WO2004022545A1

WO2004022545A1 - Protective agents for transplanted organ

Info

Publication number: WO2004022545A1
Application number: PCT/JP2003/011372
Authority: WO
Inventors: Daisuke Wakatsuki; Mayumi Watanabe; Naoya Satou
Original assignee: Mitsubishi Pharma Corporation
Priority date: 2002-09-06
Filing date: 2003-09-05
Publication date: 2004-03-18
Also published as: AU2003261968A1; JPWO2004022545A1

Abstract

It is intended to provide a novel protective agent for a transplanted organ and an agent of inhibiting ischemic reperfusion injury following organ transplantation which contain as the active ingredient an aminobenzenesulfonic acid derivative represented by the following general formula, its salt or a hydrate or a solvent of the same: (I) wherein R1 represents hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C1-4 haloalkyl, halogeno or C6-12 aryl; R2 represents hydrogen, C1-6 alkyl or C7-12 aralkyl optionally having one or more substituents selected from the group consisting of cyano, nitro, C1-6 alkoxy, halogeno, C1-6 alkyl and amino; and n is an integer of from 1 to 4.

Description

Technical field

The present invention relates to an agent for protecting a transplanted organ containing an amino diamine sulfonic acid derivative or a salt thereof, or a hydrate or solvate thereof as an active ingredient, and an agent for suppressing ischemia-reperfusion injury after organ transplantation.

Rice field

Background art

An organ for transplantation obtained from an organ donor (donor) for an organ transplant operation is in a state where blood flow is interrupted and oxygen is not supplied via blood flow (ischemic state), and it takes several minutes to transplant. Stored for 10 hours. For this reason, if the storage conditions such as storage temperature and storage solution are not properly selected, or if it takes a long time before transplantation, the transplantation can be performed when the blood flow in the transplanted organ is restored (at the time of reperfusion). Stromal or functional damage to organs may occur. For example, in heart transplantation, acute heart failure may be observed after transplantation. Such an injury is generally called post-ischemia reperfusion injury of the transplanted organ.

In order to preserve the organ for transplantation in a physiological state, a method of cooling and saving the transplanted organ in a preservation solution has been adopted. Conventionally, as a preservation solution for organs for transplantation, it has been used for Euro 'Collins Hydraulic S! A new preservation solution, UW solution, was developed in 1987, and it has been reported that the preservation time of organs for transplantation can be dramatically extended (Wahlberg, JA, et al., Ransplantation, 43, pp. .5—8, 1987, Kalayoglu, M., et al., Lancet,

19, pp. 617-619, 1988, Jamieson, N.V., Transplantation, 46, pp. 517-522, 1988). Meanwhile, an aminobenzenesulfonic acid derivative having an action of suppressing the excessive accumulation of intracellular calcium ions in cardiac muscle or vascular smooth muscle is known (JP-A-3-7263). These compounds suppress or reduce cardiomyopathy, cardiac stimulus conduction disorder, etc. without having a / 3 receptor stimulant-like action, a receptor blocker-like action, or a calcium channel antagonist-like action. It is disclosed that it can be a useful prophylactic or therapeutic agent for ischemic heart disease (for example, myocardial infarction, angina pectoris, etc.), heart failure, hypertension, arrhythmia, etc. (JP-A-3-7263 (US Japanese Patent Publication No. 5053 409, European Patent Application Publication No. 390654) and Japanese Patent Application Laid-Open No. 4-139127). Japanese Patent Application Laid-Open No. 10-298077 discloses that the compound has an effect of remarkably improving cardiac function deterioration under cardiomyopathy pathological conditions, and also improves long-term survival rate and prolongs life in sudden cardiomyopathy. The ability to have an effect S. Further, International Publication No. WO 99/40919 states that the compound has a calcium ion uptake-promoting action in cardiac sarcoplasmic reticulum, and is useful for treating or preventing diastolic dysfunction. It is disclosed that there is.

However, these publications do not disclose at all whether or not the compound is effective as an agent for protecting organs for transplantation or an agent for suppressing ischemia / reperfusion injury after organ transplantation.

