U.S. patent application number 16/989689 was filed with the patent office on 2021-07-01 for compounds for therapeutic use.
The applicant listed for this patent is Dart NeuroScience, LLC. Invention is credited to Laurent Gomez, Mark Eben Massari.
Application Number | 20210198218 16/989689 |
Document ID | / |
Family ID | 1000005451077 |
Filed Date | 2021-07-01 |
United States Patent
Application |
20210198218 |
Kind Code |
A1 |
Gomez; Laurent ; et
al. |
July 1, 2021 |
COMPOUNDS FOR THERAPEUTIC USE
Abstract
Chemical entities of Formula (I): ##STR00001## Including
enantiomers thereof, wherein R.sup.1 has any of the values
described herein, and compositions comprising such chemical
entities; their preparation; and their use in various methods,
including the treatment of depression, pain, cognitive disorders,
neurodegenerative disorders, and other neurological and peripheral
disorders.
Inventors: |
Gomez; Laurent; (San Diego,
CA) ; Massari; Mark Eben; (Ramona, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dart NeuroScience, LLC |
Dallas |
TX |
US |
|
|
Family ID: |
1000005451077 |
Appl. No.: |
16/989689 |
Filed: |
August 10, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15972966 |
May 7, 2018 |
10738018 |
|
|
16989689 |
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15253645 |
Aug 31, 2016 |
9963435 |
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15972966 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 265/16 20130101;
C07D 413/06 20130101; C07D 413/12 20130101; C07D 413/04 20130101;
C07F 11/00 20130101 |
International
Class: |
C07D 265/16 20060101
C07D265/16; C07D 413/06 20060101 C07D413/06; C07D 413/04 20060101
C07D413/04; C07F 11/00 20060101 C07F011/00; C07D 413/12 20060101
C07D413/12 |
Claims
1. A method of treating a neurological disorder, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound, or pharmaceutically acceptable salt
thereof, of Formula (I): ##STR00085## wherein: R.sup.1 is --H; or
R.sup.1 is --C.sub.1-6alkyl, optionally substituted with one or
more members, each independently selected from the group consisting
of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or R.sup.1 is
--C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each optionally
substituted with one or more members, each independently selected
from the group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and amino; or R.sup.1 is --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and amino, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; or R.sup.1 is --COR.sup.2,
--CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, or --C(OH)R.sup.11R.sup.12, wherein R.sup.2,
R.sup.3, R.sup.4, R.sup.7 and R.sup.8 are each independently
selected from the group consisting of: --H, --C.sub.1-8alkyl, and
--C.sub.1-8haloalkyl; R.sup.5 and R.sup.6 are each independently
selected from the group consisting of: --H, -halo, --NH.sub.2,
--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nCONR.sup.1AR.sup.1B,
--(CH.sub.2).sub.nNHC(.dbd.O)R.sup.1A,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; each R.sup.1A is independently selected from the group
consisting of: --H--C.sub.1-8alkyl, --(CH.sub.2).sub.nCONH.sub.2,
and --(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently
an integer selected from 0, 1, 2, 3, and 4; each R.sup.1B is
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --(CH.sub.2).sub.nCONH.sub.2, wherein n is
independently an integer selected from 0, 1, 2, 3, and 4; each
R.sup.1C is independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; R.sup.9 and R.sup.10 are
each independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl, said alkyl optionally
substituted with up to 3 members, each independently selected from
the group consisting of: -amino, -hydroxy and -carboxyl; or
optionally R.sup.9 and R.sup.10 taken together with the carbon to
which they are attached form an optionally substituted five
membered heteroaryl or heterocycloalkyl ring; and R.sup.11 and
R.sup.12 are independently selected from the group consisting of:
--H, --C.sub.1-6alkyl, and --C.sub.1-6haloalkyl, said
--C.sub.1-6alkyl, and --C.sub.1-6haloalkyl optionally substituted
with up to 3 members, each independently selected from the group
consisting of: -hydroxy and amino; wherein the neurological
disorder is selected from the group consisting of a depressive
disorder, a bipolar disorder, an anxiety disorder, a pain disorder,
a cognitive disorder, and a neurodegenerative disorder.
2. The method of claim 1, wherein: R.sup.1 is --H; or R.sup.1 is
--C.sub.1-6alkyl, optionally substituted with one or more members,
each independently selected from the group consisting of: -halo,
-hydroxy, -alkoxy, -amino and -carboxyl; or R.sup.1 is
--C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each optionally
substituted with one or more members, each independently selected
from the group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and amino; or R.sup.1 is
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; or R.sup.1 is
--CR.sup.5R.sup.6NR.sup.7R.sup.8, --CHR.sup.9R.sup.10, or
--C(OH)R.sup.11R.sup.12, wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; R.sup.5 and R.sup.6 are
each independently selected from the group consisting of: --H,
-halo, --NH.sub.2, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; each R.sup.1A is independently selected from the group
consisting of: --H--C.sub.1-8alkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; each R.sup.1B is
independently selected from the group consisting of: --H and
--C.sub.1-8alkyl, wherein n is independently an integer selected
from 0, 1, 2, 3, and 4; each R.sup.1C is independently selected
from the group consisting of: --H, --C.sub.1-8alkyl,
--C.sub.1-8haloalkyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; R.sup.9 and R.sup.10 are
each independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl, said alkyl optionally
substituted with up to 3 members, each independently selected from
the group consisting of -amino, -hydroxy, and -carboxyl; or
optionally R.sup.9 and R.sup.10 taken together with the carbon to
which they are attached can form an optionally substituted five
membered heteroaryl or heterocycloalkyl ring; and R.sup.11 and
R.sup.12 are each independently selected from the group consisting
of: --H, --C.sub.1-6alkyl, and --C.sub.1-6haloalkyl, said
--C.sub.1-6alkyl, and --C.sub.1-6haloalkyl optionally substituted
with up to 3 members, each independently selected from the group
consisting of: -hydroxy and -amino.
3. The method of claim 1, wherein: R.sup.1 is
--CR.sup.5R.sup.6NR.sup.7R.sup.8 or --CR.sup.9R.sup.10, wherein
R.sup.5 and R.sup.6 are independently selected from the group
consisting of: --H, --F, --Cl, --Br, --NH.sub.2, -methyl, -ethyl,
-n-propyl, -isopropyl, -butyl, -pentyl, --NH.sub.2,
--C.sub.1-8haloalkyl, --(CH.sub.2).sub.nCONH.sub.2,
--(CH.sub.2).sub.nCOOH, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nbenzyl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2)indole, --(CH.sub.2)imidazole,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.nheterocycloalkyl,
--(CH.sub.2).sub.npyrrolidine, --(CH.sub.2)furan, and
--(CH.sub.2).sub.nthiophene, optionally substituted with up to 3
members, each independently selected from the group consisting of:
-guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy,
-2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; each R.sup.1A is independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; each R.sup.1B is
independently selected from the group consisting of: --H and
--C.sub.1-8alkyl, wherein n is independently an integer selected
from 0, 1, 2, 3, and 4; each R.sup.1C is independently selected
from the group consisting of: --H--C.sub.1-8alkyl,
--C.sub.1-8haloalkyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; R.sup.7 and R.sup.8 are H;
and R.sup.9 and R.sup.10 are independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; or
optionally R.sup.9 and R.sup.10 taken together with the carbon to
which they are attached can form an optionally substituted five
membered heteroaryl or heterocycloalkyl ring.
4. The method of claim 1, wherein the neurological disorder is a
depressive disorder.
5. The method of claim 4, wherein the depressive disorder is a
major depressive episode associated with a bipolar disorder, a
major depressive disorder, treatment-refractory depression, or
treatment-resistant depression.
6. The method of claim 4, wherein the depressive disorder is
treatment-refractory depression or treatment-resistant
depression.
7. The method of claim 4, wherein a symptom of the depressive
disorder is suicide ideation.
8. The method of claim 4, wherein the therapeutically effective
amount is an amount sufficient to achieve remission on a depression
symptoms rating scale.
9. A method of treating a neurological disorder, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound selected from the group consisting
of:
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
(1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1-
]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
(1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-ox-
a-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-9-one;
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid;
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid;
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide;
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide;
(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine;
(1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-
-yl)-2-hydroxypropanoic acid;
2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3--
yl)methyl)-2-hydroxysuccinic acid;
5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic acid;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid;
(1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
(1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azab-
icyclo[3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
(1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one;
(1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one;
(1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one;
(1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one;
(1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo-
[3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide;
(1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one;
1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea;
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea;
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine;
1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine;
(1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one;
(1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-
-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-o-
xa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicycl-
o[3.3.1]non-3-en-9-one;
(1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one;
(1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one;
N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;
(1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
(1S,5S)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1-
]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
(1S,5S)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-ox-
a-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-9-one;
(S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid;
(S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid;
(S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide;
(S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide;
(1S,5S)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
(1S,5S)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
1-((S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine;
(1S,5S)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e;
3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-
-yl)-2-hydroxypropanoic acid;
2-(((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3--
yl)methyl)-2-hydroxysuccinic acid;
5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic acid;
3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid;
3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid;
(1S,5S)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
(1S,5S)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azab-
icyclo[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
(1S,5S)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one;
(1S,5S)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one;
(1S,5S)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one;
(1S,5S)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one;
(1S,5S)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo-
[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide;
(1S,5S)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one;
1-(4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea;
1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea;
1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine;
1-(2-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine;
(1S,5S)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one;
(1S,5S)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-
-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-o-
xa-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicycl-
o[3.3.1]non-3-en-9-one;
(1S,5S)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one;
(1S,5S)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one;
N-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;
(1S,5S)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one;
(1S,5S)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one; and pharmaceutically acceptable
salts thereof; wherein the neurological disorder is selected from
the group consisting of a depressive disorder, a bipolar disorder,
an anxiety disorder, a pain disorder, a cognitive disorder, and a
neurodegenerative disorder.
10. The method of claim 9, wherein the compound is selected from
the group consisting of:
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid;
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid;
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide;
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide;
(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one;
1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2-hydroxypropanoic acid;
2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3--
yl)methyl)-2-hydroxysuccinic acid;
5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic acid;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid;
4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide;
1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea;
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea;
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine;
1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine;
N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;
and pharmaceutically acceptable salts thereof.
11. The method of claim 9, wherein the compound is selected from
the group consisting of:
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid;
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid;
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide;
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide;
(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2-hydroxypropanoic acid;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid;
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid; and pharmaceutically acceptable salts
thereof.
12. The method of claim 9, wherein the neurological disorder is a
depressive disorder.
13. The method of claim 12, wherein the depressive disorder is a
major depressive episode associated with a bipolar disorder, a
major depressive disorder, treatment-refractory depression, or
treatment-resistant depression.
14. The method of claim 12, wherein the depressive disorder is
treatment-refractory depression or treatment-resistant
depression.
15. The method of claim 12, wherein a symptom of the depressive
disorder is suicide ideation.
16. The method of claim 12, wherein the therapeutically effective
amount is an amount sufficient to achieve remission on a depression
symptoms rating scale.
17. A method of treating a depressive disorder, comprising
administering to a patient in need thereof a therapeutically
effective amount of a compound, or pharmaceutically acceptable salt
thereof, of Formula (I): ##STR00086## wherein: R.sup.1 is --H; or
R.sup.1 is --C.sub.1-6alkyl, optionally substituted with one or
more members, each independently selected from the group consisting
of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or R.sup.1 is
--C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each optionally
substituted with one or more members, each independently selected
from the group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and amino; or R.sup.1 is --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; or R.sup.1 is --COR.sup.2,
--CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, or --C(OH)R.sup.11R.sup.12, wherein R.sup.2,
R.sup.3, R.sup.4, R.sup.7 and R.sup.8 are each independently
selected from the group consisting of: --H, --C.sub.1-8alkyl, and
--C.sub.1-8haloalkyl; R.sup.5 and R.sup.6 are each independently
selected from the group consisting of: --H, -halo, --NH.sub.2,
--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nCONR.sup.1AR.sup.1B,
--(CH.sub.2).sub.nNHC(.dbd.O)R.sup.1A,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; each R.sup.1A is independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, --(CH.sub.2).sub.nCONH.sub.2,
and --(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently
an integer selected from 0, 1, 2, 3, and 4; each R.sup.1B is
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --(CH.sub.2).sub.nCONH.sub.2, wherein n is
independently an integer selected from 0, 1, 2, 3, and 4; each
R.sup.1C is independently selected from the group consisting of:
--H, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; R.sup.9 and R.sup.10 are
each independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl, said alkyl optionally
substituted with up to 3 members, each independently selected from
the group consisting of: -amino, -hydroxy and -carboxyl; or
optionally R.sup.9 and R.sup.10 taken together with the carbon to
which they are attached form an optionally substituted five
membered heteroaryl or heterocycloalkyl ring; and R.sup.11 and
R.sup.12 are independently selected from the group consisting of:
--H, --C.sub.1-6alkyl, and --C.sub.1-6haloalkyl, said
--C.sub.1-6alkyl, and --C.sub.1-6haloalkyl optionally substituted
with up to 3 members, each independently selected from the group
consisting of: -hydroxy and amino; or pharmaceutically acceptable
salt thereof.
18. The method of claim 17, wherein: R.sup.1 is --H; or R.sup.1 is
--C.sub.1-6alkyl, optionally substituted with one or more members,
each independently selected from the group consisting of: -halo,
-hydroxy, -alkoxy, -amino and -carboxyl; or R.sup.1 is
--C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each optionally
substituted with one or more members, each independently selected
from the group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and amino; or R.sup.1 is
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; or R.sup.1 is
--CR.sup.5R.sup.6NR.sup.7R.sup.8, --CHR.sup.9R.sup.10, or
--C(OH)R.sup.11R.sup.12, wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; R.sup.5 and R.sup.6 are
each independently selected from the group consisting of: --H,
-halo, --NH.sub.2, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; each R.sup.1A is independently selected from the group
consisting of: --H--C.sub.1-8alkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; each R.sup.1B is
independently selected from the group consisting of: --H and
--C.sub.1-8alkyl, wherein n is independently an integer selected
from 0, 1, 2, 3, and 4; each R.sup.1C is independently selected
from the group consisting of: --H, --C.sub.1-8alkyl,
--C.sub.1-8haloalkyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; R.sup.9 and R.sup.10 are
each independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl, said alkyl optionally
substituted with up to 3 members, each independently selected from
the group consisting of -amino, -hydroxy, and -carboxyl; or
optionally R.sup.9 and R.sup.10 taken together with the carbon to
which they are attached can form an optionally substituted five
membered heteroaryl or heterocycloalkyl ring; and R.sup.11 and
R.sup.12 are each independently selected from the group consisting
of: --H, --C.sub.1-6alkyl, and --C.sub.1-6haloalkyl, said
--C.sub.1-6alkyl, and --C.sub.1-6haloalkyl optionally substituted
with up to 3 members, each independently selected from the group
consisting of: -hydroxy and -amino.
19. The method of claim 17, wherein: R.sup.1 is
--CR.sup.5R.sup.6NR.sup.7R.sup.8 or --CR.sup.9R.sup.10, wherein
R.sup.5 and R.sup.6 are independently selected from the group
consisting of: --H, --F, --Cl, --Br, --NH.sub.2, -methyl, -ethyl,
-n-propyl, -isopropyl, -butyl, -pentyl, --NH.sub.2,
--C.sub.1-8haloalkyl, --(CH.sub.2).sub.nCONH.sub.2,
--(CH.sub.2).sub.nCOOH, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nbenzyl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2)indole, --(CH.sub.2)imidazole,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.nheterocycloalkyl,
--(CH.sub.2).sub.npyrrolidine, --(CH.sub.2)furan, and
--(CH.sub.2).sub.nthiophene, optionally substituted with up to 3
members, each independently selected from the group consisting of:
-guanidyl, -urea, -halo, -alkyl, -hydroxy, -amino, -alkoxy,
-2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; each R.sup.1A is independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; each R.sup.1B is
independently selected from the group consisting of: --H and
--C.sub.1-8alkyl, wherein n is independently an integer selected
from 0, 1, 2, 3, and 4; each R.sup.1C is independently selected
from the group consisting of: --H--C.sub.1-8alkyl,
--C.sub.1-8haloalkyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; R.sup.7 and R.sup.8 are H;
and R.sup.9 and R.sup.10 are independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; or
optionally R.sup.9 and R.sup.10 taken together with the carbon to
which they are attached can form an optionally substituted five
membered heteroaryl or heterocycloalkyl ring.
20. The method of claim 17, wherein the depressive disorder is a
major depressive episode associated with a bipolar disorder, a
major depressive disorder, treatment-refractory depression, or
treatment-resistant depression.
Description
RELATED APPLICATIONS
[0001] Any and all priority claims identified in the Application
Data Sheet, or any correction thereto, are hereby incorporated by
reference under 37 CFR 1.57. For example, this application is a
continuation of U.S. patent application Ser. No. 15/253,645, filed
Aug. 31, 2016, the disclosure of which is incorporated herein by
reference in its entirety.
FIELD OF THE DISCLOSURE
[0002] This disclosure relates to chemical entities, including
compounds, as described herein; compositions containing them;
methods of making them; and their use in various methods, including
the treatment of depression, pain, dementia, and other neurological
and peripheral disorders.
BACKGROUND
[0003] Discovered more than 50 years ago, ketamine is an anesthetic
that is thought to act primarily by antagonizing the glutamatergic
NMDAR (N-methyl-D-aspartate receptor). It is typically administered
intramuscularly or intravenously for starting and maintaining
general anesthesia in humans and other animals, and has also been
used for anti-anxiety, sedation, and analgesic purposes. See, e.g.,
Costi et al., Curr. Behav. Neurosci. Rep. 2015, 4. 216-225; Oddo et
al., Criy. Care 2016, 20, 128-138. In addition, ketamine has shown
potent efficacy in treating depression and pain when administered
at sub-anesthetic doses; even single infusions of such doses appear
to show rapid action in treating bipolar depression and
treatment-resistant major depression. Iadarola et al., Ther. Adv.
Chronic Dis. 2015, 6, 97-114; Zarate et al., Arch. Gen. Psychiatry
2006, 63, 856-864; Lally et al. Transl. Psychiatry 2014, 4, e469;
Murrough et al., Am. J. Psychiatry 2013, 170, 1134-1142.
[0004] Clinical use of ketamine is limited, however, by its poor
oral bioavailability, abuse liability, and undesirable
psychological reactions, such as dissociative effects and
hallucinations observed at even low doses. See, e.g., Strayer and
Nelson, Am. J. Emerg. Med. 2008, 26, 985-1028; Morgan and Curran,
Addiction 2010, 107, 27-38. In addition, ketamine action is
complicated by multiple metabolites arising after its
administration, many of which do not have anesthetic properties.
See, e.g., Leung et al., J. Med. Chem. 1986, 29, 2396-2399.
[0005] Recent studies have shown that a ketamine metabolite,
(2R,6R)-hydroxynorketamine, has antidepressant activity in mice.
Zanos et al., Nature 2016, 533, 481-486. In addition,
hydroxynorketamine (HNK) metabolites have been implicated in the
analgesic efficacy of ketamine in treating pain. Moaddel et al.,
Talanta 2010, 15, 1892-1904. In contrast to ketamine, HNK is not
known to inhibit NMDAR, but is thought to modulate a different
glutamate receptor, the AMPA
(.alpha.-amino-3-hydroxy-5-methyl-isoxazole propionic acid)
receptor. Furthermore, the action of HNK does not appear to be
associated with undesired effects that can result from ketamine
therapy, such as abuse liability and anesthetic effects.
[0006] These observations highlight the need for alternative
ketamine therapeutics useful in treating depression, pain, and
other CNS disorders. The present disclosure meets these and other
needs in the art by disclosing chemical entities, including
compounds, which can act through HNK-mediated pathways.
SUMMARY
[0007] Disclosed are chemical entities of Formula (I):
##STR00002##
including the various stereoisomers and enantiomers, wherein
R.sup.1 is as described herein. Also disclosed are compositions
comprising the compounds of Formula (I); methods of making the
compounds and compositions; and their use in a wide range of
methods that include treating pain, depression, and other
neurological disorders, as well as enhancing cognitive
function.
DETAILED DESCRIPTION
[0008] The embodiments may be more fully appreciated by reference
to the following description, including the examples. Unless
otherwise defined, all technical and scientific terms used herein
have the same meaning as commonly understood by one of ordinary
skill in the art. Although methods and materials similar or
equivalent to those described herein can be used in the practice or
testing of the present embodiments, suitable methods and materials
are described herein. In addition, the materials, methods, and
examples are illustrative only and not intended to be limiting.
[0009] For the sake of brevity, all publications, including patent
applications, patents, and other citations mentioned herein, are
incorporated by reference in their entirety. Citation of any such
publication, however, shall not be construed as an admission that
it is prior art.
Abbreviations
[0010] The specification includes numerous abbreviations, whose
meanings are listed in the following Table:
TABLE-US-00001 Abbreviation Definition AcCl Acetyl Chloride ACN
Acetonitrile BSTFA N,O-Bis(trimethylsilyl)trifluoroacetamide CELITE
.RTM. Diatomaceous earth DBN 1,5-Diazabicyclo[4.3.0]non-5-ene DBU
1,8-diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane DIPEA, DIEA
N,N-ethyl-diisopropylamine or N,N-Diisopropyl- ethyl amine DMA
N,N-Dimethylacetamide DMF N,N-Dimethylformamide DMSO
Dimethylsulfoxide EtOAc, or EA Ethyl acetate EtOH Ethanol Et.sub.2O
Diethyl ether HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-
triazolo[4,5-b] HBr Hydrobromic acid HCl Hydrochloric acid HPLC
High-performance liquid chromatography LCMS, LC/MS Liquid
chromatography-mass spectrometry LiHMDS, LHMDS Lithium
bis(trimethylsilyl)amide LDA Lithium diisopropylamide mCPBA
meta-Chloroperoxybenzoic acid MeOH Methanol TMSCl or Me.sub.3SiCl
Trimethylsilyl chloride TMSI or Me.sub.3SiI Trimethylsilyl iodide
MgSO.sub.4 Magnesium sulfate Na.sub.2CO.sub.3 Sodium carbonate
NaHCO.sub.3 Sodium bicarbonate NaOH Sodium hydroxide
Na.sub.2SO.sub.3 Sodium sulfite Na.sub.2SO.sub.4 Sodium sulfate NIS
N-Iodosuccinimide i-PrOH Isopropanol i-Pr.sub.2O Diisopropyl ether
SiO.sub.2 Silica TEA, Et.sub.3N Triethylamine TFA Trifluoroacetic
acid THF Tetrahydrofuran
Terms and Definitions
[0011] The use of headings and subheadings provided in the sections
of this specification is solely for convenience of reference and
does not limit the various embodiments herein, which are to be
construed by reference to the specification as a whole.
