KR20170094584A - Oral pharmaceutical composition for prevention or treatment of immune disease and metabolic disease comprising rebamipide prodrug - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for oral administration for the prevention or treatment of immunological diseases and metabolic diseases comprising a rebamipide precursor, and more particularly to a pharmaceutical composition for oral administration comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof, The present invention also relates to a pharmaceutical composition for oral administration which can prevent or treat metabolic diseases such as rheumatoid arthritis and osteoarthritis and obesity, hyperlipemia, diabetes, diabetic complication, irritable bowel syndrome, gastric ulcer and gastritis. The pharmaceutical composition for oral administration according to the present invention can be administered orally or parenterally by incorporating a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient to provide a pharmaceutical composition for preventing or treating an immunological disease such as rheumatoid arthritis, osteoarthritis, and obesity, hyperlipidemia, diabetes, Metabolic diseases such as bowel syndrome, gastric ulcer, and gastritis can be treated more similarly to, or better than, rebamipide.

Description

TECHNICAL FIELD [0001] The present invention relates to a pharmaceutical composition for oral administration for the prevention or treatment of immune diseases and metabolic diseases including a rebamipide precursor,

The present invention relates to a pharmaceutical composition for oral administration for the prevention or treatment of immunological diseases and metabolic diseases comprising a rebamipide precursor, and more particularly to a pharmaceutical composition for oral administration comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof, The present invention also relates to a pharmaceutical composition for oral administration which can prevent or treat metabolic diseases such as rheumatoid arthritis and osteoarthritis and obesity, hyperlipemia, diabetes, diabetic complication, irritable bowel syndrome, gastric ulcer and gastritis.

In our body, the immune system, which is supposed to defend the body against external foreign substances such as bacteria, attacks our own body for reasons unknown. This state is called 'autoimmune' Chronic inflammation appears in the joint area, and sometimes it also causes muscle, lung, skin, blood vessels, nervous system, and eyes. A typical autoimmune disease is rheumatoid arthritis. Other immunological diseases include osteoarthritis. Osteoarthritis is a kind of arthritis, which is called osteoarthritis. It refers to arthritis caused by a degenerative change in the cartilage and surrounding bone in the lubricated joint. In other words, osteoarthritis is a disease characterized by gradual loss of articular cartilage, hypertrophy of bone located below cartilage, osteogenesis of joint edge region, and nonspecific synovial inflammation. Osteoarthritis is a disease caused by aging or excessive physical stress (for example, obesity, trauma, etc.) and cartilage damage. Therefore, osteoarthritis is a severe pain and movement disorder in the joints that are heavily weighted, that is, the knee (knee) joint and the hip joint (high) joint.

On the other hand, metabolic disease is a generic term for diseases caused by metabolic disorders in vivo. Metabolic disease refers to diseases caused by imbalance such as carbohydrates, lipids, proteins, vitamins, minerals and water, and is also referred to as metabolic diseases or metabolic disorders. It is difficult to develop a clear treatment method because metabolic diseases act as diverse and complex causes of diseases.

Rebamipide is a 2- (4-chlorobenzoylamino) -3- [2 (1H) -quinolin-4-yl] propionic acid having the structure of Chemical Formula 1 as a treatment for rheumatoid arthritis, osteoarthritis and various metabolic diseases (See the following prior art documents).

≪ Formula 1 >

However, only research on rebamipide itself has been carried out yet, and it is necessary to develop a rebamipide precursor which can prevent or treat immune diseases and metabolic diseases, in the absence of studies on rebamipide precursors.

Korean Patent Application No. 10-2009-0078547 Korean Patent Application No. 10-2010-0019671 Korean Patent Application No. 10-2010-0019671 Korean Patent Application No. 10-2013-0090687

Ha H et al., J Pharmacol Exp Ther; 281 (3): 1457-62, 1997 Jun. Kim YH et al., Korean Journal of Anatomy, 37 (2): 149-155, 2004. Thong-Ngam D et al., J Med Assoc Thai, 92 (9): 1207-12, 2009. sep.

Accordingly, in order to solve these problems, the present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of immunological diseases and metabolic diseases, which comprises a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient The purpose.

The immunological disease may be one selected from the group consisting of rheumatoid arthritis, osteoarthritis, and combinations thereof. The metabolic diseases include obesity, hyperlipidemia, diabetes, diabetic complication, irritable bowel syndrome, gastric ulcer, gastritis and combinations thereof ≪ / RTI >

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of immune diseases and metabolic diseases, which comprises a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

The rebamipide precursor may be a compound of the following formula (2).

(2)

In this formula,

X is (C ₃ -C ₈ heterocycloalkyl) C ₁ -C ₆ alkyl, (C ₃ -C ₈ heterocycloalkenyl) C ₁ -C ₆ alkyl or (heteroaryl) C ₁ -C ₆ alkyl.

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for preventing or treating rheumatoid arthritis comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the rebamipide precursor May be a compound of Formula 2, and the rebamipide precursor or a pharmaceutically acceptable salt thereof may be formulated into a unit dosage form suitable for oral administration at a dose of 10 to 50 mg / kg .

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for preventing or treating osteoarthritis comprising as an active ingredient a rebamipide precursor or a pharmaceutically acceptable salt thereof, wherein the rebamipide precursor May be a compound of Formula 1, and the rebamipide precursor or a pharmaceutically acceptable salt thereof may be formulated in a unit dosage form suitable for oral administration in a dose of 5 to 50 mg / kg .

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for preventing or treating obesity comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the rebamipide precursor May be a compound of Formula 2 and may be formulated in a unit dosage form suitable for oral administration at a dose of 5 to 50 mg / kg of the rebamipide precursor or a pharmaceutically acceptable salt thereof .

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for preventing or treating hyperlipidemia comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the rebamipide precursor May be a compound of Formula 2, and the rebamipide precursor or a pharmaceutically acceptable salt thereof may be formulated into a unit dosage form suitable for oral administration at a dose of 10 to 200 mg / kg. have.

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for preventing or treating diabetes or diabetic complications comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient, The complication may be Type 2 diabetes, and the rebamipide precursor may be one or more selected from the group consisting of the compounds of Formulas 3 to 5, and the rebamipide precursor or its pharmaceutically acceptable Possible salts may be formulated in a unit dosage form suitable for oral administration in dosages of 10 to 200 mg / kg.

In order to achieve the above object, the present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of irritable bowel syndrome comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient, The precursor of the feed may be a compound of Formula 2, and the rebamipide precursor or its pharmaceutically acceptable salt may be formulated into a unit dosage form suitable for oral administration at a dose of 5 to 100 mg / kg. .

There is provided a pharmaceutical composition for oral administration for the prevention or treatment of gastritis or gastric ulcer comprising, as an active ingredient, a rebamipide precursor or a pharmaceutically acceptable salt thereof, wherein said gastritis or gastric ulcer is an alcoholic Wherein the rebamipide precursor may be a compound of Formula 2 and the rebamipide precursor or a pharmaceutically acceptable salt thereof is suitable for oral administration at a dose of 5 to 100 mg / kg. May be formulated in a unit dosage form.

The pharmaceutical composition for oral administration according to the present invention can be administered orally or parenterally by incorporating a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient to provide a pharmaceutical composition for preventing or treating an immunological disease such as rheumatoid arthritis, osteoarthritis, and obesity, hyperlipidemia, diabetes, Metabolic diseases such as bowel syndrome, gastric ulcer, and gastritis can be treated more similarly to, or better than, rebamipide.

FIG. 1 is a graph showing the effect of treating the arthritis of Examples 1 to 3 on MAI (Mean Arthritis Index) after administering the pharmaceutical preparations for oral administration of Examples 1 to 3 to an animal model of CIA (Collagen-Induced Arthritis) The results are evaluated according to the scale. On the other hand, the negative control group did not inject any drug into the CIA animal model, the positive control group administered naproxen to the CIA animal model, and the normal group was the normal animal model that did not induce CIA.
FIG. 2 is a graph showing the results of the administration of the pharmaceutical preparations for oral administration of Examples 1 to 3 to an animal model of collagen-induced arthritis (CIA), and the amount of collagen- . On the other hand, the negative control group did not inject any drug into the CIA animal model, the positive control group administered naproxen to the CIA animal model, and the normal group was the normal animal model that did not induce CIA.
FIG. 3 shows the results of measurement of blood TNF-.alpha. After administration of the pharmaceutical preparations for oral administration of Examples 1 to 3 to an osteoarthritic animal model. On the other hand, in the control group, only physiological saline was injected into the osteoarthritic animal model. In the positive control group, diclofenac sodium was administered to the osteoarthritic animal model, and the normal group was the normal animal model that did not induce osteoarthritis.
FIG. 4 shows the results of measurement of IL-1β content in blood after administering the oral pharmaceutical preparations of Examples 1 to 3 to an osteoarthritic animal model. On the other hand, in the control group, only physiological saline was injected into the osteoarthritic animal model. In the positive control group, diclofenac sodium was administered to the osteoarthritic animal model, and the normal group was the normal animal model that did not induce osteoarthritis.
FIG. 5 shows the result of measurement of serum IL-6 content after administering the oral pharmaceutical preparations of Examples 1 to 3 to an osteoarthritic animal model. On the other hand, in the control group, only physiological saline was injected into the osteoarthritic animal model. In the positive control group, diclofenac sodium was administered to the osteoarthritic animal model, and the normal group was the normal animal model that did not induce osteoarthritis.
FIG. 6 shows the result of measuring the body weight over time after administering the oral pharmaceutical preparations of Examples 1 to 3 to an obesity animal model induced by high fat diet. On the other hand, the negative control group was injected with vehicle (citric acid + hypromellose 2910) only in the obese animal model, and the positive control group was administered with rebamipide in the obese animal model and the normal group was the normal animal model not fed with high fat diet .
FIG. 7 shows the dietary intake of the obese animals during the experimental period after administering the pharmaceutical preparations for oral administration of Examples 1 to 3 to an obesity animal model induced by high fat diet. On the other hand, the negative control group was injected with vehicle (citric acid + hypromellose 2910) only in the obese animal model, and the positive control group was administered with rebamipide in the obese animal model and the normal group was the normal animal model not fed with high fat diet .
8 shows the results of measuring the body weight over time after administering the pharmaceutical preparations for oral administration of Examples 1 to 3 to a model of type 2 diabetes (db / db mouse). In the negative control group, only the vehicle (citric acid + hypromellose 2910) was injected into the db / db mouse, the positive control group was administered with rebamipide in db / db mice, and the normal group was the normal animal model without diabetes.
FIG. 9 shows the results of blood glucose levels measured after administering the pharmaceutical preparations for oral administration of Examples 1 to 3 for 8 weeks to an animal model of type 2 diabetes (db / db mouse). In the negative control group, only the vehicle (citric acid + hypromellose 2910) was injected into the db / db mouse, the positive control group was administered with rebamipide in db / db mice, and the normal group was the normal animal model without diabetes.
FIG. 10 shows results of blood glucose concentration measurement after administering the pharmaceutical preparations for oral administration of Examples 1 to 3 to a diabetic animal model induced by streptozotocin. In the negative control group, only the vehicle (citric acid + hypromellose 2910) was injected into the db / db mouse, the positive control group was administered with rebamipide in db / db mice, and the normal group was the normal animal model without diabetes.
Figure 11 shows the result of measuring the body weight over time after administering the pharmaceutical preparations for oral administration of Examples 2, 4 and 5 to an animal model of irritable bowel syndrome ( Vehicle : normal group, TNBS : negative control group Syndrome animal model, TNBS + 5-ASA : 5-ASA oral administration to an irritable bowel syndrome animal model as a positive control, TNBS + Examples 2, 4, 5 : Example 2 of an irritable bowel syndrome animal model as an experimental group , 4, 5).
Figure 12 shows the result of measuring the length from the anus to the cecum after administering the pharmaceutical preparations for oral administration of Examples 2, 4 and 5 to an animal model of irritable bowel syndrome ( Vehicle : normal group, TNBS : negative control group 5-ASA : Oral administration of 5-ASA to an irritable bowel syndrome animal model as a positive control, Examples 2, 4 and 5 : Examples 2, 4, and 5 of an irritable bowel syndrome animal model as an experimental group, 5).
Figure 13 shows the result of measuring the intestinal wet weight after administration of the pharmaceutical preparations for oral administration of Examples 2, 4 and 5 to an animal model of irritable bowel syndrome ( Vehicle : Normal group, TNBS : Negative control group Model 5-ASA : 5-ASA Oral Administration to Irritable Bowel Syndrome Animal Model as a Positive Control, Examples 2, 4 and 5 : Irritable Bowel Syndrome as an Experimental Example Animal models were administered with Examples 2, 4, administration)
FIG. 14 is a photograph of the upper incision after taking the pharmacological preparations for oral administration of Examples 1 and 2, respectively, into an ethanol-induced gastric injured animal model.
FIG. 15 shows the result of calculating the area ratio (%) of the above damage after administering the pharmaceutical preparations for oral administration of Examples 1 and 2, respectively, to an ethanol-induced gastric injured animal model.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of immunological diseases and metabolic diseases, which comprises a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient, wherein said immune disease is an autoimmune disease And the immune diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, and combinations thereof. The metabolic diseases include, but are not limited to, obesity, hyperlipidemia, diabetes, irritable bowel syndrome, and gastric ulcer.

