U.S. patent application number 13/880139 was filed with the patent office on 2013-08-22 for use of malononitrilamides in neuropathic pain.
This patent application is currently assigned to AL-GIAX PHARMACEUTICALS GMBH. The applicant listed for this patent is Birgit Hasse, Guido Koopmans. Invention is credited to Birgit Hasse, Guido Koopmans.
Application Number | 20130217737 13/880139 |
Document ID | / |
Family ID | 44992853 |
Filed Date | 2013-08-22 |
United States Patent
Application |
20130217737 |
Kind Code |
A1 |
Hasse; Birgit ; et
al. |
August 22, 2013 |
Use of Malononitrilamides in Neuropathic Pain
Abstract
Provided herein are compounds and pharmaceutical compositions
for use in the treatment of neuropathic pain and the neuropathic
pain syndromes.
Inventors: |
Hasse; Birgit; (Wuppertal,
DE) ; Koopmans; Guido; (JA Sittard, NL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Hasse; Birgit
Koopmans; Guido |
Wuppertal
JA Sittard |
|
DE
NL |
|
|
Assignee: |
AL-GIAX PHARMACEUTICALS
GMBH
Erkrath
DE
|
Family ID: |
44992853 |
Appl. No.: |
13/880139 |
Filed: |
October 28, 2011 |
PCT Filed: |
October 28, 2011 |
PCT NO: |
PCT/EP11/05452 |
371 Date: |
April 18, 2013 |
Current U.S.
Class: |
514/378 ;
514/624; 514/626 |
Current CPC
Class: |
A61K 31/275 20130101;
A61P 29/00 20180101; A61P 25/04 20180101; A61K 31/167 20130101;
A61K 31/164 20130101; A61P 25/06 20180101; A61K 31/42 20130101 |
Class at
Publication: |
514/378 ;
514/626; 514/624 |
International
Class: |
A61K 31/164 20060101
A61K031/164; A61K 31/42 20060101 A61K031/42 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 29, 2010 |
EP |
10014122.5 |
Claims
1.-13. (canceled)
14. A method for treating neuropathic pain and/or neuropathic pain
syndromes in a patient, which comprises administering a
pharmaceutical composition comprising a therapeutically effective
amount of a malononitrilamide.
15. The method according to claim 14, wherein the patient is a
human.
16. The method according to claim 14, wherein the neuropathic pain
syndrome is postherpetic neuralgia (caused by Herpes Zoster), root
avulsions, painful traumatic mononeuropathy, painful polyneuropathy
(particularly due to diabetes), central pain syndromes (potentially
caused by virtually any lesion at any level of the nervous system),
postsurgical pain syndromes (eg, postmastectomy syndrome,
postthoracotomy syndrome, phantom pain), complex regional pain
syndrome (reflex sympathetic dystrophy and causalgia), and/or
migraine or migraine pain.
17. The method according to claim 14, wherein the neuropathic pain
is a central pain syndrome caused by spinal cord injury and/or
spinal cord contusion.
18. The method according to claim 14, wherein the type of
neuropathic pain is selected from those that have a cause that is
selected from the group of the following causes: systemic diseases,
diabetic neuropathy; drug-induced lesions, neuropathy due to
chemotherapy; traumatic syndrome and entrapment syndrome; lesions
in nerve roots and posterior ganglia; neuropathies after HIV
infections; neuralgia after Herpes infections; nerve root
avulsions; cranial nerve lesions; cranial neuralgias, tri-geminal
neuralgia; neuropathic cancer pain; phantom pain; compression of
peripheral nerves, neuroplexus and nerve roots; paraneoplastic
peripheral neuropathy and ganglionopathy; complications of cancer
therapies, chemotherapy, irradiation, and surgical interventions;
complex regional pain syndrome; type I lesions (previously known as
sympathetic reflex dystrophy); and type II lesions (corresponding
approximately to causalgia); migraine and migraine pain; cerebral
lesions that are predominantly thalamic; infarction, thalamic
infarction or brain stem infarction; cerebral tumors or abscesses
compressing the thalamus or brain stem; multiple sclerosis; brain
operations, thalamotomy in cases of motoric disorders; spinal cord
lesions; spinal cord injuries; spinal cord operations,
anterolateral cordotomy; ischemic lesions; anterior spinal artery
syndrome; Wallenberg's syndrome; and syringomyelia.
19. The method according to 14, wherein the neuropathic pain is a
chronic neuropathic pain.
20. The method according to 14, wherein said composition is
administered at daily dosages between 1 mg-10 g/body, preferable 5
mg-5 g/body and more preferable 10 mg-2 g/body beginning after a
damage of the nervous system.
21. A medical kit suitable for the treatment of a neuropathic pain
and/or a neuropathic pain syndrome, comprising: (a) printed
instructions for administering the compound to the patient having a
damage of the nervous system (b) a malononitrilamide compound, or
(c) a pharmaceutical composition according to claim 12 to 13.
22. The method of claim 14, wherein the malononitrilamide has the
formula ##STR00004## or pharmaceutically acceptable salt, solvate,
tautomer or stereoisomer thereof.
23. The method of claim 14, wherein the compound has the formula
##STR00005## or pharmaceutically acceptable salt, solvate, tautomer
or stereoisomer thereof.
24. The method of claim 23, wherein the tautomer of the compound is
the keto or enol form, in particular the keto form
2-cyano-3-oxo-N-[4-(trifluoromethyl) phenyl]-6-heptynamide.
25. The method of claim 14, wherein the stereoisomer of the
compound is the R or S enantiomer.
26. The method of claim 14, wherein the compound is used in the
treatment of peripheral and/or predominantly peripheral neuropathic
pain or central and/or predominantly central neuropathic pain.
27. The method of claim 26, wherein the predominantly peripheral
neuropathic pain is of a type that is selected from the following
types of neuropathic pain and/or has a cause that is selected from
the group of the following causes: systemic diseases, diabetic
neuropathy, drug-induced lesions, neuropathy due to chemotherapy;
traumatic syndrome and entrapment syndrome; lesions in nerve roots
and posterior ganglia; neuropathies after HIV infections; neuralgia
after Herpes infections; nerve root avulsions; cranial nerve
lesions; cranial neuralgias, trigeminal neuralgia; neuropathic
cancer pain; phantom pain; compression of peripheral nerves,
neuroplexus and nerve roots; paraneoplastic peripheral neuropathy
and ganglionopathy, complications of cancer therapies,
chemotherapy, irradiation, and surgical interventions; complex
regional pain syndrome; type I lesions (previously known as
sympathetic reflex dystrophy); and type II lesions (corresponding
approximately to causalgia).
28. The method of claim 26, wherein the predominantly central
neuropathic pain is of a type that has a cause that is selected
from the following group of causes: cerebral lesions that are
predominantly thalamic; infarction, thalamic infarction or brain
stem infarction; cerebral tumors or abscesses compressing the
thalamus or brain stem; multiple sclerosis; head pain syndrome
caused by central pain mechanisms including migraine or migraine
pain; brain operations, thalamotomy in cases of motoric disorders;
spinal cord lesions; spinal cord injuries; spinal cord operations,
anterolateral cordotomy; ischemic lesions; anterior spinal artery
syndrome; Wallenberg's syndrome; and syringomyelia.
29. The method of claim 14, wherein the neuropathic pain syndrome
is postherpetic neuralgia; root avulsions; painful traumatic
mononeuropathy; painful polyneuropathy; central pain syndromes;
postsurgical pain syndromes; postmastectomy syndrome;
postthoracotomy syndrome; phantom pain; complex regional pain
syndrome reflex sympathetic dystrophy and causalgia; and migraine
or migraine pain.
30. The method of claim 14, wherein the neuropathic pain is a
central pain syndrome caused by spinal cord injury or spinal cord
contusion.
31. The method of claim 14, wherein the neuropathic pain is a
chronic neuropathic pain.
32. The method of claim 14, wherein the compound is administered at
daily dosages between 1 mg-10 g/body, 5 mg-5 g/body or 10 mg-2
g/body beginning after a damage of the nervous system.
Description
FIELD OF THE DISCLOSURE
[0001] The technology provided herein relates to the novel use of
malononitrilamides and its derivatives in the treatment of
neuropathic pain and neuropathic pain syndromes.
BACKGROUND
[0002] The treatment of pain conditions is of great importance in
medicine. There is currently a world-wide need for additional pain
therapy. The pressing requirement for a specific treatment of pain
conditions is documented in the large number of scientific works
that have appeared recently in the field of applied analgesics.
[0003] Pain is defined by the International Association for the
Study of Pain (IASP) as "an unpleasant sensory and emotional
experience associated with actual or potential tissue damage, or
described in terms of such damage". Although pain is always
subjective, its causes or syndromes can be classified. One of the
most relevant pains is neuropathic pain which severely impairs the
overall quality of life, and which is one of the most devastating
forms of chronic pain.
[0004] Neuropathic pain is caused by, for example, injury or
dysfunction in a peripheral or central nervous system. Disorders
with neuropathic pain include, for example, disorders that exhibit
hyperalgesic or allodynic symptoms, such as postherpetic neuralgia,
trigeminal neuralgia, diabetic neuralgia, and persistent
postoperative or posttraumatic pain.
