• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to a pharmaceutical composition for immunomodulation, comprising benzimidazole, 3H tautomer, optically active enantiomer of Formula 1, or a pharmaceutically acceptable acid addition salt thereof: Formula 1 Wherein R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group. The pharmaceutical composition is useful for the treatment of cytokine-related diseases such as rheumatism, inflammation and allergies.
    公开号:KR20010107927A
    申请号:KR1020017005086
    申请日:1998-10-23
    公开日:2001-12-07
    发明作者:아키라 마츠모리
    申请人:아키라 마츠모리；
    IPC主号:
    专利说明:

    Pharmaceutical composition for modulating immunity
    [2] European Patent No. 0,008,391 specifically discloses 5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole, represented by the following formula (1) and substituted in position 2 thereof: 3H tautomers, optically active enantiomers and pharmaceutically acceptable acid addition salts thereof are disclosed:
    [3]
    [4] Wherein R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group. These compounds have useful pharmaceutical properties and, in particular, exhibit anti-viral activity, interferon-producing activity and ulcer inhibiting activity, as well as activity on the cardiovascular system or as a cardiac agent, antihypertensive activity and / or anti-thrombin activity. Indicates.
    [5] By definition, the term “activity on the cardiovascular system” refers to the heart and blood vessels in this European patent (in which case the activity is expressed as anti-thrombin activity and cardiac activity) as well as effect on blood pressure. It means the activity to exert.
    [6] In view of these pharmacological properties, salts of the compounds disclosed in the above European patents, 3H tautomers, optically active enantiomers and their pharmaceutically acceptable inorganic or organic acids can be used to treat and / or treat chronic heart attacks or angina pectoris. It is used for the prevention of arterial thromboembolism and arterial obstruction, as well as for the treatment of ulcers and eradication of viral and viral diseases.
    [7] More specifically, these compounds have been used as therapeutic agents for the treatment of heart attacks because of their cardiovascular activity, and likewise used for the treatment of arterial thromboembolism and arterial obstructive diseases because they have anti-thrombin activity, especially activity against platelets. Has been.
    [8] Moreover, European Patent No. 0,330,052 discloses therapeutic agents containing the benzimidazoles, in particular represented by the formula (1) above and having anti-ischemic activity against the heart. In addition, European Patent No. 0,387,762 discloses the simultaneous use of benzimidazole and β-blockers, which not only counteract the positive and negative muscle contraction effects of muscle but also improve heart function under physically tense conditions. .
    [1] The present invention relates to a pharmaceutical composition for immunomodulation comprising benzimidazole, 3H tautomer, optically active enantiomer, or a pharmaceutically acceptable acid addition salt thereof.
    [9] An object of the present invention to provide a pharmaceutical composition for immunomodulation comprising benzimidazole.
    [10] These and other objects of the present invention will become apparent from the following description and the following examples.
    [11] According to the present invention, there is provided a pharmaceutical composition for immunomodulation comprising benzimidazole, 3H tautomer, optically active enantiomer of Formula 1, or a pharmaceutically acceptable acid addition salt thereof:
    [12] Formula 1
    [13]
    [14] Wherein R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.
    [15] Surprisingly, benzimidazoles of Formula 1 show an immunomodulatory effect through the reduction of significantly higher CRP values (its normal value is below 0.3 mg / dL in healthy adults) (Robey Frank A. et al .: J. Biol. Chem. 262: 7053-7057 (1987); and Kottgen Eckart et al .: J. Immunol. 149: 445-453 (1992). Thus, the compounds are cytokine-related diseases such as rheumatism, inflammation, allergies, atherosclerosis, collagen diseases, hepatitis, pancreatitis, inflammatory bowel disease, glomerulonephritis, toxic-shock syndrome, intestinal coagulation diffuse syndrome, graft-versus It has been found to be suitably used for the treatment of host diseases, tumors and immunodeficiency diseases.
    [16] It is known that agents which exhibit an immunomodulatory effect can generally be effective in the treatment of such cytokine-related diseases.
    [17] As used herein, the term “CRP” refers to a C-reactive protein or a protein that is reactive with polysaccharides present on bacterial cell sieves of pneumococcal pneumoniae. It is not detected in the plasma of normal humans and appears immediately in the blood when tissue inflammation or collapse occurs. In various infectious diseases, large amounts of CRP appear in the blood within hours after infection and decrease and disappear as the patient recovers from the infectious disease. Moreover, the rate of positive reactions is high in the case of tissue-degenerative diseases such as rheumatic fever, chronic joint rheumatism, heart infarction and malignant tumors. By measuring these CRP values, it is possible to evaluate or judge any change in symptoms and severity.
