KR101414831B1 - Composition for treatment of KCa3.1 channel mediated diseases comprising modafinil or its derivatives - Google Patents

Abstract

The present invention relates to novel uses of modafinil or derivatives thereof as therapeutic agents for K _Ca 3.1 channel-mediated diseases. Than the present invention in detail by increasing the intracellular cAMP cell K _Ca 3.1 K _Ca 3.1 channel parameters via a channel phosphorylation include K _Ca 3.1 modafinil, or derivatives thereof, or a pharmaceutically acceptable salt thereof for inhibiting the channel current disorders the treatment or prevention the pharmaceutical compositions, methods for the treatment of K _Ca 3.1 channel-mediated diseases using the compositions and modafinil, or derivatives thereof, compound, and K which include the acceptable salts thereof Food significant _Ca 3.1 channel mediated disease prevention for Or health functional food for improvement.

Description

[0001] The present invention relates to a composition for treatment of KCa3.1 channel-mediated diseases, which comprises modafinil or derivatives thereof,

The present invention relates to novel uses of modafinil or derivatives thereof as therapeutic agents for K _Ca 3.1 channel-mediated diseases. Than the present invention in detail by increasing the intracellular cAMP cell K _Ca 3.1 K _Ca 3.1 channel parameters via a channel phosphorylation include K _Ca 3.1 modafinil, or derivatives thereof, or a pharmaceutically acceptable salt thereof for inhibiting the channel current disorders the treatment or prevention the pharmaceutical compositions, methods for the treatment of K _Ca 3.1 channel-mediated diseases using the compositions and modafinil, or derivatives thereof, compound, and K which include the acceptable salts thereof Food significant _Ca 3.1 channel mediated disease prevention for Or health functional food for improvement.

K _{Ca 3. 1} channel is distributed in nerve cells, red blood cells, fibroblasts, proliferating vascular smooth muscle cells, vascular endothelial cells, and immune cells (T cells and B cells) and contributes to controlling the functions of these cells [Kaushal V. meat al . , 2007, J. Neurosci ., 27 (1): 234-244; Anand U. et al . , 2006, Neurosci . Lett ., 399 (1-2): 51-56; Wulff H. et al . , 2004, J. Immunol ., 173 (2): 776-786; Wulff H. et al . , 2007, Curr . Med. Chem ., 14 (13): 1437-1457). Therefore, the K _Ca 3.1 channel is considered a target to treat diseases caused by these cells.

Specifically, in the cardiovascular system, the K _Ca 3.1 channel is mainly distributed in the vascular endothelial cells, and thus it is known that the K _Ca 3.1 channel dysfunction induces vascular endothelial dysfunction and increases blood pressure [Si H. et al . , 2006, Circ . Res ., 99 (5): 537-544; Kohler R. et al. , 2010, Pflugers Arch ., 459 (6): 969-976]. On the other hand, K _Ca 3.1 channel is known to inhibit the proliferation of immune cells (T cells and B cells), fibroblasts, cancer cells, vascular smooth muscle cells, etc. [Ghanshani S. et al . , 2000, J. Biol . Chem ., 275 (47): 37137-37149; Wulff H. et al . , 2004, J. Immunol ., 173 (2): 776-786; Pena TL & Rane SG, 1999, J. Membr . Biol ., 172 (3): 249-257; Chou CC et al . , 2008, Expert Rev. Mol . Diagn ., 8 (2): 179-187; Neylon CB et al . , 2004, Pflugers Arch ., 448 (6): 613-620). Therefore administration of the drug to inhibit the K _Ca 3.1 channel or suppressed if proliferation of cancer cells destroy the K _Ca 3.1 channel is atherosclerosis, renal fibrosis (renal fibrosis), proceeding the inhibition of vascular restenosis (post-angioplasty restenosis) after angioplasty [Chou CC et al . , 2008, Expert Rev. Mol . Diagn ., 8 (2): 179-187; Grgic I. et al . , 2009, Pflugers Arch ., 458 (2): 291-302; Kohler R. et al . , 2003, Circulation , 108 (9): 1119-1125; Toyama K. et al . , 2008, J. Clin . Invest ., 118 (9): 3025-3037]. And drugs inhibiting the K _Ca 3.1 channel empirically alleviated the symptoms of autoimmune encephalomyelitis and cardiovascular diseases [Chou CC et al . , 2008]. Therefore, substances that inhibit the K _Ca 3.1 channels is a minor situation report on the substance, but is expected to treat a variety of K _Ca 3.1 channel mediated diseases, effectively inhibited the K _Ca 3.1 channels.

On the other hand, modafinil narcolepsy [Ballon JS et al ., 2006, J. Clin . Psychiatry , 67 (4): 554-566] and are used in the treatment of sleep disorders such as cocaine dependence, attention deficit hyperactivity disorder, depression, seasonal affective disorder, bipolar depression, nicotine addiction, and other psychiatric disorders such as schizophrenia Clinical trials are under way for the use of [Dackisca meat al . , 2005, Neuropsychopharmacology , 30 (1): 205-211; Donovan JL et al. , 2003, Ther . Drug Monit ., 25 (2): 197-202; Minzenberg MJ meat al . , 2008, Neuropsychopharmacology, 33 (7): 1477-1502; Swanson JM meat al . , 2006, J. Clin. Psychiatry , 67 (1): 137-147]. Some preclinical evidence also demonstrates the potential for use in the treatment of neurodegenerative diseases, Parkinson's disease and cancer-related fatigue [Campos MP meat al . , 2011, Rev. Assoc . Med . Bras ., 57 (2): 211-219; Portela MA meat al . , 2011, Curr. Opin . Support Palliat . Care , 5 (2): 164-168; Wirz S. meat al . , 2010, Schmerz, 24 (6): 587-595; Zeng BY meat al . , 2004, Neurosci . Lett ., 354 (1): 6-9]. Since other medications for treatment have not yet been approved, the use of modafinil for the treatment of these psychiatric disorders is noteworthy.

