Patent Description:
Tremor or oscillation is a symptom in which a body part shakes regularly even though it was not intended. Medically, tremor is defined as an involuntary and rhythmic oscillatory movement of a part or parts of the body, resulting from alternating or irregularly synchronous contractions of antagonist muscles. Tremor can occur due to normal physiological processes, pathologic mechanisms or the uptake of certain medications and can be exacerbated by stress, anxiety, fatigue, coffee or tobacco.

Tremors are largely divided into two types; rest tremors and action tremors. Rest tremor occurs when muscle is not voluntarily activated, whereas action tremor is present with voluntary contraction of muscle. Subtypes of action tremor include postural, kinetic and isometric tremor. Postural tremor is present while voluntarily maintaining a position against gravity. Kinetic tremor may occur during any form of voluntary movement. Isometric tremor occurs when an equal degree of muscle contraction occurs for an object, such as holding the tester's hand tightly. Kinetic tremor includes (a) simple kinetic tremor that is present with non-target-directed autonomous action, (b) intention tremor referring to exacerbation of kinetic tremor toward the end of a goal-directed movement and (c) task-specific kinetic tremor that occurs during performance of certain tasks and activities.

Since practical classifications of tremor that are based upon etiologic or pathophysiologic factors are not currently available, tremor or tremor syndrome is generally classified on the basis of the clinical symptoms (syndrome) of tremor.

Essential tremor is a neurologic movement disorder with oscillating movements of unknown cause, often causing functional disorders and potentially physiological and emotional disorders. Essential tremor usually occurs in the hands, but can uncommonly occur in the head, legs or voice, which affects daily life (<NPL>). The characteristic of essential tremor is the regular oscillating movements that occur during the exercise of a voluntary muscle or while maintaining the force against gravity. Essential tremor is often misdiagnosed as Parkinson's disease because in the case of Parkinson's disease the body is stiffened and slowed, and hand shaking symptoms may appear.

Essential tremor is the most common type tremor among more than <NUM> types. Essential tremor occurs <NUM> to <NUM> times more frequently than Parkinson's disease (PD), affecting <NUM> million to <NUM> million people in the United States alone. Although the average age of onset of essential tremor is usually <NUM>, it may occur first in other age groups such as children and the elderly (<NPL>).

Although the cause of essential tremor is not well known, genetic relevance has often been reported as the cause in view of most patients' findings. However, even in the absence of family history, essential tremor may be developed. The epidemiological relevance of essential tremor is known to be due to the occurrence of abnormal signal transduction between specific parts of the brain, including the cerebellum, thalamus and brainstem (<NPL>; <NPL>).

As tremors are of various types, there are differences in their treatment methods, and the response to such treatments varies. There is no FDA-approved drug for the treatment of essential tremor, and drugs approved for the treatment of other diseases are used for tremor therapy, and its use is limited due to its efficacy and side effects. Beta-adrenoreceptor antagonists such as propranolol are known to weaken essential tremor and physiologic tremor, but may also affect the central nervous system (<NPL>).

Most essential tremor patients benefit from pharmacological therapy, and many experience a significant reduction of tremor. However, it is very rare that tremor is completely diminished, and none of the drugs work effectively for all patients. In addition, tolerance may be reported in some patients undergoing long-term therapy, by which the patients may experience rather worsening of the symptoms of tremor.

In addition, there are still limitations in the use of the drugs due to the comorbidities associated with them which result in an unsatisfactory level of therapeutic effect or due to side effects. Thus, there is a need for new drugs with improved efficacy and fewer side effects (<NPL>). <CIT> and <CIT> disclose compounds for use in the treatment of tremors but the structure of the compounds differs from the present compound. <CIT> discloses the present compound for use in the treatment of convulsion and epilepsy. <CIT> discloses the present compound only for use in the treatment of associated functional symptoms of fibromyalgia.

The present invention is intended to provide a carbamate compound of the following Formula <NUM>, or a pharmaceutically acceptable salt, solvate or hydrate thereof, for use in the prevention, alleviation or treatment of tremor or tremor syndrome, particularly essential tremor:
<CHM>.

Specifically, the
present invention provides a medicament for the prevention, alleviation or treatment of tremor or tremor syndrome, particularly essential tremor, comprising a therapeutically effective amount of a carbamate compound of the following Formula <NUM>, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
<CHM>.

