U.S. patent application number 17/839601 was filed with the patent office on 2022-09-29 for use of carbamate compound for preventing, alleviating or treating myotonia.
The applicant listed for this patent is SK BIOPHARMACEUTICALS CO., LTD.. Invention is credited to Ji Hye KIM, Hye Won SHIN.
Application Number | 20220304981 17/839601 |
Document ID | / |
Family ID | 1000006394932 |
Filed Date | 2022-09-29 |
United States Patent
Application |
20220304981 |
Kind Code |
A1 |
SHIN; Hye Won ; et
al. |
September 29, 2022 |
Use of Carbamate Compound For Preventing, Alleviating Or Treating
Myotonia
Abstract
The present invention relates to a use of a carbamate compound
represented by chemical formula 1, or a pharmaceutically acceptable
salt, a solvate or a hydrate thereof for preventing, alleviating or
treating myotonia.
Inventors: |
SHIN; Hye Won; (Gyeonggi-do,
KR) ; KIM; Ji Hye; (Gyeonggi-do, KR) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SK BIOPHARMACEUTICALS CO., LTD. |
Gyeonggi-do |
|
KR |
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|
Family ID: |
1000006394932 |
Appl. No.: |
17/839601 |
Filed: |
June 14, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16763718 |
May 13, 2020 |
11389429 |
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PCT/KR2018/013767 |
Nov 13, 2018 |
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17839601 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/41 20130101;
A61K 9/0019 20130101; A61P 21/00 20180101 |
International
Class: |
A61K 31/41 20060101
A61K031/41; A61P 21/00 20060101 A61P021/00; A61K 9/00 20060101
A61K009/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 14, 2017 |
KR |
10-2017-0151241 |
Claims
1-30. (canceled)
31. A method for preventing, alleviating or treating myotonia,
comprising administering to a subject in need thereof a
therapeutically effective amount of a carbamate compound of the
following Formula 1, or a pharmaceutically acceptable salt, solvate
or hydrate thereof: ##STR00005## wherein, R.sub.1 and R.sub.2 are
each independently selected from the group consisting of hydrogen,
halogen, C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8alkyl,
C.sub.1-C.sub.8 thioalkoxy and C.sub.1-C.sub.8alkoxy; and one of
A.sub.1 and A.sub.2 is CH, and the other is N.
32-40. (canceled)
41. A method for preventing, alleviating or treating muscle
stiffness, spasticity, distal muscle weakness, weakness of the face
and jaw muscles, difficulty in swallowing, sagging of the eyelids
(blepharosis), weakness of the neck muscles, weakness of the arm
and leg muscles, persistent muscle pain, excessive sleep, muscle
wasting, dysphagia, respiratory failure, irregular heartbeat, or
heart muscle damage, comprising: administering to a subject in need
thereof a therapeutically effective amount of a carbamate compound
of the following Formula 1, or a pharmaceutically acceptable salt,
solvate or hydrate thereof: ##STR00006## wherein, R.sub.1 and
R.sub.2 are each independently selected from the group consisting
of hydrogen, halogen, C.sub.1-C.sub.8 alkyl, halo-C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.8 thioalkoxy and C.sub.1-C.sub.8alkoxy; and
one of A.sub.1 and A.sub.2 is CH, and the other is N.
42. The method according to claim 41, wherein R.sub.1 and R.sub.2
are each independently selected from the group consisting of
hydrogen, halogen and C.sub.1-C.sub.8 alkyl.
43. The method according to claim 41, wherein the carbamate
compound of Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of the following
Formula 2: ##STR00007##
44. The method according to claim 41, wherein the subject to be
administered is a mammal.
45. The method according to claim 41, wherein the therapeutically
effective amount of the carbamate compound of Formula 1 is 50 to
500 mg based on the free form when administered once a day.
46. The method according to claim 41, wherein the carbamate
compound of Formula 1 is administered in a form of composition
comprising at least one pharmaceutically acceptable carrier.