The present invention provides an agent for protecting a transplanted organ containing an aminoaminosulfonic acid derivative or a salt thereof, or a hydrate or solvate thereof as an active ingredient, and an agent for suppressing ischemia-reperfusion injury after organ transplantation. It is an object. Disclosure of the invention

The present inventors have made intensive efforts to solve the above-mentioned problems, and as a result, a specific amino benzene sulfonic acid derivative, a salt thereof, a hydrate or a solvate thereof has been used as a transplant organ protecting agent, and a hypothesis after organ transplantation. They have found that they are useful as agents for suppressing blood reperfusion injury, and have completed the present invention.

That is, the gist of the present invention is represented by the following general formula (I)

(Wherein, R _sigma is a hydrogen atom, an alkyl group of E one C _s, C ₃ -. Cycloalkyl Le group C _7, a halogenated alkyl group having one C _4, a halogen atom, or a C _s - C _{1 2} of § Represents a reel group; R ₂ is a hydrogen atom, a Ci—Cs alkyl group, or a cyano group, a nitro group, a C ₂ -C ₆ alkoxy group, a halogen atom, a C ₆ alkyl group, and an amino group A C ₇ —C ₁₂ aralkyl group optionally having one or more substituents selected from the group; n represents an integer of 1 to 4) Or a salt thereof, or a hydrate or solvate thereof as an active ingredient in a transplant organ protecting agent.

Preferable embodiments of the present invention ^{: In} a preferred embodiment, the transplant organ protecting agent is in the form of a preservation solution of the transplanted organ, and the transplanted organ is a heart. I can fist.

Further, according to another aspect of the present invention, it is an agent for suppressing ischemia-reperfusion injury after organ transplantation, which contains the above-described aminobenzenesulfonic acid derivative or the like as an active ingredient.

In this case, a preferable embodiment is that the agent for suppressing ischemia / reperfusion injury after organ transplantation is in the form of a preparation for intravascular administration; for administration immediately before reperfusion after ischemia, and The ischemia-reperfusion injury inhibitor after organ transplantation to be administered to an individual; the ischemia-reperfusion injury inhibitor after organ transplantation is in the form of an organ preservation solution; and the organ is a heart. It is mentioned that it is. BRIEF DESCRIPTION OF THE FIGURES

Fig. 1 shows LVSP when the heart was left standing in St. Thomas' II cardioplegic solution for 10 hours, reattached to Langendorff apparatus, and reperfused with Tyrode Buffer. Figure 2 shows the + dP / dt and -dP / dt when the heart was stored in St. Thomas' II cardioplegic solution for 10 hours, reattached to the Langendorff apparatus, and reperfused with Tyrode Buffer. FIG. BEST MODE FOR CARRYING OUT THE INVENTION

Examples of the active ingredient of the drug of the present invention include the amino benzene sulfonic acid derivative represented by the above general formula (I) or a salt thereof, or a hydrate or a solvate thereof. In the general formula (I), as defined by ^ § alkyl group one C ₆ in 1 ^, for example, a methyl group, Echiru group, propyl group, isopropyl, Bunanore, Isofunanore, sec- Buchinore group, tert- Puchinore Group, pentinole group, isopentyl group, neopentyl group, tert-pentinole group, hexyl group, and isohexyl group. Examples of the C ₃ -C ₇ cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like. Examples of the C ₄ -C ₄ halogenated alkyl group include a trifluoromethyl group, a trifluoroethyl group, a pentafluoroethyl group and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom. Examples of the C ₆ —C ₁₂ aryl group include a phenyl group and a naphthyl group.

As 1 ^ preferred example, a hydrogen atom, an alkyl group of C one C _6, C ₅ - C _s of shea click port alkyl group, triflate Ruo Russia methyl group, and a halogen atom or a phenyl group, a more preferred example, R, is —C ₃ alkyl group, cyclohexyl group, trifluoromethyl group, chlorine atom, bromine atom or phenyl group, and particularly preferably methyl group or propyl group.

