U.S. patent application number 17/832282 was filed with the patent office on 2022-09-22 for organic compounds.
The applicant listed for this patent is INTRA-CELLULAR THERAPIES, INC.. Invention is credited to Robert DAVIS, Peng LI, Sharon MATES, Gretchen SNYDER, Kimberly VANOVER, Wei YAO.
Application Number | 20220296591 17/832282 |
Document ID | / |
Family ID | 1000006381455 |
Filed Date | 2022-09-22 |
United States Patent
Application |
20220296591 |
Kind Code |
A1 |
LI; Peng ; et al. |
September 22, 2022 |
ORGANIC COMPOUNDS
Abstract
The invention relates to particular substituted heterocycle
fused gamma-carbolines, their prodrugs, in free, solid,
pharmaceutically acceptable salt and/or substantially pure form as
described herein, pharmaceutical compositions thereof, and methods
of use in the treatment of diseases involving the 5-HT.sub.2A
receptor, the serotonin transporter (SERT), pathways involving the
dopamine D.sub.1 and D.sub.2 receptor signaling system, and/or the
.mu.-opioid receptor.
Inventors: |
LI; Peng; (New Milford,
NJ) ; YAO; Wei; (New Milford, NJ) ; DAVIS;
Robert; (San Diego, CA) ; MATES; Sharon; (New
York, NY) ; VANOVER; Kimberly; (New York, NY)
; SNYDER; Gretchen; (New York, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INTRA-CELLULAR THERAPIES, INC. |
New York |
NY |
US |
|
|
Family ID: |
1000006381455 |
Appl. No.: |
17/832282 |
Filed: |
June 3, 2022 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
16634055 |
Jan 24, 2020 |
11376249 |
|
|
PCT/US2018/043100 |
Jul 20, 2018 |
|
|
|
17832282 |
|
|
|
|
62682546 |
Jun 8, 2018 |
|
|
|
62639244 |
Mar 6, 2018 |
|
|
|
62537287 |
Jul 26, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 23/00 20180101;
A61K 31/137 20130101; A61P 25/36 20180101; A61K 45/06 20130101;
A61K 9/0019 20130101; A61K 31/485 20130101; A61K 31/4985 20130101;
A61K 9/1647 20130101 |
International
Class: |
A61K 31/4985 20060101
A61K031/4985; A61P 25/36 20060101 A61P025/36; A61P 23/00 20060101
A61P023/00; A61K 9/00 20060101 A61K009/00; A61K 9/16 20060101
A61K009/16; A61K 31/137 20060101 A61K031/137; A61K 31/485 20060101
A61K031/485; A61K 45/06 20060101 A61K045/06 |
Claims
1. A method for the treatment or prophylaxis of a central nervous
system disorder, comprising administering to a patient in need
thereof a compound of a Formula I: ##STR00029## wherein: X is
--NH-- or --N(CH.sub.3)--; L is selected from O, NH, NR.sup.a, and
S; Z is --CH(O--R.sub.1)--, --O-- or --C(O)--; R.sub.1 is H,
--C(O)--C.sub.1-21 alkyl, optionally saturated or unsaturated and
optionally substituted with one or more hydroxy or C.sub.1-22
alkoxy groups; R.sup.a is: halogen, C.sub.1-4 alkyl, C.sub.2-4
alkenyl, C.sub.2-4 alkynyl, or C.sub.3-6 cycloalkyl, each of which
can be independently substituted with up to three independently
selected R.sup.b groups, for example C-.sub.1-3haloalkyl or
C.sub.1-3hydroxyalkyl; or aryl optionally substituted with up to
five independently selected R.sup.b; and each R.sup.b is
independently selected from H, halogen, NH.sub.2, NO.sub.2, OH,
C(O)OH, CN, SO.sub.3, and C.sub.1-4 alkyl; in free or salt form;
optionally in an isolated or purified free or salt form; wherein
the disease or disorder is selected from a pain disorder, a drug
dependency disorder, obsessive-compulsive disorder (OCD),
obsessive-compulsive personality disorder (OCPD), general anxiety
disorder, social anxiety disorder, panic disorder, agoraphobia,
compulsive gambling disorder, compulsive eating disorder, body
dysmorphic disorder, hypochondriasis, pathological grooming
disorder, kleptomania, pyromania, attention deficit-hyperactivity
disorder (ADHD), attention deficit disorder (ADD), impulse control
disorder, and related disorders, neuropathic pain, idiopathic pain,
chronic pain, fibromyalgia, opiate dependency, cocaine dependency,
amphetamine dependency, alcohol dependency, opiate overdose, and
combinations thereof.
2. The method according to claim 1, wherein L is O.
3. The method according to claim 1, wherein Z is
--CH(O--R.sub.1)--.
4. The method according to claim 1, wherein Z is --C(.dbd.O)--.
5. The method according to claim 1, wherein Z is --O--.
6. The method according to claim 1, wherein X is --NH--.
7. The method according to claim 1, wherein X is
--N(CH.sub.3)--.
8. The method according to claim 1, wherein the compound is
selected from the group consisting of: ##STR00030##
##STR00031##
9. The method according to claim 1, wherein the compound is
selected from the group consisting of: ##STR00032##
10. The method according to claim 1 wherein the compound is in the
form of a salt.
11. The method according to claim 1, wherein the compound is
administered to the patient in the form of a pharmaceutically
acceptable composition comprising the compound in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier.
12. The method of claim 11, wherein the pharmaceutically acceptable
diluent or carrier comprises a polymeric matrix.
13. The method according to claim 12, wherein the polymeric matrix
is a biodegradable poly(d,l-lactide-co-glycolide) microsphere.
14. The method according to claim 1 wherein the central nervous
system disorder is selected from idiopathic pain, neuropathic pain,
chronic pain, fibromyalgia, dental pain, and traumatic pain,
obsessive-compulsive disorder (OCD), obsessive-compulsive
personality disorder (OCPD), general anxiety disorder, social
anxiety disorder, panic disorder, agoraphobia, compulsive gambling
disorder, compulsive eating disorder, body dysmorphic disorder,
hypochondriasis, pathological grooming disorder, kleptomania,
pyromania, attention deficit-hyperactivity disorder (ADHD),
attention deficit disorder (ADD), impulse control disorder, and
related disorders.
15. The method according to claim 14, wherein the central nervous
system disorder is neuropathic pain or traumatic pain,
obsessive-compulsive disorder (OCD) or obsessive-compulsive
personality disorder (OCPD).
16. The method according to claim 14, wherein said patient is not
responsive to or cannot tolerate the side effects from, treatment
with selective serotonin reuptake inhibitors (SSRIs), treatment
with serotonin-norepinephrine reuptake inhibitors (SNRIs),
treatment with antipsychotic agents, and/or non-narcotic analgesics
and/or opioid drugs, or wherein the use of opioid drugs are
contraindicated in said patient.
17. The method according to claim 1, wherein said patient is not
responsive to or cannot tolerate the side effects from opioid
drugs, or wherein the use of opioid drugs are contraindicated in
said patient, and said opioid drugs are selected from morphine,
codeine, thebaine, oripavine, morphine dipropionate, morphine
dinicotinate, dihydrocodeine, buprenorphine, etorphine,
hydrocodone, hydromorphone, oxycodone, oxymorphone, fentanyl,
alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,
remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,
prodine, promedol, propoxyphene, dextropropoxyphene, methadone,
diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,
nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and
anileridine, or any combinations thereof, or wherein the patient is
not response to or cannot tolerate the side effects from treatment
with SSRIs selected from citalopram, escitalopram, fluoxetine,
fluvoxamine, paroxetine, and sertraline, or (SNRIs) selected from
venlafaxine, sibutramine, duloxetine, atomoxetine, desvenlafaxine,
milnacipran, and levomilnacipran, or antipsychotic agents selected
from clomipramine, risperidone, quetiapine and olanzapine.
18. The method according to claim 14, wherein said patient also
suffers from opioid use disorder.
19. The method according to claim 14, wherein the method further
comprises administration of an additional therapeutic agent
selected from an agonist or partial agonist, or inverse agonist or
antagonist, of the mu-opiate, kappa-opiate, delta-opiate, and/or
nociceptin/orphanin receptors.
20. (canceled)
21. The method according to claim 19, wherein said additional
therapeutic agent is selected from buprenorphine, methadone,
naloxone, and naltrexone.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 62/537,287, filed on Jul. 26, 2017; 62/639,244
filed on Mar. 6, 2018; and 62/682,546, filed on Jun. 8, 2018; the
contents of each of which are incorporated by reference in their
entirety.
FIELD OF THE INVENTION
[0002] The invention relates to new methods and uses pertaining to
particular substituted heterocycle fused gamma-carbolines, their
prodrugs, in free, solid, pharmaceutically acceptable salt and/or
substantially pure form as described herein, and pharmaceutical
compositions thereof, such as methods of use in the treatment of
diseases involving the 5-HT.sub.2A receptor, the serotonin
transporter (SERT), pathways involving dopamine D.sub.1 and D.sub.2
receptor signaling systems, and/or the .mu.-opioid receptor, e.g.,
diseases or disorders such as anxiety, psychosis, schizophrenia,
sleep disorders, sexual disorders, migraine, conditions associated
with cephalic pain, social phobias, gastrointestinal disorders such
as dysfunction of the gastrointestinal tract motility and obesity;
depression and mood disorders associated with psychosis or
Parkinson's disease; psychosis such as schizophrenia associated
with depression; bipolar disorder; mood disorders; drug
dependencies, such as opiate dependency and alcohol dependency,
drug withdrawal symptoms, and other psychiatric and neurological
conditions, as well as to combinations with other agents. In
addition, such compounds and compositions are useful in methods of
treatment of obsessive-compulsive disorder (OCD),
obsessive-compulsive personality disorder (OCPD), and related
disorders. In some embodiments, the disease or disorders may
include treatment-resistant depression, cocaine dependency, and/or
amphetamine dependency, opioid use disorder and the symptoms of
opioid withdrawal.
BACKGROUND OF THE INVENTION
[0003] Substituted heterocycle fused gamma-carbolines are known to
be agonists or antagonists of 5-HT.sub.2 receptors, particularly
5-HT.sub.2A and 5-HT.sub.2C receptors, in treating central nervous
system disorders. These compounds have been disclosed in U.S. Pat.
Nos. 6,548,493; 7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S.
RE39680, and U.S. RE39679, as novel compounds useful for the
treatment of disorders associated with 5-HT.sub.2A receptor
modulation such as obesity, anxiety, depression, psychosis,
schizophrenia, sleep disorders, sexual disorders migraine,
conditions associated with cephalic pain, social phobias,
gastrointestinal disorders such as dysfunction of the
gastrointestinal tract motility, and obesity. PCT/US08/03340 (WO
2008/112280), and its U.S. equivalent US 2010/113781, and U.S.
application Ser. No. 10/786,935 (published as US 2004/209864) also
disclose methods of making substituted heterocycle fused
gamma-carbolines and uses of these gamma-carbolines as serotonin
agonists and antagonists useful for the control and prevention of
central nervous system disorders such as addictive behavior and
sleep disorders.
[0004] In addition, WO/2009/145900 (and its equivalent US
2011/071080) discloses use of particular substituted heterocycle
fused gamma-carbolines for the treatment of a combination of
psychosis and depressive disorders as well as sleep, depressive
and/or mood disorders in patients with psychosis or Parkinson's
disease. In addition to disorders associated with psychosis and/or
depression, this patent application discloses and claims use of
these compounds at a low dose to selectively antagonize 5-HT.sub.2A
receptors without affecting or minimally affecting dopamine D.sub.2
receptors, thereby useful for the treatment of sleep disorders
without the side effects associated with high occupancy of the
dopamine D.sub.2 pathways or side effects of other pathways (e.g.,
GABA.sub.A receptors) associated with convention sedative-hypnotic
agents (e.g., benzodiazepines) including but not limited to the
development of drug dependency, muscle hypotonia, weakness,
headache, blurred vision, vertigo, nausea, vomiting, epigastric
distress, diarrhea, joint pains, and chest pains. WO 2009/114181
(and its equivalent US 2011/112105) also discloses of methods of
preparing toluenesulfonic acid addition salt crystals of these
substituted heterocycle fused gamma-carbolines.
[0005] In addition, recent evidence shows that the aforementioned
substituted fused heterocycle gamma carbolines may operate, in
part, through NMDA receptor antagonism via mTOR1 signaling, in a
manner similar to that of ketamine. Ketamine is a selective NMDA
receptor antagonist. Ketamine acts through a system that is
unrelated to the common psychogenic monoamines (serotonin,
norepinephrine and dopamine), and this is a major reason for its
much more rapid effects. Ketamine directly antagonizes
extrasynaptic glutamatergic NMDA receptors, which also indirectly
results in activation of AMPA-type glutamate receptors. The
downstream effects involve the brain-derived neurotrophic factor
(BDNF) and mTORC1 kinase pathways. Similar to ketamine, recent
evidence suggests that compounds related to those of the present
disclosure enhance both NMDA and AMPA-induced currents in rat
medial prefrontal cortex pyramidal neurons via activation of D1
receptors, and that this is associated with increased mTORC1
signaling.
[0006] Metabolites of compounds disclosed in the aforementioned
publications, as well as related compounds, are also disclosed in
WO 2017/132408 and US 2017/319580.
[0007] Obsessive-compulsive disorder (OCD) and related disorders,
have become highly prevalent and are difficult to treat. OCD is
estimated to affect about 2.3% of people at some point in their
lives, and during a given year, it is estimated than 1.2% of people
worldwide suffer from the disorder. Half of people who suffer from
OCD begin to show symptoms before the age of 20, which can
seriously affect their ability to obtain an adequate and effective
education. Without effective treatment, however, the disease can
last for decades. The mainstay of pharmacologic OCD treatment is
with selective serotonin reuptake inhibitors (SSRIs). A second line
of therapy is with antipsychotic agents, such as clomipramine,
risperidone, quetiapine and olanzapine. A significant number of
patients either do not respond to these agents, or cannot handle
the side effects caused by these agents. More recently, it has been
reported that the opioid analgesic tramadol may be effective in
treating OCD. Opiates operate by an entirely different pathway from
traditional OCD treatment agents, so they offer the possibility of
treatment for people who cannot take the traditional serotonergic
agents or for whom these agents are ineffective. However, strong
opiate agents can be addictive, and their use may be
contraindicated in some patients. There thus remains an urgent need
for new treatments for pain, OCD and other disorders.
[0008] Drug dependency disorders, such as opiate use disorder
(OUD), are another group of disorders which are difficult to
successfully treat. Opioid overdoses claim approximately 100 lives
in the United States every day, and the opioid epidemic continues
to grow in the United States. Methadone, buprenorphine, and
naltrexone are the most frequently used treatments for OUD.
Methadone is a mu-opioid receptor (MOP) agonist, buprenorphine is
an MOP partial agonist, and naltrexone is an MOP antagonist. Each
of these agents has had limited success, and long-term adherence to
prescribed therapies for OUD remains low. In addition, these
treatments often exacerbate common co-morbidities associated with
OUD, such as mood and anxiety disorders, which further increases
the risk of remission. Abrupt opioid abuse withdrawal (i.e., going
"cold turkey") is also associated with severe side effects,
including dysphoria, depression and anxiety, and the common
treatment agents do not address these problems, and may make them
worse. There is thus an urgent need for improved OUD
treatments.
SUMMARY OF THE INVENTION
[0009] The compounds of the present disclosure have been
unexpectedly found to have potent activity at serotonin receptors
(e.g., 5-HT.sub.2A), serotonin transporters (SERT), dopamine
receptors (e.g., D1 and/or D2), and Mu-opiate receptor, and they
further display the unique Mu-opiate receptor activity of a biased
ligand. It is also believed that the compounds of the present
disclosure, via their D1 receptor activity, may also enhance NMDA
and AMPA mediated signaling through the mTOR pathway.
[0010] The present disclosure provides Compounds of Formula I that
are useful for the treatment or prophylaxis of central nervous
system disorders. In a first aspect, the present disclosure relates
to a compound (Compound I) of Formula I:
##STR00001## [0011] wherein: [0012] X is --NH-- or --N(CH.sub.3)--;
[0013] L is selected from O, NH, NR.sup.a, and S; [0014] Z is
--CH(O--R.sub.1)--, --O-- or --C(.dbd.O)--; [0015] R.sub.1 is H,
--C(O)--C.sub.1-21 alkyl (e.g., --C(O)--C.sub.1-5 alkyl,
--C(O)--C.sub.6-15 alkyl or --C(O)--C.sub.16-21 alkyl), preferably
said alkyl is a straight chain, optionally saturated or unsaturated
and optionally substituted with one or more hydroxy or C.sub.1-22
alkoxy (e.g., ethoxy) groups, for example R.sub.1 is C(O)--C.sub.3
alkyl, --C(O)C.sub.6 alkyl, --C(O)--C.sub.7 alkyl, --C(O)--C.sub.9
alkyl, --C(O)--C.sub.11 alkyl, --C(O)--C.sub.13 alkyl or
--C(O)--C.sub.15 alkyl; [0016] R.sup.a is: [0017] halogen,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, or C.sub.3-6
cycloalkyl, each of which can be independently substituted with up
to three independently selected R.sup.b groups, for example
C-.sub.1-3haloalkyl or C.sub.1-3hydroxyalkyl; or [0018] aryl
optionally substituted with up to five independently selected
R.sup.b; and each R.sup.b is independently selected from H,
halogen, NH.sub.2, NO.sub.2, OH, C(O)OH, CN, SO.sub.3, and
C.sub.1-4 alkyl; [0019] in free or salt form, for example in an
isolated or purified free or salt form.
[0020] The present disclosure provides additional exemplary
embodiments of the Compound of Formula I, in free or salt form, for
example in an isolated or purified free or salt form, including:
[0021] 1.1 Compound I, wherein L is --O--; [0022] 1.2 Compound I or
1.1, wherein Z is --CH(O--R.sub.1)--; [0023] 1.3 Compound I or 1.1,
wherein Z is --C(.dbd.O)--; [0024] 1.4 Compound I, wherein L is NH.
[0025] 1.5 Compound I, wherein L is NR.sup.a; [0026] 1.6 Compound
I, wherein L is S; [0027] 1.7 Compound I or any of 1.1-1.6, in
solid form, for example in solid salt form; [0028] 1.8 Compound I
or any of 1.1-1.7, wherein Z is --CH(O--R.sub.1)--; [0029] 1.9
Compound I, or any of 1.1-1.7, wherein Z is --C(.dbd.O)--; [0030]
1.10 Compound I, or any of 1.1-1.7, wherein Z is --O--; [0031] 1.11
Compound I or any of 1.1-1.10, wherein X is --NH--; [0032] 1.12
Compound I or any of 1.1-1.10, wherein X is --N(CH.sub.3)--; [0033]
1.13 Compound I or any of 1.1-1.12, wherein L is --O-- and X is
--N(CH.sub.3)--; [0034] 1.14 Compound I or any of 1.1-1.12, wherein
L is --O-- and X is --NH--; [0035] 1.15 Compound 1.13, wherein Z is
--C(.dbd.O)--; [0036] 1.16 Compound 1.14, wherein Z is
--C(.dbd.O)--; [0037] 1.17 Compound I or any of 1.1-1.14, wherein Z
is --CH(O--R.sub.1)-- and R.sub.1 is H; [0038] 1.18 Compound I or
any of 1.1-1.14, wherein Z is --CH(O--R.sub.1)-- and R.sub.1 is
--C(O)--C.sub.1-5 alkyl, --C(O)--C.sub.6-15 alkyl or
--C(O)--C.sub.16-21 alkyl; [0039] 1.19 Compound I or any of
1.1-1.14, wherein Z is --CH(O--R.sub.1)-- and R.sub.1 is selected
from the group consisting of C(O)--C.sub.3 alkyl, --C(O)C.sub.6
alkyl, --C(O)--C.sub.7 alkyl, --C(O)--C.sub.9 alkyl,
--C(O)--C.sub.11 alkyl, --C(O)--C.sub.13 alkyl or --C(O)--C.sub.15
alkyl; for example, wherein R.sup.1 is acetyl, ethylcarbonyl, or
propylcarbonyl; [0040] 1.20 Compound I or any of 1.1-1.12 or
1.17-1.19, wherein L is NR.sup.a, and wherein R.sup.a is: halogen,
C.sub.1-4 alkyl, C.sub.2-4 alkenyl, C.sub.2-4 alkynyl, or C.sub.3-6
cycloalkyl, each of which can be independently substituted with up
to three independently selected R.sup.b groups; or wherein R.sup.a
is aryl optionally substituted with up to five independently
selected R.sup.b; wherein R.sup.b is independently selected from H,
halogen, NH.sub.2, NO.sub.2, OH, C(O)OH, CN, SO.sub.3, and
C.sub.1-4 alkyl; [0041] 1.21 Compound 1.20, wherein R.sup.a is
C.sub.1-4 alkyl or C.sub.3-6 cycloalkyl, optionally substituted
with up to three independently selected R.sup.b groups; [0042] 1.22
Compound 1.20, wherein R.sup.a is aryl, optionally substituted with
up to three independently selected R.sup.b groups; [0043] 1.23
Compound 1.20, wherein R.sup.a is selected from the group
consisting of methyl, ethyl, propyl, butyl, isopropyl, isobutyl,
sec-butyl, or phenyl; [0044] 1.24 Compound I, or any of 1.1-1.14 or
1.17-1.23, wherein Z is --CH(O--R.sub.1)--; and said carbon atom CH
in the group --CH(O--R.sub.1)-- has either the R configuration or
the S configuration, or a mixture thereof; [0045] 1.25 Compound
1.24, wherein the carbon atom CH is substantially present in either
the R configuration or the S configuration, e.g., wherein the
diastereomer having the R configuration or the S configuration at
this carbon is present in greater than 70% diastereomeric excess,
for example, greater than 75%, or greater than 80%, or greater than
85%, or greater than 90%, or greater than 95%, or greater than 97%,
or greater than 98% or greater than 99%, diastereomeric excess.