47. The method according to claim 46, wherein the composition is an
oral composition.
48. The method according to claim 46, wherein the pharmaceutically
acceptable carrier is one or more components selected from fillers,
antioxidants, buffers, bacteriostats, dispersants, adsorbents,
surfactants, binders, preservatives, disintegrants, sweeteners,
flavors, glidants, release-controlling agents, wetting agents,
stabilizers, suspending agents and lubricants.
49. The method according to claim 48, wherein the fillers are
selected from the group consisting of sugar, starch, sugar alcohol,
starch hydrolysate, cellulose, and cellulose derivatives.
50. The method according to claim 48, wherein the binders are
selected from the group consisting of povidone, copovidone,
methylcellulose, hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gum,
sucrose, and starch.
51. The method according to claim 48, wherein the preservatives are
selected from the group consisting of benzoic acid, sodium
benzoate, benzyl alcohol, butylated hydroxyanisole, butylated
hydroxytoluene, chlorbutol, gallate, hydroxybenzoate, and EDTA.
52. The method according to claim 48, wherein the disintegrants are
selected from the group consisting of sodium starch glycolate,
cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starch, and microcrystalline cellulose.
53. The method according to claim 48, wherein the sweeteners are
selected from the group consisting of sucralose, saccharin, sodium
saccharin, potassium saccharin, calcium saccharin, acesulfame
potassium or sodium cyclamate, mannitol, fructose, sucrose, and
maltose.
54. The method according to claim 48, wherein the glidants are
selected from the group consisting of silica, colloidal silicon
dioxide, and talc.
55. The method according to claim 48, wherein the lubricants are
selected from the group consisting of long chain fatty acids and
salts thereof, such as magnesium stearate and stearic acid, talc,
and glyceride wax.
Description
FIELD
[0001] The present invention relates to use of carbamate compounds
of the following Formula 1, or a pharmaceutically acceptable salt,
solvate or hydrate thereof for the purpose of preventing,
alleviating or treating myotonia.
##STR00001##
[0002] wherein, R.sub.1, R.sub.2, A.sub.1 and A.sub.2 are as
defined herein.
BACKGROUND
[0003] Myotonia refers to a condition in which muscles do not relax
after contraction and appears in autosomal dominant diseases such
as myotonic dystrophy, myotonia congenita and paramyotonia
congenita.
[0004] Myotonic dystrophy is a disease that occurs in five out of
about 100,000 people, and most frequently appears in hereditary
myotonia in adults. Myotonic dystrophy is also referred to as
dystopy myotonica or Steinert's disease, and shows a condition
which progresses to myoatrophy or muscle weakness after showing
symptoms of spasticity. It is caused by the triplet repeat on the
chromosome 19 long arm. Muscular atrophy appears mainly on the
distal muscle, and shows a disorder in the extensor of the upper
limb or symptoms of facial muscle atrophy. Myotonic dystrophy
includes two major types, DM type 1 and DM type 2, and it affects
the normal expression of chloride channel-1 (CLCN1). Abnormal
chloride flow in the skeletal muscle cells and insufficient
concentration of chloride in cells cause myotonia.
[0005] Myotonia congenita is a rare disease that is inherited as
autosomal dominant or recessive. It shows a characteristic that
takes time to relax the muscles by increasing spasticity of
voluntary muscles when exercising. Muscular hypertrophy may also
occur with an increase in spasticity, and if abnormal symptoms by
muscle relaxation are expanded into the facial, ocular and tongue
muscles, it may cause speech disorders. Myotonia congenita include
two types: Becker's disease and Thomsen's disease. Both diseases
are caused by mutations in CLCN1 gene expressing chloride
channel-1, and occur a variety of phenotypes with more than 130
various mutations. Abnormalities of chloride channel-1 can lead to
myotonia as described in said myotonic dystrophy. Myotonia which
appears in myotonia congenita occurs more often in pregnant
women.
