JPWO2007086446A1 - Pharmaceutical composition for prevention or treatment of heart failure - Google Patents

Abstract

A pharmaceutical composition effective for the prevention and treatment of heart failure is provided. A pharmaceutical composition comprising a carbohydrate degrading enzyme inhibitor as an active ingredient.

Description

  The present invention relates to a pharmaceutical composition for preventing or treating heart failure, comprising a carbohydrate degrading enzyme inhibitor as an active ingredient.

  Furthermore, the present invention relates to the use of the above-mentioned compound for producing the above-mentioned medicine, or a method for preventing or treating the above-mentioned disease, wherein the medicine is administered to a warm-blooded animal (preferably a human).

  Heart failure is a collective term for a decline in cardiac function and a worsening state of general blood circulation based on it.

  In order to maintain normal systolic stress, the heart maintains normal systolic stress against the decrease in cardiac output caused by chronic mechanical load on the heart due to high blood pressure, etc., morphological changes such as ventricular enlargement, hypertrophy, and sympathetic nerves Adapt with compensatory mechanisms such as increased activity. However, when this compensatory mechanism becomes chronic, a burden is placed on the heart, and the compensatory mechanism eventually breaks down, resulting in heart failure. For this reason, cardiac hypertrophy is regarded as an important step before heart failure. It is known that cardiac hypertrophy is caused by high blood pressure as a basic disease, and that insulin resistance improving drugs used as antidiabetic drugs cause cardiac hypertrophy.

  Conventional therapeutic agents for heart failure include angiotensin converting enzyme inhibitors, β-adrenergic receptor antagonists, calcium antagonists, cardiac glycosides, and the like. Although these drugs have improved the prognosis of heart failure, they cannot be said to be sufficiently satisfactory due to problems such as safety margins.

  Carbohydrate-degrading enzyme inhibitors are known as anti-diabetic drugs because they inhibit the degradation of starch and oligosaccharides, thereby suppressing the absorption of sugar in the body and suppressing the increase of blood sugar or the action of lowering blood sugar. . For example, an α-glucosidase inhibitor is commercially available as a therapeutic agent for diabetes. In addition, α-amylase inhibitors are known to inhibit the degradation of carbohydrates (mainly starch) by inhibiting α-amylase, thereby producing an effect of lowering blood glucose levels (see, for example, Patent Documents 1 and 2). ). However, it is completely unknown that these carbohydrate degrading enzyme inhibitors are effective in treating heart failure.

Insulin sensitizers are also known as peroxisome proliferator-activated receptor (PPAR) γ activators. Drugs of this mechanism are used as antidiabetic drugs because they have an excellent blood glucose lowering effect. Pioglitazone and rosiglitazone are examples of insulin sensitizers currently on the market. However, insulin resistance ameliorating drugs are known to cause adverse events such as heart failure, cardiac hypertrophy, edema, and pleural effusion when used clinically. Attention is needed. One of currently known methods for suppressing or treating such an adverse event is a combination with a diuretic (see, for example, Patent Document 3).
JP 2004-250446 A International Publication No. WO 06/011588 Pamphlet JP 2002-255854 A (International Publication No. WO 02/051441 Pamphlet)

  As a result of intensive research aimed at developing preventive and therapeutic agents for heart failure that have a different mechanism of action from conventional therapeutic agents for heart failure, the present inventors have found that carbohydrate-degrading enzyme inhibitors have excellent cardiac hypertrophy suppression effects. And has been found useful as a pharmaceutical composition for the prevention or treatment of heart failure.

  Furthermore, the present inventors have found that the combined use of a carbohydrate-degrading enzyme inhibitor and an insulin sensitizer improves the cardiac hypertrophy caused by the insulin sensitizer.