[0046] 1.26 Compound I, or any of 1.1-1.25, wherein the compound is
selected from the group consisting of:
[0046] ##STR00002## ##STR00003## [0047] 1.27 Compound I, or any of
1.1-1.25, wherein the compound is selected from the group
consisting of:
[0047] ##STR00004## [0048] 1.28 Compound I, or any of 1.1-1.27,
wherein the compound is
##STR00005##
[0048] in free or salt form (e.g., pharmaceutically acceptable salt
form); [0049] 1.29 Compound I, or any of 1.1-1.27, wherein the
compound is [0050] 1.30
##STR00006##
[0050] in free or salt form (e.g., pharmaceutically acceptable salt
form); [0051] 1.31 Compound I, or any of 1.1-1.27, wherein the
compound is [0052] 1.32
##STR00007##
[0052] in free or salt form (e.g., pharmaceutically acceptable salt
form); [0053] 1.33 Compound I, or any of 1.1-1.32, in free form;
[0054] 1.34 Compound I, or any of 1.1-1.32 in salt form, e.g.,
pharmaceutically acceptable salt form; [0055] 1.35 Compound I or
any of 1.1-1.34 in solid form. [0056] in free or salt form, for
example in an isolated or purified free or salt form.
[0057] In a second aspect, the present disclosure relates to a
compound (Compound II) of Formula II
##STR00008##
[0058] wherein: [0059] X is --NH-- or --N(CH.sub.3)--; [0060] Y is
--CH(O--R.sub.1)-- or --C(.dbd.O)--; [0061] R.sub.1 is H,
--C(O)--C.sub.1-21 alkyl (e.g., --C(O)--C.sub.1-5 alkyl,
--C(O)--C.sub.6-15 alkyl or --C(O)--C.sub.16-21 alkyl), preferably
said alkyl is a straight chain, optionally saturated or unsaturated
and optionally substituted with one or more hydroxy or C.sub.1-22
alkoxy (e.g., ethoxy) groups, for example R.sub.1 is C(O)--C.sub.3
alkyl, --C(O)C.sub.6 alkyl, --C(O)--C.sub.7 alkyl, --C(O)--C.sub.9
alkyl, --C(O)--C.sub.11 alkyl, --C(O)--C.sub.13 alkyl or
--C(O)--C.sub.15 alkyl; [0062] in free or salt form, for example in
an isolated or purified free or salt form.
[0063] The present disclosure provides additional exemplary
embodiments of the Compound of Formula II, in free or salt form,
for example in an isolated or purified free or salt form,
including: [0064] 2.1 Compound II, wherein X is --NH--; [0065] 2.2
Compound II, wherein X is --N(CH.sub.3)--; [0066] 2.3 Compound II,
or 2.1-2.4, wherein Y is --C(.dbd.O)--; [0067] 2.4 Compound II,
wherein Y is --CH(O--R.sub.1)--; i.e., having the Formula II-A:
[0067] ##STR00009## [0068] 2.5 Compound TI, or 2.1-2.4, wherein Y
is --CH(O--R.sub.1)--; [0069] 2.6 Compound II, wherein X is NH and
Y is --C(.dbd.O)--; i.e., having the Formula II-B:
[0069] ##STR00010## [0070] 2.7 Compound II, wherein X is --NH-- and
Y is --CH(O--R.sub.1)--; [0071] 2.8 Compound II, wherein X is
--NH-- and Y is --CH(O--R.sub.1)--, wherein R.sub.1 is H; i.e.,
having the Formula II-C:
[0071] ##STR00011## [0072] 2.9 Compound II, wherein X is
--N(CH.sub.3)-- and Y is --C(.dbd.O)--; i.e., having the Formula
II-D:
[0072] ##STR00012## [0073] 2.10 Compound II, wherein X is
--N(CH.sub.3)-- and Y is --CH(O--R.sub.1)--; [0074] 2.11 Compound
II, wherein X is --N(CH.sub.3)-- and Y is --CH(O--R.sub.1)--,
wherein R.sub.1 is H; i.e. having the Formula II-E:
[0074] ##STR00013## [0075] 2.12 Compound II or any of 2.1-2.11, in
solid form, for example in solid salt form.
[0076] In a third aspect, the present disclosure relates to a
compound (Compound III) of Formula III:
##STR00014##
[0077] wherein: [0078] X is --NH-- or --N(CH.sub.3)--; [0079]
R.sub.1 is H, --C(O)--C.sub.1-21 alkyl (e.g., --C(O)--C.sub.1-5
alkyl, --C(O)--C.sub.6-15 alkyl or --C(O)--C.sub.16-21 alkyl),
preferably said alkyl is a straight chain, optionally saturated or
unsaturated and optionally substituted with one or more hydroxy or
C.sub.1-22 alkoxy (e.g., ethoxy) groups, for example R.sub.1 is
C(O)--C.sub.3 alkyl, --C(O)C.sub.6 alkyl, --C(O)--C.sub.7 alkyl,
--C(O)--C.sub.9 alkyl, --C(O)--C.sub.11 alkyl, --C(O)--C.sub.13
alkyl or --C(O)--C.sub.15;
[0080] in free or salt form, for example in an isolated or purified
free or salt form.
[0081] The present disclosure provides additional exemplary
embodiments of the Compound of Formula III, in free or salt form,
for example in an isolated or purified free or salt form.
including: [0082] 3.1 Compound III, wherein R.sub.1 is H; i.e.,
having the Formula III-A:
[0082] ##STR00015## in free or salt form, for example in an
isolated or purified free or salt form; [0083] 3.2 Compound III or
3.1, wherein X is --NH--; [0084] 3.3 Compound III or 3.1, wherein X
is --N(CH.sub.3)--; [0085] 3.4 Compound 3.1, wherein X is --NH--;
i.e., having the Formula III-B:
[0085] ##STR00016## [0086] 3.5 Compound 3.1, wherein X is
--N(CH.sub.3)--; i.e., having the Formula III-C:
[0086] ##STR00017## [0087] 3.6 Compound III or any of 3.1-3.5,
wherein the Compound has a diastereomeric excess of greater than
70%; [0088] 3.7 Compound III or any of 3.1-3.6, wherein the
Compound has a diastereomeric excess of greater than 80%; [0089]
3.8 Compound III or any of 3.1-3.7, wherein the Compound has a
diastereomeric excess of greater than 90%; [0090] 3.9 Compound III
or any of 3.1-3.8, wherein the Compound has a diastereomeric excess
of greater than 95%; [0091] 3.10 Compound III or any of 3.1-3.9,
wherein the Compound is in substantially pure diastereomeric form
(i.e., substantially free from other diastereomers) [0092] 3.11
Compound III or any of 3.1-3.10, in solid form, for example in
solid salt form.
[0093] In a fourth aspect, the present disclosure relates to a
compound (Compound IV) of Formula IV:
##STR00018##
[0094] wherein: [0095] X is --NH-- or --N(CH.sub.3)--; [0096]
R.sub.1 is H, --C(O)--C.sub.1-21 alkyl (e.g., --C(O)--C.sub.1-5
alkyl, --C(O)--C.sub.6-15 alkyl or --C(O)--C.sub.16-21 alkyl),
preferably said alkyl is a straight chain, optionally saturated or
unsaturated and optionally substituted with one or more hydroxy or
C.sub.1-22 alkoxy (e.g., ethoxy) groups, for example R.sub.1 is
C(O)--C.sub.3 alkyl, --C(O)C.sub.6 alkyl, --C(O)--C.sub.7 alkyl,
--C(O)--C.sub.9 alkyl, --C(O)--C.sub.11 alkyl, --C(O)--C.sub.13
alkyl or --C(O)--C.sub.15 alkyl;
[0097] in free or salt form, for example in an isolated or purified
free or salt form.
[0098] The present disclosure provides additional exemplary
embodiments of the Compound of Formula IV, in free or salt form,
for example in an isolated or purified free or salt form,
including: [0099] 4.1 Compound IV, wherein R.sub.1 is H; i.e.,
having the Formula IV-A:
[0099] ##STR00019## in free or salt form, for example in an
isolated or purified free or salt form. [0100] 4.2 Compound IV or
4.1, wherein X is --NH--; [0101] 4.3 Compound IV or 4.1, wherein X
is --N(CH.sub.3)--; [0102] 4.4 Compound 4.1, wherein X is --NH--;
i.e., having the Formula IV-B:
[0102] ##STR00020## [0103] 4.5 Compound 4.1, wherein X is
--N(CH.sub.3)--; i.e., having the Formula IV-C:
[0103] ##STR00021## [0104] 4.6 Compound IV or any of 4.1-4.5,
wherein the Compound has a diastereomeric excess of greater than
70% [0105] 4.7 Compound IV or any of 4.1-4.6, wherein the Compound
has a diastereomeric excess of greater than 80% [0106] 4.8 Compound
IV or any of 4.1-4.7, wherein the Compound has a diastereomeric
excess of greater than 90% [0107] 4.9 Compound IV or any of
4.1-4.8, wherein the Compound has a diastereomeric excess of
greater than 95% [0108] 4.10 Compound IV or any of 4.1-4.9, wherein
the Compound is in substantially pure diastereomeric form (i.e.,
substantially free from other diastereomers); [0109] 4.11 Compound
IV or any of 4.1-4.10, in solid form, for example in solid salt
form.
[0110] In a fifth aspect, the present disclosure provides each of
the foregoing Compound I or 1.1-1.35, Compound II or 2.1-2.12,
Compound III or 3.1-3.11, or Compound IV or 4.1-4.11 (hereinafter
collectively "Compounds of Formulas I-IV et seq." or "compounds of
the disclosure") in free or pharmaceutically acceptable salt form.
The present disclosure provides additional exemplary embodiments of
the Compounds of Formulas I-IV et seq., including: [0111] 5.1
Compounds of Formulas I-IV et seq., wherein the salt is an acid
addition salt selected from hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric, acetic, propionic, succinic,
glycolic, stearic, lactic, malic, tartaric, citric, ascorbic,
pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic,
salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, isethionic, and the
like; [0112] 5.2 Compounds of Formulas I-IV et seq., wherein the
salt is fumaric acid addition salt; [0113] 5.3 Compounds of
Formulas I-IV et seq., wherein the salt is phosphoric acid addition
salt; [0114] 5.4 Compounds of Formulas I-IV et seq., wherein the
salt is a toluenesulfonic acid addition salt; [0115] 5.5 Any of
5.1-5.4 wherein the salt is in solid form.
[0116] In a sixth aspect, the present disclosure provides a
pharmaceutical composition (Pharmaceutical Composition 6)
comprising a compound according to any one of Compound I or
1.1-1.35, Compound II or 2.1-2.12, Compound III or 3.1-3.11, or
Compound IV or 4.1-4.11 (collectively, Compounds of Formulas I-IV
et seq. or compounds of the disclosure), e.g., in admixture with a
pharmaceutically acceptable diluent or carrier. The present
disclosure provides additional exemplary embodiments of
Pharmaceutical Composition 6, including: [0117] 6.1 Pharmaceutical
Composition 6, comprising Compound I or any of 1.1-1.35; [0118] 6.2
Pharmaceutical Composition 6, comprising Compound II or any of
2.1-2.12; [0119] 6.3 Pharmaceutical Composition 6, comprising
Compound III or any of 3.1-3.11; [0120] 6.4 Pharmaceutical
Composition 6, comprising Compound IV or any of 4.1-4.11; [0121]
6.5 Pharmaceutical Composition 6 or any of 6.1-6.4, wherein the
Compound of Formula I-IV et seq. is in solid form; [0122] 6.6
Pharmaceutical Composition 6 or any of 6.1-6.5, wherein the
Compound of Formulas I-IV et seq. is in pharmaceutically acceptable
salt form as described in Compounds 5.1-5.5; [0123] 6.7
Pharmaceutical Composition 6 or any of 6.1-6.6, wherein the
Compound of Formulas I-IV et seq. is in admixture with a
pharmaceutically acceptable diluent or carrier.
[0124] In a preferred embodiment, the Pharmaceutical Composition of
the present disclosure comprises a Compound of Formula II-A, II-B,
or II-C, in free or pharmaceutically acceptable salt form, in
admixture with a pharmaceutically acceptable diluent or carrier. In
another preferred embodiment, the Pharmaceutical Composition of the
present disclosure comprises a Compound of Formula III-A, III-B or
III-C in free or pharmaceutically acceptable salt form, in
admixture with a pharmaceutically acceptable diluent or carrier. In
another preferred embodiment, the Pharmaceutical Composition of the
present disclosure comprises a Compound of Formula IV-A, IV-B or
IV-C in free or pharmaceutically acceptable salt form, in admixture
with a pharmaceutically acceptable diluent or carrier.
[0125] In a further embodiment, the Pharmaceutical Compositions of
the present disclosure, are for a sustained or delayed release,
e.g., depot, formulation. In one embodiment, the depot formulation
(Depot Formulation 6.8) is the Pharmaceutical Composition of any of
6.1-6.7, preferably in free or pharmaceutically acceptable salt
form, and preferably in admixture with a pharmaceutically
acceptable diluent or carrier, e.g., providing sustained or delayed
release as an injectable depot.
[0126] In a further embodiment, the Depot Composition (Depot
Composition 6.9) comprises Pharmaceutical Composition of any of
6.1-6.7, wherein R.sub.1 is a --C(O)--C.sub.6-15alkyl, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier.
[0127] In a further embodiment, the present disclosure provides
Pharmaceutical Composition 6.10, which is Pharmaceutical
Composition 6 or any of 6.1-6.9, wherein the Compound of Formulas
I-IV et seq. is in a polymeric matrix. In one embodiment, the
Compound of the present disclosure is dispersed or dissolved within
the polymeric matrix. In a further embodiment, the polymeric matrix
comprises standard polymers used in depot formulations such as
polymers selected from a polyester of a hydroxyfatty acid and
derivatives thereof, or a polymer of an alkyl alpha-cyanoacrylate,
a polyalkylene oxalate, a polyortho ester, a polycarbonate, a
polyortho-carbonate, a polyamino acid, a hyaluronic acid ester, and
mixtures thereof. In a further embodiment, the polymer is selected
from a group consisting of polylactide, poly d,l-lactide, poly
glycolide, PLGA 50:50, PLGA 85:15 and PLGA 90:10 polymer. In
another embodiment, the polymer is selected form poly(glycolic
acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the
foregoing, poly(aliphatic carboxylic acids), copolyoxalates,
polycaprolactone, polydioxanone, poly(ortho carbonates),
poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,
poly(glycolic acid-caprolactone), polyanhydrides, and natural
polymers including albumin, casein, and waxes, such as, glycerol
mono- and distearate, and the like. In a preferred embodiment, the
polymeric matrix comprises poly(d,l-lactide-co-glycolide).
[0128] For example, in one embodiment of Pharmaceutical Composition
6.10, the Compound is the Compound of Formula I, wherein X is
--NH-- or --N(CH.sub.3)-- and Y is --C(.dbd.O)-- or --C(H)(OH)--,
in free or pharmaceutically acceptable salt form. In another
example of Pharmaceutical Composition 6.10, the Compound is the
Compound of Formula II-A, II-B, or II-C, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier. In another example
of Pharmaceutical Composition 6.10, the Compound is the Compound of
Formula III-A, III-B or III-C in free or pharmaceutically
acceptable salt form, in admixture with a pharmaceutically
acceptable diluent or carrier. In another example of Pharmaceutical
Composition 6.10, the Compound is the Compound of Formula IV-A,
IV-B or IV-C in free or pharmaceutically acceptable salt form, in
admixture with a pharmaceutically acceptable diluent or carrier. In
another embodiment of each of the foregoing examples of
Pharmaceutical Composition 6.10, the polymeric matrix comprises a
poly(d,l-lactide-co-glycolide).
[0129] The (Pharmaceutical) Compositions 6 and 6.1-6.10 are
particularly useful for sustained or delayed release, wherein the
Compound of the present disclosure is released upon degradation of
the polymeric matrix. These Compositions may be formulated for
controlled- and/or sustained-release of the Compounds of the
present disclosure (e.g., as a depot composition) over a period of
up to 180 days, e.g., from about 14 to about 30 to about 180 days.
For example, the polymeric matrix may degrade and release the
Compounds of the present disclosure over a period of about 30,
about 60 or about 90 days. In another example, the polymeric matrix
may degrade and release the Compounds of the present disclosure
over a period of about 120, or about 180 days.
[0130] In still another embodiment, the Pharmaceutical Compositions
of the present disclosure, for example the depot composition of the
present disclosure, e.g., Pharmaceutical Composition 6.10, is
formulated for administration by injection.
[0131] In a seventh aspect, the present disclosure provides the
Compounds of Formulas I-IV et seq. as hereinbefore described, in an
osmotic controlled release oral delivery system (OROS), which is
described in WO 2000/35419 and EP 1 539 115 (U.S. Pub. No.
2009/0202631), the contents of each of which applications are
incorporated by reference in their entirety. Therefore in one
embodiment of the seventh aspect, the present disclosure provides a
pharmaceutical composition or device comprising (a) a gelatin
capsule containing a Compound of any of Formulae I-IV et seq. in
free or pharmaceutically acceptable salt form or a Pharmaceutical
Composition of the Invention, as hereinbefore described; (b) a
multilayer wall superposed on the gelatin capsule comprising, in
outward order from the capsule: (i) a barrier layer, (ii) an
expandable layer, and (iii) a semipermeable layer; and (c) and
orifice formed or formable through the wall (Pharmaceutical
Composition P.1).
[0132] In another embodiment, the invention provides a
pharmaceutical composition comprising a gelatin capsule containing
a liquid, the Compound of Formulas I-IV et seq. in free or
pharmaceutically acceptable salt form or a Pharmaceutical
Composition of the Invention, e.g., any of Pharmaceutical
Composition 6 or 6.1-6.10, the gelatin capsule being surrounded by
a composite wall comprising a barrier layer contacting the external
surface of the gelatin capsule, an expandable layer contacting the
barrier layer, a semi-permeable layer encompassing the expandable
layer, and an exit orifice formed or formable in the wall
(Pharmaceutical Composition P.2).
[0133] In still another embodiment of the seventh aspect, the
invention provides a composition comprising a gelatin capsule
containing a liquid, the Compound of Formulas I-IV et seq. in free
or pharmaceutically acceptable salt form or a Pharmaceutical
Composition of the Invention, e.g., any of Pharmaceutical
Composition 6 or 6.1-6.10, the gelatin capsule being surrounded by
a composite wall comprising a barrier layer contacting the external
surface of the gelatin capsule, an expandable layer contacting the
barrier layer, a semipermeable layer encompassing the expandable
layer, and an exit orifice formed or formable in the wall, wherein
the barrier layer forms a seal between the expandable layer and the
environment at the exit orifice (Pharmaceutical Composition
P.3).
[0134] In still another embodiment of the seventh aspect, the
invention provides a composition comprising a gelatin capsule
containing a liquid, the Compound of Formulas I-IV et seq. in free
or pharmaceutically acceptable salt form or a Pharmaceutical
Composition of the Invention, e.g., any of Pharmaceutical
Composition 6 or 6.1-6.10, the gelatin capsule being surrounded by
a barrier layer contacting the external surface of the gelatin
capsule, an expandable layer contacting a portion of the barrier
layer, a semi-permeable layer encompassing at least the expandable
layer, and an exit orifice formed or formable in the dosage form
extending from the external surface of the gelatin capsule to the
environment of use (Pharmaceutical Composition P.4). The expandable
layer may be formed in one or more discrete sections, such as for
example, two sections located on opposing sides or ends of the
gelatin capsule.
[0135] In a particular embodiment of the seventh aspect, the
Compound of the present disclosure in the Osmotic-controlled
Release Oral Delivery System (i.e., in Pharmaceutical Composition
P.1-P.4) is in a liquid formulation, which formulation may be neat,
liquid active agent, liquid active agent in a solution, suspension,
emulsion or self-emulsifying composition or the like.
[0136] Further information on Osmotic-controlled Release Oral
Delivery System composition including characteristics of the
gelatin capsule, barrier layer, an expandable layer, a
semi-permeable layer; and orifice may be found in WO 2000/35419 and
US 2001/0036472, the contents of which are incorporated by
reference in their entirety.
[0137] Other Osmotic-controlled Release Oral Delivery System for
the Compound of Formulas I-IV et seq. or the Pharmaceutical
Composition of the present disclosure may be found in EP 1 539 115
(U.S. Pub. No. 2009/0202631), the contents of which are
incorporated by reference in their entirety. Therefore, in another
embodiment of the seventh aspect, the invention provides a
composition or device comprising (a) two or more layers, said two
or more layers comprising a first layer and a second layer, said
first layer comprises the Compound of Formulas I-IV et seq., in
free or pharmaceutically acceptable salt form, or a Pharmaceutical
Composition as herein before described said second layer comprises
a polymer; (b) an outer wall surrounding said two or more layers;
and (c) an orifice in said outer wall (Pharmaceutical Composition
P.5).
[0138] Composition P.5 preferably utilizes a semi-permeable
membrane surrounding a three-layer-core: in these embodiments the
first layer is referred to as a first drug layer and contains low
amounts of drug (e.g., the Compound of Formulas I-IV et seq.) and
an osmotic agent such as salt, the middle layer referred to as the
second drug layer contains higher amounts of drug, excipients and
no salt; and the third layer referred to as the push layer contains
osmotic agents and no drug (Pharmaceutical Composition P.6). At
least one orifice is drilled through the membrane on the first drug
layer end of the capsule-shaped tablet.
[0139] Composition P.5 or P.6 may comprise a membrane defining a
compartment, the membrane surrounding an inner protective subcoat,
at least one exit orifice formed or formable therein and at least a
portion of the membrane being semi-permeable; an expandable layer
located within the compartment remote from the exit orifice and in
fluid communication with the semi-permeable portion of the
membrane; a first drug layer located adjacent the exit orifice; and
a second drug layer located within the compartment between the
first drug layer and the expandable layer, the drug layers
comprising the Compound of the Invention in free or
pharmaceutically acceptable salt thereof (Pharmaceutical
Composition P.7). Depending upon the relative viscosity of the
first drug layer and second drug layer, different release profiles
are obtained. It is imperative to identify the optimum viscosity
for each layer. In the present invention, viscosity is modulated by
addition of salt, sodium chloride. The delivery profile from the
core is dependent on the weight, formulation and thickness of each
of the drug layers.