[0005] Neuropathic pain may result from disorders of the peripheral
nervous system or the central nervous system (brain and spinal
cord). Thus, neuropathic pain may be divided into peripheral
neuropathic pain, central neuropathic pain, or mixed (peripheral
and central) neuropathic pain.
[0006] Peripheral nerve injury or dysfunction can result in
peripheral neuropathic pain. Examples are mononeuropathies (eg,
carpal tunnel syndrome, radiculopathy), plexopathies (typically
caused by nerve compression, as by a neuroma, tumor, or herniated
disk), and polyneuropathies (typically caused by various metabolic
neuropathies. Under normal circumstances, pain sensations are
carried by unmyelinated and thinly myelinated nerve fibers,
designated C-fibers and A-delta fibers respectively. After a
peripheral nervelesion, a neuroma may develop at the stump. The
neurons become unusually sensitive and develop spontaneous
pathological activity, abnormal excitability, and elevated
sensitivity to chemical, thermal and mechanical stimuli. This
phenomenon is called peripheral sensitization.
[0007] Central neuropathic pain is found in spinal cord injury,
multiple sclerosis, and in some cases of stroke. In the spinal cord
the spinothalamic tract (STT) constitutes the major ascending
nociceptive pathway. As a consequence of ongoing spontaneous
activity arising in the periphery, STT neurons in the dorsal horn
develop an increased background activity, enlarged receptive field
and increased responses to afferent impulses, including normally
innocuous tactile stimuli. This phenomenon is called central
sensitization. Central sensitization has been proposed as an
important mechanism of persistent neuropathic pain. Non-neural
glial cells and the immune response play a prominent role in
central sensitization.
[0008] Typical symptoms of neuropathic pain are dysesthesias
(spontaneous or evoked burning pain, often with a superimposed
lancinating component), but pain may also be deep and aching. Other
sensations like; hyperesthesia, hyperalgesia, allodynia (pain due
to a normoxious stimulus), and hyperpathia (particularly
unpleasant, exaggerated pain response) may also occur. Symptoms are
long-lasting, typically persisting after resolution of the primary
cause (if one was present) because the CNS has been sensitized and
remodeled.
[0009] Peripheral nerve injury provokes a reaction in peripheral
immune cells and glia at several different anatomical locations:
macrophages and Schwann cells facilitate the wallerian degeneration
of axotomized nerve fibers distal to a nerve lesion; an immune
response in the dorsal root ganglia (DRGs) is driven by
macrophages, lymphocytes and satellite cells; activation of spinal
microglia dominates the early glial response in the CNS to
peripheral nerve injury, which is followed by activation and
proliferation of astrocytes. More recently, a specific role of the
immune response and CNS-infiltrating T lymphocytes in nerve injury
induced neuropathic pain development and maintenance has been
identified (Cao and DeLeo, 2008; Costigan et al., 2009; Zenonos and
Kim).
[0010] Migraine is a common head pain syndrome, often genetically
determined, characterized by generally episodic but often chronic,
usually throbbing pain, often unilateral in distribution and often
associated with photophobia, phonophobia, osmophobia, nausea and/or
vomiting. The common occurrence of throbbing head pain was wrongly
interpreted earlier for the pain to arise from blood vessels; but
current research points to a neural origin of the migraine pain.
Several observations made over the past two decades raised the
issue that there is likely to be a central pain mechanism in
migraine (Afridi and Goadsby, 2003; Goadsby, 2002).
[0011] Current therapy for neuropathic pain aims only at reducing
symptoms, generally by suppressing neuronal activity. Thus
treatment options, e.g. NSAIDS, antidepressants, anticonvulsants,
baclofen, neuromodulation modalities or opiates, predominantly
alleviate symptoms via nonspecific reduction of neuronal
hyperexcitability rather than targeting the specific
etiologies.
[0012] Therefore, effective and improved methods and compounds that
are able to treat neuropathic pain are needed.
SUMMARY OF THE DISCLOSURE
[0013] In a first aspect, embodiments of this disclosure provide
compounds for the use in the treatment of neuropathic pain and/or
neuropathic pain syndromes.
[0014] In still another aspect, embodiments of this disclosure
provide pharmaceutical compositions, single unit dosage forms, and
kits suitable for use in the treatment of neuropathic pain which
comprise compounds according to the present disclosure.
[0015] In a further aspect, embodiments of this disclosure relate
to methods of treating and preventing neuropathic pain which
comprise administering to a patient in need of such treatment or
prevention a therapeutically or prophylactically effective amount
of a compound according to this disclosure.
[0016] Further, embodiments of this disclosure relates to
malononitrilamides, or its derivatives, pharmaceutically acceptable
salts, solvates, hydrates, stereoisomers, tautomers clathrates, or
prodrugs thereof for use in the treatment of neuropathic pain.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] FIG. 1 shows the 50% paw withdrawal threshold (g) after
contusion and oral gavage of HR325 and vehicle.
[0018] FIG. 2 shows the 50% paw withdrawal threshold (g) after
contusion and oral gavage of HR325, FK778 and vehicle.
[0019] FIG. 3 shows the duration (s) of reactivity to acetone
applied to the plantar surface of the hindpaw.
[0020] FIG. 4 shows the 50% paw withdrawal threshold (g) after
contusion and oral gavage of HR325 and vehicle
[0021] FIG. 5 shows the duration (s) of reactivity to acetone
applied to the plantar surface of the hindpaw.
[0022] FIG. 6 shows the 50% paw withdrawal threshold (g) after
constriction of the sciatic nerve and oral gavage of HR325
[0023] FIG. 7 shows the duration (s) of reactivity to acetone
applied to the plantar surface of the hind paws after constriction
of the sciatic nerve and oral gavage of HR325
[0024] FIG. 8 shows the 50% paw withdrawal threshold (g) after
partial ligation of the sciatic nerve and oral gavage of HR325
[0025] FIG. 9 shows the duration (s) of reactivity to acetone
applied to the plantar surface of the hind paws after partial
ligation of the sciatic nerve and oral gavage of HR325
DETAILED DESCRIPTION OF THIS DISCLOSURE
[0026] Disclosed herein is the use of malononitrilamides for the
treatment of neuropathic pain.
[0027] Neuropathic pain according to the present disclosure is a
pain initiated or caused by a primary lesion or dysfunction in the
nervous system.
[0028] For example, neuropathic pain syndromes include postherpetic
neuralgia (caused by Herpes Zoster), root avulsions, painful
traumatic mononeuropathy, painful polyneuropathy (particularly due
to diabetes), central pain syndromes (potentially caused by
virtually any lesion at any level of the nervous system),
postsurgical pain syndromes (eg, postmastectomy syndrome,
postthoracotomy syndrome, phantom pain), and complex regional pain
syndrome (reflex sympathetic dystrophy and causalgia).
[0029] In advantageous embodiments of the present disclosure, the
neuropathic pain have typical symptoms like dysesthesias
(spontaneous or evoked burning pain, often with a superimposed
lancinating component), but pain may also be deep and aching. Other
sensations like; hyperesthesia, hyperalgesia, allodynia (pain due
to a normoxious stimulus), and hyperpathia (particularly
unpleasant, exaggerated pain response) may also occur.
[0030] Neuropathic pain according to the present disclosure could
be divided into "peripheral" (originating in the peripheral nervous
system) and "central" (originating in the brain or spinal
cord).
[0031] In advantageous embodiments, the central neuropathic pain is
of a type that has a cause that is selected from the following
group of causes:
[0032] cerebral lesions that are predominantly thalamic;
[0033] infarction, e.g. thalamic infarction or brain stem
infarction;
[0034] cerebral tumors or abscesses compressing the thalamus or
brain stem;
[0035] multiple sclerosis;
[0036] brain operations, e.g. thalamotomy in cases of motoric
disorders;
[0037] spinal cord lesions;
[0038] spinal cord injuries;
[0039] spinal cord operations, e.g. anterolateral cordotomy;
[0040] ischemic lesions;
[0041] anterior spinal artery syndrome;
[0042] Wallenberg's syndrome; and
[0043] syringomyelia.
[0044] In an advantageous embodiment according to the present
disclosure the neuropathic pain is a central neuropathic pain
syndrome. In some examples the central neuropathic pain syndrome is
caused by spinal cord injury and/or spinal cord contusion (see
example 1 to 3).
[0045] In a further advantageous embodiment of the present
disclosure the neuropathic pain is a head pain syndrome caused by
central pain mechanisms like in migraine or migraine pain.
[0046] In further advantageous embodiments the neuropathic pain is
a peripheral neuropathic pain. In some examples, the peripheral
neuropathic pain is caused by chronic constriction injury or by
ligation of the sciatic nerve (see example 4 and 5).