In addition, the present invention provides a pharmaceutical composition for use in the prevention, alleviation or treatment of tremor or tremor syndrome, particularly essential tremor, comprising a therapeutically effective amount of the carbamate compounds of the above Formula <NUM>, or a pharmaceutically acceptable salt, solvate or hydrate thereof, and further one or more of a pharmaceutically acceptable carrier.

In addition, the present invention provides the carbamate compounds of the above Formula <NUM>, or a pharmaceutically acceptable salt, solvate or hydrate thereof for use in
the improvement of symptoms associated with tremor or tremor syndrome, particularly essential tremor. The carbamate compound of the above Formula <NUM> is carbamic acid (R)-<NUM>-(<NUM>-chlorophenyl)-<NUM>-tetrazol-<NUM>-yl-ethyl ester.

A person having ordinary skill in the art of synthesis of compounds could have easily prepared the carbamate compounds of the above Formula <NUM> using known compounds or compounds which can be easily prepared therefrom. In particular, methods for preparing the compounds of the following Formula <NUM> are described in detail in <CIT>, <CIT> and <CIT>:
<CHM>
wherein,.

The compounds of the above Formula <NUM> 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.

The carbamate compounds disclosed herein can be used for the prevention, alleviation or treatment of tremor or tremor syndrome.

Particularly, the carbamate compounds of the above Formula <NUM> can be used for the prevention, alleviation or treatment of essential tremor,
rest tremor, action tremor or combined (complex) tremor thereof.

Rest tremor includes Parkinsonian tremor syndrome, myorhythmia, cerebellar tremor syndrome, neuropathic tremor syndrome, psychogenic tremor and the like.

Action tremor may be classified as postural tremor, kinetic tremor and isometric tremor. Postural tremor includes essential tremor, physiologic tremor, enhanced physiologic tremor, dystonic tremor and the like. Kinetic tremor includes simple kinetic tremor, intention tremor, task-specific kinetic tremor and the like, and also includes cerebellar tremor syndrome, palatal tremor, partially neuropathic tremor syndrome, drug-induced and toxic tremor syndrome, myorhythmia, psychogenic tremor and the like. Isometric tremor includes primary orthostatic tremor and the like. Other complex tremors that do not belong to the aforementioned tremors include Holmes tremor, palatal myoclonus and the like.

As an example of a model for assessing the potential efficacy of therapeutic agents that can effectively treat tremor and other tremor syndromes, including essential tremor, oxotremorine-induced tremor in animals can be used (<NPL>).

The dosage of the carbamate compounds of Formula <NUM> 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 the present invention is <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>, based on the free form and once-daily administration to humans. The therapeutically effective amount is preferably <NUM> to <NUM>, more preferably <NUM> to <NUM>.

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.

The medicament or pharmaceutical composition according to one embodiment of the present invention may comprise a therapeutically effective amount of a compound selected from the group consisting of the carbamate compounds of the present invention, their pharmaceutically acceptable salts, solvates, hydrates and combinations thereof.

Examples of the pharmaceutically acceptable salts of the carbamate compounds of the above Formula <NUM> include independently, acetate, benzenesulfonate, benzoate, bitartrate, calcium acetate, camsylate, carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycoloyl arsanilate, 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.

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 of the present invention may be formulated as a plain tablet (uncoated tablet) or such that the active agent is coated or it 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.

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 <NUM> in the amount of <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, <NUM> to <NUM>, or <NUM> to <NUM>, preferably <NUM> to <NUM>, more preferably <NUM> to <NUM>, based on the free form.

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.

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.

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.

In one embodiment, suitable binders include, but are not limited to, povidone, copovidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, gelatin, gum, sucrose, starch or mixtures thereof.

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.

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.

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.

In one embodiment, suitable glidants include, but are not limited to, silica, colloidal silicon dioxide, talc and the like.

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.

As used herein, the terms "prevent," "preventing" and "prevention" refer to reducing or eliminating the likelihood of a disease.

As used herein, the terms "alleviate," "alleviating" and "alleviation" refer to ameliorating a disease and/or its accompanying symptoms altogether or in part.

As used herein, the terms "treat," "treating" and "treatment" refer to eliminating a disease and/or its accompanying symptoms altogether or in part.

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.

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.