[0140] In a particular embodiment, the invention provides
Pharmaceutical Composition P.7 wherein the first drug layer
comprising salt and the second drug layer containing no salt.
Pharmaceutical Composition P.5-P.7 may optionally comprise a
flow-promoting layer between the membrane and the drug layers.
[0141] Pharmaceutical Compositions P.1-P.7 will generally be
referred to as Osmotic-controlled Release Oral Delivery System
Composition.
[0142] In an eighth aspect, the invention provides a method (Method
1) for the treatment or prophylaxis of a central nervous system
disorder, comprising administering to a patient in need thereof a
Compound of Formulas I-IV et seq. or a Pharmaceutical Composition 6
or 6.1-6.10 or P.1-P.7, for example Method 1 wherein the compound
or composition administered is: [0143] 1.1 Compound I or any of
1.1-1.35, in free or pharmaceutically acceptable salt form; [0144]
1.2 Compound II or any of 2.1-2.12, in free or pharmaceutically
acceptable salt form; [0145] 1.3 Compound III or any of 3.1-3.11,
in free or pharmaceutically acceptable salt form; [0146] 1.4
Compound IV or any of 4.1-4.11, in free or pharmaceutically
acceptable salt form; [0147] 1.5 The Compounds of Embodiment 5 or
any of 5.1-5.5; [0148] 1.6 Compound of Formula II-A, II-B, or II-C
in free or pharmaceutically acceptable salt form, in admixture with
a pharmaceutically acceptable diluent or carrier; [0149] 1.7
Compound of Formula III-A, III-B or III-C, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier; [0150] 1.8 Compound
of Formula IV-A, IV-B or IV-C, in free or pharmaceutically
acceptable salt form, in admixture with a pharmaceutically
acceptable diluent or carrier; [0151] 1.9 a Pharmaceutical
Composition as described by any of Compositions 6 and 6.1-6.10;
[0152] 1.10 a Pharmaceutical Composition comprising a Compound of
Formula II-A, II-B, or II-C, in free or pharmaceutically acceptable
salt form, in admixture with a pharmaceutically acceptable diluent
or carrier; [0153] 1.11 a Pharmaceutical Composition comprising a
Compound of Formula III-A, III-B or III-C, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier; [0154] 1.12 a
Pharmaceutical Composition comprising a Compound of Formula IV-A,
IV-B or IV-C, in free or pharmaceutically acceptable salt form, in
admixture with a pharmaceutically acceptable diluent or carrier;
[0155] 1.13 Depot Composition as described in Depot Composition
6.09 or 6.10; [0156] 1.14 Pharmaceutical Composition P.1-P.7;
[0157] 1.15 Osmotic-controlled Release Oral Delivery System
Composition as hereinbefore described;
[0158] In a further embodiment of the eighth aspect, the present
disclosure provides Method 1 or any of Methods 1.1-1.15, wherein
the method is further as described as follows: [0159] 1.16 Method 1
or any of Methods 1.1-1.15, wherein the central nervous system
disorder is a disorder selected from a group consisting of obesity,
anxiety, depression (for example refractory depression and MDD),
psychosis (including psychosis associated with dementia, such as
hallucinations in advanced Parkinson's disease or paranoid
delusions), schizophrenia, sleep disorders (particularly sleep
disorders associated with schizophrenia and other psychiatric and
neurological diseases), sexual disorders, migraine, conditions
associated with cephalic pain, social phobias, agitation in
dementia (e.g., agitation in Alzheimer's disease), agitation in
autism and related autistic disorders, gastrointestinal disorders
such as dysfunction of the gastrointestinal tract motility, and
dementia, for example dementia of Alzheimer's disease or of
Parkinson's disease; mood disorders; and drug dependencies, for
example, opiate dependency and/or alcohol dependency, or withdrawal
from drug or alcohol dependency (e.g., opiate dependency); or binge
eating disorder; or opiate overdose; or opiate use disorder (OUD);
[0160] 1.17 Method 1 or any of Methods 1.1-1.16, wherein the
central nervous system disorder is a disorder involving serotonin
5-HT.sub.2A, dopamine D2 and/or D1 receptor system and/or serotonin
reuptake transporter (SERT) pathways as similarly described in
WO/2009/145900 and US 2011/071080, the contents of which are herein
incorporated by reference in their entirety; [0161] 1.18 Method 1
or any of Methods 1.1-1.17, wherein the central nervous system
disorder is a disorder involving the .mu.-opioid receptor; [0162]
1.19 Method 1 or any of Methods 1.1-1.18, wherein the central
nervous system disorder is a disorder selected from the following:
(i) psychosis, e.g., schizophrenia, in a patient suffering from
depression; (2) depression in a patient suffering from psychosis,
e.g., schizophrenia; (3) mood disorders associated with psychosis,
e.g., schizophrenia or Parkinson's disease; (4) sleep disorders
associated with psychosis, e.g., schizophrenia or Parkinson's
disease; and (5) substance addiction, substance use disorders
and/or substance-induced disorders, optionally wherein the patient
suffers from residual symptoms of anxiety or anxiety disorder;
[0163] 1.20 Method 1 or any of Methods 1.1-1.18, wherein the
central nervous system disorder is psychosis, e.g., schizophrenia
and said patient is a patient suffering from depression; [0164]
1.21 Method 1 or any of Methods 1.1-1.20, wherein said patient is
unable to tolerate the side effects of conventional antipsychotic
drugs, e.g., chlorpromazine, haloperidol, droperidol, fluphenazine,
loxapine, mesoridazine molindone, perphenazine, pimozide,
prochlorperazine promazine, thioridazine, thiothixene,
trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine,
risperidone and ziprasidone; [0165] 1.22 Method 1 or any of Methods
1.1-1.20, wherein said patient is unable to tolerate the side
effects of conventional antipsychotic drugs, e.g., haloperidol,
aripiprazole, clozapine, olanzapine, quetiapine, risperidone, and
ziprasidone; [0166] 1.23 Method 1 or any of Methods 1.1-1.22,
wherein said disorder is depression and said patient is a patient
suffering from psychosis, e.g., schizophrenia, or Parkinson's
disease; [0167] 1.24 Method 1 or any of Methods 1.1-1.22, wherein
said disorder is sleep disorder and said patient is suffering from
depression; [0168] 1.25 Method 1 or any of Methods 1.1-1.22,
wherein said one or more disorders is sleep disorder and said
patient is suffering from psychosis, e.g., schizophrenia; [0169]
1.26 Method 1 or any of Methods 1.1-1.22, wherein said one or more
disorders is sleep disorder and said patient is suffering from
Parkinson's disease; [0170] 1.27 Method 1 or any of Methods
1.1-1.22, wherein said one or more disorders is sleep disorder and
said patient is suffering from depression and psychosis, e.g.,
schizophrenia, or Parkinson's disease. [0171] 1.28 Method 1 or any
of 1.1-1.27, wherein said patient is suffering from a drug
dependency disorder, optionally in conjunction with any preceding
disorders, for example, wherein said patient suffers from opiate
dependency and/or alcohol dependency, or from withdrawal from drug
or alcohol dependency, optionally wherein the patient suffers from
residual symptoms of anxiety or anxiety disorder; further
optionally wherein the patient suffers from an opiate overdose;
[0172] 1.29 Any of the foregoing methods, wherein the effective
amount is 1 mg-1000 mg, preferably 2.5 mg-50 mg; [0173] 1.30 Any of
the foregoing methods, wherein the effective amount is 1 mg-100 mg
per day, preferably 2.5 mg-50 mg per day; [0174] 1.31 Any of the
foregoing methods wherein a condition to be treated is dyskinesia,
e.g. in a patient receiving dopaminergic medications, e.g.,
medications selected from levodopa and levodopa adjuncts
(carbidopa, COMT inhibitors, MAO-B inhibitors), dopamine agonists,
and anticholinergics, e.g., levodopa; [0175] 1.32 Any of the
foregoing methods wherein the patient suffers from Parkinson's
disease.
[0176] Substance-use disorders and substance-induced disorders are
the two categories of substance-related disorders defined by the
Fifth Edition of the DSM (the Diagnostic and Statistical Manual of
Mental Disorders, or DSM-V). A substance-use disorder is a pattern
of symptoms resulting from use of a substance which the individual
continues to take, despite experiencing problems as a result. A
substance-induced disorder is a disorder induced by use if the
substance. Substance-induced disorders include intoxication,
withdrawal, substance induced mental disorders, including substance
induced psychosis, substance induced bipolar and related disorders,
substance induced depressive disorders, substance induced anxiety
disorders, substance induced obsessive-compulsive and related
disorders, substance induced sleep disorders, substance induced
sexual dysfunctions, substance induced delirium and substance
induced neurocognitive disorders.
[0177] The DSM-V includes criteria for classifying a substance use
disorder as mild, moderate or severe. In some embodiments of the
methods disclosed herein, the substance use disorder is selected
from a mild substance use disorder, a moderate substance use
disorder or a severe substance use disorder. In some embodiments,
the substance use disorder is a mild substance use disorder. In
some embodiments, the substance use disorder is a moderate
substance use disorder. In some embodiments, the substance use
disorder is a severe substance use disorder.
[0178] Anxiety is a highly prevalent co-morbid disorder in patients
undergoing treatment of substance use or substance abuse. A common
treatment for substance abuse disorder is the combination of the
partial opioid agonist buprenorphine with the opioid antagonist
naloxone, but neither of these drugs has any significant effect on
anxiety, thus leading to the common result that a third drug, such
as a benzodiazepine-class anxiolytic agent. This makes treatment
regimens and patient compliance more difficult. In contrast, the
Compounds of the present disclosure provide opiate antagonism along
with serotonin antagonism and dopamine modulation. This may result
in significant enhancement of treatment of patients with substance
use or abuse disorder concomitant with anxiety. Depression is also
a highly prevalent disorder in patients undergoing substance use or
substance abuse treatment. Thus, antidepressants, such as SSRIs,
are also often used concomitantly in patients undergoing substance
abuse treatment. Compounds of the present disclosure may also
enhance treatment in such patients by providing treatment for
substance use or substance abuse as well as both anxiety and
depression.
[0179] The compounds of the present disclosure may have anxiolytic
properties ameliorating the need for treatment of a patient with an
anxiolytic agent where said patients suffers from co-morbid
anxiety. Thus, in some embodiments, the present disclosure provides
a method according to Method 1, or any of Methods 1.1-1.32, wherein
the central nervous system disorder is a substance addiction,
substance use disorders and/or substance-induced disorders, or a
substance abuse disorder, for example, in a patient suffering from
symptoms of anxiety or who is diagnosed with anxiety as a co-morbid
disorder, or as a residual disorder, wherein the method does not
comprise the further administration of an anxiolytic agent, such as
a benzodiazepine. Benzodiazepines are GABA-modulating compounds,
including those discussed with reference to Method 3.1 and 3.2
below.
[0180] In another embodiment of the eighth aspect, the present
disclosure provides Method 1 or any of Methods 1.1-1.15, wherein
the method is further as described as follows: [0181] 1.33 Method 1
or any of Methods 1.1-1.32, wherein the central nervous system
disorder is a disorder selected from obsessive-compulsive disorder
(OCD), obsessive-compulsive personality disorder (OCPD), general
anxiety disorder, social anxiety disorder, panic disorder,
agoraphobia, compulsive gambling disorder, compulsive eating
disorder, body dysmorphic disorder, hypochondriasis, pathological
grooming disorder, kleptomania, pyromania, attention
deficit-hyperactivity disorder (ADHD), attention deficit disorder
(ADD), impulse control disorder, and related disorders, and
combination thereof. [0182] 1.34 Method 1 or any one Method
1.1-1.33, wherein the central nervous system disorder is selected
from obsessive-compulsive disorder (OCD), obsessive-compulsive
personality disorder (OCPD), social anxiety disorder, panic
disorder, agoraphobia, compulsive gambling disorder, compulsive
eating disorder, body dysmorphic disorder and impulse control
disorder. [0183] 1.35 Method 1 or any one of Method 1.1-1.33,
wherein the central nervous system disorder is obsessive-compulsive
disorder (OCD) or obsessive-compulsive personality disorder (OCPD).
[0184] 1.36 Any foregoing method, wherein said patient is not
responsive to or cannot tolerate the side effects from, treatment
with selective serotonin reuptake inhibitors (SSRIs), such as
citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, and
sertraline. [0185] 1.37 Any foregoing method, wherein said patient
is not responsive to or cannot tolerate the side effects from,
treatment with serotonin-norepinephrine reuptake inhibitors
(SNRIs), such as venlafaxine, sibutramine, duloxetine, atomoxetine,
desvenlafaxine, milnacipran, and levomilnacipran. [0186] 1.38. Any
foregoing method, wherein said patient is not responsive to or
cannot tolerate the side effects from, treatment with antipsychotic
agents, such as clomipramine, risperidone, quetiapine and
olanzapine. [0187] 1.39 Method 1 or any of Method 1.1-1.33, wherein
the central nervous system disorder is a pain disorder, e.g., a
condition associated with pain, such as cephalic pain, idiopathic
pain, neuropathic pain, chronic pain (e.g., moderate to moderately
severe chronic pain, for example, in patients requiring 24-hour
extended treatment for other ailments), fibromyalgia, dental pain,
traumatic pain, or chronic fatigue. [0188] 1.40 Any foregoing
method, wherein the patient is not responsive to or cannot tolerate
the side effects of non-narcotic analgesics and/or opiate and
opioid drugs, or wherein the use of opiate drugs are
contraindicated in said patient, for example, due to prior
substance abuse or a high potential for substance abuse, such as
opiate and opioid drugs including, e.g., morphine, codeine,
thebaine, oripavine, morphine dipropionate, morphine dinicotinate,
dihydrocodeine, buprenorphine, etorphine, hydrocodone,
hydromorphone, oxycodone, oxymorphone, fentanyl,
alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,
remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,
prodine, promedol, propoxyphene, dextropropoxyphene, methadone,
diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,
nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and
anileridine, or any combinations thereof; [0189] 1.41 Method I or
any of Methods 1.1-1.40, wherein the central nervous system disease
or disorder is a drug dependency (for example, opiate dependency
(i.e., opioid use disorder), cocaine dependency, amphetamine
dependency, and/or alcohol dependency), or withdrawal from drug or
alcohol dependency (e.g., opiate, cocaine, or amphetamine
dependency), and wherein the patient also suffers from a
co-morbidity, such as anxiety, depression or psychosis; optionally
wherein the patient also suffers from an opiate overdose; [0190]
1.42 Any of the foregoing methods, wherein the effective amount is
1 mg-1000 mg, preferably 2.5 mg-50 mg; [0191] 1.43 Any of the
foregoing methods, wherein the effective amount is 1 mg-100 mg per
day, preferably 2.5 mg-50 mg per day.
[0192] In another embodiment, the present disclosure provides
Method 1 or any of Methods 1.1-1.32, or any of Methods 1.33-1.43,
wherein the Compounds of Formulas I-IV et seq. or Pharmaceutical
Composition 6 or 6.1-6.10 or P.1-P.7 comprises: [0193] 1.44 a
Compound of Formula II-A, II-B, II-C or II-D, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier; [0194] 1.45 a
Compound of Formula III-A, III-B or III-C in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier; or [0195] 1.46 a
Compound of Formula IV-A, IV-B or IV-C in free or pharmaceutically
acceptable salt form, in admixture with a pharmaceutically
acceptable diluent or carrier
[0196] In another embodiment of the eighth aspect, the invention
provides Method 1, or any of Methods 1.1-1.46, e.g., any method of
treating pain, wherein the patient suffers from a gastrointestinal
disorder and/or a pulmonary disorder. Traditional opioid analgesics
suffer from two dominant side effects: gastrointestinal
disturbances (including nausea, vomiting and constipation) and
respiratory depression. 90 to 95% of patients taking opioids for
long-term pain treatment develop serious constipation, requiring
the long-term use of laxatives and/or enemas. The stronger opioids
such as morphine, oxycodone and hydromorphone produce more severe
constipation than other opioids. Respiratory depression is the most
serious adverse effect of opioid treatment as it creates a risk of
death, especially when patients combine (intentionally or
inadvertently) prescribed opioid analgesics with other licit or
illicit respiratory depressants (including alcohol). Patients in
need of pain treatment, especially chronic pain treatment, are
therefore at particular risk of adverse effects if they suffer from
a pre-existing gastrointestinal or pulmonary disorder. Unlike
traditional opioid analgesics, the compounds of the present
invention (e.g., the compound of Formula I, e.g., of Formula 1.31),
provide analgesic relief without significant adverse
gastrointestinal effects and without significant respiratory
depression. Therefore, such compounds would provide improved safety
and efficacy for patients in need of pain treatment having these
preexisting GI and pulmonary disorders. In further embodiments, a
compound of the present invention may be combined with a
traditional opiate agent to provide improved pain control with a
dose-sparing effect as to the traditional opiate agent (and
concomitantly reduced risk of adverse effects).
[0197] Thus, in particular embodiments, the present invention
further provides: [0198] 1.47 Method 1 or any of 1.1-1.46, wherein
the patient suffers from a pre-existing or co-morbid
gastrointestinal disorder and/or pulmonary disorder; [0199] 1.48
Method 1.47, wherein the pre-existing or co-morbid disorder is
selected from the group consisting of irritable bowel syndrome,
pelvic floor disorder, diverticulitis, inflammatory bowel disease,
colon or colorectal cancer, celiac disease, non-celiac gluten
sensitivity, asthma, chronic obstructive pulmonary disease (COPD),
dyspnea, pneumonia, congestive heart failure, interstitial lung
disease, pneumothorax, bronchitis, pulmonary embolism, and
traumatic chest injury (e.g., broken sternum or ribs, bruised
intercostal muscles); [0200] 1.49 Method 1.47 or 1.48 wherein the
central nervous system disorder is a pain disorder, e.g., a
condition associated with pain, such as cephalic pain, idiopathic
pain, neuropathic pain, chronic pain (e.g., moderate to moderately
severe chronic pain, for example, in patients requiring 24-hour
extended treatment for other ailments), fibromyalgia, dental pain,
traumatic pain, or chronic fatigue; [0201] 1.50 Any of Method 1 or
1.1-1.49, wherein the central nervous system disorder is opiate use
disorder, opiate withdrawal or opiate dependency, and wherein the
method provides relief from withdrawal-induced symptoms (e.g.,
gastrointestinal symptoms such as diarrhea, anxiety, depression,
pain, sleep disturbances, or any combination thereof); [0202] 1.51
Any of Method 1 or 1.1-1.50, wherein the method further comprises
the concurrent administration of another opiate or opioid agent,
e.g., administered simultaneously, separately or sequentially;
[0203] 1.52 Method 1.51, wherein the additional opiate or opioid
agent is selected from the group consisting of morphine, codeine,
thebaine, oripavine, morphine dipropionate, morphine dinicotinate,
dihydrocodeine, buprenorphine, etorphine, hydrocodone,
hydromorphone, oxycodone, oxymorphone, fentanyl,
alpha-methylfentantyl, alfentanyl, trefantinil, brifentanil,
remifentanil, octfentanil, sufentanil, carfentanyl, meperidine,
prodine, promedol, propoxyphene, dextropropoxyphene, methadone,
diphenoxylate, dezocine, pentazocine, phenazocine, butorphanol,
nalbuphine, levorphanol, levomethorphan, tramadol, tapentadol, and
anileridine, or any combinations thereof; [0204] 1.53 Any of Method
1 or 1.1-1.52, wherein the method further comprises the concurrent
administration of a NMDA receptor antagonist, e.g., administered
simultaneously, separately or sequentially; [0205] 1.54 Method
1.53, wherein the NMDA receptor antagonist is selected from the
group consisting of ketamine (e.g., S-ketamine and/or R-ketamine),
hydroxynorketamine, memantine, dextromethorphan, dextroallorphan,
dextrorphan, amantadine, and agmatine, or any combination thereof;
[0206] 1.55 Any of methods 1.47-1.54, wherein the compound is the
compound of Formula I, wherein X is --NH--, L is O.sup.-, and Z is
--O--.
[0207] In still another embodiment, the present disclosure provides
any of the Methods 1 or 1.1-1.55 as hereinbefore described wherein
the disorder is schizophrenia or sleep disorder. In some
embodiments, said schizophrenia is associated with depression.
[0208] In still another embodiment, the present disclosure provides
any of Methods 1.1-1.55, wherein the Depot Composition of the
Invention (e.g., Depot Composition of any of formulae 6.8-6.10), or
(Pharmaceutical) Composition 6 or 6.1-6.7, or Pharmaceutical
Composition P.1-P.7, is administered for controlled- and/or
sustained-release of the Compounds of the Invention over a period
of from about 14 days, about 30 to about 180 days, preferably over
the period of about 30, about 60 or about 90 days. Controlled-
and/or sustained-release is particularly useful for circumventing
premature discontinuation of therapy, particularly for
antipsychotic drug therapy.
[0209] In still another embodiment, the invention provides any
Method 1 or 1.1-1.55 as hereinbefore described, wherein the Depot
Composition of the present disclosure is administered for
controlled- and/or sustained-release of the Compounds of the
Invention over a period of time.
