U.S. patent application number 15/338645 was filed with the patent office on 2017-02-16 for compounds for the treatment of seizures and other central nervous system disorders and conditions.
This patent application is currently assigned to Ketogen, Inc.. The applicant listed for this patent is Ketogen, Inc.. Invention is credited to John S. Andrews, Subhash C. Annedi, Joseph A. Araujo, Paula J. Estey, Guy A. Higgins, Norton W. Milgram, Jaipal R. Nagireddy, Gary L.W.G. Robinson.
Application Number | 20170044095 15/338645 |
Document ID | / |
Family ID | 54700982 |
Filed Date | 2017-02-16 |
United States Patent
Application |
20170044095 |
Kind Code |
A1 |
Araujo; Joseph A. ; et
al. |
February 16, 2017 |
COMPOUNDS FOR THE TREATMENT OF SEIZURES AND OTHER CENTRAL NERVOUS
SYSTEM DISORDERS AND CONDITIONS
Abstract
The present application relates to novel compounds comprising a
moiety that leads to the metabolic production of ketones bonded to
a ketone-potentiated anti-epileptic drug, compositions comprising
these compounds, and their use, for example for the treatment of
epilepsy, and other CNS diseases, disorders or conditions. In
particular, the present application includes compounds of Formula
I, and compositions and uses thereof: ##STR00001##
Inventors: |
Araujo; Joseph A.; (Toronto,
CA) ; Andrews; John S.; (Mississauga, CA) ;
Annedi; Subhash C.; (Mississauga, CA) ; Higgins; Guy
A.; (Toronto, CA) ; Milgram; Norton W.;
(Toronto, CA) ; Estey; Paula J.; (Neebing, CA)
; Robinson; Gary L.W.G.; (Framingham, MA) ;
Nagireddy; Jaipal R.; (Brantford, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ketogen, Inc. |
Toronto |
|
CA |
|
|
Assignee: |
Ketogen, Inc.
Toronto
CA
|
Family ID: |
54700982 |
Appl. No.: |
15/338645 |
Filed: |
October 31, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14727979 |
Jun 2, 2015 |
9481637 |
|
|
15338645 |
|
|
|
|
62006515 |
Jun 2, 2014 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 207/27 20130101;
C07C 2601/14 20170501; A61P 25/04 20180101; A61K 31/4015 20130101;
A61P 25/08 20180101; A61P 25/22 20180101; C07C 233/47 20130101;
A61P 25/28 20180101 |
International
Class: |
C07C 233/47 20060101
C07C233/47; C07D 207/27 20060101 C07D207/27 |
Claims
1. A compound of Formula I(b): ##STR00066## wherein R.sup.1 is
C.sub.4-15-n-alkyl, C.sub.8-15-branched-alkyl, C.sub.4-15alkenyl,
C.sub.3-10cycloalkyleneC.sub.1-10 alkyl,
C.sub.5-10cycloalkenyleneC.sub.1-10alkyl,
C.sub.3-10cycloalkyleneC.sub.2-10alkenyl or
C.sub.5-10cycloalkenyleneC.sub.2-10alkenyl; n and m are each
independently 0, 1, 2 or 3; and R.sup.4 and R.sup.5 are each
independently selected from H, C.sub.1-8alkyl and C.sub.2-8alkenyl,
provided that at least one of R.sup.4 and R.sup.5 is selected from
C.sub.1-8alkyl and C.sub.2-8alkenyl; or R.sup.4 and R.sup.5
together with the carbon atom to which they are bonded form a
C.sub.3-10cycloalkane or a C.sub.5-10cycloalkene, or a
pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
2. The compound of claim 1, wherein both n and m are 1.
3. The compound of claim 1, wherein n is 2 and m is 0.
4. The compound of claim 1, wherein n is 0 and m is 2.
5. The compound of claim 1, wherein at least one of R.sup.4 and
R.sup.5 is C.sub.1-8alkyl or C.sub.2-8alkenyl.
6. The compound of claim 1, wherein at least one of R.sup.4 and
R.sup.5 is C.sub.1-6alkyl or C.sub.2-8alkenyl.
7. The compound of claim 1, wherein at least one of R.sup.4 and
R.sup.5 is C.sub.1-6alkyl.
8. The compound of claim 1, wherein at least one of R.sup.4 and
R.sup.5 is 2-methylpropyl.
9. The compound of claim 1, wherein at least one of R.sup.4 and
R.sup.5 is C.sub.2-6alkenyl.
10. The compound of claim 1, wherein at least one of R.sup.4 and
R.sup.5 is vinyl.
11. The compound of claim 1, having the structure: ##STR00067##
12. The compound of claim 1, wherein R.sup.4 and R.sup.5 together
with the carbon atom to which they are bonded form a
C.sub.3-10cycloalkane or a C.sub.5-10cycloalkene.
13. The compound of claim 1, wherein R.sup.4 and R.sup.5 together
with the carbon atom to which they are bonded form a
C.sub.3-10cycloalkane.
14. The compound of claim 1, wherein R.sup.4 and R.sup.5 together
with the carbon atom to which they are bonded form a
C.sub.5-8cycloalkane
15. The compound of claim 1, having the structure: ##STR00068##
16. The compound of claim 1, wherein R.sup.1 is selected from
n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl,
3-methylheptyl, 1-propylbutyl, 3-ethylheptyl and
4-butylcyclohexyl.
17. The compound of claim 1, wherein the compound is selected from:
##STR00069## ##STR00070## or a pharmaceutically acceptable salt,
solvate and/or prodrug thereof.
18. A pharmaceutical composition comprising the compound of claim 1
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof, and a pharmaceutically acceptable carrier.
19. A method of treating a CNS disease, disorder or condition
selected from epilepsy, non-epileptic seizures, cognitive
dysfunction, cognitive performance, anxiety and chronic pain
comprising administering a compound of claim 1 or a
pharmaceutically acceptable salt, solvate and/or prodrug thereof to
a subject in need thereof.
20. The method of claim 19, wherein the CNS disease, disorder or
condition is epilepsy.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a divisional patent application
of co-pending patent application Ser. No. 14/727,979 filed on Jun.
2, 2015 which claims the benefit of priority from U.S. provisional
application No. 62/006,515 filed on Jun. 2, 2014, the contents of
both of which are incorporated herein by reference in their
entirety.
FIELD
[0002] The present application relates to novel compounds
comprising a moiety that leads to the metabolic production of
ketones bonded to a ketone-potentiated anti-epileptic drug,
compositions comprising these compounds, and their use, for example
for the treatment of epilepsy, seizures, and/or other central
nervous system disorders or conditions.
BACKGROUND
[0003] Epilepsy is a neurological condition that makes people prone
to seizures. A seizure is a change in sensation, awareness, or
behavior brought about by a brief electrical disturbance in the
brain. Seizures vary from a momentary disruption of the senses, to
short periods of unconsciousness or staring spells, to convulsions
(Fisher et al., Epilepsia 46: 470-472, 2005). Some people have just
one type of seizure. Others have more than one type. All seizures
are caused by the same thing: a sudden change in how the cells of
the brain send electrical signals to each other.
[0004] During epilepsy, a propagation of high frequency, continuous
firing is initiated, referred to as a seizure. The severity and
symptoms of this seizure will depend on the position of the initial
focal point, seizure length, frequency of the discharges and the
distance the propagation spreads. Essentially, what a patient
experiences during a seizure will depend on where in the brain the
epileptic activity begins and how widely and rapidly it spreads.
Neurons may fire up to 500 times a second during an epileptic
seizure, over six times the normal rate of about 80 times a second.
The onset of epilepsy is defined as a condition characterized by
recurrent, unprovoked seizures.
[0005] There are over 40 different types of seizures, ranging from
seizures that go totally unnoticed by others to tonic-clonic
seizures which involve muscular contraction, uncontrollable jerks
and loss of consciousness. Knowing which type of seizures a person
has is useful as this will determine which antiepileptic drug (AED)
is most likely to be of benefit. However, the choice of the AED
also depends on several other issues, including the age and sex of
the patient, requirements for compliance and the presence of
hard-to-treat epileptic syndromes. The causes of epilepsy can be
divided into three categories:
[0006] Symptomatic epilepsy has a known cause, e.g. structural
abnormality of the brain, including head trauma, birth trauma,
cerebrovascular disorders, cerebral anoxia and brain tumors.
Idiopathic epilepsy has no clear underlying cause for the sudden
start of the seizures, although it is thought that having a low
seizure threshold could be a contributing factor. Cryptogenic
epilepsy may be symptomatic or idiopathic. This form of epilepsy is
believed to be symptomatic of a hidden cause of unknown etiology,
although unlike idiopathic epilepsy, it is not thought to have
started due to a low seizure threshold.
[0007] Epilepsy is the one of the most common neurological
disorders with approximately 3.3 Million patients in North America
and almost 200,000 new cases annually (Banerjee et al., Epilepsy
Res. 85: 31-45, 2009 and Epilepsy Prevalence, Incidence and Other
Statistics (2011).
[0008] Since the introduction of barbiturates as the first
anticonvulsant therapy there have been many drugs discovered and
developed to treat the disorder. However, despite the many
therapeutic options available, a large number of patients are
refractory to antiepileptic treatments: patients either fail to
respond to any drug treatment or have a poor response with
continuing seizures.
[0009] Currently, treatment of epilepsy is symptom-focused, i.e.,
to reduce or eliminate seizure response. While many new AEDs have
been commercialized in the past 15 years with improved seizure
control and reduced side effects, there still remain important
unmet medical needs in the treatment of epilepsy. Successful
management of epilepsy still remains a significant problem as
demonstrated by the fact that despite using various combinations of
AEDs, 20-25% of epileptic patients are insensitive to currently
available medication. Therefore, there is an ongoing need to
discover and develop effective drugs or synergistic combinations of
drugs for treating epilepsy.
[0010] Following observations that fasting can decrease the
incidence of seizures in epilepsy patients, it was hypothesised
that this was due to the production of ketones as metabolism
switched from carbohydrates to lipids. Although glucose metabolism
is the primary source of brain energy, ketone metabolism provides
an alternative pathway, which normally occurs under starvation
conditions. Ketone bodies are a natural endogenous energy source
mainly produced by the liver from mobilisation of endogenous body
fat and utilised by extrahepatic tissues (brain, heart, kidney,
muscle, etc.).
[0011] The ketogenic diet was introduced in the 1920's as a high
fat diet which would produce elevated levels of ketone bodies in
the plasma (Maalouf et al., Brain Res Rev. 59: 293-315, 2009 and
Hartman et al., Pediatr Neurol. 36: 281-292, 2007). The diet proved
to be effective in many patients who failed to respond to
conventional treatment and has remained a mainstay or adjunctive
treatment for drug resistant patients. Investigations indicated
that the diet was an effective anti-seizure treatment in animals
(Hartman et al., Pediatric Neurol. 36: 281-292, 2007) as well as
humans. The diet is, however, unpalatable and failure to adhere to
the diet leads to a return or increase in seizures. In addition,
the health consequences of a high fat diet for life can be
considerable.
[0012] Studies have shown that several ketones produced in animals
and humans have anti-seizure activity in animal models (Hartman et
al., Epilepsia 49: 334-339, 2008 and Likhodii et al., Ann. Neurol.
54:219-226, 2003). Although the anticonvulsant potential of ketones
has been well-established, finding a method to translate this
activity into a therapy has proven difficult. Typical ketone bodies
such as acetone are very short lived and rapidly removed from the
body making their use as therapies impractical. Amongst the
research in this area are studies showing that specific medium
chain fatty acids, such as caprylic acid (octanoic acid), which can
be metabolised to ketones have anticonvulsant properties (Chang et
al., Neuropharmacology 69: 1-10, 2013). Accordingly, caprylic acid,
which is used in a medium chain free fatty acid ketogenic diet, has
been shown to have anticonvulsant effects (Wlaz et al.,
Neuropharmacology 62: 1882-1889, 2012).
[0013] Some ketones have demonstrated the ability to potentiate the
anticonvulsant activity of some but not all anti-epileptic drugs
(Likhodii et al., Ann. Neurol. 54: 219-226, 2003 and Zarnowska et
al., Epilepsia 50: 1132-1140, 2009). A similar effect has been
observed for caprylic acid (Wlaz et al., Neuropharmacology 62:
1882-1889, 2012).
[0014] The same mechanism which leads to anticonvulsant activity
may also produce beneficial cognitive effects. For example,
caprylic acid supplementation has been shown to significantly
improve cognitive performance in Beagle dogs (Pan et al., British
Journal of Nutrition 103: 1746-1754, 2010). A similar improvement
in cognition following medium chain fatty acids has been reported
in diabetic patients (Page et al., Diabetes 58: 1237-1244, 2009).
In addition, the cognition enhancing effects for compounds with
atypical anticonvulsant activities such as piracetam, aniracetam
and the well-used anti-epileptic drug levetiracetam are known
(Malykh and Sadaie Drugs 70: 287-312, 2010 and Genton and Vleyman
Epileptic Disorders 2: 99-105, 2000).
