JP2005281283A - Combined pharmaceutical comprising benzimidazole agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a combined drug comprising a benzimidazole agent. <P>SOLUTION: The pharmaceutical composition is prepared by combining the benzimidazole drug and at least one drug chosen from the group consisting of an angiotensin-converting enzyme inhibitor, an angiotensin II receptor antagonist and interferon. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a combination drug of a benzimidazole drug.

  2- (5-Methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole 2-substituted product (benzimidazole compound) represented by the following general formula (1), and its 3H-tautomerism The isomers, optically active enantiomers and their pharmaceutically acceptable acid addition salts are pharmacologically active, in particular 2- (4-methoxyphenyl) -5- (5-methyl-3 -Oxo-4,5-dihydro-2H-6-pyridazinyl) -benzimidazole (hereinafter referred to as “pimobendan”) is used as a therapeutic agent for chronic heart failure or angina in Japan. The compound is also known as a pharmaceutical composition for immunomodulation used for the treatment of diseases related to cytokines such as rheumatoid arthritis, and CRP level (reactive protein level) is orally administered to patients with rheumatoid arthritis. Alternatively, it is disclosed that a decrease in inflammatory protein value) and improvement of inflammatory symptoms in rheumatoid arthritis are observed (Patent Document 1).

(In the formula, R represents an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.)
Regarding the pharmacological action of pimobendan, an inhibitory action of NF-κB, which is a nuclear transcription factor, has been reported (Non-patent Document 1). NF-κB was discovered as a B cell-specific nuclear factor that binds to the enhancer of the immunoglobulin κ chain gene and activates gene transcription, and is widely used in biological reactions such as cell differentiation and proliferation, and cytokine production. Plays an important role. Since NF-κB is also involved in the inflammatory reaction, it is expected that inflammation can be suppressed by suppressing its activation (Non-patent Document 2). A substance that modifies the function of the NF-κB, for example, a substance that suppresses the activation of the substance is expected to be further applied to medicine. Currently, such a specific substance and practical application of the substance Is still under study.

On the other hand, although many drugs for the treatment of kidney disease and liver disease have been developed, there has not yet been developed a safe drug that can provide a satisfactory drug effect, and the development of such a drug is desired. Yes.
European Patent Application No. 1123703 Matsumori, A., et al., Life Science, 2000, 67, pp. 2513-2519 Ghosh, S. and Karin, M., Cell, 2002, 109, Suppl: S81-96

  An object of the present invention is to provide a new medicine, particularly a medicine effective for kidney disease and liver disease. More specifically, sufficient pharmacotherapy has not yet been established, such as glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus-related The purpose is to provide a drug useful for the prevention and treatment of nephritis, ANCA-related nephritis, viral hepatitis B, hepatitis C virus, immune rejection associated with transplantation, and the like.

  As a result of conducting research to achieve the above object, the present inventor has found that a benzimidazole drug that has been conventionally known to have an inhibitory action on NFκ-B involved in inflammation and a certain drug. It has been discovered that the combination results in a new drug with improved pharmacological action that meets the above objectives.

  The present invention has been completed as a result of further earnest research based on this knowledge. The gist of the present invention is the following items 1 to 5.

  Item 1. A pharmaceutical composition comprising a combination of a benzimidazole drug and one or more drugs selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, and interferon.

  Item 2. The group consisting of a benzimidazole compound represented by the following general formula (1), a 3H tautomer, an optically active enantiomer, and a pharmaceutically acceptable acid addition salt thereof: Item 2. The pharmaceutical composition according to Item 1, which is at least one selected from the group consisting of:

(In the formula, R represents an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.)
Item 3. The pharmaceutical composition according to Item 2, wherein the benzimidazole compound is R in the general formula (1), which is a methyl group, a 2-pentyl group, a 4-methoxyphenyl group, or a 4-hydroxyphenyl group.

  Item 4. Glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus-related nephritis, ANCA-related nephritis, viral hepatitis B, type C Item 4. The pharmaceutical composition according to any one of Items 1 to 3, which is used for prevention and treatment of viral hepatitis and immune rejection associated with transplantation.

  Item 5. The pharmaceutical composition according to any one of Items 1 to 3, glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, Use for prevention and treatment of virus-related nephritis, ANCA-related nephritis, viral hepatitis B, viral hepatitis C, and immune rejection associated with transplantation.