The present invention
(1) A pharmaceutical composition for preventing or treating heart failure, comprising a carbohydrate degrading enzyme inhibitor as an active ingredient,
(2) A pharmaceutical composition for suppressing cardiac hypertrophy, comprising a carbohydrate degrading enzyme inhibitor as an active ingredient,
(3) A pharmaceutical composition comprising a carbohydrate-degrading enzyme inhibitor as an active ingredient, which prevents or treats heart failure by suppressing cardiac hypertrophy,
(4) The pharmaceutical composition according to any one of (1) to (3) above, wherein the carbohydrate degrading enzyme inhibitor is an α-glucosidase inhibitor or an α-amylase inhibitor,
(5) The pharmaceutical composition according to any one of (1) to (3) above, wherein the carbohydrate degrading enzyme inhibitor is voglibose, acarbose or miglitol,
(6) The pharmaceutical composition according to (1) to (3) above, wherein the carbohydrate degrading enzyme inhibitor is voglibose,
(7) The pharmaceutical composition according to any one of (1) to (3) above, wherein the carbohydrate degrading enzyme inhibitor is an α-amylase inhibitor,
(8) A carbohydrate-degrading enzyme inhibitor is represented by the following general formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; Or a pharmacologically acceptable salt or ester thereof, the pharmaceutical composition according to (7) above,
(9) The pharmaceutical composition according to the above (8), wherein R ¹ is a C1-3 alkyl group, a hydroxymethyl group, a C1-3 alkoxymethyl group or a C1-3 haloalkyl group,
(10) The pharmaceutical composition according to the above (8) or (9), wherein R ¹ is a methyl group,
(11) The pharmaceutical composition according to any one of (8) to (10), wherein R ² is a hydroxymethyl group,
(12) A is the following general formula (A1)

The pharmaceutical composition according to any one of (8) to (11) above,
(13) The pharmaceutical composition according to the above (12), wherein R ³ , R ⁴ and R ⁵ are the same or different and each is a hydroxymethyl group, a hydroxyl group or a hydrogen atom,
(14) The pharmaceutical composition according to the above (12) or (13), wherein R ⁷ is a hydrogen atom,
(15) The carbohydrate degrading enzyme inhibitor is (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D -Glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside or pharmacologically The pharmaceutical composition according to any one of (1) to (3) above, which is an acceptable salt or ester,
(16) A pharmaceutical composition characterized by suppressing side effects caused by administration of an insulin sensitizer by combining a carbohydrate degrading enzyme inhibitor and an insulin sensitizer.
(17) The pharmaceutical composition according to the above (16), wherein the side effect is cardiac hypertrophy or heart failure,
(18) The pharmaceutical composition according to the above (16) or (17), wherein the carbohydrate degrading enzyme inhibitor is an α-amylase inhibitor,
(19) The pharmaceutical composition according to the above (16) or (17), wherein the insulin sensitizer is a PPARγ activator,
(20)
Insulin resistance improving drugs are represented by the following structural formula: pioglitazone, rosiglitazone, MCC-555, BMS-298585, AZ-242, LY-519818, R-483, K-111,

5- [4- (6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof (16) to (18) A pharmaceutical composition according to any one of
(21) The pharmaceutical composition according to any one of the above (16) to (18), wherein the insulin sensitizer is a thiazolidinedione insulin sensitizer.
(22) The pharmaceutical composition according to any one of (16) to (18), wherein the insulin sensitizer is pioglitazone or rosiglitazone,
(23) The pharmaceutical composition according to any one of (1) to (22) above, which is a compounding agent,
(24) The pharmaceutical composition according to any one of (16) to (22) above, wherein the active ingredient is administered separately with time.

In the present invention, the “carbohydrate-degrading enzyme inhibitor” is not particularly limited as long as it is an agent that inhibits a carbohydrate-degrading enzyme, and examples thereof include an α-glucosidase inhibitor and an α-amylase inhibitor.

  In the present invention, the “α-glucosidase inhibitor” is not particularly limited as long as it is a drug that inhibits glucosidase, which is one of the carbohydrate degrading enzymes. For example, voglibose (Takeda Pharmaceutical Co., Ltd., trade name: Actos), Acarbose (Bayer Pharmaceutical, trade name: Glucobuy), miglitol (Sanwa Chemical, trade name: Sable) and the like can be mentioned, and voglibose is preferred. Voglibose is a compound described in Japanese Patent No. 1611546. Acarbose is a compound described in Japanese Patent No. 2502551. Miglitol is a compound described in Japanese Patent No. 1444270.

  In the present invention, the “α-amylase inhibitor” is not particularly limited as long as it is a drug that inhibits amylase, which is one of the carbohydrate degrading enzymes. For example, the following is described in JP-A-2004-250446. Formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; Or a pharmacologically acceptable salt or ester thereof.