[0047] According to the present disclosure the predominantly
peripheral neuropathic pain includes a type that is selected from
the following types of neuropathic pain and/or has a cause that is
selected from the group of the following causes:
[0048] systemic diseases, e.g. diabetic neuropathy;
[0049] drug-induced lesions, e.g. neuropathy due to
chemotherapy;
[0050] traumatic syndrome and entrapment syndrome;
[0051] lesions in nerve roots and posterior ganglia;
[0052] neuropathies after HIV infections;
[0053] neuralgia after Herpes infections;
[0054] nerve root avulsions;
[0055] cranial nerve lesions;
[0056] cranial neuralgias, e.g., trigeminal neuralgia;
[0057] neuropathic cancer pain;
[0058] phantom pain;
[0059] compression of peripheral nerves, neuroplexus and nerve
roots;
[0060] paraneoplastic peripheral neuropathy and ganglionopathy;
[0061] complications of cancer therapies, e.g. chemotherapy,
irradiation, and surgical interventions;
[0062] complex regional pain syndrome;
[0063] type I lesions (previously known as sympathetic reflex
dystrophy); and
[0064] type II lesions (corresponding approximately to
causalgia)
[0065] In advantageous embodiments, the compounds used for the
treatment of neuropathic pain and/or neuropathic pain syndromes are
malononitrilamides or pharmaceutically acceptable salts, solvates,
tautomers or stereoisomers thereof.
[0066] Specific examples of compounds used for the treatment of
neuropathic pain syndromes include, but not limited to compounds
with the following structures (formula I to IV):
##STR00001##
[0067] In further advantageous embodiments, the compound is
selected from the group consisting of 1(3-methyl-4-trifluoro
methylphenyl-carbamoyl)-2-cyclopropyl-2oxo-propionitrile,
N-(4-trifluoromethyl)-phenyl-2-cyano-3-hydroxy-hept-2-en-6-in-carboxylic
acidamide, 5-(3-butynyl)-N-(4-(trifluoromethyl)
phenyl-4-isoxazolecarboxamide and
2-cyano-3-cyclopropyl-3-oxo-(4-cyanophenyl)propionamide or a
pharmaceutically acceptable salt, solvate, tautomer or stereoisomer
thereof.
[0068] In advantageous embodiments, the compound is
1(3-methyl-4-trifluoro
methylphenyl-carbamoyl)-2-cyclopropyl-2oxo-propionitrile.
[0069] In another advantageous embodiment, the compound is
N-(4-trifluoromethyl)-phenyl-2-cyano-3-hydroxy-hept-2-en-6-in-carboxylic
acidamide.
[0070] In further advantageous embodiments, the compound has the
structure with the formula II or a pharmaceutically acceptable salt
thereof.
[0071] Specific compounds of the disclosure are such derivatives
described in U.S. Pat. No. 5,532,259, in the international patent
application WO 91/717748 and in Kuo et al., (Kuo et al., 1996),
each of which is incorporated herein by reference.
[0072] In Kuo et al., (Kuo et al., 1996) examples for the
preparation of compounds according to the present description is
shown, each of which is incorporated herein by reference.
[0073] Furthermore, compounds according to the disclosure can
either be commercially purchased or prepared according to the
methods described in the publications, patents or patent
publications disclosed herein. Further, optically pure compositions
can be asymmetrically synthesized or resolved using known resolving
agents or chiral columns as well as other standard synthetic
organic chemistry techniques. Compounds used in the disclosure may
include compounds that are racemic, stereomerically enriched or
stereomerically pure, and pharmaceutically acceptable salts,
solvates, stereoisomers, and prodrugs thereof.
[0074] For example, FK778 can be manufactured according to methods
described in the U.S. Pat. No. 5,308,865 (see example 14). The
FK778 may include a conformer and a stereoisomer (see Kobayashi et
al.). As used herein, when "FK778" is specified, it is to be
understood that such conformers and isomers also included within
the scope of this disclosure. Also, FK778 can be in another
tautomer form, and such a tautomer form is also included within the
scope of this disclosure. For example, FK778 can be either in its
enol or keto form, i.e.
2-cyano-3-oxo-N-[4-(trifluoromethyl)phenyl]-6-heptynamide, as shown
in Kobayashi et al. For the use according to the present
disclosure, FK778 can be in a solvate, which is included within the
scope of the present disclosure. The solvate preferably includes a
hydrate and an ethanolate.
[0075] Preferred compounds used according to the disclosure are
small organic molecules having a molecular weight less than about
1,000 g/mol, and are not proteins, peptides, oligonucleotides,
oligosaccharides or other macromolecules.
[0076] In advantageous embodiments, the compounds used in the
treatment of neuropathic pain according to the present disclosure
are administered to the patient after a damage of the nervous
system. Preferably, HR325 or FK778 is administered to the patient
after a damage of the nervous system.
[0077] Surprisingly, the inventors have found that early-stage
administration of a compound according to the disclosure, in
particular of HR 325 or FK778, to mammalians with neuropathic pain,
minimalize the pain and the analgesic effect is maintained for
several weeks to months, also without further administration of the
compound (see FIG. 1).
[0078] Furthermore, the inventors have found that the
administration of a compound according to the disclosure, in
particular of HR 325 or FK-778, also minimize the neuropathic pain
if the pain is already established (chronic pain). These results
are shown in FIG. 2 and FIG. 4.
[0079] Neuropathic chronic pain according to the present disclosure
may be a pain that persists for an extended period time, for
example at least for more than one month. It can be a result of a
long-term illness or a lingering result of an injury. An adequate
definition for neuropathic chronic pain can be found at Bogduk, N;
Merskey, H (1994). Classification of chronic pain: descriptions of
chronic pain syndromes and definitions of pain terms (second ed.).
Seattle: IASP Press. p. 212, which is hereby incorporated by
reference.
[0080] In further advantageous embodiments, a compound according to
the present disclosure is used as the only physically active
compound in the treatment of neuropathic pain without a second
active agent.
[0081] In yet other advantageous embodiments, the disclosure
relates to pharmaceutical compositions for preventing and/or
treating neuropathic pain, which comprises a therapeutically
effective amount of a compound according to the present disclosure
in admixture with a pharmaceutical acceptable carrier or
excipient.
[0082] In advantageous embodiments, the pharmaceutical composition
according to the present disclosure comprises a compound according
to the present disclosure and no second active ingredient in the
composition. In an advanced embodiment, laflunimus is used as the
sole active agent for the treatment of neuropathic pain or
neuropathic pain syndromes. In an advanced embodiment, laflunimus
is used for the treatment of neuropathic pain without an
immunomodulatory compound as a second active agent.
[0083] In advantageous embodiments, the pharmaceutical composition
is used for preventing and/or treating neuropathic pain, whereby
the composition comprises a therapeutically effective amount of
laflunimus or a physiologically functional derivative thereof in
admixture with a pharmaceutical acceptable carrier or excipient. In
advantageous embodiments the pharmaceutical composition comprises a
malononitrilamide selected from the group consisting of
(1(3-methyl-4-trifluoro
methylphenyl-carbamoyl)-2-cyclopropyl-2oxo-propionitrile),
N-(4-trifluoromethyl)-phenyl-2-cyano-3-hydroxy-hept-2-en-6-in-carboxylic
acidamide, and
2-cyano-3-cyclopropyl-3-oxo-(4-cyanophenyl)propionamide or a
pharmaceutically acceptable salt, solvate, tautomer or stereoisomer
thereof.
[0084] As used herein and unless otherwise indicated, the term
"pharmaceutically acceptable salt" encompasses non-toxic acid and
base addition salts of the compound to which the term refers.
Acceptable non-toxic acid addition salts include those derived from
organic and inorganic acids or bases know in the art, which
include, for example, hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid,
tartaric acid, lactic acid, succinic acid, citric acid, malic acid,
maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic
acid, embolic acid, enanthic acid, and the like. Compounds that are
acidic in nature are capable of forming salts with various
pharmaceutically acceptable bases. The bases that can be used to
prepare pharmaceutically acceptable base addition salts of such
acidic compounds are those that form non-toxic base addition salts,
i.e., salts containing pharmacologically acceptable cations such
as, but not limited to, alkali metal or alkaline earth metal salts
and the calcium, magnesium, sodium or potassium salts in
particular. Suitable organic bases include, but are not limited to,
N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumaine (N-methylglucamine),
lysine, and procaine.
[0085] As used herein, and unless otherwise specified, the term
"solvate" means a compound of the present disclosure or a salt
thereof that further includes a stoichiometric or
non-stoichiometric amount of solvent bound by non-covalent
intermolecular forces. Where the solvent is water, the solvate is a
hydrate.
