WO2008032814A1

WO2008032814A1 - Aspirin-containing pharmaceutical agent

Info

Publication number: WO2008032814A1
Application number: PCT/JP2007/067910
Authority: WO
Inventors: Mayumi Watanabe
Original assignee: Mitsubishi Tanabe Pharma Corporation
Priority date: 2006-09-14
Filing date: 2007-09-14
Publication date: 2008-03-20
Also published as: JPWO2008032814A1

Abstract

Disclosed is a pharmaceutical agent effective for the prevention and/or treatment of a disease associated with the formation of a thrombus or embolus or a disease induced by the formation of a thrombus or embolus. The pharmaceutical agent comprises a combination of aspirin and any one of the following compounds (a) to (d): (a) a compound capable of acting on a calcium handling protein to modulate the intracellular calcium level or the rate of change in intracellular calcium level; (b) a compound capable of inhibiting the over-accumulation of a calcium ion in a cell; (c) a compound capable of inhibiting the over-accumulation of a sodium ion in a cell; and (d) an aminobenzenesulfonic acid derivative represented by the general formula (I), a salt thereof, or a hydrate or solvate of the derivative or the salt. (I) wherein R1 represents a C1-C6 alkyl group or the like; R2 represents a hydrogen atom or the like; and n represents an integer of 1 to 4.

Description

Technical field

[0001] The present invention relates to a medicament containing aspirin, particularly a medicament for the prevention and / or treatment of a disease associated with the formation of a thrombus or an embolus or a disease caused by the formation of a blood plug or an embolus.

Background art

[0002] Aspirin is widely used as an antipyretic anti-inflammatory analgesic. This is because aspirin acts on the arachidonic acid cascade and inhibits the production of prostaglandins that play an important role in inflammation by inhibiting the activity of cycloxygenase (COX). In addition, since cycloxygenase (COX) is a thromboxane synthase, the production of thromboxane A2 (TX A2) in platelets is suppressed when the activity of cycloxygenase (COX) is inhibited by aspirin. It is done. Therefore, aspirin is also useful as an antithrombotic drug, and the therapeutic effect of aspirin has already been established in reducing myocardial infarction and ischemic cerebrovascular disease (Patrono, C, N. Engl. J. Med., 330, 1287-1294, 1994).

[0003] On the other hand, aspirin has a function of inhibiting the production of prostacyclin (PGI2) by inhibiting vascular wall cycloxygenase (COX). Since this PGI2 has a vasodilatory action, contrary to TXA2, a thrombus is formed when the production of PGI2 is suppressed by aspirin. That is, aspirin works both in the direction in which the thrombus is not formed and in the direction in which it is formed. Thus, aspirin has two opposing actions. This action characteristic is called “aspirin dilemma” and is a clinical problem. On the other hand, the use of small amounts of aspirin was suggested as one of the solutions of the aspirin dilemma. This is because platelet cycloxygenase is sensitive to aspirin and force, but its inhibition is irreversible, whereas vessel wall cycloxygenase is relatively insensitive to aspirin. The ability to recover the inhibition early, and by giving a small amount of aspirin, selectively inhibit the COX activity of platelets rather than the COX of the blood vessel wall, increase the suppression of TXA2 production, This is to reduce generation suppression. That is, low doses of aspirin give selective platelet C Only generation of TXA2 working OX is inhibited, whereas _c is advantageous in suppressing aggregation of platelets, the general formula (I):

[0004] [Chemical 1]

[0005] (wherein R is a hydrogen atom, C-C alkyl group, C-C cycloalkyl group, C-C

1 1 6 3 7 1 represents a halogenated alkyl group, a halogen atom, or a C C aryl group; R represents water

4 6 12 2 Elementary atom, C—C alkyl group, cyano group, nitro group, C—C alkoxy group, C

1 6 1 6 1 or 2 or more selected from the group consisting of a rogen atom, a C C alkyl group, and an amino group

1 6

Represents an optionally substituted C to C aralkyl group; n represents an integer of 1 to 4

7 12

Aminobenzenesulfonic acid derivatives represented by the above formula show excessive accumulation of intracellular calcium ions in myocardium or vascular smooth muscle (Japanese Patent Laid-Open No. 3-7263) and intracellular sodium ions (see Reference Example 1 below). Inhibition, and calcium / protein handling system of sodium / canoresome (Journal of Cardiac Failure Vol.8 No.5 Suppl.2002, S230; see Reference Example 2 below), and sarcoplasmic reticulum calcium ATPase (J. pharmacology and experimental studies. 298, 1161-1166, 2001), and is known to have an action of regulating intracellular calcium concentration or intracellular calcium concentration change rate. Furthermore, it is known that the aminoamino sulfonic acid derivative of the above general formula (I) has an action of suppressing excessive accumulation of intracellular calcium ions in the myocardium or vascular smooth muscle. Suppresses or reduces myocardial damage, cardiac stimulation conduction disorder, etc. without having an action, / 3 receptor blocker-like action, or calcium channel antagonist-like action, and ischemic heart disease (eg, myocardial infarction, JP-A-3-7263 and JP-A-4-39127 disclose that it can be a useful preventive or therapeutic agent for angina pectoris), heart failure, hypertension or arrhythmia. In addition, JP-A-10-298077 discloses that the compound has the effect of remarkably improving the decrease in cardiac function in the pathology of cardiomyopathy, as well as the effect of improving the survival rate and prolonging life in the long term in sudden cardiomyopathy. Further, International Publication No. WO99 / 40919 discloses that the compound is a myocardial sarcoplasmic reticulum. It has been disclosed that it has an uptake promoting action and is useful for the treatment or prevention of diastolic disorders. However, to the best of the inventors' knowledge, the ability to use such compounds in combination with aspirin has never been reported!