The C—C s alkyl group defined for R ₂ includes, for example, the alkyl group defined for 1 ^ above. Examples of the aralkyl group of c _{7 to} c ₁₂ include a benzyl group, a phenethyl group, a naphthylmethyl group and the like. This aralkyl group includes a cyano group; a nitro group; a methoxy group, an ethoxy group, and a propoxy group. Alkoxy groups of C ₆ such as a group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, tert-pentyloxy group, hexyloxy group, etc .; Such a halogen atom; and may have one or more substituents selected from the group consisting of an alkyl group and an amino group as defined above.

Preferred examples of R ₂ include a hydrogen atom, an alkyl group of ^ _-3 , and Alkyl group E _ C _3, Ji is 1 or 2 or more may have a substituent C _{7 2} of Ararukiru group selected from an alkoxy group and a halogen atom one C _3, as a preferred example further includes R ₂ is a hydrogen atom or a C ₇ -C ₁₂ aralkyl group which may be substituted by one or more ^ -C ₃ alkoxy groups, and particularly preferably a hydrogen atom.

In the general formula (I), n is preferably 2.

Preferred specific examples of the present invention include the compounds shown in Tables 1 and 2 below.

table 1

Compound S Replacement of Ri

No. Position Ri R ₂

1-H 2 H

2 3 -CH ₃ 2 H

3 3 ― CH2CH3 2 H

4 3 1 CH2CH2CH3 2 H

5 3 -CH (CH ₃ ) ₂ 2 H

6 3 1 (CH2) 3〇H3 2 H

7 4 1 CH ₃ 2 H

8 4 1 CH2CH3 2 H

9 4 1 (〇Η2) 2〇Η3 2 H

10 4 One CH (CH ₃ ) ₂ 2 H

1 1 4 1 H2) 3 H3 2 H

12 5 1 CH ₃ 2 H

13 5 one

2 H

14 5 one (〇Η2) 2. Η3 2 H

15 5 — CH (CH ₃ ) ₂ 2 H Continued

Table 1 Continued Les A Kl \ JJ good 5 良

No. Ri n R ₂

Position

32 5 1Η2) 2〇Η3 2 -CH ₃

33 5 -CH (CH ₃ ) ₂ 2

34 5 one (〇) 3 ^ 3 2 ~ CH ₃

35 5 1 (CH24CH3 2 -CH ₃

36 5 One (CH2) 5 CH3 2 -CH ₃

37 6 -CH3 2 -CH ₃

38 6 1 CH3 2 -〇CH ₃

〇〇

39 6 ― (〇Η ₂ ) 2 3 2 -CH ₃

40 6 -CH (CH ₃ ) ₂ 2 -CH ₃

41 6 One (CH23Ch3 2

42 3 One (CH? 2CH3 2 One (CH2) 2〇H3

43 4 Η2) 2〇Η3 2 1 (CHs CHs

44 5 — CH ₃ 2 1 (CH ₂ ) 2 CH ₃

45 5 one Cri H3 2 one (ΟΗ2) 2〇Η3

46 5 one (〇) 2〇 2 one (〇Η2) 2〇Η3

47 5 One CH (CH ₃ ) ₂ 2 One (CHs CHs Table 1 continued

Table 1 continued

Table 1 continued

Table 1 Continued Compound Substitution

No. Position Ri n R ₂

85 5 1 CH2CH3 3 H

86 5 3 H 1 (〇Η2) 2〇Η3

87 5 One CH (CH ₃ ) ₂ 3 H

88 5 1 H2) 2 H3 3 H

89 5 One (CH2) 2 CH3 3

90 5 1 (〇Η2) 2 3

O 〇

91 5 2 H w

92 5 — F 2 H

93 5-CI 2 H

94 5 1 Br 2 H

95 5 One CF ₃ 2 H

96 2 H

Five

97 5 2 H

98 5 2 1 CH ₃

99 5-CI 2

Table 2

In Tables 1 and 2 above, a compound in which the substitution position of at position 5 is preferred,

: Preferred compounds include the following compounds.