[0086] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to, derivatives of compounds according to the
present disclosure that comprise biohydrolyzable moieties such as
biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable
carbamates, biohydrolyzable carbonates, biohydrolyzable ureides,
and biohydrolyzable phosphate analogues. Other examples of prodrugs
include derivatives of immunomodulatory compounds of the disclosure
that comprise --NO, --NO2, --ONO, or --ONO2 moieties. Prodrugs can
typically be prepared using well-known methods, such as those
described in Burger's Medicinal Chemistry and Drug Discovery,
172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design
of Prodrugs (H. Bundgaard ed., Elselvier, New York 1985). As used
herein and unless otherwise indicated, the terms "biohydrolyzable
amide," "biohydrolyzable ester," "biohydrolyzable carbamate,"
"biohydrolyzable carbonate," "biohydrolyzable ureide,"
"biohydrolyzable phosphate" mean an amide, ester, carbamate,
carbonate, ureide, or phosphate, respectively, of a compound that
either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties
in vivo, such as uptake, duration of action, or onset of action; or
2) is biologically inactive but is converted in vivo to the
biologically active compound. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, lower
acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl,
aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl
esters), lactonyl esters (such as phthalidyl and thiophthalidyl
esters), lower alkoxyacyloxyalkyl esters (such as
methoxycarbonyl-oxymethyl, ethoxycarbonyloxyethyl and
isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline
esters, and acylamino alkyl esters (such as acetamidomethyl
esters). Examples of biohydrolyzable amides include, but are not
limited to, lower alkyl amides, [alpha]-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of
biohydrolyzable carbamates include, but are not limited to, lower
alkylamines, substituted ethylenediamines, amino acids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0087] As used herein, and unless otherwise specified, the term
"stereoisomer" encompasses all enantiomerically/stereomerically
pure and enantiomerically/stereomerically enriched compounds of
this disclosure.
[0088] As used herein, and unless otherwise indicated, the term
"stereomerically pure" or "enantiomerically pure" means that a
compound comprises one stereoisomer and is substantially free of
its counter stereoisomer or enantiomer. For example, a compound is
stereomerically or enantiomerically pure when the compound contains
80%, 90%, or 95% or more of one stereoisomer and 20%, 10%, or 5% or
less of the counter stereoisomer, in certain cases, a compound of
the disclosure is considered optically active or
stereomerically/enantiomerically pure {i.e., substantially the
R-form or substantially the S-form) with respect to a chiral center
when the compound is about 80% ee (enantiomeric excess) or greater,
preferably, equal to or greater than 90% ee with respect to a
particular chiral center, and more preferably 95% ee with respect
to a particular chiral center.
[0089] As used herein, and unless otherwise indicated, the term
"stereomerically enriched" or "enantiomerically enriched"
encompasses racemic mixtures as well as other mixtures of
stereoisomers of compounds of this disclosure {e.g., R/S=30/70,
35/65, 40/60, 45/55, 55/45, 60/40, 65/35 and 70/30). Various
inhibitor compounds of the present disclosure contain one or more
chiral centers, and can exist as racemic mixtures of enantiomers or
mixtures of diastereomers. This disclosure encompasses the use of
stereomerically pure forms of such compounds, as well as the use of
mixtures of those forms. For example, mixtures comprising equal or
unequal amounts of the enantiomers of a particular inhibitor
compound of the disclosure may be used in methods and compositions
of the disclosure. These isomers may be asymmetrically synthesized
or resolved using standard techniques such as chiral columns or
chiral resolving agents. See, e.g., Jacques, J., et ah,
Enantiomers, Racemates and Resolutions (Wiley-Interscience, New
York, 1981); Wilen, S. H., et al, Tetrahedron 33:2725 (1977);
Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, NY,
1962); and Wilen, S. H., Tables of Resolving Agents and Optical
Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press,
Notre Dame, Ind., 1972).
[0090] As used herein, and unless otherwise indicated, the term
"tautomers" means isomers of a compound according to the present
disclosure that readily interconverts by tautomerization. This
reaction commonly results in the formal migration of a hydrogen
atom or proton, accompanied by a switch of a single bond and
adjacent double bond. Common tautomeric pairs are ketone-enol,
ketene-ynol, amide-imidic acid, lactam-lactim, an amide-imidic acid
tautomerism in heterocyclic rings, enamine-imine, enamine-enamine,
and anomers of reducing sugars in solution interconvert through an
intermediate open chain form.
[0091] For example, in an advantageous embodiment the compound
having formula II (FK778) can be either in its enol (FK778) or keto
form, i.e. 2-cyano-3-oxo-N-[4-(trifluoromethyl)
phenyl]-6-heptynamide and such a tautomer form is also included
within the scope of this disclosure.
[0092] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
[0093] The term "physiologically functional derivative" as used
herein refers to compounds which are not pharmaceutically active
themselves but which are transformed into their pharmaceutical
active form in vivo, i.e. in the subject to which the compound is
administered. Examples of physiologically functional derivatives
are prodrugs such as those described below in the present
application.
[0094] The term "derivative" as used herein refers to a compound
that is derived from a similar compound or a compound that can be
imagined to arise from another compound, if one atom is replaced
with another atom or group of atoms. The term "derivative" as used
herein refers also to a compound that at least theoretically can be
formed from the precursor compound (see Oxford Dictionary of
Biochemistry and Molecular Biology. Oxford University Press. ISBN
0-19-850673-2.) In advantageous embodiments of the present
disclosure the term "derivative" is used for derivatives from
laflunimus.
[0095] The disclosure is also directed to the use of compounds of
the formula I, II, III, IV or of formula V and of their
pharmacologically tolerable salts or physiologically functional
derivatives for the production of a medicament for the prevention
and treatment of neuropathic pain and neuropathic pain
syndromes.
[0096] Methods and uses according to the present disclosure
encompass methods of preventing, treating and/or managing
neuropathic pain and related syndromes, but are not limited to,
postherpetic neuralgia (caused by Herpes Zoster), root avulsions,
painful traumatic mononeuropathy, painful polyneuropathy
(particularly due to diabetes), central pain syndromes (potentially
caused by virtually any lesion at any level of the nervous system),
postsurgical pain syndromes (eg, postmastectomy syndrome,
postthoracotomy syndrome, phantom pain), and complex regional pain
syndrome (reflex sympathetic dystrophy and causalgia).
[0097] The symptoms, conditions and/or symptoms associated with
neuropathic pain include, but are not limited to, dysesthesias
(spontaneous or evoked burning pain, often with a superimposed
lancinating component), but pain may also be deep and aching. Other
sensations like; hyperesthesia, hyperalgesia, allodynia (pain due
to a normoxious stimulus), and hyperpathia (particularly
unpleasant, exaggerated pain response).
[0098] The suitability of a particular route of administration of
an compound according to the present disclosure employed for a
particular active agent will depend on the active agent itself
(e.g., whether it can be administered orally without decomposing
prior to entering the blood stream) and the disease being treated.
An advantageous embodiment of the route of administration for a
compound according to the present disclosure is orally. Further
routes of administration are known to those of ordinary skill in
the art.
[0099] The dosage of therapeutically effective amount of at least
one compound varies from and also depends upon the age and
condition of each individual patient to be treated. In an
embodiment of the present disclosure, the recommended daily dose
range of a compound according to the present disclosure for the
conditions and disorders described herein lies within the range of
from about, a daily dose of about 1 mg-10 g/body, preferable 5 mg-5
g/body and more preferable 10 mg-2 g/body of the active ingredient
is generally given for treating this disease, and an average single
dose of about 0.5-1 mg, 5 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg,
1 g, 2 g and 3 g is generally administered. Daily dose for
administration in humans for treating this disease (neuropathic
pain or neuropathic pain syndromes) could be in the range of about
0.1-50 mg/kg.
[0100] While the term for administering of at least one compound to
prevent this disease (neuropathic pain or neuropathic pain
syndromes) varies depending on species, and the nature and severity
of the condition to be prevented, the compound may usually be
administered to humans for a short term or a long term, i.e. for 1
week to 1 year.
[0101] Pharmaceutical compositions can be used in the preparation
of individual, single unit dosage forms. The compounds of the
present disclosure can be used in the form of pharmaceuticals
compositions, for example, in solid, semisolid or liquid form,
which contains one or more of the compounds according to the
present disclosure as active ingredient associated with
pharmaceutically acceptable carriers or excipient suitable for
oral, parenteral such as intravenous, intramuscular, intrathecal,
subcutaneous, enteral, intrarectal or intranasal administration.
The active ingredient may be compounded, for example, with the
usual non-toxic, pharmaceutically acceptable carriers for tablets,
pellets, capsules, suppositories, solutions (saline for example),
emulsion, suspensions (olive oil, for example), ointment and any
other form suitable for use. The carriers which can be used are
water, glucose, lactose gum acacia, gelatine, manitol, starch
paste, magnesium trisilicate, corn starch, keratin, colloidal
silica, potato starch, urea and other carriers suitable for use in
manufacturing preparations, in solid, semisolid or liquid form, and
in addition auxiliary, stabilizing, thickening and colouring agents
and perfumes may be used. The active object compound is included in
the pharmaceutical composition in an effective amount sufficient to
prevent and/or treat the disease.