Disclosure of the invention

Problems to be solved by the invention

[0006] The present invention suppresses the dose of aspirin by combining aspirin with a substance that can be used to prevent and / or treat a disease associated with the formation of a thrombus or embolism when used in combination with aspirin. It aims at providing the medicine which can be. Furthermore, in the formation of a thrombus or embolism characterized by the combined use of aspirin and a substance capable of preventing and / or treating a disease associated with the formation of a thrombus or embolism when used in combination with aspirin. Means for solving the problems aimed at providing a method for the prevention and / or treatment of diseases involved

[0007] As a result of diligent efforts to solve the above-mentioned problems, the present inventors have found a compound having an action of regulating intracellular calcium concentration or intracellular calcium concentration change rate by acting on a calcium handling protein on aspirin. When used in combination, the inventors have found that the object of the present invention can be achieved, and have completed the present invention.

[0008] That is, according to the present invention, (1) a pharmaceutical comprising a combination of aspirin and the compound described in any of the following (a) to (d):

(a) a compound having an action of acting on a calcium handling protein to regulate intracellular calcium concentration or intracellular calcium concentration change rate;

(b) a compound having an action of suppressing excessive accumulation of intracellular calcium ions;

(c) a compound having an action of suppressing excessive accumulation of intracellular sodium ions;

(d) The following general formula (I):

[Chemical 2]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6

Represents an optionally substituted C 1 -C 6 aralkyl group; n represents an integer of 1 to 4

7 12

To express. ) Or a salt thereof, or a hydrate or solvate thereof.

[0009] According to a preferred embodiment of the present invention, (2) the above-mentioned medicament wherein the calcium handling protein is a sodium / force lucium exchange system or a sarcoplasmic reticulum calcium ATPase; (3) aspirin and 5 methyl-2 (piperazine 1 (I) a drug according to item (1) or (2) above, which is a combination of benzenesulfonic acid or a salt thereof, or a hydrate or solvate thereof; There is provided a medicine according to the above item (1) or (2), which comprises a combination of (piperazine 1-yl) benzene sulfonic acid monohydrate.

[0010] According to another preferred embodiment of the present invention, (5) any one of the above medicaments for the prevention and / or treatment of a disease associated with the formation of a thrombus or an embolus or a disease caused by the formation of a thrombus or an embolus (6) The medicament according to (5) above, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or embolus is an ischemic disease; and (7) For the formation of a thrombus or embolus The pharmaceutical according to the above item (5), wherein the associated disease or the disease caused by the formation of a thrombus or embolus is heart failure, myocardial infarction, cerebral infarction, angina pectoris, or peripheral artery occlusion.

[0011] Furthermore, according to still another preferred embodiment of the present invention, there is provided (8) the medicament according to any one of items (1) to (4) used as an antithrombotic agent.

[0012] According to another aspect of the present invention, (9) the following general formula (I)

[Chemical 3]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6 1 6

1 or 2 or more selected from the group consisting of a rogen atom, a C C alkyl group, and an amino group

1 6

7 12

An aspirin sulfonic acid derivative or salt thereof, or a hydrate or solvate thereof, an aspirin-enhancing agent for inhibiting platelet aggregation; (10) 5 methyl 2- (piperazine 1 B) Benzenesulfonic acid or a salt thereof, or an enhancer of platelet aggregation inhibitory action of aspirin containing hydrate or solvate thereof; and (11) 5-methyl-2- (piperazine 1yl) benzenesulfonic acid ' Provided is a potentiator of the inhibitory action of aspirin on platelet aggregation including monohydrate.

According to still another aspect of the present invention, there is provided a disease associated with the formation of a thrombus or an embolus, which comprises using (12) aspirin in combination with a compound according to any one of the following (a) to (d): Methods for preventing and / or treating diseases caused by thrombus or embolism formation:

(d) The following general formula (I):

[Chemical 4]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6 1 6

1 6

Represents an optionally substituted C 1 -C 6 aralkyl group; n represents an integer of 1 to 4 To express. ) Or a salt thereof, or a hydrate or solvate thereof.