General
[0012] As used herein, the term "about" or "approximately" means
within an acceptable range for a particular value as determined by
one skilled in the art, and may depend in part on how the value is
measured or determined, e.g., the limitations of the measurement
system or technique. For example, "about" can mean a range of up to
20%, up to 10%, up to 5%, or up to 1% or less on either side of a
given value. Alternatively, with respect to biological systems or
processes, the term "about" can mean within an order of magnitude,
within 5-fold, or within 2-fold on either side of a value.
Numerical quantities given herein are approximate unless stated
otherwise, meaning that the term "about" or "approximately" can be
interred when not expressly stated.
[0013] To provide a more concise description, some of the
quantitative expressions given herein are not qualified with the
term "about". It is understood that, whether the term "about" is
used explicitly or not, every quantity given herein is meant to
refer to the actual given value, and it is also meant to refer to
the approximation of such given value that would reasonably be
inferred based on the ordinary skill in the art, including
equivalents and approximations due to the experimental or
measurement conditions for such given value. Whenever a yield is
given as a percentage, such yield refers to a mass of the entity
for which the yield is given with respect to the maximum amount of
the same entity for which that could be obtained under the
particular stoichiometric conditions. Concentrations that are given
as percentages refer to mass ratios, unless indicated
differently.
[0014] As used herein, the terms "a," "an," and "the" are to be
understood as meaning both singular and plural, unless explicitly
stated otherwise. Thus, "a," "an," and "the" (and grammatical
variations thereof where appropriate) refer to one or more.
[0015] Furthermore, although items, elements or components of the
embodiments may be described or claimed in the singular, the plural
is contemplated to be within the scope thereof, unless limitation
to the singular is explicitly stated.
[0016] The terms "comprising" and "including" are used herein in
their open, non-limiting sense. Other terms and phrases used in
this document, and variations thereof, unless otherwise expressly
stated, should be construed as open ended, as opposed to limiting.
Thus, the term "example" is used to provide exemplary instances of
the item in discussion, not an exhaustive or limiting list thereof.
Similarly, adjectives such as "conventional," "traditional,"
"normal," "criterion," "known," and terms of similar meaning should
not be construed as limiting the item described to a given time
period or to an item available as of a given time, but instead
should be read to encompass conventional, traditional, normal, or
criterion technologies that may be available or known now or at any
time in the future. Likewise, where this document refers to
technologies that would be apparent or known to one of ordinary
skill in the art, such technologies encompass those apparent or
known to the skilled artisan now or at any time in the future.
[0017] The presence of broadening words and phrases such as "one or
more," "at least," "but not limited to," or other like phrases in
some instances should not be read to mean that the narrower case is
intended or required in instances where such broadening phrases may
be absent. As will become apparent to one of ordinary skill in the
art after reading this document, the illustrated embodiments and
their various alternatives may be implemented without confinement
to the illustrated examples.
Chemistry
[0018] The term "substituted," as used herein, means that at least
one hydrogen on the designated atom or group is replaced with a
selection from the indicated group, provided that the designated
atom's normal valence is not exceeded. When a substituent is keto
(i.e., .dbd.O), then 2 hydrogen atoms on the atom are replaced.
[0019] A dash ("-") that is not between two letters or symbols is
used to indicate a point of covalent attachment for a substituent.
For example, --(CH.sub.2)C.sub.3-C.sub.7cycloalkyl is attached
through carbon of the methylene (CH.sub.2) group.
[0020] The term "alkyl" refers to a fully saturated aliphatic
hydrocarbon group. The alkyl moiety may be a straight- or
branched-chain alkyl group having from 1 to 12 carbon atoms in the
chain. Examples of alkyl groups include, but are not limited to,
methyl (Me, which also may be structurally depicted by the symbol,
""), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl,
and groups that in light of the ordinary skill in the art and the
teachings provided herein would be considered equivalent to any one
of the foregoing examples. Alkyl groups may be optionally
substituted with one or more substituents including, but not
limited to, halo, hydroxyl, alkoxy, thioalkoxy, amino, and
aminoalkyl.
[0021] The term "alkenyl" refers to optionally substituted
unsaturated aliphatic moieties having at least one carbon-carbon
double bond and including E and Z isomers of said alkenyl moiety.
Examples of alkenyl radicals include ethenyl, propenyl, butenyl,
1,4-butadienyl, cyclopentenyl, cyclohexenyl and the like.
[0022] The term "alkynyl" refers to optionally substituted
unsaturated aliphatic moieties having at least one carbon-carbon
triple bond and includes straight and branched chain alkynyl
groups. Examples of alkynyl radicals include ethynyl, propynyl,
butynyl and the like.
[0023] The term "haloalkyl" refers to a straight- or branched-chain
alkyl group having from 1 to 12 carbon atoms in the chain,
substituting one or more hydrogens with halogens. Examples of
haloalkyl groups include, but are not limited to, --CF.sub.2,
--CHF.sub.2, --CH.sub.2F, --CH.sub.2CF.sub.3, --CH.sub.2CHF.sub.2,
--CH.sub.2CH.sub.2F, --CH.sub.2CH.sub.2Cl,
--CH.sub.2CF.sub.2CF.sub.3 and other groups that in light of the
ordinary skill in the art and the teachings provided herein, would
be considered equivalent to any one of the foregoing examples.
[0024] The term "alkoxy" includes a straight chain or branched
alkyl group with an oxygen atom linking the alkyl group to the rest
of the molecule. Alkoxy includes methoxy, ethoxy, propoxy,
isopropoxy, butoxy, t-butoxy, pentoxy and so on. "Aminoalkyl,"
"thioalkyl," and "sulfonylalkyl" are analogous to alkoxy, replacing
the terminal oxygen atom of alkoxy with, respectively, NH (or NR),
S (sulfur), and SO.sub.2.
[0025] The term "haloalkoxy" refer to alkoxy groups substituting
one or more hydrogens with halogens. Examples of haloalkoxy groups
include, but are not limited to, --OCF3, --OCH2CF3, --OCH2CHF2,
--OCH2CH2Cl, --OCH2CF2CF3, --OCH(CH3)CHF2 and other groups that in
light of the ordinary skill in the art and the teachings provided
herein, would be considered equivalent to any one of the foregoing
examples.
[0026] The term "amino" refers to the --NH2 group.
[0027] The term "heteroatom" used herein refers to, for example, O
(oxygen), S (sulfur), N (nitrogen), and Selenium (Se).
[0028] The term "aryl" refers to a monocyclic, or fused or spiro
polycyclic, aromatic carbocycle (ring structure having ring atoms
that are all carbon), having from 3 to 12 ring atoms per ring
(carbon atoms in aryl groups are sp2 hybridized). Illustrative
examples of aryl groups include the following moieties:
##STR00003##
and the like.
[0029] The term "cycloalkyl" refers to a saturated or partially
saturated carbocycle, such as monocyclic, fused polycyclic, bridged
monocyclic, bridged polycyclic, spirocyclic, or spiro polycyclic
carbocycle having from 3 to 12 ring atoms per carbocycle. Where the
term cycloalkyl is qualified by a specific characterization, such
as monocyclic, fused polycyclic, bridged polycyclic, spirocyclic,
and spiro polycyclic, then such term cycloalkyl refers only to the
carbocycle so characterized. Illustrative examples of cycloalkyl
groups include the following entities, in the form of properly
bonded moieties:
##STR00004##
[0030] "Heterocycloalkyl" means a saturated cyclic group containing
from 1 to about 3 heteroatoms chosen from N, O, S, and Se with
remaining ring atoms being carbon. Heterocycloalkyl groups have
from 3 to about 8 ring atoms, and more typically have from 5 to 7
ring atoms. Examples of heterocycloalkyl groups include
morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups. A
nitrogen in a heterocycloalkyl group may optionally be quaternized.
A "heterocycloalkyl" refers to a monocyclic, or fused, bridged, or
spiro polycyclic ring structure that is saturated or partially
saturated and has from 3 to 12 ring atoms per ring structure
selected from carbon atoms and up to three heteroatoms selected
from nitrogen, oxygen, selenium, and sulfur. The ring structure may
optionally contain up to two oxo groups on carbon or sulfur ring
members. Illustrative (but not limiting) entities, in the form of
properly bonded moieties, include:
##STR00005##
[0031] The term "heteroaryl" refers to a monocyclic, fused
bicyclic, or fused polycyclic aromatic heterocycle (ring structure
having ring atoms selected from carbon atoms and up to four
heteroatoms selected from nitrogen, oxygen, and sulfur) having from
3 to 12 ring atoms per heterocycle. Illustrative examples of
heteroaryl groups include the following entities, in the form of
properly bonded moieties:
##STR00006##
[0032] Those skilled in the art will recognize that the species of
cycloalkyl, aryl, heterocycloalkyl, and heteroaryl groups listed or
illustrated above are not exhaustive, and that additional species
within the scope of these defined terms may also be selected.
[0033] The term "halogen" represents chlorine, fluorine, bromine or
iodine; and the term "halo" represents chloro, fluoro, bromo or
iodo.
[0034] The terms "optional" and "optionally" refer to the
subsequently described event or circumstance and mean that it may
or may not occur, and that the description includes instances where
the event or circumstance occurs and instances or circumstances
where it does not. For example, "optionally substituted alkyl"
encompasses both "unsubstituted alkyl" and "substituted alkyl" as
defined below. It will be understood by those skilled in the art,
with respect to any group containing one or more substituents, that
such groups are not intended to introduce any substitution or
substitution patterns that are sterically impractical,
synthetically non-feasible and/or inherently unstable.
Formulas
[0035] Certain compounds are described herein using a general
formula that includes variables, e.g. R.sup.1-R.sup.12.
[0036] Any formula disclosed herein is intended to represent
compounds having structures depicted by the structural formula as
well as certain variations or forms. In particular, compounds of
any formula given herein may have asymmetric centers and therefore
exist in different enantiomeric forms. All optical isomers and
stereoisomers of the compounds of the general formula, and mixtures
thereof, are considered within the scope of the formula. Thus, any
formula given herein is intended to represent a racemate, one or
more enantiomeric forms, one or more diastereomeric forms, one or
more atropisomeric forms, and mixtures thereof. Furthermore,
certain structures may exist as geometric isomers (i.e., cis and
trans isomers), as tautomers, or as atropisomers. The symbols are
used as meaning the same spatial arrangement in chemical structures
shown herein. Analogously, the symbols are used as meaning the same
spatial arrangement in chemical structures shown herein.
[0037] The term "chiral" refers to molecules, which have the
property of non-superimposability of the mirror image partner.
[0038] "Stereoisomers" are compounds, which have identical chemical
constitution, but differ with regard to the arrangement of the
atoms or groups in space.
[0039] A "diastereomer" is a stereoisomer with two or more centers
of chirality and whose molecules are not mirror images of one
another. Diastereomers have different physical properties, e.g.,
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis,
crystallization in the presence of a resolving agent, or
chromatography, using, for example a chiral HPLC column.
[0040] "Enantiomers" refer to two stereoisomers of a compound,
which are non-superimposable mirror images of one another. A 50:50
mixture of enantiomers is referred to as a racemic mixture or a
racemate, which may occur where there has been no stereoselection
or stereospecificity in a chemical reaction or process.
[0041] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and l or (+) and (-) are employed
to designate the sign of rotation of plane-polarized light by the
compound, with (-) or l meaning that the compound is levorotatory.
A compound prefixed with (+) or d is dextrorotatory.
[0042] A "racemic mixture" or "racemate" is an equimolar (or 50:50)
mixture of two enantiomeric species, devoid of optical activity. A
racemic mixture may occur where there has been no stereoselection
or stereospecificity in a chemical reaction or process.
Chemical Entities
[0043] As used herein, the term "chemical entity" collectively
refers to a compound, along with its salts, chelates, solvates,
conformers, non-covalent complexes, metabolites, and prodrugs.
[0044] Compounds disclosed herein are described using standard
nomenclature. Unless defined otherwise, all technical and
scientific terms used herein have the same meaning as is commonly
understood by one of skill in the art to which this disclosure
belongs.
[0045] As used herein, a "compound" refers to any one of: (a) the
actually recited form of such compound; and (b) any of the forms of
such compound in the medium in which the compound is being
considered when named. For example, reference herein to a compound
such as R--COOH, encompasses reference to any one of, for example,
R--COOH(s), R--COOH(sol), and R--COO-(sol). In this example,
R--COOH(s) refers to the solid compound, as it could be for example
in a tablet or some other solid pharmaceutical composition or
preparation; R--COOH(sol) refers to the un-dissociated form of the
compound in a solvent; and R--COO-(sol) refers to the dissociated
form of the compound in a solvent, such as the dissociated form of
the compound in an aqueous environment, whether such dissociated
form derives from R--COOH, from a salt thereof, or from any other
entity that yields R--COO-- upon dissociation in the medium being
considered.
[0046] In another example, an expression such as "exposing an
entity to a compound of formula R--COOH" refers to the exposure of
such entity to the form, or forms, of the compound R--COOH that
exists, or exist, in the medium in which such exposure takes place.
In still another example, an expression such as "reacting an entity
with a compound of formula R--COOH" refers to the reacting of (a)
such entity in the chemically relevant form, or forms, of such
entity that exists, or exist, in the medium in which such reacting
takes place, with (b) the chemically relevant form, or forms, of
the compound R--COOH that exists, or exist, in the medium in which
such reacting takes place. In this regard, if such entity is for
example in an aqueous environment, it is understood that the
compound R--COOH is in such same medium, and therefore the entity
is being exposed to species such as R--COOH(aq) and/or R--COO-(aq);
where the subscript "(aq)" stands for "aqueous" according to its
conventional meaning in chemistry and biochemistry. A carboxylic
acid functional group has been chosen in these nomenclature
examples; this choice is not intended, however, as a limitation but
it is merely an illustration. It is understood that analogous
examples can be provided in terms of other functional groups,
including but not limited to hydroxyl, basic nitrogen members, such
as those in amines, and any other group that interacts or
transforms according to known manners in the medium that contains
the compound. Such interactions and transformations include, but
are not limited to, dissociation, association, tautomerism,
solvolysis, including hydrolysis, solvation, including hydration,
protonation and deprotonation. No further examples in this regard
are provided herein because these interactions and transformations
in a given medium are known by any one of ordinary skill in the
art.
[0047] In another example, a "zwitterionic" compound is encompassed
herein by referring to a compound that is known to form a
zwitterion, even if it is not explicitly named in its zwitterionic
form. Terms such as zwitterion, zwitterions, and their synonyms
zwitterionic compound(s) are standard IUPAC-endorsed names that are
well known and part of standard sets of defined scientific names.
In this regard, the name zwitterion is assigned the name
identification CHEBI:27369 by the Chemical Entities of Biological
Interest (ChEBI) dictionary of molecular entities. As is generally
well known, a zwitterion or zwitterionic compound is a neutral
compound that has formal unit charges of opposite sign. Sometimes
these compounds are referred to by the term "inner salts". Other
sources refer to these compounds as "dipolar ions", although the
latter term is regarded by still other sources as a misnomer. As a
specific example, aminoethanoic acid (the amino acid glycine) has
the formula H.sub.2NCH.sub.2COOH and it exists in some media (in
this case in neutral media) in the form of the zwitterion
+H.sub.3NCH.sub.2COO--. Zwitterions, zwitterionic compounds, inner
salts, and dipolar ions in the known and well established meanings
of these terms are within the scope of this invention, as would in
any case be so appreciated by those of ordinary skill in the art.
Because there is no need to name each and every embodiment that
would be recognized by those of ordinary skill in the art, no
structures of the zwitterionic compounds that are associated with
the compounds of this invention are given explicitly herein. They
are, however, part of the embodiments of this invention. No further
examples in this regard are provided herein because the
interactions and transformations in a given medium that lead to the
various forms of a given compound are known by any one of ordinary
skill in the art.
[0048] Isotopes may be present in the compounds described. Each
chemical element present in a compound either specifically or
generically described herein may include any isotope of said
element. Any formula given herein is also intended to represent
unlabeled forms as well as isotopically labeled forms of the
compounds. Isotopically labeled compounds have structures depicted
by the formulas given herein except that one or more atoms are
replaced by an atom having a selected atomic mass or mass number.
Examples of isotopes that can be incorporated into compounds of the
invention include isotopes of hydrogen, carbon, nitrogen, oxygen,
phosphorus, sulfur, fluorine, chlorine, and iodine, such as .sup.2H
(deuterium), .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N,
.sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F,
.sup.36Cl, and .sup.125I, respectively.
[0049] When referring to any formula given herein, the selection of
a particular moiety from a list of possible species for a specified
variable is not intended to define the same choice of the species
for the variable appearing elsewhere. That is, where a variable
appears more than once, the choice of the species from a specified
list is independent of the choice of species for the same variable
elsewhere in the formula, unless otherwise stated.
[0050] By way of a first example on substituent terminology, if
substituent S.sup.1.sub.example is one of S.sub.1 and S.sub.2, and
substituent S.sup.2.sub.example is one of S.sub.3 and S.sub.4, then
these assignments refer to embodiments of this invention given
according to the choices S.sup.1.sub.example is S.sub.1 and
S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is S.sub.1 and
S.sup.2.sub.example is S.sub.4; S.sup.1.sub.example is S.sub.2 and
S.sup.2.sub.example is S.sub.3; S.sup.1.sub.example is S.sub.2 and
S.sup.2.sub.example is S.sub.4; and equivalents of each one of such
choices. The shorter terminology "S.sup.1.sub.example is one of
S.sub.1 and S.sub.2 and "S.sup.2.sub.example is one of S.sub.3 and
S.sub.4 is accordingly used herein for the sake of brevity but not
by way of limitation. The foregoing first example on substituent
terminology, which is stated in generic terms, is meant to
illustrate the various substituent assignments described herein.
The foregoing convention given herein for substituents extends,
when applicable, to members such as R.sup.1, R.sup.2. R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10,
R.sup.11, R.sup.12, and R.sup.13, and any other generic substituent
symbol used herein.
[0051] Furthermore, when more than one assignment is given for any
member or substituent, embodiments of this invention comprise the
various groupings that can be made from the listed assignments,
taken independently, and equivalents thereof. By way of a second
example on substituent terminology, if it is herein described that
substituent S.sub.example is one of S.sub.1, S.sub.2 and S.sub.3,
the listing refers to embodiments of this invention for which
S.sub.example is S.sub.1; S.sub.example is S.sub.2; S.sub.example
is S.sub.3; S.sub.example is one of S.sub.1 and S.sub.2;
S.sub.example is one of S.sub.1 and S.sub.3; S.sub.example is one
of S.sub.2 and S.sub.3; S.sub.example is one of S.sub.1, S.sub.2
and S.sub.3; and S.sub.example is any equivalent of each one of
these choices. The shorter terminology "S.sub.example is one of
S.sub.1, S.sub.2 and S.sub.3" is accordingly used herein for the
sake of brevity, but not by way of limitation. The foregoing second
example on substituent terminology, which is stated in generic
terms, is meant to illustrate the various substituent assignments
described herein. The foregoing convention given herein for
substituents extends, when applicable, to members such as R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8,
R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13, and any other
generic substituent symbol used herein.
[0052] The nomenclature "C.sub.1-j" with j>i, when applied
herein to a class of substituents, is meant to refer to embodiments
of this invention for which each and every one of the number of
carbon members, from i to j including i and j, is independently
realized. By way of example, the term C.sub.1-3 refers
independently to embodiments that have one carbon member (C.sub.1),
embodiments that have two carbon members (C.sub.2), and embodiments
that have three carbon members (C.sub.3).
[0053] The term C.sub.n-malkyl refers to an aliphatic chain,
whether straight or branched, with the total number N of carbon
members in the chain that satisfies n.ltoreq.N.ltoreq.m, with
m>n.
[0054] According to the foregoing interpretive considerations on
assignments and nomenclature, it is understood that explicit
reference herein to a set implies, where chemically meaningful and
unless indicated otherwise, independent reference to embodiments of
such set, and reference to each and every one of the possible
embodiments of subsets of the set referred to explicitly.
Compositions
[0055] The term "composition," as in pharmaceutical composition, is
intended to encompass a product comprising the active
ingredient(s), and the inert ingredient(s) (pharmaceutically
acceptable excipients) that make up the carrier, as well as any
product which results, directly or indirectly, from combination,
complexation, or aggregation of any two or more of the ingredients,
or from dissociation of one or more of the ingredients, or from
other types of reactions or interactions of one or more of the
ingredients. Accordingly, the pharmaceutical compositions of the
present invention encompass any composition made by admixing a
compound of Formula (I) and a pharmaceutically acceptable
excipient.
[0056] The term "therapeutically effective amount" or "effective
amount" means an amount effective, when administered to a human or
non-human patient, to provide any therapeutic benefit. A
therapeutic benefit may be an amelioration of symptoms, e.g., an
amount effective to decrease the symptoms of a depressive disorder,
cognitive disorder, or pain. A therapeutically effective amount of
a compound is also an amount sufficient to provide a significant
positive effect on any indicia of a disease, disorder, or condition
e.g. an amount sufficient to significantly reduce the frequency and
severity of depressive symptoms or pain. A significant effect on an
indicia of a disorder or condition includes a statistically
significant in a standard parametric test of statistical
significance such as Student's T-test, where p<0.05; though the
effect need not be significant in some embodiments.