SUMMARY
[0015] Compounds comprising a moiety that leads to the metabolic
production of ketones bonded to a ketone-potentiated anti-epileptic
drug have been prepared and characterized in the studies of the
present application. Compounds of the application decrease the
incidence of seizures in CD-1 mice which have received an
electrical stimulus to elicit a psychomotor seizure.
[0016] Accordingly, the present application includes a compound of
Formula I:
##STR00002##
wherein
[0017] A is a ketone-potentiated anti-epileptic drug; and
[0018] R.sup.1 is C.sub.4-15alkyl, C.sub.4-15alkenyl,
C.sub.3-10cycloalkyleneC.sub.1-10alkyl,
C.sub.5-10cycloalkenyleneC.sub.1-10alkyl,
C.sub.3-10cycloalkyleneC.sub.2-10alkenyl or
C.sub.5-10cycloalkenyleneC.sub.2-10alkenyl,
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0019] In an embodiment, A is a ketone-potentiated anti-epileptic
.gamma.-aminobutyric acid (GABA) derivative.
[0020] In a further embodiment, the compound of Formula I is a
compound of Formula I(a):
##STR00003##
wherein
[0021] R.sup.1 is as defined for the compound of Formula I; and
[0022] R.sup.2 and R.sup.3 are each independently selected from H,
C.sub.1-8alkyl and C.sub.2-8alkenyl; or
[0023] R.sup.2 and R.sup.3 together with the carbon atom to which
they are bonded form a C.sub.3-10cycloalkane or a
C.sub.5-10cycloalkene,
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0024] In another embodiment, the compound of Formula I is a
compound of Formula I(b):
##STR00004##
wherein
[0025] n and m are each independently 0, 1, 2 or 3;
[0026] R.sup.1 is as defined for the compound of Formula I; and
R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-8alkyl and C.sub.2-8alkenyl; or
[0027] R.sup.4 and R.sup.5 together with the carbon atom to which
they are bonded form a C.sub.3-10cycloalkane or a
C.sub.5-10cycloalkene,
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0028] The present application also includes a composition
comprising one or more compounds of the application and a carrier.
In an embodiment, the composition is a pharmaceutical composition
comprising one or more compounds of the application and a
pharmaceutically acceptable carrier.
[0029] In another embodiment, the compounds of the application are
used as medicaments. Accordingly, the application also includes one
or more compounds of the application for use as a medicament.
[0030] The present application includes a method of treating one or
more CNS diseases, disorders or conditions selected from epilepsy,
non-epileptic seizures, cognitive dysfunction, cognitive
performance, anxiety and chronic pain comprising administering one
or more compounds of the application to a subject in need thereof.
In particular, the present application includes a method of
treating epilepsy comprising administering one or more compounds of
the application to a subject in need thereof.
[0031] Other features and advantages of the present application
will become apparent from the following detailed description. It
should be understood, however, that the detailed description and
the specific examples, while indicating embodiments of the
application, are given by way of illustration only and the scope of
the claims should not be limited by these embodiments, but should
be given the broadest interpretation consistent with the
description as a whole.
DRAWINGS
[0032] The embodiments of the application will now be described in
greater detail with reference to the attached drawings in
which:
[0033] FIG. 1 is a plot showing the effect of increasing doses of
compound 4 (150, 300 or 600 mg/kg IP; or 600 mg/kg oral; 1 h
pretreatment) on the incidence of psychomotor seizures in CD-1 mice
in comparison to a Vehicle ("Veh") control in an exemplary
embodiment of the present application.
[0034] FIG. 2 is a plot showing the effect of increasing doses of
compound 14 (75, 150, 300 or 600 mg/kg IP or oral; 1 h
pretreatment) on the incidence of psychomotor seizures in CD-1 mice
in comparison to a Vehicle ("Veh") control in an exemplary
embodiment of the present application.
[0035] FIG. 3 is a plot showing the effect of increasing doses of
compound 21(75, 150, 300 or 600 mg/kg IP or oral; 1 h pretreatment)
on the incidence of psychomotor seizures in CD-1 mice in comparison
to a Vehicle ("Veh") control in an exemplary embodiment of the
present application.
[0036] FIG. 4 is a plot showing the effect of increasing doses of
compound 22 (75, 150, 300 or 600 mg/kg IP or oral; 1 h
pretreatment) on the incidence of psychomotor seizures in CD-1 mice
in comparison to a Vehicle ("Veh") control in an exemplary
embodiment of the present application.
[0037] FIG. 5 is a plot showing the effect of increasing doses of
compound 25 (37.5, 75, 150, 300 or 600 mg/kg IP or oral; 1 h
pretreatment) on the incidence of psychomotor seizures in CD-1 mice
in comparison to a Vehicle ("Veh") control in an exemplary
embodiment of the present application.
[0038] FIG. 6 is a plot showing the effect of increasing doses of
compound 26 (37.5, 75, 150, 300 or 600 mg/kg IP or oral; 1 h
pretreatment) on the incidence of psychomotor seizures in CD-1 mice
in comparison to a Vehicle ("Veh") control in an exemplary
embodiment of the present application.
[0039] FIG. 7 is a plot showing the effect of compound 20 (600
mg/kg IP) in comparison to a Vehicle ("Veh") control against
MES-induced tonic seizures, the incidence of which are expressed on
the vertical axis as a percentage of the total sample population
tested in an exemplary embodiment of the present application.
[0040] FIG. 8 is a plot showing the effect of compound 20 at doses
of 75, 150, 300 or 600 mg/kg given 1 hr pre-stimulation, as well as
300 mg/kg at 2 and 4 hr pre-stimulation, in comparison to a Vehicle
("Veh") control against 6 Hz-induced psychometric seizures, the
incidence of which are expressed on the vertical axis as a
percentage of the total sample population tested in an exemplary
embodiment of the present application. Compound 20 or its vehicle
was administered by either oral or intraperitoneal routes of
administration. The results are expressed as the incidence of mice
displaying at least one behavioural sign characteristic of a
psychomotor seizure following each pretreatment.
[0041] FIG. 9 is a plot showing the effect of compound 20 (300 and
600 mg/kg IP) in comparison to a Vehicle ("Veh") control against
scPTZ-induced seizures, the incidence of which are expressed on the
vertical axis as a percentage of the total sample population tested
in an exemplary embodiment of the present application.
[0042] FIG. 10 is a plot showing the effect of compound 20 (75 and
300 mg/kg) pretreatment against corneal kindled seizures in
comparison to a Vehicle "Veh" control in an exemplary embodiment of
the present application. The vertical axis represents the kindled
seizure score according to the Racine (1972) scale. Thus results
are expressed as the mean.+-.SEM kindling score following each
treatment. Compound 20 was administered by both the IP and oral
routes. Sodium Valproate (VPA, 600 mg/kg IP) was also included as a
positive control.
[0043] FIG. 11 is a plot showing the effect of compound 25 (150,
300 and 600 mg/kg IP and 600 mg/kg oral) pretreatment in comparison
to a Vehicle ("Veh") control against MES-induced tonic seizures,
the incidence of which are expressed on the vertical axis as a
percentage of the total sample population tested in an exemplary
embodiment of the present application.
[0044] FIG. 12 is a plot showing the effect of compound 25 (150,
300 and 600 mg/kg IP and 600 mg/kg oral) pretreatment in comparison
to a Vehicle ("Veh") control against scPTZ-induced seizures, the
incidence of which are expressed on the vertical axis as a
percentage of the total sample population tested in an exemplary
embodiment of the present application.
[0045] FIG. 13 is a plot showing the effect of compound 25 (150,
300 and 600 mg/kg IP and 600 mg/kg oral) pretreatment in comparison
to a Vehicle ("Veh") control against scPTZ-induced seizures in an
exemplary embodiment of the present application. The vertical axis
shows the onset latency (s) of a seizure from PTZ injection.
[0046] FIG. 14 is a plot showing the effect of compound 26 (300 and
600 mg/kg IP and 600 mg/kg oral) pretreatment in comparison to a
Vehicle ("Veh") control against MES-induced tonic seizures, the
incidence of which are expressed on the vertical axis as a
percentage of the total sample population tested in an exemplary
embodiment of the present application.
[0047] FIG. 15 is a plot showing the effect of compound 26 (150,
300 and 600 mg/kg IP and 600 mg/kg oral) pretreatment in comparison
to a Vehicle ("Veh") control against scPTZ-induced seizures, the
incidence of which are expressed on the vertical axis as a
percentage of the total sample population tested in an exemplary
embodiment of the present application.
[0048] FIG. 16 is a plot showing the effect of compound 26 (150,
300 and 600 mg/kg IP and 600 mg/kg oral) pretreatment in comparison
to a Vehicle ("Veh") control against scPTZ-induced seizures in an
exemplary embodiment of the present application. The vertical axis
shows the onset latency (s) of a seizure from PTZ injection.
DETAILED DESCRIPTION
I. Definitions
[0049] Unless otherwise indicated, the definitions and embodiments
described in this and other sections are intended to be applicable
to all embodiments and aspects of the present application herein
described for which they are suitable as would be understood by a
person skilled in the art.
[0050] In understanding the scope of the present application, the
term "comprising" and its derivatives, as used herein, are intended
to be open ended terms that specify the presence of the stated
features, elements, components, groups, integers, and/or steps, but
do not exclude the presence of other unstated features, elements,
components, groups, integers and/or steps. The foregoing also
applies to words having similar meanings such as the terms,
"including", "having" and their derivatives. The term "consisting"
and its derivatives, as used herein, are intended to be closed
terms that specify the presence of the stated features, elements,
components, groups, integers, and/or steps, but exclude the
presence of other unstated features, elements, components, groups,
integers and/or steps. The term "consisting essentially of", as
used herein, is intended to specify the presence of the stated
features, elements, components, groups, integers, and/or steps as
well as those that do not materially affect the basic and novel
characteristic(s) of features, elements, components, groups,
integers, and/or steps.
[0051] Terms of degree such as "substantially", "about" and
"approximately" as used herein mean a reasonable amount of
deviation of the modified term such that the end result is not
significantly changed. These terms of degree should be construed as
including a deviation of at least .+-.5% of the modified term if
this deviation would not negate the meaning of the word it
modifies.
[0052] As used in this application, the singular forms "a", "an"
and "the" include plural references unless the content clearly
dictates otherwise. For example, an embodiment including "a
compound" should be understood to present certain aspects with one
compound or two or more additional compounds.
[0053] In embodiments comprising an "additional" or "second"
component, such as an additional or second compound, the second
component as used herein is chemically different from the other
components or first component. A "third" component is different
from the other, first, and second components, and further
enumerated or "additional" components are similarly different.
[0054] The term "and/or" as used herein means that the listed items
are present, or used, individually or in combination. In effect,
this term means that "at least one of" or "one or more" of the
listed items is used or present. For example, the expression
"pharmaceutically acceptable salt, solvate and/or prodrug thereof"
is meant to cover combinations of these various forms of the
claimed compounds, including, for example, a solvate of a salt of a
compound of Formula I, or a solvate of a salt of a prodrug of a
compound of Formula I.
[0055] The term "suitable" as used herein means that the selection
of the particular compound or conditions would depend on the
specific synthetic manipulation to be performed, and the identity
of the molecule(s) to be transformed, but the selection would be
well within the skill of a person trained in the art. All
process/method steps described herein are to be conducted under
conditions sufficient to provide the product shown. A person
skilled in the art would understand that all reaction conditions,
including, for example, reaction solvent, reaction time, reaction
temperature, reaction pressure, reactant ratio and whether or not
the reaction should be performed under an anhydrous or inert
atmosphere, can be varied to optimize the yield of the desired
product and it is within their skill to do so.
[0056] The term "protecting group" and the like as used herein
refers to a chemical moiety which protects or masks a reactive
portion of a molecule to prevent side reactions in those reactive
portions of the molecule, while manipulating or reacting a
different portion of the molecule. After the manipulation or
reaction is complete, the protecting group is removed under
conditions that do not degrade or decompose the remaining portions
of the molecule. The selection of a suitable protecting group can
be made by a person skilled in the art. Many conventional
protecting groups are known in the art, for example as described in
"Protective Groups in Organic Chemistry" McOmie, J. F. W. Ed.,
Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M.,
"Protective Groups in Organic Synthesis", John Wiley & Sons,
3.sup.rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd
Edition, 2003, Georg Thieme Verlag (The Americas). Examples of
suitable protecting groups include, but are not limited to t-Boc,
Ac, Ts, Ms, silyl ethers such as TMS, TBDMS, TBDPS, Tf, Ns, Bn,
Fmoc, benzoyl, dimethoxytrityl, methoxyethoxymethyl ether,
methoxymethyl ether, pivaloyl, p-methyoxybenzyl ether,
tetrahydropyranyl, trityl, ethoxyethyl ethers, carbobenzyloxy,
benzoyl and the like.
[0057] t-Boc as used herein refers to the group
t-butyloxycarbonyl.
[0058] Ac as used herein refers to the group acetyl.
[0059] Ts (tosyl) as used herein refers to the group
p-toluenesulfonyl.
[0060] Ms as used herein refers to the group methanesulfonyl.
[0061] TMS as used herein refers to the group trimethylsilyl.
[0062] TBDMS as used herein refers to the group
t-butyldimethylsilyl.