[0102] Single unit dosage forms of the disclosure are suitable for
oral, mucosal (e.g., nasal, sublingual, vaginal, buccal, or
rectal), parenteral (e.g., subcutaneous, intravenous, bolus
injection, intramuscular, or intraarterial), topical (e.g., eye
drops or other ophthalmic preparations), transdermal or
transcutaneous administration to a patient. Examples of dosage
forms include, but are not limited to: tablets; caplets; capsules,
such as soft elastic gelatin capsules; cachets; troches; lozenges;
dispersions; suppositories; powders; aerosols (e.g., nasal sprays
or inhalers); gels; liquid dosage forms suitable for oral or
mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions,
or a water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
eye drops or other ophthalmic preparations suitable for topical
administration; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0103] The composition, shape, and type of dosage forms of the
disclosure will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease may contain
larger amounts of one or more of the active agents it comprises
than a dosage form used in the chronic treatment of the same
disease. Similarly, a parenteral dosage form may contain smaller
amounts of one or more of the active agents it comprises than an
oral dosage form used to treat the same disease. These and other
ways in which specific dosage forms encompassed by this disclosure
will vary from one another will be readily apparent to those
skilled in the art. See, e.g., Remington's Pharmaceutical Sciences,
18th ed., Mack Publishing, Easton Pa. (1990).
[0104] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active agents in the
dosage form. For example, the decomposition of some active agents
may be accelerated by some excipients such as lactose, or when
exposed to water. Active agents that comprise primary or secondary
amines are particularly susceptible to such accelerated
decomposition. Consequently, this disclosure encompasses
pharmaceutical compositions and dosage forms that contain little,
if any, lactose or other mono- or di-saccharides. As used herein,
the term "lactose-free" means that the amount of lactose present,
if any, is insufficient to substantially increase the degradation
rate of an active ingredient.
[0105] Lactose-free compositions of the disclosure can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,
lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0106] This disclosure further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0107] Anhydrous pharmaceutical compositions and dosage forms of
the disclosure can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprise a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected. An anhydrous pharmaceutical composition
should be prepared and stored such that its anhydrous nature is
maintained. Accordingly, anhydrous compositions are preferably
packaged using materials known to prevent exposure to water such
that they can be included in suitable formulary kits. Examples of
suitable packaging include, but are not limited to, hermetically
sealed foils, plastics, unit dose containers (e.g. vials), blister
packs, and strip packs.
[0108] The disclosure further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0109] Like the amounts and types of excipients, the amounts and
specific types of active agents in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the disclosure comprise a compound according to the
present disclosure or a pharmaceutically acceptable salt, solvate,
hydrate, stereoisomer, clathrate, or prodrug thereof in an amount
of from about 0.10 to about 150 mg. Typical dosage forms comprise a
compound according to the present disclosure or a pharmaceutically
acceptable salt, solvate, hydrate, stereoisomer, clathrate, or
prodrug thereof in an amount of about 0.1, 1, 2, 5, 7.5, 10, 12.5,
15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In a particular
embodiment, a preferred dosage form comprises
4-(amino)-2-(2,6-dioxo(3-piperidyl))-isoindoline-1,3-dione in an
amount of about 1, 2, 5, 10, 25 or 50 mg. In a specific embodiment,
a preferred dosage form comprises
3-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione in
an amount of about 5, 10, 25 or 50 mg.
[0110] Oral Dosage Forms of pharmaceutical compositions of the
disclosure that are suitable for oral administration can be
presented as discrete dosage forms, such as, but are not limited
to, tablets (e.g., chewable tablets), caplets, capsules, and
liquids (e.g., flavored syrups). Such dosage forms contain
predetermined amounts of active ingredients, and may be prepared by
methods of pharmacy well known to those skilled in the art. See
generally, Remington's Pharmaceutical Sciences, 18th ed., Mack
Publishing, Easton Pa. (1990).
[0111] Typical oral dosage forms of the disclosure are prepared by
combining the active ingredients in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
{e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0112] Because of their ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0113] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0114] Examples of excipients that can be used in oral dosage forms
of the disclosure include, but are not limited to, binders,
fillers, disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives {e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, {e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0115] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
PA), and mixtures thereof. A specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM. Examples of
fillers suitable for use in the pharmaceutical compositions and
dosage forms disclosed herein include, but are not limited to,
talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the disclosure is typically present in from about
50 to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0116] Disintegrants are used in the compositions of the disclosure
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
disclosure. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0117] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the disclosure include, but are
not limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0118] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the disclosure include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL200, manufactured by W.R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0119] A preferred solid oral dosage form of the disclosure
comprises a compound of the disclosure, anhydrous lactose,
microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,
colloidal anhydrous silica, and gelatin.
[0120] Active ingredients of the disclosure can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein can be readily
selected for use with the active ingredients of the disclosure. The
disclosure thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0121] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0122] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
[0123] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions. Suitable vehicles that can be used to provide
parenteral dosage forms of the disclosure are well known to those
skilled in the art. Examples include, but are not limited to: Water
for Injection USP; aqueous vehicles such as, but not limited to,
Sodium Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0124] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the disclosure. For example,
cyclodextrin and its derivatives can be used to increase the
solubility of a compound of the disclosure and its derivatives.
See, e.g., U.S. Pat. No. 5,134,127, which is incorporated herein by
reference.
[0125] Topical and mucosal dosage forms of the disclosure include,
but are not limited to, sprays, aerosols, solutions, emulsions,
suspensions, eye drops or other ophthalmic preparations, or other
forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 16th and 18th eds., Mack Publishing,
Easton Pa. (1980 & 1990); and Introduction to Pharmaceutical
Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985).
Dosage forms suitable for treating mucosal tissues within the oral
cavity can be formulated as mouthwashes or as oral gels.
[0126] Suitable excipients {e.g. carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage
forms encompassed by this disclosure are well known to those
skilled in the pharmaceutical arts, and depend on the particular
tissue to which a given pharmaceutical composition or dosage form
will be applied. With that fact in mind, typical excipients
include, but are not limited to, water, acetone, ethanol, ethylene
glycol, propylene glycol, butane-1,3-diol, isopropyl myristate,
isopropyl palmitate, mineral oil, and mixtures thereof to form
solutions, emulsions or gels, which are non-toxic and
pharmaceutically acceptable. Moisturizers or humectants can also be
added to pharmaceutical compositions and dosage forms if desired.
Examples of such additional ingredients are well known in the art.
See, e.g., Remington's Pharmaceutical Sciences, 16th and 18th eds.,
Mack Publishing, Easton Pa. (1980 & 1990).
[0127] The pH of a pharmaceutical composition or dosage form may
also be adjusted to improve delivery of one or more active
ingredients. Similarly, the polarity of a solvent carrier, its
ionic strength, or tonicity can be adjusted to improve delivery.
Compounds such as stearates can also be added to pharmaceutical
compositions or dosage forms to advantageously alter the
hydrophilicity or lipophilicity of one or more active ingredients
so as to improve delivery. In this regard, stearates can serve as a
lipid vehicle for the formulation, as an emulsifying agent or
surfactant, and as a delivery-enhancing or penetration-enhancing
agent. Different salts, hydrates or solvates of the active
ingredients can be used to further adjust the properties of the
resulting composition.
[0128] Typically, active ingredients of the disclosure are
preferably not administered to a patient at the same time or by the
same route of administration. This disclosure therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0129] A typical kit of the disclosure comprises a dosage form of a
compound of the disclosure, or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, prodrug, or clathrate thereof. Kits
encompassed by this disclosure can further comprise additional
active agents. Examples of the additional active agents include,
but are not limited to, those disclosed herein (see, e.g., section
4.2). Kits of the disclosure can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers. In an advantageous embodiment, a kit of the disclosure
contains laflunimus and no additional immunomodulatory
compound.
[0130] Kits of the disclosure can further comprise cells or blood
for transplantation as well as pharmaceutically acceptable vehicles
that can be used to administer one or more active ingredients. For
example, if an active ingredient is provided in a solid form that
must be reconstituted for parenteral administration, the kit can
comprise a sealed container of a suitable vehicle in which the
active ingredient can be dissolved to form a particulate-free
sterile solution that is suitable for parenteral administration.
Examples of pharmaceutically acceptable vehicles include, but are
not limited to: Water for Injection USP; aqueous vehicles such as,
but not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and
Lactated Ringer's Injection; water-miscible vehicles such as, but
not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.
[0131] Advantageous examples for compounds according to the present
disclosure for the use in the treatment of neuropathic pain: [0132]
A) HR325 (Laflunimus) (1(3-methyl-4-trifluoro
methylphenyl-carbamoyl)-2-cyclopropyl-2oxo-propionitrile) [0133] B)
FK778
(N-(4-trifluoromethyl)-phenyl-2-cyano-3-hydroxy-hept-2-en-6-in-carboxylic
acidamide) [0134] C) MNA279
(2-cyano-3-cyclopropyl-3-oxo-(4-cyanophenyl)propionamide) [0135] D)
5-(3-butynyl)-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide
[0136] The following examples and methods are offered for
illustrative purposes only, and are not intended to limit the scope
of the present disclosure in any way.
Methods and Examples
[0137] A series of non-clinical pharmacology and toxicology studies
have been performed to support the clinical evaluation of the
compounds according to the present disclosure in human subjects.
These studies were performed in accordance with internationally
recognized guidelines for study design and in compliance with the
requirements of Good Laboratory Practice (GLP) unless otherwise
noted.
Example 1
[0138] Laflunimus (HR325) treatment to suppress the development of
mechanical allodynia after severe spinal cord contusion injury in
the rat.