The rebamipide precursor is a compound capable of decomposing into the rebamipide of the following formula (1) in vivo, and means a compound having a functional group that can be easily released after being absorbed in the living body. Precursors are generally used to enhance in vivo absorption or increase solubility.

≪ Formula 1 >

The rebamipide precursor which is an effective ingredient used in the composition of the present invention may be a compound of the following formula (2).

(2)

In this formula,

X is (C ₃ -C ₈ heterocycloalkyl) C ₁ -C ₆ alkyl, (C ₃ -C ₈ heterocycloalkenyl) C ₁ -C ₆ alkyl or (heteroaryl) C ₁ -C ₆ alkyl.

The term "heterocycloalkyl" or "heterocycloalkenyl ", as used herein, refers to a saturated or unsaturated, saturated or unsaturated, saturated or unsaturated, Means that either nitrogen or oxygen is substituted for the saturated carbon, or that the same or different atoms are singly or doubly substituted or skipped over. Examples of said heterocycloalkyl or heterocycloalkenyl include aziridine, oxirane, azetidine, oxetane, pyrrolidine, pyrroline, pyrazolidine, pyrazoline, imidazolidine, imidazoline, triazolidine , Oxazolidine, tetrahydrofuran, tetrahydrothiophene, thiazolidine, dioxolane, dioxole, oxathiolane, morpholine. But are not limited to, thiomorpholine, dithiane, piperidine, piperazine, pyran, dioxane or azepane.

Furthermore, the term "heteroaryl " as used herein means an aryl in which either nitrogen, oxygen, or sulfur is substituted, or the same or different atoms are replaced by a single, double or triple neighboring or skipped substituent. Specific examples of the heteroaryl include pyrrole, imidazole, pyrazole, triazole, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, oxadiazole, thiadiazole, pyridine, pyrimidine, Benzothiazole, benzothiazole, benzofuran, benzothiophene, quinoline, isoquinoline, quinoxine, pyrazine, pyridazine, triazine, azepine, indole, benzimidazole, indazole, benzooxazole, Benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiophene, benzothiazine, chroman, chromene, benzodioxanthridine, phenothiazine, But is not limited thereto.

The compound 2 may be selected from the group consisting of compounds represented by the following general formulas (3) to (7), though not limited thereto.

(3)

The compound of Formula 3 is 2-piperidin-1-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propionate. The compound of formula (3) can be obtained by reacting rebamipide with 1- (2-chloroethyl) piperidine hydrochloride.

≪ Formula 4 >

The compound of formula (4) can be produced by reacting 2-morpholin-4-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin- (2-chloroethyl) morpholine hydrochloric acid.

≪ Formula 5 >

The compound of formula (5) can be used as 3-morpholin-4-ylpropyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin- Lt; / RTI > with methyl 3- (morpholin-4-yl) propyl hydrochloride methanesulfonate.

(6)

The compound of formula (6) can be obtained by reacting 2-azepan-1-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin- Can be obtained by reacting Mifid with 2- (hexamethyleneimino) ethyl chloride hydrochloric acid.

≪ Formula 7 >

The compound of formula (7) can be prepared by reacting 2-pyrrol-1-ylethyl 2- (4-chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin- Lt; RTI ID = 0.0 > 1- (2-bromoethyl) pyrrole. ≪ / RTI >

The pharmaceutically acceptable salt of the rebamipide precursor contained as an active ingredient in the pharmaceutical composition of the present invention refers to an acid addition salt formed by using free acid, and the free acid may be an organic acid or an inorganic acid.

The organic acid may be selected from the group consisting of citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, dichloroacetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, benzoic acid, Sulfonic acid, methanesulfonic acid, capric acid, capronic acid, caprylic acid, carboxylic acid, cinnamic acid, cyclamic acid, dodecylsulfonic acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2- Gluconic acid, succinic acid, succinic acid, tartaric acid, succinic acid, tartaric acid, succinic acid, salicylic acid, salicylic acid, Naphthalene-2-sulfonic acid, naphthoic acid, nicotinic acid, glycolic acid, succinic acid, stearic acid, stearic acid, thiocyanic acid, undecylenic acid, isobutyric acid, lauric acid, mandelic acid, , 4-toluenesulfonic acid, camphorsulfonic acid, glutamic acid, aspartic acid, salicylic acid, 4- Maleic acid, maleic acid, benzoic acid, maleic acid, maleic acid, and benzosulfonic acid. The inorganic acid may be any one selected from the group consisting of hydrochloric acid, bromic acid, sulfuric acid, nitric acid, and phosphoric acid.

In the composition according to the present invention, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be used in an amount of 1 to 50% by weight based on the total amount of the pharmaceutical composition for oral administration.

In addition, the pharmaceutical composition according to the present invention may further comprise a pharmaceutically acceptable carrier or additive. &Quot; Pharmaceutically acceptable " as used herein means physiologically acceptable and when administered to humans, does not normally cause an allergic reaction such as gastrointestinal disorder, dizziness, or the like. Examples of such additives include excipients, disintegrants, binders, lubricants, wetting agents, dispersants, stabilizers and the like. Examples of the excipient include lactose, mannitol, isomalt, microcrystalline cellulose, silicified microcrystalline cellulose, and powdered cellulose. Examples of disintegrants include low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, croscarmellose sodium, starch and the like. Examples of the binder include hydroxypropylcellulose, hypromellose, povidone, copovidone, pregelatinized starch, and the like. Examples of the lubricant include stearic acid, magnesium stearate, sodium stearyl fumarate, and the like. Examples of the wetting agent include polyoxyethylene sorbitan fatty acid ester derivatives, poloxamer, and polyoxyethylene castor oil derivatives. Examples of the dispersing agent include hypromellose, hydroxypropylcellulose, povidone, copovidone, carboxymethylcellulose sodium, methylcellulose and the like. Examples of the stabilizer include citric acid, fumaric acid, succinic acid, and the like. In addition, the pharmaceutical composition of the present invention may further comprise an anti-coagulant, a flavoring agent, an emulsifying agent and an antiseptic agent.

Furthermore, the pharmaceutical compositions of the present invention can be formulated using methods known in the art so as to provide rapid, sustained or delayed release of the active ingredient after administration to the mammal. The pharmaceutical formulation may be a powder, a granule, a tablet, a suspension, an emulsion, a syrup, an aerosol, or a soft or hard gelatin capsule, preferably a suspension formulation. The suspending agent according to the present invention contains citric acid as a stabilizer and may contain hypromellose as a suspending agent.

The rebamipide precursors do not know how much of an effect can be achieved with levamiprid in which amount. In addition, the oral administration agent is likely to be degraded or lost through various organs in the body, and it takes considerable time to reach the target site. Therefore, it is difficult to estimate how much the pharmaceutical composition for oral administration containing the rebamipide precursor as an active ingredient can be effective as the rebamipide. The pharmaceutical composition for oral administration comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof according to the present invention as an active ingredient is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof is orally administered Has a therapeutic effect similar to or better than that of levamidipa in rheumatoid arthritis. The pharmaceutical composition according to the present invention may therefore preferably be formulated as a unit dosage form suitable for oral administration of a rebamipide precursor or a pharmaceutically acceptable salt thereof in the abovementioned dosages.

 In some cases, dosage values less than the above-mentioned ranges may be more suitable, more doses may be used without causing harmful side effects, and more doses may be administered several times daily / RTI >

The present invention provides a pharmaceutical composition for oral administration for prevention or treatment of rheumatoid arthritis comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

Rheumatoid arthritis refers to chronic inflammation in the synovial membrane of the human body, which lasts for more than 6 weeks. Once rheumatoid arthritis begins, it forms a mass of 'Pannus' consisting of various inflammatory cells from the blood of synovial tissue, which destroys the cartilage, deforms the joints, and weakens the bones around the joints . This inflammation of the joint results in swelling and sore joints, limited range of motion of the joints, and around the joints become swollen and feel warm touch.

Although there have been many studies to date on the etiology of rheumatoid arthritis, the exact cause of rheumatoid arthritis remains to be determined. However, there are many clinical treatments for the treatment of rheumatoid arthritis, which include general conservative therapy, pharmacotherapy, and surgical therapy. In general, the treatment of rheumatoid arthritis is the treatment of chronic arthritis, joint pain, joint deformation, loss of function, so that the pain and inflammation, suppression of joint function is minimized to return to normal life have. Currently, the most common treatment modality is drug therapy, which includes, depending on the symptoms, aspirin and nonsteroidal anti-inflammatory drugs, low-dose oral steroids, antimalarial drugs, sulfasalazine, gold compounds, (DMARDs) such as penicillamine, immunosuppressants (methotrexate (MTX), and Immuran), injections of intraarticular steroids and tumor necrosis factor blockers (etanercept, infliximab, adalimumab), an interleukin-1 receptor antagonist (anakinra), and an anti-CD20 antibody (rituximab). However, these pharmacological treatments have disadvantages such as gastrointestinal disorders, hepatic disorders, kidney dysfunction, and infection.