[0006] Paramyotonia congenita is caused by mutations in SCN4 gene
expressing the voltage-gated sodium channel 1.4. These mutations
generate spontaneous action potential after voluntary movement by
preventing the normal channel inactivation. Myotonic symptoms
mainly appears in the face and limbs. In addition to myotonic
symptoms, a cycle of limb muscle paralysis occurs when serum
potassium rises.
[0007] Myoatrophy which appears in myotonia is caused by
hyperexcitability of the sarcolemma and causes pain and mobility
difficulty in daily life. The hyperexcitability of the sarcolemma
occurs due to the excessive action potential of the muscle cell.
Mexiletine, which is also used as a treatment for ventricular
arrhythmia, is currently in clinical trials for patients with
myotonia, and induces muscle relaxation by blocking the 1,4-type
voltage-gated sodium channel of skeletal muscles, thereby
inhibiting the action potential release during myoatrophy.
Mexiletine also alleviates the muscle weakness of myotonia
congenita caused by chloride channel-1 mutation (CLCN1 mutation).
However, mexiletine is difficult to apply as a therapeutic agent
for myotonia due to side effects and lack of drug efficacy.
Tocanide, which is oral lidocaine analogue, has also been used to
treat myotonia, but sales have been discontinued in many countries
due to serious side effects (M. De Bellis et al., 2017,
Neuropharmacology, 113: 206-216).
[0008] To date, drugs for the treatment of myotonia are being
developed in the absence of appropriate therapeutic agents.
SUMMARY
Problem to be Solved
[0009] The present invention is intended to provide a method for
the prevention, alleviation or treatment of myotonia.
[0010] In addition, the present invention is intended to provide
the use of a carbamate compound of the following Formula 1, or a
pharmaceutically acceptable salt, solvate or hydrate thereof for
the prevention, alleviation or treatment of myotonia:
##STR00002##
[0011] wherein, R.sub.1, R.sub.2, A.sub.1 and A.sub.2 are as
defined herein.
Technical Solution to the Problem
[0012] The present invention provides a medicament for the
prevention, alleviation or treatment of myotonia, comprising a
therapeutically effective amount of a carbamate compound of the
following Formula 1, or a pharmaceutically acceptable salt, solvate
or hydrate thereof:
##STR00003##
[0013] wherein,
[0014] R.sub.1 and R.sub.2 are each independently selected from the
group consisting of hydrogen, halogen, C.sub.1-C.sub.8 alkyl,
halo-C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.8 thioalkoxy and
C.sub.1-C.sub.8 alkoxy; and one of A.sub.1 and A.sub.2 is CH, and
the other is N.
[0015] In addition, the present invention provides a pharmaceutical
composition for the prevention, alleviation or treatment of
myotonia, comprising a therapeutically effective amount of the
carbamate compounds of the above Formula 1, or a pharmaceutically
acceptable salt, solvate or hydrate thereof, and further one or
more of a pharmaceutically acceptable carrier.
[0016] In addition, the present invention provides a method for
preventing, alleviating or treating myotonia, comprising
administering to the subject a therapeutically effective amount of
the carbamate compounds of the above Formula 1, or a
pharmaceutically acceptable salt, solvate or hydrate thereof.
[0017] In addition, the present invention provides the use of the
carbamate compounds of the above Formula 1, or a pharmaceutically
acceptable salt, solvate or hydrate thereof for the prevention,
alleviation or treatment of myotonia.
[0018] According to one embodiment of the present invention, in the
above Formula 1, R.sub.1 and R.sub.2 are each independently
selected from the group consisting of hydrogen, halogen and
C.sub.1-C.sub.8 alkyl.
[0019] In one embodiment, halo-C.sub.1-C.sub.8 alkyl is
perfluoroalkyl.
