,
ameliorate, delay, or prevent the onset of tuberculosis, psoriasis,
stress, and diseases or conditions where high glucocorticoid
activity shifts the immune response to a humoral response.
[0706] One of the more significant side effects associated with
topical and systemic glucocorticoid therapy is glaucoma, resulting
in serious increases in intraocular pressure, with the potential to
result in blindness (Armaly et al.; Arch Ophthalmol. 78:193-7,
1967; Stokes et al.; Invest Ophthalmol Vis Sci. 44: 5163-7, 2003).
The cells that produce the majority of aqueous humor in the eye are
the nonpigmented epithelial cells (NPE). These cells have been
demonstrated to express 11.beta.-HSD-1, and consistent with the
expression of 11.beta.-HSD-1, is the finding of elevated ratios of
cortisol:cortisone in the aqueous humor (Rauz et al. Invest
Ophthahnol Vis Sci. 42: 2037-2042, 2001). Furthermore, it has been
shown that patients who have glaucoma, but who are not taking
exogenous steroids, have elevated levels of cortisol vs. cortisone
in their aqueous humor (Rauz et al. QJM. 96: 481-490, 2003.)
Treatment of patients with the nonselective HSD1/2 inhibitor
carbenoxolone for 4 or 7 days significantly lowered intraocular
pressure and local cortisol generation within the eye (Rauz et al.;
QJM. 96: 481-490, 2003.). It is therefore expected that potent,
selective 11.beta.-HSD-1 inhibitors would treat, control,
ameliorate, delay, or prevent the onset of glaucoma.
[0707] Glucocorticoids (GCs) are known to increase bone resorption
and reduce bone formation in mammals (Turner et al. Calcif Tissue
Int. 54: 311-5, 1995; Lane, N E et al. Med Pediatr Oncol. 41:
212-6, 2003). 11.beta.-HSD-1 mRNA expression and reductase activity
have been demonstrated in primary cultures of human osteoblasts in
homogenates of human bone (Bland et al.; J. Endocrinol. 161:
455-464, 1999; Cooper et al.; Bone, 23:119-125, 2000). In surgical
explants obtained from orthopedic operations, 11.beta.-HSD-1
expression in primary cultures of osteoblasts was found to be
increased approximately 3-fold between young and old donors (Cooper
et al.; J. Bone Miner Res. 17: 979-986, 2002). Glucocorticoids,
such as prednisone and dexamethasone, are also commonly used to
treat a variety of inflammatory conditions including arthritis,
inflammatory bowl disease, and asthma. These steroidal agents have
been shown to increase expression of 11.beta.-HSD-1 mRNA and
activity in human osteoblasts (Cooper et al.; J. Bone Miner Res.
17: 979-986, 2002). These studies suggest that 11.beta.-HSD-1 plays
a potentially important role in the development of bone-related
adverse events as a result of excessive glucocorticoid levels or
activity. Bone samples taken from healthy human volunteers orally
dosed with the non-selective HSD1/2 inhibitor carbenoxolone showed
a significant decrease in markers of bone resorption (Cooper et
al.; Bone. 27: 375-81, 2000). It is therefore expected that potent,
selective 11.beta.-HSD-1 inhibitors would treat, control,
ameliorate, delay, or prevent the onset of conditions of
glucocorticoid-induced or age-dependent osteoporosis
[0708] The following diseases, disorders and conditions can be
treated, controlled, prevented or delayed, by treatment with the
compounds of this invention: (1) hyperglycemia, (2) low glucose
tolerance, (3) insulin resistance, (4) lipid disorders, (5)
hyperlipidemia, (6) hypertriglyceridemia, (9) hypercholesterolemia,
(10) low HDL levels, (11) high LDL levels, (12), atherosclerosis
and its sequelae, (13) vascular restensosis, (14) pancreatitis,
(15) obdominal obesity, (16) neurodegenerative disease, (17)
retinopathy, (18) nephropather, (19), neuropathy, (20) hypertension
and other disorders where insulin resistance is a component, and
(21) other diseases, disorders, and conditions that can benefit
from reduced local glucocorticoid levels.
Neuronal Effects of 11.beta.-HSD Inhibitors
[0709] Studies have shown that in homogenates of hippocampus, both
dehydrogenation and reduction occur (V. Lakshmi, et al.,
Endocrinol., 128, 1741-1748, 1991) and that 11.beta.-HSD-1 is
expressed in mammalian brain, and published data indicates that
glucocorticoids may cause neuronal degeneration and dysfunction (de
Quervain et al., Hum Mol Genet. 13: 47-52, 2004; Belanoff et al.,
J. Psychiatr Res., 35:127-35, 2001). Several studies have
demonstrated 11.beta.-HSD activity, immunoreactivity and mRNA
expression in hippocampal neurons (M-P Moisan, et al., Endocrinol
127, 1450-1455, 1990; V. Lakshmi, et al., Endocrinol., 128,
1741-1748, 1991; R R Sakai, et al., J Neuroendocrinol., 4, 101-106,
1992). Administration of 11 .beta.-HSD inhibitors alters functional
activity in the hippocampus in vivo (J R Seckl, et al., J
Endocrinol 136, 471-477, 1993). Evidence in rodents and humans
suggests that prolonged elevation of plasma glucocorticoid levels
impairs cognitive function that becomes more profound with aging
(A. M. Issa et al., J. Neurosci., 10: 3247-3254, 1990, S. J.