  The oligosaccharide derivative having the general formula (I) can be converted to an acid addition salt when it has a basic group according to a conventional method. Such salts include, for example, hydrohalic acid salts such as hydrofluoric acid, hydrochloric acid, hydrobromic acid and hydroiodic acid; inorganics such as nitrates, perchlorates, sulfates and phosphates. Acid salts; salts of lower alkanesulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid and ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid and p-toluenesulfonic acid; such as glutamic acid and aspartic acid Amino acid salts; examples include salts of carboxylic acids such as acetic acid, fumaric acid, tartaric acid, succinic acid, maleic acid, malic acid, succinic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, and citric acid. . Preferred is a salt of hydrohalic acid, and most preferred is hydrochloride.

  Furthermore, since the oligosaccharide derivative having the general formula (I) has a hydroxyl group, it can be converted into a metal salt according to a conventional method. Examples of such salts include alkali metal salts such as lithium, sodium and potassium; alkaline earth metal salts such as calcium, barium and magnesium; and aluminum salts. Alkali metal salts are preferred.

  The oligosaccharide derivative having the general formula (I) of the present invention can be converted into a pharmacologically acceptable ester according to a conventional method. Such an ester is not particularly limited as long as it is medically used and pharmacologically acceptable as compared with the oligosaccharide derivative having the general formula (I).

  The ester of the oligosaccharide derivative having the general formula (I) of the present invention is preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, benzyl, acetoxymethyl, 1- (acetoxy) ethyl, Propionyloxymethyl, 1- (propionyloxy) ethyl, butyryloxymethyl, 1- (butyryloxy) ethyl, isobutyryloxymethyl, 1- (isobutyryloxy) ethyl, valeryloxymethyl, 1- (valeryloxy) Ethyl, isovaleryloxymethyl, 1- (isovaleryloxy) ethyl, pivaloyloxymethyl, 1- (pivaloyloxy) ethyl, methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, propoxycarbo Ruoxymethyl, 1- (propoxycarbonyloxy) ethyl, isopropoxycarbonyloxymethyl, 1- (isopropoxycarbonyloxy) ethyl, butoxycarbonyloxymethyl, 1- (butoxycarbonyloxy) ethyl, isobutoxycarbonyloxymethyl, 1- ( Isobutoxycarbonyloxy) ethyl, t-butoxycarbonyloxymethyl, 1- (t-butoxycarbonyloxy) ethyl, cyclopentanecarbonyloxymethyl, 1- (cyclopentanecarbonyloxy) ethyl, cyclohexanecarbonyloxymethyl, 1- (cyclohexane Carbonyloxy) ethyl, cyclopentyloxycarbonyloxymethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, cyclohexyloxycarbonyloxymethyl, 1- (cyclo Xyloxycarbonyloxy) ethyl, benzoyloxymethyl, 1- (benzoyloxy) ethyl, phenoxycarbonyloxymethyl, 1- (phenoxycarbonyloxy) ethyl, (5-methyl-2-oxo-1,3-dioxolen-4- Yl) methyl or 2-trimethylsilylethyl group.

  (A1) is preferably the following general formula (A1a) or (A1b)

More preferably, the following general formula (A1c)

It is.

  (A2) is preferably represented by the following general formula (A2a) or (A2b)

More preferably, the following general formula (A2c)

It is.

  (A3) is preferably the following general formula (A3a)

It is.

R ¹ is preferably a C 1-6 alkyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, and particularly preferably a methyl group.

R ² is preferably a C 1-6 alkyl group or a hydroxymethyl group, more preferably a methyl group or a hydroxymethyl group, and particularly preferably a hydroxymethyl group.

R ³ in formulas (A1), (A1c) and (A1a) is preferably a C1-6 hydroxyalkyl group, a hydroxyl group, a halogen atom or a hydrogen atom, more preferably a C1-3 hydroxyalkyl group or hydrogen. An atom, particularly preferably a hydrogen atom. In general formulas (A2), (A2a), (A2b) and (A2c), preferably a C1-6 hydroxyalkyl group, a hydroxyl group, a hydrogen atom or a halogen atom, more preferably a C1-3 hydroxyalkyl group or hydrogen. An atom, particularly preferably a hydroxymethyl group. In general formulas (A3) and (A3a), preferably a C1-6 hydroxyalkyl group, an amino group, a hydroxyl group, a hydrogen atom or a halogen atom, more preferably a hydroxymethyl group, a hydroxyl group or an amino group, and particularly preferred Is a hydroxyl group.