[0014] According to a preferred embodiment of the present invention, (13) the above method, wherein the calcium handling protein is a sodium / force lucium exchange system or a sarcoplasmic reticulum calcium ATPase; (14) aspirin and 5 methyl-2 (piperazine 1 (I) benzenesulfonic acid or a salt thereof, or a hydrate or solvate thereof in combination, the method according to item (12) or (13) above; (15) aspirin and 5. A method according to item (12) or (13) above, characterized in that it is used in combination with methyl-2 (piperazine 1yl) benzenesulfonic acid monohydrate.

[0015] According to another preferred embodiment of the present invention, (16) from the above item (12), wherein the disease associated with the formation of a thrombus or an embolus or the disease caused by the formation of a thrombus or an embolus is an ischemic disease ( 15)! /, The method according to any one of the above; and (17) a disease associated with the formation of a thrombus or embolus or a disease caused by the formation of a thrombus or embolism is heart failure, myocardial infarction, cerebral infarction, angina A method described in any one of the above items (12) to (15) is provided.

[0016] According to still another preferred embodiment of the present invention, (18) when aspirin is administered to a patient having a chest pain attack, and reperfusion therapy is performed on the same patient, the following (a) to ( Method of preventing and / or treating a disease associated with the formation of a thrombus or an embolus or a disease caused by the formation of a thrombus or an embolus by administering the compound of any one of!

(d) The following general formula (I):

[0017] [Chemical 5]

[0018] (wherein R is a hydrogen atom, a C 1 -C alkyl group, a C—C cycloalkyl group, C—C

1 6

7 12

To express. ) Aminobenzenesulfonic acid derivative or salt thereof, or a hydrate or solvate thereof; (19) The method according to (18) above, wherein the reperfusion therapy is percutaneous coronary artery interpension (20) The method according to (18) or (19) above, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or an embolus is an ischemic disease; and (21) the thrombus Alternatively, in the above item (18) or (19), the disease associated with the formation of an embolus or the disease caused by the formation of a thrombus or embolus is heart failure, myocardial infarction, cerebral infarction, angina pectoris, or peripheral arterial occlusion. A described method is provided.

[0019] According to another aspect of the present invention, an aspirin for the manufacture of a medicament for the prevention and / or treatment of a disease associated with the formation of a thrombus or an embolus or a disease caused by the formation of a thrombus or an embolus and There is provided use of an aminobenzenesulfonic acid derivative represented by the above general formula (I) or a physiologically acceptable salt thereof, or a combination of hydrates or solvates thereof.

In the present specification, for convenience, “medicine containing aspirin” will be described as a representative example. 1S The present invention is not limited to a combination, and the compound described in any one of (a) to (d) above. It is intended that the scope of the present invention also includes the combined use of and.

The invention's effect

[0020] According to the present invention, there is provided a medicament comprising a combination of aspirin and the compound according to any one of (a) to (d). The medicament of the present invention is useful for the prevention and / or treatment of a disease associated with the formation of a thrombus or embolus or a disease caused by the formation of a thrombus or embolus, and the medicament of the present invention uses aspirin for the purpose of inhibiting platelet aggregation. It is useful for the prevention and / or treatment of the diseases used.

Brief Description of Drawings

[0021] FIG. 1 shows the platelet coagulation inhibitory effect of aspirin and caldaret monohydrate. FIG. 2 shows the effect of caldaret monohydrate on the antiplatelet aggregation activity of aspirin. BEST MODE FOR CARRYING OUT THE INVENTION

[0022] The medicament of the present invention contains aspirin (acetyl salicylic acid: CH COOC) as the first active ingredient.

Three

H COOH).

6 4

[0023] The medicament of the present invention contains one of the following forces (a) to (d) as the second active ingredient.

(a) A compound having an action of acting on a calcium handling protein to regulate intracellular calcium concentration or intracellular calcium concentration change rate.

(b) A compound having an action of suppressing excessive accumulation of intracellular calcium ions.

(c) A compound having an action of suppressing excessive accumulation of intracellular sodium ions.

(d) An aminominosulfonic acid derivative represented by the above general formula (I) or a salt thereof, or a hydrate or solvate thereof.

In addition, the enhancer of the present invention includes one of the above (a) to (d)! /.

[0024] The second active ingredient (a) of the medicament of the present invention is particularly a compound that acts on a calcium handling protein and has an action of regulating intracellular calcium concentration or intracellular calcium concentration change rate. Not limited. In this specification, calcium handling protein is a protein selected from the group consisting of voltage-dependent calcium channel, sodium / calcium exchange system, sodium / proton exchange system, cell membrane calcium ATPase, calcium release channel, and sarcoplasmic reticulum calcium ATPase. Say. Of these calcium handling proteins, the present invention! / Is preferred! / As sodium / calcium exchange system (Circ Res., 2001, 88, 864-876), and sarcoplasmic reticulum. Calcium ATPase (Circ Res., 1994, 74, 555-564). The power, power, and ability to control the intracellular calcium concentration or the rate of change in intracellular calcium concentration by the active ingredient acting on the calcium handling protein is the method of publicity, and in the case of 'J. pharmacology and experimental therpeutics. Judgment is made according to the method described in 298, 1161-1166, 2001 and Reference Example 2 of this specification.