  The pharmaceutical composition of the present invention is particularly useful for glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy for which sufficient treatment has not been established. It is useful for the prevention and treatment of virus-related nephritis, ANCA-related nephritis, viral hepatitis B, hepatitis C virus, immune rejection associated with transplantation, and the like. According to the present invention, techniques for preventing and treating such various diseases are established.

  Hereinafter, the pharmaceutical composition of the present invention will be described in detail. The pharmaceutical composition of the present invention is characterized by combining a benzimidazole drug and one or more drugs selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist and interferon.

(Benzimidazole drugs)
In the present invention, as the benzimidazole drug, any of various compounds conventionally known to have an inhibitory action on NFκ-B involved in inflammation can be used. Representative compounds include benzimidazole compounds represented by the above general formula (I), 3H tautomers, optically active enantiomers of the compounds, and pharmaceutically acceptable acid addition salts thereof. .

  Of the benzimidazole compounds represented by the general formula (1), compounds in which R is an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group, or a methoxyphenyl group are particularly preferable, and among them, R is particularly a methyl group. , 2-pentyl group, 4-methoxyphenyl group or 4-hydroxyphenyl group are preferred. The most preferred compound is a compound in which R is a 4-methoxyphenyl group, that is, pimobendan.

  Preferred benzimidazole drugs further include 3H tautomers, optically active enantiomers and pharmaceutically acceptable acid addition salts of the above compounds.

  That is, since the above compound is a carbonyl compound having a hydrogen at the α-position of the 3-position carbonyl group (keto form) as shown in the general formula (1), the enol has a form in which this hydrogen is transferred onto oxygen. It is in equilibrium with the isomeric form. In the present invention, such a tautomeric compound can be used as a benzimidazole drug. Further, the compound has an asymmetric carbon atom as shown in the general formula (1), and can take the form of an optical isomer having a configuration of a pair of enantiomers. The benzimidazole drug of the present invention may be such an optically active enantiomer. Further, the above compound can take the form of an acid addition salt by utilizing the amino group it has. The benzimidazole drug of the present invention may be a pharmaceutically acceptable acid addition salt. Typical examples of the acid addition salt include inorganic acid salts such as hydrochloride, nitrate, sulfate, hydrobromide, hydroiodide, phosphate, acetate, lactate, citrate, Organic carboxylates such as oxalate, glutarate, malate, tartrate, fumarate, mandelate, maleate, benzoate, phthalate, methanesulfonate, ethanesulfonate And organic sulfonates such as benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and the like. Of these, hydrochloride, hydrobromide, phosphate, tartrate, methanesulfonate and the like are preferable. These acid addition salts can be produced according to a conventional method.

(Combination drug)
In the present invention, the drug used in combination with the benzimidazole drug is selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, and interferon.

  Here, the angiotensin converting enzyme inhibitor is described in detail as follows. That is, in the renin-angiotensin system, which is one of the mechanisms for increasing blood pressure in the living body, angiotensin converting enzyme (hereinafter abbreviated as ACE) plays a central role. In other words, ACE has the effect of converting angiotensin I, which is inactive in increasing blood pressure, to angiotensin II, which has the effect of contracting vascular muscles. The angiotensin I is a peptide consisting of 10 amino acids, and is produced by the action of renin secreted from the renal paraglomerus on the renin substrate produced in the liver. When ACE acts on this, histidine and leucine at the terminal are removed and converted to angiotensin II. ACE also has the effect of degrading and inactivating bradykinin, which has the effect of expanding vascular muscles. ACE induces the blood pressure to increase by these actions. On the other hand, when ACE is inhibited, the production of angiotensin II, which is a pressor peptide, is suppressed, the degradation of bradykinin, which is a hypotensive peptide, is also suppressed, and blood pressure is induced in a decreasing direction.

  In the present invention, as the ACE inhibitor, conventionally, any of various drugs known as antihypertensive drugs that have an effect of suppressing an increase in blood pressure (pressurization) and as therapeutic agents that inhibit the pressurization are used. I can do it. Representative examples thereof include captolyl, elanapril, imidapril, temocapril, perindopril erbumine, lisinopril, aracepril, cilazapril and the like. In the present invention, these ACE inhibitors can be used alone or in combination of two or more.

  The angiotensin II receptor antagonist is described in detail below. That is, an angiotensin II receptor antagonist refers to a drug that antagonizes and suppresses the action of angiotensin II with an angiotensin II receptor. Since the angiotensin II antagonist inhibits the action of angiotensin II in the same manner as the ACE inhibitor, hypertension, heart disease (for example, heart failure, myocardial infarction, etc.), stroke, nephritis, arteriosclerosis, etc. It has been used for the prevention and treatment of cardiovascular diseases. In the present invention, any known angiotensin II receptor antagonist can be used. Specific examples thereof include candesartan cilexetil, losartan, valsartan, telmisartan, and the like. These can be used alone or in combination of two or more.