[0063] TBDPS as used herein refers to the group
t-butyldiphenylsilyl.
[0064] Tf as used herein refers to the group
trifluoromethanesulfonyl.
[0065] Ns as used herein refers to the group naphthalene
sulphonyl.
[0066] Bn as used herein refers to the group benzyl.
[0067] Fmoc as used herein refers to the group
fluorenylmethoxycarbonyl.
[0068] The term "alkyl" as used herein, whether it is used alone or
as part of another group, means straight or branched chain,
saturated alkyl groups. The number of carbon atoms that are
possible in the referenced alkyl group are indicated by the
numerical prefix "C.sub.n1-n2". For example, the term
C.sub.1-8alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8
carbon atoms.
[0069] The term "alkenyl" as used herein, whether it is used alone
or as part of another group, means straight or branched chain,
unsaturated alkenyl groups. The number of carbon atoms that are
possible in the referenced alkenyl group are indicated by the
numerical prefix "C.sub.n1-n2". For example, the term
C.sub.4-15alkenyl means an alkenyl group having 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14 or 15 carbon atoms and at least one double bond,
for example 1 to 3, 1 to 2 or 1 double bond.
[0070] The term "cycloalkane" as used herein, whether it is used
alone or as part of another group, means a mono- or bicyclic,
saturated alkane group. The number of carbon atoms that are
possible in the referenced cycloalkane group are indicated by the
numerical prefix "C.sub.n1-n2". For example, the term
C.sub.3-10cycloalkane means a cycloalkane group having 3, 4, 5, 6,
7, 8, 9 or 10 carbon atoms. When a cycloalkane group contains more
than one cyclic structure or rings, the cyclic structures are
fused, bridged, spiro connected or linked by a single bond.
[0071] The term "cycloalkylene" as used herein, whether it is used
alone or as part of another group, refers to a bivalent cycloalkane
group.
[0072] The term "cycloalkene" as used herein, whether it is used
alone or as part of another group, means a mono- or bicyclic,
unsaturated alkene group. The number of carbon atoms that are
possible in the referenced cycloalkene group are indicated by the
numerical prefix "C.sub.n1-n2". For example, the term
C.sub.5-10cycloalkene means a cycloalkene group having 5, 6, 7, 8,
9 or 10 carbon atoms and at least one double bond, for example 1 to
3, 1 to 2 or 1 double bond. When a cycloalkene group contains more
than one cyclic structure or rings, the cyclic structures are
fused, bridged, spiro connected or linked by a single bond.
[0073] The term "cycloalkenylene" as used herein, whether it is
used alone or as part of another group, refers to a bivalent
cycloalkene group.
[0074] A first cyclic structure being "fused" with a second cyclic
structure means the first cyclic structure and the second cyclic
structure share at least two adjacent atoms therebetween.
[0075] A first cyclic structure being "bridged" with a second
cyclic structure means the first cyclic structure and the second
cyclic structure share at least two non-adjacent atoms
therebetween.
[0076] A first cyclic structure being "spiro connected" with a
second cyclic structure means the first cyclic structure and the
second cyclic structure share one atom therebetween.
[0077] The term "halo" as used herein refers to a halogen atom and
includes F, Cl, Br and I. In an embodiment, halo is Cl, Br or
I.
[0078] The term "compound of the application" or "compound of the
present application" and the like as used herein refers to a
compound of Formula I, and pharmaceutically acceptable salts,
solvates and/or prodrugs thereof.
[0079] The term "disease, disorder or condition of the application"
as used herein refers to a disease, disorder or condition for which
a compound of the application is useful to treat. In an embodiment,
the disease, disorder or condition is a CNS disease, disorder or
condition selected from one or more of epilepsy, non-epileptic
seizures, cognitive dysfunction, cognitive performance, anxiety and
chronic pain.
[0080] The term "subject" as used herein includes all members of
the animal kingdom including mammals, and suitably refers to
humans, companion animals (e.g. dogs, cats, rodents, rabbits etc.)
and livestock (e.g. cattle, sheep, pigs, goats, equines such as
horses, mules and donkeys etc.).
[0081] The term "pharmaceutically acceptable" means compatible with
the treatment of subjects such as humans, companion animals and
livestock.
[0082] The term "pharmaceutically acceptable salt" means an acid
addition salt that is suitable for, or compatible with, the
treatment of subjects or a base addition salt that is suitable for,
or compatible with, the treatment of subjects.
[0083] An acid addition salt that is suitable for, or compatible
with, the treatment of subjects is any non-toxic organic or
inorganic salt of any basic compound. Basic compounds that form an
acid addition salt include, for example, compounds comprising an
amine group. Illustrative inorganic acids which form suitable salts
include hydrochloric, hydrobromic, sulfuric and phosphoric acids,
as well as metal salts such as sodium monohydrogen orthophosphate
and potassium hydrogen sulfate. Illustrative organic acids that
form suitable salts include mono-, di-, and tricarboxylic acids
such as glycolic, lactic, pyruvic, malonic, succinic, glutaric,
fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic,
phenylacetic, cinnamic and salicylic acids, as well as sulfonic
acids such as p-toluene sulfonic and methanesulfonic acids. Either
the mono or di-acid salts can be formed, and such salts may exist
in either a hydrated, solvated or substantially anhydrous form. In
general, acid addition salts are more soluble in water and various
hydrophilic organic solvents, and generally demonstrate higher
melting points in comparison to their free base forms. The
selection of an appropriate salt can be made by a person skilled in
the art.
[0084] A base addition salt that is suitable for, or compatible
with, the treatment of subjects is any non-toxic organic or
inorganic base addition salt of any acidic compound. Acidic
compounds that form a base addition salt include, for example,
compounds comprising a carboxylic acid group. Illustrative
inorganic bases which form suitable salts include lithium, sodium,
potassium, calcium, magnesium or barium hydroxide. Illustrative
organic bases which form suitable salts include aliphatic,
alicyclic or aromatic organic amines such as methylamine,
trimethylamine and picoline, alkylammonias or ammonia. The
selection of an appropriate salt can be made by a person skilled in
the art.
[0085] The formation of a desired acid addition salt or base
addition salt is, for example, achieved using standard techniques.
For example, the neutral compound is treated with an acid or base,
respectively, in a suitable solvent and the formed salt then
isolated by filtration, extraction and/or any other suitable
method.
[0086] Prodrugs of the compounds of the present application are,
for example, conventional esters formed with available amino or
carboxyl groups. For example, available amino groups may be
acylated using an activated acid in the presence of a base, and
optionally, in inert solvent (e.g. an acid chloride in pyridine).
Some common esters which have been utilized as prodrugs are phenyl
esters, aliphatic (C.sub.1-C.sub.24) esters, acyloxymethyl esters,
carbamates and amino acid esters.
[0087] The term "solvates" as used herein refers to complexes
formed between a compound and a solvent from which the compound is
precipitated or in which the compound is made. Accordingly, the
term "solvate" as used herein means a compound, or a salt of a
compound, wherein molecules of a suitable solvent are incorporated
in the crystal lattice. Examples of suitable solvents are ethanol,
water and the like. When water is the solvent, the molecule is
referred to as a "hydrate". The formation of solvates will vary
depending on the compound and the solvate. In general, solvates are
formed by dissolving the compound in the appropriate solvent and
isolating the solvate by cooling or using an antisolvent. The
solvate is typically dried or azeotroped under ambient conditions.
The selection of suitable conditions to form a particular solvate
can be made by a person skilled in the art.
[0088] In embodiments of the application, the compounds described
herein have at least one asymmetric center. Where compounds possess
more than one asymmetric center, they may exist as diastereomers.
It is to be understood that all such isomers and mixtures thereof
in any proportion are encompassed within the scope of the present
application. It is to be further understood that while the
stereochemistry of the compounds may be as shown in any given
compound listed herein, such compounds may also contain certain
amounts (e.g. less than 20%, suitably less than 10%, more suitably
less than 5%) of compounds of the application having alternate
stereochemistry.
[0089] The term "administered" as used herein means administration
of an effective amount of one or more compounds of the application
to a cell either in cell culture or in a subject.
[0090] As used herein, the terms "effective amount" or
"therapeutically effective amount" and the like means an amount
effective, at dosages and for periods of time necessary to achieve
a desired result. For example, in the context of treating epilepsy,
an effective amount of the one or more compounds of the application
is an amount that, for example, reduces the epilepsy compared to
the epilepsy without administration of the one or more compounds of
the application. By "reducing the epilepsy", it is meant, for
example, reducing the amount and/or frequency of epileptic
seizures. Effective amounts may vary according to factors such as
the disease state, age, sex, weight and/or species of the subject.
The amount of a given compound that will correspond to such an
amount will vary depending upon various factors, such as the given
compound, the pharmaceutical formulation, the route of
administration, the type of condition, disease or disorder being
treated, the identity of the subject being treated, and the like,
but can nevertheless be routinely determined by one skilled in the
art.
[0091] The terms "to treat", "treating" and "treatment" as used
herein and as is well understood in the art, means an approach for
obtaining beneficial or desired results, including clinical
results. Beneficial or desired clinical results include, but are
not limited to, alleviation or amelioration of one or more symptoms
of a disease, disorder or condition of the present application,
diminishment of extent of a disease, disorder or condition of the
present application, stabilized (i.e. not worsening) state of a
disease, disorder or condition of the present application,
preventing spread of a disease, disorder or condition of the
present application, delay or slowing of the progression of a
disease, disorder or condition of the present application,
amelioration or palliation of the state of a disease, disorder or
condition of the present application, diminishment of the
reoccurrence of a disease, disorder or condition of the present
application, and remission of a disease, disorder or condition of
the present application (whether partial or total), whether
detectable or undetectable. "To treat", "treating" and "treatment"
can also mean prolonging survival as compared to expected survival
if not receiving treatment. "Treating" and "treatment" as used
herein also include prophylactic treatment. For example, a subject
with early cognitive dysfunction can be treated to prevent
progression, or alternatively a subject in remission can be treated
with one or more compounds of the application to prevent
recurrence. Treating" and "treatment" as used herein also include
improving a condition, such as cognitive performance, in the
absence of a disease or disorder.
[0092] Treatment methods comprise administering to a subject a
therapeutically effective amount of one or more compounds of the
application, optionally consisting of a single administration, or
alternatively comprising a series of administrations. For example,
the compounds of the application are administered at least once a
week. However, in another embodiment, the compounds are
administered to the subject from about one time per three weeks, or
about one time per week to about once daily for a given treatment.
In another embodiment, the compounds are administered 2, 3, 4, 5 or
6 times daily. The length of the treatment period depends on a
variety of factors, such as the severity of the disease, disorder
or condition of the present application, the age of the subject,
the concentration of the one or more compounds in a formulation,
the activity of the compounds of the application, and/or a
combination thereof. It will also be appreciated that the effective
dosage of a compound used for the treatment may increase or
decrease over the course of a particular treatment regime. Changes
in dosage may result and become apparent by standard diagnostic
assays known in the art. In some instances, chronic administration
is required. For example, the one or more compounds of the
application are administered in an amount and for a duration
sufficient to treat the subject.
[0093] "Palliating" a disease, disorder or condition of the present
application means that the extent and/or undesirable clinical
manifestations of a disease, disorder or condition of the present
application state are lessened and/or time course of the
progression is slowed or lengthened, as compared to not treating
the disease, disorder or condition of the present application.
[0094] The term "prevention" or "prophylaxis", or synonym thereto,
as used herein refers to a reduction in the risk or probability of
a subject becoming afflicted with a disease, disorder or condition
of the present application.
[0095] The term "ketone-potentiated anti-epileptic drug" as used
herein means that the anticonvulsant activity of the drug is
potentiated by a ketone.
[0096] The term ".gamma.-aminobutyric acid (GABA) derivative" as
used herein means a derivative of .gamma.-aminobutyric acid
(GABA):
##STR00005##
and includes cyclic .gamma.-aminobutyric acid (GABA) derivatives
(i.e. derivatives comprising a .gamma.-lactam ring) and linear
.gamma.-aminobutyric acid (GABA) derivatives.
II. Compounds and Methods of Preparation Thereof
[0097] Compounds comprising a moiety that leads to the metabolic
production of ketones bonded to a ketone-potentiated anti-epileptic
drug have been prepared and characterized in the studies of the
present application.
[0098] Accordingly, the present application includes a compound of
Formula I:
##STR00006##
wherein
[0099] A is a ketone-potentiated anti-epileptic drug; and
[0100] R.sup.1 is C.sub.4-15alkyl, C.sub.4-15alkenyl,
C.sub.3-10cycloalkyleneC.sub.1-10 alkyl,
C.sub.5-10cycloalkenyleneC.sub.1-10alkyl,
C.sub.3-10cycloalkyleneC.sub.2-10alkenyl or
C.sub.5-10cycloalkenyleneC.sub.2-10alkenyl,
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0101] The ketone-potentiated anti-epileptic drug suitably has a
functional group that is readily bonded to the moiety that leads to
the metabolic production of ketones. For example,
ketone-potentiated anti-epileptic drugs having an amino functional
group such as but not limited to gabapentin, pregabalin and
levetiracetam or protected derivatives thereof are reacted with a
precursor (having a C(O)X functional group, wherein X is a leaving
group) to the moiety that leads to the metabolic production of
ketones under conditions to obtain a compound of the present
application. The selection of a suitable ketone-potentiated
anti-epileptic drug can be made by a person skilled in the art. In
an embodiment, the ketone-potentiated anti-epileptic drug is
selected from gabapentin, pregabalin, levetiracetam, vigabatrin,
valproate, oxcarbazepine, carbamazepine, progabide, tiagabine,
rufinamide, eslicarbazepine, and retigabine.