Since modafinil has been used as a psychostimulant for the treatment of narcolepsy, most studies on the mechanism of action of modafinil have shown that modafinil stimulates histamine, norepinephrine, serotonin, dopamine and orexin system in the brain, It was concentrated on the monoaminergic effect. Modafinil occupies and modulates dopamine and norepinephrine transporters [Madras BK et al ., 2006, J. Pharmacol . Exp . Ther. , 319 (2): 561-569; Zolkowska D. et al ., 2009, J. Pharmacol . Exp . Ther . , 329 (2): 738-746). Also, modafinil inhibits human cytochrome P450 activity [Robertson P. et al ., 2000, Drug Metab . Dispos . , 28 (6): 664-671] and has a neuroprotective function [Anronelli T. et al ., 1998, Neuroreport , 9 (18): 4209-4213; van Vliet SA et al ., 2008, Brain Res ., 1189: 219-228; van Vliet SA et al ., 2006, Behav . Pharmacol ., 17 (5-6): 453-462]. Also, modafinil inhibited GABA-activated current [Huang Q. et al. meat al . , 2008, Brain Res ., 1208: 74-78). However, its main mechanism of action is difficult to define, and studies on intracellular action sites for modafinil are needed to explain the irritant and neuroprotective effects. However, the use of modafinil for the treatment of K _Ca 3.1 channel-mediated diseases has not been elucidated.

Accordingly, the present inventors have made intensive researches to clarify the mechanism of action, and as a result, it has been confirmed that modafinil phosphorylates K _Ca 3.1 channel protein by increasing the intracellular cAMP level, thereby suppressing K _Ca 3.1 current. In addition, a number of novel derivatives thereof were synthesized to observe the _{intracellular} cAMP level and K _Ca 3 current suppression effect, and it was confirmed that some of the derivatives had an increase in intracellular cAMP concentration and a K _Ca 3 current suppressing effect. Completed.

It is an object of the present invention to provide a pharmaceutical composition for the treatment or prevention of K _Ca 3.1 channel-mediated diseases comprising as an active ingredient a modafinil or a modafinil derivative compound, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method of treating a K _Ca 3.1 channel-mediated disease comprising administering the composition to a subject.

Another object of the present invention is to provide a health functional food composition for preventing or improving K _Ca 3.1 channel-mediated diseases, which comprises the above modafinil or modafinil derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient .

In order to achieve the above object, the present invention provides a pharmaceutical composition for treating or preventing K _Ca 3.1 channel-mediated diseases comprising modafinil or a modafinil derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient .

The modafinil of the present invention is a compound having a structural formula of the following formula 1, and is currently being used as a treatment for narcolepsy, and clinical trials for use in the treatment of other psychiatric diseases are underway. As described above, the modafinil of the present invention has already been commercialized and has proved to be harmless to humans, and it can be used as a therapeutic or pharmaceutical composition for animals including humans.

[Chemical Formula 1]

The above modafinil is also called 2- (benzhydrylsulfinyl) acetamide. Modafinil can be easily synthesized chemically by those skilled in the art by a known production method or can be commercially obtained by commercial use.

In addition, a pharmaceutical composition comprising a modafinil derivative compound having a cAMP-increasing effect such as modafinil and having a structural formula (2) to (5) can be provided.

(M006)

(M008)

(M015)

(M020)

(2) is called 2- (benzhydrylthio) -N - ((tetrahydrofuran-2-yl) methyl) acetamide, , (4) is 2- (benzhydrylsulfinyl) -N-methylacetamide, and the chemical formula 5 is 2- (benzhydrylsulfinyl) -N- (tetrahydrofuran- Lt; / RTI >

Such modafinil derivatives of the formulas (2) to (5) can be chemically synthesized easily by those skilled in the art by the process of the following Reaction Scheme 1, or can be obtained by publicly known production methods or commercially available products.

[Reaction Scheme 1]

The modafinil, but well known as a therapeutic agent narcolepsy, increase intracellular cAMP by the K _Ca channel through a 3.1 phosphorylation inhibiting K _Ca channel current by 3.1 K 3.1 _Ca not been reported for that can cure channel mediated diseases. Preferably to the modafinil or a modafinil derivative having the structure of formula 2 to 5 of the invention increase the intracellular cAMP level of cells K _Ca 3.1 by inhibiting K _Ca 3.1-channel current through the channel phosphorylation, associated with the K _Ca 3.1 channel activity K _Ca 3.1 Can treat channel-mediated diseases.

The pharmaceutical composition of the present invention can be used in the form of modafinil of the above formula (1) or a modafinil derivative of the formula (2) to (5), or a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salts" of the present invention means all salts which possess the desired biological and / or physiological activity of the compounds and which exhibit minimal undesired toxicological effects. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, tartaric acid and the like can be used. Examples of the organic acid include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, But are not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is preferable to produce sodium, potassium or calcium salt particularly, but not limited thereto. The corresponding silver salt may be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the above modafinil or the modafinil derivatives of the general formulas 2 to 5, unless otherwise indicated, are acid or basic salts which may exist in the compounds of modafinil or the compounds of formulas 2 to 5, Lt; / RTI > salt. For example, pharmaceutically acceptable salts may include sodium, calcium and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, (Mesylate) and p -toluenesulfonate (tosylate) salts, which are known to those skilled in the art and which are known in the art, .

The compositions of the present invention may be used without limitation in the prevention or treatment of K _Ca 3.1 channel-mediated diseases. In the present invention, the term " K _Ca 3.1 channel-mediated disease "means a disease controlled by the activity of K _Ca 3.1 channel distributed in red blood cells, immune cells, proliferating vascular smooth muscle cells, endothelial cells, part of cancer cells, it means. In general, the K _Ca 3.1 channel is distributed in various cells as described above, and thus it is considered to be a relatively safe target. Therefore, drugs that regulate K _Ca 3.1 channel can be used as preventive or therapeutic agents for various diseases.

Thus, K _Ca 3.1 channel mediated diseases treatable by the present invention include, for example, sickle cell anemia; Immune diseases such as acute immune response and autoimmune disease; Vascular diseases such as restenosis and atherosclerosis; Brain diseases such as traumatic brain injury, cerebral ischemia, and degenerative neurological diseases; Cancer diseases such as prostate cancer and pancreatic cancer; Or secretory diarrhea, and the like.