    [18] Preferred benzimidazoles of the formula (1) are, for example, compounds of formula (1) wherein R is a methyl group, 2-pentyl group, 4-methoxyphenyl group or 4-hydroxyphenyl group, and in particular R is a 4-methoxyphenyl group Or a 4-hydroxyphenyl group, in particular a 4-methoxyphenyl group. Preferred examples thereof include 3H tautomers, optically active enantiomers and pharmaceutically acceptable acid addition salts thereof.
    [19] Acute toxicity of compounds of formula 1 wherein R is a 4-methoxyphenyl group or a 4-hydroxyphenyl group is known in the literature and the like.
    [20] In order to achieve the desired effect of the invention, the dosage of the compound of formula 1 administered to an adult is in the range of 0.1 to 5.0 mg, preferably 1.0 to 2.5 mg, once daily or twice daily, in particular per day Two doses of 1.25 mg are administered. However, the dosage should be determined by the physician taking into account various conditions, such as the symptoms and weight of the patient being treated, the type of compound selected for administration and the route of administration chosen. Accordingly, the present invention is not limited to the above specific dosage ranges.
    [21] In order to use the compounds as medicaments, the active substances are commonly used inert carriers and / or diluents, for example corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid At least one selected from the group consisting of tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose and fatty substances such as hydrogenated oils It is mixed with the member to prepare conventional herbal preparations, such as tablets without any coating, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups or suppositories. The compositions of the present invention can be administered via a variety of routes of administration, such as oral and rectal routes, as well as topical or non-oral administration such as infusion or inhalation.
    [22] The effect of the composition is measured according to the following method.
    [23] 2- (4-methoxyphenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole (hereinafter referred to as "pimobendan") As a complication, oral administration to a patient suffering from a heart attack in which malignant joint rheumatism appeared, and its CRP value were measured over time.
    [24] CRP values can be found in Claus David R. et al .: J. Lab. Clin. Med. 87: 120-128 (1976), according to the same method as disclosed in Senju Osamu, et al .: J. Clin. Lab. Immunol. 19: 99-103 (1986).
    [25] The patient's CRP value before pimovendan administration was found to be 4.7 mg / dl. Fimobendan was administered to a patient at a dose of 1.25 mg, which reduced its CRP value, and therefore the compound was administered at a dose of 1.25 mg twice a day after the next day (defined as the start of administration).
    [26] The patient was diagnosed with an ultrasound cardiac examination and found to have improved heart function. Therefore, administration of pimovendan was discontinued. Thereafter, pimobendan was again administered to the patient at a dose of 1.25 mg twice a day to confirm the effect of the drug on decreasing CRP values. As a result, the CRP value was reduced again and it was found that the inflammation caused by malignant joint rheumatism was restored.
    [27] Table 1 below shows some of the CRP values measured during the test period.
    [28]
    [29] The results shown in Table 1 clearly show that the administered compounds can suitably reduce the CRP values to clinically satisfactory levels.
    [30] This new finding clearly suggests that the compositions of the invention, in particular pimovendan, are suitably used for the treatment of cytokine-related diseases.
    [31] Thus, according to the present invention, it is possible to provide a pharmaceutical composition that exhibits an immuno-modulatory effect through the reduction of abnormally high CRP values.
    [32] The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these specific embodiments at all.
    [33] Example 1 Tablet containing 0.5 mg of 2- (4-methoxyphenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole Manufacture
    [34] Composition:
    [35]
    [36] Preparation: The materials (01) to (03) are mixed together, then the resulting mixture is converted into particles with an ethanol solution of material (04), the resulting particles are dried and classified and the particles ) And (06) and the resulting mixture was compressed into tablets.
    [37] Example 2: of tablets containing 1.25 mg of 2- (4-methoxyphenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole Produce
    [38] Composition:
    [39]
    [40] Preparation: The materials (01) to (03) are mixed together, then the resulting mixture is converted into particles with an ethanol solution of material (04), the resulting particles are dried and classified and the particles ) And (06) and the resulting mixture was compressed into tablets.
    [41] Example 3: of a capsule containing 2.00 mg of 2- (4-methoxyphenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole Produce
    [42] Composition:
    [43]
    [44] Preparation: The above materials (01) to (05) were mixed together and the resulting mixture was then filled into capsules of size 4.