[0025] The second active ingredient (b) of the medicament of the present invention is not particularly limited as long as it is a compound having an action of suppressing the excessive accumulation of intracellular calcium ions. Whether it is a compound that suppresses intracellular calcium ion overaccumulation or not is disclosed in Japanese Patent Laid-Open No. 3-7263 and Reference Example 3 shown below. It can be determined according to the method described above.

[0026] The second active ingredient (c) of the medicament of the present invention is not particularly limited as long as it is a compound having an action of suppressing the excessive accumulation of intracellular sodium ions. Whether or not the compound suppresses intracellular sodium ion overaccumulation can be determined according to the method described in Reference Example 2 below.

[0027] The compound represented by the above general formula (I), which is the second active ingredient (d) of the medicament of the present invention, can be mentioned as a substance that enhances the platelet aggregation inhibitory action of aspirin. As shown in the following examples, the compound enhances the platelet aggregation inhibitory action of aspirin, so that the aspirin dose can be kept low by using it together with aspirin. In the above general formula (I), the C C alkyl group defined by R includes, for example, a methyl group, ethyl

1 1 6

Group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butynol group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexynole group, isohexyl group, etc. It is done. The C—C cycloalkyl group includes cyclopropyl

3 7

A pinole group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Examples of the C—C halogenated alkyl group include trifluoromethyl.

14

Group, trifluoroethyl group, pentafluoroethyl group and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. c c

Examples of the 6 12 group include a phenyl group and a naphthyl group.

[0028] Preferred examples of R include a hydrogen atom, a C 1 -C alkyl group, and a C—C cycloalkyl group.

1 1 6 5 6

Group, a trifluoromethyl group, a halogen atom or a phenyl group, and more preferable examples include an alkyl group, a cyclohexyl group, a trifluoromethyl group, chlorine, wherein R is C C

1 1 3

An atom, a bromine atom or a phenyl group can be mentioned, and a methyl group or a propyl group is particularly preferable.

[0029] Examples of the C C alkyl group defined by R include, for example,

2 1 6 1

Examples include an alkyl group. Examples of the aralkyl group of c-c include a benzyl group and a phenol.

7 12

A netyl group, a naphthylmethyl group, etc. are mentioned. The aralkyl group includes a cyano group; a nitro group; a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a tert-pentyloxy group. An alkoxy group of CC, such as a silyl group or a hexyloxy group; a halogen as defined above for R

1 6 1

1 atom selected from the group consisting of an alkyl group and an amino group as defined above for R

1

Has two or more substituents! /, May! /.

[0030] Preferred examples of R include a hydrogen atom; a C 1 -C alkyl group; or a C—C alkyl group.

1 2 or more substitutions selected from 2 1 3 1 3 group, C C alkoxy group and no, rogen atom

13

A C 1 -C 3 aralkyl group which may have a group, more preferably, R is water

7 12 2 Elementary C 1 or 2 or more C 2 -C anoalkoxy groups optionally having C 1 -C 2

1 3 7 12 aralkyl group is exemplified, and a hydrogen atom is particularly preferable. In addition, the above general formula (I

), N is preferably 2.

[0031] Specific examples of the compound represented by the general formula (I) include compounds shown in Tables 1 to 9 below.

[0032] [Table 1]

2]

Table 1 continued Substitution of compound Ri η R ₂

No. position

16 5 — (Ch2) 30H ₃ 2 H

17 5 ― (^ H ₂ ) 4 ^ H ₃ 2 H

丄

18 5 1 (^ Η ₂ ) 5 ^ Η ₃ 2 H

19 6 — CH ₃ 2 H

20 6 ― CH Η 2 H

21 6 ― (CH 2CH 3 2 H

22-Η 2 1 CH ₃

Yes

O O O

23 3 1 Η2 * -Ή ^ 2 — Cé H ₃ ww

24 3 1 Η ₂ ) 2 Η ₃ 2 — CH ₃

25 3 -CH (CH ₃ ) ₂ 2

26 3 — (d ₂ ) 3Cn ₃ 2 — CH ₃

27 4 2

28 4 — GH Η 2 -CH ₃

29 4 - (〇_Ita ₂₎ 2_Rei_ita3 2

30 5 1 CH ₃ 2

31 5 One H H 2 — CH ₃ 3]

Table 1 Continued Replacement of Compound Ri

n R ₂

No. Ri

Position

32 5 1 2) 2 H3 2

33 5 1 CH (CH ₃ ) ₂ 2

○ ο

Ω

34 5 one _{_{(Cn 2) 3Cn 3 2 -CH}} 3

35 5 H ₂ ) 4 H ₃ 2

36 5 one .eta.2) 5_Rei_pai3 2 -CH ₃

37 6 2 — CH ₃

38 6 ― CH2CH3 2 -CH ₃ o

O ○ O

39 6 1 (CH2) 2 H3 2 -CHee ₃ ω ω

40 6 — CH (CH ₃ ) ₂ 2 -CH ₃

41 6 - (Οπ2) 3_Rei_ita ₃ 2

42 3 One (Y ^ 2) 2 3 2 ― (CH2) 20H3

43 4 Η2) 20Η3 2 ― (ΟΗ ₂ ) 2 ^ Η ₃

44 5 2 ― (CH2) 20 H3

45 5 2 — (CH2) 2CH3

46 5 i (tooth ^{π 2) 2 Η3 2 - (} CH2) 2CH 3

47 5 — CH (CH ₃ ) ₂ 2 ― (〇Η2) 20〇Η ₃ Four]