[0139] Surgical Methods
[0140] Thirteen week-old female Lewis rats (Charles River, Sulzfeld
Germany) were housed under a 12:12 h dark/light regime and allowed
free access to water and food. After one week of habituation the
animals underwent general anesthesia with a mixture of isoflurane
and air (induction: 5% isoflurane, maintenance: 2.2% isofluorane).
A Th10 laminectomy was performed without rupturing the dura and a
severe contusive SCI (25 gcm NYU/MASCIS II impactor) {Gruner,
1992#3} was induced. After suturing muscle and skin, a subcutaneous
(s.c.) injection of 5 ml of Ringers Lactate was given. Bladders
were emptied manually 2 times a day until spontaneous voiding
returned (usually within 1 week). The lesion severity was verified
by the impact velocity and contusion depth of the impactor rod.
Animals with an impact velocity error >5% were excluded from
further analysis. After injury, individual rats were randomly
assigned into a treatment group. The following groups were
used:
Group 1: SCI+vehicle (1.5% CMC in sterile water) by gavage for 7
days, from DPO 1 till DPO 7 Group 2: SCI+HR 325 (10 mg/kg/day) in
vehicle by gavage for 7 days, from DPO 1 till DPO 7 Group 3: SCI+RR
325 (20 mg/kg/day) in vehicle by gavage for 7 days, from DPO 1 till
DPO 7 Group 4: SCI+HR 325 (30 mg/kg/day) in vehicle by gavage for 7
days, from DPO 1 till DPO 7
[0141] Assessment of Mechanical Sensitivity:
[0142] The mechanical sensitivity response was measured as the
direct pressure stimulus required eliciting foot withdrawal in
nonrestrained conditions. All tests were conducted in the morning
between 7:30 and 10:30 am and the person performing the behavioral
tests was blinded to the experimental groups. Animals were
habituated to the testing apparatus for at least 20 min before
testing. Each animal was subjected to the stimulation of a series
of von Frey filaments ranging from 0.4 to 15 g (log force 3.61,
3.84, 4.08, 4.31, 4.56, 4.74, 4.93 and 5.18) using the Up-Down
paradigm according to Chaplan (Chaplan et al., 1994). The selected
von Frey filament was pressed against the plantar surface of the
hind paw to the point of 30.degree. bending for 3 s. Paw withdrawal
response was considered as the positive response. The 50% threshold
force needed for paw withdrawal was calculated for both hind paws
of each rat and the mean value of both hind paws was used to
represent the mechanical sensitivity of this animal.
[0143] Results:
[0144] Mechanical Sensitivity
[0145] The mechanical sensitivity (indicated by the 50% threshold
force for paw withdrawals) was determined by the Up-Down method
using von Frey filaments. All rats were baseline tested before
surgery and tested again on day 28 post surgery, because this is
the first time point at which all rats can sit with the hind paws
in plantar position. At baseline all animals reached the maximal
50% threshold force of 15 g, as consequence there were no
differences between the two groups. As expected, both the vehicle
treated as well as the HR-325 treated animals showed mechanical
hypersensitivity at DPO 28. However, as consequence of the HR-325
treatment the mechanical hypersensitivity was significantly reduced
in all HR-325 treated dosage groups at DPO 28 (one-way ANOVA;
F.sub.3.53=19.93 p<0.001, see FIG. 1). This statistically
significant difference between the treated animals and the vehicle
controls remained till the end of the experiment at DPO 63 (one-way
ANOVA; F.sub.3.53=35.34 p<0.001, see FIG. 1). Thus, all tested
HR-325 dosages (i.e. 10, 20 and 30 mg/kg/d) are able to suppress
the development of mechanical allodynia after experimental spinal
cord injury (see FIG. 1).
Example 2
[0146] HR325 and FK778 treatment can both reverse central
neuropathic pain induced by severe spinal cord contusion injury in
the rat.
[0147] Surgical Methods
[0148] For surgical methods see example 1.
[0149] After injury, individual rats were randomly assigned into a
treatment group. The following groups were used:
Group 1: SCI+vehicle (1.5% CMC in sterile water) by gavage for 7
days, from DPO 28 till DPO 35 Group 2: SCI+HR 325 (10 mg/kg/day) in
vehicle by gavage for 7 days, from DPO 28 till DPO 35 Group 3:
SCI+FK 778 (10 mg/kg/day) in vehicle by gavage for 7 day, from DPO
28 till DPO 35
[0150] Assessment of Mechanical Sensitivity:
[0151] For the assessment of mechanical sensitivity see example
1.
[0152] The Acetone Test:
[0153] A slightly modified method of De la Calle and colleagues (De
la Calle et al., 2002) was used for the determination of the
reactivity to a cold chemical stimulus. The rat was placed in
acrylic cages on top of a wire mesh grid, which allowed access to
the paws, and acetone was applied to the plantar surface of the
hind paw. To do this, 100 .mu.l of acetone was sprayed onto the
plantar surface of the rat's hind leg from below the grid with a
syringe holding 2.5 ml. The time spent with the leg withdrawn from
floor during the 60 s following exposure to acetone was recorded.
Both hind legs were tested in each animal with an interval of 5-10
min between each test. The average reaction time between the two
legs was taken for further analysis. A minimal value of 1 s was
assigned to convey a fast or brisk reaction, while 0 was assigned
if there was no reaction at all. This acetone test has been
described as composing of cold, chemical, and possibly mechanical
stimulation.
[0154] Results:
[0155] Mechanical Sensitivity
[0156] The mechanical sensitivity (indicated by the 50% threshold
force for paw withdrawals) was determined by the Up-Down method
using von Frey filaments. All rats were baseline tested before
surgery and tested again on day 28 post surgery, because this is
the first time point at which all rats can sit with the hind paws
in plantar position. At baseline all animals reached the maximal
50% threshold force of 15 g, as consequence there were no
differences between the two groups. As expected, all animals showed
severe mechanical hypersensitivity at DPO 28, the withdrawal
threshold dropped from 15 grams before injury to 2.7, 3.0 and 3.1
grams in vehicle control animals, HR-325 treated animals and FK-778
treated animals, respectively. Then from DPO 28 till DPO 35 we
started the oral treatment with HR-325, FK-778 or vehicle which
tremendously affected the mechanical hypersensitivity. At DPO 35
the withdrawal threshold was significantly higher in both HR-325
and FK-778 treated animals when compared to vehicle control animals
(one-way ANOVA; F.sub.2.35=12.6 p<0.001, see FIG. 2). This
statistically significant difference between the treated animals
and the vehicle controls remained till the end of the experiment at
DPO 77 (one-way ANOVA; F.sub.2.35=24.2 p<0.001, see FIG. 2).
Thus, HR-325 and FK-778 are both able to reverse mechanical
allodynia after experimental spinal cord injury.
[0157] The Acetone Test
[0158] The acetone test was used for the determination of the
reactivity to a cold chemical stimulus. The obtained results show
clearly that before injury the acetone does not evoke any reaction
at all when applied to the plantar surface of the hind paws.
However, at DPO 28 all animals showed a clear reaction to the
acetone exposure. The following 7 days up to DPO 35 the treatment
started with either HR-325, FK-778 or vehicle. As a consequence of
the treatment the first significant differences between the
treatment groups became obvious at DPO 35. The FK-778 treated
animals responded significantly shorter to the acetone exposure
than the vehicle controls (one-way ANOVA; F.sub.2.34=5.6 p<0.01,
see FIG. 3). Three weeks later at DPO 56 there was still a marked
difference between the groups (one-way ANOVA; F.sub.2.34=21.0
p<0.001, see FIG. 3), a Bonferroni post-hoc test revealed that
both FK-778 and HR-325 treated animals responded significantly
shorter to the acetone exposure than the vehicle controls. These
differences remained unchanged till the end of the experiment at
DPO 70 (one-way ANOVA; F.sub.2.34=12.3 p<0.01, see FIG. 3).
Thus, HR-325 and FK-778 are both able to reverse cold allodynia
after experimental spinal cord injury.
Example 3
[0159] HR325 treatment can reverse chronic central neuropathic pain
three months after spinal cord contusion injury.
[0160] Surgical Methods
[0161] For surgical methods see example 1.
[0162] After injury, individual rats were randomly assigned into a
treatment group. The following groups were used:
Group 1: SCI+vehicle (1.5% CMC in sterile water) by gavage for 7
days, from DPO 84 till DPO 91 Group 2: SCI+HR 325 (10 mg/kg/day) in
vehicle by gavage for 7 days, from DPO 84 till DPO 91
[0163] Assessment of Mechanical Sensitivity:
[0164] For the assessment of mechanical sensitivity see example
1.
[0165] The Acetone Test:
[0166] For the assessment of mechanical sensitivity see example
2.