[0057] A "pharmaceutical compositions" is a composition comprising
at least one active agent, such as a compound, or pharmaceutically
acceptable salt thereof, of Formula (I), and at least one other
substance, such as a carrier, excipient, or diluent.
[0058] The term "carrier" applies to pharmaceutical compositions of
the disclosure and refers to a diluent, adjuvant, excipient, or
vehicle with which an active compound is administered.
[0059] The term "pharmaceutically acceptable," as used in
connection with compositions of the invention, refers to molecular
entities and other ingredients of such compositions that are
physiologically tolerable and do not typically produce untoward
reactions when administered to an animal (e.g., human). The term
"pharmaceutically acceptable" may also mean approved by a
regulatory agency of the Federal or a state government or listed in
the U.S. Pharmacopeia or other generally recognized pharmacopeia
for use in animals (e.g. mammals), and more particularly in
humans.
[0060] A "pharmaceutically acceptable excipient" refers to a
substance that is non-toxic, biologically tolerable, and otherwise
biologically suitable for administration to a subject, such as an
inert substance, added to a pharmacological composition or
otherwise used as a vehicle, carrier, or diluents to facilitate
administration of an agent and that is compatible therewith.
Examples of excipients include calcium carbonate, calcium
phosphate, various sugars and types of starch, cellulose
derivatives, gelatin, vegetable oils, and polyethylene glycols.
Suitable pharmaceutical carriers include those described in
Remington: The Science and Practice of Pharmacy, 21.sup.st Ed.,
Lippincott Williams & Wilkins (2005).
[0061] A "pharmaceutically acceptable salt" is intended to mean a
salt of a free acid or base of a compound represented by Formula
(I) that is non-toxic, biologically tolerable, or otherwise
biologically suitable for administration to the subject. See,
generally, G. S. Paulekuhn et al., J. Med. Chem. 2007, 50,
6665-6672; Berge et al., J. Pharm. Sci. 1977, 66, 1-19; Stahl and
Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and
Use: 2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011).
Examples of pharmaceutically acceptable salts are those that are
pharmacologically effective and suitable for contact with the
tissues of patients without undue toxicity, irritation, or allergic
response. A compound of Formula (I) may possess a sufficiently
acidic group, a sufficiently basic group, or both types of
functional groups, and accordingly react with a number of inorganic
or organic bases, and inorganic and organic acids, to form a
pharmaceutically acceptable salt bases, and inorganic and organic
acids, to form a pharmaceutically acceptable salt.
[0062] The term "carrier" refers to an adjuvant, vehicle, or
excipients, with which the compound is administered. In preferred
embodiments of this invention, the carrier is a solid carrier.
Suitable pharmaceutical carriers include those described in
Remington: The Science and Practice of Pharmacy, 21.sup.st Ed.,
Lippincott Williams & Wilkins (2005).
[0063] The term "dosage form," as used herein, is the form in which
the dose is to be administered to the subject or patient. The drug
is generally administered as part of a formulation that includes
nonmedical agents. The dosage form has unique physical and
pharmaceutical characteristics. Dosage forms, for example, may be
solid, liquid or gaseous. "Dosage forms" may include for example, a
capsule, tablet, caplet, gel caplet (gelcap), syrup, a liquid
composition, a powder, a concentrated powder, a concentrated powder
admixed with a liquid, a chewable form, a swallowable form, a
dissolvable form, an effervescent, a granulated form, and an oral
liquid solution. In a specific embodiment, the dosage form is a
solid dosage form, and more specifically, comprises a tablet or
capsule.
[0064] As used herein, the term "inert" refer to any inactive
ingredient of a described composition. The definition of "inactive
ingredient" as used herein follows that of the U.S. Food and Drug
Administration, as defined in 21 C.F.R. 201.3(b)(8), which is any
component of a drug product other than the active ingredient.
Methods and Uses
[0065] As used herein, the term "disorder" is used interchangeably
with "disease" or "condition". For example, a neurological disorder
also means a neurological disease or a neurological condition.
[0066] As used herein, the term "cognitive impairment" is used
interchangeably with "cognitive dysfunction" or "cognitive
deficit," all of which are deemed to cover the same therapeutic
indications.
[0067] The terms "treating," "treatment," and "treat" cover
therapeutic methods directed to a disease-state in a subject and
include: (i) preventing the disease-state from occurring, in
particular, when the subject is predisposed to the disease-state
but has not yet been diagnosed as having it; (ii) inhibiting the
disease-state, e.g., arresting its development (progression) or
delaying its onset; and (iii) relieving the disease-state, e.g.,
causing regression of the disease state until a desired endpoint is
reached. Treating also includes ameliorating a symptom of a disease
(e.g., reducing the pain, discomfort, or deficit), wherein such
amelioration may be directly affecting the disease (e.g., affecting
the disease's cause, transmission, or expression) or not directly
affecting the disease.
[0068] As used in the present disclosure, the term "effective
amount" is interchangeable with "therapeutically effective amount"
and means an amount or dose of a compound or composition effective
in treating the particular disease, condition, or disorder
disclosed herein, and thus "treating" includes producing a desired
preventative, inhibitory, relieving, or ameliorative effect. In
methods of treatment according to the invention, "an effective
amount" of at least one compound according to the invention is
administered to a subject (e.g., a mammal). In some embodiments, an
"effective amount" also means an amount or dose of a compound or
composition effective to modulate an HNK-associated signaling
pathway, such as a glutamatergic pathway. The "effective amount"
will vary, depending on the compound, the disease, the type of
treatment desired, and its severity, and age, weight, of the
subject, etc.
[0069] The term "animal" is interchangeable with "subject" and may
be a vertebrate, in particular, a mammal, and more particularly, a
human, and includes a laboratory animal in the context of a
clinical trial or screening or activity experiment. Thus, as can be
readily understood by one of ordinary skill in the art, the
compositions and methods of the present invention are particularly
suited to administration to any vertebrate, particularly a mammal,
and more particularly, a human. Medical treatment can include
treatment of an existing condition, such as a disease or disorder,
prophylactic or preventative treatment, or diagnostic treatment. In
some embodiments the patient is a human patient.
[0070] As used herein, a "control animal" or a "normal animal" is
an animal that is of the same species as, and otherwise comparable
to (e.g., similar age, sex), the animal that is trained under
conditions sufficient to induce transcription-dependent memory
formation in that animal.
[0071] A "patient" means any human or non-human animal in need of
medical treatment. Medical treatment can include treatment of an
existing condition, such as a disease or disorder, prophylactic or
preventative treatment, or diagnostic treatment. In some
embodiments the patient is a human patient.
[0072] "Administering" means introducing into the body of a subject
a chemical entity, such as a compound or pharmaceutically
acceptable salt thereof, or a composition containing such a
chemical entity, for use via any appropriate route, for example,
oral administration in either solid or liquid dosage form.
[0073] By "enhance," "enhancing," or "enhancement" is meant the
ability to potentiate, increase, improve or make greater or better,
relative to normal, a biochemical or physiological action or
effect. For example, enhancing long term memory formation refers to
the ability to potentiate or increase long term memory formation in
an animal relative to (or "compared to") the normal long term
memory formation of the animal or controls. As a result, long term
memory acquisition is faster or better retained. Enhancing
performance of a cognitive task refers to the ability to potentiate
or improve performance of a specified cognitive task by an animal
relative to the normal performance of the cognitive task by the
animal or controls.
[0074] As used herein, the terms "training protocol," or
"training," refer to either "cognitive training" or "motor
training."
[0075] Reference will now be made to the embodiments of the present
invention, examples of which are illustrated by and described in
conjunction with the accompanying drawings and examples. While
certain embodiments are described herein, it is understood that the
described embodiments are not intended to limit the scope of the
invention. On the contrary, the present disclosure is intended to
cover alternatives, modifications, and equivalents that can be
included within the invention as defined by the appended
claims.
Compounds and Chemical Entities
[0076] The disclosure relates to compounds and chemical entities of
Formula (I), and their use in the disclosed methods.
[0077] In some embodiments, the disclosure provides a chemical
entity of Formula (I):
##STR00007## [0078] wherein: [0079] R.sup.1 is --H; or [0080]
R.sup.1 is --C.sub.1-6alkyl, optionally substituted with one or
more members, each independently selected from the group consisting
of: -halo, -hydroxy, -alkoxy, -amino and -carboxyl; or [0081]
R.sup.1 is --C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each
optionally substituted with one or more members, each independently
selected from the group consisting of: -halo, -hydroxy, --C.sub.1-4
alkyl, --C.sub.1-4alkoxy, and amino; or [0082] R.sup.1 is
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, and 4; or [0083] R.sup.1 is
--COR.sup.2, --CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, or --C(OH)R.sup.11R.sup.12, [0084] wherein
R.sup.2, R.sup.3, R.sup.4, R.sup.7 and R.sup.8 are each
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; [0085] R.sup.5 and
R.sup.6 are each independently selected from the group consisting
of: --H, -halo, --NH.sub.2, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nCONR.sup.1AR.sup.1B,
--(CH.sub.2).sub.nNHC(.dbd.O)R.sup.1A,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; [0086] each R.sup.1A is independently selected from the group
consisting of: --H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, said --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl each optionally substituted with
one or more members, each independently selected from the group
consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; [0087] each R.sup.1B s
independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; [0088] each R.sup.1C is
independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; [0089] R.sup.9 and
R.sup.10 are each independently selected from the group consisting
of --H, --C.sub.1-8alkyl, and --C.sub.1-8haloalkyl, said alkyl
optionally substituted with up to 3 members, each independently
selected from the group consisting of: -amino, -hydroxy and
-carboxyl; or optionally R.sup.9 and R.sup.10 taken together with
the carbon to which they are attached can form an optionally
substituted five membered heteroaryl or heterocycloalkyl ring; and
[0090] R.sup.11 and R.sup.12 are each independently selected from
the group consisting of: --H, --C.sub.1-6alkyl, and
--C.sub.1-6haloalkyl, said --C.sub.1-6alkyl, and
--C.sub.1-6haloalkyl optionally substituted with up to 3 members,
each independently selected from the group consisting of: -hydroxy
and amino.
[0091] In some embodiments, a chemical entity corresponds to the
(1R,5R) enantiomer of Formula (I):
##STR00008##
[0092] In some embodiments, a chemical entity corresponds to the
(1S,5S) enantiomer of Formula (I):
##STR00009##
[0093] In some embodiments, R.sup.1 is --H; or [0094] R.sup.1 is
--C.sub.1-6alkyl, optionally substituted with one or more members,
each independently selected from the group consisting of: -halo,
-hydroxy, -alkoxy, -amino and -carboxyl; or [0095] R.sup.1 is
--C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each optionally
substituted with one or more members, each independently selected
from the group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and amino; or [0096] R.sup.1 is
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, 3, 4; or [0097] R.sup.1 is
--CR.sup.5R.sup.6NR.sup.7R.sup.8, --CHR.sup.9R.sup.10, or
--C(OH)R.sup.11R.sup.12, [0098] wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; [0099] R.sup.5 and
R.sup.6 are each independently selected from the group consisting
of: --H, -halo, --NH.sub.2, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, wherein n
is independently an integer selected from 0, 1, 2, 3, and 4; [0100]
R.sup.9 and R.sup.10 are each independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, and --C.sub.1-8haloalkyl,
said alkyl optionally substituted with up to 3 members, each
independently selected from the group consisting of -amino,
-hydroxy, and -carboxyl; or optionally R.sup.9 and R.sup.10 taken
together with the carbon to which they are attached can form an
optionally substituted five membered heteroaryl or heterocycloalkyl
ring; and [0101] R.sup.11 and R.sup.12 are independently selected
from the group consisting of: --H, --C.sub.1-6alkyl, and
--C.sub.1-6haloalkyl, said --C.sub.1-6alkyl, and
--C.sub.1-6haloalkyl optionally substituted with up to 3 members,
each independently selected from the group consisting of: -hydroxy
and -amino.
[0102] In some embodiments, R.sup.1 is --H; or [0103]
--C.sub.1-6alkyl, optionally substituted with one or more members,
each independently selected from the group consisting of: -halo,
-hydroxy, -alkoxy, -amino and -carboxyl; or [0104]
--C.sub.3-8alkenyl or --C.sub.3-8alkynyl, each optionally
substituted with one or more members, each independently selected
from the group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and amino; or [0105] --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, or
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4 alkoxy, and -amino, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; or [0106] --COR.sup.2,
--CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, and --C(OH)R.sup.11R.sup.12, [0107] wherein
R.sup.2, R.sup.3, R.sup.4, R.sup.7 and R.sup.8 are independently
selected from the group consisting of: --H, --C.sub.1-8alkyl, and
--C.sub.1-8haloalkyl; [0108] R.sup.5 and R.sup.6 are independently
selected from the group consisting of: --H, -halo, --NH.sub.2,
--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, 2,3-dihydro-1H-pyrrole-1-carboxamide, wherein n is
independently an integer selected from 0, 1, 2, 3, and 4; [0109]
R.sup.9 and R.sup.10 are independently selected from the group
consisting of: --H, --C.sub.1-8alkyl, and --C.sub.1-8haloalkyl,
said alkyl optionally substituted with up to 3 members, each
independently selected from the group consisting of: -amino,
-hydroxy and -carboxyl; or optionally R.sup.9 and R.sup.10 taken
together with the carbon to which they are attached can form a five
membered heteroaryl or heterocycloalkyl ring; and [0110] R.sup.11
and R.sup.12 are independently selected from the group consisting
of: --H, --C.sub.1-6alkyl, and --C.sub.1-6haloalkyl, optionally
substituted with up to 3 members, each independently selected from
the group consisting of: -hydroxy and amino.
[0111] In some embodiments, R.sup.1 is
--CR.sup.5R.sup.6NR.sup.7R.sup.8 or --CR.sup.9R.sup.10, [0112]
wherein R.sup.5 and R.sup.6 are independently selected from the
group consisting of: --H, --F, --Cl, --Br, --NH.sub.2, -methyl,
-n-propyl, -isopropyl, -butyl, -pentyl, --NH.sub.2,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nbenzyl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2)indole,
--(CH.sub.2)imidazole, --(CH.sub.2).sub.ncycloalkyl,
--(CH.sub.2).sub.nheterocycloalkyl; --(CH.sub.2).sub.npyrrolidine,
--(CH.sub.2)furan, and --(CH.sub.2).sub.nthiophene, optionally
substituted with up to 3 members, each independently selected from
the group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4; [0113] each R.sup.1A is independently selected from the group
consisting of: --H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl;
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein ii is independently an
integer selected from 0, 1, 2, 3, and 4; [0114] each R.sup.1B is
independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; [0115] each R.sup.1C is
independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; [0116] R.sup.7 and R.sup.8
are --H; and [0117] R.sup.9 and R.sup.10 are independently selected
from the group consisting of: --H, --C.sub.1-8alkyl, and
--C.sub.1-8haloalkyl; or optionally R.sup.9 and R.sup.10 taken
together with the carbon to which they are attached can form an
optionally substituted five membered heteroaryl or heterocycloalkyl
ring.
[0118] In some embodiments, R.sup.1 includes --H.
[0119] In some embodiments, R.sup.1 includes --C.sub.1-6alkyl,
optionally substituted with one or more members, each independently
selected from the group consisting of: -halo, -hydroxy, -alkoxy,
-amino and -carboxyl.
[0120] In some embodiments, R.sup.1 includes --C.sub.3-8alkenyl,
optionally substituted with one or more members, each independently
selected from the group consisting of: -halo, -hydroxy, --C.sub.1-4
alkyl, --C.sub.1-4alkoxy, and -amino.
[0121] In some embodiments, R.sup.1 includes --C.sub.3-8alkynyl,
each optionally substituted with one or more members, each
independently selected from the group consisting of: -halo,
-hydroxy, --C.sub.1-4 alkyl, --C.sub.1-4alkoxy, and -amino.
[0122] In some embodiments, R.sup.1 includes
--(CH.sub.2).sub.naryl, optionally substituted with one or more
members, each independently selected from the group consisting of:
-halo, -hydroxy, --C.sub.1-4 alkyl, --C.sub.1-4alkoxy, and -amino,
wherein n is independently an integer selected from 0, 1, 2, 3, and
4;
[0123] In some embodiments, R.sup.1 includes
--(CH.sub.2).sub.nheteroaryl, optionally substituted with one or
more members, each independently selected from the group consisting
of: -halo, -hydroxy, --C.sub.1-4 alkyl, --C.sub.1-4alkoxy, and
-amino; wherein n is independently an integer selected from 0, 1,
2, 3, and 4;
[0124] In some embodiments, R.sup.1 includes
--(CH.sub.2).sub.ncycloalkyl, optionally substituted with one or
more members, each independently selected from the group consisting
of: -halo, -hydroxy, --C.sub.1-4 alkyl, --C.sub.1-4alkoxy, and
-amino; wherein n is independently an integer selected from 0, 1,
2, 3, and 4;
[0125] In some embodiments, R.sup.1 includes
--(CH.sub.2).sub.nheterocycloalkyl, optionally substituted with one
or more members, each independently selected from the group
consisting; of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and -amino; wherein n is independently an
integer selected from 0, 1, 2, 3, and 4.
[0126] In some embodiments, R.sup.1 includes --COR.sup.2, wherein
R.sup.2 is selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl.
[0127] In some embodiments, R.sup.1 includes --CONR.sup.3R.sup.4,
wherein R.sup.3 and R.sup.4 are independently selected from the
group consisting of: --H, --C.sub.1-8alkyl, and
--C.sub.1-8haloalkyl.
[0128] In some embodiments, R.sup.1 includes
--CR.sup.5R.sup.6NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; and R.sup.5 and R.sup.6
are independently selected from the group consisting of: --H,
-halo, --NH.sub.2, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-alkoxy, -2,3-dihydro-1H-pyrrole-1-carboxamide, wherein n is
independently an integer, selected from 0, 1, 2, 3, and 4.
[0129] In some embodiments, R.sup.1 includes
--CR.sup.5R.sup.6NR.sup.7R.sup.8, wherein R.sup.7 and R.sup.8 are
independently selected from the group consisting of: --H,
--C.sub.1-8alkyl, and --C.sub.1-8haloalkyl; and R.sup.5 and R.sup.6
are each independently selected from the group consisting of: --H,
--NH.sub.2, --C.sub.1-8alkyl, --(CH.sub.2).sub.nCONH.sub.2,
--(CH.sub.2).sub.nCOOH, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, each optionally substituted
with one or more members, each independently selected from the
group consisting of: -guanidyl, -urea, -halo, -alkyl, -hydroxy,
-amino, -alkoxy, 2,3-dihydro-1H-pyrrole-1-carboxamide,
--(CH.sub.2).sub.nCONR.sup.1AR.sup.1B,
--(CH.sub.2).sub.nNHC(.dbd.O)R.sup.1A,
--(CH.sub.2).sub.nNR.sup.1AR.sup.1B, --(CH.sub.2).sub.nOR.sup.1C,
--(CH.sub.2).sub.nSR.sup.1C and --(CH.sub.2).sub.nSeR.sup.1C,
wherein n is independently an integer selected from 0, 2, 3, and 4;
[0130] each R.sup.1A is independently selected from the group
consisting of: --H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, said --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl each optionally substituted with
one or more members, each independently selected from the group
consisting of: -halo, -hydroxy, --C.sub.1-4 alkyl,
--C.sub.1-4alkoxy, and -amino, wherein ii is independently an
integer selected from 0, 1, 2, 3, and 4; [0131] each R.sup.1B is
independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4; and [0132] each R.sup.1C
is independently selected from the group consisting of:
--H--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and
--(CH.sub.2).sub.nheterocycloalkyl, wherein n is independently an
integer selected from 0, 1, 2, 3, and 4.
[0133] In some embodiments, R.sup.1 includes --CHR.sup.9R.sup.10,
wherein R.sup.9 and R.sup.10 are independently selected from the
group consisting of: --H, --C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
said alkyl optionally substituted with up to 3-amino, -hydroxy, and
-carboxyl groups; or optionally R.sup.9 and R.sup.10 taken together
with the carbon to which they are attached can form an optionally
substituted five-membered heteroaryl or heterocycloalkyl ring.
[0134] In some embodiments, R.sup.1 includes
--C(OH)R.sup.11R.sup.12, wherein R.sup.11 and R.sup.12 are
independently selected from the group consisting of: --H,
--C.sub.1-6alkyl and --C.sub.1-6haloalkyl, optionally substituted
with up to 3 members, each independently selected from the group
consisting of: -hydroxy and -amino.
[0135] In some embodiments, the heteroatom is selected from the
group consisting of N (nitrogen), O (oxygen), and S (sulfur).
[0136] In some embodiments, the heteroatom is selected from the
group consisting of N (nitrogen), O (oxygen), Se (selenium), and S
(sulfur).
[0137] In some embodiments, the heteroatom includes N
(nitrogen).
[0138] In some embodiments, the heteroatom includes O (oxygen).
[0139] In some embodiments, the heteroatom includes S (sulfur).
[0140] In some embodiments, the heteroatom includes Se
(selenium).
[0141] In some embodiments, the disclosure provides a chemical
entity of Formula (I), wherein R.sup.1 includes an analog of a
naturally occurring amino acid.
[0142] In some embodiments, the disclosure provides a chemical
entity of Formula (I), wherein R.sup.1 includes an analog of a
known, non-naturally occurring amino acid. Such known,
non-naturally occurring, amino acids include .beta.-amino acids
(.beta.3 and .beta.2), homo-amino acids, proline- and pyruvic acid
derivatives, triple-substituted alanine derivatives, glycine
derivatives, ring-substituted phenylalanine and tyrosine
derivatives, linear core amino acids, and N-methyl amino acids.