5-Methinole 2- (1-piperazinyl) benzenesnorenoic acid;

5-triphnorelolomethyl-2_ (1-piperazinyl) benzenesulfonic acid;

'5-n-propyl-2- (1-piperazinyl) benzenesulfonic acid; 5-phenyl-1- (1-pirazuranole) benzenesnolephonic acid;

5- (1-piperazinyl) benzenesulfonic acid;

5-promo 21- (1-pirazolene) benzenesnolefonic acid;

5—iso_propyl—2— (1-piperazul) benzenesulfonic acid; 5-cyclohexynole-1- (1-piperazinyl) benzenesulfonic acid; 5-n-propyl-1-2- (1-homopiperazini) Nore) benzenesulfonic acid; 5—n—propyl — 2— [4- (2,3,4-trimethoxybenzyl) -11-piperazinyl] benzenesulfonic acid;

5-n-Propyl-2- (4- (3,4-dimethoxybenzyl) _1-piperazinole) Benzenesulfonic acid

Of the above compounds, particularly preferred examples include 5-methyl-2- (1-piperazinyl) benzenesulfonic acid and 5-n-propyl-2 -_ (1-piperazinyl) benzenesulfonic acid.

Also, pharmaceutically acceptable salts of the compounds mentioned above are included in the scope of the present invention. Salts of the above compounds include, for example, alkali metal salts such as sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt or alkaline earth metal salt; lower alkylamine salts such as ammonium salt, triethylamine salt and the like; Hydroxy lower alkylamine salts such as 2-hydroxyl, bis- (2-hydroxyl) amine, tris (hydroxymethyl) aminomethane, N-methyl-D-glucamine, dicyclohexylamine, etc. Salts of cycloanolequinoleamine, such as N, N-dibenzylinoleethylenediamine, and other amine salts such as dibenzylamine; hydrochlorides, hydrobromides, sulfates, and phosphates And inorganic salts such as fumarate, succinate, oxalate and lactate. I can do it.

In addition, any hydrate or solvate thereof may be used as an active ingredient of the medicament of the present invention, in addition to a salt or a compound in a free form. Examples of the solvent that can form a solvate of the above compound include methanol, ethanol, isopropyl alcohol, acetone, ethyl acetate, and methylene chloride.

The most preferred active ingredient of the medicament of the present invention is 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate.

The amino benzene sulfonic acid derivative represented by the above general formula (I) is a known compound, and is disclosed in, for example, Japanese Patent Application Laid-Open Nos. 3-7263 and 91-221479, European Patent Application Publication Nos. 39 06 5 54 and 77 9 28 3 and the United States It is a compound that can be easily synthesized by the methods described in Patent Publication Nos. 5,530,409 and 5,990,113 and the like and can be easily obtained by those skilled in the art. The agent for suppressing ischemia / reperfusion injury after organ transplantation of the present invention is administered to a recipient, for example, during transplantation surgery and / or before and / or after transplantation of the recipient, and is preferably transplanted to the recipient. Administer immediately before blood flow is restored to the heart (reperfusion after ischemia). The route of administration of the above drug is not particularly limited, and it can be administered orally or parenterally. In general, parenteral intravascular administration is preferred. It is not necessary to administer to the donor before, during, or during surgery to remove the organ for transplantation from the organ donor, but it does not preclude administration to the donor.

Dosage forms for oral administration include granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or solutions, and the like. In addition, dosage forms for parenteral administration include injections, suppositories, and transdermals.

The active ingredient of the medicament of the present invention is commonly used in the above dosage forms such as solid or liquid pharmaceutical carriers or excipients, stabilizers, lubricants, sweeteners, preservatives, suspending agents and the like. It is contained together with a pharmaceutical additive, and the content of the therapeutically or prophylactically active ingredient in the carrier component is preferably in the range of 1% by weight to 90% by weight.

Examples of solid components used include lactose, porcelain clay, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, acacia, stearic acid, magnesium stearate, lecithin, sodium salt and sodium salt. Can be Examples of the liquid carrier include syrup, glycerin, peanut oil, polyvinylpyrrolidone, olive oil, ethanolace, benzyl realcone, propylene glycolone, and water.

The dose of the medicament of the present invention to be used as an active ingredient is appropriately determined for each active ingredient in consideration of the condition and size of the organ to be transplanted, the condition of the patient (transplanter, non-transplanter), weight, age, sex, and the like. The compound represented by the above general formula (I) is a typical example. Usually, about 0.01 mg to 1000 mg can be administered orally per day for an adult. It is advisable to administer such a dosage in one or several divided doses per day.

