Patent Application
20220117941
The present invention relates to use of a carbamate compound of the following Formula 1 for the purpose of preventing, alleviating or treating acute stress disorder or post-traumatic stress disorder by administering a pharmaceutical composition comprising said carbamate compound:
wherein,
R1, R2, A1 and A2 are as defined herein.
“Acute stress disorder” is a psychological condition defined in Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision, published by the American Psychiatric Association, Washington, D.C., 2000 (“DSM-IV-TR”). DSM-IV-TR defines “acute stress disorder” as being characterized by symptoms that occur within one month after exposure to an extreme traumatic stressor. DSM-IV-TR lists generally recognized criteria for diagnosing and classifying acute stress disorder.
“Post-traumatic stress disorder (PTSD)” is a psychological condition defined in DSM-IV-TR. DSM-IV-TR defines “post-traumatic stress disorder” as being characterized by continuous re-experiencing of extreme traumatic event(s). DSM-IV-TR lists generally recognized criteria for diagnosing and classifying post-traumatic stress disorder. Extreme traumatic events are events that cause mental trauma which is extreme stresses such as physical abuse, violence, war, life-threatening serious accidents and natural disasters. Most such traumas occur suddenly, causing severe pain for the person experiencing them and reducing their ability to cope with stress. In general, it occurs 5 to 10% of the population, and the prevalence rate of women is about twice as high as that of men.
Symptoms of post-traumatic stress disorder include full or partial amnesia of mental trauma or situation (traumatic events), flashback re-experiencing traumatic events by intrusive memories of that time even though the traumatic events had passed, avoidance of stimuli associated with traumatic events—e.g., activities or places associated with traumatic events, nightmares associated with traumatic events, irritability, hyperarousal (enhanced state of threat sensitivity with the potential for danger), hypervigilance, rage, poor concentration and emotional withdrawal (Nature Reviews Disease Primers volume 1, Article number: 15057 (2015)).
Pharmacological treatment and non-pharmacological treatment can be provided for post-traumatic stress disorder. Only two medications—sertraline and paroxetine, which are anti-depressants having mechanism of action as selective serotonin reuptake inhibitors (SSRIs)—have received approval from the FDA for the treatment of post-traumatic stress disorder. Anti-depressants including these medications are used as the first-line treatment for post-traumatic stress disorder. However, not all patients with PTSD respond to SSRIs and the use of SSRIs is also limited due to adverse effects such as insomnia. In addition to these medications, many medications are used off label for the treatment of post-traumatic stress disorder. Propranolol and prazosin—which have a mechanism of noradrenergic regulation—show partial efficacy in reducing physical symptoms caused by anxiety and alleviating nightmares, respectively. Anti-epileptic drugs—which show efficacy on the kindling model acting on the limbic system of the brain—have been used for alleviating symptoms of anxiety, fear and post-traumatic stress disorder by reducing exaggerated responses to stressors. In addition, various medications such as atypical antipsychotics are also prescribed for each symptom (Journal of Psychiatric Research 36 (2002) 355-367, Curr Psychiatry Rep. 2007 August; 9(4): 291-300).
Meanwhile, as a non-pharmacological treatment, behavioral psychotherapy such as cognitive behavior therapy (CBT) or prolonged exposure therapy (PET) is also used to treat post-traumatic stress disorder (Front Behav Neurosci. 2018; 12: 258).
As described above, various pharmacological treatments and non-pharmacological treatments are used to alleviate the symptoms of post-traumatic stress disorder. However, selective serotonin reuptake inhibitors are considered first-line treatment but they are ineffective to all PTSD patients and not tolerated due to adverse effects including insomnia, sexual dysfunction, gastrointestinal symptom, dizziness and headaches. As such, there is a need for new drugs with improved efficacy and safety.
The present invention is intended to provide a method for the prevention, alleviation or treatment of acute stress disorder or post-traumatic stress disorder.
The present invention is also 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 acute stress disorder or post-traumatic stress disorder:
wherein,
R1, R2, A1 and A2 are as defined herein.
The present invention provides a medicament for the prevention, alleviation or treatment of acute stress disorder or post-traumatic stress disorder, comprising a therapeutically effective amount of a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and
one of A1 and A2 is CH, and the other is N.
In addition, the present invention provides a pharmaceutical composition for the prevention, alleviation or treatment of acute stress disorder or post-traumatic stress disorder, 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.
In addition, the present invention provides a method for preventing, alleviating or treating acute stress disorder or post-traumatic stress disorder, in a subject, 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.
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 acute stress disorder or post-traumatic stress disorder, or for the improvement of symptoms associated therewith.