[0020] According to another embodiment of the present invention,
the carbamate compound of the above Formula 1 is carbamic acid
(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester of the following
Formula 2:
##STR00004##
[0021] A person having ordinary skill in the art of synthesis of
compounds could have easily prepared the carbamate compounds of the
above Formulas 1 and 2 using known compounds or compounds which can
be easily prepared therefrom. In particular, methods for preparing
the compounds of the above Formula 1 are described in detail in
International Publication Nos. WO 2006/112685 A1, WO 2010/150946 A1
and WO 2011/046380 A2, the disclosures of which are incorporated
herein by reference. The compounds of Formula 1 can be chemically
synthesized by any of the methods described in the above documents,
but the methods are merely exemplary ones, and the order of the
unit operation and the like may be selectively changed if
necessary. Hence, the above methods are not intended to limit the
scope of the invention.
[0022] The carbamate compounds of the above Formula I can be used
for the prevention, alleviation or treatment of myotonia.
[0023] According to one embodiment of the present invention, the
disease which represents myotonia may be one or more selected from
myotonia congenita comprising myotonic dystrophy (Steinert's
disease); Becker's disease and Thomsen's disease; and paramyotonia
congenita. The myotonic dystrophy may be type 1 or type 2.
[0024] According to one embodiment, myotonia may be a sporadic
etiology or a hereditary etiology involving a family history. In
addition, myotonia may be caused by abnormality of the gene (CLCN1)
expressing chloride channel-1 or the gene (SCN4) expressing the
voltage-gated sodium channel 1.4. In addition, sustained
excitability maintenance of muscle cells by hyperexcitability of
muscle cells in this disease is one of the main mechanisms
(Kwiecinski et al., 1984, Muscle & Nerve, 7(1): 60-5; Lossin et
al., 2008, Advances in Genetics, 63: 25-55). Myotonia related to
CLCN1 gene mutations includes Thomsen's disease, Becker's disease,
myotonia congenita, generalized myotonia, myotonia levior. Diseases
related to SCN4A gene mutations include paramyotonia congenita,
potassium aggravated myotonia, myotonic fluctuans, myotonia
permanens or acetazolamide responsive myotonia.
[0025] Symptoms of myotonic dystrophy begin with muscle weakness in
the hands, feet, neck or face, and the muscle weakness gradually
progresses to other muscles including the heart. Problems of
executive function and symptoms of hypersomnia may occur.
[0026] Adult-onset myotonic dystrophy type 1 can cause cataracts,
myotonia and diabetes. In serious cases, muscle weakness may occur
in specific muscles (upper eyelid levators, masticator muscles,
neck muscles, specific limb muscles, etc.). Muscle pain and fatigue
are common symptoms. Initiation of adolescent myotonic dystrophy
type 1 may have symptoms of muscle weakness or spasticity. They may
have difficulty with a learning deficiency or a social behavior and
may have disorders with speech or hearing. They may have
heart-related symptoms such as arrhythmia, which may not be
accompanied by other symptoms. Adolescent myotonic dystrophy type 2
has weaker symptoms than type 1. From birth, congenital myotonic
dystrophy type 1 is the most serious type of myotonic dystrophy. It
shows serious muscle weakness and muscular hypotonia symptoms at
birth. Some infants show deteriorating eyesight, hyperopia and
astigmatism. Intellectual disabilities can occur, and learning and
behavioral disorder can continue to develop as they grow. In
addition, growth deficiency due to dietary disorders may occur, and
gastroparesis can cause persistent digestive symptoms such as
nausea. Congenital myotonic dystrophy disease can cause respiratory
problems due to muscle weakness. This is a major cause of death of
the disease. Congenital myotonic dystrophy disease develops as
adult-onset myotonic dystrophy and causes heart-related problems.
Myotonic dystrophy type 2 shows muscle weakness, muscle pain,
spasticity or cataract, and some patients do not have these
symptoms. The degree of symptoms and the types of symptoms appear
differently for each individual patient. Cardiac function
abnormalities appear less frequently than in type 1, but can rarely
cause death.