Already K_CaMuch research has been done on 3.1 channel inhibitors. K_Ca3.1 channel inhibitors have been disclosed to prevent erythropoiesis in sickle cell anemia [Brugnara, C. et al.meat get ., 2001,Drug News Perspect . ,14: 208; De Franceschi, L.meat get ., 1994,J. Clin . Invest ., 93: 1670; Brugnara, C.meat get ., 1996,J. Clin . Invest., 97: 1227], K_Ca3.1 Blocker ICA-17043 is in clinical trials in combination with hydroxyurea [Swerdlow, P.meat get ., 2006,Blood, 108: Abstract 685]. Therefore,_CaIt is clear that 3.1 channel inhibitors can be used to prevent or treat sickle cell anemia. K_Ca3.1 Inhibitory effect of channel inhibitor on T-cell calcium ion signal [Ghanshani, S.meat get ., 2000,J. Biol . Chem ., 275: 37137; Jensen, B. S.meat al., 1999,Proc . Natl . Acad . Sci . USA, 96: 10917], central memory T cell inhibitory effect [Chandy, K.G.meat get ., 2004,Trends Pharmacol . Sci ., 25: 280; Wulff, H.meat al., 2003,J. Clin . Invest ., 111: 1703; Vennekamp, J.meat get ., 2004,Mol . Pharmacol., 65: 1364], an acute immune response inhibitory effect [Wulff, H.meat get ., 2004,J. Immunol., 173: 776; Wulff, H.meat get ., 2000,Proc . Natl . Acad . Sci . USA, 97: 8151], and examples used for the treatment of autoimmune diseases [Khanna, R. et al.meat get ., 2001,Am. J. Physiol . Cell Physiol ., 280: C796; Chung, I.meat get ., 2002,J. Neuroimmunol., 122: 40]. Therefore,_Ca3.1 It is clear that channel inhibitors can be used to prevent or treat immune diseases. Also, K_Ca3.1 channel inhibitors have been shown to have vascular smooth muscle cell and fibroblast proliferation inhibitory effects [Kohler, R. et al.meat get ., 2003,Circulation, 108: 1119; Pena, T.L.meat get ., 2000,J. Biol . Chem ., 275: 13677; Neylon, C. B., 2002Vasc . Pharmacol ., 38:35; Tharp, D. L.meat get ., 2006,Am . J. Physiol . Heart Circ . Physiol ., 291: H2493], and KCa3.1 channels play an important role in vascular remodeling in the heart after ischemia [Saito, T. et al.meat al., 2002,Clin . Exp . Pharmacol . Physiol ., 29: 324]. Therefore,_Ca3.1 It is clear that channel inhibitors can be used for the prevention or treatment of vascular diseases. Incidentally, K_Ca3.1 Channel inhibitors may lower the pressure in the brainstem and the two after acute subdural hematoma due to shock [Mauler, F. et al.meat get ., 2004,Eur . J. Neurosci ., 20: 1761] and microglial cells, thereby reducing nerve cell death [Khanna, R. et al.meat get ., 2001,Am . J. Physiol . Cell Physiol ., 280: C796; Kaushal, V.meat get ., 2007,J. Neurosci ., 27: 234]. Therefore, the K_Ca3.1 It is clear that channel inhibitors can be used to prevent or treat brain diseases. K_Ca3.1 channel inhibitors also inhibit prostate cancer cell lines [Parihar, A.S.meat get ., 2003,Eur . J. Pharmacol., 471: 157], pancreatic cancer cell line [Jager, H.meat get ., 2004, S.Mol . Pharma, ≪ / RTI > 65: 630], and inhibits angiogenesis [Grgic, I.meat get ., 2005,Arterioscler . Thromb . Vasc . Biol ., 25: 704] can also be used as a drug to inhibit tumor angiogenesis. Therefore, the K_Ca3.1 It is clear that channel inhibitors can be used for the prevention or treatment of cancer diseases. Finally, K_Ca3.1 channel inhibitors have been shown to inhibit secretory diarrhea by inhibiting cholera toxin-secreting epithelial cells [Rufo, P.A.meat get ., 1997,J. Clin . Invest ., 100: 3111; Lencer, W. I.meat get ., 1996, US 5,889,038]. Therefore,_Ca3.1 Channel inhibitors can also be used to prevent or treat secretory diarrhea.

According to one embodiment of the present invention, it was confirmed that the modafinil of the present invention or the modafinil derivatives of Chemical Formulas 2 to 5 increased intracellular cAMP, phosphorylated the K _Ca 3.1 channel and inhibited the K _Ca 3.1 current 1 to 5). Therefore, it was confirmed that the modafinil or the modafinil derivatives of the formulas (2) to (5) of the present invention inhibit the K _Ca 3.1 channel to treat immune diseases, vascular diseases, brain diseases, cancer or secretory diarrhea.

Accordingly, the composition of the present invention can inhibit the K _Ca 3.1 channel by increasing intracellular cAMP concentration, thereby treating the K _Ca 3.1 channel-mediated disease.

Currently, there is a drug such as TRAM-34 as a drug that directly inhibits the K _Ca 3.1 channel. When K _Ca 3.1 channel is directly inhibited, vascular endothelial cell function is inhibited, resulting in increased vasoconstriction and increased blood pressure. However, the modafinil of the present invention relaxes the vascular smooth muscle through the increase of cAMP, which is advantageous in that the above-mentioned therapeutic effect can be obtained without increasing the blood pressure as compared with the K _Ca 3.1 channel inhibitor.

In the present invention, the term "prevention" means any action that inhibits or delays the onset of K _Ca 3.1 channel-mediated disease by administration of the pharmaceutical composition according to the present invention, and "treatment" Refers to all actions that alleviate or alleviate symptoms caused by atherosclerosis, cancer, renal fibrosis, and postangiplasty restenosis.