[0167] Results:
[0168] Mechanical Sensitivity
[0169] The mechanical sensitivity (indicated by the 50% threshold
force for paw withdrawals) was determined by the Up-Down method
using von Frey filaments. All rats were baseline tested before
surgery and tested again on day 28 post surgery, because this is
the first time point at which all rats can sit with the hind paws
in plantar position. At baseline all animals reached the maximal
50% threshold force of 15 g, as consequence there were no
differences between the two groups. As expected, all animals showed
severe mechanical hypersensitivity at DPO 28, the withdrawal
threshold dropped from 15 grams before injury to 3.2 and 2.7 grams
in vehicle control animals and HR-325 treated animals,
respectively. Thereafter the 50% threshold force remained stable
for the next two months up to DPO84 at which the oral treatment
with either HR-325 or vehicle was started. As a consequence of this
7 days treatment the 50% threshold force increased, at DPO 91 the
withdrawal threshold was significantly higher in HR-325 treated
animals when compared to vehicle control animals (Student T-test;
t=5.33 p<0.001, see FIG. 4). A comparable difference between the
groups was noted at the end of the experiment at DPO 105 (Student
T-test; t=7.68 p<0.001, see FIG. 4). Thus, HR-325 can reverse a
chronic mechanical allodynia caused by spinal cord trauma even
after lasting 3 months.
[0170] The Acetone Test
[0171] The acetone test was used for the determination of the
reactivity to a cold chemical stimulus. The obtained results show
clearly that before injury the acetone does not evoke any reaction
at all when applied to the plantar surface of the hind paws.
However, at DPO 35 all animals showed a clear reaction to the
acetone exposure. The following 2 months up to DPO 84 the reaction
to the acetone exposure remained unchanged. However, at DPO 84 the
7 days oral treatment started with either HR-325 or vehicle. As a
consequence of the treatment the first significant differences
between the two groups became obvious at DPO 91 (Student T-test;
t=4.70 p<0.001, see FIG. 5). A comparable difference between the
groups was noted at the end of the experiment at DPO 105 (Student
T-test; t=3.54 p<0.01, see FIG. 5). Thus, HR-325 can reverse a
chronic cold allodynia caused by spinal cord trauma even after
lasting 3 months.
[0172] Altogether, the data presented in these examples clearly
demonstrate that, HR-325 treatment (i.e. 10, 20 and 30 mg/kg/d) can
suppress the development of mechanical allodynia after spinal cord
trauma. Moreover, Laflunimus (HR-325) and FK-778 treatment are able
to reverse both mechanical- and thermal allodynia after spinal cord
injury. Finally, HR-325 treatment can reverse spinal cord trauma
indiced mechanical- and cold allodynia that is ongoing for 3
months.
Example 4
[0173] HR325 treatment can attenuate peripheral neuropathic pain
after chronic constriction injury (CCI) of the sciatic nerve.
[0174] Surgical Methods
[0175] Surgery was performed according to the methods of Bennett
and Xie (1988). The common sciatic nerve was exposed at the level
of the middle of the thigh by blunt dissection through the biceps
femoris. Proximal to the sciatic trifurcation, about 7 mm of nerve
was freed of adhering tissue, and four ligatures (5.0 chromic
catgut) were tied loosely around the nerve with about 1-mm spacing.
Great care was taken to tie the ligatures, such that the diameter
of the nerve was seen to be just barely constricted. This
constriction of the nerve leads to intraneural oedema, focal
ischemia, and an axonal degeneration. As a consequence, this model
results in cold and mechanical allodynia, and some symptoms of
spontaneous pain which lasts for a period of more than 2 months
(Attal et al., 1990; Bennett and Xie, 1988)
[0176] Fourteen days (DPO 14) after injury, all individual rats
were treated daily with HR-325 for 7 days up to DPO 21.
[0177] Assessment of Mechanical Sensitivity:
[0178] The mechanical sensitivity response was measured as the
direct pressure stimulus required eliciting foot withdrawal in
nonrestrained conditions. Animals were habituated to the testing
apparatus for at least 20 min before testing. Each animal was
subjected to the stimulation of a series of von Frey filaments
ranging from 1.0 to 60 g using the Up-Down paradigm according to
Chaplan (Chaplan et al., 1994). The selected von Frey filament was
pressed against the plantar surface of the hind paw to the point of
30.degree. bending for 3 s. Paw withdrawal response was considered
as the positive response. The 50% threshold force needed for paw
withdrawal was calculated for both hind paws of each rat.
[0179] The Acetone Test
[0180] A slightly modified method of De la Calle and colleagues (De
la Calle et al., 2002) was used for the determination of the
reactivity to a cold chemical stimulus. The rat was placed in
acrylic cages on top of a wire mesh grid, which allowed access to
the paws, and acetone was applied to the plantar surface of the
hind paw. To do this, 100 .mu.l of acetone was sprayed onto the
plantar surface of the rat's hind leg from below the grid with a
syringe holding 2.5 ml. The time spent with the leg withdrawn from
floor during the 60 s following exposure to acetone was recorded.
Both hind legs were tested in each animal with an interval of 5-10
min between each test.
[0181] Results:
[0182] Mechanical Sensitivity
[0183] The mechanical sensitivity (indicated by the 50% threshold
force for paw withdrawals) was determined by the Up-Down method
using von Frey filaments. All rats were baseline tested before
surgery and tested again on day 7 and 14 post surgery. At baseline
all animals reached the maximal 50% threshold force of 60 g in both
the contra- and ipsilateral paw. As expected, all animals showed
severe mechanical hypersensitivity in the ipsilateral paw at DPO 7
and DPO 14. The withdrawal threshold dropped from 60 grams before
injury to 10 grams 14 days after injury, which was significantly
lower when compared to the contralateral paw. Then from DPO 14 till
DPO 21 the oral treatment with HR-325 (black bar; FIG. 6) was
given. At DPO 21 the withdrawal threshold in the ipsilateral paw
significantly increased up to 47 grams, which was not significantly
different from the contralateral paw (T-test; n.s., see FIG. 6).
One week later at DPO 28 the treatment affect of HR-325 remained
stable since the withdrawal threshold in the ipsilateral paw was
still comparable with the contralateral paw.
[0184] The Acetone Test
[0185] The acetone test was used for the determination of the
reactivity to a cold chemical stimulus. The obtained results show
clearly that before injury the acetone does not evoke any reaction
at all when applied to the plantar surface of the hind paws.
However, at DPO 7 and DPO 14 most animals showed a clear reaction
to the acetone exposure in the ipsilateral paw, an average reaction
time of 16 and 23 seconds respectively. Since the contralateral paw
did not react at all a statistically significant difference was
noted between the two hind paws. The following 7 days up to DPO 21
the animals were treated with daily 10 mg/kg HR-325 (black bar;
FIG. 7). As a consequence of the treatment the reactivity to the
acetone almost diminished in the ipsilateral paw. One week later at
DPO 28 the reactivity to the acetone exposure was still very low
and comparable to the reactivity in the contralateral paw (T-test;
n.s., see FIG. 7).
Example 5
[0186] HR325 treatment can attenuate peripheral neuropathic pain
after partial ligation of the sciatic nerve.
[0187] Surgical Methods
[0188] The methods of Seltzer et al. (1990) were followed. The
dorsum of the sciatic nerve was carefully freed from surrounding
connective tissues at a site near the trochanter just distal to the
point at which the posterior biceps semitendinosus nerve branches
off the common sciatic nerve. The nerve was fixed in its place by
pinching the epineurium on its dorsal aspect, taking care not to
press the nerve against underlying structures. An 8-0 (Polyamide 6)
suture was inserted into the nerve and tightly ligated so that the
dorsal 1/3-1/2 of the nerve thickness was trapped in the ligature
(Seltzer et al., 1990).
[0189] Fourteen days (DPO 14) after injury, all individual rats
were treated daily with FIR-325 for 7 days up to DPO 21.
[0190] Assessment of Mechanical Sensitivity:
[0191] For the assessment of mechanical sensitivity see example
4.
[0192] The Acetone Test
[0193] For the assessment of mechanical sensitivity see example
4.
[0194] Results:
[0195] Mechanical Sensitivity
[0196] The mechanical sensitivity (indicated by the 50% threshold
force for paw withdrawals) was determined by the Up-Down method
using von Frey filaments. All rats were baseline tested before
surgery and tested again on day 7 and 14 post surgery. At baseline
all animals reached the maximal 50% threshold force of 60 g in both
the contra- and ipsilateral paw. As expected, all animals showed
severe mechanical hypersensitivity in the ipsilateral paw at DPO 7
and DPO 14. The withdrawal threshold dropped from 60 grams before
injury to 19 grams 14 days after injury, which was significantly
lower when compared to the contralateral paw. Then from DPO 14 till
DPO 21 the oral treatment with HR-325 (black bar; FIG. 8) was
given. At DPO 21 the withdrawal threshold in the ipsilateral paw
significantly increased up to 54 grams, which was not significantly
different from the contralateral paw (T-test; n.s., see FIG. 8).
One week later at DPO 28 the treatment affect of HR-325 remained
stable since the withdrawal threshold in the ipsilateral paw was
still comparable with the contralateral paw.
[0197] The Acetone Test
[0198] The acetone test was used for the determination of the
reactivity to a cold chemical stimulus. The obtained results show
clearly that before injury the acetone does not evoke any reaction
at all when applied to the plantar surface of the hind paws.