Lupien, et. al., Nat. Neurosci., 1:69-73 1998, J. L. Yau et al.,
Neuroscience, 66: 571-581, 1995). Chronic excessive cortisol levels
in the brain may result in neuronal loss and neuronal dysfunction.
(See, D. S. Kerr et al., Psychobiology 22:123-133, 1994, C.
Woolley, Brain Res. 531: 225-231, 1990, P. W. Landfield, Science,
272:1249-1251, 1996). Furthermore, glucocorticoid-induced acute
psychosis exemplifies a more pharmacological induction of this
response, and is of major concern to physicians when treating
patients with these steroidal agents (Wolkowitz et al., Ann NY Acad
Sci. 1032:191-4, 2004). Thekkapat et al have recently shown that
11.beta.-HSD-1 mRNA is expressed in human hippocampus, frontal
cortex and cerebellum, and that treatment of elderly diabetic
individuals with the non-selective 11.beta.-HSD-1 and
11.beta.-HSD-2 inhibitor carbenoxolone improved verbal fluency and
memory (Proc Natl Acad Sci USA. 101: 6743-9, 2004). In addition,
Walker et al have examined 11.beta.-HSD activity and its function
in primary cultures of fetal hippocampus cells (U.S. Pat. No.
7,122,531; U.S. Pat. No. 7,087,400; Rajan V, et al., J Neurosci.,
16, 65-70 (1996)), the contents of which are incorporated herein by
reference.
[0710] Therefore, the CNS diseases, disorders and conditions can be
treated, controlled, prevented or delayed, by treatment with the
compounds of this invention. Administration of a therapeutic dose
of an 11.beta.-HSD-1 inhibitor may reduce, ameliorate, control
and/or prevent disorders such as the cognitive impairment
associated with aging, neuronal dysfunction, dementia,
steroid-induced acute psychosis, decline in cognitive function in
Alzheimer's and associated dementias, cognitive deficits associated
with aging and neurodegeneration, dementia, senile dementia, AIDS
dementia, depression, major depressive disorder, psychotic
depression, treatment resistant depression, anxiety, panic
disorder, post traumatic stress disorder, depression in Cushing's
syndrome, steroid-induced acute psychosis, cognitive deficits
associated with diabetes, attention deficit disorder in general,
attention deficit hyperactivity disorder (ADHD), mild cognitive
impairment, and schizophrenia.
[0711] HSD-1 related disorders include, but are not limited to,
non-insulin dependent type 2 diabetes, insulin resistance, obesity,
lipid disorders, metabolic syndrome, hyperglycemia, low glucose
tolerance, hyperlipidemia, hypertriglyceridemia,
hypercholesterolemia, low HDL levels, high LDL levels,
atherosclerosis and its sequelae, vascular restensosis,
pancreatitis, abdominal obesity, retinopathy, nephropather,
neuropathy, hypertension, other disorders where insulin resistance
is a component, cognitive impairment associated with aging,
neuronal dysfunction, dementia, steroid-induced acute psychosis,
decline in cognitive function in Alzheimer's disease and associated
dementias, cognitive deficits associated with aging and
neurodegeneration, dementia, senile dementia, AIDS dementia,
anxiety, panic disorder, post traumatic stress disorder,
steroid-induced acute psychosis, cognitive deficits associated with
diabetes, attention deficit disorder in general, attention deficit
hyperactivity disorder (ADHD), mild cognitive impairment,
schizophrenia, and depression including major depressive disorder,
psychotic depression, depression in Cushing's syndrome, and
treatment resistant depression.
[0712] Accordingly, an embodiment is a method of inhibiting
11-beta-hydroxysteroid dehydrogenase Type I enzyme, comprising
administering to a mammal, a therapeutically effective amount of a
compound of formula (I). Another embodiment is treating or
prophylactically treating the above disorders in a mammal. The
disorders may be mediated by excessive glucocorticoid action in a
mammal.
Therapeutic Compositions-Administration-Dose Ranges
[0713] Therapeutic compositions of the present compounds comprise
an effective amount of the same formulated with one or more
therapeutically suitable excipients. The term "therapeutically
suitable excipient," as used herein, generally refers to
pharmaceutically suitable, solid, semi-solid or liquid fillers,
diluents, encapsulating material, formulation auxiliary and the
like. Examples of therapeutically suitable excipients include, but
are not limited to, sugars, cellulose and derivatives thereof,
oils, glycols, solutions, buffers, colorants, releasing agents,
coating agents, sweetening agents, flavoring agents, perfuming
agents and the like. Such therapeutic compositions may be
administered parenterally, intracisternally, orally, rectally,
intraperitoneally or by other dosage forms known in the art.