The rebamipide precursor contained as an active ingredient in the pharmaceutical composition for preventing or treating rheumatoid arthritis is not limited thereto, but may be the compound of Formula 2, preferably the compound of Formula 3 to 5 It can be one or more selected.

In addition, the dosage of the rebamipide precursor or its pharmaceutically acceptable salt for use in the pharmaceutical composition for the prevention or treatment of rheumatoid arthritis may vary depending on the subject to be treated, the severity of the disease or condition, the rate of administration, . For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a rate of 10 to 100 mg / kg (body weight), 10 to 50 mg / kg (body weight), 10 to 30 mg / kg body weight, 10 to 25 mg / kg body weight, 12 to 24 mg / kg body weight, 10 to 15 mg / kg body weight, 20 to 30 mg / kg body weight, 20 to 28 mg / or a dose of 22 to 26 mg / kg (body weight), may have a therapeutic effect similar or superior to rheumatoid arthritis in the treatment of rheumatoid arthritis.

Accordingly, the pharmaceutical composition for the prevention or treatment of rheumatoid arthritis according to the present invention is characterized in that the rebamipide precursor or pharmaceutically acceptable salt thereof is administered at a dose of 10 to 100 mg / kg (body weight), 10 to 50 mg / kg Kg body weight, 10 to 25 mg / kg body weight, 12 to 24 mg / kg body weight, 10 to 15 mg / kg body weight, 20 to 30 mg / kg body weight, ), 20 to 28 mg / kg (body weight), or 22 to 26 mg / kg (body weight), per unit dosage form suitable for oral administration.

On the other hand, the present invention provides a method for preventing or treating rheumatoid arthritis in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to a subject suffering from rheumatoid arthritis or at risk of developing rheumatoid arthritis, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 10 to 100 mg / kg (body weight), 10 to 50 mg / kg (body weight), 10 to 30 mg / kg 10 to 25 mg / kg body weight, 12 to 24 mg / kg body weight, 10 to 15 mg / kg body weight, 20 to 30 mg / kg body weight, 20 to 28 mg / kg body weight, Or a dose of 22 to 26 mg / kg (body weight), and the administration period may be one week, two weeks, three weeks, four weeks or more, The subject may be selected according to the severity of the disease.

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of rheumatoid arthritis. The pharmaceutical composition comprises 10 to 100 mg / kg body weight, 10 to 50 mg / kg body weight, 10 to 30 mg / kg body weight, 10 to 100 mg / kg body weight, or a pharmaceutically acceptable salt thereof, 10 to 15 mg / kg body weight, 20 to 30 mg / kg body weight, 20 to 28 mg / kg body weight, or 22 mg / kg body weight, To a unit dosage form suitable for oral administration at a dose of 26 mg / kg (body weight).

The present invention provides a pharmaceutical composition for oral administration for preventing or treating osteoarthritis comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

The rebamipide precursor included as an active ingredient in the pharmaceutical composition for preventing or treating osteoarthritis is not limited thereto, but may be the compound of Formula 2, preferably the compound of Formula 3 to 5 It can be more than one.

The dose of the rebamipide precursor or its pharmaceutically acceptable salt used in the pharmaceutical composition for preventing or treating osteoarthritis according to the present invention may vary depending on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician . For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a rate of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight), 10 to 40 mg / kg body weight, 10 to 30 mg / kg body weight, 10 to 25 mg / kg body weight, 10 to 20 mg / kg body weight, 5 to 15 mg / kg body weight, 10 to 15 mg / orally at a dose of about 10 mg / kg body weight, 15 to 30 mg / kg body weight, or 15 to 25 mg / kg body weight, so as to have an osteoarthritis treatment effect similar or better than the levamipadate oral administration .

Accordingly, the pharmaceutical composition for oral administration according to the present invention is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof is administered at a dose of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight) kg body weight, 10 to 30 mg / kg body weight, 10 to 25 mg / kg body weight, 10 to 20 mg / kg body weight, 5 to 15 mg / kg body weight, 10 to 15 mg / it may be preferred to be made in a unit dosage form suitable for oral administration at a dose of about 10 mg / kg body weight, 15 to 30 mg / kg body weight, or 15 to 25 mg / kg body weight. have.

On the other hand, the present invention provides a method for preventing or treating osteoarthritis in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to a subject suffering from osteoarthritis or at risk of developing osteoarthritis, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight), 10 to 40 mg / kg (body weight) 10 to 30 mg / kg body weight, 10 to 25 mg / kg body weight, 10 to 20 mg / kg body weight, 5 to 15 mg / kg body weight, 10 to 15 mg / The dosage may be orally administered once a day at a dose of 15 to 30 mg / kg (body weight), or 15 to 25 mg / kg (body weight), and the administration period is not limited to one week but two weeks or more , 3 weeks or more, and 4 weeks or more, and the administration period can be selected according to the progress of the disease of the subject.

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of osteoarthritis. The pharmaceutical composition comprises 5 to 100 mg / kg body weight, 5 to 50 mg / kg body weight, 10 to 40 mg / kg body weight, 10 to 100 mg / kg body weight, or a pharmaceutically acceptable salt thereof, Kg body weight, 10 to 25 mg / kg body weight, 10 to 20 mg / kg body weight, 5 to 15 mg / kg body weight, 10 to 15 mg / kg body weight, A unit dosage form suitable for oral administration at a dose of 30 mg / kg (body weight), or 15 to 25 mg / kg (body weight).

The present invention provides a pharmaceutical composition for oral administration for prevention or treatment of obesity comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

The pharmaceutical composition for preventing or treating obesity may contain at least one compound selected from the group consisting of the compounds represented by formulas (3) to (5), and the rebamipide precursor contained as the active ingredient may be the compound represented by formula (2).

The dosage of the rebamipide precursor or its pharmaceutically acceptable salt for use in the pharmaceutical composition for the prevention or treatment of obesity according to the present invention may vary depending on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician . For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a rate of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight), 10 to 40 mg / orally at a dose of 10 mg / kg body weight, 10-30 mg / kg body weight, or 15-25 mg / kg body weight, .

Accordingly, the pharmaceutical composition for oral administration according to the present invention is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof is administered at a dose of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight) it may be preferred to be made in a unit dosage form suitable for oral administration at a dose of 10 mg / kg body weight, 10-30 mg / kg body weight, or 15-25 mg / kg body weight. have.

On the other hand, the present invention provides a method for preventing or treating obesity in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to a subject suffering from obesity or at risk of becoming obese, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight), 10 to 40 mg / kg (body weight) The dosage may be orally administered twice a day, in a dose of 10 to 30 mg / kg (body weight), or 15 to 25 mg / kg (body weight), and the administration period is 1 week to 2 weeks, Week, more than 5 weeks, more than 6 weeks, more than 7 weeks, or more than 8 weeks, and the administration period can be appropriately selected depending on the condition of the subject to be applied.

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of obesity. The pharmaceutical composition comprises 5 to 100 mg / kg body weight, 5 to 50 mg / kg body weight, 10 to 40 mg / kg body weight, 10 to 100 mg / kg body weight, or a pharmaceutically acceptable salt thereof, A unit dosage form suitable for oral administration at a dose of 30 mg / kg (body weight), or 15 to 25 mg / kg (body weight).

The present invention provides a pharmaceutical composition for oral administration for prevention or treatment of hyperlipidemia comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

The rebamipide precursor included in the pharmaceutical composition for the prevention or treatment of hyperlipidemia is not limited thereto, but may be the compound of Formula 2, and preferably the compound of Formula 3 to 5 ≪ / RTI >

The dosage of the rebamipide precursor or its pharmaceutically acceptable salt for use in the pharmaceutical composition for the prevention or treatment of hyperlipidemia according to the present invention may vary depending on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician . For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a rate of 10 to 200 mg / kg (body weight), 10 to 190 mg / kg (body weight), 10 to 180 kg body weight, 10 to 170 mg / kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / kg body weight, 10 to 120 mg / kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, kg body weight, 20 to 80 mg / kg body weight, 20 to 70 mg / kg body weight, 30 to 70 mg / kg body weight, or 40 to 60 mg / By oral administration, it may have a hyperlipidemic therapeutic effect similar to or better than the levamipadic oral dosage form.

Accordingly, the pharmaceutical composition for oral administration according to the present invention is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof is administered in an amount of 10 to 200 mg / kg (body weight), 10 to 190 mg / kg (body weight) kg body weight, 10 to 170 mg / kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / kg body weight, 10 to 120 mg / kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, kg body weight, 20 to 80 mg / kg body weight, 20 to 70 mg / kg body weight, 30 to 70 mg / kg body weight, or 40 to 60 mg / It may be desirable to be made in a unit dosage form suitable for oral administration.

On the other hand, the present invention provides a method of preventing or treating hyperlipemia in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to a subject suffering from hyperlipidemia or at risk of developing hyperlipemia, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 10 to 200 mg / kg (body weight), 10 to 190 mg / kg (body weight), 10 to 180 mg / kg (body weight) 10 to 170 mg / kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / 10 to 120 mg / kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, 10 to 80 mg / Administered orally twice daily at a dose of 20 to 80 mg / kg body weight, 20 to 70 mg / kg body weight, 30 to 70 mg / kg body weight, or 40 to 60 mg / kg body weight The duration of administration may be at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, or at least eight weeks. subject. < / RTI >

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of hyperlipidemia. The pharmaceutical composition comprises 10 to 200 mg / kg body weight, 10 to 190 mg / kg body weight, 10 to 180 mg / kg body weight, 10 to 100 mg / kg body weight of the rebamipide precursor or a pharmaceutically acceptable salt thereof, Kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / kg body weight, Kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, 10 to 80 mg / kg body weight, A unit dosage form suitable for oral administration at a dose of 80 mg / kg (body weight), 20 to 70 mg / kg (body weight), 30 to 70 mg / kg (body weight), or 40 to 60 mg / Unit dosage form.

The present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of diabetic or diabetic complications comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

The diabetes may be type 1 diabetes and type 2 diabetes, and in particular may be type 2 diabetes. In addition, the diabetic complication refers to a disease caused by diabetes mellitus, and may be, but is not limited to, hyperlipemia. Hypertriglyceridemia is the most common hyperlipidemia due to lipid metabolism abnormality commonly seen in patients with type 2 diabetes, and the increase in blood triglyceride (TG) thus promotes insulin resistance and exacerbates blood glucose control This is a cause of arteriosclerosis. Since the rebamipide precursor or its pharmaceutically acceptable salt according to the present invention has an effect of lowering the blood triglyceride and cholesterol content in an animal model induced by type 2 diabetes, it is very excellent in treating diabetic complications related to lipid metabolism Do.