[0210] In a ninth aspect, the invention provides a method (Method
2) for the prophylaxis or treatment of one or more sleep disorders
comprising administering to a patient in need thereof a Compound of
Formulas I-IV et seq. or a Pharmaceutical Composition 6 or 6.1-6.10
or P.1-P.7, (Method 2) for example Method 2 wherein the compound or
composition administered is: [0211] 2.1 Compound I or 1.1-1.35, in
free or pharmaceutically acceptable salt form; [0212] 2.2 Compound
II or 2.1-2.12, in free or pharmaceutically acceptable salt form;
[0213] 2.3 Compound III or 3.1-3.11, in free or pharmaceutically
acceptable salt form; [0214] 2.4 Compound IV or 4.1-4.11, in free
or pharmaceutically acceptable salt form; [0215] 2.5 Compound 5 or
5.1-5.5; [0216] 2.6 Compound of Formula II-A, II-B, II-C or II-D,
in free or pharmaceutically acceptable salt form, in admixture with
a pharmaceutically acceptable diluent or carrier; [0217] 2.7
Compound of Formula III-A, III-B or III-C, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier; [0218] 2.8 Compound
of Formula IV-A, IV-B or IV-C, in free or pharmaceutically
acceptable salt form, in admixture with a pharmaceutically
acceptable diluent or carrier; [0219] 2.9 a Pharmaceutical
Composition as described by any of Compositions 6 and 6.1-6.10;
[0220] 2.10 a Pharmaceutical Composition comprising a Compound of
Formula II-A, II-B, or II-C, in free or pharmaceutically acceptable
salt form, in admixture with a pharmaceutically acceptable diluent
or carrier; [0221] 2.11 a Pharmaceutical Composition comprising a
Compound of Formula III-A, III-B or III-C, in free or
pharmaceutically acceptable salt form, in admixture with a
pharmaceutically acceptable diluent or carrier; [0222] 2.12 a
Pharmaceutical Composition comprising a Compound of Formula IV-A,
IV-B or IV-C, in free or pharmaceutically acceptable salt form, in
admixture with a pharmaceutically acceptable diluent or carrier;
[0223] 2.13 Depot Composition as described in Depot Composition
6.09 or 6.10; [0224] 2.14 Pharmaceutical Composition P.1-P.7;
[0225] 2.15 Osmotic-controlled Release Oral Delivery System
Composition as hereinbefore described;
[0226] In a further embodiment of the ninth aspect, the invention
provides Method 2, or 2.1-2.15, wherein the sleep disorder includes
sleep maintenance insomnia, frequent awakenings, and waking up
feeling unrefreshed; for example: [0227] 2.16 Any of the foregoing
methods, wherein the sleep disorder is sleep maintenance insomnia;
[0228] 2.17 Any of the foregoing methods, wherein the effective
amount is 1 mg-5 mg, preferably 2.5-5 mg, per day; [0229] 2.18 Any
of the foregoing methods, wherein the effective amount is 2.5 mg or
5 mg, per day; [0230] 2.19 Any of the foregoing methods wherein the
sleep disorder is in a patient suffering from or at risk of
dyskinesia, e.g., a patient receiving dopaminergic medications,
e.g., selected from levodopa and levodopa adjuncts (carbidopa, COMT
inhibitors, MAO-B inhibitors), dopamine agonists, and
anticholinergics, e.g., receiving levodopa; [0231] 2.20 Any of the
foregoing methods wherein the patient suffers from Parkinson's
disease.
[0232] In a further embodiment of the ninth aspect, the invention
provides Method 2, or any of 2.1-2.20, wherein the sleep disorder
includes sleep maintenance insomnia, frequent awakenings, and
waking up feeling unrefreshed.
[0233] The Compounds of the present disclosure, the Pharmaceutical
Compositions of the present disclosure or the Depot Compositions of
the present disclosure may be used in combination with a second
therapeutic agent, particularly at lower dosages than when the
individual agents are used as a monotherapy so as to enhance the
therapeutic activities of the combined agents without causing the
undesirable side effects commonly occur in conventional
monotherapy. Therefore, the Compounds of the present disclosure may
be simultaneously, sequentially, or contemporaneously administered
with other anti-depressant, anti-psychotic, other hypnotic agents,
and/or agents use to treat Parkinson's disease or mood disorders.
In another example, side effects may be reduced or minimized by
administering a Compound of the present disclosure in combination
with one or more second therapeutic agents in free or salt form,
wherein the dosages of (i) the second therapeutic agent(s) or (ii)
both Compound of the present disclosure and the second therapeutic
agents, are lower than if the agents/compounds are administered as
a monotherapy. In a particular embodiment, the Compounds of the
present disclosure are useful to treat dyskinesia in a patient
receiving dopaminergic medications, e.g., selected from levodopa
and levodopa adjuncts (carbidopa, COMT inhibitors, MAO-B
inhibitors), dopamine agonists, and anticholinergics, e.g., such as
are used in the treatment of Parkinson's disease.
[0234] In some further embodiments of the present disclosure, the
Pharmaceutical Compositions of the present disclosure or the Depot
Compositions of the present disclosure may be used in combination
with a second therapeutic agent, particularly at lower dosages than
when the individual agents are used as a monotherapy so as to
enhance the therapeutic activities of the combined agents without
causing the undesirable side effects, wherein the second
therapeutic agent is an opiate antagonist (e.g., naloxone). The
Compounds of the present disclosure may be simultaneously,
sequentially, or contemporaneously administered with such opiate
antagonists.
[0235] Therefore, in a tenth aspect, the present disclosure
provides Method 1, or any of Methods 1.1-1.55, or Method 2 or any
of 2.1-2.20, further comprising the administration of one or more
therapeutic agents to the patient, wherein the one or more
therapeutic agents are selected from compounds that modulate GABA
activity (e.g., enhances the activity and facilitates GABA
transmission), a GABA-B agonist, a 5-HT receptor modulator (e.g., a
5-HT.sub.1A agonist, a 5-HT.sub.2A antagonist, a 5-HT.sub.2A
inverse agonist, etc.), a melatonin receptor agonist, an ion
channel modulator (e.g., blocker), a serotonin-2
antagonist/reuptake inhibitor (SARIs), an orexin receptor
antagonist, an H3 agonist or antagonist, a noradrenergic agonist or
antagonist, a galanin agonist, a CRH antagonist, human growth
hormone, a growth hormone agonist, estrogen, an estrogen agonist, a
neurokinin-1 drug, an anti-depressant, an opiate agonist and/or
partial opiate agonist, an opiate antagonist and/or opiate inverse
agonist, and an antipsychotic agent, e.g., an atypical
antipsychotic agent, in free or pharmaceutically acceptable salt
form (Method 1-A and 2-A respectively; collectively, "Method
3").
[0236] In further embodiments of the tenth aspect, the present
disclosure provides Method 1, or any of Methods 1.1-1.55, or Method
2 or any of 2.1-2.20, further comprising the administration to the
patient of one or more therapeutic agents selected from the
foregoing and further selected from agonists or partial agonists,
or inverse agonists or antagonists, of the mu-opiate, kappa-opiate,
delta-opiate, and/or nociceptin/orphanin receptors. In further
embodiments of the tenth aspect, the present disclosure also
provides Method 1, or any of Methods 1.1-55, or Method 2 or any of
2.1-2.20, further comprising the administration to the patient of
one or more therapeutic agents selected from a serotonin HT6
receptor antagonist, and an mGluR-2, -3 or -5 receptor agonist or
antagonist (including both positive and negative modulators and
partial agonists).
[0237] In a further embodiment of the tenth aspect, the invention
provides Method 3 (i.e., Method 1-A or 2-A), wherein the method
further comprises the administration to the patient of one or more
therapeutic agents, as follows: [0238] 3.1 Method 1-A or 2-A,
wherein the therapeutic agent(s) is compounds that modulate GABA
activity (e.g., enhances the activity and facilitates GABA
transmission); [0239] 3.2 Method 1-A or 2-A or 3.1, wherein the
GABA compound is selected from a group consisting of one or more of
doxepin, alprazolam, bromazepam, clobazam, clonazepam, clorazepate,
diazepam, flunitrazepam, flurazepam, lorazepam, midazolam,
nitrazepam, oxazepam, temazepam, triazolam, indiplon, zopiclone,
eszopiclone, zaleplon, Zolpidem, gaboxadol, vigabatrin, tiagabine,
EVT 201 (Evotec Pharmaceuticals) and estazolam; [0240] 3.3 Method
1-A or 2-A, wherein the therapeutic agent is an additional 5HT2a
antagonist; [0241] 3.4 Method 1-A or 2-A or 3.3, wherein said
additional 5HT2a antagonist is selected from one or more of
ketanserin, risperidone, eplivanserin, volinanserin
(Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis,
France), HY 10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San
Diego, Calif.), and AVE8488 (Sanofi-Aventis, France); [0242] 3.5
Method 1-A or 2-A, wherein the therapeutic agent is a melatonin
receptor agonist; [0243] 3.6 Method 1-A or 2-A or 3.5, wherein the
melatonin receptor agonist is selected from a group consisting of
one or more of melatonin, ramelteon (ROZEREM.RTM., Takeda
Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville,
Md.), PD-6735 (Phase II Discovery) and agomelatine; [0244] 3.7
Method 1-A or 2-A, wherein the therapeutic agent is an ion channel
blocker; [0245] 3.8 Method 1-A or 2-A or 3.7, wherein said ion
channel blocker is one or more of lamotrigine, gabapentin and
pregabalin; [0246] 3.9 Method 1-A or 2-A, wherein the therapeutic
agent is an orexin receptor antagonist; [0247] 3.10 Method 1-A or
2-A or 3.9, wherein the orexin receptor antagonist is selected from
a group consisting of orexin, a 1,3-biarylurea, SB-334867-a
(GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline) and a benzamide
derivative; [0248] 3.11 Method 1-A or 2-A, wherein the therapeutic
agent is the serotonin-2 antagonist/reuptake inhibitor (SARI);
[0249] 3.12 Method 1-A or 2-A or 3.11, wherein the serotonin-2
antagonist/reuptake inhibitor (SARI) is selected from a group
consisting of one or more Org 50081 (Organon-Netherlands),
ritanserin, nefazodone, serzone and trazodone; [0250] 3.13 Method
1-A or 2-A, wherein the therapeutic agent is the 5HTIa agonist;
[0251] 3.14 Method 1-A or 2-A or 3.13, wherein the 5HTIa agonist is
selected from a group consisting of one or more of repinotan,
sarizotan, eptapirone, buspirone and MN-305 (MediciNova, San Diego,
Calif.); [0252] 3.15 Method 1-A or 2-A, wherein the therapeutic
agent is the neurokinin-1 drug; [0253] 3.16 Method 1-A or 2-A or
3.15, wherein the neurokinin-1 drug is Casopitant
(GlaxoSmithKline); [0254] 3.17 Method 1-A or 2-A, wherein the
therapeutic agent is an antipsychotic agent; [0255] 3.18 Method 1-A
or 2-A or 3.17, wherein the antipsychotic agent is selected from a
group consisting of chlorpromazine, haloperidol, droperidol,
fluphenazine, loxapine, mesoridazine, molindone, perphenazine,
pimozide, prochlorperazine promazine, thioridazine, thiothixene,
trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine,
risperidone, ziprasidone and paliperidone; [0256] 3.19 Method 1-A
or 2-A, wherein the therapeutic agent is an anti-depressant; [0257]
3.20 Method 1-A or 2-A or 3.19, wherein the anti-depressant is
selected from amitriptyline, amoxapine, bupropion, citalopram,
clomipramine, desipramine, doxepin, duloxetine, escitalopram,
fluoxetine, fluvoxamine, imipramine, isocarboxazid, maprotiline,
mirtazapine, nefazodone, nortriptyline, paroxetine, phenelzine
sulfate, protriptyline, sertraline, tranylcypromine, trazodone,
trimipramine, and venlafaxine; [0258] 3.21 Method 1-A or 2-A, 3.17
or 3.18, wherein the antipsychotic agent is an atypical
antipsychotic agent; [0259] 3.22 Method 1-A or 2-A, or any of
3.17-3.21, wherein the atypical antipsychotic agent is selected
from a group consisting of clozapine, aripiprazole, olanzapine,
quetiapine, risperidone, ziprasidone, and paliperidone; [0260] 3.23
Method 1-A or 2-A, wherein the therapeutic agent is selected from
any of methods 3.1-3.22, e.g., selected from a group consisting of
modafinil, armodafinil, doxepin, alprazolam, bromazepam, clobazam,
clonazepam, clorazepate, diazepam, flunitrazepam, flurazepam,
lorazepam, midazolam, nitrazepam, oxazepam, temazepam, triazolam,
indiplon, zopiclone, eszopiclone, zaleplon, Zolpidem, gaboxadol,
vigabatrin, tiagabine, EVT 201 (Evotec Pharmaceuticals), estazolam,
ketanserin, risperidone, eplivanserin, volinanserin
(Sanofi-Aventis, France), pruvanserin, MDL 100907 (Sanofi-Aventis,
France), HY 10275 (Eli Lilly), APD 125 (Arena Pharmaceuticals, San
Diego, Calif.), AVE8488 (Sanofi-Aventis, France), repinotan,
sarizotan, eptapirone, buspirone, MN-305 (MediciNova, San Diego,
Calif.), melatonin, ramelteon (ROZEREM.RTM., Takeda
Pharmaceuticals, Japan), VEC-162 (Vanda Pharmaceuticals, Rockville,
Md.), PD-6735 (Phase II Discovery), agomelatine, lamotrigine,
gabapentin, pregabalin, orexin, a 1,3-biarylurea, SB-334867-a
(GlaxoSmithKline, UK), GW649868 (GlaxoSmithKline), a benzamide
derivative, Org 50081 (Organon-Netherlands), ritanserin,
nefazodone, serzone, trazodone, Casopitant (GlaxoSmithKline),
amitriptyline, amoxapine, bupropion, citalopram, clomipramine,
desipramine, doxepin, duloxetine, escitalopram, fluoxetine,
fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine,
nefazodone, nortriptyline, paroxetine, phenelzine sulfate,
protriptyline, sertraline, tranylcypromine, trazodone,
trimipramine, venlafaxine, chlorpromazine, haloperidol, droperidol,
fluphenazine, loxapine, mesoridazine, molindone, perphenazine,
pimozide, prochlorperazine promazine, thioridazine, thiothixene,
trifluoperazine, clozapine, aripiprazole, olanzapine, quetiapine,
risperidone, ziprasidone and paliperidone; [0261] 3.24 Method 1-A
or 2-A wherein the therapeutic agent is an H3 agonist; [0262] 3.25
Method 1-A or 2-A, wherein the therapeutic agent is an H3
antagonist; [0263] 3.26 Method 1-A or 2-A, wherein the therapeutic
agent is a noradrenergic agonist or antagonist; [0264] 3.27 Method
1-A or 2-A, wherein the therapeutic agent is a galanin agonist;
[0265] 3.28 Method 1-A or 2-A, wherein the therapeutic agent is a
CRH antagonist; [0266] 3.29 Method 1-A or 2-A, wherein the
therapeutic agent is a human growth hormone; [0267] 3.30 Method 1-A
or 2-A, wherein the therapeutic agent is a growth hormone agonist;
[0268] 3.31 Method 1-A or 2-A, wherein the therapeutic agent is
estrogen; [0269] 3.32 Method 1-A or 2-A, wherein the therapeutic
agent is an estrogen agonist; [0270] 3.33 Method 1-A or 2-A,
wherein the therapeutic agent is a neurokinin-1 drug; [0271] 3.34
Method 1-A or 2-A, wherein a therapeutic agent is combined with
compounds of Formula (I) and the therapeutic agent is an
anti-Parkinson agent such as L-dopa, co-careldopa, duodopa,
stalevo, Symmetrel, benztropine, biperiden, bromocriptine,
entacapone, pergolide, pramipexole, procyclidine, ropinirole,
selegiline and tolcapone; [0272] 3.35 Method 1-A or 2-A, wherein
the therapeutic agent is an opiate agonist or partial opiate
agonist, for example, a mu-agonist or partial agonist, or a
kappa-agonist or partial agonist, including mixed
agonist/antagonists (e.g., an agent with partial mu-agonist
activity and kappa-antagonist activity); [0273] 3.36 Method 3.35,
wherein the therapeutic agent is buprenorphine, optionally, wherein
said method does not include co-treatment with an anxiolytic agent,
e.g., a GABA compound or benzodiazepine; [0274] 3.37 Method 1-A or
2-A, wherein compounds of Formula (I) may be used to treat sleep
disorders, depression, psychosis, or any combinations thereof, in
patients suffering from the listed diseases and/or Parkinson's
disease; [0275] 3.38 Method 1-A or 2-A, wherein the disorder is
selected from at least one or more of psychosis, e.g.,
schizophrenia, depression, mood disorders, sleep disorders (e.g.,
sleep maintenance and/or sleep onset) or any combination of
disorders thereof; [0276] 3.39 Method 1-A or 2-A, wherein the
therapeutic agent(s) is an opiate receptor antagonist or inverse
agonist, e.g, a full opiate antagonist, for example, selected from
naloxone, naltrexone, nalmefene, methadone, nalorphine,
levallorphan, samidorphan, nalodeine, cyprodime, or
norbinaltorphimine. [0277] 3.40 Any of the foregoing methods
wherein the disorder is sleep disorder; [0278] 3.41 Any of the
foregoing methods, wherein the disorder is sleep disorder
associated with psychosis, e.g., schizophrenia or Parkinson's
disease; in free or pharmaceutically acceptable salt form.
[0279] In an eleventh aspect of the invention, the combination of a
Compound of the present disclosure and one or more second
therapeutic agents as described in Methods 1-A, 2-A or any of
Methods 3 or 3.1-3.41 may be administered to the patient as a
Pharmaceutical Composition or a depot Composition as hereinbefore
described. The combination compositions can include mixtures of the
combined drugs, as well as two or more separate compositions of the
drugs, which individual compositions can be, for example,
co-administered together to a patient.
[0280] In a particular embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41
comprises administering to a patient in need thereof, a Compound of
the Invention in combination with an atypical antipsychotic agent,
e.g., a compound selected from clozapine, aripiprazole, olanzapine,
quetiapine, risperidone, ziprasidone, or paliperidone, in free or
pharmaceutically acceptable salt form, for example wherein the
dosage of the atypical antipsychotic agent is reduced and/or side
effects are reduced.
[0281] In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41
comprises administering to a patient in need thereof, a Compound of
the Invention in combination with an anti-depressant, e.g.,
amitriptyline, amoxapine, bupropion, citalopram, clomipramine,
desipramine, doxepin, duloxetine, escitalopram, fluoxetine,
fluvoxamine, imipramine, isocarboxazid, maprotiline, mirtazapine,
nefazodone, nortriptyline, paroxetine, phenelzine sulfate,
protriptyline, sertraline, tranylcypromine, trazodone,
trimipramine, or venlafaxine, in free or pharmaceutically
acceptable salt form. Alternatively, the anti-depressant may be
used as an adjunct medication in addition to the compound of the
Invention.
[0282] In still another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41
comprises administering to a patient in need thereof, a Compound of
the Invention in combination with a compound that modulates GABA
activity, e.g., a compound selected from doxepin, alprazolam,
bromazepam, clobazam, clonazepam, clorazepate, diazepam,
flunitrazepam, flurazepam, lorazepam, midazolam, nitrazepam,
oxazepam, temazepam, triazolam, indiplon, zopiclone, eszopiclone,
zaleplon, Zolpidem, gaboxadol, vigabatrin, tiagabine, EVT 201
(Evotec Pharmaceuticals), estazolam or any combinations thereof, in
free or pharmaceutically acceptable salt form. In other
embodiments, the methods disclosed herein do not further comprise
administration of an GABA compound, a benzodiazepine or any other
anxiolytic agent.
[0283] In another preferred embodiment, Methods 1-A, 2-A, 3 or
3.1-3.41 comprises administering to a patient in need thereof, a
Compound of the Invention in combination with doxepin in free or
pharmaceutically acceptable salt form. Dosages of doxepin can vary
in any range known to a person of ordinary skill in the art. In one
example, a 10 mg dose of doxepin may be combined with any dosage of
a compound of the Invention.
[0284] In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41
comprises administering to a patient in need thereof, a Compound of
the Invention in combination (including as part of a daily dosage
regimen) with an atypical stimulant, e.g., a modafinil, adrafinil,
or armodafinil. A regimen incorporating a Compound of the Invention
with such drugs promotes more regular sleep, and avoids side
effects such as psychosis or mania associated with higher levels of
such drugs, e.g., in the treatment of bipolar depression, cognition
associated with schizophrenia, and excessive sleepiness and fatigue
in conditions such as Parkinson's disease and cancer.
[0285] In another embodiment, Methods 1-A, 2-A, 3 or 3.1-3.41
comprises administering to a patient in need thereof, a Compound of
the Invention in combination (including as part of a daily dosage
regimen) with an opiate receptor antagonist or inverse agonist,
e.g., a full opiate antagonist, for example, selected from
naloxone, naltrexone, nalmefene, methadone, nalorphine,
levallorphan, samidorphan, nalodeine, cyprodime, or
norbinaltorphimine.
[0286] In some of the foregoing embodiments, of each of the
Compounds of Formulas I-IV et seq.; Pharmaceutical Compositions 6
and 6.1-6.8; Depo Compositions 6.9 and 6.10; Pharmaceutical
Compositions P.1-P.7; Methods 1 and 1.1-1.55; and Methods 2 and
2.1-2.20; the compound of the present disclosure is substantially
free of the compound of Formula A and/or substantially free of the
compound of Formula B.
[0287] In a twelfth aspect, the invention provides use of a
compound as described in the following: [0288] 11.1 Compound I or
1.1-1.35, in free or pharmaceutically acceptable salt form; [0289]
11.2 Compound II or 2.1-2.12, in free or pharmaceutically
acceptable salt form; [0290] 11.3 Compound III or 3.1-3.11, in free
or pharmaceutically acceptable salt form; [0291] 11.4 Compound IV
or 4.1-4.11, in free or pharmaceutically acceptable salt form;
[0292] 11.5 Compound 5 or 5.1-5.5; [0293] 11.6 a Compound of
Formula II-A, II-B, II-C, II-D, or II-E in free or pharmaceutically
acceptable salt form; [0294] 11.7 a Compound of Formula III-A,
III-B or III-C, in free or pharmaceutically acceptable salt form;
[0295] 11.8 a Compound of Formula IV-A, IV-B or IV-C, in free or
pharmaceutically acceptable salt form; [0296] 11.9 Pharmaceutical
Composition 6 and 6.1-6.10; [0297] 11.10 Pharmaceutical Composition
P.1-P.7; [0298] 11.11 Osmotic-controlled Release Oral Delivery
System Composition as hereinbefore described; (in the manufacture
of a medicament) for the treatment or prophylaxis of one or more
disorders as disclosed hereinbefore, e.g., in any of Method 1 or
1.1-1.55, any of Method 2 and 2.1-2.20, and Method 3 or 3.3-3.41,
or any methods described in the eleventh aspect of the
invention.