[0027] Myotonia congenita is a disease of the voluntary muscles
(skeletal muscles) abnormality that responds to hyperexcitability
of the specific muscular fibers and causes cramps, abnormal muscle
stiffness and spasticity. Symptoms tend to occur when a patient
uses specific muscles after a refractory period. Myotonia congenita
patients mostly develop abnormal hypertrophy of the voluntary
muscles.
[0028] Paramyotonia congenita is a rare non-progressive genetic
disorder that affects skeletal muscles. The main symptoms are
muscle stiffness and spasticity, which are mainly shown in the
muscles of the face, neck and upper limbs, and may also occur in
muscles related to breathing or deglutition movement or back
muscles. It shows no muscular atrophy, and partly appears as muscle
hypertrophy. The severity of muscle stiffness varies from person to
person, and some patients are accompanied by pain with
spasticity.
[0029] The carbamate compounds of the above Formula 1 may be
applied to myotonia by suppressing the excitability maintenance of
neuron cells. In addition, the carbamate compounds of the above
Formula 1 may be used to prevent, alleviate or treat various
symptoms related to myotonia--for example, muscle stiffness,
spasticity, distal muscle weakness, weakness of the face and jaw
muscles, difficulty in swallowing, sagging of the eyelids
(blepharosis), weakness of the neck muscles, weakness of the arm
and leg muscles, persistent muscle pain, excessive sleep, muscle
wasting, dysphagia, respiratory failure, irregular heartbeat, heart
muscle damage etc.
[0030] The efficacy for myotonia of the compounds of the above
Formula 1 can be confirmed by the use of known models. For example,
the efficacy of the compounds of the above Formula 1 may be
evaluated in a myotonia model caused by anthracene-9-carboxylic
acid (9-AC). Anthracene-9-carboxylic acid can cause myotonic
conditions by blocking the chloride channel-1 of muscle cells.
Myotonic conditions are induced by intraperitoneal injection once
to experimental animals (rats), and can be evaluated by measuring
the righting reflex time. Righting reflex is a reflex behavior in
which the animal's body returns from an abnormal position to a
normal position, and the degree of myotonia can be evaluated by
measurement of righting reflex behavior due to abnormality of
muscle tension/relaxation after 9-AC treatment. Specifically, the
degree of spasticity is evaluated by measuring the time that it
takes for the four feet of the experimental animal to land normally
when the experimental animal is turned upside down and the posture
is straightened (time of righting reflex, TRR).
[0031] The dosage of the carbamate compounds of Formula 1 for the
prevention, alleviation or treatment of the above diseases may
typically vary depending on the severity of the disease, the body
weight and the metabolic status of the subject. A "therapeutically
effective amount" for an individual patient refers to an amount of
the active compound sufficient to achieve the above pharmacological
effect--i.e., the therapeutic effect as described above. The
therapeutically effective amount of the compounds of Formula 1 is
50 to 500 mg, 50 to 400 mg, 50 to 300 mg, 100 to 400 mg, 100 to 300
mg, 50 to 200 mg or 100 to 200 mg, based on the free form and
once-daily administration to humans.
[0032] The compounds of the present invention may be administered
by any conventional method used for administration of a therapeutic
agent, such as oral, parenteral, intravenous, intramuscular,
subcutaneous or rectal administration.
[0033] The medicament or pharmaceutical composition according to
one embodiment of the present invention may comprise compounds
selected from the group consisting of the carbamate compounds of a
therapeutically effective amount of the present invention, their
pharmaceutically acceptable salts, solvates, hydrates and
combinations thereof.