[0143] In some embodiments, the chemical entity is selected from
the group consisting of compounds of Formula (I), pharmaceutically
acceptable salts of compounds of Formula (I), pharmaceutically
acceptable chelates of compounds of Formula (I), pharmaceutically
acceptable solvates of compounds of Formula (I), pharmaceutically
acceptable metabolites of compounds of Formula (I), and
pharmaceutically acceptable prodrugs of compounds of Formula
(I).
[0144] In some embodiments, the chemical entity is selected from
the group consisting of compounds of Formula (I) and
pharmaceutically acceptable salts of compounds of Formula (I).
[0145] In some embodiments, the disclosure provides a compound
selected from the group consisting of: [0146]
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one,
[0147]
(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0148]
(1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]no-
n-3-en-9-one; [0149]
(1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0150]
(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0151]
(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one, [0152]
(1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; [0153]
(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0154]
(1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne; [0155]
(1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0156]
(1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one, [0157]
(1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one; [0158]
(1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one; [0159]
(1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one; [0160]
(1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-ox-
a-4-azabicyclo[3.3.1]non-3-en-9-one; [0161]
(1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-9-one; [0162]
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid; [0163]
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid, [0164]
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide; [0165]
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide; [0166]
(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one; [0167]
(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one; [0168]
(1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0169]
(1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0170]
1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine; [0171]
(1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e; [0172]
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-3-yl)-2-hydroxypropanoic acid; [0173]
2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3--
yl)methyl)-2-hydroxysuccinic acid; [0174]
5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic acid; [0175]
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid; [0176]
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid; [0177]
(1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne; [0178]
(1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one; [0179]
(1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one; [0180]
(1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0181]
(1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one, [0182]
(1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0183]
(1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one; [0184]
(1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0185]
(1R,5R)-3-(i-amino-3-hydroxypropyl)-S-(2-chlorophenyl)-2-oxa-4-azabicyclo-
[3.3.1]non-3-en-9-one; [0186]
(1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0187]
4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide; [0188]
(1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one, [0189]
1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea; [0190]
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea; [0191]
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine; [0192]
1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine; [0193]
(1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; [0194]
(1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-
-oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0195]
(1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0196]
(1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-o-
xa-4-azabicyclo[3.3.1]non-3-en-9-one; [0197]
(1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicycl-
o[3.3.1]non-3-en-9-one; [0198]
(1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; [0199]
(1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one; [0200]
(1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0201]
N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;
[0202]
(1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; [0203]
(1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one, [0204]
(1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one; [0205]
(3R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; and [0206]
(1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
[0207] or
pharmaceutically acceptable salts thereof.
[0208] In some embodiments, the disclosure provides a compound
selected from the group consisting of: [0209]
(1S,5S)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
[0210]
(1S,5S)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0211]
(1S,5S)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]no-
n-3-en-9-one; [0212]
(1S,5S)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one, [0213]
(1S,5S)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0214]
(1S,5S)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one, [0215]
(1S,5S)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; [0216]
(1S,5S)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0217]
(1S,5S)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne; [0218]
(1S,5S)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one, [0219]
(1S,5S)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one; [0220]
(1S,5S)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one; [0221] 1
S,5S)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one; [0222]
(1S,5S)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one; [0223]
(1S,5S)-3-((S)-1-amino-2-(1H-imidazo-4-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one; [0224]
(1S,5S)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-9-one; [0225]
(S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid: [0226]
(S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid; [0227]
(S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide; [0228]
(S)-3-amino-3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide; [0229]
(1S,5S)-3-((S)-1-amino-3-(methylthio)propy)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; [0230]
(1S,5S)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one, [0231]
(1S,5S)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0232]
(1S,5S)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0233]
1-((S)-4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine; [0234]
(1S,5S)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e; [0235]
3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-3-yl)-2-hydroxypropanoic acid; [0236]
2-(((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3--
yl)methyl)-2-hydroxysuccinic acid; [0237]
5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic acid, [0238]
3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid; [0239]
3-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid; [0240]
(1S,5S)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne; [0241]
(1S,5S)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one, [0242]
(1S,5S)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one; [0243]
(1S,5S)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0244]
(1S,5S)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one; [0245]
(1S,5S)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0246]
(1S,5S)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one; [0247]
(1S,5S)-3-(3-aminophenyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0248]
(1S,5S)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo-
[3.3.1]non-3-en-9-one; [0249]
(1S,5S)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0250]
4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide; [0251]
(1S,5S)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one; [0252]
1-(4-amino-4-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea; [0253]
1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea; [0254]
1-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine, [0255]
1-(2-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine; [0256]
(1S,5S)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; [0257]
(1S,5S)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-
-oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0258]
(1S,5S)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0259]
(1S,5S)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-o-
xa-4-azabicyclo[3.3.1]non-3-en-9-one; [0260]
(1S,5S)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicycl-
o[3.3.1]non-3-en-9-one, [0261]
(1S,5S)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; [0262]
(1S,5S)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one; [0263]
(1S,5S)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0264]
N-(5-amino-5-((1S,5S)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;
[0265]
(1S,5S)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one, [0266]
(1S,5S)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0267]
(1S,5S)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one, [0268]
(1S,5S)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; and [0269]
(1S,5S)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
[0270] or
pharmaceutically acceptable salts thereof.
[0271] In some embodiments, the disclosure provides a compound
selected from the group consisting of: [0272]
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
[0273]
(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0274]
(1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]no-
n-3-en-9-one; [0275]
(1R,5R)-3-((S)-1-amino-2-methylpropy)-S-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one; [0276]
(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0277]
(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one; [0278]
(1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; [0279]
(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0280]
(1R,5R)-5-(2-chlorophenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne; [0281]
(1R,5R)-3-((1S,2R)-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one, [0282]
(1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one; [0283]
(1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one, [0284]
(1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one; [0285]
(1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one, [0286]
(1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-ox-
a-4-azabicyclo[3.3.1]non-3-en-9-one; [0287]
(1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-9-one; [0288]
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic acid; [0289]
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic acid, [0290]
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide; [0291]
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide; [0292]
(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-S-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one; [0293]
(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one; [0294]
(1R,5R)-3-((S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0295]
(1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; and [0296]
1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine; [0297] or pharmaceutically
acceptable salts thereof.
[0298] In some embodiments, the disclosure provides a compound
selected from the group consisting of: [0299]
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-one;
[0300]
(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one, [0301]
(1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4-azabicyclo[3.3.1]no-
n-3-en-9-one; [0302]
(1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one, [0303]
(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one; [0304]
(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one; [0305]
(1R,5R)-5-(2-chlorophenyl)-3-((S)-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; and [0306]
(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
[0307] or
pharmaceutically acceptable salts thereof.
[0308] In some embodiments, the disclosure provides a compound
selected from the group consisting of: [0309]
(1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0310]
(1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one; [0311]
(1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one;
(1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one, [0312]
(1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0313]
(1R,5R)-3-(4-aminobutyl)-S-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one; [0314]
(1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0315]
(1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo-
[3.3.1]non-3-en-9-one; [0316]
(1R,5R)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one; [0317]
4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide; [0318]
(1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one, [0319]
1-(4-amino-4-((1R,3R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea; [0320]
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea, [0321]
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine; [0322]
1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine; [0323]
(1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one; [0324]
(1R,5R)-3-(2-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-S-(2-chlorophenyl)-2-
-oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0325]
(1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one; [0326]
(1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)ethyl)-5-(2-chlorophenyl)-2-o-
xa-4-azabicyclo[3.3.1]non-3-en-9-one; [0327]
(1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicycl-
o[3.3.1]non-3-en-9-one; [0328]
(1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; [0329]
(1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one; [0330]
(1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one; [0331]
N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamide;
[0332]
(1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; [0333]
(1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one; [0334]
(1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one; [0335]
(1R,5R)-3-(l-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one; and [0336]
(1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one;
[0337] or
pharmaceutically acceptable salts thereof.
[0338] In some embodiments, the disclosure provides a compound
selected from the group consisting of: [0339]
(1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e; [0340]
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-3-yl)-2-hydroxypropanoic acid; [0341]
2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)methyl)-2-hydroxysuccinic acid; [0342]
5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic acid; [0343]
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic acid; [0344]
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic acid; and [0345]
(1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne;
[0346] or
pharmaceutically acceptable salts thereof.
[0347] In some embodiments, a chemical entity of the present
disclosure includes an amino acid conjugate. Preferably, the amino
acids of the present technology are Generally Regarded As Safe
(GRAS) or non-toxic at the concentrations released into the
systemic circulation.
[0348] Amino acids suitable for use in compounds and compositions
can be broadly classified into standard amino acids, non-standard
amino acids, and synthetic amino acids.
[0349] Standard amino acids, or proteinogenic amino acids, include
but are not limited to the currently known amino acids that make up
the monomeric units of proteins that are encoded in the universal
genetic code of organisms. Standard amino acids include alanine,
arginine, asparagine, aspartic acid, cysteine, glutamic acid,
glutamine, glycine, histidine, isoleucine, leucine, lysine,
methionine, phenylalanine, proline, serine, threonine, tryptophan,
tyrosine and valine.
[0350] Non-standard amino acids are not encoded by the standard
genetic code and include chemical modifications of standard amino
acids already incorporated in the proteins, as well as amino acids
not found in proteins but still present in living organisms.
Examples of non-standard amino acids include ornithine,
homoarginine, citrulline, homocitrulline, homoserine, theanine,
.gamma.-aminobutyric acid, sarcosine, cartinine, 2-aminoadipic
acid, pantothenic acid, taurine, hypotaurine, lanthionine,
thiocysteine, cystathionine, homocysteine, .beta.-amino acids such
as .beta.-alanine, .beta.-aminoisobutyric acid, .beta.-leucine,
.beta.-lysine, .beta.-arginine, .beta.-tyrosine,
.beta.-phenylalanine, isoserine, .beta.-glutamic acid,
.beta.-tyrosine, .beta.-dopa (3,4-dihydroxy-L-phenylalanine),
.alpha.,.alpha.-disubstituted amino acids such as 2-aminoisobutyric
acid, isovaline, di-n-ethylglycine, N-methyl acids such as
N-methyl-alanine, L-abrine, hydroxy-amino acids such as
4-hydroxyproline, 5-hydroxylysine, 3-hydroxyleucine,
4-hydroxyisoleucine, 5-hydroxy-L-tryptophan, cyclic amino acids
such as 1-aminocyclopropyl-1-carboxylic acid,
azetidine-2-carboxylic acid and pipecolic acid. Non-standard amino
acids also include selenocysteine and pyrolysine, which are
incorporated into proteins by unique synthetic mechanisms.
[0351] Synthetic amino acids do not occur in nature and must be
synthesized. Examples of synthetic amino acids include
allylglycine, cyclohexylglycine, N-(4-hydroxyphenyl)glycine,
N-(chloroacetyl)gly cline ester, 2-(trifluoromethyl)-phenylalanine,
4-(hydroxymethyl)-phenylalanine, 4-amino-phenylalanine,
2-chlorophenylglycine, 3-guanidino propionic acid,
3,4-dehydro-proline, 2,3-diaminobenzoic acid,
2-amino-3-chlorobenzoic acid, 2-amino-5-fluorobenzoic acid,
allo-isoleucine, tert-leucine, 3-phenylserine, isoserine,
3-aminopentanoic acid, 2-amino-octanedioic acid,
4-chloro-.beta.-phenylalanine, .beta.-homoproline,
.beta.-homoalanine, 3-amino-3-(3-methoxyphenyl)propionic acid,
N-isobutyryl-cysteine, 3-amino-tyrosine, 5-methyl-tryptophan,
2,3-diaminopropionic acid, 5-aminovaleric acid, and
4-(dimethylamino)cinnamic acid.
[0352] In some embodiments, a chemical entity of the present
disclosure includes a carboxylic acid conjugate. Preferably, the
carboxylic acids of the present disclosure are Generally Regarded
As Safe (GRAS) or non-toxic at the concentrations released into the
systemic circulation.
[0353] In some embodiments, Formula (I) compounds are hydrolyzed
chemically, enzymatically or by a combination of chemical and
enzymatic processes, and release HNK upon administration to a
subject. In some embodiments, Formula. (I) compounds may be
pharmacologically inactive or have pharmacological activity that is
limited or different from HNK, and consequently, in certain
embodiments, may follow a metabolic pathway that differs from
HNK.
[0354] In some embodiments, the chemical entity is a salt, solvate,
conformer, polymorph, or a prodrug of a compound of Formula
(I).
Salts
[0355] In some embodiments, the disclosure provides
pharmaceutically acceptable salts of the compounds represented by
Formula (I), and the use of such salts in methods of the present
invention.
[0356] Examples of pharmaceutically acceptable salts include
sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,
phosphates, monohydrogen-phosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides,
acetates, borate, nitrate, propionates, decanoates, caprylates,
acrylates, formates, isobutyrates, caproates, heptanoates,
propiolates, oxalates, malonates, succinates, suberates, sebacates,
fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,
benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,
hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
xylenesulfonates, phenylacetates, phenyl propionates,
phenylbutyrates, citrates, lactates, y-hydroxybutyrates,
glycolates, tartrates, methane-sulfonates, propanesulfonates,
naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate,
mesylate and mandelates.
[0357] When the compound of Formula (I) contains a basic nitrogen,
the desired pharmaceutically acceptable salt may be prepared by any
suitable method available in the art, for example, treatment of the
free base with an inorganic acid, such as hydrochloric acid,
hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric
acid, phosphoric acid, and the like, or with an organic acid, such
as acetic acid, phenylacetic acid, propionic acid, stearic acid,
lactic acid, ascorbic acid, maleic acid, hydroxymaleic acid,
isethionic acid, succinic acid, valeric acid, fumaric acid, malonic
acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,
oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such
as mandelic acid, citric acid, or tartaric acid, an amino acid,
such as aspartic acid, glutaric acid or glutamic acid, an aromatic
acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid,
or cinnamic acid, a sulfonic acid, such as laurylsulfonic acid,
p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid,
any compatible mixture of acids such as those given as examples
herein, and any other acid and mixture thereof that are regarded as
equivalents or acceptable substitutes in light of the ordinary
level of skill in this technology.
[0358] When the compound of Formula (I) is an acid, such as a
carboxylic acid or sulfonic acid, the desired pharmaceutically
acceptable salt may be prepared by any suitable method, for
example, treatment of the free acid with an inorganic or organic
base, such as an amine (primary, secondary or tertiary), an alkali
metal hydroxide, alkaline earth metal hydroxide, any compatible
mixture of bases such as those given as examples herein, and any
other base and mixture thereof that are regarded as equivalents or
acceptable substitutes in light of the ordinary level of skill in
this technology. Illustrative examples of suitable salts include
organic salts derived from amino acids, such as
N-methyl-O-glucamine, lysine, choline, glycine and arginine,
ammonia, carbonates, bicarbonates, primary, secondary, and tertiary
amines, and cyclic amines, such as tromethamine, benzylamines,
pyrrolidines, piperidine, morpholine, and piperazine, and inorganic
salts derived from sodium, calcium, potassium, magnesium,
manganese, iron, copper, zinc, aluminum, and lithium.
Solvates
[0359] In some embodiments, the disclosure provides a solvate of a
compound of Formula (I), or a solvate of a pharmaceutically
acceptable salt of a compound of Formula (I), and the use of such
solvates in methods of present invention.
[0360] Solvates can be formed from the interaction or complexes of
compounds of the invention with one or more solvents, either in
solution or as a solid or crystalline form. Such solvent molecules
are those commonly used in the pharmaceutical art, which are known
to be innocuous to the recipient, e.g., water, ethanol, ethylene
glycol, and the like. Other solvents may be used as intermediate
solvates in the preparation of more desirable solvates, such as
methanol, methyl t-butyl ether, ethyl acetate, methyl acetate,
(S)-propylene glycol, (R)-propylene glycol, 1,4-butyne-diol, and
the like. Hydrates include compounds formed by an incorporation of
one or more water molecules.
Polymorphs
[0361] In certain embodiments, compounds of Formula (I) may exist
in crystalline form. A polymorph (or crystalline form) is a
composition having the same chemical formula, but a different solid
state or crystal structure. In addition, certain crystalline forms
of compounds of Formula (I) or pharmaceutically acceptable salts of
compounds of Formula (I) are obtainable as co-crystals.
Prodrugs
[0362] The term "prodrug" means a precursor of a designated
compound that; following administration to a subject, yields the
compound in vino via one or more physiochemical or physiological
processes, such as chemical hydrolysis or enzymatic cleavage. In
some embodiments, more than one process may be required to yield
the compound in vivo. For example, a compound of Formula (I), upon
administration in vivo, may undergo both hydrolysis and enzymatic
conversion.
[0363] In some embodiments, the chemical entities of Formula (I)
are prodrugs designed to yield, in vivo, a suitable yield of the
ketamine metabolite, HNK. That is, in some embodiments, chemical
entities of Formula (I) are precursors of HNK and therefore can
yield biologically available HNK upon administration to a
subject.
[0364] In some embodiments, prodrugs may be obtained from further
derivatization of compounds of Formula (I). Prodrugs may be
generated using techniques known or available in the art (e.g.,
Bundgard (ed.), 1985, Design of prodrugs, Elsevier;
Krogsgaard-Larsen et al., (eds.), 1991, Design and Application of
Prodrugs, Harwood Academic Publishers). Prodrugs may be produced,
for instance, by derivatizing free carboxyl groups of structures of
Formula (I) as amides or alkyl esters, or by derivatizing free
hydroxy groups using groups including hemisuccinates, phosphate
esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls,
following procedures such as those outlined in Fleisher et al.,
Adv. Drug Delivery Rev. 1996, 19, 115-130.
Metabolites
[0365] The present disclosure also relates to a metabolite of a
compound of Formula (I), as defined herein, and salts thereof. The
present invention further relates to the use of such metabolites,
and salts thereof, in methods of present invention, including
therapeutic methods.
[0366] Metabolites of a compound may be determined using routine
techniques known or available in the att. For example, isolated
metabolites can be enzymatically and synthetically produced (e.g.,
Bertolini et al., J. Med. Chem. 1997, 40, 2011-2016; Shan et al.,
J. Pharm. Sci. 1997, 86, 765-767; Bagshawe, Drug Dev. Res. 1995,
34, 220-230; and Bodor, Adv Drug Res. 1984, 13, 224-231).
[0367] In preferred embodiments, the metabolite corresponds to HNK.
Without being limited by mechanism, compounds of Formula (I) may
undergo one or more physiological processes following
administration, resulting in HNK and other byproducts. In some
embodiments, the byproduct of such processes may include an amino
acid or carboxylic acid.
Compositions
[0368] Compounds disclosed herein can be administered as the neat
chemical, but are preferably administered as a composition. The
term "composition," as in pharmaceutical composition, is intended
to encompass a product comprising the active ingredients) and the
inert ingredient(s) (pharmaceutically acceptable excipients) that
make up the carrier, as well as any product which results, directly
or indirectly, from combination, complexation, or aggregation of
any two or more of the ingredients, or from dissociation of one or
more of the ingredients, or from other types of reactions or
interactions of one or more of the ingredients.
[0369] Accordingly, in some embodiments, the disclosure provides a
pharmaceutical composition comprising a chemical entity of any of
the embodiments and examples disclosed herein; and a
pharmaceutically acceptable carrier. In some embodiments, a
pharmaceutical composition comprises a compound, or
pharmaceutically acceptable salt thereof, of any of the embodiments
and examples disclosed herein; and a pharmaceutically acceptable
carrier. In specific embodiments, a pharmaceutical composition
comprises a compound of any one of Examples 1-61, and a
pharmaceutically acceptable carrier.
[0370] The pharmaceutical composition may contain a compound or
salt of Formula (I) as the only active agent, but preferably
contains at least one additional active agent. In certain
embodiments the pharmaceutical composition is an oral dosage form
that contains from about 0.1 mg to about 1000 mg, from about 1 mg
to about 500 mg, or from about 10 mg to about 200 mg of a compound
of Formula (I) and optionally from about 0.1 mg to about 2000 mg,
from about 10 mg to about 1000 mg, from about 100 mg to about 800
mg, or from about 200 mg to about 600 mg of an additional active
agent in a unit dosage form.
[0371] In some embodiments, compounds of Formula (I), and
pharmaceutically acceptable salts thereof, are used, alone or in
combination with one or more additional active ingredients, to
formulate pharmaceutical compositions.
Formulations and Administration
[0372] Procedures for preparing various formulations suitable for
administering are known in the art. Examples of potential
formulations and preparations are contained, for example, in the
Handbook of Pharmaceutical Excipients, American Pharmaceutical
Association (current edition); Pharmaceutical Dosage Forms: Tablets
(Lieberman, Lachman and Schwartz, editors) current edition,
published by Marcel Dekker, Inc., as well as Remington's
Pharmaceutical Sciences (Osol, ed.), 1980, 1553-1593.
[0373] Any suitable route of administration may be employed for
providing an animal, especially a human, with an effective dosage
of a compound of the present invention. For example, oral, rectal,
topical, parenteral, ocular, pulmonary, nasal, buccal, and the like
may be employed. Dosage forms include tablets, troches,
dispersions, suspensions, solutions, capsules, creams, ointments,
aerosols, and the like.
[0374] Suitable carriers, diluents and excipients are well known to
those skilled in the art and include materials such as
carbohydrates, waxes, water soluble and/or swellable polymers,
hydrophilic or hydrophobic materials, gelatin, oils, solvents,
water, and the like. The particular carrier, diluent, or excipient
used will depend upon the means and purpose for which the compound
of the present invention is being applied. Some carriers may be
listed in more than one class, for example vegetable oil may be
used as a lubricant in some formulations and a diluent in others.