R ⁴ is preferably a C1-6 hydroxyalkyl group, a hydrogen atom, a hydroxyl group or a halogen atom in the general formulas (A1), (A1c) and (A1a), more preferably a hydroxyl group or a halogen atom, particularly A hydroxyl group or a fluorine atom is preferred, and a hydroxyl group is most preferred. In general formulas (A2), (A2a), (A2b) and (A2c), a C1-6 hydroxyalkyl group, a hydrogen atom, a halogen atom or a hydroxyl group is preferred, and a hydroxyl group is more preferred. In general formulas (A3) and (A3a), preferably a C1-6 hydroxyalkyl group, an amino group, a hydroxyl group, a halogen atom or a hydrogen atom, more preferably a hydroxyl group, a halogen atom or a hydrogen atom, particularly preferably. Is a hydroxyl group.

R ⁵ in the general formulas (A1), (A1c) and (A1a) is preferably a hydroxyl group, a halogen atom, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group or a hydrogen atom, more preferably C1- A 6-hydroxyalkyl group, particularly preferably a C1-3 hydroxyalkyl group, and most preferably a hydroxymethyl group. In the general formulas (A3) and (A3a), preferably a C1-6 hydroxyalkyl group, a hydroxyl group, a hydrogen atom, a halogen atom or an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxyalkyl group, 1 or 2 may be substituted), more preferably an amino group (the amino group may be substituted with 1 or 2 C1-6 alkyl group or C1-6 hydroxyalkyl group), Particularly preferred is an amino group.

R ⁶ is preferably a C1-6 hydroxyalkyl group, amino group, hydroxyl group, hydrogen atom or halogen atom in the general formulas (A3) and (A3a), more preferably a C1-6 hydroxyalkyl group, Particularly preferred is a C1-3 hydroxyalkyl group, and most preferred is a hydroxymethyl group.

R ⁷ is preferably a hydrogen atom, a C 1-6 hydroxyalkyl group or a C 1-6 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

R ⁸ and R ⁹ are preferably a C1-3 hydroxyalkyl group, a halogen atom, a hydrogen atom or a hydroxyl group, more preferably a hydrogen atom or a hydroxyl group.

R ¹⁰ is preferably a C 1-6 hydroxyalkyl group, more preferably a C 1-3 hydroxyalkyl group, and particularly preferably a hydroxymethyl group.

R ¹¹ is preferably a hydroxyl group.

  n is preferably 1.

  A is preferably the following general formula (A1) or (A2)

More preferably, (A1).

  The general formula (I) is preferably the following general formula (IA) or (IB)

More preferably, the following general formula (Ia)

And particularly preferably (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D- Glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside or its pharmacologically acceptable Salt or ester.

  In the present invention, “insulin resistance ameliorating drug” is a general term for drugs that improve insulin dysfunction and lower blood glucose levels. For example, pioglitazone, rosiglitazone, MCC-555, BMS- 298585, AZ-242, LY-519818, R-483, K-111,

Mention may be made of 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione and pharmacologically acceptable salts thereof. Pioglitazone hydrochloride, rosiglitazone maleate, 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione hydrochloride These are thiazolidinedione insulin sensitizers, and these compounds are also known as drugs that activate peroxisome proliferator-activated receptor (PPAR) γ.

  Pioglitazone is a compound described in US Pat. No. 4,687,777. Roziglitazone is a compound described in US Pat. No. 5,002,953. MCC-555 is a compound described in US Pat. No. 5,594,016. BMS-298585 is a compound described in WO 01/21602 pamphlet. AZ-242 is a compound described in WO99 / 62872 pamphlet. LY-519818 is a compound described in WO 02/100813 pamphlet. 5- [4- (6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione and its salts are disclosed in JP-A-9-295970, EP 0745600, USA It can be produced according to the methods described in Patent No. 5,886,014 and International Publication No. 00/71540 pamphlet.

In the present invention, the “C1-3 alkyl group” is a linear or branched alkyl group having 1 to 3 carbon atoms, for example, a methyl, ethyl, n-propyl or isopropyl group. Can be mentioned. R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are preferably methyl groups.

In the present invention, the “C1-6 alkyl group” is a linear or branched alkyl group having 1 to 6 carbon atoms. For example, as the “C1-3 alkyl group”, Listed groups or n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methyl Pentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3 Mention may be made of -dimethylbutyl or 2-ethylbutyl groups. R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ³ , R ⁴ , R ⁵ , R ⁶ are preferably substituted with 1 to 3 carbon atoms. And most preferably a methyl group.