The rebamipide precursor contained in the pharmaceutical composition for preventing or treating diabetes or diabetic complication according to the present invention is not limited thereto but may be one or more selected from the group consisting of the compounds represented by Chemical Formulas 3 to 5 .

The dosage of the rebamipide precursor or its pharmaceutically acceptable salt for use in the pharmaceutical composition for the prevention or treatment of diabetes or diabetic complications according to the present invention will depend on the subject, the severity of the disease or condition, the rate of administration, . For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a rate of 10 to 200 mg / kg (body weight), 10 to 190 mg / kg (body weight), 10 to 180 kg body weight, 10 to 170 mg / kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / kg body weight, 10 to 120 mg / kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, kg body weight, 10 to 70 mg / kg body weight, 20 to 90 mg / kg body weight, 30 to 70 mg / kg body weight or 40 to 60 mg / kg body weight, As such, it may have a therapeutic effect similar to or better than diabetes mellitus or diabetic complications as the levamipadate oral administration agent.

Accordingly, the pharmaceutical composition for oral administration according to the present invention is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof is administered in an amount of 10 to 200 mg / kg (body weight), 10 to 190 mg / kg (body weight) kg body weight, 10 to 170 mg / kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / kg body weight, 10 to 120 mg / kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, kg body weight, 10 to 70 mg / kg body weight, 20 to 90 mg / kg body weight, 30 to 70 mg / kg body weight or 40 to 60 mg / kg body weight, It may be desirable to be made in a unit dosage form suitable for administration.

On the other hand, the present invention provides a method for the prevention or treatment of diabetic or diabetic complications in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to a subject suffering from diabetes or diabetic complications or a subject at risk of developing diabetes or diabetic complications, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 10 to 200 mg / kg (body weight), 10 to 190 mg / kg (body weight), 10 to 180 mg / kg (body weight) 10 to 170 mg / kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / 10 to 120 mg / kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, 10 to 80 mg / Administered orally once daily at a dose of 10 to 70 mg / kg body weight, 20 to 90 mg / kg body weight, 30 to 70 mg / kg body weight or 40 to 60 mg / kg body weight The duration of administration may be at least one week, at least two weeks, at least three weeks, at least four weeks, at least five weeks, at least six weeks, at least seven weeks, or at least eight weeks. ). ≪ / RTI >

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of diabetes or diabetic complications. The pharmaceutical composition comprises 10 to 200 mg / kg body weight, 10 to 190 mg / kg body weight, 10 to 180 mg / kg body weight, 10 to 100 mg / kg body weight of the rebamipide precursor or a pharmaceutically acceptable salt thereof, Kg body weight, 10 to 160 mg / kg body weight, 10 to 150 mg / kg body weight, 10 to 140 mg / kg body weight, 10 to 130 mg / kg body weight, Kg body weight, 10 to 110 mg / kg body weight, 10 to 100 mg / kg body weight, 10 to 90 mg / kg body weight, 10 to 80 mg / kg body weight, Unit dosage form suitable for oral administration at a dose of 70 mg / kg body weight, 20-90 mg / kg body weight, 30-70 mg / kg body weight or 40-60 mg / kg body weight dosage form.

The present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of irritable bowel syndrome comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.

The rebamipide precursor contained in the pharmaceutical composition for oral administration for the prevention or treatment of irritable bowel syndrome is not limited thereto, but may be the compound of Formula 2, preferably the compound of Formula 4, 6, 7. ≪ / RTI >

The dose of the rebamipide precursor or its pharmaceutically acceptable salt used in the composition according to the present invention depends on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a rate of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight), 5 to 40 mg / kg body weight, 10-50 mg / kg body weight, 10-40 mg / kg body weight, 15-45 mg / kg body weight, 15-35 mg / kg body weight, 20-50 mg / orally administered at a dose of 10 mg / kg (body weight), 20 to 40 mg / kg (body weight), or 25 to 35 mg / kg (body weight), and thus can have an excellent therapeutic effect on irritable bowel syndrome.

Accordingly, the pharmaceutical composition for oral administration according to the present invention is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof contains 5 to 100 mg / kg body weight, 5 to 50 mg / kg body weight, 5 to 40 mg / kg body weight, 10-50 mg / kg body weight, 10-40 mg / kg body weight, 15-45 mg / kg body weight, 15-35 mg / kg body weight, 20-50 mg / it may be preferred to be made in a unit dosage form suitable for oral administration at a dose of 20 to 40 mg / kg (body weight), or 25 to 35 mg / kg (body weight). have.

On the other hand, the present invention provides a method of preventing or treating irritable bowel syndrome in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to a subject suffering from irritable bowel syndrome or a subject at risk of developing irritable bowel syndrome, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 5 to 100 mg / kg (body weight), 5 to 50 mg / kg (body weight), 5 to 40 mg / kg (body weight) 10 to 50 mg / kg body weight, 10 to 40 mg / kg body weight, 15 to 45 mg / kg body weight, 15 to 35 mg / kg body weight, 20 to 50 mg / The dosage can be orally administered once a day at a dose of 20 to 40 mg / kg (body weight) or 25 to 35 mg / kg (body weight), and the administration period is 1 day, 1 day, More than 4 days, more than 5 days, more than 6 days, more than 7 days, more than 8 days, more than 9 days, or more than 10 days, and the administration period is appropriately selected according to the condition of the subject .

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of irritable bowel syndrome. The pharmaceutical composition comprises 5 to 100 mg / kg body weight, 5 to 50 mg / kg body weight, 5 to 40 mg / kg body weight, 10 to 100 mg / kg body weight of the rebamipide precursor or a pharmaceutically acceptable salt thereof, Kg body weight, 10-40 mg / kg body weight, 15-45 mg / kg body weight, 15-35 mg / kg body weight, 20-50 mg / kg body weight, 20-50 mg / A unit dosage form suitable for oral administration at a dose of 40 mg / kg (body weight), or 25 to 35 mg / kg (body weight).

The present invention provides a pharmaceutical composition for oral administration for the prevention or treatment of gastritis or gastric ulcer comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient. The gastritis or gastric ulcer may be, but is not limited to, an alcoholic gastritis or an alcoholic gastric ulcer.

The present invention is not limited thereto, but it may be a compound of Formula 2, preferably a compound of Formula 3 or 4, or a compound of Formula 3 or 4, Lt; / RTI >

Alcoholic gastritis or alcoholic gastric ulcers are one of the most common diseases in people today, and many suffer from it. In addition to social stress, frequent consumption of alcohol causes severe gastritis or gastric ulcer, and many medicines and health functional foods are being sold to improve it. Studies have focused on lowering alcohol concentration by activating mainly ADH and ALDH. However, there are few effective substances that exhibit significant detoxification effects over a short period of time. In the case of gastric ulcer treatment such as pantoprazole, which is a hydrogen ion pump inhibitor, it is effective for gastric ulcers caused by other causes, but it is not effective for alcoholic gastric ulcers (Cao et al ., Journal of Health Science 50 1-8, 2004). Therefore, it is not easy to predict that rebamipide has a therapeutic effect of gastric ulcer, but that the rebamipide precursor has a therapeutic effect of alcoholic gastric ulcer or alcoholic gastritis.

The dose of the rebamipide precursor or its pharmaceutically acceptable salt used in the composition according to the present invention depends on the subject to be treated, the severity of the disease or condition, the rate of administration and the judgment of the prescribing physician. For example, the rebamipide precursor or a pharmaceutically acceptable salt thereof may be administered at a dose of 5 to 100 mg / kg (body weight), 10 to 90 mg / kg (body weight), 10 to 80 mg / kg (body weight) 10 to 70 mg / kg body weight, 10 to 60 mg / kg body weight, 20 to 90 mg / kg body weight, 20 to 80 mg / kg body weight, 20 to 70 mg / , 30 to 70 mg / kg (body weight), 30 to 60 mg / kg (body weight), or 40 to 60 mg / kg (body weight) It can have a therapeutic effect.

Accordingly, the pharmaceutical composition for oral administration according to the present invention is characterized in that the rebamipide precursor or a pharmaceutically acceptable salt thereof is used in an amount of 5 to 100 mg / kg (body weight), 10 to 90 mg / kg (body weight) kg body weight, 10-70 mg / kg body weight, 10-60 mg / kg body weight, 20-90 mg / kg body weight, 20-80 mg / kg body weight, 20-70 mg / a unit dosage form suitable for oral administration at a dose of about 30 mg / kg body weight, 30 to 70 mg / kg body weight, 30 to 60 mg / kg body weight, or 40 to 60 mg / kg body weight dosage form. < / RTI >

On the other hand, the present invention provides a method of preventing or treating a gastric ulcer in a subject, comprising administering a rebamipide precursor or a pharmaceutically acceptable salt thereof to a subject in need thereof. The subject refers to an object that is suffering from a gastric ulcer, or at risk of becoming a gastric ulcer, such as a mammal, preferably a human.

The method comprises administering the rebamipide precursor or a pharmaceutically acceptable salt thereof in an amount of 5 to 100 mg / kg (body weight), 10 to 90 mg / kg (body weight), 10 to 80 mg / kg (body weight) 10 to 70 mg / kg body weight, 10 to 60 mg / kg body weight, 20 to 90 mg / kg body weight, 20 to 80 mg / kg body weight, 20 to 70 mg / kg body weight, At least once, at least 2 times, at least 3 times, at least 4 times at a dose of 30 to 70 mg / kg (body weight), 30 to 60 mg / kg (body weight), or 40 to 60 mg / More than 5 times, and the number of administration can be appropriately determined according to the state of the administration object.

The present invention also provides the use of a rebamipide precursor or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the prevention or treatment of gastric ulcers. The pharmaceutical composition comprises 5 to 100 mg / kg of body weight, 10 to 90 mg / kg of body weight, 10 to 80 mg / kg of body weight, 10 to 100 mg / kg body weight of a rebamipide precursor or a pharmaceutically acceptable salt thereof, Kg body weight, 20-70 mg / kg body weight, 10-60 mg / kg body weight, 20-90 mg / kg body weight, 20-80 mg / kg body weight, 20-70 mg / kg body weight, A unit dosage form suitable for oral administration at a dose of 70 mg / kg (body weight), 30 to 60 mg / kg (body weight), or 40 to 60 mg / kg (body weight).

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

EXPERIMENTAL EXAMPLE 1: Analysis of drug efficacy using an animal model of rheumatoid arthritis [

The therapeutic effect of rheumatoid arthritis of Examples 1 to 3 (Rebamipide precursor of Chemical Formulas 3 to 5, Samjin Pharmaceutical) was confirmed by the following method.

Experimental Example 1-1. Preparation of Collagen-Induced Arthritis (CIA) Animal Model and Administration of Rebamipide Precursor

Male DBA / 1J mice of 5 weeks of age were used as test animals. Dissolve type II Bovine type collagen (CII) in 0.05 M acetic acid solution to 2 mg / ml. They were then mixed with equivalent amounts of Complete Freud's adjuvant (CFA, Chondrex) containing M. tuberculosis and subcutaneously injected into the base of the tail of the mouse to inject 100 μl of the immunogen (200 μg / 100 μl) per mouse (First inoculation). Two weeks later, the same CII was mixed with the same amount of imcomplete Freud's adjuvant (IFA, Chondrex), and then 100 μl (ie 200 μg / 100 μl) was injected into the upper part of the mouse tail (2nd inoculation, amplification).