Table 1 continued

Five]

Table 1 continued

6]

Table 1 continued Compound substitution

n R ₂

No. position

_{72 4 2 - (CH 2)} 2 - - CH 3

73 5 One (h ₂ ) 2 ^ H ₃ 2 — CH ₂ —-CH ₃

74 6 One CH (CH ₃ ) ₂ 2 — CH ₂ — — CH ₃

75 3 ― (〇Η2) 2 3 2 — CH ₂ — -CI

76 4 ― (〇Π2) 2〇Η3 2 — CH ₂ — -CI

_{77 5 - (CH 2) 2Cn} 3 2 - CH 2 - -CI

78 6 ― (Cn _2j (2Ch3 2 — CH ₂ — — CI

79 3 (2) 20 0 3 2 — CH ₂ — <-OCH ₃

80 4 ― (CH? 2CH; 3 2

81 5 ― (2) 2 * ^ 3 2 One (CH ₂ ) ₂ --OCH3

82 6 H ₂ ) ₂ CH ₃ 2 — C ₂ — -OCH3

83-H 3 H

84 5 — CH ₃ 3 H 7]

Table 1 continued

[0039] [Table 8] Table 1 continued

[0040] [Table 9] Table 2

(CH ₂ ) _n

, S0 ₃ H · HCI

Acid

Acid;

Among the compounds listed in Tables 1 to 9, a more preferable compound is that R is substituted at the 5-position.

1

And specific examples include the following compounds.

5-Methyl-2- (piperazine 1

5-Trifluoromethyl-2- (piperazine 1

5- -n Propinole 2— (piperazine

One 1

5--Phenenole 2- (piperazine 1-inore) acid;

5-Chloro-2- (piperazine 1-inore) betic acid;

5-Bromo-2- (piperazine 1-inore) betic acid;

5- -i _S0 propyl 1- (piperazine 1-yl)

5-Cyclohexinole 2- (piperazine 1-inore)

5- -n Propinole 1- (Homopiperazine 1-yl)

5- -n Propyl 2- [4— (2, 3, 4 Trimethoxy 7- Nore] benzene sulfonic acid;

5— n Propinole 2— [4— (3,4 Dimethoxybenzyl) 1 piperazine 1—yl] Benzenorephonic acid

Among the above compounds, particularly preferred examples include 5-methyl-2- (piperazine 1yl) benzenesulfonic acid and 5-n-propyl2 (piperazine 1yl) benzenesulfonic acid.

[0043] In addition, pharmaceutically acceptable salts of the compounds listed above are also included in the scope of the present invention. In addition to salts and free form compounds, any hydrate or solvate of these may be used as the active ingredient of the medicament of the present invention.

[0044] As the second active ingredient of the medicament of the present invention, 5-methyl-2- (piperazine-1-yl) benzenesulfonic acid monohydrate is most preferable.

[0045] The aminobenzenesulfonic acid derivative represented by the above general formula (I) is a known compound, for example, Japanese Patent Application Nos. 3-7263 and 9 221479, European Patent Application Publications. It is a compound that can be easily synthesized by methods described in Japanese Patent Publication Nos. 390654 and 779283, US Patent Publication Nos. 5053409 and 5990113, and can be easily obtained by those skilled in the art.

[0046] The form of the medicament of the present invention is not particularly limited and can take various forms available to those skilled in the art, and can be administered orally or parenterally. Examples of the dosage form for oral administration include granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids. Examples of the dosage form for parenteral administration include injections, suppositories, and transdermal agents.

[0047] In the above dosage form, the active ingredient is a commonly used pharmaceutical additive such as a solid or liquid pharmaceutical carrier or excipient, stabilizer, lubricant, sweetener, preservative, suspending agent, etc. The content of the therapeutically or prophylactically active ingredient with respect to the carrier ingredient is preferably in the range of 1% by weight to 90% by weight! /.

[0048] Examples of solid components used include lactose, white clay, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, sodium chloride and the like. . Examples of liquid carriers are syrup, glycerin , Peanut oil, polybutylpyrrolidone, olive oil, ethanol, benzyl alcohol, propylene glycol, water and the like.

[0049] The dose may be appropriately determined for each active ingredient in consideration of the patient's symptoms, weight, age, sex, etc., but the first active ingredient aspirin is 0.01 to 1000 mg / kg body weight, the second active ingredient is 5-methyl-2 (piperazine 1 yl) benzenesulfonic acid 'monohydrate as a representative example, ; 1000 mg / kg body weight can be administered 1 to several times a day.