Solvents are generally selected based on solvents recognized by
persons skilled in the art as safe (GRAS) to be administered to an
animal. In general, safe solvents are non-toxic aqueous solvents
such as water and other non-toxic solvents that are soluble or
miscible in water. Suitable aqueous solvents include water,
ethanol, propylene glycol, polyethylene glycols (e.g., PEG-400,
PEG300), etc. and mixtures thereof. The formulations may also
include one or more buffers, stabilizing agents, surfactants,
wetting agents, lubricating agents, emulsifiers, suspending agents,
preservatives, antioxidants, opaquing agents, glidants, processing
aids, colorants, sweeteners, perfuming agents, flavoring agents and
other known additives to provide an elegant presentation of the
drug (i.e., a compound of the present invention or pharmaceutical
composition thereof) or aid in the manufacturing of the
pharmaceutical product (i.e., medicament).
[0375] The formulations may be prepared using conventional
dissolution and mixing procedures. For example, the bulk drug
substance (i.e., a compound of the present invention or stabilized
form of the compound (e.g., complex with a cyclodextrin derivative
or other known complexation agent)) is dissolved in a suitable
solvent in the presence of one or more of the excipients described
above. The compound of the present invention is typically
formulated into pharmaceutical dosage forms to provide an easily
controllable and appropriate dosage of the drug.
[0376] The pharmaceutical composition (or formulation) for
application may be packaged in a variety of ways, depending upon
the method used to administer the drug. Generally, an article for
distribution includes a container having deposited therein the
pharmaceutical formulation in an appropriate form. Suitable
containers are well-known to those skilled in the art and include
materials such as bottles (plastic and glass), sachets, ampoules,
plastic bags, metal cylinders, and the like. The container may also
include a tamper-proof assemblage to prevent indiscreet access to
the contents of the package. In addition, the container has
deposited thereon a label that describes the contents of the
container. The label may also include appropriate warnings.
[0377] The present compounds may be systemically administered,
e.g., orally, in combination with a pharmaceutically acceptable
vehicle such as an inert diluent or a similar edible carrier. They
may be enclosed in hard or soft shell gelatin capsules, may be
compressed into tablets, or may be incorporated directly with the
food of the patient's diet. For oral therapeutic administration,
the active compound may be combined with one or more excipients and
used in the form of ingestible tablets, buccal tablets, troches,
capsules, elixirs, suspensions, syrups, wafers, and the like. Such
compositions and preparations should contain at least 0.1% of
active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be
between about 2 to about 60% of the weight of a given unit dosage
form. The amount of active compound in such therapeutically useful
compositions is such that an effective dosage level will be
obtained.
[0378] The tablets, troches, pills, capsules, and the like may also
contain the following: binders such as gum tragacanth, acacia, corn
starch or gelatin; excipients such as dicalcium phosphate; a
disintegrating agent such as corn starch, potato starch, alginic
acid and the like; a lubricant such as magnesium stearate; and a
sweetening agent such as sucrose, fructose, lactose or aspartame or
a flavoring agent such as peppermint, oil of wintergreen, or cherry
flavoring may be added. When the unit dosage form is a capsule, it
may contain, in addition to materials of the above type, a liquid
carrier, such as a vegetable oil or a polyethylene glycol. Various
other materials may be present as coatings or to otherwise modify
the physical form of the solid unit dosage form. For instance,
tablets, pills, or capsules may be coated with gelatin, wax,
shellac or sugar and the like. A syrup or elixir may contain the
active compound, sucrose or fructose as a sweetening agent, methyl
and propylparabens as preservatives, a dye and flavoring such as
cherry or orange flavor. Of course, any material used in preparing
any unit dosage form should be pharmaceutically acceptable and
substantially non-toxic in the amounts employed. In addition, the
active compound may be incorporated into sustained-release
preparations and devices.
[0379] Carriers may include excipients and diluents and must be of
sufficiently high purity and sufficiently low toxicity to render
them suitable for administration to the patient being treated. The
carrier can be inert or it can possess pharmaceutical benefits of
its own. The amount of carrier employed in conjunction with the
compound is sufficient to provide a practical quantity of material
for administration per unit dose of the compound.
[0380] Useful solid carriers may include finely divided solids such
as talc, clay, microcrystalline cellulose, silica, alumina, and the
like. Useful liquid carriers include water, alcohols or glycols or
water-alcohol/glycol blends, in which the present compounds can be
dissolved or dispersed at effective levels, optionally with the aid
of non-toxic surfactants. Adjuvants such as fragrances and
additional antimicrobial agents can be added to optimize the
properties for a given use. The resultant liquid compositions can
be applied from absorbent pads, used to impregnate bandages and
other dressings, or sprayed onto the affected area using pump-type
or aerosol sprayers.
[0381] Thickeners such as synthetic polymers, fatty acids, fatty
acid salts and esters, fatty alcohols, modified celluloses or
modified mineral materials can also be employed with liquid
carriers to form spreadable pastes, gels, ointments, soaps, and the
like, for application directly to the skin of the user.
[0382] The pharmaceutical compositions can be formulated for oral
administration. Preferred oral dosage forms are formulated for once
a day or twice a day administration. The compositions contain
between 0.1 and 99% weight of a compound of Formula (I). In some
embodiments, compositions contain at least about 5% weight of a
compound of Formula (I). In some embodiments, compositions contain
from about 25% to about 50% weight of a compound of Formula (I), or
about 5% to 75% weight of a compound of Formula (I).
Dosages
[0383] Useful dosages of the compounds of Formula (I) can be
determined by comparing their in vitro activity and in vivo
activity in animal models. Methods for the extrapolation of
effective dosages in mice, and other animals, to humans are known
to the art. Useful dosages of the compounds of Formula (I) can be
determined by comparing their in vitro activity, and in vivo
activity in animal models. Methods for the extrapolation of
effective dosages in mice, and other animals, to humans are known
to the art (e.g., U.S. Pat. No. 4,938,949).
[0384] Optimal dosages to be administered in the therapeutic
methods of the present invention may be determined by those skilled
in the art and will depend on multiple factors, including the
particular composition in use, the strength of the preparation, the
mode and time of administration, and the advancement of the disease
or condition. Additional factors may include characteristics on the
subject being treated, such as age, weight, gender, and diet.
[0385] In general, however, a suitable dose will be in the range
from about 0.01 to about 100 mg/kg, more specifically from about
0.1 to about 100 mg/kg, such as 10 to about 75 mg/kg of body weight
per day, 3 to about 50 mg per kilogram body weight of the recipient
per day, 0.5 to 90 mg/kg/day, or 1 to 60 mg/kg/day (or any other
value or range of values therein). The compound is conveniently
administered in a unit dosage form; for example, containing about 1
to 1000 mg, particularly about 10 to 750 mg, and more particularly,
about 50 to 500 mg of active ingredient per unit dosage form.
[0386] The desired dose may conveniently be presented in a single
dose or as divided doses administered at appropriate intervals, for
example, as two, three, four or more sub-doses per day. The
sub-dose itself may be further divided, e.g., into a number of
temporally-distinct administrations used according to the
compositions and methods of the present invention.
[0387] Effective amounts or doses of the active agents of the
present invention may be ascertained by routine methods such as
modeling, dose escalation studies or clinical trials, and by taking
into consideration routine factors, e.g., the mode or route of
administration or drug delivery, the pharmacokinetics of the agent,
the severity and course of the disease, disorder, or condition, the
subject's previous or ongoing therapy, the subject's health status
and response to drugs, and the judgment of the treating physician.
Such compositions and preparations should contain at least 0.1% of
active compound. The percentage of the compositions and
preparations may, of course, be varied and may conveniently be
between 2 to about 60% of the weight of a given unit dosage form.
The amount of active compound in such therapeutically useful
composition is such that an effective dosage level will be
obtained. An exemplary dose is in the range from about 0.001 to
about 200 mg of active agent per kg of subject's body weight per
day, preferably about 0.05 to 100 mg/kg/day, or about 1 to 35
mg/kg/day, or about 0.1 to 10 mg/kg/daily in single or divided
dosage units (e.g., BID, TID, QID). For a 70-kg human, an
illustrative range for a suitable dosage amount is from 1 to 200
mg/day, or about 5 to 50 mg/day.
[0388] In certain embodiments a therapeutically effect amount is an
amount that provide a plasma Cmax of HNK of about of 0.25 mcg/mL to
about 125 mcg/mL, or about 1 mcg/mL to about 50 mcg/mL.
Methods and Uses
Uses of Isotopically-Labeled Compounds
[0389] In one aspect, the present invention provides a method of
using isotopically labeled compounds the present invention in: (i)
metabolic studies (preferably with .sup.14C), reaction kinetic
studies (with, for example .sup.2H or .sup.3H); (ii) detection or
imaging techniques, including drug or substrate tissue distribution
assays; or (iii) in radioactive treatment of patients.
[0390] Isotopically labeled compounds and prodrugs of the invention
thereof can generally be prepared by carrying out the procedures
disclosed in the schemes or in the examples and preparations
described below by substituting a readily available isotopically
labeled reagent for a non-isotopically labeled reagent. An .sup.18F
or .sup.11C labeled compound may be particularly preferred for PET,
and an I.sup.123 labeled compound may be particularly preferred for
SPECT studies. Further substitution with heavier isotopes such as
deuterium (i.e., .sup.2H) may afford certain therapeutic advantages
resulting from greater metabolic stability, for example increased
in vivo half-life or reduced dosage requirements.
[0391] Recent research suggests that low-dose ketamine can act as a
novel, rapid-acting antidepressant [Naughton et al. 2014]. In fact,
a single subanesthetic dose infusion of ketamine has rapid and
potent antidepressant effects in treatment-resistant major
depression and bipolar depression [Iadarola et al. 2015]. Ketamine
as an antidepressant agent is of great interest as an alternative
to the delayed onset to efficacy, repeated administration and
unwanted side effects of current pharmacotherapeutics, behavioral
therapies and electroconvulsive therapy (ECT).
Therapeutic Methods
Generally
[0392] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of treating
certain disorders by administering to a subject in need thereof an
effective amount of a chemical entity of the present invention. In
some embodiments, the chemical entity is a compound of Formula (I),
or a pharmaceutically acceptable salt thereof. In some embodiments,
the subject is a human.
[0393] In some embodiments, a chemical entity of Formula (I) may be
the only active agent administered in methods disclosed herein or
may be administered together with an additional active agent.
[0394] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of enhancing
neuronal plasticity an essential property of the brain that can be
augmented in healthy animals and impaired in numerous CNS
disorders. Without being limited by mechanism, such chemical
entities may enhance neuronal plasticity by enhancing cyclic
adenosine monophosphate (cAMP) response element binding protein
(CREB) pathway function in cells, resulting in the modulation of
transcription of genes involved in synaptic plasticity. See, e.g.,
Tully et al., Nat. Rev. Drug Discov. 2003, 2, 267-277; Alberini,
Physiol. Rev. 2009, 89, 121-145. Accordingly, the present invention
provides a method of enhancing neuronal plasticity, comprising
administering to a subject in need thereof an effective amount of a
chemical entity of the present invention. In some embodiments, the
chemical entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof, in preferred embodiments, the subject is a
human.
[0395] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) to augment the
efficiency of training protocols, which facilitate functional
reorganization in targeted "domains" (or "functions") in the brain.
Training protocols can be directed to rehabilitating or enhancing a
cognitive or motor function. The training protocol (cognitive or
motor training) induces neuronal activity in specific brain regions
and produces improved performance of a specific brain (cognitive or
motor) function. In such protocols, chemical entities may act as
"augmenting agents" to shorten the time that methods of
rehabilitating (or enhancing) a cognitive or motor function result
in improved performance or a functional gain.
[0396] Such augmented training therefore comprises a specific
training protocol for a particular brain function, such as that
underlying declarative memory, performance of a fine motor skill, a
specific locomotor function, language acquisition, executive
function, etc., and a general administration of an augmenting
agent.
Neurological Disorders
[0397] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of treating a
neurological disorder, comprising administering to a subject in
need thereof an effective amount of a chemical entity or
composition of the present disclosure. In some embodiments, the
chemical entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof. In preferred embodiments, the subject is a
human.
[0398] In some embodiments, the methods are directed to a cognitive
deficit ("cognitive impairment") or motor deficit ("motor
impairment") associated with (or "due to") the neurological
disorder. Accordingly, in some embodiments, the disclosure provides
a method for treating a cognitive deficit associated with a
neurological disorder, comprising administering to a subject in
need thereof an effective amount of a chemical entity of Formula
(I).
[0399] A neurological disorder (or condition or disease) is any
disorder of the body's nervous system. Neurological disorders can
be categorized according to the primary location affected, the
primary type of dysfunction involved, or the primary type of cause.
The broadest division is between peripheral nervous system (PNS)
disorders and central nervous system (CNS) disorders (such as
mental and psychiatric disorders). Neurological disorders are
well-known in the art, and they include, but are not limited to,
the following mental and psychiatric disorders:
[0400] Neurodevelopmental (or "developmental" disorders), such as
intellectual disability disorders (e.g., Rubinstein-Taybi syndrome,
Down syndrome); communication disorders; autism-spectrum disorders;
attention-deficit/hyperactivity disorders; specific learning,
language, or reading (e.g., dyslexia) disorders; motor disorders;
fetal alcohol spectrum disorders (FASD); and other
neurodevelopmental disorders;
[0401] Schizophrenia spectrum and other psychotic disorders, such
as schizophrenia, schizotypal (personality) disorder, delusional
disorder, and schizophreniform disorder, and other schizophrenia
spectrum and psychotic disorders;
[0402] Bipolar and related disorders, such as Bipolar I and II
disorders, cyclothymic disorders, and other bipolar and related
disorders;
[0403] Depressive disorders, such as major depressive disorder
(MDD), persistent depressive disorder (dysthymia), and other
depressive disorders;
[0404] Anxiety disorders, such as specific phobia, social anxiety
disorder, panic disorder, and generalized anxiety disorder (social
phobia);
[0405] Obsessive-compulsive and related disorders, such as
obsessive-compulsive disorder, body dysmorphic disorder, and other
obsessive-compulsive and related disorders;
[0406] Dissociative disorders, such as dissociative identity
disorder, dissociative amnesia, and other dissociative
disorders;
[0407] Disruptive, impulse-control, and conduct disorders, such as
conduct disorders, antisocial personality disorders, and other
disruptive, impulse-control, and conduct disorders;
[0408] Trauma- and stressor-related disorders, such as
posttraumatic stress disorder (PTSD), acute stress disorder (ASD),
adjustment disorders, and other trauma- and stressor-related
disorders;
[0409] Feeding and eating disorders, such as anorexia nervosa,
bulimia nervosa, and binge-eating disorder;
[0410] Sleep-wake disorders, such as insomnia, narcolepsy,
parasomnias, and other sleep-wake disorders;
[0411] Sexual disorders, such as arousal disorders, desire
disorders, substance and medication-induced dysfunctions, and other
sexual disorders;
[0412] Substance-related and addictive disorders, such as those
involving alcohol, drugs, stimulants, opioids, tobacco, and
non-substance-related disorders; and other substance-related and
addictive disorders; and
[0413] Personality disorders, such as paranoid personality
disorders, antisocial and borderline personality disorders,
avoidance personality disorders, and other personality
disorders.
[0414] In particular embodiments, the disorder is
schizophrenia.
[0415] In other embodiments, the neurological disorder is an
acquired disorder, in which the primary clinical feature is
impaired cognition. In other words, it is a disorder in which the
primary cognitive deficit has not been present since birth or very
early life and therefore represents a decline from a previously
attained level of functioning. Such disorders, which may be
referred to herein as "cognitive disorders" or "neurocognitive
disorders" include one or more of the following:
[0416] Delirium, such as substance-intoxication (or withdrawal)
delirium, medication-induced delirium, and other forms of
delirium;
[0417] Dementias and other cognitive impairments due to
neurodegenerative diseases, such as Alzheimer's disease,
Parkinson's disease, Huntington's disease, Lewy body disease,
Pick's disease, a prion disease (e.g., Creutzfeldt-Jakob disease),
Amyotrophic lateral sclerosis (ALS), multiple sclerosis,
frontotemporal lobar degeneration, and corticobasal degeneration;
dementia due to a vascular disease ("vascular disease"); and other
dementias and neurodegenerative diseases;
[0418] In some embodiments, the disclosure provides a method of
treating a neurological disorder, comprising administering to a
patient in need thereof an effective amount of a pharmaceutical
composition, wherein the neurological disorder is selected from the
group consisting of a depressive disorder, a pain disorder, a
cognitive disorder, and a neurodegenerative disorder, and a sleep
disorder.
[0419] Age-associated cognitive deficits, including age-associated
memory impairment (AAMI), also referred to as age-related memory
impairment (AMI) (See, e.g., Crook et al., Devel. Neuropsychol.
1986, 2, 261-276); and deficits affecting patients in early stages
of cognitive decline; as in Mild Cognitive Impairment (MCI) (See,
e.g., Arnaiz and Almkvist, Acta Neurol. Scand. Suppl. 2003, 179,
34-41).
[0420] Trauma-dependent losses of cognitive function, such as
vascular diseases due to stroke (e.g., ischemic or hemorrhagic
stroke) or ischemia; microvascular disease arising from diabetes or
arthrosclerosis; traumatic brain injury (TBI), such as brain
trauma, including subdural hematoma and brain tumor; head trauma
(closed and penetrating); head injury; tumors, such as nervous
system cancers, including cerebral tumors affecting the thalamic or
temporal lobe; hypoxia, and viral infection (e.g., encephalitis);
excitotoxicity; and seizures.
[0421] Cognitive impairments due to chemotherapy, such as
post-chemotherapy cognitive impairments (PCCI);
chemotherapy-induced cognitive dysfunction or impairments; chemo
brain; or chemo fog.
[0422] Such acquired disorders are not necessarily limited to
cognitive impairments. For example, trauma related disorders, such
as stroke, traumatic brain injury, head trauma, and head injury,
may also include impairments in other neurological functions, such
as impairments in motor functions.
[0423] Migraine variants, such as chronic migraine, basilar
migraine, vertebrobasilar migraine, status migrainosus, and other
forms of migraine;
[0424] As used herein, the terms "Neurodevelopment disorders,"
"Schizophrenia spectrum and other psychotic disorders," "Mood
disorders," "Bipolar and related disorders," "Depressive
disorders," "Anxiety disorders," "Obsessive-compulsive and related
disorders," "Dissociative disorders," "Disruptive, impulse-control,
and conduct disorders," "Trauma- and stressor-related disorders,"
"Feeding and eating disorders," "Sleep-wake disorders," "Sexual
disorders," "Substance-related and addictive disorders,"
Personality disorders," "Delirium," "Neurocognitive disorders,"
"Delirium," "Dementias," and "Trauma" includes treatment of those
mental disorders as described in the Diagnostic and Statistical
Manual of Mental Disorders (DSM-5; 5.sup.th ed., 2013, American
Psychiatric Association). The skilled artisan will recognize that
there are alternative nomenclatures and classification systems for
mental disorders, and that these systems evolve with medical and
scientific progress. Thus the terms described in this paragraph are
intended to include like disorders that are described in other
diagnostic sources.
Depressive Conditions
[0425] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of treating a
depressive condition (disorder), comprising administering to a
subject in need thereof an effective amount of a chemical entity or
composition of the present disclosure. In one aspect, the chemical
entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof. For example, anti-depressant-like effects
of low ketamine doses are associated with elevated AMPA receptor
function, supporting favorable physiochemical properties for HNK in
disclosed methods. See, e.g., Tizabi et al., Neuroscience 2012,
213, 72-80.
[0426] In a specific aspect, the depressive disorder is major
depressive disorder (MDD) (also referred to as "major depression"
or "clinical depression"). In another aspect, the depressive
disorder is persistent depressive disorder (dysthymia), MDD and
dysthymia are among the most common depressive disorders. Other
depressive disorders that can be treated include, but are not
limited to, psychotic depression, postpartum depression, seasonal
affective disorder (SAD), a mood disorder; depression due to
another medical condition such as cancer, chronic pain, chronic
stress, post-traumatic stress disorder, or a bipolar disorder.
[0427] A depressive condition is characterized by one or more
depressive symptoms. "Depressive symptoms" may include feelings of
persistent anxiousness, sadness, helplessness, hopelessness,
worthlessness, or pessimism; low energy; low mood; restlessness;
irritability; fatigue; loss of interest in pleasurable activities
or hobbies; aversion to activity; poor concentration or
indecisiveness; excessive guilt; insomnia; excessive sleepiness;
overeating; loss of appetite; thoughts of suicide; and suicide
attempts.
[0428] The presence, severity, frequency, and duration of
depressive symptoms vary on a case to case basis. In some
embodiments, a patient may have at least one, at least two, at
least three, at least four, or at least five of these symptoms.
Depressive symptoms may occur in the context of depressive
disorders, bipolar disorders, mood disorders due to a general
medical condition, substance-induced mood disorders, and other
unspecified mood disorders. In addition, depressive symptoms may
also be present in association with other psychiatric disorders,
including, but not limited to, psychotic disorders, cognitive
disorders, eating disorders, anxiety disorders and personality
disorders. The longitudinal course of the disorder, the hi story,
and type of symptoms, and etiologic factors help distinguish the
various forms of mood disorders from each other.
[0429] A "depression symptoms rating scale" refers to any one of a
number of standardized questionnaires, clinical instruments, or
symptom inventories utilized to measure symptoms and symptom
severity in depression. Such rating scales are often used in
clinical studies to define treatment outcomes, based on changes
from the study's entry point(s) to endpoint(s). Such depression
symptoms rating scales include, but are not limited to, The Quick
Inventory of Depressive-Symptomatology Self-Report (QIDS-SR16), the
17-Item Hamilton Rating Scale of Depression (HRSD17), the 30-Item
Inventory of Depressive Symptomatology (IDS-C30), or The
Montgomery-Asperg Depression Rating Scale (MADRS). Such ratings
scales may involve patient self-report or be clinician rated. A 50%
or greater reduction in a depression ratings scale score over the
course of a clinical trial (starting point to endpoint) is
typically considered a favorable response for most depression
symptoms rating scales. "Remission" in clinical studies of
depression often refers to achieving at, or below, a particular
numerical rating score on a depression symptoms rating scale (for
instance, less than or equal to 7 on the HRSD17; or less than or
equal to 5 on the QIDS-SR16; or less than or equal to 10 on the
MADRS). Such a score generally corresponds to minimal symptoms and
therefore a clinically desired outcome.