After the second inoculation, the rebamipide precursors of Formulas 1 to 3 (Examples 1 to 3) were each prepared in suspension form with vehicle (0.1% citric acid & 2% HEPROMELOSE 2910 (Pharmacoat 615, Shin-etsu) , Orally administered by oral gavage twice daily for 28 days (4 weeks) to each of the different groups so that the doses of Examples 1 to 3 were 12 mg / kg (body weight) and 24 mg / kg (body weight) . In addition, naproxen as a positive control was administered at 10 mg / kg to another different group to which the example was not applied, and the negative control did not administer the drug after inducing rheumatoid arthritis. Each group was divided into 10 groups.

Experimental Example 1-2. Assessment of Rheumatoid Arthritis Therapeutic Activity using MAI Assessment

From 2 weeks after the first inoculation, 2 observers were evaluated for perception of joint inflammation three times a week for 4 weeks after drug administration. At this time, evaluation of arthritis was performed by evaluating each leg according to the mean arthritic index scale, and the evaluation results are shown in FIG. The highest index of disease in a rat is 16 because the highest arthritis index in the marine is 4 points.

Mean arthritic index (MAI) scale score Symptom (each foot) 0 If you do not have swelling or swelling One Mild swelling and redness limited to the foot or ankle joint 2 Mild swelling and redness from ankle joint to foot 3 Moderate edema and flare across the ankle joint to the tribe 4 Edema and redness throughout the legs from the ankle

In FIG. 1, it can be seen that the effects of Examples 1 to 3 are significantly better than those of CII-induced negative control. In particular, Example 3 (24 mg / kg) was more effective than Example 2 (12 mg / kg, 24 mg / kg) for the positive control Naproxen (10 mg / kg).

Experimental Example 3. Serological tests (measurement of antibody specific for collagen)

Serological tests were performed to determine the changes of CII-specific immune antibodies (total IgG) by enzyme-linked immunosorbent assay (ELISA). The serum of each test group was diluted to 1: 8000 and the serum IgG antibody specific for CII was measured. The results are shown in FIG.

In FIG. 2, it can be confirmed that the amount of IgG produced in the group administered the Example is similar to or less than that of the Naproxen administration group, which is a positive control group. In particular, in Example 2, the production of IgG was significantly reduced as compared with the positive control.

<Experimental Example 2: Analysis of efficacy using an animal model of osteoarthritis>

The therapeutic effects of osteoarthritis of Examples 1 to 3 (rebamipide precursors of Formulas 3 to 5, striking drug) were confirmed by the following method.

Experimental Example 2-1. Preparation of Osteoarthritis Animal Model

The test animals were adapted to the general diet for 1 week using C57BL / 6J mouse, an osteoarthritis model of 8 weeks old, and then used in the experiment. The temperature and humidity of the breeding room were maintained at 20 ± 2 ℃ and 50 ± 10%, respectively. During the experiment, feed and water were freely available. After adaptation, body weight was measured and 8 rats were assigned to each group uniformly.

The normal group was orally administered with 0.2 ml of physiological saline solution for 6 days to the right knee. In the control, positive control, and experimental groups, 6 ㎕ of papain was injected into the right knee joint to induce osteoarthritis. The control group received saline and the positive group received diclofenac sodium (DS / Sigma-Aldrich Co., St. Louis, 2 mg / kg. The experimental groups were prepared by dissolving Examples 1 to 3 in an excipient for oral administration (0.1% Citric acid + 2% Pharmacoat 615, Shin-etsu) Each group was orally administered once daily once daily for 28 days to each different group so that the doses were 10 mg / kg and 20 mg / kg, respectively.

  The osteoarthritis model was induced by the method described in the efficacy test guideline of herbal medicine prescribed by the Food and Drug Administration. (Papain, type IV, double crystallized, 15 units / mg, Sigma, USA) was adjusted to a concentration of 1% (w / v) to supplement papain with 0.03 ml-cystein HCl After passing through the patella ligaments, the right knee joint was given 6ul to induce osteoarthritis. Papain solution was flitered through a 0.2um syringe filter before administration.

Experimental Example 2-2. Determination of cytokine content in blood

The contents of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) in blood were measured by ELISA (Komabiotech, Seoul, Korea) Are shown in Figs.

3 to 5, the blood levels of inflammatory cytokines such as TNF-α, IL-1β, and IL-6 were significantly higher in the control group than in the normal group and significantly lower in the positive control group and the control group than the control group Can be confirmed. Also, there was no significant difference in the blood content of cytokines according to the dose of the examples.

Experimental Example 2-3. Evaluation of proteoglycan content of articular cartilage

The knee joints were fixed in 10% formalin for 24 hours and then demineralized for 72 hours with 10% formic acid before paraffin embedding. The coronal section of the demineralized tibial proximal section was made and subjected to general tissue treatment, paraffin embedded, attached to the slide with a thickness of 5 μm. To confirm proteoglycan denaturation in proximal articular cartilage of tibia, saffronin O and hematoxylin control staining was performed on the sliced surface. The average transmittance of all articular cartilages was measured using a color image analyzer (Media Cybernetics, Image-ProPlusm, Rockville, MD, USA). The assessments were as follows: D for 10 to 20% increase in C, 20 to 30% for B, 30% for A, 5 to 10% for D, 10 to 20% for papain treated negative control And the results are shown in Table 2 below.

Proteoglycan content in cartilage induced by Papain induced osteoarthritis group Proteoglycan content (%) 10 mg / kg 20 mg / kg Normal group A Control (N / C) - Positive control group A A Example 1 Administration group C B Example 2 Administration group A A Example 3 Administration group B B

In Table 2, it can be seen that the amount of the proteoglycan is increased by 10% or more as compared with the control group. Particularly, the administration group of Example 2 showed a remarkably superior effect that the proteoglycan content was increased by more than 30% than the control group.

Experimental Example 2-4. Evaluation of Osteoarthritis Index

The medial condyle of the femur and tibia and the sagittal plane of the knee joint including the joint surface and the knee capsule were made and subjected to general tissue treatment, followed by paraffin embedding and cutting to a thickness of 5 μm. Knee thin sections were stained with hematoxylin and eosin (H & E) and safranin O-fast green, and histopathological changes of cartilage and synovial membrane were observed by optical microscope. The pathological histologic lesions observed in articular cartilage and synovial membrane were quantified by using the osteoarthritic index of Table 3 according to the method of Rudolphi et al., And the results are shown in Table 4 below.

Osteoarthritis index table Organizational structure cytoplasm 0 normal 0 normal One Surface abnormality 2 decrease 3 Thin fiber spasm 5 Many reductions 6 Depth breaks 8 Reduced both cartilage and cell 8 Large loss of cartilage - Cartilage Synovial membrane 0 normal 0 normal 3 Remodeling process 3 Mild hyperplasia 8 Strong, strong sclerosis 5 Acute hyperplasia - 8 Inflammatory cell infiltration and hyperplasia

Histopathological evaluation of osteoarthritis index group Organizational structure cytoplasm Cartilage Synovial membrane sum Control group 6.3 6.0 5.4 6.4 24.1 ± 4.6 Positive control group 3.5 2.3 1.2 1.6 8.6 ± 3.1 Example 1 Administration group
(10 mg / kg) 3.7 4.2 3.8 3.8 15.5 ± 2.2 Example 1 Administration group
(20 mg / kg) 3.5 3.9 3.3 3.1 13.8 ± 3.3 Example 2 Administration group
(10 mg / kg) 3.3 3.2 2.7 3.4 12.6 ± 5.1 Example 2 Administration group
(20 mg / kg) 3.0 2.9 2.5 2.5 10.9 ± 2.3 Example 3 Administration group
(10 mg / kg) 4.2 4.1 3.9 3.6 15.8 ± 4.6 Example 3 Administration group
(20 mg / kg) 4.0 3.8 3.5 3.1 14.4 ± 3.0

In Table 4, the osteoarthritic index of the control group was significantly higher than that of the control group and the osteoarthritic index was significantly lower in the positive control group and the control group than the control group. In particular, the osteoarthritic index of the 20 mg / kg administration group of Example 2 was lower than that of the 10 mg / kg administration group, but there was no significant difference.

<Experimental Example 3: Analysis of efficacy using obesity animal model>

The effects of the examples 1 to 3 (rebamipide precursors of formulas 3 to 5, striking drug) in obesity treatment were confirmed by the following method.

Experimental Example 3-1. 3T3-L1 adipocytes were used to examine the effect of obesity treatment

3T3-L1 preadipocytes were distributed from the American Type Culture Collection (ATCC; USA). The pre-sale received 3T3-L1 preadipocytes are 10% FBS (fetal bovine serum, FBS) is containing DMEM (Dulbecco's Modified Eagle Medium, Life technologies, Inc.) at 37 ℃ and 95% oxygen and 5% CO ₂ in And replaced with fresh medium every 2 days.

After 3 passages, the cells were divided into 6 well plates at a concentration of 5 × 10 ⁴ cells / well in order to induce the differentiation of adipocytes into adipocytes. After 3 days of culture, 5 μg / ml insulin, 0.5 mM 3-isobutyl-1-methylxanthine and 1 μM dexamethasone and 10% FBS The medium was exchanged with DMEM containing. Rebamipide and Examples 1 to 3 were also added in an amount of 20 [mu] M each. The medium and drug were changed every 2 days, and the medium was changed twice and the drug was administered.

 After induction of differentiation for 7 days, experiments were conducted to measure the inhibitory effect on cell differentiation ability. The cultured cells were washed with PBS, fixed with 10% formalin solution at room temperature for 30 minutes, and washed twice with distilled water. Then, 4% Oil-red O dyeing reagent was added, and after 1 hour of dyeing, the dyeing material was dissolved in 60% isopropanol for 10 minutes. Thereafter, the absorbance at a wavelength of 540 nm was measured, and the inhibition rate of triglyceride formation was calculated using the following equation, and the results are shown in Table 5 below.

* A: absorbance of levamisfeed added group

* B: Absorbance of the addition group of the Example

Inhibitory effect of triglyceride formation group % Inhibition Rebamipid added group - Example 1 Additive group 32.5 Example 2 Addition group 47.7 Example 3 Addition group 29.4

 In Table 5, it can be seen that Examples 1 to 3 inhibit the differentiation of adipocytes and thus the effect of inhibiting the production of triglycerides is much better than that of rebamipide.

Experimental Example 3-2. Prove the effect of obesity animal model

<3-2-1> Obesity Induction Model Preparation of Animals and Samples

Five week old male C57BL / 6 mice (body weight 19 ~ 21 g) were obtained from Korean BioLink and quarantined for 7 days. The animals were maintained in a laboratory environment with a temperature of 25 ± 5 ° C, humidity of 55 to 70%, light for 12 hours and dark for 12 hours. Diets were fed normal diet (D12450B (10% kcal from fat, Rodent Diets) The induction model was a high-fat diet (D12492 (60% kcal from fat, Rodent Diets)) and the composition of the feeds is shown in Table 6 below. Water was freely consumed using filtered water.