  Furthermore, interferon (hereinafter abbreviated as “IFN”) is an antiviral protein, and is known to have cell proliferation action, cytokine induction / suppression action and the like in addition to antiviral action. As the IFN, various types of α type, β type, γ type, consensus type, and hybrid type are known. Any of these may be used as the IFN that can be used in the present invention. In addition, there are various origins such as a natural type, a gene recombination type, and a chemical synthesis type.

(Pharmaceutical composition of the present invention)
In the pharmaceutical composition of the present invention, it is important to combine the benzimidazole drug and one or more drugs selected from the group consisting of an ACE inhibitor, an angiotensin II receptor antagonist and IFN. The combination is not particularly limited, and (1) a combination of a benzimidazole drug and an ACE inhibitor, (2) a combination of a benzimidazole drug and an angiotensin II receptor antagonist, (3) a benzimidazole drug Combination with IFN, (4) Combination of benzimidazole with ACE inhibitor and angiotensin II receptor antagonist, (5) Combination of benzimidazole with ACE inhibitor and IFN, (6) Benzimidazole Combinations of drugs with angiotensin II receptor antagonists and IFN, and (7) combinations of benzimidazole drugs with ACE inhibitors, angiotensin II receptor antagonists and IFN are included.

  More specifically, the combination of (1) above includes at least one ACE inhibitor selected from the group consisting of benzimidazole drugs, particularly pimobendan, and captolyl, elanapril, imidapril, temocapril, perindopril erbumine, lisinopril, alacepril and cilazapril. Combinations with drugs are included.

  The combination (2) includes at least one combination selected from the group consisting of benzimidazole drugs, particularly pimobendan, and candesartan cilexetil, losartan, valsartan, and telmisartan.

  The combination (3) includes a combination of a benzimidazole drug, particularly pimobendan, and at least one selected from the group consisting of IFN-α, IFN-β and IFN-γ.

  These combinations are glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus-related nephritis, ANCA-related nephritis, type B viral It is useful for the prevention and treatment of hepatitis, viral hepatitis C, and immune rejection associated with transplantation. Among these, for renal diseases such as glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus-related nephritis, ANCA-related nephritis The combination of (1), (2), (4) and (7) is effective. The combination of (3), (5), (6) and (7) is effective for liver diseases such as viral hepatitis B and viral hepatitis C. In the case of prevention and treatment of immune rejection associated with transplantation, the combination of (1), (2), (4) and (7) is effective for kidney transplantation, and the above (3) for liver transplantation. ), (5), (6) and (7) are effective.

  In the pharmaceutical composition of the present invention, the combined dose of the combination drug can be determined so that the dose of each combination drug is as follows in any combination. That is, the benzimidazole drug can be in an effective amount that exhibits an anti-inflammatory action based on the NF-κB inhibitory action of the benzimidazole drug. More specifically, the effective amount can be about 0.1 to 5.0 mg, preferably about 1.0 to 2.5 mg as an adult daily dose. This is not limited to once a day administration, but can be divided into two or more divided doses per day. In particular, it is desirable to administer about 1.25 mg of a benzimidazole drug in two divided doses per day. Of course, this dose can be determined as appropriate in consideration of the situation including the symptoms and body weight of the patient to be treated, the type of compound to be administered and the route of administration. Therefore, the above dose range is merely a guide and does not limit the dose range. The acute toxicity of benzimidazole drugs, particularly pimobendan, is known from the literature.

  The ACE inhibitor and the angiotensin II receptor antagonist can be used in effective amounts capable of exhibiting the ACE inhibitory action and the angiotensin II receptor antagonistic action, respectively. The effective amount naturally varies depending on the type of each drug, but in general, the dose per day for an adult can be appropriately determined from the range of 1 μg to 100 mg for any drug. Of course, this dose can be increased or decreased as appropriate in consideration of the situation including the symptoms and body weight of the patient to be treated, the route of administration of the drug, etc., as in the case of the benzimidazole drug.

  In general, the IFN can be appropriately determined from the range of 1 million units to 10 million units per day for an adult. Of course, this dose can also be increased or decreased as appropriate in consideration of the situation including the symptoms and weight of the patient to be treated, the route of administration of the drug, and the like.