[0299] In the thirteenth aspect, the invention provides a
pharmaceutical composition as hereinbefore described, e.g.: [0300]
12.1 Pharmaceutical Composition 6 and 6.1-6.10; [0301] 12.2
Pharmaceutical Composition P.1-P.7; [0302] 12.3 Osmotic-controlled
Release Oral Delivery System Composition as hereinbefore
described,
[0303] for use in the treatment or prophylaxis of one or more
disorders as disclosed hereinbefore, e.g., in any of Methods 1 and
1.1-1.55, Methods 2 and 2.1-2.20, Methods 1-A, 2-A, 3 or 3.1-3.41
or any methods described in the eleventh or twelfth aspect of the
invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0304] FIG. 1 shows the mu-receptor antagonist activity of the
compound of Example 3 compared to naloxone, as described in Example
10.
[0305] FIG. 2 shows the mu-receptor agonist activity of the
compounds of Examples 1 and 3 compared to DAMGO and buprenorphine,
as described in Example 10.
DETAILED DESCRIPTION OF THE INVENTION
[0306] If not otherwise specified or clear from context, the
following terms as used herein have the following meetings:
[0307] "Alkyl" as used herein is a saturated or unsaturated
hydrocarbon moiety, e.g., one to twenty-one carbon atoms in length,
which may be linear or branched (e.g., n-butyl or tert-butyl),
preferably linear, unless otherwise specified. For example,
"C.sub.1-21 alkyl" denotes alkyl having 1 to 21 carbon atoms. In
one embodiment, alkyl is optionally substituted with one or more
hydroxy or C.sub.1-22alkoxy (e.g., ethoxy) groups. In another
embodiment, alkyl contains 1 to 21 carbon atoms, preferably
straight chain and optionally saturated or unsaturated, for example
in some embodiments wherein R.sub.1 is an alkyl chain containing 1
to 21 carbon atoms, preferably 6-15 carbon atoms, 16-21 carbon
atoms, e.g., so that together with the --C(O)-- to which it
attaches, e.g., when cleaved from the compound of Formula I, forms
the residue of a natural or unnatural, saturated or unsaturated
fatty acid.
[0308] The term "pharmaceutically acceptable diluent or carrier" is
intended to mean diluents and carriers that are useful in
pharmaceutical preparations, and that are free of substances that
are allergenic, pyrogenic or pathogenic, and that are known to
potentially cause or promote illness. Pharmaceutically acceptable
diluents or carriers thus exclude bodily fluids such as example
blood, urine, spinal fluid, saliva, and the like, as well as their
constituent components such as blood cells and circulating
proteins. Suitable pharmaceutically acceptable diluents and
carriers can be found in any of several well-known treatises on
pharmaceutical formulations, for example Anderson, Philip O.;
Knoben, James E.; Troutman, William G, eds., Handbook of Clinical
Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor,
eds., Principles of Drug Action, Third Edition, Churchill
Livingston, N.Y., 1990; Katzung, ed., Basic and Clinical
Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and
Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth
Edition, McGraw Hill, 2001; Remington's Pharmaceutical Sciences,
20th Ed., Lippincott Williams & Wilkins., 2000; and Martindale,
The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical
Press, London, 1999); all of which are incorporated by reference
herein in their entirety.
[0309] The terms "purified," "in purified form" or "in isolated and
purified form" for a compound refers to the physical state of said
compound after being isolated from a synthetic process (e.g., from
a reaction mixture), or natural source or combination thereof.
Thus, the term "purified," "in purified form" or "in isolated and
purified form" for a compound refers to the physical state of said
compound after being obtained from a purification process or
processes described herein or well known to the skilled artisan
(e.g., chromatography, recrystallization, LC-MS and LC-MS/MS
techniques and the like), in sufficient purity to be
characterizable by standard analytical techniques described herein
or well known to the skilled artisan.
[0310] The Compounds of Formula I, wherein Z is --(C.dbd.O)-- or
--(CH(OH))--, including for example the Compounds of Formulae II-B
and II-C, may be produced as metabolites of a compound of Formula
A, and/or as metabolites of a compound of Formula B:
##STR00022##
[0311] The compound of Formula A is known to provide effective
treatment of 5-HT.sub.2A, SERT and/or D.sub.2 receptor related
disorders without significant extrapyramidal side effects, as
similarly disclosed and claimed in WO 2009/145900 and US
2011/0071080, the contents of which are incorporated by reference
in their entirety. The plasma levels of compounds of Formulas II-B
and II-C produced from metabolism of a compound of Formula A are,
however, quite low and probably do not contribute significantly to
the therapeutic activity of the compound of Formula A. Compounds of
Formulae II-D and II-E could also be present as metabolites,
although this has so far not been detected. The Compounds of
Formula I have unexpectedly been found to have activity as
antagonists of the .mu.-opioid receptor. This is unexpected because
the compound of Formula A has not been known or understood to have
any .mu.-opioid receptor activity or binding. Compounds of Formula
I wherein X is --NH-- and wherein L is --O-- are shown to have
particularly good .mu.-opioid receptor antagonism. Such Compounds
of Formula I may therefore be useful in the treatment of drug
dependency, such as opiate dependency and/or alcohol dependency, by
inhibiting the endogenous opiate response to illicit drug
administration, as well as by inhibiting the direct effects of
ingestion of illicit opiate drugs.
[0312] It is surprising that metabolites of a compound of Formula A
have somewhat different relative receptor binding affinity that
compounds of Formula A. For example, the receptor binding profile
of the compound for Formula II-B is very unique, with a combination
of antagonist activities at 5-HT.sub.2A, D.sub.1 and Mu opiate
receptors, making this compound very interesting for treating mood
disorders. The compound of Formula A is not active at the Mu opiate
receptor, for example.
[0313] It has also unexpectedly been found that compounds according
to Formula I, particularly wherein X is --NH, L is O, and Z is
--O--, demonstrate potent 5-HT.sub.2A, D.sub.1 and Mu opiate
antagonism, along with moderate D.sub.1, D.sub.2 and SERT
antagonism. Furthermore, it has been unexpectedly found that such
compounds may operate as "biased" Mu opiate ligands. This means
that when the compounds bind to Mu opiate receptors, they may
operate as partial Mu agonists via G-protein coupled signaling, but
as Mu antagonists via beta-arrestin signaling. This is in contrast
to the traditional opiate agonists morphine and fentanyl, which
tend to strongly activate both G-protein signaling and
beta-arrestin signaling. The activation of beta-arrestin signaling
by such drugs is thought to mediate the gastrointestinal
dysfunction and respiratory suppression typically mediated by
opiate drugs. Compounds according to the present invention, in
particular compounds according to Formula I, are therefore expected
to result in pain amelioration with less severe gastrointestinal
and respiratory side effects than existing opiate analgesics. This
effect has been shown in pre-clinical studies and Phase II and
Phase III clinical trials of the biased Mu agonist oliceridine.
Oliceridine has been shown to result in biased mu agonism via
G-protein coupled signaling with reduced beta-arresting signaling
compared to morphine, and this has been linked to its ability to
produce analgesia with reduced respiratory side effects compared to
morphine. Furthermore, because compounds according to the present
antagonize the beta-arrestin pathway, they are expected to be
useful in treating opiate overdose, because they will inhibit the
most severe opiate adverse effects while still providing pain
relief. Furthermore, the Compounds of the present disclosure also
have sleep maintenance effect due to their serotonergic activity.
As many people suffering from chronic pain have difficulty sleeping
due to the pain, these compounds can help such patients sleep
through the night due to the synergistic effects of serotonergic
and opiate receptor activities.
[0314] Thus, in certain embodiments, the Compounds of the present
disclosure may be used in a method of treating opiate use disorder
(OUD), opiate overdose, or opiate withdrawal, either alone, or in
conjunction with an opiate antagonist or inverse agonist (e.g.,
naloxone or naltrexone). It is particularly noteworthy that the
Compounds of the present disclosure (e.g., the compound of Formula
I, wherein X is --NH, L is O, and Z is --O--), shows a strong
ability to mitigate the dysphoria and psychiatric comorbidities
associated with drug withdrawal (e.g., mood and anxiety disorders,
sleep disturbances), and it also provides potent analgesia but
without the adverse effects (e.g., GI effects and pulmonary
depression) and abuse potential seen with other opioid treatments
(e.g., oxycodone, methadone or buprenorphine). Data suggests the
unique pharmacologic profile of these compounds will also mitigate
the risks of adverse drug-drug interactions (e.g., alcohol). These
compounds are therefore particularly suited to treat opiate use
disorder and the symptoms associated with opiate withdrawal. In
addition, to the compounds' direct effect on mu receptor activity,
the compounds' effect on serotonergic pathways results in
anti-depressant, sleep maintenance, and anxiolytic effects. Because
depression and anxiety are key factors leading susceptible patients
to opioid use in the first place, the compounds of the present
disclosure would both reduce the symptoms of opiate withdrawal at
the same time that they reduce the psychiatric co-morbidities which
promote opioid use-a two-pronged strategy to reduce the risk of
remission. The sleep maintenance provided by these compounds would
further improve the quality of life of patients undergoing OUD
treatment.
[0315] Unless otherwise indicated, the Compounds of the present
disclosure, e.g., Compound I or 1.1-1.35, Compound II or 2.1-2.18,
Compound III or 3.1-3.13, or Compound IV or 4.1-4.13 (collectively,
Compounds of Formulas I-IV et seq.) may exist in free or salt,
e.g., as acid addition salts, form. An acid-addition salt of a
compound of the invention which is sufficiently basic, for example,
an acid-addition salt with, for example, an inorganic or organic
acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric,
acid acetic, trifluoroacetic, citric, maleic acid, toluene
sulfonic, propionic, succinic, glycolic, stearic, lactic, malic,
tartaric, citric, ascorbic, pamoic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic acid, and the like. In addition, a salt of a
compound of the invention which is sufficiently acidic is an alkali
metal salt, for example a sodium or potassium salt, an alkaline
earth metal salt, for example a calcium or magnesium salt, an
ammonium salt or a salt with an organic base which affords a
physiologically-acceptable cation, for example a salt with
methylamine, dimethylamine, trimethylamine, piperidine, morpholine
or tris-(2-hydroxyethyl)-amine. In a particular embodiment, the
salt of the Compounds of the Invention is a toluenesulfonic acid
addition salt. In another particular embodiment, the salt of the
Compounds of the Invention is a fumaric acid addition salt. In a
particular embodiment, the salt of the Compounds of the Invention
is a phosphoric acid addition salt.
[0316] The Compounds of the present disclosure are intended for use
as pharmaceuticals, therefore pharmaceutically acceptable salts are
preferred. Salts which are unsuitable for pharmaceutical uses may
be useful, for example, for the isolation or purification of free
Compounds of the Invention and are therefore also included within
the scope of the compounds of the present disclosure.
[0317] The Compounds of the present disclosure may comprise one or
more chiral carbon atoms. The compounds thus exist in individual
isomeric, e.g., enantiomeric or diastereomeric form or as mixtures
of individual forms, e.g., racemic/diastereomeric mixtures. Any
isomer may be present in which the asymmetric center is in the
(R)-, (S)-, or (R,S)-configuration. The invention is to be
understood as embracing both individual optically active isomers as
well as mixtures (e.g., racemic/diastereomeric mixtures) thereof.
Accordingly, the Compounds of the Invention may be a racemic
mixture or it may be predominantly, e.g., in pure, or substantially
pure, isomeric form, e.g., greater than 70%
enantiomeric/diastereomeric excess ("ee"), preferably greater than
80% ee, more preferably greater than 90% ee, most preferably
greater than 95% ee. The purification of said isomers and the
separation of said isomeric mixtures may be accomplished by
standard techniques known in the art (e.g., column chromatography,
preparative TLC, preparative HPLC, simulated moving bed and the
like).
[0318] Geometric isomers by nature of substituents about a double
bond or a ring may be present in cis (Z) or trans (E) form, and
both isomeric forms are encompassed within the scope of this
invention.
[0319] It is also intended that the compounds of the present
disclosure encompass their stable and unstable isotopes. Stable
isotopes are nonradioactive isotopes which contain one additional
neutron compared to the abundant nuclides of the same species
(i.e., element). It is expected that the activity of compounds
comprising such isotopes would be retained, and such compound would
also have utility for measuring pharmacokinetics of the
non-isotopic analogs. For example, the hydrogen atom at a certain
position on the compounds of the disclosure may be replaced with
deuterium (a stable isotope which is non-radioactive). Examples of
known stable isotopes include, but not limited to, deuterium,
.sup.13C, .sup.15N, .sup.18O. Alternatively, unstable isotopes,
which are radioactive isotopes which contain additional neutrons
compared to the abundant nuclides of the same species (i.e.,
element), e.g., .sup.123I, .sup.131I, .sup.125I, .sup.11C,
.sup.18F, may replace the corresponding abundant species of I, C
and F. Another example of useful isotope of the compound of the
invention is the .sup.11C isotope. These radio isotopes are useful
for radio-imaging and/or pharmacokinetic studies of the compounds
of the invention. In addition, the substitution of atoms of having
the natural isotopic distributing with heavier isotopes can result
in desirable change in pharmacokinetic rates when these
substitutions are made at metabolically liable sites. For example,
the incorporation of deuterium (.sup.2H) in place of hydrogen can
slow metabolic degradation when the position of the hydrogen is a
site of enzymatic or metabolic activity.
[0320] In addition to the unique characteristic of the Compounds of
the present disclosure, the Compounds of Formula I, wherein Y is
--C(H)(OH)-- may also be esterified to form physiologically
hydrolysable and acceptable ester prodrugs. As used herein,
"physiologically hydrolysable and acceptable esters" means esters
of Compounds of the present disclosure which are hydrolysable under
physiological conditions to yield hydroxy on the one hand and acid,
e.g., carboxylic acid on the other, which are themselves
physiologically tolerable at doses to be administered. For Example,
the Compound of Formula I or Formula II wherein Y is --C(H)(OH) may
be esterified to form a prodrug, i.e., a Compound of Formula I
Formula II wherein R.sub.1 is --C(O)--C.sub.1-21 alkyl. In some
preferred embodiments, R.sub.1 is --C(O)--C.sub.1-21alkyl, e.g.,
acyl acid esters, e.g., heptanoic, octanoic, decanoic, dodecanoic,
tetradecanoic or hexadecanoic acid ester.
[0321] Similarly, wherein the Compounds of the present disclosure
contain an amine group, prodrug of such amine, e.g., methyl amine
prodrugs may also exist wherein the prodrug is cleaved to release
the amine metabolite in vivo following administration.
[0322] The prodrugs of the Compounds of the present disclosure
wherein R.sub.1 is --C(O)--C.sub.1-21alkyl, preferably
--C.sub.6-21alkyl, more preferably C.sub.6-15alkyl, more preferably
linear, saturated or unsaturated and optionally substituted with
one or more hydroxy or alkoxy groups, are particularly useful for
sustained- and/or delayed release so as to achieve a long acting
effect, e.g., wherein the Compounds of the present disclosure is
released over a period of from about 14 to about 30 to about 180
days, preferably over about 30 or about 60 or about 90 days, for
example as described in any of depot composition as described
herein. Preferably, the sustained and/or delayed-release
formulation is an injectable formulation.
[0323] Alternatively, and/or additionally, the Compounds of the
present disclosure may be included as a depot formulation, e.g., by
dispersing, dissolving or encapsulating the Compounds of the
Invention in a polymeric matrix as described in any of Composition
6 and 6.1-6.10, such that the Compound is continually released as
the polymer degrades over time. The release of the Compounds of the
Invention from the polymeric matrix provides for the controlled-
and/or delayed- and/or sustained-release of the Compounds, e.g.,
from the pharmaceutical depot composition, into a subject, for
example a warm-blooded animal such as man, to which the
pharmaceutical depot is administered. Thus, the pharmaceutical
depot delivers the Compounds of the Invention to the subject at
concentrations effective for treatment of the particular disease or
medical condition over a sustained period of time, e.g., 14-180
days, preferably about 30, about 60 or about 90 days.
[0324] Polymers useful for the polymeric matrix in the Composition
of the Invention (e.g., Depot composition of the Invention) may
include a polyester of a hydroxyfatty acid and derivatives thereof
or other agents such as polylactic acid, polyglycolic acid,
polycitric acid, polymalic acid, poly-beta.-hydroxybutyric acid,
epsilon.-capro-lactone ring opening polymer, lactic acid-glycolic
acid copolymer, 2-hydroxybutyric acid-glycolic acid copolymer,
polylactic acid-polyethyleneglycol copolymer or polyglycolic
acid-polyethyleneglycol copolymer), a polymer of an alkyl
alpha-cyanoacrylate (for example poly(butyl 2-cyanoacrylate)), a
polyalkylene oxalate (for example polytrimethylene oxalate or
polytetramethylene oxalate), a polyortho ester, a polycarbonate
(for example polyethylene carbonate or polyethylenepropylene
carbonate), a polyortho-carbonate, a polyamino acid (for example
poly-gamma.-L-alanine, poly-.gamma.-benzyl-L-glutamic acid or
poly-y-methyl-L-glutamic acid), a hyaluronic acid ester, and the
like, and one or more of these polymers can be used.
[0325] If the polymers are copolymers, they may be any of random,
block and/or graft copolymers. When the above
alpha-hydroxycarboxylic acids, hydroxydicarboxylic acids and
hydroxytricarboxylic acids have optical activity in their
molecules, any one of D-isomers, L-isomers and/or DL-isomers may be
used. Among others, alpha-hydroxycarboxylic acid polymer
(preferably lactic acid-glycolic acid polymer), its ester,
poly-alpha-cyanoacrylic acid esters, etc. may be used, and lactic
acid-glycolic acid copolymer (also referred to as
poly(lactide-alpha-glycolide) or poly(lactic-co-glycolic acid), and
hereinafter referred to as PLGA) are preferred. Thus, in one aspect
the polymer useful for the polymeric matrix is PLGA. As used
herein, the term PLGA includes polymers of lactic acid (also
referred to as polylactide, poly(lactic acid), or PLA). Most
preferably, the polymer is the biodegradable
poly(d,l-lactide-co-glycolide) polymer.
[0326] In a preferred embodiment, the polymeric matrix of the
invention is a biocompatible and biodegradable polymeric material.
The term "biocompatible" is defined as a polymeric material that is
not toxic, is not carcinogenic, and does not significantly induce
inflammation in body tissues. The matrix material should be
biodegradable wherein the polymeric material should degrade by
bodily processes to products readily disposable by the body and
should not accumulate in the body. The products of the
biodegradation should also be biocompatible with the body in that
the polymeric matrix is biocompatible with the body. Particular
useful examples of polymeric matrix materials include poly(glycolic
acid), poly-D,L-lactic acid, poly-L-lactic acid, copolymers of the
foregoing, poly(aliphatic carboxylic acids), copolyoxalates,
polycaprolactone, polydioxanone, poly(ortho carbonates),
poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,
poly(glycolic acid-caprolactone), polyanhydrides, and natural
polymers including albumin, casein, and waxes, such as, glycerol
mono- and distearate, and the like. The preferred polymer for use
in the practice of this invention is dl(polylactide-co-glycolide).
It is preferred that the molar ratio of lactide to glycolide in
such a copolymer be in the range of from about 75:25 to 50:50.
[0327] Useful PLGA polymers may have a weight-average molecular
weight of from about 5,000 to 500,000 Daltons, preferably about
150,000 Daltons. Dependent on the rate of degradation to be
achieved, different molecular weight of polymers may be used. For a
diffusional mechanism of drug release, the polymer should remain
intact until all of the drug is released from the polymeric matrix
and then degrade. The drug can also be released from the polymeric
matrix as the polymeric excipient bioerodes.
[0328] The PLGA may be prepared by any conventional method, or may
be commercially available. For example, PLGA can be produced by
ring-opening polymerization with a suitable catalyst from cyclic
lactide, glycolide, etc. (see EP-0058481B2; Effects of
polymerization variables on PLGA properties: molecular weight,
composition and chain structure).
[0329] It is believed that PLGA is biodegradable by means of the
degradation of the entire solid polymer composition, due to the
break-down of hydrolysable and enzymatically cleavable ester
linkages under biological conditions (for example in the presence
of water and biological enzymes found in tissues of warm-blooded
animals such as humans) to form lactic acid and glycolic acid. Both
lactic acid and glycolic acid are water-soluble, non-toxic products
of normal metabolism, which may further biodegrade to form carbon
dioxide and water. In other words, PLGA is believed to degrade by
means of hydrolysis of its ester groups in the presence of water,
for example in the body of a warm-blooded animal such as man, to
produce lactic acid and glycolic acid and create the acidic
microclimate. Lactic and glycolic acid are by-products of various
metabolic pathways in the body of a warm-blooded animal such as man
under normal physiological conditions and therefore are well
tolerated and produce minimal systemic toxicity.
[0330] In another embodiment, the polymeric matrix useful for the
invention may comprise a star polymer wherein the structure of the
polyester is star-shaped. These polyesters have a single polyol
residue as a central moiety surrounded by acid residue chains. The
polyol moiety may be, e. g., glucose or, e. g., mannitol. These
esters are known and described in GB 2,145,422 and in U.S. Pat. No.
5,538,739, the contents of which are incorporated by reference.