 (Normal diet), negative control (high fat diet + food), positive fat diet (control diet), and positive control (high fat diet + diet) to test the effects of Examples 1 to 3 after induction of obesity through the high fat diet Control group (high-fat diet + levamipide (100 mg / kg)) and experimental group (high fat diet + Examples 1 to 3 (20 mg / kg)). Each group consists of 10 animals.

The vehicle is 0.1% citric acid and 2% Pharmacoat 615 (Shin-etsu). The vehicle was used to prepare a pharmaceutical preparation for oral administration containing rebamipide, Examples 1 to 3, respectively, and oral gavage twice a day for 8 weeks. Normal group did not inject any medication other than normal diet.

Ingredients and Content of General Diet and High Fat Diet (g) ingredient A normal diet Highland method Casein, 30 Mesh 200 200 L-Cystine 3 3 Corn Starch 315 0 Maltodextrin 10 35 125 Sucrose 350 68.8 Cellulose, BW200 50 50 Soybean Oil 25 25 Lard 20 245 Mineral Mix S10026 10 10 DiCalcium Phosphate 13 13 Calcium Carbonate 5.5 5.5 Potassium Citrate, 1 H2O 16.5 16.5 Vitamin Mix V10001 10 10 Choline Bitartrate 2 2 FD & C Blue Dye # 1 0.05 0.05

&Lt; 3-2-2 > Measurement of weight loss effect and weight dietary efficiency

The body weight gain of the experimental animals of Experimental Example 3-2-1 was measured during the experiment. The dietary intake was measured once a week by subtracting the remaining feed weight from the feed supply, and the results of the body weight measurement were shown in FIG. 6 and Table 7, and the dietary intake was shown in FIG. The body weight gain / food intake (FER) obtained by dividing the average weight gain of the experimental animals by the average food intake is shown in Table 8 below.

Weight (g) Measurement Table 1 parking 2 parking 3 parking 4 parking 5 parking 6 parking 7 parking 8 parking Normal group 25.1 25.5 25.9 26.7 27.5 28.9 30.4 31.2 Negative control group 25.2 27.0 29.5 31.4 34.0 36.1 38.7 40.1 Rebamipide 24.8 26.0 27.3 29.0 30.9 32.7 34.9 36.8 Example 1 Administration group 25.4 26.2 27.1 28.4 30.0 31.8 34.0 35.9 Example 2 Administration group 25.3 26.1 27.2 28.5 29.8 31.2 32.6 34.2 Example 3 Administration group 25.1 25.9 27.0 28.6 30.7 31.9 33.7 35.2

 6 and 7, in the case of body weight, it can be confirmed that the body weight of the administration group of Examples 1 to 3 and the administration group of levamisidifib is similar to each other. In the case of administration of 100 mg / kg of rebamipide, kg, it can be seen that the effect of suppressing the body weight gain of Examples 1 to 3 is remarkably superior to that of Re-panipide by about 5 times.

Food efficiency ratio (FER) Normal group Negative control group Rebamipide Example 1 Example 2 Example 2 FER (%) 7.66 19.60 15.67 14.20 11.92 13.22

The low efficiency of body weight means that the absorption of nutrients is well inhibited. In Table 8, in Examples 1 to 3, the efficiency of body weight dieting was remarkably smaller than that of rebamipide. Considering that 100 mg / kg of rebamipide and 20 mg / kg of Examples 1 to 3 were administered, It can be seen that the nutrient absorption inhibiting effect of Examples 1 to 3 is remarkably superior to that of rebamipide.

<3-2-3> Prevention and treatment of high neutropenia

After the end of the drug administration period, the concentration of triglyceride in the blood of the experimental animal was checked. After the animal was anesthetized, blood was collected through cardiac blood collection, and centrifugation was carried out at 4 ° C for 30 minutes at 3000 rpm for 30 minutes to obtain a plasma. Blood triglyceride, total cholesterol and LDL-cholesterol were analyzed by blood auto-biochemical analyzer. The results are shown in Tables 9 to 11 below.

Analysis of Triglyceride in Blood Drug dose
(mg / kg / day) Triglyceride (mg / dl) Rate of increase / decrease (%) Normal group - 21.16 ± 2.85 - Negative control group - 45.56 ± 5.11 0.00 Rebamipide 100 40.04 + - 4.84 -12.16 Example 1 20 37.88 + - 4.01 -16.86 Example 2 20 31.42 + - 4.22 -31.04 Example 3 20 39.14 + - 3.42 -14.09

Blood total cholesterol analysis results Drug dose
(mg / kg / day) Total cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 93.52 + - 3.87 - Negative control group - 155.41 + - 8.41 0.00 Rebamipide 100 137.19 ± 16.96 -11.72 Example 1 20 132.85 ± 17.61 -14.51 Example 2 20 114.14 ± 17.88 -26.56 Example 3 20 130.66 + - 16.07 -15.93

Results of blood LDL-cholesterol analysis Drug dose
(mg / kg / day) LDL-cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 2.52 ± 0.57 - Negative control group - 7.08 + - 0.42 0.00 Rebamipide 100 6.03 ± 1.04 -14.83 Example 1 20 5.67 ± 1.29 -19.92 Example 2 20 4.91 ± 1.13 -30.65 Example 3 20 5.76 ± 1.64 -18.64

In the above Tables 9 to 11, it can be seen that the triglyceride, total cholesterol and LDL-cholesterol contents in the blood are significantly lower in the administration group than in the levamisidase administration group. Considering that 100 mg / kg of rebamipide was administered and 20 mg / kg of each of Examples 1 to 3 was administered, it was found that the effects of Examples 1 to 3 were more than five times superior, and in Example 2, It can be seen that it is excellent.

<3-2-4> Measuring effect of lowering body fat

The measurement of the body fat reduction effect was carried out by sacrificing the experimental animal's abdomen of Experimental Example 2-1 raised for 8 weeks and cardiac blood collection of Experimental Example 2-3. The epididymal and adipose tissues of the test animals were excised and removed, washed with physiological saline, and water was removed with a filter paper. The extracted fat was then weighed with an electronic balance and the results are shown in Table 12 below.

Fat accumulation (g) Normal group Negative control group Rebamipide Example 1 Example 2 Example 3 Fat mass 1.54 + - 0.42 5.42 ± 0.74 4.31 ± 0.61 3.94 1.01 3.43 ± 0.86 4.17 ± 0.75

 In Table 12, it can be seen that Examples 1 to 3 are superior to levamipipide in inhibiting adipose tissue formation. It can be seen that the effect of inhibiting adipose tissue formation in Examples 1 to 3 is remarkably better than that of rebamipide, considering that 100 mg / kg of rebamipide is administered and 20 mg / kg of administration of Examples 1 to 3 is taken into consideration.

<Experimental Example 4: Analysis of efficacy using an animal model of hyperlipidemia>

The therapeutic effect of hyperlipemia of Examples 1 to 3 (rebamipide precursors of Chemical Formulas 3 to 5, Samjin Pharmaceutical) was confirmed by the following method.

Experimental Example 4-1. Blood analysis of Triron WR-1339-induced hyperlipidemia animal model

6-week-old female Sprague-Dawley (SD) rats (body weight 170 ~ 10g) were obtained from BioLink and quarantined for 7 days. (~ 14 wt%), fats (~ 10 wt%) as a standardized feed, and the normal laboratory diet is maintained at 25 ± 5 ℃, 55 ~ 70% Contains carbohydrate (~ 76 wt%). After the adaptation period, the average body weight and standard deviation of each rat were calculated and divided into 8 groups per group evenly among the groups.

Rebamipide and Examples 1 to 3 were each prepared by vehicle (0.1% citric acid + 2% HEPROMELOSE 2910 (Pharmacoat 615, Shin-etsu)) in the experimental animals and were orally administered twice daily for 14 days and 28 days Oral gavage. Levamipide was orally administered to the rats at a dose of 100 mg / kg, and in Examples 1 to 3 at a dose of 50 mg / kg. On the other hand, in the normal group, the drug or vehicle was not administered to the normal rats. In the negative control group, the vehicle was administered twice daily for 14 days and 28 days. In the positive control group, simvastatin was administered to the vehicle (21.5% ) At a dose of 20 mg / kg once a day for 14 days and 28 days.

Triton WR-1339 (Tyloxapol, Sigma, St. Louis, MO) was injected into the tail vein at a dose of 200 mg / kg to induce hyperlipemia in the experimental animals.

Eighteen hours after injection, the rats in each group were anesthetized and blood was drawn from the heart using an injection. The plasma was centrifuged at 4 ° C for 15 minutes at 3000 rpm for 30 minutes, and the supernatant was collected and stored at -70 ° C for analysis. Triglyceride, total cholesterol, LDL-cholesterol, and HDL-cholesterol were analyzed by a blood auto-biochemical analyzer. The results are shown in Tables 13 to 16 below.

Results of blood triglyceride (TG) analysis group Drug dose
(mg / kg / day) Triglyceride (mg / dl) Rate of increase / decrease (%) Normal group - 72.40 ± 10.06 - Negative control group - 442.60 ± 44.82 0.00 Simvastatin 20 329.31 + - 68.60 -25.60 Example 1 50 367.27 ± 62.40 -17.02 Example 2 50 314.41 + - 78.94 -28.96 Example 3 50 373.84 ± 73.20 -15.54 Rebamipide 100 331.24 + - 64.78 -25.16

Blood total cholesterol analysis results group Drug dose
(mg / kg / day) Total cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 76.20 ± 11.30 - Negative control group - 159.75 +/- 34.75 0.00 Simvastatin 20 125.52 ± 17.05 -21.43 Example 1 50 135.57 ± 25.21 -15.14 Example 2 50 111.54 ± 17.54 -30.18 Example 3 50 135.14 ± 21.58 -15.41 Rebamipide 100 128.45 + - 19.47 -19.59

Results of blood LDL-cholesterol analysis group Drug dose
(mg / kg / day) LDL-cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 8.98 ± 1.36 - Negative control group - 43.47 ± 12.19 0.00 Simvastatin 20 33.89 + - 4.89 -22.04 Example 1 50 36.85 ± 7.25 -15.23 Example 2 50 31.44 + 5.08 -27.67 Example 3 50 39.12 + - 8.32 -10.01 Rebamipide 100 35.08 + - 6.58 -19.30

Results of blood HDL-cholesterol analysis group Drug dose
(mg / kg / day) HDL-cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 30.60 + - 4.70 - Negative control group - 25.54 ± 3.77 0.00 Simvastatin 20 26.01 + - 4.76 +1.84 Example 1 50 25.95 ± 4.32 +1.61 Example 2 50 26.50 ± 2.61 +3.76 Example 3 50 25.23 + - 5.21 -1.21 Rebamipide 100 25.84 + - 3.48 +1.17

In Tables 13 to 16, when Examples 1 to 3 were orally administered to a hyperlipemia rat model, it was confirmed that triglyceride, total cholesterol, and LDL-cholesterol in the serum were effectively reduced. In addition, considering that Examples 1 to 3 are much less administered than rebamipide, it can be seen that the therapeutic effects of Examples 1 to 3 in hyperlipemia are significantly superior to that of rebamipide. In particular, the therapeutic effect of Example 2 on hyperlipidemia is remarkably superior to those of other Examples 1 to 2 as well as rebamipide.