According to the embodiment of the present invention, on the other hand, there is an effect of suppressing the current of K _Ca 3.1 when modafinil is applied (Fig. 1), and the K _Ca 3.1 current suppression effect of this modafinil is inhibited by protein kinase A (PKA) Inhibitor H89 and protein kinase inhibitor (PKI) inhibited PKA activator forskolin, which inhibited K _Ca 3.1 current, like modafinil, and the effect of PKA inhibitor was suppressed by PKA inhibitor (Fig. 2). These results show that modafinil activates PKA. And modafinil increased intracellular cAMP concentration (FIG. 3) and phosphorylated K _Ca 3.1 channel protein (FIG. 4). On the other hand, activity of K _Ca 3.1 channel (single channel conductivity and current size) was not influenced by modafinil, and it was confirmed that the effect of modafinil K _Ca 3.1 current suppression was not directly inhibited by K _Ca 3.1 channel (Fig. 5). Thus, the inventors were able to modafinil activates the PKA by increasing the intracellular cAMP concentration and cell infer the mechanism of action of modafinil that can inhibit the K _Ca channel 3.1 to phosphorylate K 3.1 _Ca channel. In addition, it was confirmed that the compounds having the structures of Formulas 2 to 5 were also effective in increasing intracellular cAMP similar to modafinil and inhibiting K _Ca 3.1 current (FIGS. 6 and 7)

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable" of the present invention means that it exhibits properties that are not toxic to the cells or humans exposed to the composition. Such carriers may be used without limitation as long as they are known in the art such as buffers, preservatives, wetting agents, solubilizers, isotonic agents, stabilizers, bases, excipients and lubricants. Examples of carriers, excipients and diluents that can be included in the pharmaceutical composition of the present invention include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium Silicates, cellulose, methylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, a diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, or a surfactant is usually used. Typical usable surfactants that facilitate membrane-mediated migration include those derived from steroids or those derived from N- [1- (2,3-dioloyl) propyl-N, N, N-trimethylammonium chloride] ), Or cholesterol hemi-succinate and the like.

In another aspect, the present invention provides a method of preventing or treating K _Ca 3.1 channel-mediated diseases, comprising administering the pharmaceutical composition to a subject in need thereof.

In the present invention, the term "object" is by means all animals including humans which can onset hayeotgeona onset the above K _Ca 3.1 channel mediated diseases, such as, and administering a pharmaceutical composition of the present invention to a subject the K _Ca 3.1 channel parameters The disease can be effectively prevented or treated. The pharmaceutical composition of the present invention can be administered in combination with a conventional K _Ca 3.1 channel-mediated disease therapeutic agent.

The term "administering" of the present invention means introducing a predetermined substance into a patient in an appropriate manner, and the administration route of the composition can be administered through any conventional route as long as it can reach the target tissue. But are not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrathecal, rectal. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain, in addition to the composition, at least one excipient such as starch, calcium carbonate, sucrose, Gelatin and the like. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions, syrups, and the like. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agent sweeteners, fragrances and preservatives are included . However, since the peptide is prone to digestion upon oral administration, it is preferable to formulate the oral composition so as to coat the active agent or protect it from decomposition at the top. Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. The supplements of suppositories are etwesol, macrogol, tween 61. Cacao butter, laurin, glycerogelatin and the like can be used. To increase the stability or absorbability of the peptide, carbohydrates such as glucose, sucrose, and dextran, antioxidants such as ascorbic acid, glutathione, chelating agents, low molecular proteins or other stabilizing agents may be used.

In addition, the pharmaceutical composition of the present invention may be administered by any device capable of moving the active substance to the target cell. The preferred modes of administration and formulations are intravenous, subcutaneous, intradermal, intramuscular, and drip injections. The injectable solution may be a non-aqueous solvent such as an aqueous solvent such as a physiological saline solution or a ring gel solution, a vegetable oil, a higher fatty acid ester (e.g., oleic acid), an alcohol (e.g., ethanol, benzyl alcohol, propylene glycol, glycerin, etc.) (For example, ascorbic acid, sodium hydrogen sulfite, sodium pyrophosphate, BHA, tocopherol, EDTA and the like), an emulsifier, a buffer for pH control, a microbial growth inhibitor And a pharmaceutical carrier such as a preservative (e.g., mercury nitrate, thimerosal, benzalkonium chloride, phenol, cresol, benzyl alcohol, etc.).

Meanwhile, the pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and not causing side effects, and the effective dose level is determined by the patient's sex, Including, but not limited to, medicaments and other medical fields that are used in combination, or in combination with, or in combination with, a pharmaceutically acceptable carrier, excipient, Can be readily determined by those skilled in the art according to known factors. Generally, the active substance may be administered at a dose of from about 0.01 mg / kg / day to 1000 mg / kg / day. When administered orally, a dose of 50 to 500 mg / kg may be appropriate, and may be administered at least once a day.

In another aspect, the present invention relates to a method for preventing or ameliorating a K _Ca 3.1 channel-mediated disease comprising modafinil of the above-mentioned formula 1 or a modafinil derivative of the formula 2 to 5, or a pharmaceutically acceptable salt thereof, Lt; / RTI > When the composition of the present invention is used as a food additive, the above modafinil or its derivative may be directly added or used together with other food or food ingredients, and may be suitably used according to a conventional method. The amount of the active ingredient to be mixed can be suitably determined according to the intended use (prevention, health or therapeutic treatment).

The term " health functional food " of the present invention refers to a food prepared by processing a specific ingredient as a raw material for the purpose of health assisting or by extracting, concentrating, refining, mixing or the like a specific ingredient contained in a food raw material, Refers to foods that are designed and processed so that the body control function such as bio-defense, regulation of bodily rhythm, prevention and recovery of disease can be sufficiently exhibited to the living body, and the composition for health food is used for prevention of diseases, Can perform related functions.