[0034] Examples of the pharmaceutically acceptable salts of the
carbamate compounds of the above Formula 1 include independently,
for example, acetate, benzenesulfonate, benzoate, bitartrate,
calcium acetate, camsylate, carbonate, citrate, edetate, edisylate,
estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
glycoloylarsanilate, hexylresorcinate, hydravamine, hydrobromide,
hydrochloride, hydrogencarbonate, hydroxynaphthoate, iodide,
isethionate, lactate, lactobionate, malate, maleate, mandelate,
mesylate, methylnitrate, methylsulfate, mucate, napsylate, nitrate,
pamoate (embonate), pantothenate, phosphate/diphosphate,
polygalacturonate, salicylate, stearate, subacetate, succinate or
hemi-succinate, sulfate or hemi-sulfate, tannate, tartrate, oxalate
or hemi-tartrate, teoclate, triethiodide, benzathine,
chloroprocaine, choline, diethanolamine, ethylenediamine,
meglumine, procaine, aluminum, ammonium, tetramethylammonium,
calcium, lithium, magnesium, potassium, sodium and zinc.
[0035] The medicament or pharmaceutical composition according to
one embodiment of the present invention may be administered orally
or parenterally. The parenteral administration may include
intravenous injection, subcutaneous injection, intramuscular
injection, intraperitoneal injection, endothelial administration,
topical administration, intranasal administration, intravaginal
administration, intrapulmonary administration, rectal
administration and the like. In the case of oral administration,
the pharmaceutical composition according to one embodiment may be
formulated as a plain tablet (uncoated tablet) or such that the
active agent is coated or is protected against degradation in the
stomach. In addition, the composition can be administered by any
device capable of transferring the active substance to a target
cell. The route of administration may vary depending upon the
general condition and age of the subject to be treated, the nature
of the treatment condition and the active ingredient selected.
[0036] A suitable dosage of the medicament or pharmaceutical
composition according to one embodiment of the present invention
may vary depending on factors such as the formulation method,
administration method, age, body weight and gender of patients,
pathological condition, diet, administration time, administration
route, excretion rate and reaction sensitivity, and doctors having
ordinary skill can easily determine and prescribe dosages that are
effective for the desired treatment or prophylaxis. The
pharmaceutical composition according to one embodiment may be
administered in one or more doses, for example, one to four times
per day. The pharmaceutical composition according to one embodiment
may contain the compounds of Formula 1 in the amount of 50 to 500
mg, 50 to 400 mg, 50 to 300 mg, 100 to 400 mg, 100 to 300 mg, 50 to
200 mg, or 100 to 200 mg, preferably 50 to 300 mg, based on the
free form.
[0037] The medicament or pharmaceutical composition according to
one embodiment of the present invention may be formulated using a
pharmaceutically acceptable carrier and/or excipient according to a
method that a person having ordinary skill in the art could easily
carry out, thereby to be prepared in a unit dose form or to be
contained in a multi-dose container. The above formulation may be a
solution in oil or an aqueous medium, a suspension or an emulsion
(emulsified solution), an extract, a powder, granules, a tablet, or
a capsule, and may further include a dispersing or stabilizing
agent. In addition, the pharmaceutical composition may be
administered in the form of suppositories, sprays, ointments,
creams, gels, inhalants or skin patches. The pharmaceutical
composition may also be prepared for mammalian administration, more
preferably for human administration.
[0038] Pharmaceutically acceptable carriers may be solid or liquid,
and may be one or more selected from fillers, antioxidants,
buffers, bacteriostats, dispersants, adsorbents, surfactants,
binders, preservatives, disintegrants, sweeteners, flavors,
glidants, release-controlling agents, wetting agents, stabilizers,
suspending agents and lubricants. In addition, the pharmaceutically
acceptable carriers may be selected from saline, sterile water,
Ringer's solution, buffered saline, dextrose solution, maltodextrin
solution, glycerol, ethanol and mixtures thereof.