[0102] In an embodiment, A is a ketone-potentiated anti-epileptic
.gamma.-aminobutyric acid (GABA) derivative. In another embodiment,
the ketone-potentiated anti-epileptic .gamma.-aminobutyric acid
(GABA) derivative is selected from gabapentin, pregabalin,
levetiracetam and vigabatrin. In a further embodiment, the
ketone-potentiated anti-epileptic .gamma.-aminobutyric acid (GABA)
derivative is selected from gabapentin, pregabalin, levetiracetam
and vigabatrin, each of which is covalently bonded to the
R.sup.1C(O) group of the compound of Formula I via an amino group.
It is an embodiment that the ketone-potentiated anti-epileptic
.gamma.-aminobutyric acid (GABA) derivative is selected from
gabapentin, pregabalin and levetiracetam, each of which is
covalently bonded to the R.sup.1C(O) group of the compound of
Formula I via an amino group.
[0103] In a further embodiment, the compound of Formula I is a
compound of Formula I(a):
##STR00007##
wherein
[0104] R.sup.1 is as defined for the compound of Formula I; and
[0105] R.sup.2 and R.sup.3 are each independently selected from H,
C.sub.1-8alkyl and C.sub.2-8alkenyl; or
[0106] R.sup.2 and R.sup.3 together with the carbon atom to which
they are bonded form a C.sub.3-10cycloalkane or a
C.sub.5-10cycloalkene,
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0107] In an embodiment, at least one of R.sup.2 and R.sup.3 is
C.sub.1-8alkyl or C.sub.2-8alkenyl. In another embodiment, at least
one of R.sup.2 and R.sup.3 is C.sub.1-8alkyl. In a further
embodiment, at least one of R.sup.2 and R.sup.3 is C.sub.1-6alkyl.
It is an embodiment that at least one of R.sup.2 and R.sup.3 is
C.sub.1-4alkyl. In another embodiment of the present application,
at least one of R.sup.2 and R.sup.3 is ethyl.
[0108] In an embodiment, R.sup.2 is H and R.sup.3 is C.sub.1-8alkyl
or C.sub.2-8alkenyl. In another embodiment, R.sup.2 is H and
R.sup.3 is C.sub.1-8alkyl. In a further embodiment, R.sup.2 is H
and R.sup.3 is C.sub.1-6alkyl. It is an embodiment that R.sup.2 is
H and R.sup.3 is C.sub.1-4alkyl. In another embodiment of the
present application, R.sup.2 is H and R.sup.3 is ethyl.
[0109] In another embodiment, A has the structure:
##STR00008##
[0110] In an embodiment, both R.sup.2 and R.sup.3 are H.
[0111] In another embodiment, the compound of Formula I is a
compound of Formula I(b):
##STR00009##
wherein
[0112] n and m are each independently 0, 1, 2 or 3;
[0113] R.sup.1 is as defined for the compound of Formula I; and
[0114] R.sup.4 and R.sup.5 are each independently selected from H,
C.sub.1-8alkyl and C.sub.2-8alkenyl; or
[0115] R.sup.4 and R.sup.5 together with the carbon atom to which
they are bonded form a C.sub.3-10cycloalkane or a
C.sub.5-10cycloalkene,
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0116] In another embodiment, n+m=2. In a further embodiment, both
n and m are 1. It is an embodiment that n is 2 and m is 0. In
another embodiment of the present application, n is 0 and m is
2.
[0117] In an embodiment, at least one of R.sup.4 and R.sup.5 is
C.sub.1-8alkyl or C.sub.2-8alkenyl. In another embodiment, at least
one of R.sup.4 and R.sup.5 is C.sub.1-6alkyl or C.sub.2-8alkenyl.
In a further embodiment, at least one of R.sup.4 and R.sup.5 is
C.sub.1-6alkyl. It is an embodiment that at least one of R.sup.4
and R.sup.5 is 2-methylpropyl (isobutyl). In another embodiment of
the present application, at least one of R.sup.4 and R.sup.5 is
C.sub.2-6alkenyl. In a further embodiment, at least one of R.sup.4
and R.sup.5 is vinyl.
[0118] In an embodiment, R.sup.4 is H and R.sup.5 is C.sub.1-8alkyl
or C.sub.2-8alkenyl. In another embodiment, R.sup.4 is H and
R.sup.5 is C.sub.1-6alkyl or C.sub.2-6alkenyl. In a further
embodiment, R.sup.4 is H and R.sup.5 is C.sub.1-6alkyl. It is an
embodiment that R.sup.4 is H and R.sup.5 is 2-methylpropyl
(isobutyl). In another embodiment of the present application,
R.sup.4 is H and R.sup.5 is C.sub.2-6alkenyl. In a further
embodiment, R.sup.4 is H and R.sup.5 is vinyl.
[0119] In an embodiment, A has the structure:
##STR00010##
[0120] In another embodiment, A has the structure:
##STR00011##
[0121] In an embodiment, R.sup.4 and R.sup.5 together with the
carbon atom to which they are bonded form a C.sub.3-10cycloalkane
or a C.sub.5-10cycloalkene. In another embodiment, R.sup.4 and
R.sup.5 together with the carbon atom to which they are bonded form
a C.sub.3-10cycloalkane. In a further embodiment, R.sup.4 and
R.sup.5 together with the carbon atom to which they are bonded form
a C.sub.5-8cycloalkane. It is an embodiment that A has the
structure:
##STR00012##
[0122] In an embodiment, R.sup.1 is C.sub.4-15alkyl,
C.sub.4-15alkenyl, C.sub.3-10cycloalkyleneC.sub.1-10alkyl or
C.sub.3-10cycloalkyleneC.sub.2-10alkenyl. In another embodiment,
R.sup.1 is C.sub.8-12alkyl, C.sub.8-12alkenyl,
C.sub.3-8cycloalkyleneC.sub.1-8alkyl or
C.sub.3-8cycloalkyleneC.sub.1-8alkenyl. In a further embodiment,
R.sup.1 is C.sub.5-11alkyl or C.sub.5-11alkenyl. In an embodiment,
R.sup.1 is C.sub.4-15alkyl. It is an embodiment that R.sup.1 is
C.sub.6-12alkyl. In a further embodiment, R.sup.1 is
C.sub.5-11alkyl. In another embodiment, R.sup.1 is
C.sub.3-8cycloalkyleneC.sub.1-8alkyl. In a further embodiment,
R.sup.1 is cyclohexyleneC.sub.1-8alkyl. It is an embodiment that
R.sup.1 is
##STR00013##
[0123] In an embodiment, R.sup.1 is selected from n-pentyl,
n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl,
3-methylheptyl, 1-propylbutyl, 3-ethylheptyl and 4-butylcyclohexyl.
In another embodiment, R.sup.1 is selected from n-pentyl, n-hexyl,
n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, 3-methylheptyl and
1-propylbutyl. In a further embodiment, R.sup.1 is n-heptyl,
n-octyl, n-nonyl, 3-ethylheptyl or 4-butylcyclohexyl. In another
embodiment, R.sup.1 is n-heptyl, n-octyl or n-nonyl. In a further
embodiment, R.sup.1 is n-heptyl. It is an embodiment that R.sup.1
is n-octyl. In another embodiment, R.sup.1 is n-nonyl. It is an
embodiment that R.sup.1 is 3-ethylheptyl. In another embodiment of
the present application, R.sup.1 is 4-butylcyclohexyl.
[0124] In an embodiment, the compound of Formula I is selected
from:
##STR00014## ##STR00015## ##STR00016##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0125] In an embodiment, the compound of Formula I is selected
from:
##STR00017##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0126] In an embodiment, the compound of Formula I is selected
from:
##STR00018##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0127] In an embodiment, the compound of Formula I is selected
from:
##STR00019##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0128] In an embodiment, the compound of Formula I is selected
from:
##STR00020##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0129] In another embodiment, the compound of Formula I is selected
from:
##STR00021##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0130] In an embodiment, the compound of Formula I is:
##STR00022##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0131] In another embodiment, the compound of Formula I is:
##STR00023##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0132] In a further embodiment, the compound of Formula I is:
##STR00024##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0133] It is an embodiment that the compound of Formula I is:
##STR00025##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0134] In another embodiment, the compound of Formula I is:
##STR00026##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0135] In a further embodiment, the compound of Formula I is:
##STR00027##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0136] In another embodiment of the present application, the
compound of Formula I is selected from:
##STR00028##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0137] In an embodiment, the compound of Formula I is:
##STR00029##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0138] In another embodiment, the compound of Formula I is:
##STR00030##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0139] It is an embodiment that the compound of Formula I is:
##STR00031##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0140] In another embodiment of the present application, the
compound of Formula I is selected from:
##STR00032##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0141] In another embodiment, the compound of Formula I is:
##STR00033##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0142] In a further embodiment, the compound of Formula I is:
##STR00034##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0143] In another embodiment, the compound of Formula I is:
##STR00035##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0144] In a further embodiment, the compound of Formula I is:
##STR00036##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0145] In another embodiment of the present application, the
compound of Formula I is selected from:
##STR00037##
or a pharmaceutically acceptable salt, solvate and/or prodrug
thereof.
[0146] The compounds of the application are prepared by processes
analogous to those established in the art, for example, by the
reaction sequences shown in general synthetic schemes 1-2.
[0147] In an embodiment of the application, a compound of Formula
I(a) is prepared under suitable standard alkylating conditions by
treating a compound of Formula II(a) with a compound of Formula IV,
or a suitably protected derivative thereof, wherein R.sup.1,
R.sup.2 and R.sup.3 are as defined herein for the compounds of the
present application and X is a leaving group such as halogen e.g.,
a chloro, bromo or iodo-group, under conditions to form the
compound of Formula I(a), as shown in Scheme 1.
##STR00038##
[0148] Conditions to effect the alkylation of the compound of
Formula II(a) with a compound of Formula IV include reacting at
room temperature or heating with or without a solvent, for example
with a suitable solvent such as THF, DMF, DMSO, or diethyl ether,
in the presence of a base such as but not limited to DMAP, NaH,
.sup.tBuOK, .sup.tBuONa, pyridine, or diisopropyl ethylamine. If
the compound of Formula IV is not commercially available, it can be
prepared from the corresponding acid of Formula III under suitable
conditions for the formation of the compound of Formula IV; i.e.
with or without heating, either without a solvent or in the
presence of a suitable solvent such as CH.sub.2Cl.sub.2 or DMSO, in
the presence of a reagent such as thionyl chloride or oxalyl
chloride (Scheme 1).
[0149] Similarly, in another embodiment of the application, the
compound of Formula I(b), wherein n, m, R.sup.1, R.sup.4 and
R.sup.5 are as defined herein for the compounds of the present
application, is prepared, for example, from a compound of Formula
II(b) under conditions comprising using a suitable solvent such as
DMF, DMSO, THF or diethyl ether in presence of a suitable base such
as but not limited to NaH, .sup.tBuOK, .sup.tBuONa, pyridine or
DMAP, as shown in Scheme 2.
##STR00039##
[0150] In some embodiments of the present application, the
chemistry outlined above is modified, for example by the use of a
suitable protecting group for the carboxylic acid moiety in the
compounds of Formula I(b) to prevent side reactions. This is
achieved, for example by means of conventional protecting groups as
described, for example, in Greene's protective groups in organic
synthesis, P. G. M. Wuts and T. W. Greene, John Wiley & Sons,
2012.
[0151] The compounds of the application and their intermediates are
isolatable from their reaction mixtures and purifiable using
conventional laboratory techniques including, for example, solvent
extraction, column chromatography using silica gel as well as
alumina, distillation, crystallization, recrystallization and/or
chiral separation.
[0152] The formation of a desired salt of the compounds of the
present application is achieved using standard techniques. For
example, a basic addition salt is prepared by treating a neutral
compound with a base such as NaOH or KOH in a suitable solvent and
the salt isolated by filtration, extraction, and/or evaporation of
solvent or any other suitable method.
[0153] Preparation of an optical isomer of a compound of the
application is performed, for example by the reaction of the
appropriate optically active starting material under reaction
conditions which will not cause racemization or alternatively the
individual enantiomer or diastereomer (with more than one chiral
center) is isolated by the separation of a racemic mixture using
standard techniques such as fractional crystallization, chiral salt
formation and/or chiral HPLC separation.
III. Compositions
[0154] The present application also includes a composition
comprising one or more compounds of the application and a carrier.
The compounds of the application are suitably formulated into
pharmaceutical compositions for administration to subjects in a
biologically compatible form suitable for administration in vivo.
Accordingly, the present application further includes a
pharmaceutical composition comprising one or more compounds of the
application and a pharmaceutically acceptable carrier.