However, at DPO 7 and DPO 14 most animals showed a clear reaction
to the acetone exposure in the ipsilateral paw, an average reaction
time of 4 and 8 seconds respectively. Since the contralateral paw
did not react at all a statistically significant difference was
noted between the two hind paws. The following 7 days up to DPO 21
the animals were treated with daily 10 mg/kg HR-325 (black bar;
FIG. 9). As a consequence of the treatment the reactivity to the
acetone completely diminished in the ipsilateral paw. One week
later at DPO 28 the animals did still not show any reactivity to
the acetone exposure Thus, the cold chemical stimulus was not
painful anymore (see FIG. 9).
[0199] The results show that a controlled pharmacotherapy by
malononitrilamides can be used for treating neuropathic pain and
neuropathic pain syndromes.
[0200] The embodiments of the disclosure described above are
intended to be merely exemplary, and those skilled in the art will
recognize, or will be able to ascertain using no more than routine
experimentation, numerous equivalents of specific compounds,
materials, and procedures. All such equivalents are considered to
be within the scope of the disclosure.
[0201] Additional References
[0202] The following additional publications are incorporated
herein by references: [0203] Afridi, S., Goadsby, P. J., 2003. New
onset migraine with a brain stem cavernous angioma. J Neurol
Neurosurg Psychiatry. 74, 680-2. [0204] Attal, N., et al., 1990.
The bidirectional dose-dependent effect of systemic naloxone is
also related to the intensity and duration of pain-related
disorders: a study in a rat model of peripheral mononeuropathy.
Brain Res. 525, 170-4. [0205] Bennett, G. J., Xie, Y. K., 1988. A
peripheral mononeuropathy in rat that produces disorders of pain
sensation like those seen in man. Pain. 33, 87-107. [0206] Cao, L.,
DeLeo, J. A., 2008. CNS-infiltrating CD4+T lymphocytes contribute
to murine spinal nerve transection-induced neuropathic pain. Eur J.
Immunol. 38, 448-58. [0207] Chaplan, S. R., et al., 1994.
Quantitative assessment of tactile allodynia in the rat paw. J
Neurosci Methods. 53, 55-63. [0208] Costigan, M., et al., 2009.
T-cell infiltration and signaling in the adult dorsal spinal cord
is a major contributor to neuropathic pain-like hypersensitivity.
J. Neurosci. 29, 14415-22. [0209] Davis, J. P., et al., 1996. The
immunosuppressive metabolite of leflunomide is a potent inhibitor
of human dihydroorotate dehydrogenase. Biochemistry. 35, 1270-3.
[0210] De la Calle, J. L., et al., 2002. Intrathecal
transplantation of neuroblastoma cells decreases heat hyperalgesia
and cold allodynia in a rat model of neuropathic pain. Brain Res
Bull. 59, 205-11. [0211] Goadsby, P. J., 2002. Neurovascular
headache and a midbrain vascular malformation: evidence for a role
of the brainstem in chronic migraine. Cephalalgia. 22, 107-11.
[0212] Greene, S., et al., 1995. Inhibition of dihydroorotate
dehydrogenase by the immunosuppressive agent leflunomide. Biochem
Pharmacol. 50, 861-7. [0213] Kuo, E. A., et al., 1996. Synthesis,
structure-activity relationships, and pharmacokinetic properties of
dihydroorotate dehydrogenase inhibitors:
2-cyano-3-cyclopropyl-3-hydroxy-N-[3'-methyl-4'-(trifluoromethyl)phenyl]p-
ropenamide and related compounds. J Med. Chem. 39, 4608-21. [0214]
Seltzer, Z., et al., 1990. A novel behavioral model of neuropathic
pain disorders produced in rats by partial sciatic nerve injury.
Pain. 43, 205-18. [0215] Williamson, R. A., et al., 1995.
Dihydroorotate dehydrogenase is a high affinity binding protein for
A77 1726 and mediator of a range of biological effects of the
immunomodulatory compound. J Biol. Chem. 270, 22467-72. [0216]
Zenonos, G., Kim, J. E., A T cell-orchestrated immune response in
the adult dorsal spinal cord as a cause of neuropathic pain-like
hypersensitivity after peripheral nerve damage: a door to novel
therapies? Neurosurgery. 66, N24-5. [0217] Zielinski, T., et al.,
1995. Leflunomide, a reversible inhibitor of pyrimidine
biosynthesis? Inflamm Res. 44 Suppl 2, S207-8.
[0218] In summary, examples of the present disclosure pertain:
[0219] to compounds for use in treating neuropathic pain and/or
neuropathic pain syndrome, wherein the compounds are
malononitrilamides.
[0220] to a compound that has the formula (I)
##STR00002##
or derivatives or pharmaceutically acceptable salt, solvate,
tautomer or stereoisomer thereof.
[0221] to derivative which are selected from the group consisting
of [0222] i) (1(3-methyl-4-trifluoro
methylphenyl-carbamoyl)-2-cyclopropyl-2oxo-propionitrile), [0223]
ii)
N-(4-trifluoromethyl)-phenyl-2-cyano-3-hydroxy-hept-2-en-6-in-carboxylic
acidamide, [0224] iii)
2-cyano-3-cyclopropyl-3-oxo-(4-cyanophenyl)propionamide and [0225]
iv)
5-(3-butynyl)-N-[4-(trifluoromethyl)phenyl]-4-isoxazolecarboxamide
and or a pharmaceutically acceptable salt, solvate, tautomer or
stereoisomer thereof.
[0226] to derivative which are selected from the group consisting
of the following compounds with the formula II to IV:
##STR00003##
or a pharmaceutically acceptable salt, solvate, tautomer or
stereoisomer thereof. [0227] to stereoisomers of a compound
according to the present disclosure which are the R or S
enantiomer. [0228] to tautomers of a compound according to the
present disclosure which are the keto or enol form.
[0229] The neuropathic pain syndrome according to the present
disclosure may be postherpetic neuralgia (caused by Herpes Zoster),
root avulsions, painful traumatic mononeuropathy, painful
polyneuropathy (particularly due to diabetes), central pain
syndromes (potentially caused by virtually any lesion at any level
of the nervous system), postsurgical pain syndromes (eg,
postmastectomy syndrome, postthoracotomy syndrome, phantom pain),
and complex regional pain syndrome (reflex sympathetic dystrophy
and causalgia).
[0230] In some embodiments, the neuropathic pain is a central pain
syndrome caused by spinal cord injury.
[0231] In some embodiments, the neuropathic pain is a central pain
syndrome caused by a spinal cord contusion.
[0232] The present disclosure pertains also to pharmaceutical
compositions for the use in the treatment of neuropathic pain and
neuropathic pain syndromes comprising a malononitrilamide in free
form or in the form of pharmaceutically acceptable salt or
physiologically functional derivative, together with
pharmaceutically acceptable diluents or carriers.
[0233] The present disclosure pertains further to pharmaceutical
compositions for the use in the treatment of neuropathic pain and
neuropathic pain syndromes comprising a compound of formula II in
free form or in the form of pharmaceutically acceptable salt or
physiologically functional derivative, together with
pharmaceutically acceptable diluents or carriers.
[0234] Furthermore, the present disclosure pertains further to
pharmaceutical compositions for the use in the treatment of
neuropathic pain and neuropathic pain syndromes comprising a
compound of one of the compounds with the formula II to V in free
form or in the form of pharmaceutically acceptable salt or
physiologically functional derivative, together with
pharmaceutically acceptable diluents or carriers.
[0235] The present disclosure pertains further to pharmaceutical
compositions for preventing and/or treating neuropathic pain and
neuropathic pain syndromes, which comprises a therapeutically
effective amount of a malononitrilamide or a physiologically
functional derivative thereof in admixture with a pharmaceutical
acceptable carrier or excipient.
[0236] The present disclosure pertains further to pharmaceutical
compositions for preventing and/or treating neuropathic pain and
neuropathic pain syndromes, which comprises a therapeutically
effective amount of a compound with the formula II or a
physiologically functional derivative thereof in admixture with a
pharmaceutical acceptable carrier or excipient.
[0237] The present disclosure pertains further to pharmaceutical
compositions for preventing and/or treating neuropathic pain and
neuropathic pain syndromes, which comprises a therapeutically
effective amount of a compound of one of the compounds with the
formula II to V or a physiologically functional derivative thereof
in admixture with a pharmaceutical acceptable carrier or
excipient.
[0238] The treated neuropathic pain syndrome may be postherpetic
neuralgia (caused by Herpes Zoster), root avulsions, painful
traumatic mononeuropathy, painful polyneuropathy (particularly due
to diabetes), central pain syndromes (potentially caused by
virtually any lesion at any level of the nervous system),
postsurgical pain syndromes (eg, postmastectomy syndrome,
postthoracotomy syndrome, phantom pain), and complex regional pain
syndrome (reflex sympathetic dystrophy and causalgia).
[0239] In some embodiments the neuropathic pain is a central pain
syndrome caused by spinal cord injury.
[0240] In some embodiments the neuropathic pain is a central pain
syndrome caused by spinal cord contusion.
* * * * *