[0430] Accordingly, in some embodiments, the disclosure provides a
method for treating a symptom of depression, comprising
administering to a subject in need thereof a therapeutically
effective amount of a chemical entity of Formula (I). In one
aspect, the chemical entity is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof. In preferred embodiments,
the subject is a human. In one aspect, a therapeutically effective
amount is an amount effective to achieve remission on a depression
symptoms rating scale. In one aspect, the rating scale is HRSD17,
QIDS-R16, or MADRS. In another aspect, a therapeutically effective
amount is an amount effective to decrease symptoms, wherein a
decrease in depressive symptoms is at least a 50% reduction of
symptoms identified on a depression symptom rating scale, or a
score less than or equal to 7 on the HRSD17, or less than or equal
to 5 on the QID-SR16, or less than or equal to 10 on the MADRS.
[0431] In some embodiments, the methods of the present disclosure
can be used to treat major depressive disorder, Major depressive
disorder is typically defined as the presence of one or more major
depressive episodes that are not better accounted for by psychotic
disorder or bipolar disorder. For major depressive disorder, an
essential feature is a period of at least 2 weeks during which
there is either depressed mood or the loss of interest or pleasure
is nearly all activities, and for persistent depressive disorder,
an essential feature is a depressed mood that occurs for most of
the day, for more days that not, for at least 2 years, or at least
1 year for children and adolescents. See, American Psychiatry
Association Diagnostic and Statistical Manual of Mental Disorders
(5th edition).
[0432] In connection with treatment, "recovery" means that
remission, as defined herein, has sufficiently been sustained,
e.g., for 4 months or more, without a "relapse" (such that
continued well-being is expected). A relapse means that the patient
has experienced a return of the same index major depressive episode
(e.g., severe major depression) before reaching achieving the
criteria for recovery. A "recurrence" refers to the development of
a new major depressive disorder following recovery.
[0433] Accordingly, in some embodiments, chemical entities of the
present invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of treating
major depressive disorder, comprising administering to a subject in
need thereof a therapeutically effective amount of a chemical
entity or composition of the present disclosure. In one aspect, the
chemical entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof. In some embodiments, treatment results in
recovery without a relapse. In some embodiments, treatment prevents
relapse in subjects who previously achieved symptom remission. In
some embodiments, treatment prevents recurrence in subjects who
previously attained recovery from an initial major depressive
disorder. In some embodiments, treatment prevents recurrence for a
period of 6 months, 1 year, 2 years, or longer.
[0434] In some embodiments, the methods of the present disclosure
can be used to treat treatment resistant (or "treatment
refractory") depression. A treatment resistant patient may be
identified as one who fails to experience alleviation of one or
more symptoms of depression (e.g., persistent anxious or sad
feelings, feelings of helplessness, hopelessness, pessimism)
despite undergoing one or more standard pharmacological or
non-pharmacological treatment. In certain embodiments, a
treatment-resistant patient is one who fails to experience
alleviation of one or more symptoms of depression despite
undergoing treatment with two different antidepressant drugs. In
other embodiments, a treatment-resistant patient is one who fails
to experience alleviation of one or more symptoms of depression
despite undergoing treatment with four different antidepressant
drugs. A treatment-resistant patient may also be identified as one
who is unwilling or unable to tolerate the side effects of one or
more standard pharmacological or non-pharmacological treatment.
[0435] Accordingly, in certain embodiments, the invention relates
to methods for treating treatment-resistant depression by
administering to a subject in need thereof an effective amount of a
compound of Formula (I) or composition of the present disclosure.
In some embodiments, the treatment-resistant depression is unipolar
depression, including major depression, including unipolar major
depression. In some embodiments, the treatment-resistant depression
is bipolar depression, including a major depressive episode
associated with a bipolar disorder. In some embodiments, methods of
treating depression are contemplated when a patient has suffered
depression for e.g., 5, 6, 7, 8 or more weeks, or for a month or
more. In a specific aspect, the chemical entity is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0436] In some embodiments, the disclosure provides methods of
treating suicidal ideation. Suicidal ideations is generally
associated with depressive and other mood disorder. In addition, it
also can be associated with other mental disorders, life events,
and family events, all of which may increase the risk of suicidal
ideation. For example, many individuals with borderline personality
disorder exhibit recurrent suicidal behavior and suicidal thoughts.
Ketamine (and its metabolites) can offer a therapeutic option in
patients at imminent risk of suicide. See, Ballard et al., J.
Psych. Res. 2014, 58, 161-166; Wilkinson and Sanacora, Depress.
Anxiety 2016, 33, 711-717.
[0437] Accordingly, in specific embodiments, the disclosure
provides a method of treating suicidal ideation, comprising
administering to a subject in need thereof an effective amount of a
chemical entity of Formula (I) or composition of the present
disclosure. In a specific aspect, the chemical entity is a compound
of Formula (I), or a pharmaceutically, acceptable salt thereof. In
a specific aspect, suicidal ideation is associated with a
depressive disorder.
[0438] In some embodiments, the present disclosure provides methods
for rapidly treating a depressive disorder or condition. Current
antidepressants generally take several weeks or more to produce a
response. Recent research, however, suggests that a single low-dose
of ketamine can act as a novel, rapid-acting antidepressant with
minimal side effects. Naughton et al., J. Affect. Dis 2014, 156,
24-35; Muller et al., Ther. Adv. Psychopharmacol 2016, 6, 185-192.
Moreover; recent work indicates that the metabolism of
(R,S)-ketamine to HNK is essential for its antidepressant effects,
and that the (2R,6R)-HNK enantiomer exerts behavioral,
electroencephalographic, electrophysiological and cellular
antidepressant-related actions in mice. Zanos et al., Nature 2016,
533, 481-486. These results underscore favorable physiochemical
properties for HNK that are pertinent in the development of rapid
acting agents in depression--with particular importance to
treatment-resistant depressive disorders and depressive disorders
with suicidal ideation. See, e.g., DiazGranados et al., J Clin
Psychiatry 2010, 71, 1605-1611; Cusin et al., Am. J. Psych. 2012,
169, 868-869; Larkin et al., Int. Neuropsych. 14, 1127-1131;
Abdallah et al., Depress. Anxiety 2016, 33, 689-697.
Obsessive Compulsive Disorders
[0439] In some embodiments, the disclosure provides methods of
treating an obsessive-compulsive disorder (OCD). Without being
limited by mechanisms, several lines of neurochemical and genetic
evidence suggest that glutamate dysregulation may contribute to
obsessive-compulsive disorder (OCD) and that targeting glutamate
may be beneficial in treating refractory disease. Kariuki-Nyuthe et
al., Curr. Opin. Psych. 2014, 27, 32-37; Rodriguez et al.,
Neuropsychopharmacology. 2013, 38, 2475-2483; Pittenger, Psychiatr.
Ann. 2015, 45, 308-315. OCD may there therefore be amenable to
treatment by modulators of glutamate signaling, which can include
chemical entities of the present disclosure.
[0440] Accordingly, in certain embodiments, the disclosure provides
methods for treating OCD, comprising administering to a subject in
need thereof an effective amount of a chemical entity of Formula
(I) or composition of the present disclosure. In a specific aspect,
the chemical entity is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
Anxiety
[0441] In some embodiments, the disclosure provides methods of
treating an anxiety disorder, comprising administering to a subject
in need thereof an effective amount of a chemical entity of Formula
(I) or composition of the present disclosure. In a specific aspect,
the chemical entity is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
[0442] In a specific embodiment, chemical entities, including
compounds, of the present disclosure are used as anti-anxiety
(anxiolytic) agents to treat an anxiety disorder.
Bipolar Disorders
[0443] In some embodiments, the disclosure provides methods of
treating a bipolar disorder, comprising administering to a subject
in need thereof an effective amount of a chemical entity of Formula
(I) or composition of the present disclosure. In a specific aspect,
the chemical entity is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
[0444] In a specific embodiment, the bipolar disorder is bipolar I
disorder, bipolar II disorder, cyclothymic disorder, or other
bipolar and related disorders.
Trauma- and Stressor-Related Disorders
[0445] In some embodiments, the disclosure provides methods of
treating trauma- and stressor-related disorders, comprising
administering to a subject in need thereof an effective amount of a
chemical entity of Formula (I) or composition of the present
disclosure. In a specific aspect, the chemical entity is a compound
of Formula (I), or a pharmaceutically acceptable salt thereof.
Trauma- and stressor-related disorders involve exposure to a
traumatic or stressful event. See, e.g., Zhang et al.,
Psychopharmacology 2015, 232, 663-672. In one embodiment, the
disorder is post-traumatic stress disorder (PTSD), including
chronic PTSD. See, e.g., Feder et al., JAMA Psychiatry 2014, 71,
681-688. In another embodiment, the disorder is acute stress
disorder (ASD).
[0446] In some embodiments, the disclosure provides methods of
treating pain. For example, sub-anesthetic does of (R,S)-ketamine
have demonstrated efficacy in treating neuropathic and chronic
pain, including the treatment of patients suffering from complex
regional pain syndrome (CRPS). Goldberg et al., Pain Physician
2010, 13, 379-387. Moreover, analysis of plasma samples obtained
from CRPS patients receiving (R,S)-ketamine as a 5-day continuous
infusion reveals that the primary drug, (R,S)-ketamine, is not
primarily responsible for the therapeutic response and instead that
the active agents responsible for the therapeutic response may
include HNK metabolites. Moaddel et al., Talanta 2010, 15,
1892-1904. More generally, ketamine may be useful as an effective
analgesic in treating postoperative pain, chronic pain, intractable
cancer pain, uncontrolled severe pain, acute and subacute pain in
opioid-tolerant patients, and pain in palliative care patients.
See, e.g., Hirota and Lambert, Br. J. Anaesth. 2001, 107, 123-126;
Lossignol et at, Support Care Cancer 2005, 13, 188-93; Chazan et
al., J. Opioid Manag. 2008, 4, 173-180; Carstensen and Mollerand,
Br. J. Anaesth. 2010, 104, 410-406; Beaudoin et al., Acad. Emerg.
Med. 2014, 11, 1193-1202.
[0447] Accordingly, in certain embodiments, the disclosure provides
methods for treating pain, comprising administering to a subject in
need thereof an effective amount of a chemical entity of Formula
(I). In a specific aspect, the chemical entity is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0448] In some embodiments, an effective amount is an amount
effective to decrease painful symptoms, wherein a decrease in
painful symptom is at least a 50% reduction of painful symptoms on
a pain rating scale.
[0449] In some embodiments, pain is associated with a neurological
disorder. In particular embodiments, pain is associated with
complex regional pain syndrome (CRPS). In some embodiments, pain is
associated with chronic fatigue syndrome or fibromyalgia, and may
include muscle pain, myofascial pain, temporal summation, and
referred pain. See, e.g., Graven-Nielsen et al., Pain. 2000, 85,
483-491; Bennett, Curr. Opin. Rheumatol. 1998, 10, 95-103.
[0450] In some embodiments, the pain is chronic pain, acute pain,
subacute pain, neuropathic pain, post-operative pain; cancer pain,
inflammatory pain, visceral pain, migraine pain, headache, and
menstrual pain. In a specific embodiment, the pain is migraine
pain. See, Kaube et al., Neurology 2000, 55, 139-141. In a specific
embodiment, the pain is a headache, including a cluster headache.
See, e.g., Krusz et al., J. Pain 2010, 11, S43; Granata et al.,
Schmerz 2016, 30, 286-288. In a specific embodiment, the pain is
menstrual pain. See, e.g., U.S. Patent Appl. No. 2015-0313892;
Udoji and Ness, Pain Manag. 2013, 3, 387-394.
Other Indications
[0451] Studies have reported that glutamate receptor subunits are
expressed in cells found in many different tumors and cancers, such
as glioma, colorectal and gastric cancer, oral squamous cell
carcinoma, prostate cancer, melanoma, and osteosarcoma. See, e.g.,
Stepulak et al., Histochem. Cell Biol. 2009, 132, 435-445.
Accordingly, in certain embodiments, the disclosure provides
methods for treating cancer, comprising administering to a subject
in need thereof an effective amount of a chemical entity of Formula
(I). In a specific aspect, the chemical entity is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0452] Several studies indicate that ketamine action is associated
with anti-inflammatory effects in vivo and in some clinical
settings. See, e.g., Roytblat et al., Anesth. Analg. 1998, 87,
266-271; Mazar et al., Anesthesiology. 2005, 102; 1174-1181;
Suliburk et al., Surgery 2005, 138, 134-140; De Kock et al., CNS
Neurosci. Ther. 2013, 19, 403-410. Accordingly, in certain
embodiments, the disclosure provides methods for treating various
inflammatory conditions, such as autoimmune, acquired immune, or
drug-induced immune conditions, or inflammation caused by another
condition, comprising administering to a subject in need thereof an
effective amount of a chemical entity of Formula (I). In a specific
aspect, the chemical entity is a compound of Formula (I), or a
pharmaceutically acceptable salt thereof.
[0453] Studies suggest that intermittent ketamine infusions can
suppress compulsive behavior in eating disorders. See, e.g., Mills
et al., QJM 1998, 91, 493-503. Accordingly, in certain embodiments,
the disclosure provides methods for treating an eating disorder,
comprising administering to a subject in need thereof a
therapeutically effective amount of a chemical entity of Formula
(I). In a specific aspect, the chemical entity is a compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
[0454] In some embodiment, the present disclosure provides a method
of treating a seizure. See, e.g., Sheth et al., Neurology 1998, 51,
1765-1766. Accordingly, in certain embodiments, the disclosure
provides methods for treating a seizure, comprising administering
to a subject in need thereof a therapeutically effective amount of
a chemical entity of Formula (I). In a specific aspect, the
chemical entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof.
Cognitive Enhancement and Performance
[0455] Chemical entities of Formula (I) are also useful in
enhancing learning and memory, as well as other cognitive functions
that involve glutamatergic signaling, including attention and
alertness. For example, AMPA Receptor trafficking underlies
numerous experience-driven phenomena that range from forming
neuronal circuits to modifying behavior. See, e.g., Kessels and
Malinow, Neuron 2009, 12, 340-350; Anggono and Hugnair, Curr. Opin.
Neurobiol. 2012, 22, 461-469; Henley and Wilkinson, Dialogs in
Clinical Neuroscience 2013, 15, 11-27.
[0456] In addition, RMPA Receptor modulation has been implicated in
human cognitive performance, alertness, and recovery sleep. Boyle
et al., J. Psychopharm. 2012, 26, 1047-1057; Partin, Curr. Opin.
Pharmacol. 2015, 20, 46-53; Hagewoud et al., J. Sleep. Res. 2010,
19, 280-288. Accordingly, in some embodiments, the disclosure
provides methods of enhancing memory and cognition, as well as
treating memory and other cognitive deficits associated with normal
aging and age-related neurological disorders, comprising
administering to a subject in need thereof an effective amount of a
chemical entity of Formula (I). In a specific aspect, the chemical
entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof.
[0457] In other embodiments, the disclosure provides a method of
modulating sleep, comprising administering to a subject in need
thereof an effective amount of a chemical entity of Formula (I). In
some embodiments, the method of modulating sleep is promoting sleep
recovery after sleep deprivation. In a specific aspect, the
chemical entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof.
[0458] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of enhancing the
efficacy of cognitive behavioral therapy (CBT) for a neurological
disorder. CBT is a psychosocial intervention that is a widely used
for treating mental disorders. See, e.g., Hofmann et al., J.
Cognit. Ther. Res. 2012, 36, 427-440. CBT focuses on the
development of personal coping strategies that target solving
current problems and changing unhelpful patterns in cognitions
(e.g., thoughts, beliefs, and attitudes), behaviors, and emotional
regulation. Although originally designed to treat depression, CBT
can be used for a number of neurological disorders, including
obsessive compulsive disorder, generalized anxiety disorder, and
trauma- and stressor-related disorders, such as PTSD.
[0459] In some embodiments, chemical entities of the present
invention are useful in methods (or in the manufacture of a
medicament or composition for use in such methods) of enhancing the
efficacy of dialectical behavior therapy (DBT) for a neurological
disorder. DBT is a specific type of cognitive-behavioral
psychotherapy designed to help people change patterns of behavior
that are not helpful, such as self-harm, suicidal thinking, and
substance abuse. Since its development, it has also been used for
the treatment of other kinds of mental health disorders.
[0460] Accordingly, in some embodiments, the present disclosure
provides a method of administering to a subject undergoing CBT or
DBT for a neurological disorder a therapeutically effective amount
of a chemical entity of Formula (I). In a specific aspect, the
chemical entity is a compound of Formula (I), or a pharmaceutically
acceptable salt thereof. In a specific aspect, the neurological
disorder is depression. In another aspect, the neurological
disorder is obsessive compulsive disorder. In another aspect, the
neurological disorder is generalized anxiety disorder. In another
aspect, the neurological disorder is selected from trauma- and
stressor disorders, such as PTSD.
Treatment Combinations
[0461] In some embodiments, a compound of Formula (I) is
administered with another active agent to treat an indication
disclosed herein. In specific embodiments, the combination is
administered to treat depression, schizophrenia, Alzheimer's
disease, migraine variants with or without pain, Lou Gehrig's
disease (also called amyotrophic lateral sclerosis or ALS), or
pain. Such administration may be simultaneously or
sequentially.
[0462] Exemplary agents for treating depression include selective
serotonin reuptake inhibitors (SSRIs), such as sertraline,
fluoxetine, citalopram, escitalopram, paroxetine, fluvoxamine. and
trazodone, serotonin and norepinephrine reuptake inhibitors
(SNRIs), such as desvenlafaxine, duloxetine, levomilnacipran, and
venlafaxine; tricyclic antidepressants (TCAs), such as
amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, nortriptyline, protriptyline, and trimipramine;
monoamine oxidase inhibitors (MAOIs), such as isocarboxazid,
phenelzine, selegiline, and tranylcypromine; and other classes of
drugs, such as maprotiline, bupropion, vilazodone, nefazodone,
trazodone, vortioxetine, and mirtazapine.
[0463] Exemplary agents for treating schizophrenia include:
clozapine, aripiprazole, brexpiprazole, cariprazine, lurasidone,
paliperidone, quetiapine, risperidone, olanzapine, ziprasidone, and
iloperidone.
[0464] Exemplary agents for treating Alzheimer's Dementia include,
but are not limited to, donepezil, rivastigmine, galantamine,
marijuana-like cannabinoids, and memantine.
[0465] Exemplary agents for treating Migraines include, but are not
limited to, caffeine; acetaminophen; nonsteroidal anti-inflammatory
drugs (NSAIDs), such as aspirin, ibuprofen, naproxen, ketoprofen,
tolmetin, etodolac, nabumetone, piroxicam, and droxican;
cyclo-oxygenease-2 (Cox-2) inhibitors such as celcoxib; topiramate;
amitriptyline; sumatriptan, frovatriptan, rizatriptan, naratriptan;
almotriptan; eletriptan; botulinum toxin; narcotic pain medications
such as codeine, fentanyl, hydrocodone, hydromorphone, meperidine,
methadone, morphine, and oxycodone, centrally acting analgesics,
such as tramadol; and other classes of drugs, such as certain
anticonvulsants, antidepressants, psychostimulants, marijuana-like
cannabinoids, and corticosteroids.
[0466] Exemplary agents for treating ALS include riluzole.
[0467] Exemplary agents for treating pain include, but are not
limited to, acetaminophen; nonsteroidal anti-inflammatory drugs
(NSAIDs), such as aspirin, ibuprofen, naproxen, ketoprofen,
tolmetin, etodolac, nabumetone, piroxicam, and droxican;
cyclo-oxygenease-2 (Cox-2) inhibitors such as celcoxib narcotic
pain medications such as codeine, fentanyl, hydrocodone,
hydromorphone, meperidine, methadone, morphine, and oxycodone;
centrally acting analgesics, such as tramadol; and other classes of
drugs, such as certain anticonvulsants, antidepressants,
psychostimulants, marijuana-like cannabinoids, and
corticosteroids.
[0468] The preceding list of additional active agents is meant to
be exemplary rather than fully inclusive. Additional active agents
not included in the above list may be administered in combination
with a compound of Formula (I). The additional active agent will be
dosed according to its approved prescribing information, though in
some embodiments the additional active agent will be dosed at less
the typically prescribed dose and in some instances less than the
minimum approved dose.
EXAMPLES
[0469] The present disclosure is further illustrated by the
following non-limiting Examples. These Examples are understood to
be exemplary only, and they are not to be construed as limiting the
scope of the present disclosure.
[0470] Exemplary compounds can be described by reference to the
illustrative synthetic schemes for their general preparation below
and the specific examples to follow.
[0471] One skilled in the art will recognize that, to obtain the
various compounds herein, starting materials may be suitably
selected so that the ultimately desired substituents will be
carried through the reaction scheme with or without protection as
appropriate to yield the desired product. Alternatively, it may be
necessary or desirable to employ, in the place of the ultimately
desired substituent, a suitable group that may be carried through
the reaction scheme and replaced as appropriate with the desired
substituent. Unless otherwise specified, the variables are as
defined above in reference to Formula (I). Reactions may be
performed between -100.degree. C. and the reflux temperature of the
solvent. Reactions may be heated employing conventional heating or
microwave heating. Reactions may also be conducted in sealed
pressure vessels above the normal reflux temperature of the
solvent.
Synthetic Schemes
##STR00010##
[0473] In accordance with Scheme A, hydroxylimine compounds can
undergo a thermal rearrangement to give 2-aminocyclohexanones when
heated in the presence of a heat transfer fluid such as Dowtherm-A
at temperatures ranging from 100 to 240.degree. C.