Another preferred form of the medicament of the present invention is a form of a preservative solution. In this case, the content of the active ingredient should be determined for each active ingredient as appropriate, taking into account the condition and size of the organ to be transplanted, the symptoms of the patient (transplanter, non-transplant recipient), weight, age, sex, etc. good, when a representative example the compound represented by the above formula (I), it is preferably 1 0 one ⁹ ~ 10- ⁴ M. As the additive, for example, physiologically acceptable buffers such as physiological saline, phosphate buffered saline, and citrate buffer and isotonic solutions can be used. According to the present invention, Euro-Collins solution which has been clinically used as a preservation solution for organs for transplantation (contains the following composition in 100 ml of final preparation solution: 740 mg of hydrogen phosphate monophosphate; phosphorus It is commercially available as dihydrogen acid phosphate 205 mg; chloride chloride 112 mg; sodium bicarbonate 84 mg; and glucose 3.5 g) and UW solution (for example, “Biaspan”). Includes composition: 50 g of pentafraction; 35.83 g of lactobionic acid; 3.4 g of potassium dihydrogen phosphate; 1.23 g of magnesium sulfate; 17.83 g of raffinose; 1.34 g of adenosine; 0.136 g of aloprinol; 0.922 g of reduced daltathione; potassium hydroxide , An appropriate amount; sodium hydroxide, adjusted to pH 7.4). Further, glycine, ketoglutamic acid, hydroxyshethyl starch and the like can be added. The concentration of the active ingredient is not particularly limited, but in the case of glycine or hyketoglutamic acid, it is generally in the range of about 0.1 to 10 mM, preferably about 2πιΜ, and in the case of hydroxyxethyl starch, Generally, it is in the range of about 3 to 7.5%, preferably about 5.

In general, the removed organ for transplantation may be immersed in the preservation solution of the above embodiment, and stored preferably at about 4 ° C. until transplantation. It is preferable to immerse the transplanted organs in the above preservation solution after subjecting them to the initial washing operation. The preservation solution of the above embodiment may be used. In addition, the preservative of the above embodiment can be used for final washing immediately before transplantation. When the above-mentioned storage solution is used as a washing solution, it is preferable to cool the solution to about 4 ° C in advance. Example

Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to the following examples unless it exceeds the gist.

The compound of the present invention shown in the following examples is 5-methyl-2- (1-piperazinyl) benzenesulfonic acid monohydrate (hereinafter, also sometimes referred to as “MCC-135”). The one manufactured according to the method described in Example 1 of JP-A-9-1221479 was used. Example 1

(experimental method)

Rat hearts were excised and Tyrode Buffer (in mM; NaCl 115, KCl 4.8, MgS04-7H20 1, CaC12-2H20 2, KH2P04 1.2, NaHC03 25, glucose 10; pH 7.4, 37 ° C according to the Langendorff method ) For 10 minutes. St. Thomas' II cardioplegic solution (in mM; NaCl 110, KCl 16, Ca C12-2H20 1.2, MgC12-6H20 16, NaHC03 10; pH7.8, 4 ° C) Then, the cells were left standing for 10 hours in St. Thomas' II cardioplegic solution. After 10 hours of refrigerated storage, the heart was re-mounted on the Langendorff apparatus. After reperfusion of Tyrode Buffer, a balloon was introduced into the left ventricle, and left ventricular systolic pressure (LV SP), + dP / dt, and -dP / dt were measured under pacing of 360 beats / min. In MCC- 135 group (drug-administered group) was performed all operations heart臓摘Dego at MCC- 135 10- ⁵ M presence. In the fresh group, the operation of attaching and detaching the heart from the Langendorff apparatus was omitted, a balloon was inserted into the left ventricle immediately after the heart was removed, and cardiac function was measured thereafter as in the other groups. (result)

The results are shown in Figs. After leaving the heart to stand in St. Thomas' II cardioplegic solution for 10 hours, reattached to Langendorff apparatus and reperfused Tyrode Buffer, LVSP, + dP / dt and -dP / dt decreased compared to the Fresh group. In the drug-administered group, there was no decrease in cardiac function unlike the drug-untreated group.