In the present invention, the “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and in R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁸ , R ⁹ and R ¹¹ , preferably , A fluorine atom.

In the present invention, the “C1-3 haloalkyl group” or the “C1-6 haloalkyl group” is a group in which the “halogen atom” is substituted for the “C1-3 alkyl group” or the “C1-6 alkyl group”, respectively. is there. As the `` C1-3 haloalkyl group '', for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 2,2-dibromoethyl groups can be mentioned, and R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁰ are preferably a fluoromethyl group. Examples of the “C1-6 haloalkyl group” include the groups listed as examples of the “C1-3 haloalkyl group”, or 4-iodobutyl, 4-fluorobutyl, 4-chlorobutyl, 5-iodopentyl, and 5-fluoropentyl. , 5-chloropentyl, 6-iodohexyl, 6-fluorohexyl, 6-chlorohexyl group, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^10. Is preferably a C1-3 haloalkyl group, more preferably a fluoromethyl group.

In the present invention, the “C1-3 hydroxyalkyl group” or “C1-6 hydroxyalkyl group” is a group in which a hydroxyl group is substituted on the “C1-3 alkyl group” or “C1-6 alkyl group”, respectively. Examples of the “C1-3 hydroxyalkyl group” include a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, and R ³ , R ⁴ , R ⁵ , R ⁶ and R ¹⁰ are preferably a hydroxymethyl group. It is. Examples of the “C1-6 hydroxyalkyl group” include the groups mentioned as examples of the “C1-3 hydroxyalkyl group”, and hydroxybutyl, hydroxypentyl, and hydroxyhexyl groups, and R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹⁰ , R ¹¹ and R ¹ are preferably a C 1-3 hydroxyalkyl group, and more preferably a hydroxymethyl group.

In the present invention, the “C1-3 alkoxy group” or “C1-6 alkoxy group” is a group in which the “C1-3 alkyl group” or “C1-6 alkyl group” is bonded to an oxygen atom, respectively. Examples of the “C1-3 alkoxy group” include methoxy, ethoxy, n-propoxy, and isopropoxy groups. Examples of the “C1-6 alkoxy group” include the groups listed as examples of the “C1-3 alkoxy group”, or n-butoxy, isobutoxy, s-butoxy, tert-butoxy, n-pentoxy, isopentoxy, 2- Methylbutoxy, neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1 , 2-dimethylbutoxy, 1,3-dimethylbutoxy, 2,3-dimethylbutoxy group, and R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are preferably C1-3 alkoxy Group, more preferably a methoxy group.

In the present invention, the “C1-3 alkoxymethyl group” or “C1-6 alkoxymethyl group” is a group in which the “C1-3 alkoxy group” or “C1-6 alkoxy group” is bonded to a methyl group, respectively. . Examples of the “C1-3 alkoxymethyl group” include methoxymethyl, ethoxymethyl, n-propoxymethyl and isopropoxymethyl groups, and R ¹ and R ² are preferably methoxymethyl groups. As the “C1-6 alkoxymethyl group”, for example, the groups mentioned as examples of the above “C1-3 alkoxymethyl group”, or n-butoxymethyl, isobutoxymethyl, s-butoxymethyl, tert-butoxymethyl, n -Pentoxymethyl, isopentoxymethyl, 2-methylbutoxymethyl, neopentoxymethyl, n-hexyloxymethyl, 4-methylpentoxymethyl, 3-methylpentoxymethyl, 2-methylpentoxymethyl, 3, Examples include 3-dimethylbutoxymethyl, 2,2-dimethylbutoxymethyl, 1,1-dimethylbutoxymethyl, 1,2-dimethylbutoxymethyl, 1,3-dimethylbutoxymethyl, and 2,3-dimethylbutoxymethyl groups. R ¹ and R ² are preferably a “C1-3 alkoxymethyl group”, and more preferably a methoxymethyl group.

The compound which is an active ingredient of the present invention may have various isomers. The present invention includes all of these various isomers and their isolates and mixtures of isomers in various proportions.

  Furthermore, the present invention includes all of the compounds that are active ingredients when they form pharmacologically acceptable salts, esters or solvates (eg hydrates). In addition, the active ingredient of the present invention includes a compound having a crystal polymorphism, and includes all of these crystal forms.