[0331] The star polymers may be prepared using polyhydroxy
compounds, e. g., polyol, e.g., glucose or mannitol as the
initiator. The polyol contains at least 3 hydroxy groups and has a
molecular weight of up to about 20,000 Daltons, with at least 1,
preferably at least 2, e.g., as a mean 3 of the hydroxy groups of
the polyol being in the form of ester groups, which contain
polylactide or co-polylactide chains. The branched polyesters,
e.g., poly (d, l-lactide-co-glycolide) have a central glucose
moiety having rays of linear polylactide chains.
[0332] The depot compositions of the invention (e.g., Compositions
6 and 6.1-6.10, in a polymer matrix) as hereinbefore described may
comprise the polymer in the form of microparticles or
nanoparticles, or in a liquid form, with the Compounds of the
Invention dispersed or encapsulated therein. "Microparticles" is
meant solid particles that contain the Compounds of the Invention
either in solution or in solid form wherein such compound is
dispersed or dissolved within the polymer that serves as the matrix
of the particle. By an appropriate selection of polymeric
materials, a microparticle formulation can be made in which the
resulting microparticles exhibit both diffusional release and
biodegradation release properties.
[0333] When the polymer is in the form of microparticles, the
microparticles may be prepared using any appropriate method, such
as by a solvent evaporation or solvent extraction method. For
example, in the solvent evaporation method, the Compounds of the
Invention and the polymer may be dissolved in a volatile organic
solvent (for example a ketone such as acetone, a halogenated
hydrocarbon such as chloroform or methylene chloride, a halogenated
aromatic hydrocarbon, a cyclic ether such as dioxane, an ester such
as ethyl acetate, a nitrile such as acetonitrile, or an alcohol
such as ethanol) and dispersed in an aqueous phase containing a
suitable emulsion stabilizer (for example polyvinyl alcohol, PVA).
The organic solvent is then evaporated to provide microparticles
with the Compounds of the Invention encapsulated therein. In the
solvent extraction method, the Compounds of the Invention and
polymer may be dissolved in a polar solvent (such as acetonitrile,
dichloromethane, methanol, ethyl acetate or methyl formate) and
then dispersed in an aqueous phase (such as a water/PVA solution).
An emulsion is produced to provide microparticles with the
Compounds of the Invention encapsulated therein. Spray drying is an
alternative manufacturing technique for preparing the
microparticles.
[0334] Another method for preparing the microparticles of the
invention is also described in both U.S. Pat. Nos. 4,389,330 and
4,530,840.
[0335] The microparticle of the present invention can be prepared
by any method capable of producing microparticles in a size range
acceptable for use in an injectable composition. One preferred
method of preparation is that described in U.S. Pat. No. 4,389,330.
In this method the active agent is dissolved or dispersed in an
appropriate solvent. To the agent-containing medium is added the
polymeric matrix material in an amount relative to the active
ingredient that provides a product having the desired loading of
active agent. Optionally, all of the ingredients of the
microparticle product can be blended in the solvent medium
together.
[0336] Solvents for the Compounds of the Invention and the
polymeric matrix material that can be employed in the practice of
the present invention include organic solvents, such as acetone;
halogenated hydrocarbons, such as chloroform, methylene chloride,
and the like; aromatic hydrocarbon compounds; halogenated aromatic
hydrocarbon compounds; cyclic ethers; alcohols, such as, benzyl
alcohol; ethyl acetate; and the like. In one embodiment, the
solvent for use in the practice of the present invention may be a
mixture of benzyl alcohol and ethyl acetate. Further information
for the preparation of microparticles useful for the invention can
be found in U.S. Patent Publication Number 2008/0069885, the
contents of which are incorporated herein by reference in their
entirety.
[0337] The amount of the Compounds of the present disclosure
incorporated in the microparticles usually ranges from about 1 wt %
to about 90 wt. %, preferably 30 to 50 wt. %, more preferably 35 to
40 wt. %. By weight % is meant parts of the Compounds of the
present disclosure per total weight of microparticle.
[0338] The pharmaceutical depot compositions may comprise a
pharmaceutically-acceptable diluent or carrier, such as a water
miscible diluent or carrier.
[0339] Details of Osmotic-controlled Release Oral Delivery System
composition may be found in EP 1 539 115 (U.S. Pub. No.
2009/0202631) and WO 2000/35419, the contents of each of which are
incorporated by reference in their entirety.
[0340] A "therapeutically effective amount" is any amount of the
Compounds of the invention (for example as contained in the
pharmaceutical depot) which, when administered to a subject
suffering from a disease or disorder, is effective to cause a
reduction, remission, or regression of the disease or disorder over
the period of time as intended for the treatment.
[0341] Dosages employed in practicing the present invention will of
course vary depending, e.g. on the particular disease or condition
to be treated, the particular Compound of the Invention used, the
mode of administration, and the therapy desired. Unless otherwise
indicated, an amount of the Compound of the Invention for
administration (whether administered as a free base or as a salt
form) refers to or is based on the amount of the Compound of the
Invention in free base form (i.e., the calculation of the amount is
based on the free base amount).
[0342] Compounds of the Invention may be administered by any
satisfactory route, including orally, parenterally (intravenously,
intramuscular or subcutaneous) or transdermally, but are preferably
administered orally. In certain embodiments, the Compounds of the
Invention, e.g., in depot formulation, are preferably administered
parenterally, e.g., by injection.
[0343] In general, satisfactory results for Method 1 and 1.1-1.55,
Method 2 and 2.1-2.20, and Method 3 and 3.1-3.40, or use of the
Compounds of the present disclosure as hereinbefore described, e.g.
for the treatment of a combination of diseases such as a
combination of at least depression, psychosis, e.g., (1) psychosis,
e.g., schizophrenia, in a patient suffering from depression; (2)
depression in a patient suffering from psychosis, e.g.,
schizophrenia; (3) mood disorders associated with psychosis, e.g.,
schizophrenia, or Parkinson's disease; (4) sleep disorders
associated with psychosis, e.g., schizophrenia, or Parkinson's
disease; and (5) substance addiction, substance use disorders
and/or substance-induced disorders, as set forth above are
indicated to be obtained on oral administration at dosages of the
order from about 1 mg to 100 mg once daily, preferably 2.5 mg-50
mg, e.g., 2.5 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg or 50 mg, once
daily, preferably via oral administration.
[0344] Satisfactory results for Method 2 or 2.1-2.20 or use of the
Compounds of the present disclosure as hereinbefore described, e.g.
for the treatment of sleep disorder alone are indicated to be
obtained on oral administration at dosages of the order from about
2.5 mg-5 mg, e.g., 2.5 mg, 3 mg, 4 mg or 5 mg, of a Compound of the
Invention, in free or pharmaceutically acceptable salt form, once
daily, preferably via oral administration.
[0345] Satisfactory results for Method I-A or Method II-A, or any
of 3.1-3.40 are indicated to be obtained at less than 100 mg,
preferably less than 50 mg, e.g., less than 40 mg, less than 30 mg,
less than 20 mg, less than 10 mg, less than 5 mg, less than 2.5 mg,
once daily. Satisfactory results for Method II-A or any of 3.1-3.41
are indicated to be obtained at less than 5 mg, preferably less
than 2.5 mg.
[0346] For treatment of the disorders disclosed herein wherein the
depot composition is used to achieve longer duration of action, the
dosages will be higher relative to the shorter action composition,
e.g., higher than 1-100 mg, e.g., 25 mg, 50 mg, 100 mg, 500 mg,
1,000 mg, or greater than 1000 mg. Duration of action of the
Compounds of the present disclosure may be controlled by
manipulation of the polymer composition, i.e., the polymer:drug
ratio and microparticle size. Wherein the composition of the
invention is a depot composition, administration by injection is
preferred.
[0347] The pharmaceutically acceptable salts of the Compounds of
the present disclosure can be synthesized from the parent compound
which contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting the free
base forms of these compounds with a stoichiometric amount of the
appropriate acid in water or in an organic solvent, or in a mixture
of the two; generally, non-aqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Further
details for the preparation of these salts, e.g., toluenesulfonic
salt in amorphous or crystal form, may be found in PCT/US08/03340
and/or U.S. Provisional Appl. No. 61/036,069 (each equivalent to US
2011/112105).
[0348] Pharmaceutical compositions comprising Compounds of the
present disclosure may be prepared using conventional diluents or
excipients (an example include, but is not limited to sesame oil)
and techniques known in the galenic art. Thus, oral dosage forms
may include tablets, capsules, solutions, suspensions and the
like.
[0349] The term "concurrently" when referring to a therapeutic use
means administration of two or more active ingredients to a patient
as part of a regimen for the treatment of a disease or disorder,
whether the two or more active agents are given at the same or
different times or whether given by the same or different routes of
administrations. Concurrent administration of the two or more
active ingredients may be at different times on the same day, or on
different dates or at different frequencies.
[0350] The term "simultaneously" when referring to a therapeutic
use means administration of two or more active ingredients at or
about the same time by the same route of administration.
[0351] The term "separately" when referring to a therapeutic use
means administration of two or more active ingredients at or about
the same time by different route of administration
Methods of Making the Compounds of the Invention:
[0352] The Compounds of the present disclosure wherein X is --NH--
or --N(CH.sub.3)-- and Y is --C(.dbd.O) may be prepared by reacting
(6bR,
10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,-
3-de]quinoxaline or its 1-methyl analog with
4-chloro-4'-fluorobutyrophenone, in accordance with Scheme 1
below:
##STR00023##
[0353] Compounds of the present disclosure wherein X is --NH-- or
--N(CH.sub.3)-- and Y is --CH(OH)-- may be prepared by reacting the
4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrr-
olo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one
produced in Scheme 1 (or its 1-methyl analog) with a reducing
agent, in accordance with Scheme 2, below:
##STR00024##
[0354] The reducing agent may be a metal hydride, e.g., sodium
borohydride, sodium cyanoborohydride, lithium aluminum hydride,
aluminum hydride, diisobutylaluminum hydride, preferably sodium
borohydride. Further reagents for reduction of ketones may be found
in Jerry March, Advanced Organic Chemistry, Reactions Mechanisms
and Structures, p. 910-911, (1992, John Wiley & Sons, Inc.),
Fourth Edition, the contents of which are incorporated by
reference.
[0355] Isolation or purification of the diastereomers of the
Compounds of the Invention may be achieved by conventional methods
known in the art, e.g., column purification, preparative thin layer
chromatography, preparative HPLC, crystallization, trituration,
simulated moving beds and the like.
[0356] The Compounds of Formula I wherein Y is --CH(O--R.sub.1)--
and R.sub.1 is other than H can be prepared by several commonly
used esterification methods such as alcoholysis of acyl halides,
anhydrides or active esters. For example, The Compound of Formula
I, wherein R.sub.1 is --C(O)-- alkyl may be prepared by reacting:
[0357] (a) L-C(O)--C.sub.1-21alkyl, wherein L is a leaving group
such as a halo group (for example, chloro or bromo),
trifluoromethylsulfonyloxy (--OSO.sub.2CF.sub.3), tosyloxy
(--O--S(O).sub.2--C.sub.6H.sub.4--CH.sub.3), methylsulfonyloxy
(--O--S(O).sub.2--CH.sub.3), 1H-benzo[d][1,2,3]triazol-1-yloxy or
succinimidyloxy group, [0358] with [0359] (b) the Compound of
Formula I wherein Y is --C(H)(OH), preferably in the presence of a
base (e.g., diisopropylamine, triethyl amine or pyridine). For
example L-C(O)--C.sub.1-21alkyl is an acetyl halide, decanoyl
halide or heptanoyl halide, which may be prepared by reacting
HO--C(O)--C.sub.1-21alkyl, e.g., with thionyl chloride, P(X').sub.3
or P(X').sub.5 wherein X' is Cl or Br. Wherein L is
tosyloxy-C(O)--C.sub.1-21alkyl or
methylsulfonyloxy-C(O)--C.sub.1-21alkyl, these compounds may be
prepared by reacting HO--C(O)--C.sub.1-21alkyl with tosyl-chloride
or mesyl-chloride, preferably in the presence of a base such as
pyridine. Synthesis of the Compound of Formula II-A where R.sub.1
is other than H may be summarized in Scheme 3 below:
##STR00025##
[0360] Alternatively, the synthesis of the compound of Formula II-A
where R.sub.1 is other than H maybe achieved by reacting
HO--C(O)--C.sub.1-21alkyl with (i) a compound of Formula I wherein
Y is --C(H)(OH) in the presence of a base such as DIEPA and
NEt.sub.3, and (ii) a dehydrating or coupling reagent such as
2-fluoro-1-ethyl pyridinium tetrafluoroborate (FEP),
tetramethylfluoroamidinium hexafluorophosphate (TFFH) or
1,1,3,3-bis(tetramethylene) chlorouronium hexafluorophosphate
(PyClU).
[0361] Salts of the Compounds of the present disclosure may be
prepared as similarly described in U.S. Pat. Nos. 6,548,493;
7,238,690; 6,552,017; 6,713,471; 7,183,282; U.S. RE39680; U.S.
RE39679; and WO 2009/114181 (US 2011/112105), the contents of each
of which are incorporated by reference in their entirety.
[0362] Diastereomers of prepared compounds can be separated by, for
example, HPLC using CHIRALPAK.RTM. AY-H, 5.mu., 30.times.250 mm at
room temperature and eluted with 10% ethanol/90% hexane/0.1%
dimethylethylamine. Peaks can be detected at 230 nm to produce
98-99.9% ee of the diastereomer.
Example 1: Synthesis of
4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrr-
olo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one
##STR00026##
[0364] (6bR,
10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,-
3-de]quinoxaline-8-carboxylic acid ethyl ester (6.4 g, 21.2 mmol)
is suspended in HBr acetic acid solution (64 mL, 33% w/w) at room
temperature. The mixture is heated at 50.degree. C. for 16 h. After
cooling, and treatment with ethyl acetate (300 mL), the mixture is
filtered. The filter cake is washed with ethyl acetate (300 mL),
and then dried under vacuum. The obtained HBr salt is then
suspended in methanol (200 mL), and cooled with dry ice in
isopropanol. Under vigorous stirring, ammonia solution (10 mL, 7N
in methanol) is added slowly to the suspension to adjust the pH of
the mixture to 10. The obtained mixture is dried under vacuum
without further purification to give crude (6bR,
10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,-
3-de]quinoxaline (8.0 g), which is used directly in the next step.
MS (ESI) m/z 230.2 [M+H].sup.+.
[0365] The crude (6bR,
10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrrolo[1,2,-
3-de]quinoxaline (1.4 g) is dissolved in DMF (14 mL), and then KI
(2.15 g) and 4-Chloro-4'-fluorobutyrophenone (2 mL) are added
successively. The mixture is degassed with argon, followed by
adding N,N-diisopropylethylamine (DIPEA, 2 mL). The mixture is
heated at 78.degree. C. for 2 h. After cooling, the solvents are
removed under reduced pressure. The dark brown residue is suspended
in dichloromethane (100 mL) and then extracted with water (30 mL).
The organic layer is separated, and dried over K.sub.2CO.sub.3.
After filtration, the solvents are removed under reduced pressure.
The obtained crude product is purified by silica gel column
chromatography eluting with 0-10% of methanol in ethyl acetate
containing 0.1% of 7N ammonia in methanol to yield
4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,-
5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one
as a light yellow solid (767 mg). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.3 (s, 1H), 8.1-8.0 (m, 2H), 7.3 (dd,
J=8.86 Hz, 2H), 6.8 (d, J=7.25 Hz, 1H), 6.6 (dd, J=7.55 Hz, 1H),
6.6 (d, J=7.74 Hz, 1H), 3.8 (d, J=14.49 Hz, 1H), 3.3-3.3 (m, 1H),
3.2-3.2 (m, 1H), 3.1-3.0 (m, 1H), 3.0 (t, J=6.88 Hz, 2H), 2.8-2.8
(m, 1H), 2.6-2.5 (m, 1H), 2.3-2.2 (m, 2H), 2.1-2.0 (m, 1H), 1.9-1.8
(m, 1H), 1.8 (t, J=6.99 Hz, 2H), 1.6 (t, J=11.25 Hz, 2H). MS (ESI)
m/z 394.2 [M+H].sup.+.
Example 2: Synthesis of
4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrr-
olo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-ol
##STR00027##
[0367]
4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,-
5]pyrrolo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-one
(50 mg, 0.127 mmol) is dissolved in methanol (5 mL). Under
stirring, NaBH.sub.4 (31 mg, 0.82 mmol) is added in batches. After
the completion of the addition, the mixture is stirred at room
temperature for 30 min. Methanol is evaporated under reduced
pressure. The residue is dissolved in dichloromethane (10 mL) and
then extracted with water (2.times.0.5 mL). The combined organic
phase is dried over K.sub.2CO.sub.3. After filtration, the filtrate
is concentrated under reduced pressure and then further dried under
vacuum to give
4-((6bR,10aS)-2-oxo-2,3,6b,9,10,10a-hexahydro-1H,7H-pyrido[3',4':4,5]pyrr-
olo[1,2,3-de]quinoxalin-8-yl)-1-(4-fluoro-phenyl)-butan-1-ol as a
pale yellow foamy solid (45 mg, yield 90%). .sup.1H NMR (500 MHz,
DMSO-d.sub.6) .delta. 10.3 (s, 1H), 7.4-7.3 (m, 2H), 7.2-7.1 (m,
2H), 6.7 (d, J=7.29 Hz, 1H), 6.7-6.6 (m, 1H), 6.6 (d, J=7.74 Hz,
1H), 5.4 (s, 1H), 4.7-4.4 (m, 1H), 3.8 (d, J=14.49 Hz, 1H), 3.3-3.3
(m, 1H), 3.3-3.2 (m, 1H), 3.2-3.1 (m, 1H), 2.8-2.7 (m, 1H), 2.6-2.5
(m, 1H), 2.3-2.1 (m, 2H), 2.1-2.0 (m, 1H), 2.0-1.9 (m, 1H), 1.8-1.7
(m, 1H), 1.7-1.5 (m, 3H), 1.5-1.4 (m, 1H), 1.4-1.3 (m, 1H). MS
(ESI) m/z 396.2 [M+H].sup.+.
Example 3: Synthesis of
(6bR,10aS)-8-(3-(4-fluorophenoxy)propyl)-6b,7,8,9,10,10a-hexahydro-1H-pyr-
ido[3',4':4,5]pyrrolo[1,2,3-de]quinoxalin-2(3H)-one
##STR00028##
[0369] A mixture of
(6bR,10aS)-6b,7,8,9,10,10a-hexahydro-1H-pyrido[3',4':4,5]pyrrolo[1,2,3-de-
]quinoxalin-2(3H)-one (100 mg, 0.436 mmol),
1-(3-chloroproxy)-4-fluorobenzene (100 .mu.L, 0.65 mmol) and KI
(144 mg, 0.87 mmol) in DMF (2 mL) is degassed with argon for 3
minutes and DIPEA (150 .mu.L, 0.87 mmol) is added. The resulting
mixture is heated to 78.degree. C. and stirred at this temperature
for 2 h. The mixture is cooled to room temperature and then
filtered. The filter cake is purified by silica gel column
chromatography using a gradient of 0-100% ethyl acetate in a
mixture of methanol/7N NH.sub.3 in methanol (1:0.1 v/v) as an
eluent to produce partially purified product, which is further
purified with a semi-preparative HPLC system using a gradient of
0-60% acetonitrile in water containing 0.1% formic acid over 16 min
to obtain the title product as a solid (50 mg, yield 30%). MS (ESI)
m/z 406.2 [M+1].sup.+. .sup.1H NMR (500 MHz, DMSO-d.sub.6) .delta.
10.3 (s, 1H), 7.2-7.1 (m, 2H), 7.0-6.9 (m, 2H), 6.8 (dd, J=1.03,
7.25 Hz, 1H), 6.6 (t, J=7.55 Hz, 1H), 6.6 (dd, J=1.07, 7.79 Hz,
1H), 4.0 (t, J=6.35 Hz, 2H), 3.8 (d, J=14.74 Hz, 1H), 3.3-3.2 (m,
3H), 2.9 (dd, J=6.35, 11.13 Hz, 1H), 2.7-2.6 (m, 1H), 2.5-2.3 (m,
2H), 2.1 (t, J=11.66 Hz, 1H), 2.0 (d, J=14.50 Hz, 1H), 1.9-1.8 (m,
3H), 1.7 (t, J=11.04 Hz, 1H).
Example 4: Cellular and Nuclear Receptor Functional Assays
[0370] Cellular and Nuclear Receptor Functional Assays are
performed on the compounds of Formula II-B and II-C (Examples 1 and
2, respectively) according to the procedure of Wang, J. B. et al.
(1994), FEBS Lett., 338:217-222. The compounds are tested at
several concentrations to determine their IC.sub.50 or EC.sub.50.
Cellular agonist effects are calculated as percent of control
response to a known reference agonist for each target and cellular
antagonist effect is calculated as a percent inhibition of control
reference agonist response for each target.
[0371] The following assay is performed to determine the effect of
the Compound of Formula II-B on the .mu. (MOP) (h) receptor:
TABLE-US-00001 Assay Incu- Measured Detection (Receptor) Source
Stimulus bation Component Method .mu. (MOP) human none 10 min cAMP
HTRF (h) (agonist recombinant (0.3 .mu.M @ effect) MOP DAMGO
37.degree. C. receptor for control) (CHO cells) .mu. (MOP) human
DAMGO 10 min cAMP HTRF (h) recombinant (20 nM) @ (antagonist MOP
37.degree. C. effect) receptor (CHO cells)
[0372] For the antagonists, the apparent dissociation constants
(K.sub.B) are calculated using the modified Cheng Prusoff
equation:
K B = I .times. C 5 .times. 0 1 + ( A / EC 5 .times. 0 .times. A )
##EQU00001##
where A=concentration of reference agonist in the assay, and
EC.sub.50A=EC.sub.50 value of the reference agonist.
[0373] The compound of Formula II-B is found to have a .mu. (MOP)
(h) (antagonist effect) with an IC.sub.50 of 1.3.times.10.sup.-6 M;
and a K.sub.B of 1.4.times.10.sup.-7 M; and the compound of Formula
II-C is found to have an IC.sub.50 greater than 1.times.10.sup.-5,
which was the highest concentration tested.