There is no limitation on the kind of health food to which the composition of the present invention can be used. The composition comprising the modafinil or derivatives thereof of the present invention as an active ingredient may be prepared by mixing other appropriate ingredients and known additives that may be contained in the health functional food according to the choice of a person skilled in the art. Examples of foods that can be added include dairy products, such as meat, sausage, bread, chocolates, candies, snacks, confectionery, pizza, ramen, other noodles, gums, ice cream, various soups, drinks, tea, Vitamin complex, and the like. The compound of the present invention can be added to juice, tea, jelly, juice and the like prepared from the extract as a main component.

The modafinil of the present invention can increase the intracellular cAMP concentration and phosphorylate the K _Ca 3.1 channel to inhibit its activity. The same effect was also confirmed in the newly synthesized derivatives of modafinil. Accordingly, the modafinil and novel derivatives thereof of the present invention can be usefully used as a pharmaceutical composition for the treatment or prevention of diseases such as atherosclerosis, cancer, renal fibrosis, and postangiplasty restenosis.

Figure 1 shows the effect of modafinil on K _Ca 3.1 current. Cells injected into the 1 μM Ca ² through glass micro pipetreul ⁺ next exposed to 3.1 K _Ca channel activator 1-EBIO (100 μM) was activated the current K _Ca 3.1. (AC) Current data at 50 mV of the recorded current during repetitive ramp stimulation was collected (top), and the current-voltage curve obtained at the point indicated at the top was shown in the lower trace. (D) K _Ca 3.1 The current is recorded by applying a voltage step (left) and the current-voltage curve of the current activated at the center of the voltage step is shown in the right trace. (E) The relationship between the concentration of modafinil and the reaction. The degree of K _Ca 3 current suppression in each treatment was expressed as a percentage of the initial K _Ca 3 current density at 50 mV (n = 7).
Figure 2 shows the role of PKA in K _Ca 3.1 current suppression by modafinil. K 3.1 _Ca current is activated by Ca ^{2 +} (1 μM) injection and 1-EBIO (100 μM) applied. Data were collected at 50 mV during repetitive ramp stimulation (top left), and the current-voltage curve obtained at the point shown at the top is shown in the bottom right. The effect of PKA inhibitors H89 (A) and PKI _14-22 (B) on the K _Ca 3 current suppression effect of (A and B) modafinil was observed. Inhibition effect of modafinil on K _Ca 3.1 current was not observed in cells pretreated with H89 or PKI _{14 -22} injected into cells with a micropipette. (C and D) The effect of the PKA activator, phoscholine, on the K _Ca 3.1 current (C) and the effect of the PKA inhibitor PKI _{14 -22} (D) on it. K _{Ca 3. 1} current was inhibited by phosholin and the inhibitory effect of phosholin was not shown by the intracellular injection of PKI _{14 -22} . These results demonstrate that modafinil activates PKA like phocolin and inhibits K _Ca 3.1 current.
Figure 3 shows the effect of modafinil on intracellular cAMP content. Modafinil affects cAMP levels in NIH-3T3 cells. In other words, intracellular cAMP concentration was increased in a dose dependent manner. Ilofost and phoscholin also increased cAMP concentration, with 1 μM of modafinil being more or less than 1 μM of Irolofost and 10 μM of phoscholine. Each point is the mean ± standard error of three separate experiments. * p < 0.05: ** p < 0.01.
Figure 4 shows the phosphorylation of the modafinil-induced K _Ca 3.1 channel. Modafinil induces K _Ca 3.1 channel phosphorylation in NIH-3T3 cells. (A) Immunoblotted with anti-K _Ca 3.1 antibody (left panel) to confirm the presence of K _Ca 3.1 channel in cells not exposed to modafinil or phocolin. The arrow indicates the presence of K _Ca 3.1 channel. The cells were pretreated for 30 minutes in the presence (or absence) of the PKA inhibitor H89 and then exposed to modafinil or phocolin for 5 minutes in incomplete media (right panel). The lysates were immunoblot analyzed as indicated. (B) shows the modafinil and phoscholine-induced phosphorylation of the K _Ca 3.1 channel (n = 3). The modafinil phosphorylated the K _Ca 3.1 channel and the effect of modafinil was inhibited by the PKA inhibitor H89. * p < 0.05: ** p < 0.01.
Figure 5 shows the effect of modafinil on K _Ca 3.1 channel activity in NIH-3T3 cells. (A) In a membrane patch, single-channel currents were activated by 1 μM Ca ²⁺ and 1-EBIO, and the activated current was abolished by the specific K _Ca 3.1 channel blocker TRAM-34. This indicates that the activated single-channel current is a K _Ca 3.1 channel current. (A and B) shows the effect of single channel current and modafinil on the holding potential. The single channel current at each rectification potential was not changed by modafinil. (C) shows the current-voltage relationship of a single channel under the control condition (?) And 30 nM modafinil application (?). The single channel current did not change even with modafinil treatment. The experimental results modafinil represents a direct action on the _Ca 3.1 K channel does not modulate the activity of the K _Ca channel 3.1.
Figure 6 shows the effect of modafinil derivatives (Formula 2-5, M006, M008, M015, M020, respectively) on intracellular cAMP content. Modapinyl derivatives (M006, M008, M015, M020) affect cAMP levels in NIH-3T3 cells. In other words, intracellular cAMP concentration was increased in a dose dependent manner. Each point is the mean ± standard error of three separate experiments. ** p < 0.01: *** p < 0.001.
Figure 7 shows the effect of modafinil derivatives (M006, M008, M015, M020) on K _Ca 3.1 current. The effect of these derivatives was very similar to that of modafinil, inhibiting the K _Ca 3.1 channel current.

Hereinafter, the constitution and effects of the present invention will be described in more detail through examples. These examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.

Example  1: Isolation and culture of cells

NIH-3T3 fibroblast cells (CRL-2795; American Type Culture Collection, VA, USA) were inoculated into Dulbecco's FBS supplemented with 10% fetal bovine serum (FBS), 100 unit / ml penicillin and 100 μg / ml streptomycin And cultured in a single layer in Modified Eagle Medium (DMEM; Hyclone, Logan, UT, USA). All cells were maintained at 37 ° C in 5% CO2 wet conditions. The medium was changed twice a week and the culture was subcultured at a ratio of 1: 5 every week. The cells were maintained for a specified period while the medium was removed and replaced with fresh medium.