In the present invention, one or more carbohydrate degrading enzyme inhibitors can be used. Moreover, 1 type (s) or 2 or more types can also be used for an insulin resistance improving agent.

  The carbohydrate degrading enzyme inhibitor and the insulin sensitizer can be administered in the form of a combination drug. Moreover, each single agent can also be administered simultaneously. In addition, each single agent can be administered in succession at an appropriate interval. The dosing interval allowed to achieve the effect brought about by the administration of such a drug can be confirmed clinically or by animal experiments.

The pharmaceutical composition of the present invention is administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like. For example, in the case of tablets, pills, powders, syrups, solutions, suspensions, emulsions, granules and capsules, they are administered orally.

  These various preparations are prepared by using known adjuvants that can be generally used in the field of known pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, solubilizers, flavoring agents, and coating agents according to conventional methods. It can be formulated.

  In molding into tablets, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Form, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone and other binders, dry starch, sodium alginate, agar powder, laminaran powder Sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose and other disintegrants, sucrose, stearin, cacao butter, hydrogenated oil and other disintegration inhibitors, Class Ammonius Absorption accelerators such as bases, sodium lauryl sulfate, humectants such as glycerin and starch, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, boric acid powder, polyethylene glycol, etc. A lubricant can be exemplified. Further, the tablets can be made into tablets with ordinary coatings as necessary, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets.

  In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and other excipients, gum arabic powder, Examples thereof include binders such as tragacanth powder, gelatin and ethanol, and disintegrants such as lamina lankanten.

  Furthermore, you may contain a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, and other pharmaceuticals as needed.

  The amount of the active ingredient compound contained in the pharmaceutical preparation is not particularly limited and is appropriately selected within a wide range, but is usually 1 to 70% by weight, preferably 1 to 30% by weight in the total composition. Is appropriate.

  The dose and dose ratio of each drug used in the present invention can vary greatly depending on various conditions such as activity of individual substances, patient symptoms, age, body weight and the like.

  As described above, the dose of the drug used in the present invention can vary greatly, but it is usually 0.001 mg (preferably 0.01 mg, more preferably 0.1 mg) as the lower limit for adults per day, and the upper limit. 2,000 mg (preferably 200 mg, more preferably 100 mg).

  The administration ratio of the carbohydrate degrading enzyme inhibitor and other drugs can also vary greatly, but is usually in the range of 0.001 to 100 (w / w) by weight.

  In the present invention, the carbohydrate-degrading enzyme inhibitor and the other drug are each administered at the same time or separately at different times by dividing the above dose once or several times a day.

  According to the present invention, a carbohydrate-degrading enzyme inhibitor is useful as a pharmaceutical composition for preventing or treating heart failure because it has an excellent effect of suppressing cardiac hypertrophy. Moreover, the side effect of a carbohydrate decomposing enzyme inhibitor can be effectively suppressed by using together with the medicine which has cardiac hypertrophy as a side effect. In particular, since both a carbohydrate-degrading enzyme inhibitor and an insulin resistance ameliorating agent have an antidiabetic action, the combined use is extremely useful in the treatment of diabetes.

  EXAMPLES Next, although an Example and a formulation example are given and this invention is demonstrated further in detail, this invention is not limited to these.

  (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside (hereinafter referred to as Compound A) ) Can be produced according to the method described in JP-A-2004-250446.

<Test Example 1>
Inhibition of left ventricular hypertrophy by a carbohydrate-degrading enzyme inhibitor (1) Animal used Rat (Wistar, male, 9 weeks old when used, sold by Japan SLC Co., Ltd.)
(2) Experimental method and results After anesthesia with pentobarbital (50 mg / kg ip), a midline incision was made and the abdominal aorta between the right and left renal arteries was detached. A 22G needle was placed along the artery, and the artery was ligated with silk thread together with the needle. The needle was then withdrawn to complete the abdominal aortic stenosis and the abdomen was closed. The sham-operated group was closed without ligation. Compound A was mixed with powdered feed (FR-2 powdered feed, Funabashi Farm Co., Ltd.) to a concentration of 300 ppm (w / w) and voglibose at 20 ppm (w / w). A diet was administered to the eyes. The sham-operated group and the control group were given a powdered feed not mixed with the test substance. On the 23rd day after preparation of the stenosis, the body weight was measured, and the heart was removed after decapitation. The left ventricle was excised from the excised heart, the wet weight was measured, and the left ventricular weight / body weight ratio (mg / g) was calculated. Furthermore, the amount of change in the left ventricular weight / body weight ratio (mg / g) was calculated by subtracting the value (mean value) of the sham operation group from the left ventricular weight / body weight ratio (mg / g) of each group. Table 1 shows the results.