[0374] The agonist activity results are expressed as a percent of
control agonist response:
measured .times. response control .times. response .times. 100
##EQU00002##
and antagonist activity as a percent inhibition of control agonist
maximum response:
100 - ( measured .times. response control .times. response .times.
100 ) ##EQU00003##
obtained in the presence of the Compound of Formula II-B or
II-C.
[0375] The EC.sub.50 values (concentration producing a half-maximal
response) and IC.sub.50 values (concentration causing a
half-maximal inhibition of the control agonist response) are
determined by non-linear regression analysis of the
concentration-response curves generated with mean replicate values
using Hill equation curve fitting:
Y = D + [ A - D 1 + ( C / C 50 ) n .times. H ] ##EQU00004##
where Y=response, A=left asymptote of the curve, D=right asymptote
of the curve, C.dbd.compound concentration, and C.sub.50=EC.sub.50
or IC.sub.50, and nH=slope factor. The analysis is performed using
software developed in-house and validated by comparison with data
generated by the commercial software SigmaPlot.RTM. 4.0 for
Windows.RTM. (.COPYRGT. 1997 by SPSS Inc.).
Example 5: Receptor Binding Profile of Compound of Formulas II-B,
II-C and Ex. 3
[0376] Receptor binding is determined for the Compounds of Formulas
II-B and II-C using the tosylate salt of the compound of Formula A
as a control. The following literature procedures are used, each of
which reference is incorporated herein by reference in their
entireties: 5-HT.sub.2A: Bryant, H. U. et al. (1996), Life Sci.,
15:1259-1268; D2: Hall, D. A. and Strange, P. G. (1997), Brit. J.
Pharmacol., 121:731-736; D1: Zhou, Q. Y. et al. (1990), Nature,
347:76-80; SERT: Park, Y. M. et al. (1999), Anal. Biochem.,
269:94-104; Mu opiate receptor: Wang, J. B. et al. (1994), FEBS
Lett., 338:217-222.
[0377] In general, the results are expressed as a percent of
control specific binding:
m .times. e .times. a .times. sured .times. specific .times.
binding control .times. specific .times. binding .times. 100
##EQU00005##
and as a percent inhibition of control specific binding:
100 - ( m .times. e .times. a .times. sured .times. specific
.times. binding control .times. specific .times. binding .times.
100 ) ##EQU00006##
obtained in the presence of the test compounds.
[0378] The IC.sub.50 values (concentration causing a half-maximal
inhibition of control specific binding) and Hill coefficients (nH)
are determined by non-linear regression analysis of the competition
curves generated with mean replicate values using Hill equation
curve fitting:
Y = D + [ A - D 1 + ( C / C 50 ) n .times. H ] ##EQU00007##
where Y=specific binding, A=left asymptote of the curve, D=right
asymptote of the curve, C=compound concentration,
C.sub.50=IC.sub.50, and nH=slope factor. This analysis was
performed using in-house software and validated by comparison with
data generated by the commercial software SigmaPlot.RTM. 4.0 for
Windows.RTM. (.COPYRGT. 1997 by SPSS Inc.). The inhibition
constants (Ki) were calculated using the Cheng Prusoff
equation:
Ki = IC 50 ( 1 + L / K D ) ##EQU00008##
where L=concentration of radioligand in the assay, and
K.sub.D=affinity of the radioligand for the receptor. A Scatchard
plot is used to determine the K.sub.D.
[0379] The following receptor affinity results are obtained, using
the tosylate salt of a Compound of Formula A as a control:
TABLE-US-00002 Formula Formula Formula A II-B II-C (tosylate (Ex.
1) (Ex. 2) Example 3 salt) Receptor Ki (nM) or maximum inhibition
5-HT.sub.2A 11 31% inhibition 8.3 10 at 240 nM D2 47% inhibition
11% inhibition 160 49 at 240 nM at 240 nM D1 22 13% inhibition 50
41 at 100 nM SERT 44% inhibition No inhibition 590 16 at 240 nM
seen Mu opiate 22 85 11 >10,000 receptor Delta opioid No
inhibition Kappa opioid 16% @ 100 nM NOP No inhibition (Nociceptin
Receptor)
Example 6: DOI-Induced Head Twitch Model in Mice
[0380] R-(-)-2,5-dimethoxy-4-iodoamphetamine (DOI) is an agonist of
the serotonin 5-HT.sub.2 receptor family. When administered to
mice, it produces a behavioral profile associated with frequent
head twitches. The frequency of these head twitches during a
predetermined period of time can be taken as an estimate of
5-HT.sub.2 receptor agonism in the brain. Conversely, this
behavioral assay can be used to determine 5-HT.sub.2 receptor
antagonism in the brain by administering the DOI with or without an
antagonist and recording the reduction in DOI-induced head twitches
after the administration of the antagonist.
[0381] The method of Darmani et al., Pharmacol Biochem Behav.
(1990) 36:901-906 (the contents of which are incorporated by
reference in their entirety) is used with some modifications.
(.+-.)-DOI HCl is injected subcutaneously and the mice are
immediately placed in a conventional plastic cage. The number of
head twitches is counted during 6 min, beginning 1 min after DOI
administration. The tested compound is administered orally 0.5 hr
before the injection of DOI. Results area calculated as the EC50
for reducing DOI-induced head twitches. The results are shown in
the following Table:
TABLE-US-00003 Compound EC.sub.50 (mg/kg, p.o.) Example 1 (Formula
II-B) 0.23 Example 2 (Formula II-C) 2.03 Example 3 0.44 Formula A
0.09 Formula B 0.31
The results show that the compounds of Example 1 and 3 potently
block DOI head twitch, comparable to the reference compounds
Formula A and C, and consistent with the in-vitro 5-HT.sub.2A
results shown in Example 5. In contrast, the compound of Example 2
is relatively inactive in this functional assay, confirming that
this compound is relatively weaker in its serotonin receptor
antagonism than other structurally similar compounds.
Example 7: Mouse Tail Flick Assays
[0382] The Mouse Tail Flick Assay is a measure of analgesia,
indicated by the pain reflex threshold of restrained mice. Male
CD-1 mice are positioned with their tails under a focused beam of a
high-intensity infrared heat source, resulting in heating of the
tail. The animal can withdraw its tail from the heat source at any
time that it becomes uncomfortable. The amount of time (latency)
between turning on the heating instrument and the flicking of the
mouse's tail out of path of the heat source is recorded.
Administration of morphine results in analgesia, and this produces
a delay in the mouse's reaction to the heat (increased latency).
Prior administration of a morphine (MOR) antagonist, i.e., naloxone
(NAL), reverses the effect and results in normal latency time. This
test is used as a functional assay to gauge antagonism of mu-opiate
receptors.
Example 7a: Antagonism of Morphine-Induced Analgesia by Compounds
of Examples 1 and 3
[0383] Ten male CD-1 mice (about 8 weeks of age) are assigned to
each of five treatment groups. The groups are treated as follows:
Group (1) [negative control]: administered 0.25% methylcellulose
vehicle p.o., 60 minutes before the tail flick test, and saline
vehicle 30 minutes before the tail flick test; Group (2) [positive
control]: administered 0.25% methylcellulose vehicle p.o., 60
minutes before the test, and 5 mg/kg morphine in saline 30 minutes
before the test; Group (3) [positive control]: administered 3 mg/kg
naloxone in saline 50 minutes before the test, and 5 mg/kg morphine
in saline 30 minutes before the test; Groups (4)-(6): administered
either 0.1 mg/kg, 0.3 mg/kg or 1 mg/kg of the test compound in
0.25% methylcellulose vehicle p.o., 60 minutes before the test, and
5 mg/kg morphine in 30 minutes before the test. The experiment is
repeated for the compounds of Example 1 and Example 3. The results
are shown in the following table as mean latency measured in
seconds:
TABLE-US-00004 Group Group Group Group 4 Group 5 Group 6 1 2 3
Cmpd/ Cmpd/ Cmpd/ Veh/ Veh/ Nal/ Mor Mor Mor Veh Mor Mor (0.1
mg/kg) (0.3 mg/kg) (1 mg/kg) Ex. 1 1.028 9.361 2.496 8.870 6.907
6.240 Ex. 3 0.887 8.261 3.013 6.947 5.853 6.537
[0384] The results demonstrate that the compounds of Example 1 and
Example 3 both exert a dose-dependent blockade of morphine-induced
mu-opiate receptor activity.
Example 7b: Analgesia by Compound of Example 3, Inhibited by
Naloxone
[0385] In a second study using the mouse tail flick assay as
described above, the compound of Example 3 is further compared at
doses of 1.0 mg/kg, 3.0 mg/kg and 10 mg/kg against morphine at 5
mg/kg with and without pre-dosing with naloxone at 3 mg/kg
(intraperitoneal). In the pre-treatment groups, the naloxone is
administered 20 minutes prior to the tail flick test. In the
non-pre-treatment controls, saline is administered 20 minutes prior
to the tail flick test. In each group, the vehicle, morphine or
compound of Example 3 is administered 30 minutes before the tail
flick test. The results are shown in the table below as mean
latency in seconds:
TABLE-US-00005 Ex. 3 at Ex. 3 at Ex. 3 at Vehicle Morphine 1 mg/kg
3 mg/kg 10 mg/kg Saline pre- 0.9 9.8 4.1 7.4 9.8 treatment Naloxone
0.8 1.5 1.3 1.7 2.1 pre-treatment
[0386] It is found that administration of the compound of Example 3
at all doses significantly increased the latency to tail flick, and
that this effect is attenuated by pre-treatment with naloxone. This
result demonstrates a dose-dependent analgesic effect produced by
the Compound of Example 3, and further suggests that this effect is
mediated by mu-opioid receptor agonism.
Example 7c: Time Course for Analgesia, Compound of Example 3
[0387] The tail flick assay as described above is repeated to
determine the time course of analgesia resulting from
administration of the compound of Example 3. Mice are administered
s.c. either (1) vehicle 30 minutes prior to assay, (2) 5 mg/kg
morphine 30 minutes prior to assay, or (3)-(7) the 1 mg/kg of
compound of Example 3 30 minutes, 2 hours, 4 hours, 8 hours or 24
hours prior to assay. The results are shown in the table below as
mean latency in seconds:
TABLE-US-00006 Treatment TF Latency (s) Vehicle, 30 min prior 1.30
Morphine, 30 min prior 7.90 Cmpd. Ex. 3, 30 min prior 5.77 Cmpd.
Ex. 3, 2 h prior 2.42 Cmpd. Ex. 3, 4 h prior 1.48 Cmpd. Ex. 3, 6 h
prior 1.36 Cmpd. Ex. 3, 24 h prior 1.29
[0388] The results show that the Compound of Example 3 produces
effective analgesia when administered 30 minutes or 2 hours prior
to the tail flick assay (ANOVA, P<0.001 vs. vehicle). When
administered 4 hours, 8 hours, or 24 hours prior to the tail flick
assay, the compound of Example 3 at 1 mg/kg does not produce an
analgesic effect significantly different from the vehicle control.
Thus, the compound of Example 3 does not produce prolonged
analgesia, which means that it would have a lower potential for
abuse and a lower risk of drug-drug interactions compared to other
opiate analgesics.
Example 7d: Analgesia from Chronic Administration of the Compound
of Example 3
[0389] The tail flick assay described above is repeated using a
test model in which animals receive a 14-day chronic treatment
regimen, followed by an acute treatment 30 minutes prior to the
tail flick assay. The mice are divided into three broad groups with
six sub-groups of 10 mice each. The three groups receive as the
chronic treatment either (A) vehicle, (B) compound of Example 3 at
0.3 mg/kg, or (C) compound of Example 3 at 3.0 mg/kg. Each
sub-group further receives as the acute treatment either (1)
vehicle, or (2)-(6) the compound of Example 3 at 0.01, 0.03, 0.1,
0.3 or 1.0 mg/kg. All treatments are administered s.c. The results
are shown in the table below as mean latency to tail flick in
seconds:
TABLE-US-00007 Chronic Acute Latency Group Treatment Treatment (s)
(A) Vehicle Vehicle 1.09 Vehicle Ex. 3, 0.01 mg/kg 1.87 Vehicle Ex.
3, 0.03 mg/kg 2.50 Vehicle Ex. 3, 0.1 mg/kg 5.26 Vehicle Ex. 3, 0.3
mg/kg 8.26 Vehicle Ex. 3, 1.0 mg/kg 9.74 (B) Ex. 3, 0.3 mg/kg
Vehicle 0.893 Ex. 3, 0.3 mg/kg Ex. 3, 0.01 mg/kg 1.66 Ex. 3, 0.3
mg/kg Ex. 3, 0.03 mg/kg 1.30 Ex. 3, 0.3 mg/kg Ex. 3, 0.1 mg/kg 2.60
Ex. 3, 0.3 mg/kg Ex. 3, 0.3 mg/kg 3.93 Ex. 3, 0.3 mg/kg Ex. 3, 1.0
mg/kg 5.64 (C) Ex. 3, 3.0 mg/kg Vehicle 1.04 Ex. 3, 3.0 mg/kg Ex.
3, 0.01 mg/kg 1.64 Ex. 3, 3.0 mg/kg Ex. 3, 0.03 mg/kg 1.80 Ex. 3,
3.0 mg/kg Ex. 3, 0.1 mg/kg 3.94 Ex. 3, 3.0 mg/kg Ex. 3, 0.3 mg/kg
4.84 Ex. 3, 3.0 mg/kg Ex. 3, 1.0 mg/kg 7.94
[0390] It is found that 0.1, 0.3 and 1.0 mg/kg acute treatment with
the compound of Example 3 produces a statistically significant
dose-dependent analgesic effect compared to in-group acute
treatment with vehicle. This is true for each of the chronic groups
(A), (B) and (C). As compared to pre-treatment with vehicle,
pre-treatment with the compound of Example 3 at 0.3 mg/kg or 3.0
mg/kg generally showed a statistically significant decrease in tail
flick latency when the same acute treatment subgroups are compared.
These results demonstrate that while some tolerance to the
analgesic effect of the compound of Example 3 occurs after 14-days
of chronic treatment, the analgesia obtained remains effective
despite chronic pre-treatment.
Example 8: CNS Phosphoprotein Profile
[0391] A comprehensive molecular phosphorylation study is also
carried out to examine the central nervous system (CNS) profile of
the compounds of Example 1 and Example 3. The extent of protein
phosphorylation for selected key central nervous system proteins is
measured in mice nucleus accumbens. Examined proteins include ERK1,
ERK2, Glu1, NR2B and TH (tyrosine hydroxylase), and the compounds
of Example 1 and 3 were compared to the antipsychotic agents
risperidone and haloperidol.
[0392] Mice were treated with the compound of Example 1 or 3 at 3
mg/kg, or with haloperidol at 2 mg/kg. Mice were killed 30 minutes
to 2 hours post-injection by focused microwave cranial irradiation,
which preserves brain phosphoprotein as it exists at the time of
death. The nucleus accumbens was then dissected from each mouse
brain, sliced and frozen in liquid nitrogen. Samples were further
prepared for phosphoprotein analysis via SDS-PAGE electrophoresis
followed by phosphoprotein-specific immunoblotting, as described in
Zhu H, et al., Brain Res. 2010 Jun. 25; 1342:11-23. Phosphorylation
at each site was quantified, normalized to total levels of the
protein (non-phosphorylated), and expressed as percent of the level
of phosphorylation in vehicle-treated control mice.
[0393] The results demonstrate that neither the compound of Example
1 nor of Example 3 has a significant effect on tyrosine hydroxylase
phosphorylation at Ser40 at 30 minutes or 60 minutes, in contrast
to haloperidol which produces a greater than 400% increase, and
risperidone which produces a greater than 500% increase, in TH
phosphorylation. This demonstrates that inventive compounds do not
disrupt dopamine metabolism.
[0394] The results further demonstrate that neither the compound of
Example 1 nor of Example 3 has a significant effect on NR2B
phosphorylation at Tyr1472 at 30-60 minutes. The compounds produce
a slight increase in GluR1 phosphorylation at Ser845, and a slight
decrease in ERK2 phosphorylation at Thr183 and Tyr185. Protein
phosphorylation at various sites in particular proteins are known
to be linked to various activities of the cell such as protein
trafficking, ion channel activity, strength of synaptic signaling
and changes in gene expression. Phosphorylation the Tyr1472 in the
NMDA glutamate receptor has been shown to be essential for the
maintenance of neuropathic pain. Phosphorylation of Ser845 of the
GluR1 AMPA type glutamate receptor is associated with several
aspects of strengthening synaptic transmission and enhanced
synaptic localization of the receptor to support long term
potentiation associated with cognitive abilities. It has also been
reported that phosphorylation of this residue results in an
increased probability of channel opening. Phosphorylation of ERK2
kinase, a member of the MAP kinase cascade, at residues T183 and
Y185 is required for full activation of this kinase, ERK2 is
involved in numerous aspects of cell physiology including cell
growth, survival and regulation of transcription. This kinase has
been reported to be important in synaptogenesis and cognitive
function.
Example 9: Mouse Marble-Burying Study (OCD Model)
[0395] The marble burying test is used to measure repetitive and
anxiety-related behavior in rodents. It is based on the observation
that rats and mice will bury either harmful or harmless objects in
their bedding, and it has been used as an animal model to measure
the effect of pharmacological interventions in treatment of
repetitive behavior disorders, such as OCD.
[0396] Mice are first divided up into four treatment groups: (1)
vehicle negative control, (2) 0.3 mg/kg compound of Example 3, (3)
1.5 mg/kg compound of Example 3, and (4) 20 mg/kg MPEP
(2-methyl-6-(phenylethynyl)pyridine) positive control. MPEP is a
selective mGluR5 glutamate receptor antagonist. Mice in groups (2)
and (3) are orally administered the compound of Example 3 at the
stated dosage in a 0.5% methylcellulose aqueous vehicle 30 minutes
prior to the test. Mice in groups (1) are orally administered the
vehicle, and mice in group (4) are given an intraperitoneal
injection of MPEP just prior to the start of the test.
[0397] The test is conducted in rectangular cages with 4-5 cm of
wood chip bedding in a room with the window shades lowered and the
door closed to minimize distractions. Fifteen clean marbles are
evenly spaced on top of the bedding in three rows of five marbles.
One mouse is placed in each cage. The mouse and cage is left
undisturbed for 30 minutes. At the end of the test, the mouse is
removed and the number of marbles buried to at least 2/3 of their
depth is counted. The results are shown in the following table:
TABLE-US-00008 Group Marbles Buried (1) Vehicle 13.2 (2) 0.3 mg/kg
Ex. 3 9.3 (3) 1.5 mg/kg Ex. 3 4.7 (4) MPEP 0.2
[0398] The results demonstrate that compared to the control, there
is a statistically significant decrease in marble burying for the
mice treated with 0.3 mg/kg of the compound of Example 3
(p<0.01) and with 1.5 mg/kg of the compound of Example 3
(p<0.001). In addition, there is a clear dose-response
relationship evident. The results support the potential utility of
Example 3 in OCD therapeutic indications.
Example 10: Mu-Opiate Receptor Activity Assays
[0399] The compounds of Example 1 and 3 are tested in CHO-K1 cells
expressing hOP3 (human mu-opiate receptor .mu.1 subtype) using an
HTRF-based cAMP assay kit (cAMP Dynamic2 Assay Kit, from Cisbio,
#62AM4PEB). Frozen cells are thawed in a 37.degree. C. water bath
and are resuspended in 10 mL of Ham's F-12 medium containing 10%
FBS. Cells are recovered by centrifugation and resuspended in assay
buffer (5 nM KCl, 1.25 mM MgSO.sub.4, 124 mM NaCl, 25 mM HEPES,
13.3 mM glucose, 1.25 mM KH.sub.2PO.sub.4, 1.45 mM CaCl.sub.2), 0.5
g/L protease-free BSA, supplemented with 1 mM IBMX). Buprenorphine,
a mu-opiate receptor partial agonist, and naloxone, a mu-opiate
receptor antagonist, and DAMGO, a synthetic opioid peptide full
agonist, are run as controls.
[0400] For agonist assays, 12 .mu.L of cell suspension (2500
cells/well) are mixed with 6 .mu.L forksolin (10 .mu.M final assay
concentration), and 6 .mu.L of the test compound at increasing
concentrations are combined in the wells of a 384-well white plate
and the plate is incubated for 30 minutes at room temperature.
After addition of lysis buffer and one hour of further incubation,
cAMP concentrations are measured according to the kit instructions.
All assay points are determined in triplicate. Curve fitting is
performed using XLfit software (IDBS) and EC.sub.50 values are
determined using a 4-parameter logistic fit. The agonist assay
measures the ability of the test compound to inhibit
forskolin-stimulated cAMP accumulation.
[0401] For antagonist assays, 12 .mu.L of cell suspension (2500
cells/well) are mixed with 6 .mu.L of the test compound at
increasing concentrations, and combined in the wells of a 384-well
white plate and the plate is incubated for 10 minutes at room
temperature. 6 .mu.L of a mixture of DAMGO
(D-Ala.sup.2-N-MePhe.sup.4-Gly-ol-enkephelin, 10 nM final assay
concentration) and forksolin (10 .mu.M final assay concentration)
are added, and the plates are incubated for 30 minutes at room
temperature. After addition of lysis buffer, and one hour of
further incubation, cAMP concentrations are measured according the
kit instructions. All assay points are determined in triplicate.
Curve fitting is performed using XLfit software (IDBS) and
IC.sub.50 values are determined using a 4-parameter logistic fit.
Apparent dissociation constants (K.sub.B) are calculated using the
modified Cheng-Prusoff equation. The antagonist assay measures the
ability of the test compound to reverse the inhibition of
forskolin-induced cAMP accumulation caused by DAMGO.