According to one embodiment of the present invention, in the above Formula 1, R1 and R2 are each independently selected from the group consisting of hydrogen, halogen and C1-C8 alkyl.
In one embodiment of the present invention, the halo C1-C8 alkyl is perfluoroalkyl.
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:
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. Specifically, 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 the above 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.
The carbamate compounds of the above Formula 1 can be used for the prevention, alleviation or treatment of acute stress disorder or post-traumatic stress disorder.
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 the present invention 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. The therapeutically effective amount is preferably 50 to 300 mg, more preferably 50 to 200 mg.
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 1 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 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, more preferably 50 to 200 mg, 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.
According to still another embodiment of the present invention, there is provided a combination for the prevention, alleviation or treatment of acute stress disorder or post-traumatic stress disorder, comprising (a) a therapeutically effective amount of a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof; and (b) a selective serotonergic reuptake inhibitor (SSRI):
wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and
one of A1 and A2 is CH, and the other is N.
According to still another embodiment of the present invention, the selective serotonergic reuptake inhibitor may be one or more selected from the group consisting of fluoxetine, sertraline, paroxetine and a pharmaceutically acceptable salt thereof, but is not limited thereto.
According to still another embodiment of the present invention, in the combination, the weight ratio (a:b) of the ingredient (a) and the ingredient (b) may be within the scope of 1,000:1 to 1:1,000. According to still another embodiment of the present invention, in the combination, the weight ratio (a:b) of the ingredient (a) and the ingredient (b) may be within the scope of 100:1 to 1:100.
According to still another embodiment of the present invention, the combination may comprise the compound of Formula 1 in an amount of 12.5 to 500 mg, based on the free form.
According to still another embodiment of the present invention, the selective serotonergic reuptake inhibitor may be fluoxetine or a pharmaceutically acceptable salt thereof. According to still another embodiment of the present invention, the selective serotonergic reuptake inhibitor may be fluoxetine hydrochloride.
According to still another embodiment of the present invention, the combination may comprise fluoxetine in an amount of 10 to 60 mg, based on the free form.
According to still another embodiment of the present invention, there is provided a medicament for the prevention, alleviation or treatment of symptom of post-traumatic stress disorder, comprising a therapeutically effective amount of a carbamate compound of the following Formula 1, or a pharmaceutically acceptable salt, solvate or hydrate thereof:
wherein,
R1 and R2 are each independently selected from the group consisting of hydrogen, halogen, C1-C8 alkyl, halo-C1-C8 alkyl, C1-C8 thioalkoxy and C1-C8 alkoxy; and
one of A1 and A2 is CH, and the other is N.
According to still another embodiment of the present invention, the symptom of post-traumatic stress disorder is one or more selected from the group consisting of full or partial amnesia of traumatic event, flashback in a patient re-experiencing traumatic event or avoidance of stimulus associated with traumatic event, nightmare, irritability, hyperarousal, hypervigilance, rage, poor concentration and emotional withdrawal.
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 combination according to the present invention can effectively prevent, alleviate and treat acute stress disorder or post-traumatic stress disorder.
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)-1-(2-chlorophenyl)-2-tetrazol-2-yl)ethyl ester (hereinafter referred to as “Test Compound”) was prepared according to the method described in Preparation Example 50 of International Publication No. WO 2010/150946.
Adult male rats (Sprague-Dawley, 200 to 230 g) were used. The experimental animals were maintained at a light-and-darkness cycle of 12 hours (illuminated from 7 pm to 7 am), a temperature of 22 to 25° C., a relative humidity of 40 to 60%, and free access to water and food. The animals were randomly divided into three groups as follows:
Induction of Post-Traumatic Stress Disorder
To establish optimal post-traumatic stress disorder, animal model induced by single prolonged stress (SPS). The animals expressing post-traumatic stress disorder was established by exposure to stress under various conditions (2 hours of restraint stress, 20 minutes of forced swimming, 15 minutes of rest, exposure to ether vapor).
Post-traumatic stress disorder was induced in Group 2 and Group 3 as described above. Following SPS stressors, rats were housed in theft cages alone and left undisturbed for seven days to induce post-traumatic stress. All experimental animals were measured daily for changes in mortality and body weight to determine whether post-traumatic stress disorder was well induced.
Administration
For 15 days from the day following the exposure to single prolonged stress, Group 2 was orally administered with saline as a vehicle and Group 3 with 30 mg/kg (3 ml/kg) of Test Compound.