    [45] Example 4 of Tablets Containing 2.50 mg of 2- (4-methoxyphenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole Produce
    [46] Composition:
    [47]
    [48] Preparation: The materials (01) to (03) are mixed together, then the resulting mixture is converted into particles with an ethanol solution of material (04), the resulting particles are dried and classified and the particles ) And (06) and the resulting mixture was compressed into tablets each having a diameter of 7 mm.
    [49] Example 5: A small, containing 1.00 mg of 2- (4-methoxyphenyl) -5- (5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole Preparation of graduated coated tablets that can be cut into pieces
    [50] Composition:
    [51]
    [52] Preparation: The materials (01) to (03) are mixed together, then the resulting mixture is converted into particles with an ethanol solution of material (04), the resulting particles are dried and classified and the particles ) And (06) and the resulting mixture was compressed into tablets each having a diameter of 7 mm. The resulting cores were then coated with the coating according to conventional methods.
    权利要求:
    Claims (18)
    [1" claim-type="Currently amended] A pharmaceutical composition for immunomodulation comprising benzimidazole, 3H tautomer, optically active enantiomer of Formula 1 or a pharmaceutically acceptable acid addition salt thereof:
    Formula 1

    Wherein R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.
    [2" claim-type="Currently amended] 2. The pharmaceutical composition of claim 1, wherein substituent R of formula 1 represents a methyl, 2-pentyl, 4-methoxyphenyl or 4-hydroxyphenyl group.
    [3" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein substituent R of Formula 1 represents a 4-methoxyphenyl or 4-hydroxyphenyl group.
    [4" claim-type="Currently amended] The pharmaceutical composition of claim 1, wherein substituent R of formula 1 represents a 4-methoxyphenyl group.
    [5" claim-type="Currently amended] The pharmaceutical composition of claim 1, which is used for the treatment of cytokine-related diseases.
    [6" claim-type="Currently amended] 6. The method of claim 5, wherein the cytokine-related disease is rheumatoid, inflammation, allergy, atherosclerosis, collagen disease, hepatitis, pancreatitis, inflammatory bowel disease, glomerulonephritis, toxic-shock syndrome, intestinal coagulation diffuse syndrome, graft-versus-host A pharmaceutical composition selected from the group consisting of diseases, tumors and immunodeficiency diseases.
    [7" claim-type="Currently amended] Use of benzimidazole, 3H tautomer, optically active enantiomer or a pharmaceutically acceptable acid addition salt thereof in the preparation of a pharmaceutical composition for immunomodulation:
    Formula 1

    Wherein R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.
    [8" claim-type="Currently amended] 8. Use according to claim 7, wherein substituent R in formula 1 represents a methyl, 2-pentyl, 4-methoxyphenyl or 4-hydroxyphenyl group.
    [9" claim-type="Currently amended] 8. Use according to claim 7, wherein substituent R in formula 1 represents a 4-methoxyphenyl or 4-hydroxyphenyl group.
    [10" claim-type="Currently amended] 8. Use according to claim 7, wherein substituent R in formula 1 represents a 4-methoxyphenyl group.
    [11" claim-type="Currently amended] Use according to claim 7, wherein the pharmaceutical composition for immunomodulation is a therapeutic composition for the treatment of cytokine-related diseases.
    [12" claim-type="Currently amended] The method of claim 11, wherein the cytokine-related disease is rheumatoid, inflammation, allergy, atherosclerosis, collagen disease, hepatitis, pancreatitis, inflammatory bowel disease, glomerulonephritis, toxic-shock syndrome, intestinal coagulation diffuse syndrome, graft-versus-host Use selected from the group consisting of diseases, tumors and immunodeficiency diseases.
    [13" claim-type="Currently amended] A method of immunomodulation comprising administering to a patient a benzimidazole of formula 1, a 3H tautomer, an optically active enantiomer, or a pharmaceutically acceptable acid addition salt thereof:
    Formula 1

    Wherein R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.
    [14" claim-type="Currently amended] 14. The process of claim 13, wherein substituent R in formula 1 represents a methyl, 2-pentyl, 4-methoxyphenyl or 4-hydroxyphenyl group.
    [15" claim-type="Currently amended] The method of claim 13, wherein the substituent R of formula 1 represents a 4-methoxyphenyl or 4-hydroxyphenyl group.
    [16" claim-type="Currently amended] 14. The process of claim 13, wherein substituent R in formula 1 represents a 4-methoxyphenyl group.
    [17" claim-type="Currently amended] The method of claim 13, wherein the cytokine-related disease is treated.