[0155] The compounds of the application can be administered to a
subject in a variety of forms depending on the selected route of
administration, as will be understood by those skilled in the art.
In an embodiment, the one or more compounds of the application are
administered to the subject, or used, by oral (including sublingual
and buccal) or parenteral (including intravenous, intraperitoneal,
subcutaneous, intramuscular, transepithelial, nasal,
intrapulmonary, intrathecal, rectal, topical, patch, pump and
transdermal) administration and the compound(s) formulated
accordingly. For example, the compounds of the application are
administered by injection, in a spray, in a tablet/caplet, in a
powder, topically, in a gel, in drops, by a patch, by an implant,
by a slow release pump or by any other suitable method of
administration, the selection of which can be made by a person
skilled in the art.
[0156] In an embodiment, the one or more compounds of the
application are orally administered, for example, with an inert
diluent or with an assimilable edible carrier, or enclosed in hard
or soft shell gelatin capsules, or compressed into tablets, or
incorporated directly with the food of the diet. In an embodiment,
for oral therapeutic administration, the one or more compounds of
the application are incorporated with excipient and used in the
form of ingestible tablets, buccal tablets, troches, capsules,
elixirs, suspensions, syrups, wafers, and the like. Oral dosage
forms also include modified release, for example immediate release
and timed-release, formulations. Examples of modified-release
formulations include, for example, sustained-release (SR),
extended-release (ER, XR, or XL), time-release or timed-release,
controlled-release (CR), or continuous-release (CR or Contin),
employed, for example, in the form of a coated tablet, an osmotic
delivery device, a coated capsule, a microencapsulated microsphere,
an agglomerated particle, e.g., as of molecular sieving type
particles, or, a fine hollow permeable fiber bundle, or chopped
hollow permeable fibers, agglomerated or held in a fibrous packet.
Timed-release compositions can be formulated, e.g. liposomes or
those wherein the active compound is protected with differentially
degradable coatings, such as by microencapsulation, multiple
coatings, etc. Liposome delivery systems include, for example,
small unilamellar vesicles, large unilamellar vesicles and
multilamellar vesicles. In an embodiment, liposomes are formed from
a variety of phospholipids, such as cholesterol, stearylamine
and/or phosphatidylcholines.
[0157] In another embodiment of the application, the one or more
compounds of the application are freeze dried and the lyophilizates
obtained, are used for example, for the preparation of products for
injection.
[0158] In another embodiment, the one or more compounds of the
application are administered parenterally. Solutions of the one or
more compounds of the application are, for example, prepared in
water suitably mixed with a surfactant such as
hydroxypropylcellulose. In a further example, dispersions are
prepared in glycerol, liquid polyethylene glycols, DMSO and
mixtures thereof with or without alcohol, and in oils. Under
ordinary conditions of storage and use, these preparations contain
a preservative to prevent the growth of microorganisms. A person
skilled in the art would know how to prepare suitable
formulations.
[0159] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists.
[0160] Compositions for nasal administration are, for example,
conveniently formulated as aerosols, drops, gels or powders.
Aerosol formulations typically comprise a solution or fine
suspension of the active substance in a physiologically acceptable
aqueous or non-aqueous solvent and are usually presented in single
or multidose quantities in sterile form in a sealed container,
which, for example, take the form of a cartridge or refill for use
with an atomising device. Alternatively, the sealed container is a
unitary dispensing device such as a single dose nasal inhaler or an
aerosol dispenser fitted with a metering valve which is intended
for disposal after use. Where the dosage form comprises an aerosol
dispenser, it will contain a propellant which is, for example, a
compressed gas, such as compressed air or an organic propellant
such as a fluorochlorohydrocarbon. In another embodiment, the
aerosol dosage forms take the form of a pump-atomizer.
[0161] Compositions suitable for buccal or sublingual
administration include tablets, lozenges, and pastilles, wherein
the active ingredient is formulated with a carrier such as sugar,
acacia, tragacanth, gelatin and/or glycerine. Compositions for
rectal administration are, for example, conveniently in the form of
suppositories containing a conventional suppository base such as
cocoa butter.
[0162] In another embodiment, the one or more compounds of the
application are coupled with soluble polymers as targetable drug
carriers. Such polymers include, for example, polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxy-ethylaspartamide-phenol, or
polyethyleneoxide-polylysine substituted with palmitoyl residues.
In another embodiment, the one or more compounds of the application
are coupled to a class of biodegradable polymers useful in
achieving controlled release of a drug, for example, polylactic
acid, polyglycolic acid, copolymers of polylactic and polyglycolic
acid, polyepsilon caprolactone, polyhydroxy butyric acid,
polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates
and crosslinked or amphipathic block copolymers of hydrogels.
IV. Methods of Treatment and Uses
[0163] The compounds of the present application are new therefore,
the present application includes all uses for compounds of the
application, including use in therapeutic methods, diagnostic
assays, and as research tools whether alone or in combination with
another active pharmaceutical ingredient.
[0164] The compounds of the application have been shown to decrease
the incidence of seizures in CD-1 mice which have received an
electrical stimulus to elicit a psychomotor seizure. The compounds
of the application comprise known and atypical anticonvulsant
moieties which operate alone or together (additively or
synergistically) to suppress seizure activity as manifested by
physical symptoms and/or electrical activity of the brain as
measured by EEG or other standard methods of measurement. Combining
a relevant anticonvulsant moiety i.e. one that is potentiated by a
ketone, with a moiety which leads to the metabolic production of
ketones and related species, including medium chain free fatty
acids, in one structure provides a mechanism to develop a unique
series of dual action anticonvulsant drugs. In an embodiment, the
compounds of the application act as carriers and pro-drugs for each
anticonvulsant element therein.
[0165] Therefore, in one embodiment, the compounds of the present
application are useful as medicaments. Accordingly, the present
application includes one or more compounds of the application for
use as a medicament. In a further embodiment, the compounds of the
application are useful for treating CNS diseases, disorders or
conditions such as one or more of epilepsy, non-epileptic seizures,
cognitive dysfunction, cognitive performance, anxiety, and chronic
pain in subjects such as humans and animals.
[0166] Accordingly, the present application includes a method of
treating epilepsy comprising administering one or more compounds of
the application to a subject in need thereof. The present
application also includes a use of one or more compounds of the
application for treating epilepsy in a subject; a use of one or
more compounds of the application for preparation of a medicament
for treating epilepsy in a subject; and one or more compounds of
the application for use to treat epilepsy in a subject.
[0167] In an embodiment, the compounds of the application are
useful as an adjunct therapy with other epilepsy treatments such as
anti-epileptic drugs and ketogenic (i.e. high fat, low
carbohydrate) diets. Accordingly, the present application includes
a method of treating epilepsy comprising administering, to a
subject in need thereof, one or more compounds of the application
in combination with an adjunct epilepsy treatment. The present
application also includes a use of one or more compounds of the
application in combination with an adjunct epilepsy treatment for
treating epilepsy in a subject; a use of one or more compounds of
the application in combination with an adjunct epilepsy treatment
for preparation of a medicament for treating epilepsy in a subject;
and one or more compounds of the application in combination with an
adjunct epilepsy treatment for use to treat epilepsy in a subject.
In an embodiment, the adjunct epilepsy treatment is a ketogenic
diet. In another embodiment, the adjunct epilepsy treatment is an
anti-epileptic drug.
[0168] In an embodiment, the administration or use of a compound of
the application in combination with an anti-epileptic drug reduces
the dose of the anti-epileptic drug that is effective for treatment
of epilepsy. In another embodiment, the administration or use of a
compound of the application in combination with a ketogenic diet
reduces the fat:carbohydrate ratio that is effective for treatment
of epilepsy and thereby makes the ketogenic diet more tolerable to
the subject.
[0169] In an embodiment, the epilepsy is symptomatic epilepsy. In
another embodiment, the epilepsy is idiopathic epilepsy. In a
further embodiment, the epilepsy is cryptogenic epilepsy. In
another embodiment, the epilepsy is therapy resistant epilepsy;
i.e. epilepsy that is unresponsive, partially responsive,
incompletely responsive or poorly responsive to known methods for
the treatment of epilepsy including but not limited to known
anti-epilepsy drugs and all variants of ketogenic (i.e. high fat,
low carbohydrate) diets.
[0170] In a further embodiment, the compounds of the application
are useful in the treatment of all types of seizures and for
suppressing seizure activity as manifested by physical symptoms
and/or electrical activity of the brain as measured by EEG or other
standard methods of measurement, in subjects, the seizures being of
multiple origins of known or unknown aetiology leading to a
diagnosis of epilepsy or another seizure disorder, for e.g.
traumatic injury (such as due to accident, surgery, war, or
deliberately induced and where trauma may be of recent or of
distant origin and leading to seizures and a diagnosis of epilepsy
or another seizure disorder), drug induced e.g. allergic reaction,
drug reaction or poisoning including overdose, spontaneous or
idiopathic where there is no known aetiology, due to developmental
problems or a known genetic pre-disposition or seizures that are a
consequence of a bacterial or viral illness e.g. meningitis.
[0171] Accordingly, the present application includes a method of
treating seizures comprising administering one or more compounds of
the application to a subject in need thereof. The present
application also includes a use of one or more compounds of the
application for treating seizures in a subject; a use of one or
more compounds of the application for preparation of a medicament
for treating seizures in a subject; and one or more compounds of
the application for use to treat seizures in a subject. In an
embodiment of the present application, the seizure is any seizure
of known or unknown etiology leading to a diagnosis of epilepsy or
another seizure disorder. In another embodiment, the seizure is
induced by traumatic injury (e.g. due to accident, surgery, war or
deliberately induced), drugs (e.g. an allergic reaction, a drug
reaction or poisoning including overdose), developmental problems
or a known genetic pre-disposition, a bacterial or viral infection
(e.g. meningitis) or is spontaneous or idiopathic.
[0172] In an embodiment, the same mechanism which leads to
anticonvulsant activity also produces beneficial cognitive effects.
Compounds combining an anticonvulsant bonded to a moiety that leads
to the metabolic production of ketones are therefore also useful to
improve cognitive function and/or moderate cognitive decline in
subjects such as humans and animals. In an embodiment, compounds of
the application are used in the treatment of cognitive dysfunction
in subjects, the cognitive dysfunction being of multiple origins of
known or unknown aetiology e.g. cognitive decline with aging or due
to traumatic injury, drug reaction, genetic pre-disposition,
illness of bacterial, viral or genetic origin or cognitive decline
as a consequence of disorders such as Parkinson's disease,
Alzheimer's disease and other dementias and neurological deficits
as defined in subjects such as humans and animals.
[0173] Accordingly, the present application includes a method of
treating cognitive dysfunction comprising administering one or more
compounds of the application to a subject in need thereof. The
present application also includes a use of one or more compounds of
the application for treating cognitive dysfunction in a subject; a
use of one or more compounds of the application for preparation of
a medicament for treating cognitive dysfunction in a subject; and
one or more compounds of the application for use to treat cognitive
dysfunction in a subject.
[0174] In an embodiment of the present application, the cognitive
dysfunction is any cognitive dysfunction of known or unknown
etiology. In another embodiment, the cognitive dysfunction is
cognitive decline with aging or due to traumatic injury, drug
reaction, genetic pre-disposition, illness of bacterial, viral or
genetic origin or as a consequence of disorders such as Parkinson's
disease, Alzheimer's disease and other dementias and neurological
deficits.
[0175] The present application also includes a method of improving
cognitive performance comprising administering one or more
compounds of the application to a subject. The present application
also includes a use of one or more compounds of the application for
improving cognitive performance in a subject; a use of one or more
compounds of the application for preparation of a medicament for
improving cognitive performance in a subject; and one or more
compounds of the application for use to improve cognitive
performance in a subject. In an embodiment, the subject does not
have cognitive dysfunction; i.e. the compound of the application is
administered to enhance cognitive performance in a subject without
cognitive dysfunction.
[0176] The present application also includes a method of treating
anxiety comprising administering one or more compounds of the
application to a subject in need thereof. The present application
also includes a use of one or more compounds of the application for
treating anxiety in a subject; a use of one or more compounds of
the application for preparation of a medicament for treating
anxiety in a subject; and one or more compounds of the application
for use to treat anxiety in a subject. In an embodiment, the
anxiety is related to cognitive decline. In another embodiment, the
anxiety is unrelated to cognitive decline.
[0177] The present application also includes a method of treating
chronic pain comprising administering one or more compounds of the
application to a subject in need thereof. The present application
also includes a use of one or more compounds of the application for
treating chronic pain in a subject; a use of one or more compounds
of the application for preparation of a medicament for treating
chronic pain in a subject; and one or more compounds of the
application for use to treat chronic pain in a subject.
[0178] In an embodiment, the subject is a mammal. In another
embodiment, the subject is a human, a companion animal, or
livestock. In a further embodiment, the subject is a human. It is
an embodiment that the subject is a companion animal. In another
embodiment, the companion animal is a dog, cat, rodent or rabbit.
In a further embodiment, the subject is livestock. It is an
embodiment that the livestock is cattle, sheep, pigs, goats or
equines.