[0474] Subsequent halogenation, under conditions known to one
skilled in the art, provides the haloketone. For example, treatment
of compounds of formula (II) with bromine in 48% hydrobromic acid
at temperatures ranging from 40 to 100.degree. C. affords
bromoketones of formula (III) as the hydrobromide salt.
[0475] Subsequent dehalogenation under basic conditions known to
one skilled in the art affords the enone. For example, treatment of
compounds of formula (III) in the presence of a base such as DBN,
DBU and the like, in a solvent such as ACN, at reflux, affords
compounds of formula (IV).
##STR00011##
[0476] In accordance with Scheme B, compounds of formula (IX) can
be synthesized in five steps from a compound of formula (II):
[0477] Treatment of compounds of formula (II) with an alkyl
chloroformate, under basic conditions known to one skilled in the
art, provides compounds of formula (V). For instance, treatment of
the 2-aminocyclohexanone of formula (II) with methyl chloroformate
in the presence of a base, such as Na.sub.2CO.sub.3 or the like, in
a solvent such a benzene, toluene, or the like, at temperatures
ranging from 65-110.degree. C., affords the methyl carbamate of
formula (V).
[0478] Subsequent treatment with a base, such as LDA or the like,
followed by a silylating agent such as TMSCl, or the like, in a
solvent, such as THF, and at temperatures between -78.degree. C.
and 22.degree. C. affords the corresponding trimethylsilyl enol
ether.
[0479] Oxidation with an oxidizing agent, such as mCPBA, in the
presence of a base, such as Na.sub.2CO.sub.3, and a solvent, such
as hexanes, at room temperature affords the hydroxyketone of
formula (VII).
[0480] Subsequent treatment with BSTFA in the presence of a base,
such as pyridine or the like, in a solvent, such as DCM, chloroform
or the like, at temperatures ranging from 30 to 80.degree. C.
affords the trimethylsilyl ether.
[0481] Deprotection of the carbamate protecting group and of the
trimethylsilyl ether affords compounds of formula (IX). For
example, treatment of trimethylsilyl ether (VIII) with TMSI in a
solvent, such as DCM, chloroform or the like, and methanol at room
temperature affords the amino alcohol of formula (IX).
##STR00012##
[0482] In accordance with Scheme C, imidates of Formula (XI) can be
synthesized in two steps from a 2-amino-6-bromocyclohexanone of
formula (III):
[0483] Treatment of compounds of formula (III) with an acid
chloride in the presence of a base, under conditions known to one
skilled in the art, provides compounds of formula (X).
Alternatively, treatment of the 2-amino-6-bromocyclohexanone with a
carboxylic acid and a coupling reagent, in the presence of a base,
under conditions known to one skilled in the art, also provides the
amide of formula (X). For example, treatment of compounds of
formula. (III) with an acid chloride, in the presence of a base,
such as TEA or the like, in a solvent such as chloroform, DCM or
the like affords an amide of formula (X).
[0484] Subsequent treatment with a base, such as NaH or the like,
in a solvent such as DMF, DMA or the like, affords an imidate of
formula (XI), wherein, R.sup.a.dbd.--H, --C.sub.1-6alkyl,
--C.sub.1-6haloalkyl, --C.sub.3-8alkenyl, --C.sub.3-8alkynyl,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, --(CH.sub.2).sub.nheterocycloalkyl,
--COR.sup.2, --CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, or --C(OH)R.sup.11R.sup.12.
##STR00013##
[0485] In accordance with Scheme D, imidates of Formula (XI) can be
synthesized in three steps from a 6-aminocyclohex-2-enone of
Formula (IV):
[0486] Treatment of compounds of formula (IV) with an acid chloride
in the presence of a base, under conditions known to one skilled in
the art, provides the amide of Formula (XII). Alternatively,
treatment of the 6-aminocyclohex-2-enone with a carboxylic acid and
a coupling reagent, in the presence of a base, under conditions
known to one skilled in the art, also provides the amide of Formula
(XII). For example, treatment of compounds of formula (IV) with an
acid chloride, in the presence of a base, such as TEA or the like,
in a solvent such as chloroform, DCM or the like, affords an amide
of formula (XII).
[0487] Subsequent treatment with a halogenation reagent, such as
NIS or the like, in the presence of a base, such as Et.sub.3N or
the like, in a solvent, such as DCM or chloroform, affords the
iodinated imidate of formula (XIII).
[0488] Subsequent treatment with Bu.sub.3SnH in a solvent, such as
DCM or the like, at temperatures ranging from 20 to 60.degree. C.
provides an imidate of formula (XI), wherein, R.sup.a.dbd.--H;
--C.sub.1-6alkyl, --C.sub.1-6haloalkyl, --C.sub.3-8alkenyl,
--C.sub.3-8alkynyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl,
--(CH.sub.2).sub.nheterocycloalkyl, --COR.sup.2,
--CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, or --C(OH)R.sup.11R.sup.12.
##STR00014##
[0489] In accordance with Scheme E, imidates of Formula (XI) can be
synthesized in two steps from a 2-amino-6-hydroxy-cyclohexanone of
Formula (IX).
[0490] Treatment of compounds of formula (IX) with an acid chloride
in the presence of a base, under conditions known to one skilled in
the art, provides the amide of Formula (XIV). Alternatively,
treatment of the 2-amino-6-hydroxycyclohexanone derivative with a
carboxylic acid and a coupling reagent, in the presence of a base,
under conditions known to one skilled in the art, also provides the
amide of Formula (IX). For example, treatment of the
2-amino-6-hydroxy-2-(2-chlorophenyl)cyclohexanone of Formula (IX)
with an acid chloride, in the presence of a base, such as TEA or
the like, in a solvent such as chloroform, DCM or the like affords
an amide of formula (XIV).
[0491] Subsequent treatment with ethylene glycol in the presence of
a base, such as NaOH or the like, at temperatures ranging from
150-22.degree. C. provides an imidate of formula (XI), wherein,
R.sup.a.dbd.--H, --C.sub.1-6alkyl, --C.sub.1-6haloalkyl,
--C.sub.3-8alkenyl, --C.sub.3-8alkynyl, --(CH.sub.2).sub.naryl,
--(CH.sub.2).sub.nheteroaryl, --(CH.sub.2).sub.ncycloalkyl,
--(CH.sub.2).sub.nheterocycloalkyl, --COR.sup.2,
--CONR.sup.3R.sup.4, --CR.sup.5R.sup.6NR.sup.7R.sup.8,
--CHR.sup.9R.sup.10, or --C(OH)R.sup.11R.sup.12. Alternatively,
heating intermediates of formula (XIV) at a temperature ranging
between 180-250.degree. C. and a pressure less than 0.5 mmHg for a
period of 1-5 h, followed by cooling to room temperature then
treatment with a solution of tetraethylammonium hydroxide in a
solvent, such as DCM or the like, then subsequent removal of
solvent and heating again at reduced pressure as previously
described, affords imidate compounds of formula (XI).
##STR00015##
[0492] In accordance with Scheme E, deprotection of a nitrogen
protecting group is performed under the appropriate conditions
known to one skilled in the art, depending on which protecting
group is used. In one instance, deprotection of carbamate
intermediates of formula (XV), wherein the carbamate protecting
group is 9-fluorenylmethyl carbamate (Fmoc), 2-trimethylsilylethyl
carbamate (TeOC), t-butyl carbamate (Boc), allyl carbamate (Alloc),
benzyl carbamate (Cbz) or the like, can be achieved under
conditions known to one skilled in the art. For example, FMC
deprotection with piperidine provides a compounds of formula (XVI),
wherein each R.sup.b independently=--H, -halo, --NH.sub.2,
--C.sub.1-8alkyl, --C.sub.1-8haloalkyl,
--(CH.sub.2).sub.nCONH.sub.2, --(CH.sub.2).sub.nCOOH,
--(CH.sub.2).sub.naryl, --(CH.sub.2).sub.nheteroaryl,
--(CH.sub.2).sub.ncycloalkyl, and --(CH.sub.2).sub.n
heterocycloalkyl, each optionally substituted, wherein n is
independently an integer selected from 0, 1, 2, 3, and 4; and
R.sup.c.dbd.--H, --C.sub.1-4alkyl, and --C.sub.1-4haloalkyl.
Alternatively, deprotection of sulfonamide intermediates of formula
(XV), wherein the sulfonamide protecting group is p-toluenesulfonyl
(Ts), trifluoromethanesulfonyl, trimethylsilylethanesulfonamide
(SES), tert-butylsulfonyl (Bus) or the like, can be achieved under
conditions known to one skilled in the art. For example, treatment
of a Ts protected compound of formula (XV) with a strong acid, such
as HBr or the like, in a solvent, such as acetic acid or the like,
provides a compound of formula (XVI), wherein R.sup.b and R.sup.c
are described above.
Chemistry:
[0493] In some embodiments, the following experimental and
analytical protocols, unless otherwise indicated, can be used to
obtain the resulting compounds.
[0494] Unless otherwise stated, reaction mixtures are magnetically
stirred at room temperature (rt) under an atmosphere of nitrogen.
Where solutions are "dried," they are generally dried over a drying
agent such as Na.sub.2SO.sub.4 or MgSO.sub.4. Where mixtures,
solutions, and extracts are "concentrated," they are typically
concentrated on a rotary evaporator under reduced pressure.
[0495] Reactions under microwave irradiation conditions are carried
out in a CEM Discover-SP with Activent microwave reaction
apparatus, model number 909150, or Biotage initiator, model number
355302.
[0496] Normal-phase flash column chromatography (FCC) is performed
on Silica (SiO.sub.2) using packed or prepackaged cartridges,
eluting with the indicated solvents.
[0497] Analytical LC/MS is obtained on a Waters 2695 Separations
Unit, 2487 Dual Absorbance Detector, Micromass ZQ fitted with ESI
Probe, or a Waters Acquity.TM. Ultra performance LC (UPLC) with PDA
e.lamda. and SQ detectors. Alternatively, LC-MS is performed on a
Waters Acquity UPLC-MS instrument equipped with a Acquity UPLC BEEF
C.sub.18 column (1.7 .mu.m, 2.1.times.50 mm) and the solvent system
A: 0.1% HCOOH in H.sub.2O and B: 0.1% HCOOH in ACN. Column
temperature is 45.degree. C.
[0498] Analytical SFC-MS is performed on a Waters UPC.sup.2-MS
instrument equipped with a Acquity UPC.sup.2 BEH 2-ethylpyridine
column (1.7 .mu.m, 2.1.times.50 mm) and the solvent system A:
CO.sub.2 and B: 0.1% NH.sub.4OH in MeOH. Column temperature is
55.degree. C. All compounds are run using the same elution
gradient, i.e., 3% to 35% solvent B in 0.75 min with a flow rate of
2.5 mL/min.
[0499] Preparative HPLC is performed on a Shimadzu SIL-10AP system
using a Waters SunFire.TM. OBD 30 mm.times.100 mm.times.2.5 .mu.m
(particle size) C.sup.18 column with a 15-minute gradient of
10-100% acetonitrile in water and 0.05% trifluoroacetic acid added
as a modifier to both phases. Elution profiles are monitored by IN
at 254 and 220 nm. Alternatively, preparative HPLC is performed on
a Waters Fractionlynx system equipped with a XBridge Prep C.sub.18
OBD column (5 .mu.m, 19.times.50 mm) and the solvent system:
H.sub.2O:ACN and 2% TFA in H.sub.2O. Specific elution gradients are
based on retention times obtained with an analytical UPLC-MS,
however, in general all elution gradients of H.sub.2O and ACN are
run over a 5.9 min run time with a flow rate of 40 mL/min. An
autoblend method is used to ensure a concentration of 0.1% TFA
throughout each run.
[0500] Preparative SEC-MS is run on a Waters Prep100 SEC-MS system
equipped with a Viridis 2-ethylpyridine OBD column (5 .mu.m,
30.times.100 mm) and the solvent system: CO.sub.2:MeOH and 1%
NH.sub.4OH in MeOH. Specific elution gradients are based on
retention times obtained with an analytical UPC.sup.2-MS; however,
in general all elution gradients of CO.sub.2 and MeOH, are run over
a 3.6 min run time with a flow rate of 100 ml/min and a column
temperature of 55.degree. C. An autoblend method is used to ensure
a concentration of 0.2% NH.sub.4OH throughout each run.
[0501] Nuclear magnetic resonance (NMR) spectra can be obtained in
a Varian 400 MHz or Bruker 400 MHz NAIR.
[0502] Chemical names can be generated using ChemBioDraw Ultra 12.0
(CambridgeSoft Corp., Cambridge, Mass.) or ChemAxon (Budapest,
Hungary).
Intermediate 1. 2-amino-6-bromo-2-(2-chlorophenyl)cyclohexanone
Hydrobromide
##STR00016##
[0504] This compound may be prepared in the manner described in J.
Org. Chem., 1981, 46, 5055-5060, for example, in accordance with
the following:
[0505] Step 1. 2-Amino-2-(2-chlorophenyl)cyclohexanone. A solution
of 655 g (2.93 mol) of
1-((2-chlorophenyl)(imino)methyl)cyclopentanol in 750 mL of i-PrOH
is saturated with anhydrous HCl and then diluted to 1.5 L with
anhydrous Et.sub.2O. The crystals that form are removed by
filtration and dried to give
1-((2-chlorophenyl)(imino)methyl)cyclopentanol as the hydrochloride
salt. To 3 L of Dowtherm-A at 200.degree. C. is added 379 g (1.46
mol) of 1-((2-chlorophenyl)(imino)methyl)cyclopentanol
(hydrochloride salt) which causes the temperature to fall to
180.degree. C., where it is maintained for 7 min. The reaction
mixture is cooled to 10.degree. C., and the solid is removed by
filtration and dissolved in H.sub.2O. The filtrate is diluted to 3
L with Et.sub.2O and extracted with H.sub.2O. The combined aqueous
fractions are washed with Et.sub.2O, made basic with 50% aqueous
NAM, and extracted with Et.sub.2O. The ether layer is washed with
water, dried, de-colorized with charcoal, filtered through Celite,
and concentrated. The residue is distilled to give the title
compound.
[0506] Step 2: 2-Bromo-6-amino-6-(2-chlorophenyl)cyclohexanone
Hydrobromide. A solution of 298 g (1.33 mol) of
2-Amino-2-(2-chlorophenyl)cyclohexanone in 1.2 L of 48% aqueous HBr
is heated to 70.degree. C., and 216 g (1.35 mot) of bromine is
added dropwise. The mixture is stirred for 10 min after the
addition is complete and cooled to 5.degree. C., The crystals are
removed by filtration, washed copiously, with acetone, and dried to
give 408 g of the title compound, mp 142-145.degree. C. A second
crop (30 g, mp 142-145.degree. C.) is obtained by decolorizing and
concentrating the acetone washes. An NMR is run in D.sub.2O and
shows the presence of excess protons in the HOD peak. The entire
yield of 441 g is azeotroped in 500 mL of xylene, with the recovery
being 420 g (82%; mp 209-210.degree. C.) and the water collected in
a Dean-Stark trap corresponding to a monohydrate.
Intermediate 2. 1-amino-2'-chloro-5,6-dihydro-2(1H)-one
Hydrobromide
##STR00017##
[0508] This compound may be prepared in the manner described in J.
Org. Chem., 1981, 46, 5055-5060, for example, in accordance with
the following:
[0509] 6-Amino-6-(2-chlorophenyl)-2-cyclohexen-1-one. A solution of
35 g (0.28 mol) of 1,5-diazabicyclo[3.3.1]non-5-ene, 200 mL of
acetonitrile, and 74 g (0.25 mol) of
-Bromo-6-amino-6-(2-chlorophenyl)cyclohexanone (free base) is
refluxed for 20 h. The solvent is evaporated and the residue
diluted with ether and 5% aqueous NaOH. The layers are separated,
and the organic layer is extracted with 5% aqueous HCl. The
combined acid-water layers are decolorized with charcoal, filtered
through Celite, and made basic with 50% aqueous NaOH. The
crystalline precipitate is removed by filtration, is washed with
water, and is dried to give 31 g (57%) of the title compound, nip
120-123.degree. C.
Intermediate 3.
2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone
##STR00018##
[0511] This compound may be prepared in the manner described in J.
Med. Chem., 1986, 29, 2396-2399, for example, in accordance with
the follows:
[0512] Step 1.
2-(o-Chlorophenyl)-2-[(methoxycarbonyl)-aminocyclohexanone. To a
mixture of 2-amino-2-(2-chlorophenyl)cyclohexanone (3.0 g, 14 mmol)
in anhydrous benzene (100 mL) and Na.sub.2CO.sub.3 (4.5 g) is added
a solution of methyl chloroformate (3.0 mL, 40 mmol) in anhydrous
benzene (10 mL). After heating under reflux for 3 h, the reaction
mixture is cooled to room temperature and washed in turn with
H.sub.2O, 10% Na.sub.2CO.sub.3, and H.sub.2O again. The product is
diluted with either, dried (MgSO.sub.4), and concentrated under
reduced pressure, wherein the title compound precipitates as a
white solid.
[0513] Step 2.
2-(o-Chlorophenyl)-2-[(methoxycarbonyl)amino]-6-hydroxycyclohexanone.
To a cooled (0.degree. C.) mixture of diisopropylamine (4 mL, 28
mmol) and dry THF (30 mL) is added a solution of n-butyllithium in
hexane (1.6 M, 17 mL, 28 mmol). The reaction mixture is stirred at
0.degree. C. for 1 h, cooled to -78.degree. C., and treated
dropwise with a solution of
2-(o-Chlorophenyl)-2-[(methoxycarbonyl)-aminocyclohexanone (3.2 g,
11 mmol) in dry THY (20 mL). After stirring for a period of 2 h,
Me.sub.3SiCl (4 mL, 28 mmol) is added, and the reaction mixture is
stirred for 20 min before warming to room temperature over 45 min.
Hexane is then added, and the resulting solution is washed with 10%
NaHCO.sub.3 and H.sub.2O and dried (MgSO.sub.4), and the solvent is
removed in vacuo to afford the crude product as a yellow oil.
Purification by column chromatography on silica gel (75 g, 70-325
mesh, EtOAc as eluent) gives methyl
(2'-chloro-6-((trimethylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-biphen-
yl]-1-yl)carbamate as a clear yellow oil, yield 4.5 g (100%). To a
mixture of methyl
(2'-chloro-6-((trimethylsilyl)oxy)-1,2,3,4-tetrahydro-[1,1'-bip-
henyl]-1-yl)carbamate (4.46 g, 12.6 mmol) in hexane (60 mL) and
Na.sub.2CO.sub.3 (2.5 g) is added mCPBA (4.5 g, 20.8 mmol). The
reaction mixture is stirred at room temperature for 3 h, and the
product is washed (10% Na.sub.2SO.sub.3, then H.sub.2O), dried
(MgSO.sub.4), and evaporated to give a white solid. Column
chromatography on silica gel (75 g, 70-325 mesh, 5% CH.sub.3CN in
CH.sub.2Cl.sub.2 as eluent) gives the title compound as an oil.
[0514] Step 3. 2-(o-Chlorophenyl)-2-amino-6-hydroxycyclohexanone
(6-Hydroxynorketamine). To a solution of
2-(o-Chlorophenyl)-2-[(methoxycarbonyl)amino]-6-hydroxycyclohexanone
(3.5 g, 12 mmol) in anhydrous CH.sub.2Cl.sub.2 (80 mL) is added
BSTFA (4 mL, 15 mmol) and dry pyridine (0.2 mL). The mixture is
heated under reflux for 1 h, and excess reagents are removed in
vacuo to give methyl
(1-(2-chlorophenyl)-2-oxo-3-((trimethylsilyl)oxy)cyclohexyl)carbamate
as a white solid: A solution of methyl
(1-(2-chlorophenyl)-2-oxo-3-((trimethylsilyl)oxy)cyclohexyl)carbamate
(4.5 g, 12 mmol) in dry CH.sub.2Cl.sub.2 (80 mL) is treated
dropwise with Me.sub.3SiI (3 mL, 17 mmol), and the resulting
mixture is stirred at room temperature for 30 min. Methanol (80 mL)
is then added, the mixture is washed (10% Na.sub.2SO.sub.3, then
H.sub.2O) and dried (Na.sub.2SO.sub.4), and the solvent is
evaporated to give the crude product as a yellow oil (1.0 g).
Column chromatography on silica gel (10 g, 70-325 mesh, EtOAc as
eluent) gives the title compounds as a pure oil.
Intermediate 4.
N-(3-bromo-1-(2-chlorophenyl)-2-oxocyclohexyl)formamide
##STR00019##
[0516] To a suspension of
2-amino-6-bronco-2-(2-chlorophenyl)cyclohexanone hydrobromide
(Intermediate 1, 1.0 equiv) in DMF (0.2 M) is added DIEA (3
equiv.), HATU (1.2 equiv) and formic acid (1.5 equiv.) then the
reaction mixture is stirred at room temperature for 2 h, and then
the reaction is quenched with a saturated solution of NaHCO.sub.3.
The aqueous layer is extracted with EtOAc (3.times.). The combined
organic layer is dried (Na.sub.2SO.sub.4) and evaporated. The
residue is purified to give the title compound.
Intermediate 5.
(1S,5R,8S)-5-(2-chlorophenyl)-8-iodo-3-(1-((4-methoxybenzyl)oxy)ethyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one
##STR00020##
[0518] This compound may be prepared by methods known in the art,
such as that described in Molecules, 2011, 16, 7691-7705.
[0519] Step 1. To a suspension of
1-amino-2'-chloro-5,6-dihydro-[1,1'-biphenyl]-2(1H)-one
hydrobromide (Intermediate 2, 1.0 equiv.) in CHCl.sub.3 (0.26 M) is
added. Et.sub.3N (2 equiv.) and 2-((4-methoxybenzyl)oxyl)propanoyl
chloride (1.15 equiv.) and the reaction mixture is stirred at room
temperature for 2 h, and then washed with H.sub.2O two times. The
aqueous layer is extracted with EtOAc three times. The combined
organic layer is dried (Na.sub.2SO.sub.4) and evaporated, and the
residue is recrystallized to give
N--((R)-2'-chloro-6-oxo-1,2,3,6-tetrahydro-[1,1'-biphenyl]-1-yl)-2-((4-me-
thoxybenzyl)oxy)propanamide.