Example  2: electrophysiology analysis

<2-1> Electrophysiology analysis method

An electrophysiological analysis was performed according to the method reported by Nilius et al . [Nilius et al ., 1993, Pflugers Arch. , 424 (3-4): 285-293). The pach-clamp technique was used for whole cells and patch configurations were cut at room temperature. Whole cell currents were measured using ruptured pieces. The current was monitored using a suitable amplifier (EPC-10, HEKA, Lambrecht, Germany). In whole-cell experiments, a voltage ramp or holding potential of -100 mV to +100 mV at 10-second intervals (650 msec duration) from -60 mV to -100 mV to +100 mV (1 sec duration) at 20 mV increments every 5 seconds. The current was recorded with a sampling rate of 1 to 4 kHz. A glass electrode having a terminal resistance of 8 to 10 M? Was used to perform internal and external conduction voltage clamping. Data were filtered at 1 KHz and stored in a computer for analysis using standard software (Axoscope 9.0, Axon Instruments, Foster City, Calif., USA). For some experiments, channel activity was expressed as the product of the number of channels and the open probability ( NP _O );

At this time, NP _O = Σ [(open time × number of open channels) / total time recorded].

The standard solution contains the following materials in a NaOH solution at pH 7.4; 150 mM NaCl, 6 mM KCl, 1.5 mM CaCl 2, 1 mM MgCl 2, 10 mM HEPES, 10 mM glucose. The osmotic concentration of this solution was 320 ± 5 mOsm as determined by an osmometer (Fiske, Norwood, MA, USA). In the inner and outer conduction modes, the bath solution contained in the KOH solution at pH 7.2: 150 mM KCl, 0.5 mM MgCl ₂ , 10 mM HEPES, pipette solution contains the following materials in NaOH solution at pH 7.4; 150 mM NaCl, 6 mM KCl, 1 mM MgCl 2, 10 mM HEPES, 10 mM glucose, 5 mM EGTA. The free Ca ²⁺ concentration in the pipette or bath solution was measured using an appropriate amount of Ca ²⁺ (CaBuf software; G. Droogmans, Leuven, ftp://ftp.cc.kuleuven.ac.be) in the presence of 5 mM EGTA /pub/droogmans/cabuf.zip) was added to adjust to 1 [mu] M.

K _Ca 3.1 current was obtained by adding 1-ethyl-2-benzimidazolinone (1-EBIO, 100 μM) to the external solution and pipetting the whole cell-fixed NIH-3T3 fibroblasts And activated with 1 μM Ca ^{2 +} .

&Lt; 2-2 > K _Ca 3 .1 suppression of current

When cells were loaded with 1 [mu] M Ca &lt; ^{2 +} &gt; through a scraping pipette and exposed to 1-EBIO, the outward current slowly developed as shown in Fig. The current-voltage curve due to the ramp or step pulse was linear at negative potential for 50 mV and bent toward the horizontal axis above positive for 50 mV. This current was inhibited by the specific K _Ca 3.1 channel blocker TRAM-34 (Figure 1A). These results indicate that the activated current is K _Ca 3.1 current.

The present inventors then confirmed the effect of modafinil on the K _Ca 3.1 current (FIGS. 1B to 1D). As a result, modafinil inhibited K _Ca 3.1 current in a concentration-dependent manner. When adjusting this current suppression to the Hill's equation for each modafinil concentration, the required concentration for the half-maximal inhibition (IC ₅₀ ) of modafinil for current suppression was 6.8 +/- 0.7 nM and the maximum inhibition The concentration of modafinil was 100.0 ± 5.7 nM. These results indicate that modafinil is very sensitive to suppression of K _Ca 3.1 current.

<2-3> PKA  The inhibitor of modafinil K _Ca 3 .1 Inhibition of Current Suppression Effect

It has been reported that the K _Ca 3.1 channel is inhibited by PKA-induced phosphorylation of channel proteins [Neylon CB et al ., 2004, Pflugers Arch ., 448 (6): 613-620). This means that modafinil can inhibit K _Ca 3.1 current by activating PKA. Thus, we examined whether PKA inhibition by the PKA inhibitors H89 and PKI _14-22 could block the inhibitory effect of modafinil on the K _Ca 3.1 current and are shown in FIGS. 2A and 2B.

The K _Ca 3.1 current was activated in cells pretreated with H89 (10 μM), and then added with external solution to apply modafinil to the cells. The activated K _Ca 3.1 current, which reached the steady state, was not inhibited by modafinil in cells pretreated with H89 (FIG. 2A). Also, when PKI _{14 -22} (10 [mu] M) was applied to the cells by addition to the pipette solution, K _Ca 3.1 current was not affected by modafinil (Fig. 2B).

In addition, the present inventors have tested whether the PKA activator forcolin inhibits K _Ca 3.1 current. When activated K _Ca 3.1 current reached a rectified state, phosholin (10 μM) was added to the external solution. At this time, the K _Ca 3.1 current decreased with application (FIG. 2C). On the other hand, when PKI _14-22 (10 μM) was applied to the cells in addition to the pipette solution, the K _Ca 3.1 current was not affected by the phoscholine (FIG. 2D). These results indicate that modafin-induced inhibition of K _Ca 3 currents is mediated through PKA-mediated processes.

Example  3: intracellular cAMP  Measure

NIH-3T3 fibroblasts were incubated with modafinil for 3 minutes in incomplete media. Concentrations of adenosine 3 ', 5'-cyclic monophosphate (cAMP) from the lysates were measured by the manufacturer's instructions using the Parameter cAMP assay kit (R & D systems) in each sample.

PKA is activated by cAMP and phosphorylates intracellular proteins such as the K _Ca 3.1 protein. Therefore, the present inventors observed an increase in cAMP concentration by modafinil.

As a result, as shown in Fig. 3, when the NIH-3T3 cells were exposed to modafinil for 3 minutes, it was confirmed that intracellular cAMP concentration was increased in a modafinil concentration-dependent manner.