[0039] In one embodiment, suitable fillers include, but are not
limited to, sugar (e.g., dextrose, sucrose, maltose and lactose),
starch (e.g., corn starch), sugar alcohol (e.g., mannitol,
sorbitol, maltitol, erythritol and xylitol), starch hydrolysate
(e.g., dextrin and maltodextrin), cellulose or cellulose
derivatives (e.g., microcrystalline cellulose) or mixtures
thereof.
[0040] In one embodiment, suitable binders include, but are not
limited to, povidone, copovidone, methylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
hydroxyethylcellulose, gelatin, gum, sucrose, starch or mixtures
thereof.
[0041] In one embodiment, suitable preservatives include, but are
not limited to, benzoic acid, sodium benzoate, benzyl alcohol,
butylated hydroxyanisole, butylated hydroxytoluene, chlorbutol,
gallate, hydroxybenzoate, EDTA or mixtures thereof.
[0042] In one embodiment, suitable disintegrants include, but are
not limited to, sodium starch glycolate, cross-linked
polyvinylpyrrolidone, cross-linked carboxymethylcellulose, starch,
microcrystalline cellulose or mixtures thereof.
[0043] In one embodiment, suitable sweeteners include, but are not
limited to, sucralose, saccharin, sodium saccharin, potassium
saccharin, calcium saccharin, acesulfame potassium or sodium
cyclamate, mannitol, fructose, sucrose, maltose or mixtures
thereof.
[0044] In one embodiment, suitable glidants include, but are not
limited to, silica, colloidal silicon dioxide, talc and the
like.
[0045] In one embodiment, suitable lubricants include, but are not
limited to, long chain fatty acids and salts thereof, such as
magnesium stearate and stearic acid, talc, glyceride wax or
mixtures thereof.
[0046] As used herein, the terms "prevent," "preventing" and
"prevention" refer to reducing or eliminating the likelihood of a
disease.
[0047] As used herein, the terms "alleviate," "alleviating" and
"alleviation" refer to ameliorating a disease and/or its
accompanying symptoms altogether or in part.
[0048] As used herein, the terms "treat," "treating" and
"treatment" refer to eliminating a disease and/or its accompanying
symptoms altogether or in part.
[0049] As used herein, the term "subject" refers to an animal that
is the object of therapy, observation or experiment, preferably a
mammal (such as primates (e.g., a human), cattle, sheep, goats,
horses, dogs, cats, rabbits, rats, mice, etc.), most preferably a
human.
[0050] As used herein, the term "therapeutically effective amount"
refers to the amount of active compound or pharmaceutical
formulation that elicits a biological or medical response in the
system, animal or human, including alleviation of the symptoms of
the disease or disorder to be treated, wherein said amount is
sought by a researcher, veterinarian, doctor (physician) or other
clinician.
[0051] As used herein, the term "composition" encompasses a product
that contains a specified amount of a particular ingredient and any
product that results directly or indirectly from a combination of
specified amounts of particular ingredients.
Effect of the Invention
[0052] The medicament and the pharmaceutical composition according
to the present invention can effectively treat and prevent
myotonia. The medicament and the pharmaceutical composition can not
only relieve the burst of muscle cell action potential, but also
suppress the onset of the burst.
BRIEF DESCRIPTION OF THE DRAWINGS
[0053] FIG. 1 is a result through righting reflex test to confirm
whether the spasticity conditions are alleviated, and the
spasticity conditions are induced when 15 mg/kg and 20 mg/kg of
carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester
(hereinafter referred to as "test compound") prepared in the
Preparation Example was injected intraperitoneally into rats,
respectively, and then after 20 minutes, anthracene-9-carboxylic
acid (9-AC) was injected intraperitoneally. Righting reflex was
measured after 30 minutes and 1 hour, respectively, after
administration of 9-AC. The control group was administered only 30%
PEG 300 without the addition of the test compound.
[0054] FIG. 2 is a result of comparing and confirming the righting
reflex time with the control group: the righting reflex time was
measured when 15 mg/kg or 20 mg/kg of the test compound was
respectively administered, and then after 20 minutes, 9-AC was
administered, and after 30 minutes.