  From the results in Table 1, it can be seen that compound A and voglibose, which are carbohydrate degrading enzyme inhibitors, markedly suppresses left ventricular hypertrophy. Therefore, carbohydrate degrading enzyme inhibitors are useful as therapeutic and preventive agents for cardiac hypertrophy and heart failure.

<Test Example 2>
Suppressive effect of cardiac hypertrophy caused by administration of an insulin sensitizer with a carbohydrate-degrading enzyme inhibitor (1) Animals used Diabetic mice (BKS.Cg- + Lepr [db] / + Lepr [db] / Jcl, female, used) 7 weeks old, sold by Nippon Clare Co., Ltd.)
(2) Experimental method and results The mice were divided into groups based on the blood glucose level and body weight of the mice, and the control group was allowed to freely ingest powdered feed (FR-2 powdered feed, Funabashi Farm Co., Ltd.) for 2 weeks. In the pioglitazone group and the combination group, pioglitazone was mixed with powdered feed at a concentration of 30 ppm, and in the compound A group and the combination group at a concentration of 100 ppm (w / w), and mixed administration was performed. Two weeks after the start of compound administration, blood glucose level and ventricular muscle weight were measured. Blood was collected from the tail vein of the mouse, and the blood glucose level was measured using a simple blood glucose meter (Glucoloader GXT, manufactured by A & T Corp.). Furthermore, the amount of change in blood glucose level (mg / dL) was calculated by subtracting the value (average value) of the control group from the blood glucose level (mg / dL) of each group. The results are shown in Table 2.

  After blood collection, the heart was removed after exsanguination from the carotid artery. The left and right atria were removed from the excised heart and the wet weight of the ventricular muscle was measured. Furthermore, the amount of change in ventricular muscle weight (mg) was calculated by subtracting the value (average value) of the control group from the ventricular muscle weight (mg) of each group. Table 3 shows the ventricular muscle weight.

  From Tables 2 and 3, the combined use of a carbohydrate-degrading enzyme inhibitor and an insulin sensitizer improves the effect of treating diabetes, while the carbohydrate-degrading enzyme inhibitor causes cardiac hypertrophy caused by the insulin sensitizer It turns out that it is suppressing.

上記で示される各成分の粉末を良く混合し、カプセルに詰めることによりカプセル剤を製造することができる。
（２）錠剤

上記で示される各成分の粉末を良く混合し、各150mg重量の錠剤に圧縮成型する。必要ならば、これらの錠剤は糖またはフィルムで被覆してもよい。
（３）顆粒剤

上記で示される各成分の粉末を良く混合し、純水で湿らし、バスケット式顆粒化機で顆粒化し、乾燥して顆粒剤を得る。
（４）カプセル剤

上記で示される各成分の粉末を良く混合し、カプセルに詰めることによりカプセル剤を製造することができる。
（５）錠剤

上記で示される各成分の粉末を良く混合し、各150mg重量の錠剤に圧縮成型する。必要ならば、これらの錠剤は糖またはフィルムで被覆してもよい。
Therefore, the carbohydrate-degrading enzyme inhibitor is not only useful as a therapeutic / preventive agent for diabetes in combination with a single agent and an insulin sensitizer, but also for cardiac hypertrophy in diabetic patients taking the insulin sensitizer. It is also useful as a therapeutic / preventive agent for heart failure.
<Formulation example>
(1) Capsule

Capsules can be produced by thoroughly mixing the powders of the components shown above and filling the capsules.
(2) Tablet

The powder of each component shown above is mixed well and compressed into tablets each weighing 150 mg. If necessary, these tablets may be coated with sugar or film.
(3) Granules

The powder of each component shown above is mixed well, moistened with pure water, granulated with a basket type granulator, and dried to obtain granules.
(4) Capsule

Capsules can be produced by thoroughly mixing the powders of the components shown above and filling the capsules.
(5) Tablet

The powder of each component shown above is mixed well and compressed into tablets each weighing 150 mg. If necessary, these tablets may be coated with sugar or film.