[0520] Step 2. A solution of
N--((R)-2'-chloro-6-oxo-1,2,3,6-tetrahydro-[1,
1'-biphenyl]-1-yl)-2-((4-methoxybenzyl)oxyl)propanamide (1.0 equiv)
in CH.sub.2Cl.sub.2 (0.13 M) is treated with MS (1.0 equiv) and
subsequently stirred for 14 h at room temperature. When the
reaction is complete, the mixture is washed with 10% NaOH solution
three times. The aqueous solution is extracted with
CH.sub.2Cl.sub.2 three times and the combined organic phase is
dried (Na.sub.2SO.sub.4) and evaporated to give the title
compound.
Intermediate 6.
N-(1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)acetamide
##STR00021##
[0522] This compound may be prepared in a manner analogous to that
described in J. Med. Chem, 2007, 50, 5311-5323, for example, as
follows.
[0523] To a solution of
2-amino-2-(2-chlorophenyl)-6-hydroxycyclohexanone (Intermediate 3,
1.0 equiv) in methanol (0.05 M) is added acetic anhydride (1.1
equiv.) and the reaction mixture is stirred at room temperature for
4 h. Upon completion of the reaction, the solution is neutralized
with a 10% sodium bicarbonate solution (pH=8) then made basic with
a 10% ammonia solution (pH=10). The organic layer is extracted with
dichloromethane, washed with brine, dried (Na.sub.2SO.sub.4) and
then the solvent is evaporated. The crude residue is purified by
column chromatography to give the title compound.
Example 1.
(1R,5R)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-en-9--
one
##STR00022##
[0525] This compound may be prepared in a manner analogous to that
described in J. Org. Chem., 2007, 72, 8656-8670, J. Org. Chem.,
2011, 76, 680-683, and Org. Lett., 2016, 18, 948-951, for example,
as follows.
[0526] A solution of
N-(3-bromo-1-(2-chlorophenyl)-2-oxocyclohexyl)formamide
(Intermediate 4, 1.0 equiv) in dry DMF (0.06 M) is treated with NaH
(1.0 equiv) at 0.degree. C. The reaction mixture is stirred at
0.degree. C. for 15 min and then at room temperature until TLC or
LCMS reveals the disappearance of the starting material Next, the
reaction mixture is quenched with H.sub.2O and extracted three
times with Et.sub.2O. The combined organic layers are washed with
H.sub.2O three times and dried over Na.sub.2SO.sub.4. Flash
chromatography on silica gel affords the desired compound.
Example 2. (1R,5R)-5-(2-chlorophenyl)-3-(1-hydroxyethyl)-2-oxa-4
azabicyclo[3.3.1]non-3-en-9-one
##STR00023##
[0528] This compound may be prepared in a manner analogous to that
described in Molecules, 2011, 16, 7691-7705, as follows.
[0529] Step 1. Bu.sub.3SnH (2.1 equiv.) is added to a solution of
(1S,5R,8S)-5-(2-chlorophenyl)-8-iodo-3-(1-((4-methoxybenzyl)oxy)ethyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one (Intermediate 5, 1.0 equiv)
in dry CH.sub.2Cl.sub.2 (0.1 M) under Ar. After stirring for 20 h
at 40.degree. C., the solvent is evaporated off and the residue is
purified by column chromatography on silica gel (n-hexane:EtOAc
10:1) to afford
(1R,5R)-5-(2-chlorophenyl)-3-(1-(0-methoxybenzyl)oxy)ethyl)-2-oxa-4-azabi-
cyclo[3.3.1]non-3-en-9-one.
[0530] Step 2. To a solution of
(1R,5R)-5-(2-chlorophenyl)-3-(1-((4-methoxybenzyl)oxy)ethyl)-2-oxa-4-azab-
icyclo[3.3.1]non-3-en-9-one (1.0 equiv) in a mixture of
dichloromethane/water (100:1, 0.06 M) at 0.degree. C. is added DDQ
(1.2 equiv) and the resulting mixture is stirred at room
temperature for several hours. Upon completion of the reaction, the
reaction mixture is washed with a 40% aqueous sodium
hydrogencarbonate solution, followed by brine. The organic layer is
dried (Na.sub.2SO.sub.4) and solvent is removed under reduced
pressure. The crude product is purified to give the title
compound.
Example 3.
(1R,5R)-5-(2-chlorophenyl)-3-methyl-2-oxa-4-azabicyclo[3.3.1]no-
n-3-en-9-one
##STR00024##
[0532] This compound may be prepared in a manner analogous to that
described in J Med. Chem., 2007, 50, 5311-5323, as follows.
[0533] Step 1. To a suspension of
N-(1-(2-chlorophenyl)-3-hydroxy-2-oxocyclohexyl)acetamide
(Intermediate 6, 1.0 equiv) in freshly distilled ethylene glycol
(0.02 M) is added sodium hydroxide (0.2 equiv). After heating at
215 for 6 h. the mixture is then made basic with a 10% ammonia
solution (pH=10) and extracted with dichloromethane. The organic
layer is dried over Na.sub.2SO.sub.4 and filtered, and the solvent
is evaporated to give the title compound.
[0534] The compounds of Examples 4-61, corresponding to the (1R,5R)
enantiomers, may each be prepared in a manner analogous to those of
Examples 1-3, with appropriate starting material substitutions and
protection or deprotection steps as would be appreciated by those
of skill in the art. In addition, the corresponding (1S,5S)
enantiomers of Examples 1-61 can be synthesized in a manner similar
to that described using the appropriate starting material
substitutions and synthetic procedures as known to one skilled in
the art.
Example 4.
(1R,5R)-3-((S)-1-amino-2-methylpropyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one
##STR00025##
[0535] Example 5.
(1R,5R)-3-(aminomethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-3-
-en-9-one
##STR00026##
[0536] Example 6.
(1R,5R)-5-(2-chlorophenyl)-3-fluorocarbonyl-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one
##STR00027##
[0537] Example 7.
(1R,5R)-5-(2-chlorophenyl)-3-(S))-1,5-diaminopentyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one
##STR00028##
[0538] Example 8.
(1R,5R)-3-((S)-1-aminoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one
##STR00029##
[0539] Example 9.
(1R,5R)-5-(2-chlorphenyl)-3-phenyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e
##STR00030##
[0540] Example 10.
(1R,5R)-3-((1S,2R))-1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-aza-
bicyclo[3.3.1]non-3-en-9-one
##STR00031##
[0541] Example 11.
(1R,5R)-3-((S)-1-amino-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one
##STR00032##
[0542] Example 12.
(1R,5R)-3-((S)-1-amino-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one
##STR00033##
[0543] Example 13.
(1R,5R)-3-((S)-1-amino-2-(4-hydroxyphenyl)-5-(2-chlorophenyl)-2-oxa-4-aza-
bicyclo[3.3.1]non-3-en-9-one
##STR00034##
[0544] Example 14.
(1R,5R)-3-((S)-1-amino-2-(1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-
-azabicyclo[3.3.1]non-3-en-9-one
##STR00035##
[0545] Example 15.
(1R,5R)-3-((S)-1-amino-2-(1H-imidazol-4-yl)ethyl)-5-(2-chlorophenyl)-2-ox-
a-4-azabicyclo[3.3.1]non-3-en-9-one
##STR00036##
[0546] Example 16.
(1R,5R)-5-(2-chlorophenyl)-3-(pyrrolidin-2-yl)-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-9-one
##STR00037##
[0547] Example 17.
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanoic Acid
##STR00038##
[0548] Example 18.
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanoic Acid
##STR00039##
[0549] Example 19.
(S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)butanamide
##STR00040##
[0550] Example 20.
(S)-3-amino-3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-3-yl)propanamide
##STR00041##
[0551] Example 21.
(1R,5R)-3-((S)-1-amino-3-(methylthio)propyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one
##STR00042##
[0552] Example 22.
(1R,5R)-3-((R)-1-amino-2-mercaptoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one
##STR00043##
[0553] Example 23.
(1R,5R)-3-(S)-1-amino-2-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyc-
lo[3.3.1]non-3-en-9-one
##STR00044##
[0554] Example 24.
(1R,5R)-3-((S)-1-amino-2-methoxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one
##STR00045##
[0555] Example 25.
1-((S)-4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3-
.1]non-3-en-3-yl)butyl)guanidine
##STR00046##
[0556] Example 26.
(1R,5R)-5-(2-chlorophenyl)-3-ethyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-on-
e
##STR00047##
[0557] Example 27.
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2-hydroxypropanoic Acid
##STR00048##
[0558] Example 28.
2-(((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3--
yl)methyl)-2-hydroxysuccinic Acid
##STR00049##
[0559] Example 29.
5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)pentanoic Acid
##STR00050##
[0560] Example 30.
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)-2,3-dihydroxypropanoic Acid
##STR00051##
[0561] Example 31.
3-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en-3-y-
l)propanoic Acid
##STR00052##
[0562] Example 32.
(1R,5R)-5-(2-chlorophenyl)-3-heptyl-2-oxa-4-azabicyclo[3.3.1]non-3-en-9-o-
ne
##STR00053##
[0563] Example 33.
(1R,5R)-3-(1-amino-2-hydroselenoethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one
##STR00054##
[0564] Example 34.
(1R,5R)-5-(2-chlorophenyl)-3-(2-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one
##STR00055##
[0565] Example 35.
(1R,5R)-5-(2-chlorophenyl)-3-(1,2-diaminoethyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one
##STR00056##
[0566] Example 36.
(1R,5R)-3-(2-amino-1-hydroxyethyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[-
3.3.1]non-3-en-9-one
##STR00057##
[0567] Example 37.
(1R,5R)-3-(3-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one
##STR00058##
[0568] Example 38.
(1R,5R)-3-(4-aminobutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non--
3-en-9-one
##STR00059##
[0569] Example 39.
(1R,5R)-3-(3-aminopentyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one
##STR00060##
[0570] Example 40.
(1R,5R)-3-(1-amino-3-hydroxypropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo-
[3.3.1]non-3-en-9-one
##STR00061##
[0571] Example 41.
(1R,S1)-5-(2-chlorophenyl)-3-(1,4-diaminobutyl)-2-oxa-4-azabicyclo[3.3.1]-
non-3-en-9-one
##STR00062##
[0572] Example 42.
4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non--
3-en-3-yl)-N-ethylbutanamide
##STR00063##
[0573] Example 43.
(1R,5R)-5-(2-chlorophenyl)-3-(1,5-diamino-4-hydroxypentyl)-2-oxa-4-azabic-
yclo[3.3.1]non-3-en-9-one
##STR00064##
[0574] Example 44.
1-(4-amino-4-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)butyl)urea
##STR00065##
[0575] Example 45.
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)urea
##STR00066##
[0577] Example 46.
1-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)guanidine
##STR00067##
Example 47.
1-(2-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]non-3-en--
3-yl)ethyl)guanidine
##STR00068##
[0578] Example 48.
(1R,5R)-3-(1-amino-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3-
.3.1]non-3-en-9-one
##STR00069##
[0579] Example 49.
(1R,5R)-3-(1-amino-2-(5-hydroxy-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2-
-oxa-4-azabicyclo[3.3.1]non-3-en-9-one
##STR00070##
[0580] Example 50.
(1R,5R)-3-(1-amino-2-(5-methyl-1H-indol-3-yl)ethyl)-5-(2-chlorophenyl)-2--
oxa-4-azabicyclo[3.3.1]non-3-en-9-one
##STR00071##
[0581] Example 51.
(1R,5R)-3-(2-(1H-indol-3-yl)-1-(methylamino)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one
##STR00072##
[0582] Example 52.
(1R,5R)-5-(2-chlorophenyl)-3-(4-hydroxypyrrolidin-2-yl)-2-oxa-4-azabicycl-
o[3.3.1]non-3-en-9-one
##STR00073##
[0583] Example 53.
(1R,5R)-3-(1-amino-2-hydroxy-3-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one
##STR00074##
[0584] Example 54.
(1R,5R)-5-(2-chlorophenyl)-3-(1-(methylamino)ethyl)-2-oxa-4-azabicyclo[3.-
3.1]non-3-en-9-one
##STR00075##
[0585] Example 55.
(1R,5R)-3-(2-aminopropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicyclo[3.3.1]non-
-3-en-9-one
##STR00076##
[0586] Example 56.
N-(5-amino-5-((1R,5R)-5-(2-chlorophenyl)-9-oxo-2-oxa-4-azabicyclo[3.3.1]n-
on-3-en-3-yl)pentyl)-3-methyl-3-methyl-3,4-dihydro-2H-pyrrole-2-carboxamid-
e
##STR00077##
[0587] Example 57.
(1R,5R)-3-(1-amino-3-hydroxy-2-methylbutyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one
##STR00078##
[0588] Example 58.
(1R,5R)-3-(1-amino-2,2-dimethylpropyl)-5-(2-chlorophenyl)-2-oxa-4-azabicy-
clo[3.3.1]non-3-en-9-one
##STR00079##
[0589] Example 59.
(1R,5R)-3-(amino(3-amino-4-hydroxyphenyl)methyl)-5-(2-chlorophenyl)-2-oxa-
-4-azabicyclo[3.3.1]non-3-en-9-one
##STR00080##
[0590] Example 60.
(1R,5R)-3-(1-amino-2-hydroxy-2-phenylethyl)-5-(2-chlorophenyl)-2-oxa-4-az-
abicyclo[3.3.1]non-3-en-9-one
##STR00081##
[0591] Example 61.
(1R,5R)-3-(1-amino-2-(4-methoxyphenyl)ethyl)-5-(2-chlorophenyl)-2-oxa-4-a-
zabicyclo[3.3.1]non-3-en-9-one
##STR00082##
[0592] Models for Evaluating Anti-Depressant Activity
[0593] In this prophetic example, animal behavioral tests known in
the art are used to evaluate the antidepressant efficacy of
exemplary compounds of Formula (I). Such tests may be based on
various attributes of depression, such as behavioral despair (e.g.,
Forced Swim), anxiety (e.g., Novelty Suppressed Feeding test), or
exposure to uncontrollable stressors (e.g., Learned
Helplessness).
Forced Swim Test
[0594] The Forced Swim Test (FST) is a widely used tool in
depression research particularly for evaluating the acute efficacy
of candidate antidepressants. In the FST, mice are placed in an
inescapable transparent tank filled with water and are evaluated
for their escape related mobility behavior. See, e.g., Can et al.,
2012, J. Vis. Exp. 59, e3638.
[0595] In some embodiments, mice are administered exemplary
compounds of Formula (I) and exhibit a longer duration of
escape-directed behaviors in the FST, compared to
vehicle-administered controls.
Novelty Suppressed Feeding Test:
[0596] The Novelty Suppressed Feeding Test (MSFT) is based on the
rationale that feeding to novelty is an anxiety symptom in rodents
that can be evoked by novel environmental features, including novel
food, novel testing area, and novel food containers. See, e.g.,
Santarelli el al., 2003, Science 301, 805-809. The test reflects
the anti-anxiety effects of antidepressants, with a response
measured after administration with candidate antidepressants.
[0597] In some embodiments, mice are administered exemplary
compounds of Formula (I) and exhibit a decreased latency to feed in
the NSFT, compared to vehicle-administered controls.
Learned Helplessness:
[0598] The learned helplessness test (LHT) is based on the
observation that animals develop deficits in escape, cognitive and
rewarded behaviors when subjected to repeated unavoidable and
uncontrollable shocks. See, e.g., J. B. Overmier and Seligman,
1967, J. Comp. Physiol. Psychol. 63, 28-33; Chourbaji et al., 2005,
Brain Res. Brain Res. Protoc. 16, 70-78; Zanos et al., 2016, Nature
533, 481-486.
[0599] In some embodiments, mice are administered exemplary
compounds of Formula (I) and exhibit reduced deficits in the
compared to vehicle-administered controls.
Pharmacokinetic Studies
[0600] In this prophetic example, pharmacokinetic profiles of
Formula (I) compounds are obtained by standard means known in the
art. For example, the pharmacokinetic profiles can be obtained from
animals, such as mammals, including primates (e.g., monkeys such as
Rhesus Macaques (Macaca mulatta), or humans).
[0601] Comparisons between pharmaceutical compositions can be
readily achieved through the examination of pharmacokinetic
profiles and/or parameters measured after administration of a
composition. Generally, a blood baseline drug concentration is
obtained prior to administration.
[0602] Post-administration, blood is drawn at various time points
for drug analysis. Typically, serum or plasma is isolated from the
blood samples and analyzed to determine the concentrations of the
therapeutic agent. Drug concentrations in plasma (or serum) samples
are analyzed by liquid chromatography-mass spectroscopy using
appropriate parameters for each compound.
[0603] Typically, a graph is created of the time (x-axis) versus
drug concentration (y-axis) and from this graph various
pharmacokinetic parameters can be derived. Alternately, the data
can be entered into a software program that will derive the
pharmacokinetic parameters and fit them to a graph of the measured
values.
[0604] Useful pharmacokinetic parameters in which to compare
formulations include maximal blood therapeutic concentration
(Cmax), time to reach Cmax (Tmax), time to reach a blood
concentration of 1/2 of Cmax (T1/2), and bioavailability (BA).
Typically, BA is measured by determining an area under the curve
(AUC) of a blood therapeutic concentration versus time graph. For
comparative analysis between pharmaceutical compositions, the
pharmacokinetic parameters can be compared individually, or in
various combinations. Numerous, but non-limiting, pharmacokinetic
software programs can be used in practicing the teachings of the
present disclosure, such Phoenix WinNonlin software, version
5.2.
[0605] Exemplary compounds of the present disclosure are tested for
oral bioavailability. For such studies, the compounds can be
dissolved in various vehicles (e.g. PEG 400 solution and CMC
suspension) for intravenous and oral dosing in the rats. Following
administration, plasma samples are obtained and extracted. The
plasma concentrations of the starting compound and HNK metabolite
are determined by high performance liquid chromatography/tandem
mass spectrometry (LC/MS/MS) methods. Pharmacokinetic analyses are
performed based on the plasma concentration data.
[0606] In some embodiments, pharmacokinetic data are analyzed, and
significant levels of HNK metabolite are observed following oral
administration of formula (I) compounds. Without being limited by
mechanism, conversion of exemplary compounds of Formula (I) to the
HNK may include one or more of a physiochemical, metabolic, or
enzymatic process.
Therapeutic Administration of Formula (I) Compositions
[0607] The ability of compounds of the present disclosure to treat
the disorders described herein can be evaluated using a suitably
designed clinical study, such as that summarized below for a
depressive disorder.
[0608] In this prophetic example, a clinical trial comprises a
randomized, double-blind, placebo-controlled, multiple (21-day)
dose study in twenty otherwise-healthy male and female patients
with moderate-to-severe, major depressive disorder (as defined by
the American Psychiatry Association Diagnostic and Statistical
Manual of Mental Disorders (5th edition) and confirmed by the Mini
International Neuropsychiatric Interview) of severity (as assessed
by the Montgomery-.ANG.sberg Depression Rating Scale).
[0609] The patients are randomized into 2 cohorts. Subjects in
cohort 1 receive single doses of a Formula (I) solid dosage
formulation on days 1-21. Subject in cohort 2 are identical to
those for cohort 1, except that they receive single doses of
placebo on days 1-21.
[0610] For each cohort, multiple parameters, including
pharmacokinetics (PK), safety, and pharmacodynamics (PD) data are
evaluated. In addition, cognitive function in Cohorts 1 and 2 is
assessed using the CogState testing method, which comprises a
customizable range of computerized cognitive tasks able to measure
baseline and change in all cognitive domains. Specialized tasks in
CogState can assess attention, memory, executive function, as well
as language and social-emotional cognition.
[0611] Under the dosing duration of 3 weeks (21 days), there is
evidence of Formula (I) compound-induced changes on PD endpoints
that indicate an antidepressant effect. There is also evidence of a
rapid onset of antidepressant effects, in some cases following a
single dose. In addition, there is evidence of compound-induced
changes in cognitive domain function.
[0612] In another prophetic example, comparable results are
obtained from a similarly-designed clinical trial evaluating the
efficacy of Formula (I) compounds in treating male and female
patients with treatment-resistant depression (as defined by the
American Psychiatry Association Diagnostic and Statistical Manual
of Mental Disorders (5th Edition.
Conversion of Formula (I) Compositions
[0613] In this prophetic example, exemplary compounds of Formula
(I) yield HNK upon administration to a subject, such as a patient
in a clinical trial, in one or more steps. For example, in one
possible pathway illustrated in the following schematic, exemplary
compounds of Formula (I) may yield HNK in a two-step process,
consisting of hydrolysis in Step 1 under acid conditions, such as
those in the stomach, and subsequent enzymatic conversion by
esterase action.
##STR00083##
[0614] As a more specific example, a compound of Example 2 may give
rise to HNK and lactic acid by the proposed two-step process, as
illustrated in the following schematic.
##STR00084##
[0615] The preceding schematics are for illustration purposes only
and not intended to be limited to a particular mechanism or
pathway, as other scenarios are also possible.
[0616] While certain embodiments are described herein, it is
understood that the described embodiments are not intended to limit
the scope of the disclosure as defined by the appended claims. On
the contrary, the present disclosure is intended to cover
alternatives, modifications and equivalents that may be included
within the spirit and scope of the invention as defined by the
appended claims. Furthermore, certain details in the present
disclosure are provided to convey a thorough understanding of the
invention defined by the appended claims. However, it will be
apparent to those skilled in the art that certain embodiments may
be practiced without these details. In certain instances,
well-known methods, procedures, or other specific details have not
been described to avoid unnecessarily obscuring aspects of the
invention defined by the appended claims.
* * * * *