[0402] The results are shown in FIGS. 1 and 2, and in the Table
below. The results demonstrate that the compound of Example 3 is a
weak antagonist of the Mu receptor, showing much higher IC.sub.50
compared to naloxone, and that it is a moderately high affinity,
but partial agonist, showing only about 22% agonist activity
relative to DAMGO (as compared to about 79% activity for
buprenorphine relative to DAMGO). The compound of Example 1 is also
shown to have moderately strong partial agonist activity.
TABLE-US-00009 Antagonist Agonist K.sub.B Compound IC.sub.50 (nM)
EC.sub.50 (nM) (nM) Naloxone 5.80 -- 0.65 DAMGO -- 1.56 --
Buprenorphine -- 0.95 -- Cmpd. Ex. 3 641 64.5 71.4 Cmpd Ex. 1 --
140 --
[0403] Buprenorphine is a drug used for chronic pain treatment and
for opiate withdrawal, but it suffers from the problem that users
can become addicted due to its high partial agonist activity. To
offset this, the commercial combination of buprenorphine with
naloxone is used (sold as Suboxone). Without being bound by theory,
it is believed that the compounds of the present invention, which
are weaker partial Mu agonists than buprenorphine, with some
moderate antagonistic activity, will allow a patient to be more
effectively treated for pain and/or opiate withdrawal with lower
risks of addiction.
[0404] In additional related study using a recombinant human
MOP-beta-arresting signaling pathway, it is found that the Compound
of Example 3 does not stimulate beta-arrestin signaling via the MOP
receptor at concentrations up to 10 .mu.M, but that it is an
antagonist with an IC.sub.50 of 0.189 .mu.M. In contrast, the full
opioid agonist Met-enkephalin stimulates beta-arrestin signaling
with an EC.sub.50 of 0.08 .mu.M.
Example 11: Rat Tolerance/Dependence Study
[0405] The compound of Example 3 is assessed during repeated (28
day) daily subcutaneous administration to male Sprague-Dawley rats
to monitor drug effects on dosing and to determine if
pharmacological tolerance occurs. In addition, behavioral, physical
and physiological signs in the rats is monitored following abrupt
cessation of repeated dosing to determine whether the compound
induces physical dependence on withdrawal. Further, a
pharmacokinetic study is performed in parallel with the tolerance
and dependence study to determine the plasma drug exposure levels
of the compound at the specific doses used in the tolerance and
dependence study. Morphine is used as a positive control to ensure
validity of the model and as a reference comparator from a similar
pharmacological class.
[0406] The compound of Example 3 is evaluated at two doses, 0.3 and
3 mg/kg, administered subcutaneously four times per day. Repeated
administration is found to produce peak plasma concentrations of 15
to 38 ng/mL (average, n=3) for 0.3 mg/kg dosing, and 70 to 90 ng/mL
(average, n=3) for 3 mg/kg dosing. Peak concentration is reached at
30 minutes to 1.5 hours post-administration with comparable results
obtained on the 1st, 14th and 28th day of administration.
[0407] At both doses of Example 3, it is found that there is no
significant effect on animal body weight, food and water intake or
body temperature during either the on-dose or withdrawal phase. The
predominant behavioral and physical effects caused by repeated
administration at 0.3 mg/kg is found to be hunched posture, Straub
tail and piloerection during the dosing phase. At the higher dose,
the main behavioral and physical signs observed are hunched
posture, subdued behavior, Straub tail, tail rattle and
piloerection.
[0408] A similar profile of behavioral and physical signs is
observed following abrupt cessation of the compound on Day 28 of
the study. While rearing and increased body tone were not observed
during the on-dose phase for at 0.3 mg/kg, it is found to be
significantly increased during the withdrawal phase. At the higher
dose, mild rearing is observed during the on-dose phase, but during
the withdrawal phase, rearing is more pronounced and increased body
tone is observed.
[0409] As a positive control, morphine is doses at 30 mg/kg orally
twice per day. This dosing regimen, as expected, is observed to be
associated with changes in body weight, food and water intake,
rectal temperature and clinical signs consistent with the
development of tolerance and withdrawal-induced dependence. Body
weight was significantly increased compared with the
vehicle-treated control group on Days 2 and 3, while it was
significantly decreased from Day 5. Morphine decreased food intake
significantly on Days 1-9. Thereafter food intake is generally
observed to be lower than for the control group, but was not
significantly different from controls on Days 9, 13, 14 16, 18, 21,
22 and Day 25. These effects on body weight and food intake
demonstrate tolerance to the effect of morphine.
[0410] Water intake of the morphine-treated group is also found to
be significantly lower than the control group on 25 out of 28 days
during the on-dose phase. Body temperature is also generally lower
than the control group during the on-dose phase, significantly so
on Days 20, 21 and 27. The predominant behavioral effects induced
by morphine during the on-dose phase are observed to be Straub
tail, jumping, digging, increased body tone, increased locomotor
activity, explosive movements and exopthalmus.
[0411] Furthermore, withdrawal of morphine administration on Day 28
is observed to result in an initial further decrease in food intake
followed by rebound hyperphagia, with significantly increased food
intake on Day 33 versus the control group. Food intake returns to
control levels by Day 35. Similarly, rats which had previously
received morphine also are observed to have an initial reduction in
water intake on Day 29, followed by rebound hyperdipsia (water
consumption returns to control levels by Day 31). In addition,
statistically significant decreases in rectal body temperature are
observed during dosing, but body temperature returns to control
levels during the withdrawal phase.
[0412] Moreover, new behavioral and physical signs are observed
during the withdrawal phase from morphine, and this demonstrates
the presence of dependence. These signs include piloerection,
ataxia/rolling gait, wet dog shakes and pinched abdomen. Other
abnormal behaviors observed during the on-dose phase gradually
disappear during the withdrawal phase. By Day 35, rearing was the
only behavior or physical sign observed with high incidence in the
rats that had previously received morphine.
[0413] Thus, repeated morphine administration is shown to produce
clear signs of tolerance and dependence in this study, with changes
in body weight, food and water intake, rectal temperature and
clinical signs consistent with the development of tolerance and
withdrawal induced dependence. This demonstrates the validity of
the study method in detecting physiological alterations during
administration and cessation of dosing.
[0414] In contrast, repeated administration of the Compound of
Example 3, at both 0.3 and 3 mg/kg four times, does not produce
tolerance during subcutaneous dosing for 28 days. Furthermore, on
withdrawal, a similar but decreasing profile of behavioral and
physical signs is observed at the highest dose, which is not
considered to be of clinical significance. Thus, overall the
Compound of Example 3 was found not to produce a syndrome of
physical dependence upon cessation of dosing.
Example 12: Oxycodone-Dependent Withdrawal Study in Mice
[0415] Oxycodone is administered to male C57BL/6J mice for 8 days
at an increasing dose regimen of 9, 17.8, 23.7, and 33 mg/kg b.i.d.
(7 hours between injections) on days 1-2, 3-4, 5-6 and 7-8
respectively. On the morning of the ninth day, the mice are
administered the compound of Example 3 at either 0.3, 1 or 3 mg/kg
subcutaneous. This is followed 30 minute later by either an
injection of vehicle or with an injection of 3 mg/kg of naloxone.
Another cohort of mice serve as negative controls, and instead of
oxycodone, these mice are administered saline on days 1 to 8. On
day 9, these mice are administered either vehicle (followed by
naloxone, as above) or the compound of Example 3 at 3 mg/kg, s.c.
(followed by naloxone, as above).
[0416] On day 9, immediately after the injection of naloxone (or
vehicle), the mice are individually placed in clear, plastic cages
and are observed continuously for thirty minutes. The mice are
monitored for common somatic signs of opiate withdrawal, including
jumping, wet dog shakes, paw tremors, backing, ptosis, and
diarrhea. All such behaviors are recorded as new incidences when
separated by at least one second or when interrupted by normal
behavior. Animal body weights are also recorded immediately before
and 30 minutes after the naloxone (or vehicle) injections. Data is
analyzed with ANOVA followed by the Tukey test for multiple
comparisons, when appropriate. Significant level is established at
p<0.05.
[0417] The results are shown in the Table below:
TABLE-US-00010 Dosing: (1) on days 1-8, Total Body (2) on day 9,
followed by Number Paw Weight (3) 30 minutes later of Signs Tremors
Jumps Loss (1) Saline; (2) Vehicle, 2.2 0.87 0 0.5% (3) Naloxone
(1) Saline; (2) Compound 5.3 0.12 0 0.4% 3.0 mg/kg, (3) Naloxone
(1) Oxycodone; (2) 155.1 73.6 63.2 7.8% Compound 3.0 mg/kg, (3)
Vehicle (1) Oxycodone; (2) 77.5 19.6 40.6 7.5% Compound 0.3 mg/kg,
(3) Naloxone 3 mg/kg (1) Oxycodone; (2) 62.5 14.8 34.8 6.0%
Compound 1.0 mg/kg, (3) Naloxone 3 mg/kg (1) Oxycodone; (2) 39.5
0.5 26.6 4.0% Compound 3.0 mg/kg, (3) Naloxone 3 mg/kg
[0418] Total number of signs includes paw tremors, jumps, and wet
dog shakes. In oxycodone-treated mice, it is found that naloxone
elicits a significant number of total signs, paw tremors, jumps and
body weight change (p.ltoreq.0.0001 for each). At all doses tested,
the compound of Example 3 produces a significant decrease in total
number of signs and paw tremors. In addition, at 3.0 mg/kg, the
compound also produces a significant decrease in jumps and
attenuated body weight loss.
[0419] These results demonstrate that the compound of Example 3
dose-dependently reduces the signs and symptoms of opiate
withdrawal after the sudden cessation of opiate administration in
opiate-dependent rats.
Example 13: Formalin Paw Test (Inflammatory Pain Model)
[0420] Sub-plantar administration of chemical irritants, such as
formalin, causes immediate pain and discomfort in mice, followed by
inflammation. Subcutaneous injection of 2.5% formalin solution (37
wt % aqueous formaldehyde, diluted with saline) into the hind paw
results in a biphasic response: an acute pain response and a
delayed inflammatory response. This animal model thus provides
information on both acute pain and sub-acute/tonic pain in the same
animal.
[0421] C57 mice are first habituated in an observation chamber. 30
minutes prior to formalin challenge, mice are administered either
vehicle injected subcutaneously, 5 mg/kg of morphine (in saline)
injected subcutaneously, or the compound of Example 3 (in 45% w/v
aqueous cyclodextrin) injected subcutaneously at either 0.3, 1.0 or
3.0 mg/kg. In addition, another set of mice are treated with the
control vehicle or the compound of Example 3 at 3.0 mg/kg, via oral
administration, rather than subcutaneous injection.
[0422] The mice are then given a subcutaneous injection into the
plantar surface of the left hind paw of 20 .mu.L of 2.5% formalin
solution. Over the next 40 minutes, the total time spent licking or
biting the treated hind-paw is recorded. The first 10 minutes
represent the acute nociceptic response, while the latter 30
minutes represents the delayed inflammatory response. At one minter
intervals, each animal's behavior is assessed using "Mean
Behavioral Rating," which is scored on a scale of 0 to 4:
[0423] 0: no response, animal sleeping
[0424] 1: animal walking lightly on treated paw, e.g., on
tip-toe
[0425] 2: animal lifting treated paw
[0426] 3: animal shaking treated paw
[0427] 4: animal licking or biting treated paw
Data are analyzed by ANOVA followed by post-hoc comparisons with
Fisher tests, where appropriate. Significance is established at
p<0.05.
[0428] The results are shown in the Table below.
TABLE-US-00011 Mean Behavior Rating Mean Licking Time (0-4) (min)
0-10 11-40 0-6 16-40 0-10 11-40 0-6 16-40 Min min min min min min
min min Vehicle 1.4 1.4 2.1 1.5 34 75 32 76 (SC) Vehicle 1.2 0.9
1.9 1.0 29 50 33 40 (PO) Morphine 1.1 0.2 1.7 0.2 11 0 11 0 Cmpd,
1.5 1.0 2.3 1.2 31 68 34 70 SC 0.3 mg/kg Cmpd, 1.3 1.0 1.9 1.1 26
60 26 65 SC 1.0 mg/kg Cmpd, 0.8 0.1 1.3 0.1 14 36 11 36 SC 3.0
mg/kg Cmpd, 0.9 0.8 1.5 0.9 11 3 9 3 PO 3.0 mg/kg
[0429] The results demonstrate a significant treatment effect
during both the early phase (0-10 min) and late phase (11-40 min)
response periods. Post-hoc comparisons show that, compared to
vehicle treatment, subcutaneous injection of morphine or the
compound of Example 3 (at 3 mg/kg) significantly attenuates the
pain behavior rating induced by formalin injection, as well as
significantly reducing licking time. Post-hoc comparisons also show
that subcutaneous injection of morphine or the compound of Example
3 (at 3 mg/kg), as well as the compound of Example 3 orally (at 3
mg/kg), significantly reduces time spent licking. While the mean
pain behavior rating was also reduced using 1.0 mg/kg of compound
subcutaneous and at 3.0 mg/kg oral, these effects were not
statistically significant in this study. Licking time was similarly
reduced using 1.0 mg/kg of the compound of Example 3
subcutaneously, but the result was not statistically significant in
this study. It was also found that no mice in the study underwent
significant changes in body weight in any of the study groups.
Example 14: Self Administration in Heroin-Maintained Rats
[0430] A study is performed to determine whether heroin-addicted
rats self-administer the compound of Example 3, and it is found
that they do not, further underscoring the non-addictive nature of
the compounds of the present disclosure.
[0431] The study is performed in three stages. In the first stage,
rats are first trained to press a lever for food, and they are then
provided with an in-dwelling intravenous jugular catheter and
trained to self-administer heroin. In response to a cue (the
lighting of a light in the cage), three presses of the lever by the
animal results in a single heroin injection via the catheter. The
heroin is provided at an initial dose of 0.05 mg/kg/injection, and
later increased to 0.015 mg/kg/injection. This trained response is
then extinguished by replacing the heroin supply with saline. In
the second phase, the saline solution is replaced by a solution of
the compound of Example 3, at one of four doses: 0.0003
mg/kg/injection, 0.001 mg/kg/injection, 0.003 mg/kg/injection, and
0.010 mg/kg/injection. Each individual rat is provided with either
one or two different doses of the compound in rising fashion. This
response is then extinguished with saline injections, followed by
the third phase, which repeats the use of heroin at 0.015
mg/kg/injection. The purpose of the third phase is to demonstrate
that the rats still show addictive behavior to heroin at the end of
the study. The study results are shown in the table below:
TABLE-US-00012 Treatment Animals (n) Mean Lever presses Saline
Extinction 1 21 4.08 Heroin Acquisition (0.015 mg/kg/inj) 21 19.38*
Cmpd. Ex. 3 at 0.0003 mg/kg/inj 8 3.17** Cmpd. Ex. 3 at 0.0003
mg/kg/inj 8 3.29** Cmpd. Ex. 3 at 0.0003 mg/kg/inj 8 3.99** Cmpd.
Ex. 3 at 0.0003 mg/kg/inj 8 4.87** Saline Extinction 2 19 3.60**
Heroin Reinstatement (0.015 mg/kg/inj) 19 17.08** *P < 0.001 for
heroin acquisition vs. saline extinction 1 (multiple t test); **P
< 0.001 for Cmpd of Ex. 3 vs. heroin acquisition (Dunnett`s
test); P > 0.7 for all comparisons between Cmpd. of Ex. 3 and
saline extinction 1 (William`s test)
[0432] The results demonstrate that there is a statistically
significant increase in lever pressing by the rats when being
administered heroin, but that there was no significant difference
when being administered saline or the compound of Example 3. Thus,
the results suggest that rats do not become addicted to the
compound of Example 3.
Example 15: Animal Pharmacokinetic Data
[0433] Using standard procedures, the pharmacokinetic profile of
the compound of Example 3 is studied in several animals.
Example 15a: Rat PK Studies
[0434] In a first study, rats are administered the compound of
Example 2 either by intravenous bolus (IV) at 1 mg/kg in 45%
Trapposol vehicle, or orally (PO) at 10 mg/kg in 0.5% CMC vehicle
(N=3 each group). In a second study, rats are administered the
compound of Example 2 at 10 mg/kg PO or 3 mg/kg subcutaneously
(SC), each in 45% Trapposol vehicle (N=6 for each group). Plasma
concentrations of the drug are measured at time points from 0 to 48
hours post dose. Representative results are tabulated below (*
indicates plasma concentration below measurable level of
quantitation):
TABLE-US-00013 Study One Study Two IV PO PO SC (1 mg/kg) (10 mg/kg)
(10 mg/kg) (3 mg/kg) 30 min (ng/mL) 99.0 30.7 54.9 134.4 1 hour
(ng/mL) 47.3 37.2 60.6 140.9 6 hours (ng/mL) 1.1 9.4 21.0 18.2 24
hours (ng/mL) * 0.1 0.4 1.9 48 hours( ng/mL) * * ND ND Cmax (ng/mL)
314.8 37.2 60.6 140.9 AUC (ng-hr/mL) 182 215 409 676
Bioavailability 100% 12% 22% 123% t-1/2 (hr) 3.1 9.5
Example 15b: Mice PK Studies
[0435] A similar study in mice is performed using 10 mg/kg PO
administration of the compound of Formula 3, and the following
results are obtained: Tmax=0.25 hours; Cmax=279 ng/mL; AUC (0-4
h)=759 ng-hr/mL; blood-plasma ratio (0.25-4 h) ranges from 3.7 to
6.6. The study is also conducted at a dose of 0.1 mg/kg SC.
Representative results are shown in the table below:
TABLE-US-00014 PO, 10 mg/kg SC, 0.1 mg/kg Study: (0.5% CMC veh)
(45% Trapposol veh) Time Plasma Brain Plasma Brain (hr) (ng/mL)
(ng/g) (ng/mL) (ng/g) 0.25 279 1288 27.5 57.1 0.5 179 1180 31.1
71.9 1 258 989 29.2 78.5 2 153 699 14.6 38.7 4 199 734 4.7 32.6
Tmax (hr) 0.25 0.25 0.5 1.0 Cmax 279 1288 31.1 78.5 (ng/mL) AUC0-4
h 759 2491 67 191 (ng-hr/mL) B/P Ratio 3.3 2.8
[0436] Together these results show that the compounds of the
present disclosure are well-absorbed and distributed to the brain
and tissues and are retained with a reasonably long half-life to
enable once-daily administration of therapeutic doses.
Example 16: Gastrointestinal Function
[0437] The effect of the compound of Example 3 on gastrointestinal
motility in rats is examined by monitoring the rate of intestinal
transit of an activated charcoal bolus. Rats were treated with
either (1) aqueous carboxymethyl cellulose vehicle, (2) morphine (5
mg/kg, SC), or (3) the compound of Example 3 (at 0.3, 1.0 or 3.0
mg/kg, SC) 30 minutes prior to an oral bolus of 15% aqueous
activated charcoal. The measured outcome is motility ratio,
calculated as the distance traveled by the charcoal as a fraction
of the full length of the animal's intestine. The results are shown
in the table below:
TABLE-US-00015 Group (n = 10 each) Treatment Motility Ratio 1
Vehicle 0.55 2 Cmpd. Ex. 3, 0.3 mg/kg 0.50 3 Cmpd. Ex. 3, 1 mg/kg
0.55 4 Cmpd. Ex. 3, 3 mg/kg 0.50 5 Morphine, 5 mg/kg 0.27
[0438] These results show that the compound of Example 3 has no
significant effect on gastrointestinal motility at a dose up to 3
mg/kg. In contrast, and as expected, morphine results in
approximately a 50% reduction in gastric motility.
[0439] In a further experiment, rats were pre-treated 60 minutes
prior to the charcoal bolus with either vehicle, morphine (5
mg/kg), or the compound of Example 3 (3 mg/kg), each SC, followed
by treatment with either morphine (5 mg/kg), morphine plus compound
of Ex. 3 (0.3 mg/kg or 3 mg/kg), or compound of Ex. 3 (3 mg/kg)
alone. The results are shown in the table below. For groups 2 and
3, morphine was injected first, followed immediately by the
injection of the compound of Example 3:
TABLE-US-00016 Group Pre- Motility (n = 8 each) Treatment Treatment
Ratio 1 Vehicle Morphine, 5 mg/kg 0.21 2 None Morphine, 5 mg/kg +
0.26 Cmpd. Ex. 3, 0.3 mg/kg 3 None Morphine, 5 mg/kg + 0.32 Cmpd.
Ex. 3, 3 mg/kg 4 Morphine, Cmpd. Ex. 3, 3 mg/kg 0.41 5 mg/kg 5
Cmpd. Ex. 3, Morphine, 5 mg/kg 0.30 3 mg/kg
[0440] The results show that the compound of Example 3 reverses the
inhibition of gastrointestinal motility caused by morphine when
given either concurrently or sequentially prior to morphine, with
the blockade of morphine's effect stronger when pre-treatment is
used.
[0441] Without being bound by theory, it is believed that these
differences result from the compounds of the present disclosure
acting as biased MOP ligands and their failure to activate
beta-arrestin signaling pathways downstream, which pathways have
been shown to mediate opiate-linked side effects, including
constipation and respiratory depression.
Example 17: Pulmonary Function
[0442] The effect of the compound of Example 3 on pulmonary
function in rats is examined by monitoring respiratory rate, tidal
volume and minute volume in rats following the subcutaneous
administration of the compound of Example 3 at 0.3, 1.0 and 3.0
mg/kg, compared to vehicle control. Measurements are taken at 0,
15, 60, 120, and 240 minutes following administration of the
compound. It is found that there are no significant differences
between the vehicle and any of the test groups at any time point.
Results are shown below for 60 minutes, which is typical of the
results obtained:
TABLE-US-00017 RR (breaths/min) TV (mL) MV (mL/min) Vehicle 188
1.10 195 Cmpd. Ex. 3, 0.3 mg/kg 181 1.06 181 Cmpd. Ex. 3, 1.0 mg/kg
203 0.86 169 Cmpd. Ex. 3, 3.0 mg/kg 190 0.97 179
* * * * *