  The pharmaceutical composition of the present invention may be prepared as a single-dose preparation form in which the medicines obtained by combining the above-mentioned respective drugs are contained in one agent, or a plurality of dosage-form forms each separately containing each agent. May be prepared. The dosage unit form of the medicament of the present invention may be any of various forms that can be taken by this type of pharmaceutical preparation. Specific examples of the form include tablet forms such as plain tablets and coated tablets, granules, capsules, powders, suspensions, drops, ampoules, syrups, suppositories, and the like. it can. In particular, benzimidazole drugs are preferably prepared in a solid dosage form for oral administration such as the above-mentioned tablet form, and ACE inhibitors and angiotensin II receptor antagonists are similarly prepared in a solid dosage form for oral administration. Advantageously. IFN is generally prepared in an injectable form.

  Preparations for each form are generally well known pharmaceutically acceptable carriers (excipients or diluents) and various other additives (binders, fillers, extenders, moisturizers). , Disintegrants, surfactants, lubricants, etc.) and can be carried out according to conventional methods.

  As the carrier used for the preparation of each form, typically, for example, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / Mention may be made of fatty substances such as glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose, hydrogenated oil and the like.

  The above tablets, granules, capsules, powders, drops, syrups, etc. are administered orally, suppositories are administered rectally, and suspensions, ampoules, etc. are administered topically or parenterally such as injection or inhalation. Is done.

  The pharmaceutical preparation of the present invention prepared in a plurality of dosage unit forms is usually administered at the same time, but need not be simultaneously, and the interval between administration times of the drugs of each form is about 1 to It does not matter if it is about 3 hours away.

(Use and treatment method of the medicament of the present invention)
The present invention, together with the above-described pharmaceutical composition of the present invention, includes glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, Provided for use as a prophylactic and therapeutic agent for virus-related nephritis, ANCA-related nephritis, viral hepatitis B, hepatitis C virus and immune rejection associated with transplantation.

  Further, the present invention provides a glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous, characterized by administering an effective amount of the above-described pharmaceutical composition of the present invention to a patient who requires treatment. Also provided are methods for the prevention and treatment of nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus-related nephritis, ANCA-related nephritis, viral hepatitis B, hepatitis C virus and immune rejection associated with transplantation.

  Hereinafter, examples will be given to describe the present invention more specifically, but the present invention is not limited to these examples.

Preparation of tablets containing 1.25 mg of pimobendan 1.25 mg of pimobendan, 66.75 mg of lactose and 70.00 mg of corn starch as active substances were weighed and mixed, and the mixture was granulated into granules using an ethanol solution containing 8.00 mg of polyvinylpyrrolidone and dried. After sieving, the granules obtained were then mixed with 3.00 mg Aerosil and 1.00 mg magnesium stearate and the mixture was compressed into tablets (total amount 150.00 mg).

Combination of pimobendan and ACE inhibitor for kidney injury
Wister rats (6 weeks old, male, average 190 g), control group (group receiving vehicle without active substance), group receiving pimobendan as active substance (comparative group), and administration of pimobendan And enalapril maleate administration were divided into 3 groups (group of the present invention) simultaneously (3 mice in each group).

  In this study, pimobendan was administered directly into the stomach once a day using a sonde in the form of 10 mg / kg / day suspended in physiological saline, and enalapril maleate was 0.2 mg. / kg / day was administered directly into the stomach with a sonte in the same manner once a day in a liquid form suspended in physiological saline.

  To induce renal injury, Thy1.1 antibody was administered to each test rat via the tail vein at 0.72 mL / head. The first day of administration was defined as day 0, and administration was started 3 hours before intravenous administration of the antibody on day 0 and continued until day 7.

  Proteinuria was measured before dosing and on day 7. In addition, the histological image of the kidney was examined after the completion of the administration on day 7, and the mesagium cell proliferation and the degree of extracellular matrix increase (degree of renal fibrosis) were averaged and compared with 10 renal glomeruli per slice. The determination of mesagium cell proliferation and the extent of extracellular matrix increase were both rated on a four-point scale (+1: 0-25% increase over the control group, +2: 25-50% increase, +3 : 50-75% increase, +4: 75-100% increase). The measurement results are shown as the average value of 3 rats.

  The results obtained are shown in Table 1.