[0050] The medicament of the present invention is effective as an antithrombotic drug because it has a platelet aggregation inhibitory action and can prevent thrombus formation. Therefore, the medicament of the present invention is a disease associated with the formation of a thrombus or an embolus or a disease caused by the formation of a thrombus or an embolus, such as an ischemic disease, more specifically heart failure, myocardial infarction, cerebral infarction, angina pectoris, It is effective for the prevention and / or treatment of diseases selected from the group consisting of arteriosclerosis and peripheral arterial occlusion.

Further, since the medicament of the present invention can enhance the platelet aggregation inhibitory action of aspirin, diseases using aspirin for the purpose of inhibiting platelet aggregation, such as heart failure, myocardial infarction, cerebral infarction, angina pectoris, arteriosclerosis, Aspirin used in combination with prevention and / or treatment of a disease selected from the group consisting of peripheral arterial occlusions can enhance the effect of prevention and / or treatment of the disease. Furthermore, it is effective for the treatment of the above-mentioned diseases in which reperfusion therapy (coronary artery bypass, percutaneous coronary intervention, thrombolysis, etc.) is performed.

[0051] The administration route of the medicament of the present invention is not particularly limited, and can be administered orally or parenterally. For example, the medicament of the present invention can be orally administered prophylactically to prevent the onset of the above-mentioned diseases, and can be administered prophylactically during or before surgery by parenteral administration such as injection or infusion. You can also. In addition, it can be administered to a patient who has developed the above diseases by injection into a vein, artery or heart for the purpose of preventing the deterioration of the symptoms or reducing the symptoms.

[0052] The dosage form of the medicament of the present invention is not particularly limited, and aspirin, which is the first active ingredient, and the second active ingredient are combined at the time of administration! Examples of such dosage forms include (1) administration of a single preparation obtained by simultaneously formulating the first active ingredient and the second active ingredient, and (2) first active ingredient and the second active ingredient. Obtained by separately formulating the active ingredients of (3) Sequential administration of two preparations obtained by separate formulation of the first active ingredient and the second active ingredient through the same administration route (4) Simultaneous administration of two different preparations obtained by separately formulating the first active ingredient and the second active ingredient through different administration routes, (5) First active ingredient and second active ingredient There are two types of preparations obtained by formulating the active ingredient separately and sequential administration by different administration routes. In the case of sequential administration, the first active ingredient and the second active ingredient may be administered in any order. Specifically, it is exemplified that the first active ingredient and the second active ingredient are separately used as oral preparations such as tablets, and the oral preparations are administered simultaneously or sequentially.

[0053] The "combination" medicament of the present invention refers to a medicament having a dosage form in which the first active ingredient aspirin and the second active ingredient compound are combined, and from the above (1) Including the case according to the administration form (5).

Similarly, in the method of the present invention, the term “used in combination” includes the cases of the above-mentioned application forms (1) to (5).

Example

[0054] Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples.

The compound shown in the following examples is 5 methyl-2 (piperazine 1yl) benzenesulfonic acid monohydrate (hereinafter referred to as caldaret monohydrate).

A product produced according to the method described in Example 1 of 9-221479 was used.

[0055] Example 1

(experimental method)

Male Sprague-Dawley rats (SLC Japan) weighing 262.8-299.6 g were used. The animals were fasted for 16 hours before the experiment.

After puncturing the abdominal aorta of an ether-anesthetized rat, a blood sample was collected in a 3.8% sodium citrate solution (0.1 volume of blood). Platelet-rich plasma (PRP) is obtained by centrifugation (using HITACHI, SCT5BA) at room temperature for 15 minutes at room temperature. Platelet-poor plasma (PPP) is obtained at room temperature. Obtained by centrifugation at 3000 rpm for 10 minutes. The experiment used 30 rats and one PRP sample was Contains PRP accumulated from 5 rats.

[0056] the platelet suspension (PRP samples), aspirin 3 X 10- ⁵ M dissolved in methanol, 1

It was added to a final concentration of ^{X 10- 4 M, 3 X 10-} 4 M. To this solution was added at a final concentration of ion-exchanged water only (Behiku Honoré), or Karudaretto monohydrate dissolved in deionized water ^{1 X 10- 1Q M, 1 X} 10_ 8 M, 1 X 10- 6 M It was. 100 μl of the above-mentioned platelet suspension (PRP sample) mixed with drug (caldaret monohydrate) or vehicle is incubated for 1 minute at 37 ° C with constant stirring. Induced by adding. Taking into account the potential difference in reactivity to collagen in the samples, the minimum collagen concentration that exhibited the maximum platelet aggregation response was measured for each PRP sample. Platelet aggregation is determined by HEMA TRACER 801 (MC MEDICAL) according to the turbidimetric method (Bom, GVR, Cross, MJ., J. Physiol., 168, 178-195, 1963). The product was monitored for 6 minutes after collagen stimulation. PPP was used as a blank.

[0057] The degree of aggregation was expressed as a percentage of the maximum aggregation amplitude. The results were expressed as the inhibition rate (%) of collagen-induced aggregation according to the following formula.