[0179] The one or more compounds of the application are used alone
or, as noted above, in combination with other known agents useful
for treating a disease, disorder or condition of the present
application. For example, in an embodiment, the disease, disorder
or condition of the present application is cognitive dysfunction
and the one or more compounds of the application are used in
combination with one or more other known agents useful for treating
cognitive dysfunction. When used in combination with other known
agents useful in treating a disease, disorder or condition of the
present application, it is an embodiment that the one or more
compounds of the application are administered contemporaneously
with those agents. As used herein, "contemporaneous administration"
of two substances to a subject means providing each of the two
substances so that they are both biologically active in the
individual at the same time. The exact details of the
administration will depend on the pharmacokinetics of the two
substances in the presence of each other, and include, for example,
administering the two substances at the same time, within a few
hours of each other, or administering one substance within 24 hours
of administration of the other, if the pharmacokinetics are
suitable. Design of suitable dosing regimens is routine for one
skilled in the art. In particular embodiments, two substances will
be administered substantially simultaneously, i.e., within minutes
of each other, or in a single composition that contains both
substances. It is a further embodiment of the present application
that a combination of agents is administered to a subject in a
non-contemporaneous fashion.
[0180] The dosage of compounds of the application can vary
depending on many factors such as the pharmacodynamic properties of
the compound, the mode of administration, the age, health and
weight of the recipient, the nature and extent of the symptoms of
the disease, disorder or condition of the present application, the
frequency of the treatment and the type of concurrent treatment, if
any, and the clearance rate of the compound in the subject to be
treated. One of skill in the art can determine the appropriate
dosage based on the above factors. In an embodiment, the compounds
of the application are administered initially in a suitable dosage
that is optionally adjusted as required, depending on the clinical
response. As a representative example, oral dosages of one or more
compounds of the application will range between about 1 mg per day
to about 1000 mg per day for a human adult or an animal. In an
embodiment of the present application, the pharmaceutical
compositions are formulated for oral administration and the
compounds are, for example in the form of tablets containing 0.25,
0.5, 0.75, 1.0, 5.0, 10.0, 20.0, 25.0, 30.0, 40.0, 50.0, 60.0,
70.0, 75.0, 80.0, 90.0, 100.0, 150, 200, 250, 300, 350, 400, 450,
500, 550, 600, 650, 700, 750, 800, 850, 900, 950 or 1000 mg of
active ingredient per tablet. In an embodiment, the compounds of
the application are administered in a single daily dose or the
total daily dose may be divided into two, three or four daily
doses.
[0181] Assessing a compound of the application's activity for
treating, for example, epilepsy can be done using any one or more
of known assays. Examples of such assays include, but are not
limited to, maximal electroshock seizure (MES) test,
pentylenetetrazole (PTZ) test, amygdala kindling assay, mouse
corneal kindling assay, genetic absence epileptic (GAERS) rat assay
and/or 6-Hz psychomotor seizure model. These assays and other
strategies for identifying improved anti-epileptic drugs are
performed, for example, as described in Loscher, W. et al. Nature
Reviews, 12: 757-776 (2013) or as described in the examples for
MES, PTZ, 6-Hz psychomotor seizure and mouse corneal kindling
tests.
[0182] The following non-limiting examples are illustrative of the
present application:
EXAMPLES
Example 1
Synthesis and Characterization of Compounds
(a) Synthesis of 2-(1-(hexanamidomethyl)cyclohexyl)acetic acid
(compound 1)
##STR00040##
[0184] A suspension of 2-(1-(aminomethyl) cyclohexyl)acetic acid
(2.0 g, 11.7 mmol) and 4-dimethylaminopyridine (DMAP; 1.43 g, 11.7
mmol) in anhydrous THF (40 mL) was treated with hexanoyl chloride
(1.34 mL, 9.7 mmol) drop-wise over a period of 5 min. at room
temperature and stirred overnight (18 h). Solvent was removed under
reduced pressure, crude was taken in H.sub.2O (200 mL) and
acidified to pH .about.1 with 6 N HCl. The crude product was
extracted into EtOAc (2.times.150 mL). The combined organic layer
was washed with brine (50 mL), dried (Na.sub.2SO.sub.4) and
concentrated under reduced pressure to obtain the crude product.
The crude was purified by column chromatography (EtOAc: Hexanes,
1:1) on silica gel to obtain the title compound 1 (1.4 g, 54%) as a
white to off-white solid. .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.
6.32 (s, 1H), 3.25 (d, J=6.6 Hz, 2H), 2.26-2.24 (m, 4H), 1.64-1.62
(m, 2H), 1.50-1.41 (m, 7H), 1.32-1.25 (m, 7H), 0.88-0.85 (m, 3H).
ESI-MS (m/z, %): 268 (M-H, 100), 207 (50).
(b) Synthesis of 2-(1-(heptanamidomethyl)cyclohexyl)acetic acid
(compound 2)
##STR00041##
[0186] The title compound 2 was prepared from
2-(1-(aminomethyl)cyclohexyl)acetic acid (2.0 g, 11.7 mmol), DMAP
(1.43 g, 11.7 mmol) and heptanoyl chloride (1.51 mL, 9.7 mmol) as
described for compound 1. White to off-white solid (1.4 g, 51%).
.sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.45 (s, 1H), 3.25 (d,
J=6.6 Hz, 2H), 2.26-2.24 (m, 4H), 1.63-1.61 (m, 2H), 1.50-1.41 (m,
7H), 1.31-1.26 (m, 9H), 0.855 (t, J=6.6 Hz, 3H). ESI-MS (m/z, %):
282 (M-H, 100).
(c) Synthesis of 2-(1-(octanamidomethyl)cyclohexyl)acetic acid
(compound 3)
##STR00042##
[0188] The title compound 3 was prepared from
2-(1-(aminomethyl)cyclohexyl)acetic acid (4.27 g, 24.9 mmol), DMAP
(3.05 g, 24.9 mmol) and octanyl chloride (3.58 mL, 20.8 mmol) as
described for compound 1. Pale yellow oil (2.2 g, 30%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.25 (s, 1H), 3.26-3.24 (m, 2H),
2.26-2.23 (m, 4H), 1.63-1.60 (m, 2H), 1.53-1.41 (m, 7H), 1.34-1.24
(m, 11H), 0.87-0.85 (m, 3H). ESI-MS (m/z, %): 296 (M-H, 100).
(d) Synthesis of 2-(1-(nonanamidomethyl)cyclohexyl)acetic acid
(compound 4)
##STR00043##
[0190] The title compound 4 was prepared from
2-(1-(aminomethyl)cyclohexyl)acetic acid (2.0 g, 11.7 mmol), DMAP
(1.71 g, 14.0 mmol) and nonanoyl chloride (2.63 mL, 14.0 mmol) as
described for compound 1. White solid (2.1 g, 58%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.40 (s, 1H), 3.25 (d, J=7.2 Hz, 2H),
2.26-2.24 (m, 4H), 1.63-1.61 (m, 2H), 1.50-1.41 (m, 7H), 1.29-1.23
(m, 13H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS (m/z, %): 310 (M-H,
100).
(e) Synthesis of 2-(1-(decanamidomethyl)cyclohexyl)acetic acid
(compound 5)
##STR00044##
[0192] The title compound 5 was prepared from
2-(1-(aminomethyl)cyclohexyl)acetic acid (2.0 g, 11.7 mmol), DMAP
(1.71 g, 14.0 mmol) and decanoyl chloride (2.89 mL, 14.0 mmol) as
described for compound 1. White solid (1.7 g, 45%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.33 (s, 1H), 3.25 (d, J=6.6 Hz, 2H),
2.26-2.24 (m, 4H), 1.63-1.61 (m, 2H), 1.50-1.41 (m, 7H), 1.29-1.23
(m, 15H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS (m/z, %): 324 (M-H,
100).
(f) Synthesis of 2-(1-(undecanamidomethyl)cyclohexyl)acetic acid
(compound 6)
##STR00045##
[0194] The title compound 6 was prepared from 2-(1-(aminomethyl)
cyclohexyl)acetic acid (2.0 g, 11.7 mmol), DMAP (1.43 g, 11.7 mmol)
and undecanoyl chloride (2.14 mL, 9.7 mmol) as described for
compound 1. White to off-white solid (1.5 g, 45%). .sup.1H NMR (600
MHz, CDCl.sub.3) .delta. 6.31 (s, 1H), 3.25 (d, J=7.2 Hz, 2H),
2.26-2.24 (m, 4H), 1.63-1.61 (m, 2H), 1.53-1.41 (m, 7H), 1.29-1.23
(m, 17H) 0.85 (t, J=6.6 Hz, 3H). ESI-MS (m/z, %): 338 (M-H,
100).
(g) Synthesis of 2-(1-(dodecanamidomethyl)cyclohexyl)acetic acid
(compound 7)
##STR00046##
[0196] The title compound 7 was prepared from 2-(1-(aminomethyl)
cyclohexyl)acetic acid (2.0 g, 11.7 mmol), DMAP (1.43 g, 11.7 mmol)
and dodecanoyl chloride (2.31 mL, 9.7 mmol) as described for
compound 1. White to off-white solid (1.8 g, 53%). .sup.1H NMR (600
MHz, CDCl.sub.3) .delta. 6.43 (s, 1H), 3.25 (d, J=6.6 Hz, 2H),
2.26-2.24 (m, 4H), 1.63-1.59 (m, 2H), 1.50-1.39 (m, 7H), 1.30-1.23
(m, 19H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS (m/z, %): 352 (M-H,
100).
(h) Synthesis of 2-(1-((4-methyloctanamido)methyl)cyclohexyl)acetic
acid (compound 8)
##STR00047##
[0198] A solution of 4-methyl octanoic acid (1.5 g, 9.47 mmol) in
CH.sub.2Cl.sub.2 (15 mL) was treated with SOCl.sub.2 (2.07 mL, 28.4
mmol) drop-wise over a period of 5 min. at room temperature. The
reaction was then heated to reflux for 3 h. The reaction was cooled
to room temperature, then solvent and excess SOCl.sub.2 were
removed under reduced pressure to obtain the crude 4-methyl
octanoyl chloride as a pale yellow oil. The title compound 8 was
prepared from 2-(1-(aminomethyl)cyclohexyl)acetic acid (2.6 g, 15.1
mmol), DMAP (1.8 g, 15.1 mmol) and the above crude 4-methyl
octanoyl chloride as described for compound 1. Colourless oil (1.4
g, 35%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 6.23 (brs, 1H),
3.25 (d, J=6.6 Hz, 2H), 2.29-2.23 (m, 4H), 1.68-1.62 (m, 1H),
1.53-1.37 (m, 10H), 1.30-1.19 (m, 8H), 1.12-1.08 (m, 1H), 0.88-0.85
(m, 6H). ESI-MS (m/z, %): 310 (M-H, 100).
(i) Synthesis of
2-(1-((2-propylpentanamido)methyl)cyclohexyl)acetic acid (compound
9)
##STR00048##
[0200] The title compound 9 was prepared from 2-propylpentanoic
acid (5 g, 34.7 mmol; prepared as described for the 4-methyl
octanoyl chloride used in the preparation of compound 8),
2-(1-(aminomethyl)cyclohexyl)acetic acid (7.1 g, 41.6 mmol) and
DMAP (5.08 g, 41.6 mmol) as described for compound 1. White to
off-white solid (3 g, 29%). .sup.1H NMR (600 MHz, CDCl.sub.3) 6.35
(s, 1H), 3.26 (d, J=6 Hz, 2H), 2.26 (s, 2H), 2.18-2.12 (m, 1H),
1.62-1.23 (m, 18H), 0.91-0.89 (m, 6H). ESI-MS (m/z, %): 296 (M-H,
100).
(j) Synthesis of (S)-3-(hexanamidomethyl)-5-methylhexanoic acid
(compound 10)
##STR00049##
[0202] The title compound 10 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.0 g, 12.6 mmol), DMAP
(1.50 g, 12.6 mmol) and hexanoyl chloride (1.40 mL, 10.5 mmol) as
described for compound 1. Colourless oil (1.0 g, 40%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.08 (s, 1H), 3.36-3.31 (m, 1H),
3.20-3.15 (m, 1H), 2.33 (dd, J=4.2, 15 Hz, 1H), 2.24 (dd, J=7.8, 15
Hz, 1H), 2.19 (t, J=7.8 Hz, 2H), 2.09-2.04 (m, 1H), 1.70-1.59 (m,
3H), 1.30-1.23 (m, 4H), 1.18-1.16 (m, 2H), 0.89-0.85 (m, 9H).
ESI-MS (m/z, %): 256 (M-H, 100).
(k) Synthesis of (S)-3-(heptanamidomethyl)-5-methylhexanoic acid
(compound 11)
##STR00050##
[0204] The title compound 11 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.0 g, 12.6 mmol), DMAP
(1.50 g, 12.6 mmol) and heptanoyl chloride (1.60 mL, 10.5 mmol) as
described for compound 1. Colourless oil (0.9 g, 32%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.07 (s, 1H), 3.36-3.32 (m, 1H),
3.20-3.16 (m, 1H), 2.32 (dd, J=4.8, 15 Hz, 1H), 2.24 (dd, J=8.4, 15
Hz, 1H), 2.19 (t, J=7.8 Hz, 2H), 2.10-0.04 (m, 1H), 1.70-1.59 (m,
3H), 1.30-1.23 (m, 6H), 1.18-1.16 (m, 2H), 0.89-0.84 (m, 9H).