Example  4: Western Blot  analysis

After modafinil treatment, cells were washed once with ice-cold phosphate buffered saline (PBS) and lysed in protein extraction buffer containing protease inhibitor cocktail. The protein concentration in the supernatant was determined by Bradford protein analysis. For Western blot analysis, 30 μg of protein was added to SDS-PAGE, and the protein was transferred to a nitrocellulose membrane. The membrane was blocked with TBST (10 mM Tris-HCl, 150 mM NaCl, and 1% (v / v) Tween-20, pH 7.6) containing 5% BSA for 1 hour at room temperature. The blots were incubated with rabbit anti-P-PKA substrate antibody for 3 hours and incubated for 1 hour with horseradish peroxidase-conjugated secondary antibody. The band was visualized by chemiluminescence. Data acquisition and processing were performed using a luminescent image analyzer (LAS-3000) and IMAGE GAUSE software (Fuji film, Japan).

As mentioned in Example 3 above, PKA is activated by cAMP and phosphorylates intracellular proteins such as K _Ca 3.1 protein. Thus, phosphorylation of K _Ca 3.1 by modafinil was observed in this Example. In conclusion, as shown in Fig. 4, modafinil increases K _Ca 3.1 phosphorylation in a concentration-dependent manner, and this phosphorylation was inhibited by the PKA inhibitor H89.

First, the presence of K _Ca 3.1 channel was confirmed by Western blotting (Fig. 4A, left panel). Phosphorylation of the K _Ca 3.1 channel occurred in the dormant state, and this channel phosphorylation was increased by treatment with modafinil or phoscholine for 5 minutes (Fig. 5A right panel). Dormancy and channel phosphorylation by phosholin were completely eliminated by H89. Accordingly, these results indicate that the modafinil is to increase the cAMP activating PKA, inhibit K 3.1 _Ca channel sikimeuro phosphorylate the target protein, such as a K 3.1 _Ca channel.

These results suggest that modafinil increases intracellular cAMP, activates PKA, and PKA phosphorylates K _Ca 3.1 channel and inhibits K _Ca 3.1 current. In addition, modafinil phosphorylates the K _Ca 3.1 channel protein at a very low concentration of nanomole units, suggesting that ion channels can be inhibited.

Example  5: Modafinil and K _Ca 3 .1 Verifying Independence of Channel Activity

Because the K _{Ca 3. 1} channel is activated by intracellular Ca ^{2 +} , modafinil can inhibit the K _Ca 3 current by decreasing the Ca ^{2 +} sensitivity. Thus, the present inventors tested whether modafinil is adjusted to 3.1 K _Ca current by changing the Ca ^{2 +} sensitivity. Modafinil (30 nM) did not affect the Ca ^{2 +} EC ₅₀ for _Ca 3.1 K current.

In order to show that K _Ca 3.1 current suppression by modafinil is not the result of a direct interaction between K _Ca 3.1 channel and modafinil, we have examined whether modafinil affects K _Ca 3.1 channel activity. At around conductive pieces, K 3.1 _Ca channel was activated by holding the Ca ^{2 +} concentrations in the 1 μM of the bath liquor and applying the 1-EBIO. And the holding potential was varied from -70 to +50 mV (Figure 5). Single channel current was suppressed by TRAM-34. This means that the activated current penetrates the K _Ca 3.1 channel (FIG. 5A). The present inventors applied modafinil (30 or 100 nM) to the bath solution. Modafinil did not alter single channel activity of the K _Ca 3.1 channel. The openability was also unchanged by modafinil (Figs. 5A and 5B). From the linear pits for data between 50 and -70 mV, slope conductivities of 38.1 pS and 39.4 pS were obtained in the control and modafinil groups, respectively (Fig. 5C). The single channel conductivity recorded under control conditions was very close to that of the group with modafinil (30 μM). This indicates that the conductivity of the single channel was not changed by modafinil.

Example  6: Effect of modafinil derivatives

The effects of modafinil derivatives on cultured fibroblast NIH-3T3 cells cAMP concentration and K _Ca 3.1 current were observed in the same manner as in Examples 2 and 3 above.

Among the synthesized modafinil derivatives, four derivatives of M006, M008, M015, and M020 of Formula 2, and M020 of Formula 5 have similar effects to modafinil and modafinil observed in the above examples Respectively. The intracellular cAMP concentration increase by these modafinil derivatives M006, M008, M015 and M020 is shown in Fig. 6, and the muscle contraction and K _Ca 3.1 current suppression effect are shown in Fig. When treated with the modafinil derivative, the concentration of intracellular cAMP was increased about 2-fold for 1 μM and 5-fold or more for 100 μM (FIG. 6). In addition, it was confirmed that the current suppression effect of K _Ca 3.1 was similar to that of modafinil treatment (FIG. 7). These results suggest that the derivatives of the present invention not only increase intracellular cAMP but also inhibit K _Ca 3.1 channel similarly to modafinil and have a therapeutic effect of K _Ca 3.1 channel mediated diseases.

Example  7: General of the modafinil derivatives Synthetic example

The carboxylic acid compound (0.77 mmol) represented by the following formula 6 or 7 was dissolved in dimethylformamide (DMF, 40 ml), and then HOBt [208 mg, 1.54 mmol, (1-hydroxybenzotriazole; (295 mg, 1.54 mmol, ethyl (dimethylaminopropyl) carbodiimide (ethyl (dimethylaminopropyl) carbodiimide)] was added to the solution, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was stirred at room temperature for 1 hour and then washed with ethylacetate (100 ml) and saturated brine (100 ml). The organic layer was separated, dried and concentrated under reduced pressure After removing the solvent, the residue is separated and purified by a tube chromatography method to obtain the desired compound modafinil derivative.

[Chemical Formula 6]

(7)

Manufacturing example  1: 2- ( Benzhydrithio ) -N - (( Tetrahydrofuran -2 days) methyl ) Acetamide  ( M006 )

The objective compound was prepared by carrying out the reaction in the same manner as in the above Example 7 using the compound of the formula 6 as a starting material and the tetrahydroperfurylamine as the amine compound in the above Example 7, and the characteristics were as follows.