Percent inhibition (%) = Maximum aggregation amplitude of control Maximum aggregation amplitude of drug / maximum aggregation amplitude of control

X 100

The effect of the drug (MCC-135) was analyzed by 95% confidence interval (95% C. I). All data are expressed as mean soil standard error (MEAN soil SEM).

[0058] (Experimental result)

Figure 1 shows the platelet aggregation inhibitory effect of aspirin and caldaret monohydrate. Aspirin alone had a dose-dependent inhibitory effect on collagen-induced platelet aggregation, whereas caldaret monohydrate alone had no such inhibitory effect (Fig. 1). .

Figure 2 shows the effect of caldaret monohydrate on the antiplatelet aggregation activity of aspirin. Caldaret monohydrate improved the antiplatelet aggregation activity of aspirin (Figure 2). Hand, Karudaretto monohydrate has been to improve the low concentrations of aspirin ^{(3 X 10- 5 M, 1} X 10- 4 M) of the anti-platelet aggregation activity, higher concentrations of aspirin (3 X 10- ^{In 4} M), the activity was not improved (Table 10). This result shows that caldaret monohydrate has a blood serum of aspirin. It has the effect of enhancing the ability to suppress plate aggregation, suggesting that the use of caldaret monohydrate in combination can reduce the dose of aspirin.

[Table 10]

[0060] Reference Example 1 Evaluation method of compounds that suppress increase in sodium ion content in cardiomyocytes (Experimental method)

The rat heart was removed and Krebs buffer (in mM; NaCl 119, C1 4.6, MgSO-7H O 1.2, CaCl-2H O 1.3, NaHCO 25, H PO 1.2, g) according to the Langendorff method.

4 2 2 2 3 2 4 Lucose 11; Perfused at pH 7.4, 37 (C). A thread was sewn to the apex, and the end was connected to a tension transducer to measure the contraction tension. After stabilizing the specimen, myocardial ischemia was induced by reducing the perfusion pressure (45 minutes). After 30 minutes of reperfusion, the heart was thawed in nitric acid and the total sodium content of the ventricles was measured by atomic absorption spectrometry. The contraction tension was measured throughout the experiment, and the recovery rate of the contraction tension at 30 minutes after reperfusion with respect to the contraction tension at the start of the experiment was used as an index of cardiac contractility.

[0061] (Result)

The results are shown in Table 11 below. In the table, ** indicates P is less than 0.01 by Dunnett's multiple comparison test for control, ** indicates P is less than 0.001 by Dunnet's multiple comparison test for control, and # # is , P by normal t-test is less than 0.01, # # # indicates P by normal t-test is less than 0.001.

In the ischemia / reperfusion heart (control), an increase in total ventricular sodium content (sodium overload) and a decrease in contractile tension recovery rate were observed compared to the normal heart. When the compound of the present invention was added to the reperfusion solution, the increase in ventricular sodium content caused by ischemia reperfusion was suppressed, and the decrease in contractile tension recovery rate was improved. Amiguchi Ride (Amil ₀ ride, sodium 'proton exchange inhibitor, purchased from Sigma) improved the decrease in systolic tension recovery at high doses, but did not affect the increase in ventricular sodium content.

[0062] [Table 11]

[0063] From the above results, it was shown that caldaret monohydrate is effective in suppressing the increase in sodium ion content in cardiomyocytes induced by ischemia / reperfusion.

[0064] Reference Example 2 Evaluation method of compound that suppresses increase in calcium content in cardiomyocytes

(experimental method)

The rat heart is removed and the Kreps buffer (in mM; NaCl 119, C1 4.6, MgSO · 7Η O 1.2, CaCl-2H O 1.3, NaHCO 25, KH PO 1.2, glucose according to the Langendorff method.

4 2 2 2 3 2 4

11; Perfusion was performed at pH 7.4 and 37 (C). A thread was sewed to the apex, and the end was connected to a tension transducer to measure the contraction tension. Contains monensin (5 M; sodium ionophore) After 10 minutes of perfusion with murine perfusate, ischemia was induced by reducing the coronary perfusion rate to 0 (15 minutes). After 30 minutes of reperfusion, the heart was thawed in nitric acid, and the total calcium content of the ventricle was measured by absorption analysis of raw paper. The contraction tension was measured throughout the experiment, and the recovery rate of the contraction tension at 30 minutes after reperfusion with respect to the contraction tension at the start of the experiment was used as an index of cardiac contractility.

[0065] (Result)

The results are shown in Table 12 below. In the table, ** indicates P is less than 0.01 by Dunnet's multiple comparison test for control, and ** indicates P is less than 0.001 by Dunnet's multiple comparison test for control.