ESI-MS (m/z, %): 270 (M-H, 100).
(l) Synthesis of (S)-5-methyl-3-(octanamidomethyl)hexanoic acid
(compound 12)
##STR00051##
[0206] The title compound 12 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.65 g, 16.6 mmol), DMAP
(2.03 g, 16.6 mmol) and octanoyl chloride (2.39 mL, 13.9 mmol) as
described for compound 1. Pale yellow oil (0.9 g, 22%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 5.95 (brs, 1H), 3.39-3.35 (m, 1H),
3.23-3.19 (m, 1H), 2.35 (dd, J=4.2, 14.4 Hz, 1H), 2.28-2.20 (m,
3H), 2.11-2.05 (m, 1H), 1.70-1.62 (m, 3H), 1.31-1.16 (m, 10H),
0.92-0.87 (m, 9H). ESI-MS (m/z, %): 284 (M-H, 100).
(m) Synthesis of (S)-5-methyl-3-(nonanamidomethyl)hexanoic acid
(compound 13)
##STR00052##
[0208] The title compound 13 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.0 g, 12.6 mmol), DMAP
(1.84 g, 15.1 mmol) and nonanoyl chloride (2.83 mL, 15.1 mmol) as
described for compound 1. Off-white solid (1.6 g, 42%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 5.95 (s, 1H), 3.37-3.33 (m, 1H),
3.21-3.16 (m, 1H), 2.32 (dd, J=4.8, 15 Hz, 1H), 2.24 (dd, J=7.8, 15
Hz, 1H), 2.19 (t, J=7.8 Hz, 2H), 2.08-2.02 (m, 1H), 1.67-1.59 (m,
3H), 1.28-1.12 (m, 12H), 0.89-81 (m, 9H). ESI-MS (m/z, %): 298
(M-H, 100).
(n) Synthesis of (S)-3-(decanamidomethyl)-5-methylhexanoic acid
(compound 14)
##STR00053##
[0210] The title compound 14 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.0 g, 12.6 mmol), DMAP
(1.84 g, 15.1 mmol) and decanoyl chloride (13.10 mL, 15.1 mmol) as
described for compound 1. Off-white solid (2.0 g, 50%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 5.96 (s, 1H), 3.36-3.33 (m, 1H),
3.19-3.17 (m, 1H), 2.33 (dd, J=4.8, 15 Hz, 1H), 2.24 (dd, J=7.8, 15
Hz, 1H), 2.19 (t, J=7.2 Hz, 2H), 2.09-2.02 (m, 1H), 1.70-1.59 (m,
3H), 1.27-1.22 (m, 14H), 0.90-0.81 (m, 9H). ESI-MS (m/z, %): 312
(M-H, 100).
(o) Synthesis of (S)-5-methyl-3-(undecanamidomethyl)hexanoic acid
(compound 15)
##STR00054##
[0212] The title compound 15 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.0 g, 12.6 mmol), DMAP
(1.5 g, 12.6 mmol) and undecanoyl chloride (2.3 mL, 10.5 mmol) as
described for compound 1. Colourless oil (1.2 g, 35%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.02 (s, 1H), 3.36-3.32 (m, 1H),
3.20-3.15 (m, 1H), 2.32 (dd, J=4.2, 14.4 Hz, 1H), 2.24 (dd, J=7.8,
14.4 Hz, 1H), 2.19 (t, J=7.8 Hz, 2H), 2.10-2.04 (m, 1H), 1.70-1.59
(m, 3H), 1.30-1.22 (m, 14H), 1.18-1.16 (m, 2H), 0.89-0.84 (m, 9H).
ESI-MS (m/z, %): 326 (M-H, 100).
(p) Synthesis of (S)-3-(dodecanamidomethyl)-5-methylhexanoic acid
(compound 16)
##STR00055##
[0214] The title compound 16 was prepared from
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.0 g, 12.6 mmol), DMAP
(1.50 g, 12.6 mmol) and dodecanoyl chloride (2.50 mL, 10.5 mmol) as
described for compound 1. White solid (0.7 g, 19%). .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 6.02 (s, 1H), 3.35-3.32 (m, 1H),
3.20-3.17 (m, 1H), 2.32 (dd, J=10.2, 15 Hz, 1H), 2.24 (dd, J=7.8,
15 Hz, 1H), 2.18 (t, J=7.8 Hz, 2H), 2.10-2.04 (m, 1H), 1.70-1.58
(m, 3H), 1.27-1.23 (m, 16H), 1.18-1.16 (m, 2H), 0.89-0.84 (m, 9H).
ESI-MS (m/z, %): 340 (M-H, 100).
(q) Synthesis of
(S)-5-methyl-3-((2-propylpentanamido)methyl)hexanoic acid (compound
17)
##STR00056##
[0216] The title compound 17 was prepared from 2-propylpentanoic
acid (2 g, 13.8 mmol; prepared as described for the 4-methyl
octanoyl chloride used in the preparation of compound 8),
(S)-3-(aminomethyl)-5-methylhexanoic acid (2.6 g, 16.6 mmol) and
DMAP (2.0 g, 16.6 mmol) as described for compound 1. Pale yellow
oil (1.1 g, 28%). .sup.1H NMR (600 MHz, CDCl.sub.3) 6.07 (s, 1H),
3.38-3.34 (m, 1H), 3.21-1.18 (m, 1H), 2.33 (dd, J=7.2, 15 Hz, 1H),
2.25 (dd, J=8.4, 15 Hz, 1H), 2.08-2.05 (m, 2H), 1.70-1.62 (m, 1H),
1.60-1.53 (m, 2H), 1.40-1.36 (m, 2H), 1.31-1.23 (m, 4H), 1.18-1.15
(m, 2H), 1.89-0.85 (m, 12H). ESI-MS (m/z, %): 284 (M-H, 100).
(r) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)hexanamide (compound
18)
##STR00057##
[0218] A suspension of (S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g,
11.7 mmol) in THF (30 mL) was treated with NaH (1.41 g, 35.2 mmol,
60% in mineral oil) portion-wise at 0.degree. C. The reaction was
allowed to warm to room temperature and stirred for a further 30
min. The reaction was treated with hexanoyl chloride (1.94 mL, 14.1
mmol) in THF (10 mL) drop-wise over a period of 5 min. at 0.degree.
C. The reaction was allowed to warm to room temperature and stirred
overnight (16 h). The reaction was then quenched with H.sub.2O (200
mL) and the product was extracted into EtOAc (2.times.150 mL). The
combined organic layer was washed with brine (3.times.50 mL), dried
(Na.sub.2SO.sub.4) and evaporated under reduced pressure to obtain
the crude product. The crude was then purified by column
chromatography (EtOAc:Hexanes, 1:1) on silica gel to obtain the
title compound 18 (0.65 g, 21%) as a pale yellow oil. .sup.1H NMR
(600 MHz, CDCl.sub.3) .delta. 8.85 (s, 1H), 4.55 (dd, J=3, 9 Hz,
1H), 3.42-3.38 (m, 2H), 2.63 (t, J=7.2 Hz, 2H), 2.46-2.42 (m, 2H),
2.07-2.03 (m, 2H), 1.97-1.93 (m, 1H), 1.71-1.59 (m, 3H), 1.30-1.28
(m, 4H), 0.91-0.85 (m, 6H). ESI-MS (m/z, %): 269 (MH.sup.+,
100).
(s) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)heptanamide (compound
19)
##STR00058##
[0220] The title compound 19 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g, 11.7 mmol) in THF (30
mL), NaH (1.41 g, 35.2 mmol, 60% in mineral oil) and heptanoyl
chloride (2.18 mL, 14.1 mmol) as described for compound 18. Pale
yellow oil (1.7 g, 51%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta.
8.75 (s, 1H), 4.53 (dd, J=2.4, 6.6 Hz, 1H), 3.41-3.38 (m, 2H), 2.64
(t, J=7.2 Hz, 2H), 2.46-2.42 (m, 2H), 2.06-2.02 (m, 2H), 1.99-1.92
(m, 1H), 1.73-1.58 (m, 3H), 1.33-1.23 (m, 6H), 0.92-0.85 (m, 6H).
ESI-MS (m/z, %): 283 (MH.sup.+, 100).
(t) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)octanamide (compound
20)
##STR00059##
[0222] The title compound 20 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g, 11.7 mmol), NaH (1.41
g, 35.2 mmol, 60% in mineral oil) and octanoyl chloride (2.43 mL,
14.1 mmol) as described for compound 18. Pale yellow oil (0.375 g,
37%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.76 (s, 1H),
4.54-4.51 (m, 1H), 3.41-3.38 (m, 2H), 2.64 (t, J=7.2 Hz, 2H),
2.46-2.42 (m, 2H), 2.07-1.95 (m, 3H), 1.71-1.56 (m, 3H), 1.30-1.22
(m, 8H), 0.90 (t, J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS
(m/z, %): 297 (MH.sup.+, 100)
(u) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)nonanamide (compound
211
##STR00060##
[0224] The title compound 21 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g, 11.7 mmol), NaH (1.41
g, 35.2 mmol, 60% in mineral oil) and nonanoyl chloride (2.65 mL,
14.1 mmol) as described for compound 18. Pale yellow oil (2.163 g,
60%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.77 (s, 1H),
4.55-4.52 (m, 1H), 3.41-3.38 (m, 2H), 2.64 (t, J=7.2 Hz, 2H),
2.46-2.42 (m, 2H), 2.07-1.95 (m, 3H), 1.71-1.58 (m, 3H), 1.30-1.22
(m, 10H), 0.90 (t, J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS
(m/z, %): 311 (MH.sup.+, 100).
(v) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)decanamide (compound
22)
##STR00061##
[0226] The title compound 22 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g, 11.7 mmol), NaH (1.41
g, 35.2 mmol, 60% in mineral oil) and nonanoyl chloride (2.9 mL,
14.1 mmol) as described for compound 18. Pale yellow oil (1.98 g,
52%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.73 (s, 1H),
4.54-4.51 (m, 1H), 3.40-3.38 (m, 2H), 2.64 (t, J=7.2 Hz, 2H),
2.46-2.43 (m, 2H), 2.07-1.95 (m, 3H), 1.72-1.58 (m, 3H), 1.30-1.23
(m, 12H), 0.91 (t, J=7.2 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS
(m/z, %): 325 (MH.sup.+, 100).
(w) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)undecanamide (compound
23)
##STR00062##
[0228] The title compound 23 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g, 11.7 mmol), NaH (1.41
g, 35.2 mmol, 60% in mineral oil) and undecanoyl chloride (3.35 mL,
14.1 mmol) as described for compound 18. White to off-white solid
(1.6 g, 39%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.72 (s,
1H), 4.52 (dd, J=3, 9 Hz, 1H), 3.39 (dt, J=1.2, 7.8 Hz, 2H), 2.64
(t, J=7.8 Hz, 2H), 2.46-2.43 (m, 2H), 2.09-2.02 (m, 2H), 1.99-1.93
(m, 1H), 1.72-1.68 (m, 1H), 1.62-1.58 (m, 2H), 1.30-1.22 (m, 14H),
0.92-0.89 (m, 3H), 0.88-0.85 (m, 3H). ESI-MS (m/z, %): 338
(MH.sup.+, 100).
(x) Synthesis of
(S)--N-(2-(2-oxopyrrolidin-1-yl)butanoyl)dodecanamide (compound
24)
##STR00063##
[0230] The title compound 24 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (2 g, 11.7 mmol), NaH (1.41
g, 35.2 mmol, 60% mineral oil) and dodecanoyl chloride (3.10 mL,
14.1 mmol) as described for compound 18. White to off-white solid
(1.6 g, 40%). .sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.75 (s,
1H), 4.53 (dd, J=2.4, 9 Hz, 1H), 3.39 (m, 2H), 2.64 (t, J=7.2 Hz,
2H), 2.46-2.43 (m, 2H), 2.07-2.04 (m, 2H), 1.98-1.95 (m, 1H),
1.72-1.68 (m, 1H), 1.61-1.58 (m, 2H), 1.30-1.23 (m, 16H), 0.91 (t,
J=7.8 Hz, 3H), 0.85 (t, J=7.2 Hz, 3H). ESI-MS (m/z, %): 353
(MH.sup.+, 100).
(y) Synthesis of
4-ethyl-N--((S)-2-(2-oxopyrrolidin-1-yl)butanoyl)octanamide
(compound 25)
##STR00064##
[0232] The title compound 25 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (3.56 g, 20.89 mmol), NaH
(1.95 g, 51.08 mmol, 60% in mineral oil) and 4-ethyloctanoyl
chloride (prepared from 4-ethyloctanoic acid (4.4 mL, 23.21 mmol)
and thionyl chloride (5.0 mL, 69.65 mmol) as described for compound
8) as described for compound 18. Pale yellow oil (4.9 g, 72%).