White solid. mp 117.8 [deg.] C; _Rf = 0.3 (ethyl acetate / n-hexane = 1: 1, v / v); IR _max (CHCl ₃ , KBr) 3304, 3060, 3027, 2926, 2870, 1651, 1531, 1494, 1450, 1384, 1304, 1078, 1030, 922, 750, 702, 629, 587, 507 cm ^-1 ; ^{1 H NMR (250 MHz, CDCl} 3) δ = 7.43-7.20 (m, 10H), 6.99 (s, 1H), 5.20 (s, 1H), 3.99-3.75 (m, 3H), 3.58-3.52 (m, 1H), 3.19-3.09 (m, 3H), 2.02-1.87 (m, 4H); ¹³ C-NMR (63 MHz, CDCl ₃ )? = 168.5, 140.3, 128.8, 128.4, 127.6, 68.2, 54.8, 43.5, 36.1, 29.8, 25.9; LC-MS (ESI +) m / z 364 - [M + Na].

Manufacturing example  2: 2- ( Benzhydrithio ) -N- Phenylacetamide  ( M008 )

In Example 7, the target compound was prepared by conducting the reaction in the same manner as in Example 7 using the compound of Formula 6 as the starting material and the amine compound as the aniline, and the characteristics were as follows.

White solid. mp 98.9 [deg.] C; R _f = 0.43 (ethyl acetate / n-hexane = 1: 2, v / v); IR _max (CHCl ₃ , KBr) 3301, 3060, 3019, 2913, 1659, 1601, 1540, 1495, 1442, 1319, 1242, 1074, 1029, 747, 690, 625, 584, 498 cm ^-1 ; ¹ H NMR (250 MHz, CDCl ₃ )? = 8.45 (s, 1H), 7.49-7.08 (m, 15H), 5.19 (s, 1H), 3.23 (s, 2H); ¹³ C-NMR (63 MHz, CDCl ₃ )? = 166.7, 140.3, 137.7, 129.2, 129.0, 128.5, 127.9, 124.8, 119.9, 54.3, 37.2; LC-MS (ESI &lt; + &gt;) m / z 356- [M + Na].

Manufacturing example  3: 2- ( Benzhydryl sulfinyl ) -N- Methyl acetamide  ( M015 )

The objective compound was prepared by carrying out the reaction in the same manner as in Example 7 using the compound of the formula 7 and the amine compound of the compound 7 as the starting materials.

White liquid. R _f = 0.08 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 2961, 2926, 1736, 1494, 1451, 1282, 1117, 1053, 1031, 967, 753, 702 cm ^-1 ; ^{1 H NMR (250 MHz, CDCl} 3) δ = 7.50-7.34 (m, 10H), 7.09 (s, 1H), 5.21 (s, 1H), 3.43 (d, J = 13.90 Hz, 1H), 3.15 (d , J = 13.90 Hz, 1 H), 2.79 (d, J = 4.74 Hz, 3H); ¹³ C-NMR (63 MHz, CDCl ₃ )? = 164.9, 135.0, 129.7, 129.6, 129.0, 128.8, 72.3, 52.7, 26.6; LC-MS (ESI &lt; + &gt;) m / z 310- [M + Na].

Manufacturing example  4: 2- ( Benzhydryl sulfinyl ) -N - (( Tetrahydrofuran -2 days) methyl ) Acetamide  ( M020 )

The objective compound was prepared by carrying out the reaction in the same manner as in Example 7, using the compound of the formula (7) as the starting material and the tetrahydroperfurylamine as the amine compound in the above Example 7, and the characteristics were as follows.

White liquid. _Rf = 0.1 (ethyl acetate / n-hexane = 2: 1, v / v); IR _max (CHCl ₃ , KBr) 3287, 3064, 2926, 2871, 2243, 1738, 1667, 1556, 1495, 1451, 1383, 1304, 1257, 1136, 1080, 1031, 911, 732, 703, 646, 595, 498 cm ^-1 ; ^{1 H NMR (250 MHz, CDCl} 3) δ = 7.53-7.27 (m, 11H), 5.28 (s, 1H), 4.03-3.99 (m, 1H), 3.88-3.82 (m, 1H), 3.76 (t, J = 6.79 Hz, 1H), 3.49-3.42 (m, 2H), 3.19-3.10 (m, 2H), 2.04-1.86 (m, 4H); ¹³ C-NMR (63 MHz, CDCl ₃ ) 164.5, 135.2, 129.4, 128.9, 128.7, 71.3, 68.2, 52.9, 52.6, 43.6, 28.8, 25.9; LC-MS (ESI &lt; + &gt;) m / z 380- [M + Na].

Claims (8)

An immunological disease including sickle cell anemia, an acute immune response or an autoimmune disease, prostate cancer or pancreatic cancer, comprising modafinil or a modafinil derivative compound of the following formulas 2 to 5, or a pharmaceutically acceptable salt thereof, cancer diseases, traumatic brain injury, neurodegenerative disease and secretory diarrhea consisting of 3.1 K _Ca channel mediated any treatment of a disease or prophylactic pharmaceutical composition is selected from the diseases.
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

delete The composition of claim 1, further comprising a pharmaceutically acceptable carrier.
The composition of claim 1, wherein said composition inhibits K _Ca 3.1 channel by increasing intracellular cAMP concentration.
An immunological disease including sickle cell anemia, an acute immune response or an autoimmune disease, cancer diseases including prostate cancer or pancreatic cancer, trauma brain injury, One way to prevent or treat a disease selected from a neurodegenerative disease and secretory diarrhea K _Ca 3.1 channel mediated diseases consisting of.
delete An immunological disease including sickle cell anemia, an acute immune response or an autoimmune disease comprising the modafinil of the above-mentioned 1 or a modafinil derivative of the following general formulas 2 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient, prostate cancer or pancreatic cancer cancer, traumatic brain injury, neurodegenerative diseases and secretion consisting of diarrhea K _Ca 3.1 channel parameters either in prevention or dietary supplement composition for the improvement of the disease is selected from diseases including.
(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

delete

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