[0714] Liquid dosage forms for oral administration include, but are
not limited to, emulsions, microemulsions, solutions, suspensions,
syrups and elixirs. Liquid dosage forms may also contain diluents,
solubilizing agents, emulsifying agents, inert diluents, wetting
agents, emulsifiers, sweeteners, flavorants, perfuming agents and
the like.
[0715] Injectable preparations include, but are not limited to,
sterile, injectable, aqueous, oleaginous solutions, suspensions,
emulsions and the like. Such preparations may also be formulated to
include, but are not limited to, parenterally suitable diluents,
dispersing agents, wetting agents, suspending agents and the like.
Such injectable preparations may be sterilized by filtration
through a bacterial-retaining filter. Such preparations may also be
formulated with sterilizing agents that dissolve or disperse in the
injectable media or other methods known in the art.
[0716] The absorption of the compounds of the present invention may
be delayed using a liquid suspension of crystalline or amorphous
material having poor water solubility. The rate of absorption of
the compounds generally depends upon the rate of dissolution and
crystallinity. Delayed absorption of a parenterally administered
compound may also be accomplished by dissolving or suspending the
compound in oil. Injectable depot dosage forms may also be prepared
by microencapsulating the same in biodegradable polymers. The rate
of drug release may also be controlled by adjusting the ratio of
compound to polymer and the nature of the polymer employed. Depot
injectable formulations may also prepared by encapsulating the
compounds in liposomes or microemulsions compatible with body
tissues.
[0717] Solid dosage forms for oral administration include, but are
not limited to, capsules, tablets, gels, pills, powders, granules
and the like. The drug compound is generally combined with at least
one therapeutically suitable excipient, such as carriers, fillers,
extenders, disintegrating agents, solution retarding agents,
wetting agents, absorbents, lubricants and the like. Capsules,
tablets and pills may also contain buffering agents. Suppositories
for rectal administration may be prepared by mixing the compounds
with a suitable non-irritating excipient that is solid at ordinary
temperature but fluid in the rectum.
[0718] The present drug compounds may also be microencapsulated
with one or more excipients. Tablets, dragees, capsules, pills and
granules may also be prepared using coatings and shells, such as
enteric and release or rate controlling polymeric and nonpolymeric
materials. For example, the compounds may be mixed with one or more
inert diluents. Tableting may further include lubricants and other
processing aids. Similarly, capsules may contain opacifying agents
that delay release of the compounds in the intestinal tract.
[0719] Transdermal patches have the added advantage of providing
controlled delivery of the present compounds to the body. Such
dosage forms are prepared by dissolving or dispensing the compounds
in suitable medium. Absorption enhancers may also be used to
increase the flux of the compounds across the skin. The rate of
absorption may be controlled by employing a rate controlling
membrane. The compounds may also be incorporated into a polymer
matrix or gel.
[0720] For a given dosage form, disorders of the present invention
may be treated, prophylatically treated, or have their onset
delayed in a patient by administering to the patient a
therapeutically effective amount of compound of the present
invention in accordance with a suitable dosing regimen. In other
words, a therapeutically effective amount of any one of compounds
of formulas (I) is administered to a patient to treat and/or
prophylatically treat disorders modulated by the
11-beta-hydroxysteroid dehydrogenase type 1 enzyme. The specific
therapeutically effective dose level for a given patient population
may depend upon a variety of factors including, but not limited to,
the specific disorder being treated, the severity of the disorder;
the activity of the compound, the specific composition or dosage
form, age, body weight, general health, sex, diet of the patient,
the time of administration, route of administration, rate of
excretion, duration of the treatment, drugs used in combination,
coincidental therapy and other factors known in the art.
[0721] The present invention also includes therapeutically suitable
metabolites formed by in vivo biotransformation of any of the
compounds of formula (I). The term "therapeutically suitable
metabolite", as used herein, generally refers to a pharmaceutically
active compound formed by the in vivo biotransformation of
compounds of formula (I). For example, pharmaceutically active
metabolites include, but arc not limited to, compounds made by
adamantane hydroxylation or polyhydroxylation of any of the
compounds of formulas (I). A discussion of biotransformation is
found in Goodman and Gilman's, The Pharmacological Basis of
Therapeutics, seventh edition, MacMillan Publishing Company, New
York, N.Y., (1985).
[0722] The total daily dose (single or multiple) of the drug
compounds of the present invention necessary to effectively inhibit
the action of 11-beta-hydroxysteroid dehydrogenase type 1 enzyme
may range from about 0.01 mg/kg/day to about 50 mg/kg/day of body
weight and more preferably about 0.1 mg/kg/day to about 25
mg/kg/day of body weight. Treatment regimens generally include
administering from about 10 mg to about 1000 mg of the compounds
per day in single or multiple doses.
[0723] It is understood that the foregoing detailed description and
accompanying examples are merely illustrative and are not to be
taken as limitations upon the scope of the invention, which is
defined solely by the appended claims and their equivalents.
Various changes and modifications to the disclosed aspects will be
apparent to those skilled in the art. Such changes and
modifications, including without limitation those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of use of the invention, may
be made without departing from the spirit and scope thereof.
* * * * *