Meanwhile, Group 1—in which post-traumatic stress disorder was not induced—was orally administered with saline at the same time when oral administration was started in Group 2 and Group 3.
Forced Swimming Test
To carry out a forced swimming test in the rats of Groups 1 to 3, water of 25° C. was filled to a height of 30 cm in a transparent cylinder (20 cm in diameter×50 cm in height). The forced swimming test consisted of two sessions. On the first day, rats were acclimated in the cylinder filled with water for 15 minutes. After 24 hours, rats were inserted into the cylinder for 5 minutes and the escape behavior of rats was recorded and measured using a video camera. Rats' behaviors were divided into climbing, immobility and swimming behaviors. Climbing behavior measured the time to climb upward, immobility behavior measured the time to not escape, and swimming behavior measured the time to move horizontally in the cylinder. The results are represented in
Statistics
The efficacy of the compound was expressed as mean±standard error of mean (SEM), and statistical significance was recognized when data had a difference of p<0.05. Statistical analysis was carried out by using one-way ANOVA in Prism 7.04.
From the above results, it was confirmed that Test Compound can be used as a medication for the prevention, alleviation or treatment of post-traumatic stress disorder by showing efficacy on alleviating symptoms associated with post-traumatic stress disorder.
Adult male rats (Sprague-Dawley, 200 to 230 g) were used. The experimental animals were maintained at a light-and-darkness cycle of 12 hours (illuminated from 7 pm to 7 am), a temperature of 22 to 25° C., a relative humidity of 40 to 60%, and free access to water and food. The animals were randomly divided into three groups as follows:
Induction of Post-Traumatic Stress Disorder
To establish optimal post-traumatic stress disorder, animal model induced by single prolonged stress (SPS). The animals expressing post-traumatic stress disorder was established by exposure to stress under various conditions (2 hours of restraint stress, 20 minutes of forced swimming, 15 minutes of rest, exposure to ether vapor).
Post-traumatic stress disorder was induced in Group 2 and Group 3 as described above. Following SPS stressors, rats were housed in their cages alone and left undisturbed for seven days to induce post-traumatic stress. All experimental animals were measured daily for changes in mortality and body weight to determine whether post-traumatic stress disorder was well induced.
Administration
For 15 days from the day following the exposure to single prolonged stress, Group 2 was orally administered with saline as a vehicle and Group 3 with 30 mg/kg (3 ml/kg) of Test Compound.
Meanwhile, Group 1—in which post-traumatic stress disorder was not induced—was orally administered with saline at the same time when oral administration was started in Group 2 and Group 3.
Measurement of Corticoid in Blood
Rats were sacrificed rapidly by decapitation on the day after the forced swimming test, and blood was quickly collected via the abdominal aorta. The blood sample was centrifuged at 4,000 g for 10 minutes, and serum was collected and stored at −20° C. The corticoid concentration was measured by enzyme-linked immunoassay (ELISA) using a Novus Biologicals Corticosterone kit. The results were measured by means of an ELISA reader (MultiRead 400) to calculate the concentration of corticoid.
Statistics
The efficacy of the compound was expressed as mean±standard error of mean (SEM), and statistical significance was recognized when data had a difference of p<0.05. Statistical analysis was carried out by using one-way ANOVA in Prism 7.04.
As can be seen from
Adult mice (CD-1) were used. The experimental animals were maintained at a light-and-darkness cycle of 12 hours (illuminated from 7 pm to 7 am), a temperature of 22 to 25° C., a relative humidity of 40 to 60%, and free access to water and food. The animals were randomly divided into four groups as follows:
Forced Swimming Test
To perform a forced swimming test in the mice of Groups 1 to 4, water of 25° C. was filled to a height of 20 cm in a transparent cylinder. 30 Min after injection, mice were acclimated in water for 2 minutes, and the duration of despair behavior that did not move was measured for 4 minutes using a timer. The results are represented in
Statistics
The effect of the compound was expressed as mean±standard error of mean (SEM), and statistical significance was recognized when data had a difference of p<0.05. Statistical analysis was carried out by using one-way ANOVA in Prism 7.04.
From the above results, a combination of Test Compound and selective serotonergic reuptake inhibitor (fluoxetine)—which are at an ineffective dose, respectively—was shown to be synergistic in a forced swimming test. With this, it was confirmed that co-administration of Test Compound and selective serotonergic reuptake inhibitor—which has been used as the first-line treatment for post-traumatic stress disorder—may have synergistic efficacy.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/KR2019/012183 | 9/20/2019 | WO | 00 |
| Number | Date | Country | |
|---|---|---|---|
| 62734403 | Sep 2018 | US |