Claims (24)

  A pharmaceutical composition for preventing or treating heart failure, comprising a carbohydrate degrading enzyme inhibitor as an active ingredient.   A pharmaceutical composition for suppressing cardiac hypertrophy, comprising a carbohydrate-degrading enzyme inhibitor as an active ingredient.   A pharmaceutical composition comprising a carbohydrate-degrading enzyme inhibitor as an active ingredient, which prevents or treats heart failure by suppressing cardiac hypertrophy.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the carbohydrate degrading enzyme inhibitor is an α-glucosidase inhibitor or an α-amylase inhibitor.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the carbohydrate degrading enzyme inhibitor is voglibose, acarbose or miglitol.   The pharmaceutical composition according to claim 1, wherein the carbohydrate degrading enzyme inhibitor is voglibose.   The pharmaceutical composition according to any one of claims 1 to 3, wherein the carbohydrate degrading enzyme inhibitor is an α-amylase inhibitor. The carbohydrate degrading enzyme inhibitor is represented by the following general formula (I)

[Wherein A represents the following general formula (A1), (A2) or (A3)

R ¹ and R ² are the same or different and each represents a C 1-6 alkyl group, a hydroxymethyl group, a C 1-6 alkoxymethyl group or a C 1-6 haloalkyl group, and R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, a C1-6 haloalkyl group, an amino group (the amino group is a C1-6 alkyl group or a C1-6 hydroxy group). 1 or 2 may be substituted with an alkyl group), a hydroxyl group, a hydrogen atom or a halogen atom, R ⁷ is a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 hydroxyalkyl group, C1-6 A haloalkyl group, a hydroxyl group or a hydrogen atom; n represents an integer of 1 or 2; The pharmaceutical composition of Claim 7 which is a compound represented by these, its pharmacologically acceptable salt, or ester. The pharmaceutical composition according to claim 8, wherein R ¹ is a C1-3 alkyl group, a hydroxymethyl group, a C1-3 alkoxymethyl group or a C1-3 haloalkyl group. The pharmaceutical composition according to claim 8 or 9, wherein R ¹ is a methyl group. The pharmaceutical composition according to any one of claims 8 to 10, wherein R ² is a hydroxymethyl group. A is the following general formula (A1)

The pharmaceutical composition according to any one of claims 8 to 11. The pharmaceutical composition according to claim 12, wherein R ³ , R ⁴ and R ⁵ are the same or different and each is a hydroxymethyl group, a hydroxyl group or a hydrogen atom. The pharmaceutical composition according to claim 12 or 13, wherein R ⁷ is a hydrogen atom.   The carbohydrate degrading enzyme inhibitor is (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-α-D-glucopyranosyl) -α-D-glucopyranoside, (2R, 3R, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidin-3-yl 4-O- (6-deoxy-β-D-glucopyranosyl) -α-D-glucopyranoside or a pharmacologically acceptable salt thereof The pharmaceutical composition according to any one of claims 1 to 3, which is a salt or an ester.   A pharmaceutical composition characterized by suppressing side effects caused by administration of an insulin sensitizer by combining a carbohydrate degrading enzyme inhibitor and an insulin sensitizer.   The pharmaceutical composition according to claim 16, wherein the side effect is cardiac hypertrophy or heart failure.   The pharmaceutical composition according to claim 16 or 17, wherein the carbohydrate degrading enzyme inhibitor is an α-amylase inhibitor.   The pharmaceutical composition according to claim 16 or 17, wherein the insulin sensitizer is a PPARγ activator. Insulin resistance improving drugs are represented by the following structural formula: pioglitazone, rosiglitazone, MCC-555, BMS-298585, AZ-242, LY-519818, R-483, K-111,

The compound according to any one of claims 16 to 18, which is 5- [4- (6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy) benzyl] thiazolidine-2,4-dione or a pharmacologically acceptable salt thereof. A pharmaceutical composition according to one.   The pharmaceutical composition according to any one of claims 16 to 18, wherein the insulin sensitizer is a thiazolidinedione insulin sensitizer.   The pharmaceutical composition according to any one of claims 16 to 18, wherein the insulin sensitizer is pioglitazone or rosiglitazone.   The pharmaceutical composition according to any one of claims 1 to 22, which is a compounding agent. 23. A pharmaceutical composition according to any one of claims 16 to 22 for administering the active ingredients separately over time.