    [18" claim-type="Currently amended] The method of claim 17, wherein the cytokine-related disease is rheumatoid, inflammation, allergy, atherosclerosis, collagen disease, hepatitis, pancreatitis, inflammatory bowel disease, glomerulonephritis, toxic-shock syndrome, intestinal coagulation diffuse syndrome, graft-versus-host Disease, tumor, and immunodeficiency disease.
    类似技术:
    公开号 | 公开日 | 专利标题
    CA2404152C|2008-08-05|Inhibition of cyclooxygenase-2 activity
    ES2165474T5|2011-06-08|SYNERGIC COMBINATION THAT INCLUDES AN INSULIN SENSITIZER AND AN INHIBITOR OF THE HMG-CoA REDUCTASE FOR THE TREATMENT OF ARTERIOESCLEROSIS.
    US7767225B2|2010-08-03|Capsule formulation of pirfenidone and pharmaceutically acceptable excipients
    AU702106B2|1999-02-11|Use of carbazole compounds for the treatment of congestive heart failure
    KR100386229B1|2003-08-21|Inhibition of smooth muscle migration and proliferation of hydroxycarbazole compounds
    AU725637B2|2000-10-19|Reparation and prevention of fibrotic lesions
    EP0268956B1|1994-04-06|Pyridine derivatives, pharmaceutical compositions comprising the same, the use of the same for the manufacture of medicaments having therapeutic or preventative value, and a process for preparing the same
    DE60118547T2|2007-02-01|Pharmaceutical composition for the treatment of colorectal cancer containing thalidomide and irinotecane
    EP0169466B1|1990-04-04|Mixture of xanthin derivatives and o-acetyl-salicylic acid, or their pharmacologically acceptable salts, and its use
    EP1458447B1|2009-09-09|Combination of cytochome p 450 dependent protease inhibitors
    KR0148589B1|1998-11-02|Compositions, methods and kits for potentiating antitumor effect and for treating tumor
    DE60023518T3|2014-08-28|Use of ramipril for the prophylaxis of congestive heart failure
    ES2230657T3|2005-05-01|Method and composition for use in the treatment and prevention of hyperuricemia.
    US20040138209A1|2004-07-15|Treatment of inflammatory disorders with 2,3- benzodiazepines
    RU2388466C2|2010-05-10|Phenoxyalkyl carbonic acids derivative in treatment of inflammatory diseases
    AU737038B2|2001-08-09|Anti-viral pharmaceutical compositions containing saturated 1,2-dithiaheterocyclic compounds and uses thereof
    BRPI0618239A2|2011-08-23|use of flibanserin for the treatment of premenopausal sexual desire disorders
    CZ229297A3|1998-02-18|Tablets containing valaciclovirus and process for preparing thereof
    KR20160074018A|2016-06-27|Methods for improving the pharmacokinetics of hiv integrase inhibitors
    SK7542003A3|2003-12-02|Medicinal compositions containing aspirin
    EP0323745B1|1992-12-16|Pharmaceutical preparations
    KR100298807B1|2001-11-22|Pharmaceutical Compositions Including Lirusol for Treatment of Parkinson's Disease and Parkinson's Syndrome
    JP2001518477A|2001-10-16|Use of steroid saponins for prevention or treatment of dementia, and novel steroid saponin compounds
    US5079261A|1992-01-07|Use of lipoxin a4 and its derivatives as antagonists for slow-reacting substances of anaphylaxis
    HUT73176A|1996-06-28|Biologically active 3-substituted oxindole derivatives useful as anti-angiogenic agents
    同族专利:
    公开号 | 公开日
    EP1123703B1|2004-04-14|
    WO2000024397A1|2000-05-04|
    EP1123703A4|2002-11-20|
    CN1148190C|2004-05-05|
    EP1123703A1|2001-08-16|
    KR100515918B1|2005-09-20|
    AT264104T|2004-04-15|
    DE69823240D1|2004-05-19|
    ES2215327T3|2004-10-01|
    CN1314815A|2001-09-26|
    US6710046B1|2004-03-23|
    DE69823240T2|2005-04-28|
    CA2347939C|2006-10-10|
    CA2347939A1|2000-05-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1998-10-23|Application filed by 아키라 마츠모리
    1998-10-23|Priority to PCT/JP1998/004804
    2001-12-07|Publication of KR20010107927A
    2005-09-20|Application granted
    2005-09-20|Publication of KR100515918B1
    优先权:
    申请号 | 申请日 | 专利标题
    PCT/JP1998/004804|WO2000024397A1|1998-10-23|1998-10-23|Immunomodulatory drug composition|
    [返回顶部]