Experimental Example 4-2. Blood analysis of animal models of hyperlipidemia induced by high cholesterol diet

6-week-old female Sprague-Dawley (SD) rats (body weight 170 ~ 10g) were obtained from BioLink and quarantined for 7 days. The diets were then fed with a high fat diet to induce hyperlipidemia for 4 weeks and the high fat diet contained 5.5 wt% corn oil, 2 wt% cholesterol, 1 wt% cholic acid, 91.5 wt% do.

 (High fat diet + levamipidine (100 mg / kg)), drug-treated group (high-fat diet + simvastatin (20 mg / kg) High fat diet + example (50 mg / kg)). Normal diets fed to normal rats contain protein (~ 14 wt%), fats (~ 10 wt%) and carbohydrates (~ 76 wt%) in standard rat feeds. Levamipide and the example were orally administered twice a day and simvastatin was orally administered once a day.

 Administration was oral gavage of vehicle and drug daily for 28 days. After anesthetizing the rats in each group, the blood was collected through cardiac blood collection and centrifuged at 4 ° C for 30 minutes at 3000 rpm for 30 minutes to obtain a plasma. The plasma was obtained at -70 ° C And stored. Triglyceride, total cholesterol, LDL-cholesterol, and HDL-cholesterol were analyzed by a blood auto-biochemical analyzer. The results are shown in Tables 17 to 20 below.

Results of blood triglyceride (TG) analysis group Drug dose
(mg / kg / day) Triglyceride (mg / dl) Rate of increase / decrease (%) Normal group - 62.23 + - 12.42 - Negative control group - 397.22 ± 36.85 0.00 Simvastatin 20 291.54 ± 51.62 -26.60 Example 1 50 339.76 + - 68.42 -14.47 Example 2 50 292.42 ± 59.34 -31.42 Example 3 50 348.24 ± 72.31 -12.33 Rebamipide 100 315.34 + - 61.83 -20.61

Blood total cholesterol analysis results group Drug dose
(mg / kg / day) Total cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 76.21 + - 15.92 - Negative control group - 169.42 ± 29.46 0.00 Simvastatin 20 128.14 ± 28.72 -24.37 Example 1 50 143.91 + - 19.57 -15.06 Example 2 50 118.21 ± 32.82 -30.23 Example 3 50 147.39 ± 30.33 -13.00 Rebamipide 100 133.71 + - 25.40 -21.08

Results of blood LDL-cholesterol analysis group Drug dose
(mg / kg / day) LDL-cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 14.85 ± 4.14 - Negative control group - 38.41 + - 7.22 0.00 Simvastatin 20 28.12 ± 12.12 -26.79 Example 1 50 32.94 ± 10.09 -14.24 Example 2 50 27.12 + - 9.18 -29.39 Example 3 50 33.75 + - 7.20 -12.13 Rebamipide 100 29.91 + - 7.16 -22.13

Results of blood HDL-cholesterol analysis group Drug dose
(mg / kg / day) HDL-cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 33.48 + - 6.42 - Negative control group - 18.71 + - 4.55 0.00 Simvastatin 20 22.49 + - 8.17 +20.20 Example 1 50 21.19 ± 6.91 +13.25 Example 2 50 22.46 + - 8.16 +20.04 Example 3 50 20.17 ± 4.03 +7.80 Rebamipide 100 21.92 + - 7.21 +17.16

In Tables 17 to 20, when Examples 1 to 3 were orally administered to a rat model in which hyperlipemia was induced by high cholesterol diet, it was confirmed that triglyceride, total cholesterol, and LDL-cholesterol in the serum were effectively reduced. Considering that Examples 1 to 3 are administered in a significantly smaller amount than rebamipide, it is believed that Examples 1 to 3 are significantly superior to Rebamipide in treating hyperlipidemia induced by high cholesterol diet Able to know. Particularly, Example 2 exhibits a far superior therapeutic effect than Examples 1 and 3 as well as rebamipide.

<Experimental Example 5: Analysis of efficacy using an animal model of diabetes or diabetic complication>

The therapeutic effect of diabetes on Examples 1 to 3 (rebamipide precursors of Formulas 3 to 5, striking pharmacopoeia) was confirmed by the following method.

Experimental Example 5-1. Experiment with diabetic mouse model

<5-1-1> Preparation of experimental animals and drug administration

 Six weeks old female C57BL / 6 mice (body weight 26-30 g) and BKS.Cg- + Leprdb / + Leprdb / OlaHsd mice (db / db mice) Day quarantine and purification. D12450B (10% kcal from fat, Rodent Diets) was used as a general diet, and the animal laboratory environment was maintained at a temperature of 25 ± 5 ° C, humidity of 55 ~ 70% It was freely consumed using filtered water.

 Db / db mouse control, negative control (vehicle), positive control (metformin; 100 mg / ml) to verify the effect of the novel rebamipide prodrug obtained in Example 1 after 7 days of adaptation period. kg), the control group (rebamipide 150 mg / kg), and the experimental group 3 (Examples 1 to 3, 50 mg / kg). The mean weight and standard deviation of each mouse were calculated and divided into 8 groups of 8 groups per group.

The above Examples 1-3, metformin and rebamipide were each prepared with vehicle (0.1% citric acid + 2% Pharmacoat 615, Shin-etsu) and administered orally once daily for 8 weeks ). On the other hand, in the normal group, no drug or vehicle was administered to the normal mice, and in the negative control group, only the vehicle was orally administered once a day.

<5-1-2> Measurement of change in body weight

The weight gain of the experimental animals of Experimental Example 5-1-1 was measured during the 8-week experimental period, and the results are shown in FIG. FIG. 8 shows the body weight measured every one week. The db / db mouse was a type 2 diabetic model animal and showed an increase in body weight at the beginning of the experiment even though it was the same age as C57BL / 6 mice. The weight gain rate (%) during the 56- Respectively.

Weight gain (%) Normal group db / db control group voice
Control group positivity
Control group Example 1 Example 2 Example 3 Levami
Feed 14.93 23.01 22.56 20.73 20.14 18.38 20.99 20.04

8 and 21, it can be seen that the effect of suppressing weight gain of Examples 1 to 3 is remarkably superior to that of metformin and rebamipide, considering that the doses of Examples 1 to 3 are much smaller.

<5-1-3> Measurement of blood glucose and blood analysis

After 8 weeks of treatment, the fasting plasma glucose level was measured and the blood glucose was measured from the blood of the tail vein using a blood glucose meter (Breeze 2, Bayer HealthCare LLC, US) The results are shown in Fig.

In addition, blood was collected from the abdominal part of the animal under anesthesia, and blood was collected through cardiac blood collection. Plasma was obtained after centrifugation for 10 minutes at 4 ° C and 3000 rpm within 30 minutes for plasma separation. Triglyceride, total cholesterol, and glycated hemoglobin were measured using an automatic biochemical analyzer, and the results are shown in Tables 22 to 24.

Analysis of Triglyceride in Blood Drug dose
(mg / kg / day) Triglyceride (mg / dl) Rate of increase / decrease (%) Normal group - 42.63 + - 23.44 - db / db control group - 108.73 + - 15.11 - Negative control group - 105.47 ± 24.51 0 Positive control group 100 87.57 + - 14.69 -16.97 Example 1 50 87.01 + - 24.21 -17.49 Example 2 50 84.70 ± 23.42 -19.68 Example 3 50 88.59 ± 15.15 -15.99 Rebamipide 150 88.54 + 26.18 -16.04

Results of total cholesterol analysis Drug dose
(mg / kg / day) Total cholesterol (mg / dl) Rate of increase / decrease (%) Normal group - 60.25 + - 11.21 - db / db control group - 152.56 ± 20.60 - Negative control group - 153.54 ± 13.14 0 Positive control group 100 124.58 + - 10.17 -18.86 Example 1 50 125.58 ± 15.91 -18.21 Example 2 50 123.63 ± 14.38 -19.48 Example 3 50 132.40 + - 15.04 -13.77 Rebamipide 150 134.49 + 16.14 -12.40

Analysis of blood glycosylated hemoglobin (HbA1c) results HbA1c (%) Normal group 5.77 ± 0.51 db / db control group 8.99 + - 0.43 Negative control group 9.04 ± 0.19 Positive control group 6.61 + - 0.40 Example 1 7.93 + 0.66 Example 2 6.50 ± 0.51 Example 3 7.74 ± 0.39 Rebamipide 7.99 ± 0.29

 As shown in FIG. 9, the diabetic mouse control group showed an increase in blood glucose level compared with the normal mouse control group. In the experimental group administered with diabetes mice in Examples 1 to 3, metformin (Metformin) and showed better blood glucose lowering effect and blood glucose lowering effect than rebamipide. Also, as shown in Tables 22 to 24 above, concentrations of blood triglyceride, cholesterol, and glycated hemoglobin in the experimental group ingested in Examples 1 to 3 were measured to be similar or lower than those of metformin and rebamipide.

When the results of FIGS. 9, 22 to 24 were evaluated in consideration of the doses of Examples 1 to 3, metformin and rebamipide, the results of Examples 1 to 3 are shown to be higher than those of metformin and Re- The effect of lowering the concentration of fat, cholesterol, and glycated hemoglobin is remarkably excellent.

Experimental Example 5-2. Experiments using a rat model that induced diabetes by administration of streptozotocin

<5-2-1> Preparation of experimental animals and drug administration

6-week-old female Sprague-Dawley (SD) rats (body weight 170 ~ 10g) were obtained from BioLink and quarantined for 7 days. Animal laboratory conditions were kept at 25 ± 5 ℃, humidity 55 ~ 70%, light 12 hours bright / 12 hours dark, and D12450B (10% kcal from fat, Rodent Diets) , And water was freely consumed using filtered water.

 After 7 days of adaptation period, the normal group, the negative control (diabetes induced and vehicle administration), the positive control (metformin; 150 mg / kg), the comparison group (rebamipide; 100 mg / kg), and experimental group 3 (Examples 1 to 3; 150 mg / kg). After the adaptation period, the average body weight and standard deviation of each rat were calculated and divided into 8 groups per group evenly among the groups. Then, Examples 1 to 3 and rebamipide were each prepared as a vehicle (0.1% citric acid + 2% HPMC2901) and administered once twice before 2 hours before the measurement of blood glucose.