[0055] FIG. 3 is a result of comparing and confirming the righting
reflex time with the control group: the righting reflex time was
measured when 15 mg/kg or 20 mg/kg of the test compound was
respectively administered, and then after 20 minutes, 9-AC was
administered, and after 1 hour.
DETAILED DESCRIPTION
[0056] Hereinafter, the present invention will be explained in more
detail thorough working examples. However, the following working
examples are only intended to illustrate one or more embodiments
and are not intended to limit the scope of the invention.
Preparation Example: Preparation of carbamic acid
(R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl ester
[0057] Carbamic acid (R)-1-(2-chlorophenyl)-2-tetrazol-2-yl-ethyl
ester (test compound) was prepared according to the method
described in Preparation Example 50 of International Publication
No. WO 2010/150946.
Example: Experiment Using Myotonia Induction Model by Drug (9-AC)
Treatment
[0058] In the experimental animal model of myotonia induction by
drug (9-AC) treatment, it was reported that the time to return to
normal posture after righting reflex was delayed when measuring the
rat's spasticity conditions using righting reflex (Desaphy et al.,
2013, Neuropharmacology, 65: 21-27).
[0059] As an experimental model, Sprague-Dawley rats (350-400 g, 10
weeks old, a total of 36 males) were used (Orient Bio Inc.). The
drug anthracene-9-carboxylic acid (9-AC) used to induce myotonia is
a drug that inhibits chloride channel-1 of skeletal muscle cells
and induces hyperexcitation of muscle cells. The control group (30%
PEG300) or test compound was intraperitoneally administered to the
rat once in each dose (15, 20 mg/kg). Test compounds were diluted
in 30% PEG300 solution to a final dose of 5 ml/kg. After 20 minutes
of administration of control group or test compound, 0.3%
NaHCO.sub.3 solution containing 6 mg/ml of 9-AC was
intraperitoneally administered by 10 ml/kg. After administration of
9-AC, righting reflex tests were performed at 30 minutes and 1
hour, respectively, and the time to return to normal posture (time
of righting reflex, TRR) was measured.
[0060] When 30 minutes and 1 hour had elapsed after the spasticity
was induced, the test compound showed results of a decrease in time
to return to normal posture compared to the control group in
righting reflex test. Over time, the control group showed results
of an increase in the time to return to the normal posture in the
righting reflex test, but in the group treated with the test
compound, this tendency was alleviated (FIG. 1). These results
demonstrate that the test compound can alleviate myotonia.
Differential time reduction results were shown depending on the
dose of the test compound, and at both 30 minutes and 1 hour, the
20 mg/kg dose of the test compound showed a significant time
reduction effect compared to the control group (P<0.05) (FIG. 2,
FIG. 3). Statistical analysis was used for the one-way ANOVA (1-way
ANOVA) and Tukey's multiple comparison test, and outliers were
excluded through the ROUT outlier analysis test (Q=1%) (in the
30-minute test, excluding each one in the control group and the 20
mg/kg treatment group; in the 1-hour test, excluding one in the 20
mg/kg treatment group). The results were derived from three
repeated experiments. The average value of the righting reflex time
measured for each group is shown in Table 1 below.
TABLE-US-00001 TABLE 1 Average Righting Control Test compound Test
compound reflex time (TRR) group 15mg/kg 20mg/kg 30 minutes 3 .+-.
0.254 2.282 .+-. 0.304 1.85 .+-. 0.266 (n=8) (n=9) (n=8) 1 hour
9.397 .+-. 2.834 4.978 .+-. 0.944 2.515 .+-. 0.328 (n=9) (n=9)
(n=8)
[0061] From the above results, by showing the efficacy of
alleviating spasticity which appears in myotonia, it was confirmed
that the compound of Formula 1 (test compound) can be used as a
drug for the prevention and treatment of myotonia.
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