  As is clear from the results shown in Table 1, the comparative group (pimobendan alone administration group) showed a tendency to improve renal damage, and this renal disorder improvement effect was the effect of the present invention group (combination of pimobendan administration and enalapril maleate administration group). ) Was found to be even more prominent.

Combined use of pimobendan and angiotensin receptor antagonist for renal injury
Wister rats (6 weeks old, male, average 190 g), control group (group receiving vehicle containing no active substance), group receiving pimobendan as active substance (comparative group), and administration of pimobendan And candesartan and cilexetil administration (group of the present invention) were divided into 3 groups (3 mice in each group).

  In this study, pimobendan was administered in the form of a suspension of 10 mg / kg / day in physiological saline directly into the stomach once a day using a sonde, and candesartan cilexetil was administered at 5.0 mg. / kg / day was administered directly into the stomach with a sonde in the same manner once a day in a liquid form suspended in physiological saline.

  To induce renal injury, Thy1.1 antibody was administered to each test rat via the tail vein at 0.72 mL / head. The first day of administration was defined as day 0, and administration was started 3 hours before intravenous administration of the antibody on day 0 and continued until day 7.

  Proteinuria was measured before dosing and on day 7. In addition, the histological image of the kidney was examined after completion of the administration on day 7, and the degree of mesagium cell proliferation and extracellular matrix increase (degree of renal fibrosis) in 10 renal glomeruli per section was the method described in Example 2. And evaluated in the same manner.

  The results obtained are shown in Table 2.

  As is clear from the results shown in Table 2, it was found that there was a tendency to improve kidney damage in the comparative group, and this effect was more prominent in the present invention group.

Combination of pimobendan and IFN-β for liver injury
DBA / 2 mice (4 weeks old, male, average 20 g), control group (group receiving methylcellulose as solvent), comparison group 1 (group receiving pimobendan as active substance), comparison group 2 (mouse) The group was divided into 4 groups (groups administered with interferon β) and the present invention group (group where administration of pimobendan and mouse interferon β was administered simultaneously) (5 mice in each group).

In this test, pimobendan was directly administered into the stomach once a day using a sonde in the form of 1 mg / kg / day suspended in physiological saline. Mouse interferon β was injected intraperitoneally once a day in the form of 10 ⁶ U / kg / day dissolved in physiological saline.

  The mice were inoculated intraperitoneally with 10 pfu of encephalomyocarditis virus. The day of inoculation was day 0, and the administration was started 3 hours before the inoculation of the virus on day 0 and continued until day 7.

  Histopathological examination of the liver and heart 7 days after virus inoculation was performed. That is, the frequency of cell necrosis and cell invasion of each organ is classified into +1 to +4 (Iwasaki, A., et al., J. Am. Col.l Cardiol., 1999; 33: 1400-1407 ), The average value of each group of mice was compared.

  The results are shown in Table 3.

As is clear from the results shown in Table 3, in the comparative group 1 administered with pimobendan alone and in the comparative group 2 administered with interferon β alone, these were combined in comparison with the slight improvement in liver damage and myocardial damage. It was found that the administered group of the present invention exerts a remarkable effect of improving liver damage and myocardial damage.

Claims (5)

A pharmaceutical composition comprising a combination of a benzimidazole drug and one or more drugs selected from the group consisting of an angiotensin converting enzyme inhibitor, an angiotensin II receptor antagonist, and interferon. The benzimidazole drug is selected from the group consisting of a benzimidazole compound represented by the following general formula (1), a 3H tautomer, an optically active enantiomer, and a pharmaceutically acceptable acid addition salt thereof. 2. The pharmaceutical composition according to claim 1, wherein there is at least one.

(In the formula, R represents an alkyl group having 1 to 5 carbon atoms, a hydroxyphenyl group or a methoxyphenyl group.) 3. The pharmaceutical composition according to claim 2, wherein in the benzimidazole compound, R is a methyl group, a 2-pentyl group, a 4-methoxyphenyl group or a 4-hydroxyphenyl group in the general formula (1). Glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus related nephritis, ANCA related nephritis, viral hepatitis B, viral hepatitis C 4. The pharmaceutical composition according to claim 1, which is used for prevention / treatment of immune rejection associated with transplantation. The pharmaceutical composition according to any one of claims 1 to 3, glomerulonephritis, IgA nephropathy, nephrosis, glomerulosclerosis, membranous nephropathy, glomerulonephritis, lupus nephritis, diabetic nephropathy, virus Use for prevention and treatment of related nephritis, ANCA-related nephritis, viral hepatitis B, hepatitis C, and immune rejection associated with transplantation.