In the heart combined with monensin treatment and ischemia / reperfusion (control), an increase in ventricular total calcium content and a decrease in the recovery rate of contractile tension were observed compared to the normal perfused heart (normal). The increased calcium content here was dependent on intracellular sodium, and therefore was thought to have flowed through the sodium-calcium exchange system. In addition, the decrease in the recovery rate of shrinkage tension was small in the absence of monensin, so it was considered to be a change associated with an increase in calcium content. The compound of the present invention improved the increase in ventricular calcium content and the decrease in contraction tension recovery rate caused by monensin treatment and ischemia reperfusion. Diltiazem (Diltiazem, calcium antagonist, purchased from Sigma) and Amiguchi Ride did not show these effects.

[0066] [Table 12]

The medicament of the present invention is useful for the prevention and / or treatment of diseases in which aspirin is used for the purpose of inhibiting platelet aggregation.

This application is based on Japanese Patent Application No. 2006-248890 filed in Japan, the contents of which are incorporated in full herein.

Claims

A pharmaceutical comprising a combination of aspirin and the following compounds (a) to (d): (a) a calcium handling protein acting on a calcium handling protein or an intracellular calcium concentration (B) a compound having an action of suppressing intracellular calcium ion overaccumulation; (c) a compound having an action of inhibiting intracellular sodium ion overaccumulation; The following general formula (I):

[Chemical 1]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6

7 12

To express. Or a salt thereof, or a hydrate or solvate thereof.

[2] Calcium handling protein is sodium / calcium exchange system or sarcoplasmic reticulum calcium

The medicament according to claim 1, which is an ATPase.

[3] The medicament according to claim 1 or 2, wherein aspirin is combined with 5 methyl-2 (piperazine 1yl) benzenesulfonic acid or a salt thereof, or a hydrate or solvate thereof.

[4] The medicament according to claim 1 or 2, comprising a combination of aspirin and 5-methyl-2- (piperazine 1yl) benzenesulfonic acid 'monohydrate.

[5] The medicament according to any one of claims 1 to 4, for the prevention and / or treatment of a disease associated with the formation of a thrombus or embolus or a disease caused by the formation of a thrombus or embolus.

6. The medicament according to claim 5, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or embolus is an ischemic disease.

[7] The disease according to claim 5, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or embolus is heart failure, myocardial infarction, cerebral infarction, angina pectoris, or peripheral artery occlusion. Medicine.

[8] The medicament according to any one of claims 1 to 4, which is used as an antithrombotic agent.

[9] The following general formula (I)

[Chemical 2]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6

7 12

An aspirin sulfonic acid derivative or a salt thereof, or a hydrate or solvate thereof, an aspirin-enhancing agent for inhibiting platelet aggregation.

[10] An enhancer of platelet aggregation inhibitory action of aspirin containing 5-methyl-2- (piperazine 1yl) benzenesulfonic acid or a salt thereof, or a hydrate or solvate thereof.

[11] 5 Methyl-2- (piperazine 1yl) benzenesulfonic acid 'Enhancer of platelet aggregation inhibitory action of aspirin containing monohydrate.

[12] Aspirin and the following (a) to (d) !, or a compound described in any one of the above, are used in combination with a disease associated with the formation of a thrombus or embolism or the formation of a thrombus or embolism Methods for preventing and / or treating diseases:

(b) a compound having an action of suppressing excessive accumulation of intracellular calcium ions; (c) a compound having an action of suppressing excessive accumulation of intracellular sodium ions;

(d) The following general formula (I):

[Chemical 3]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6

7 12

To express. Or a salt thereof, or a hydrate or solvate thereof.

[13] calcium handling protein is sodium / calcium exchange system or sarcoplasmic reticulum;

13. The method according to claim 12, which is an ATPase.

[14] Aspirin and 5-methyl 2- (piperazine 1-

14. The method according to claim 12 or 13, wherein a salt or a hydrate or solvate thereof is used in combination.

[15] The method according to claim 12 or 13, wherein aspirin and 5 methyl-2 (piperazine 1yl) benzenesulfonic acid monohydrate are used in combination.

16. The method according to any one of claims 12 to 15, wherein the disease associated with the formation of a thrombus or an embolus or the disease caused by the formation of a thrombus or an embolus is an ischemic disease.

[17] The disease according to any one of claims 12 to 15, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or embolus is heart failure, myocardial infarction, cerebral infarction, angina pectoris, or peripheral arterial occlusion. The method according to any one of the above.

[18] Administer aspirin to a patient with chest pain, and administer the following compounds (a) to (d): Prevent and prevent diseases associated with thrombus or embolism formation or diseases caused by thrombus or embolism formation / Or how to treat:

(d) The following general formula (I):

[Chemical 4]

(Where R is a hydrogen atom, a C-C alkyl group, a C-C cycloalkyl group, a C-C

1 6

7 12

To express. Or a salt thereof, or a hydrate or solvate thereof.

[19] The method according to claim 18, wherein the reperfusion therapy is percutaneous coronary intervention.

20. The method according to claim 18 or 19, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or embolus is an ischemic disease.

[21] The disease according to claim 18 or 19, wherein the disease associated with the formation of a thrombus or embolus or the disease caused by the formation of a thrombus or embolus is heart failure, myocardial infarction, cerebral infarction, angina pectoris, or peripheral arterial occlusion. The method according to any one of the above.