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.

The medicament and the pharmaceutical composition according to the present invention can effectively treat and prevent tremor or tremor syndrome, especially multiple essential tremor.

<FIG> is a graph showing the results of the oxotremorine-induced tremor experiments performed in Example <NUM>.

Hereinafter, the present invention will be explained in more detail through 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.

Carbamic acid (R)-<NUM>-(<NUM>-chlorophenyl)-<NUM>-tetrazol-<NUM>-yl-ethyl ester (the compound of Formula <NUM>, hereinafter referred to as "the test compound") was prepared according to the method described in Preparation Example <NUM> of <CIT>.

As a model for assessing the potential efficacy of therapeutic agents that can effectively treat essential tremor and other tremor syndromes, oxotremorine-induced tremor in rats was used [<NPL>].

Male SD rats (CrjBgi:CD(SD)IGS) were purchased from Orient Bio, Inc. of Korea, and placed in a wire mesh cage under conditions of ambient temperature of <NUM> to <NUM>, <NUM> to <NUM>% relative humidity, an automatically controlled light-and-darkness cycle of <NUM> hours and free access to feed (purchased from Agri Brands Purina Korea, Inc. ) and water. The rats were housed and maintained in accordance with the Laboratory Animal Care Standards of the Institutional Animal Care and Use Committee (IACUC). After about one week of stabilization, rats weighing <NUM> to <NUM> were used in the experiment. The rats to be used for the experiment were fasted by removing the feed <NUM> hours before the experiment, and placed in a tremor measurement device (Tremor Monitor™, San Diego Instruments, CA) <NUM> hours before the experiment and adapted for <NUM> minutes.

The test compound was prepared by dissolving it in <NUM>% polyethylene glycol <NUM> (purchased from Sigma) used as a vehicle <NUM>-<NUM> minutes before each experiment. The vehicle and the test compound (<NUM>, <NUM> and <NUM>/kg dose) were administered into the oral cavity, respectively, in a volume of <NUM> per <NUM> body weight of the rat. After <NUM> minutes, oxotremorine (oxotremorine sesquifumarate salt, <NUM>-(<NUM>-[<NUM>-Pyrrolidinyl]-<NUM>-butynyl)-<NUM>-pyrrolidinone sesquifumarate; purchased from Sigma) dissolved in saline and prepared in a volume of <NUM>/kg or a saline were subcutaneously injected into the back of the rat neck in a volume of <NUM> per <NUM> body weight of the rat. Oxotremorine-administered rats were immediately placed in a tremor measurement device (filter frequency <NUM>, band-width <NUM>, filter number <NUM>), and the number of tremor behaviors that progressed for at least <NUM> seconds in <NUM>,<NUM> seconds were automatically measured and recorded. The number of rats per group was <NUM>.

All data were expressed as mean ± SEM. The number of oxotremorine-induced tremor behaviors in the group treated with the test compound was expressed as % inhibition compared to the vehicle group. Statistical analysis of the number of tremor behaviors between groups was performed using one-way ANOVA (one-way analysis of variance) and Dunnett's multiple comparison test by using the GraphPad Prism ver. <NUM> program. The mean number of tremor behaviors in the vehicle/oxotremorine group was observed as <NUM> ± <NUM>, and the mean number of tremor behaviors in the vehicle/saline group was observed as <NUM> ± <NUM>. In the test compound administered group, tremor behaviors were inhibited in a dose dependent manner, showing inhibition rates of <NUM>% at <NUM>/kg, <NUM>% at <NUM>/kg and <NUM>% at <NUM>/kg. Median Effective Dose (ED<NUM>) value was calculated to be <NUM>/kg. The test compound showed significant pharmacological activity in the oxotremorine-induced tremor behavior model, which is a representative animal model of essential tremor syndrome. Table <NUM> summarizes the experimental data (inhibition rate), and the experimental results are shown in <FIG>.

Claim 1:
A carbamate compound which is carbamic acid (R)-<NUM>-(<NUM>-chlorophenyl)-<NUM>-tetrazol-<NUM>-yl-ethyl ester of the following Formula <NUM>, or a pharmaceutically acceptable salt, solvate or hydrate thereof for use in the prevention, alleviation or treatment of essential tremor, rest tremor, action tremor or combined (complex) tremor thereof:
<CHM>