.sup.1H NMR (600 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H), 4.51 (dd,
J=2.4, 6.6 Hz, 1H), 3.38 (t, J=7.2 Hz, 2H), 2.64-2.61 (m, 2H),
2.46-2.43 (m, 2H), 2.07-2.05 (m, 2H), 2.02-1.95 (m, 1H), 1.75-1.65
(m, 1H), 1.57-1.55 (m, 2H), 1.28-1.20 (m, 9H), 0.90 (t, J=7.2 Hz,
3H), 0.86 (t, J=4.2 Hz, 3H), 0.82 (t, J=7.2 Hz, 3H); ESI-MS (m/z,
%): 325 (MH.sup.+, 100).
(z) Synthesis of
(S)-4-butyl-N-(2-(2-oxopyrrolidin-1-yl)butanoyl)cyclohexane-1-carboxamide
(compound 26)
##STR00065##
[0234] The title compound 26 was prepared from
(S)-2-(2-oxopyrrolidin-1-yl)butanamide (3.13 g, 18.38 mmol), NaH
(1.85 g, 48.46 mmol, 60% in mineral oil) and
4-butylcyclohexane-1-carbonyl chloride (prepared from
4-butylcyclohexane-1-carboxylic acid (3.5 g, 18.99 mmol) and
thionyl chloride (4.1 mL, 56.69 mmol) as described for compound 8)
as described for compound 18. White solid (3.95 g, 64%). .sup.1H
NMR (600 MHz, CDCl.sub.3) .delta. 8.81 (s, 1H), 4.55 (dd, J=6.0,
9.0 Hz, 1H), 3.44-3.38 (m, 2H), 2.65-2.55 (m, 1H), 2.45-2.41 (m,
2H), 2.05-1.77 (m, 8H), 1.42-1.38 (m, 2H), 1.26-1.10 (m, 7H),
0.92-0.75 (m, 8H); ESI-MS (m/z, %): 337 (MH.sup.+, 100).
Example 2
Efficacy in 6-Hz Psychomotor Seizure Model Predictive of
Therapy-Resistant Epilepsy
[0235] I. Materials and Methods
[0236] Male, experimentally naive CD-1 mice were used in these
experiments. At a defined time following drug or vehicle
pretreatment, all mice received an electrical stimulus (6 Hz, 0.2
ms pulse width, 3 s duration, 32 mA) via corneal electrodes
moistened with saline (ECT unit 57800; Ugo Basile). Preliminary
experiments established that these stimulus parameters elicited a
psychomotor seizure, defined as the expression of at least one of
the following behaviors: stun/immobility, forelimb clonus, straub
tail, lateral head movement, in >95% of control animals.
Protection was defined as complete absence of all the above
behaviors within 20 s of stimulus delivery. The effective dose of
compound necessary to protect against psychomotor seizures to 50%
of controls (i.e ED.sub.50) was determined by curve fitting
program.
[0237] II. Results and Discussion
[0238] As can be seen in FIG. 1, pretreatment of compound 4
(150-600 mg/kg IP; 1 h pretreatment) produced a dose-related
decrease in the incidence of seizures, such that all mice treated
with compound 4 at 600 mg/kg IP were protected. In comparison, in
mice treated with Vehicle (Veh), all mice had a seizure following
6-Hz stimulus. No mice were protected following oral pretreatment
with compound 4 at 600 mg/kg.
[0239] As can be seen in FIG. 2, pretreatment of compound 14
(75-600 mg/kg IP and oral routes; 1 h pretreatment) produced a
dose-related decrease in the incidence of seizures, such that all
mice treated with compound 14 at 300-600 mg/kg IP were protected.
In comparison, in mice treated with Vehicle (Veh), all mice had a
seizure following 6-Hz stimulus.
[0240] As can be seen in FIG. 3, pretreatment of compound 21(75-600
mg/kg IP and oral routes; 1 h pretreatment) produced a dose-related
decrease in the incidence of seizures, such that all mice treated
with compound 21 at 300-600 mg/kg IP were protected. In comparison,
in mice treated with Vehicle (Veh), all mice had a seizure
following 6-Hz stimulus.
[0241] As can be seen in FIG. 4, pretreatment of compound 22
(75-600 mg/kg IP and oral routes; 1 h pretreatment) produced a
dose-related decrease in the incidence of seizures, such that all
mice treated with compound 22 at 600 mg/kg IP were protected. In
comparison, in mice treated with Vehicle (Veh), all mice had a
seizure following 6-Hz stimulus.
[0242] As can be seen in FIG. 5, pretreatment of compound 25
(37.5-600 mg/kg IP and oral routes; 1 h pretreatment) produced a
dose-related decrease in the incidence of seizures, such that all
mice treated with compound 25 at 300 and 600 mg/kg IP were
protected. In comparison, in mice treated with Vehicle (Veh), all
mice had a seizure following 6-Hz stimulus.
[0243] As can be seen in FIG. 6, pretreatment of compound 26
(37.5-600 mg/kg IP and oral routes; 1 h pretreatment) produced a
dose-related decrease in the incidence of seizures, such that all
mice treated with compound 26 at 300 and 600 mg/kg IP were
protected. In comparison, in mice treated with Vehicle (Veh), all
mice had a seizure following 6-Hz stimulus.
Example 3
Effect of Compounds 20, 25 and 26 in Mouse Seizure Tests
[0244] I. Methods
[0245] Male mice (body wt. 20-40 g) were used for all studies. Mice
were used in one of the following 4 seizure tests: maximal
electroshock seizure (MES) test, subcutaneous injection of
pentylenetetrazol (scPTZ) test, seizures induced by 6 Hz
stimulation (6 Hz), and corneal kindled seizures. These tests were
selected because no single test detects all known anti-epileptic
drugs (AED's), but all currently known AED's are detected as active
(i.e. prevent seizures) in at least one of these tests. Subjects
were tested in one of the 4 seizure tests following a defined time
after treatment with either test drug or vehicle control. Following
administration of test drug or vehicle by either the oral,
subcutaneous or intraperitoneal route, the animals were tested
according to one of the methods outlined below (1-4). Typically the
pretreatment time was 60 minutes although in some cases this varied
from 30 min to 4 h. With the exception of the corneal kindling
model, once the animal had entered into a seizure, or passed a
predetermined timepoint to demonstrate protection from a seizure,
the endpoint was reached and the animal was immediately
euthanised.
1. Maximal Electroshock Test (MES Test):
[0246] Male CD-1 mice received a maximal electroshock (45 mA, 0.2 s
duration, 60 Hz) via corneal electrodes moistened with saline
(shock stimulator type 221; Harvard apparatus). This stimulus
intensity should elicit a full tonic seizure in >95% of control
animals. Protection is defined as absence of a full tonic seizure
within 15 s of stimulus delivery. To establish drug efficacy, test
drug or vehicle was administered at a defined timepoint prior to
the MES test, to separate experimental groups. The experiment was
terminated immediately once the endpoint was met.
2. s.c. Pentylenetetrazol Seizure Test (PTZ Test):
[0247] Male CD-1 mice received a single subcutaneous injection of
pentylenetetrazol (PTZ: 85 mg/kg). This dose of PTZ should elicit a
clonic seizure in >95% of control animals. Following PTZ
injection, the animals were immediately transferred to single
observation cages and observed continuously for 30 min. To
establish drug efficacy, test drug or vehicle was administered at a
defined timepoint prior to the PTZ administration, to separate
experimental groups. The effect of treatment on subsequent seizure
was noted. Protection is defined as complete absence of a clonic
seizure, including a forelimb clonus, over the 30 min observation
period. In the event of a seizure, the onset latency from PTZ
injection was recorded. The experiment was terminated immediately
once the endpoint was met, or in the case of protection, at the
completion of the 30 min test period.
3. 6 Hz Psychomotor Seizure Test:
[0248] Male CD-1 mice received an electrical stimulus (6 Hz, 0.2 ms
pulse width, 3 s duration, 32 mA) via corneal electrodes moistened
with saline (ECT unit 57800; Ugo Basile). These stimulus parameters
should elicit a psychomotor seizure, defined as the expression of
at least one of the following behaviours: stun/immobility, forelimb
clonus, straub tail, vibrissae tremor, lateral head movement, in
>95% of control animals within 30 s of stimulus delivery. To
establish drug efficacy, test drug or vehicle was administered at a
defined timepoint prior to the 6 Hz test, to separate experimental
groups. The effect of treatment on subsequent seizure was noted.
Protection is defined as complete absence of all the above
behaviours within 20 s of stimulus delivery. The experiment was
terminated immediately once the endpoint was met.
4. Mouse Corneal Kindling:
[0249] Male CD-1 mice (body wt. 20-40 g) were used for these
studies. There are 3 phases to the procedure: (1) kindling
development phase, (2) kindling stability/persistence phase, and
(3) drug testing phase.
1. Kindling Development Phase:
[0250] Male mice received a mild electroshock (mice: 3 mA, 3 s
duration, 60 Hz) via corneal electrodes moistened with saline
(shock stimulator type 221; Harvard apparatus). This stimulus
intensity should not initially elicit seizures, rather a mild
behavioural response, e.g. brief (<5 s) immobility, stare. Mice
received 2 such stimulations per day separated by a minimum period
of 4 h (i.e. an a.m. stimulation and a p.m. stimulation), and daily
for up to 25 days. Over a period of approximately 15 days, the
animals developed transient behavioural changes typified by brief
motor seizures for approximately 30 s following stimulation. These
progressive behavioural changes were rated according to a scale
developed by Racine (1972), i.e.
[0251] 0=no reaction or immobility
[0252] 1=jaw clonus
[0253] 2=myoclonic twitches in the forelimbs, sometimes associated
with head nodding
[0254] 3=clonic convulsions limited to the forelimbs
[0255] 4=clonic convulsions in the forelimbs with rearing and
falling
[0256] 5=generalised clonic convulsions associated with immediate
loss of balance
[0257] During repeated corneal stimulation, mice exhibiting a stage
3, 4 or 5 were defined as responders. Based on published validation
studies (Matagne et al, 1998; Rowley et al, 2010) these should
emerge after 10-15 days. Once the animals demonstrate at least 4
consecutive stage 3-5 seizures they were considered to be kindled
and progressed to phase 2. Animals which did not reach stage 3-5
seizures by 25 consecutive days were considered non-responders and
were removed from the study and euthanized.
2. Kindling Stability/Persistence Phase:
[0258] Before drug testing, an assessment of the persistence and
stability of the kindled state was performed. This was achieved by
giving test subjects a minimum of 2 days (maximum 10 days) without
stimulation before resuming the twice daily stimulation protocol as
described. Mice which demonstrated 4 consecutive stage 3-5 seizures
at this point were considered to have a persistent and stable
kindled state and ready for drug testing in phase 3. Mice that did
not demonstrate 4 consecutive stage 3-5 seizures by 10 sessions of
this second phase were removed from the study and euthanized.
3. Drug Testing Phase:
[0259] Drug testing was conducted using a repeated measures design
with mice receiving up to 4 doses of a test drug and control
treatments in a counterbalanced sequence. Drug test days were run
with a 2-3 day interval with no stimulations administered on the
intervening days. On a drug test day, the a.m. stimulation was
preceded by a vehicle injection, and the p.m. stimulation was
preceded by a drug injection. For each stimulation, the kindling
score was assessed according to the Racine (1972) rating scale.
Test compound or vehicle was administered by either the oral,
subcutaneous or intraperitoneal route. Typically the pretreatment
time was 1 h.
[0260] II. Results and Discussion
[0261] FIGS. 7-10 show the results of testing compound 20 in the
above-described seizure tests. As can be seen in FIGS. 7-10,
pretreatment of mice with compound 20 reduced seizures in
comparison to a vehicle control.
[0262] FIGS. 11-13 show the results of testing compound 25 in the
above-described seizure tests. As can be seen in FIGS. 11-13,
pretreatment of mice with compound 25 reduced seizures in
comparison to a vehicle control.
[0263] FIGS. 14-16 show the results of testing compound 26 in the
above-described seizure tests. As can be seen in FIGS. 14-16,
pretreatment of mice with compound 26 reduced seizures in
comparison to a vehicle control.
[0264] Table 1 shows the ED50 values for compounds 20, 25 and 26 in
the above tests.
[0265] All publications, patents and patent applications are herein
incorporated by reference in their entirety to the same extent as
if each individual publication, patent or patent application was
specifically and individually indicated to be incorporated by
reference in its entirety. Where a term in the present application
is found to be defined differently in a document incorporated
herein by reference, the definition provided herein is to serve as
the definition for the term.
TABLE-US-00001 TABLE 1 Compound Mouse 20 25 26 seizure models Dose
route IP PO IP PO IP PO 6 Hz EC50 (mg/kg) 90 130 46 50 80 88 EC50
(mmol/kg) 0.3 0.44 0.14 0.15 0.24 0.26 MES EC50 (mg/kg) >600
>600 397 >600 >600 >600 EC50 (mmol/kg) >2.02
>2.02 1.22 >1.85 >1.78 >1.78 ScPTZ EC50 (mg/kg) >600
>600 310 600 230 300 EC50 (mmol/kg) >2.02 >2.02 0.95 1.85
0.68 0.89
* * * * *