<5-2-2> Blood analysis of streptozotocin (STZ) induced diabetic rat model

In order to induce hyperlipemia, streptozotocin (STZ) was used as a hyperlipemia inducing drug. Streptozotocin (STZ) was dissolved in 0.01 M citrate buffer (pH 4.5) to a concentration of 30 mg / kg, and 0.1 ml per 100 g of body weight of the rats was intraperitoneally administered once a day for 3 days. After 72 hours, the animals were fasted for 2 hours and the drug was administered. Two hours later, blood was drawn through the tail vein of each group of rats. In order to measure fasting plasma glucose, blood was taken from the blood of the tail vein using a blood glucose meter (Breeze 2, Bayer HealthCare LLC, US) and the results are shown in FIG. 10 and Table 25 Respectively.

Increase in blood glucose (%) Normal group db / db control group voice
Control group positivity
Control group Example 1 Example 2 Example 3 Levami
Feed - - 0 -17.05 -15.63 -19.60 -13.64 -9.09

 As shown in FIGS. 10 and 25, the blood glucose level of the normal rats was measured to be within the normal range of 100 mg / dl or less, but the blood glucose level was significantly higher in the diabetic rats (negative control group) than in the normal group. In addition, the administration groups of Examples 1 to 3 showed a decrease in blood glucose levels as compared to the negative control groups, and Examples 1 to 3, when considering the doses of Examples 1 to 3, metformin and rebamipide, The effect of lowering blood sugar is significantly superior to that of USFeed.

<Experimental Example 6: Analysis of efficacy using an animal model of irritable bowel syndrome>

Examples 2, 4 and 5 (rebamipide precursors of Formulas 4, 6 and 7, striking pharmacopoeia) were tested for the therapeutic effect of irritable bowel syndrome in the following manner.

Experimental Example 6-1. Preparation of an Irritable Bowel Syndrome Animal Model

Seven-week-old Sprague Dawley (SD) rats were purchased from BioLink and purified for 7 days before use in the experiment. The temperature of the laboratory animal room was maintained at 23 ± 2 ℃ and the relative humidity was 55 ± 15%. During the experimental period, feed and water were supplied freely, and the animals were divided into 8 animals per group so that their average body weight was 180 ± 10 g.

Twenty-four hour fasting SD rats were anesthetized with diethyl ether and a 3 mL of 3% TNBS (Trinitrobenzene) diluted in 50% ethanol (v / v) was injected into the lumen of the large intestine via an anal using a 1 mL syringe connected with polyethylene catheter sulphonic acid (0.8 mL). To prevent leakage into the anus, SD rats were placed upside down for 60 seconds after administration. Negative controls received vehicle [50% ethanol (v / v)].

TNBS Treatment For the next five days, Examples 1 to 3 were prepared at a concentration of 30 mg / kg in a vehicle (0.1% citric acid + 2% hypromellose 2910 (Pharmacoat 615, Shin-etsu) And 5-ASA, an active metabolite of sulfasalazine (anti-inflammatory agent), was administered at a dose of 300 mg / kg as a positive control.

Experimental Example 6-2. Weight change measurement

Using a digital scale, weighing between 1 and 6 days was observed from the fasting stage to the administration of TNBS and the drug administration. As a result of comparing the body weights between the control and the 5% TNBS-treated group, the positive control group and the treated groups of Examples 1 to 3, the body weight was remarkably decreased in the group treated with 5% TNBS, Particularly, the inhibitory effect of Examples 2 and 5 was excellent (see Fig. 11). Also, taking into account the dosage of 5-ASA and the examples, it can be seen that the treatment effects of colitis in Examples 2, 4 and 5 are significantly superior to 5-ASA.

Experimental Example 6-3. Length and weight measurement

All SD rats were sacrificed at 7 days post dose. Animals were dissected and the length from the anus to the cecum was measured (see Fig. 12), and the tissue located 5 to 6 cm from the anus was incised 1 cm to measure the intestinal wet weight (see Fig. 13). The length of the colon of rats induced with irritable bowel syndrome by 3% TNBS was decreased in comparison with that of the normal control group. In the case of intestinal wet weight, the TNBS treatment group was significantly increased compared to the normal control group, but in the case of the treatment group, TNBS inhibited the increase of the wet weight.

It can be seen from Examples 5-1 to 5-3 that Examples 2, 4 and 5 according to the present invention are excellent for treating irritable bowel syndrome.

<Experimental Example 7: Analysis of efficacy using the damaged animal model>

The therapeutic effect of gastritis or gastric ulcer of Examples 1 and 2 (rebamipide precursors of Formulas 3 and 4, striking pharmacological) was confirmed by the following method.

Experimental Example 7-1. Preparation of experimental animals and drug administration

Seven-week-old male Sprague-Dawley (SD) rats (body weight: 200 ~ 250 g) were obtained from BioLink and quarantined for 7 days. The animal laboratory environment is maintained at a temperature of 25 ± 5 ° C, humidity of 55 to 70%, light intensity of 12 hours / 12 hours dark, and the normal diet is protein (~ 14 wt% Carbohydrates (~ 76 wt%) were contained, and water was freely consumed using filtered water.

After an adaptation period of 7 days, the normal group, the negative control (vehicle), the comparative group (rebamipide; 150 mg / kg) and the two experimental groups (Examples 1, 2; 50 mg / kg). After the adaptation period, the average body weight and standard deviation of each rat were calculated and divided into 5 groups per group evenly among the groups. Thereafter, Example 1, Example 2 and rebamipide were prepared by oral gavage with vehicle (0.1% citric acid + 2% HEPROMELOSE 2910 (Pharmacoat 615, Shin-etsu)).

Experimental Example 7-2. Therapeutic efficacy in ethanol-induced gastric injured animal models

In order to confirm the effects of gastritis or gastric ulcer treatment of Examples 1 and 2, the injured rat model was prepared. (50 mg / kg) and rebamipide (150 mg / kg) were orally gavaged to each group, and the animals were fasted for 6 hours, 12 hours, 24 hours After that time, 1 ml of a hydrochloric acid-ethanol mixture (HCl-Ethanol) containing 150 mM hydrochloric acid was orally administered to 60% ethanol and left for 1 hour. After anesthesia with ether, the stomach was removed and the pylorus and esophagus were ligated. 10 ml of 2% formalin solution was placed in the stomach and fixed for 10 minutes. A digital camera (Digital Camera) As shown in Fig.

As shown in FIG. 14, in the negative control group, the occurrence of stomach injury was seriously caused, and a lot of ulcer masses were observed, and some improvement was observed in the rebamipide treatment group. In the experimental group to which Examples 1 and 2 were administered, it was found that the gastric damage was suppressed to a considerable level. Considering the administration dose of rebamipide and the examples, the gastric or gastric ulcer treatment effects of Examples 1 and 2 according to the present invention Is significantly superior to rebamipide.

 In addition, the damage length (mm) was measured, and it was 1 point for small bleeding erosion, 2 points for bleeding erosion less than 1 mm, 3 points for bleeding erosion about 1 ~ 2 mm, and 2 4 points for bleeding erosion of ~ 3 mm in length, and 5 points for longer than 4 mm. When the wound has a width of 1 mm or more, the score is doubled. The experimental values are shown as mean ± standard deviation and shown in Table 1. The area of the damaged area is calculated in% with respect to the total frontal area, and is shown in Fig.

Stomach injury index 6 hours 12 hours 24 hours Normal group 0 0 0 Negative control group 24 ± 6.5 32 ± 5.1 66 ± 9.8 Rebamipide 13 ± 3.6 18 ± 6.9 40 ± 8.6 Example 1 14 ± 4.5 28 ± 7.9 56 ± 9.1 Example 2 7 ± 2.4 15 ± 4.7 35 ± 7.3

As shown in Table 26, the damage index analyzed after 24 hours was about 66 points in the negative control group, about 40 points in the group treated with rebamipide, about 56 points in the group treated with Example 1, Group showed about 35 points. Rebamipide and Examples 1 and 2 were found to be effective in treating gastritis or gastric ulcer, and in particular, the effect of treating gastritis or gastric ulcer in Example 2 was excellent. In Fig. 15, it was confirmed that the lesion area of the rebamipide and the administration groups of Examples 1 and 2 was smaller than that of the negative control group, and it was confirmed that the effect of Example 2 was remarkably excellent. Considering the administration dose of rebamipide and the examples, it can be seen that the effect of treating gastritis or gastric ulcer in the examples is remarkably excellent.

 Thus, it can be seen that Examples 1 and 2 of the present invention are highly effective in the treatment of gastritis or gastric ulcer, especially alcoholic gastritis or alcoholic gastric ulcer.

Claims (25)

A pharmaceutical composition for oral administration for the prevention or treatment of immune diseases and metabolic diseases, which comprises a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
The method according to claim 1,
Wherein the rebamipide precursor is a compound of formula 2:
(2)

In this formula,
X is (C ₃ -C ₈ heterocycloalkyl) C ₁ -C ₆ alkyl, (C ₃ -C ₈ heterocycloalkenyl) C ₁ -C ₆ alkyl or (heteroaryl) C ₁ -C ₆ alkyl.
A pharmaceutical composition for oral administration for prevention or treatment of rheumatoid arthritis comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
The method of claim 3,
Wherein the rebamipide precursor is a compound of formula (2).
The method of claim 3,
Wherein the rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 10 to 50 mg / kg.
A pharmaceutical composition for oral administration for preventing or treating osteoarthritis comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
The method according to claim 6,
Wherein the rebamipide precursor is a compound of formula (2).
The method according to claim 6,
Wherein said rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 5 to 50 mg / kg.
A pharmaceutical composition for oral administration for the prevention or treatment of obesity comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The method of claim 9,
Wherein the rebamipide precursor is a compound of formula (2).
10. The method of claim 9,
Wherein said rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 5 to 50 mg / kg.
A pharmaceutical composition for oral administration for prevention or treatment of hyperlipidemia comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
13. The method of claim 12,
Wherein the rebamipide precursor is a compound of formula (2).
13. The method of claim 12,
Wherein the rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 10 to 200 mg / kg.
A pharmaceutical composition for oral administration for the prevention or treatment of diabetic or diabetic complications comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
16. The method of claim 15,
Wherein said diabetes is Type 2 diabetes.
16. The method of claim 15,
Wherein the rebamipide precursor is a compound of formula (2).
16. The method of claim 15,
Wherein the rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 10 to 200 mg / kg.
A pharmaceutical composition for oral administration for the prevention or treatment of irritable bowel syndrome comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
20. The method of claim 19,
Wherein the rebamipide precursor is a compound of formula (2).
20. The method of claim 19,
Wherein the rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 5 to 100 mg / kg.
A pharmaceutical composition for oral administration for the prevention or treatment of gastritis or gastric ulcer comprising a rebamipide precursor or a pharmaceutically acceptable salt thereof as an active ingredient.
23. The method of claim 22,
Wherein the gastritis or gastric ulcer is an alcoholic gastritis or an alcoholic gastric ulcer.
23. The method of claim 22,
Wherein the rebamipide precursor is a compound of formula (2).
23. The method of claim 22,
Wherein the rebamipide precursor or a pharmaceutically acceptable salt thereof is formulated in a unit dosage form suitable for oral administration at a dose of 5 to 100 mg / kg.

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