The above results indicate that the compound of the present invention suppresses cardiac function decline in a heart transplantation model. Industrial applicability

According to the present invention, it is possible to provide an agent for protecting a transplanted organ and an agent for suppressing ischemia-reperfusion injury after organ transplantation, and it is effective in suppressing a decrease in cardiac function that occurs during heart transplantation. All the contents described in the specification of Japanese Patent Application No. 200-26 18 35, which is the Japanese patent application on which the priority claimed in the present application is based, are incorporated herein by reference in their entirety as a part of the disclosure of this specification. It shall be incorporated by reference in the book.

Claims

The scope of the claims

1. The following general formula (I)

(Wherein 1 ^ is hydrogen, Ji E - c _s alkyl group, c ₃ - Shikuroa alkyl group c _7, halogenated alkyl groups one c _4, halogen atom, or c ₆ -

Represents a C ₁₂ aryl group; R ₂ is a hydrogen atom, a C _s alkyl group, or a cyano group, a nitro group, a c _x -c ₆ alkoxy group, a halogen atom, c—

A C ₇ -C ₁₂ aralkyl group which may have one or two or more substituents selected from the group consisting of a C ₅ alkyl group and an amino group; n represents an integer of 1 to 4)

Or a salt thereof, or a hydrate or solvate thereof, as an active ingredient.

2. The agent for protecting a transplanted organ according to item 1, wherein the substitution position of 2. is 5. '

3. The transplant organ protective agent according to paragraph 1 or 2, wherein n is 2.

4. R ₂ is a hydrogen atom, chromatography alkyl group, or - an alkyl group, one or more have a location substituent good C ₇ be _C selected from an alkoxy group and a halogen atom of one C ₃ Item 4. The transplant organ protecting agent according to any one of Items 1 to 3, which is ₁₂ aralkyl groups.

5.2 Any one of the above items 1 to 4, wherein ₂ is a hydrogen atom or a C _{7 to} C ₁₂ aralkyl group which may be substituted by one or more 1-C ₃ alkoxy groups. Transplant organ protectant.

6. The transplant organ protecting agent according to any one of items 1 to 5, wherein R ₂ is a hydrogen atom.

7. is a hydrogen atom, Ci—Cs alkyl group, C ₅ —C ₆ cycloalkyl group, 7. The transplant organ protecting agent according to any one of Items 1 to 6, which is a trifluoromethyl group, a halogen atom, or a phenyl group.

8. 1 ^ Alkyl groups one C _3, a cyclohexyl group, triflate Ruo Russia methyl group, a chlorine atom, transplanted organ protecting agent any crab description of paragraph 7 from the first term is a bromine atom or a phenyl group.

9. The transplant organ protection agent according to any one of Items 1 to 8, wherein R ₁ is a methyl group or a propyl group.

10. The transplant organ protecting agent according to item 1, wherein the active ingredient is selected from the following compounds.

5-Methylenol 21- (1-piperazinyl) benzenesulfonic acid;

5—Triphnoreolomethyl-2- (1-pidazul) benzenesulfonic acid;

5 _n-Propyl 2- (1-piperazinyl) benzenesnolephonic acid; 5-Feninole _ 2— (1-piperazinole) benzenesnolefonic acid;

5-chloro-2- (1-piperjunole) benzenesnolefonic acid;

5-bromo-2- (1-piperazinyl) benzenesulfonic acid;

5-iso-propynoley 2- (1-piperazinyl) benzenesnolephonic acid; 5-cyclohexyl-1- (1-piperazinyl) benzenesulfonic acid; 5-n-propynoley 2- (1-homopiperazininole) benzene 5-n-propynole-1- [4- (2,3,4-trimethoxybenzinole) -1-piperazinole] benzene snolefonic acid;

5-11-propynolee 2 _ [4- (3,4-dimethoxybenzyl) 1-1-piperazinole] benzenesulfonic acid

11. The transplant organ protecting agent according to item 10, wherein the active ingredient is selected from the following compounds.

5-methyl-2- (1-piperazinyl) benzenesulfonic acid;

5-n-Propyl-2- (1-pirazinyl) benzenesulfonic acid

12. The transplantation organ protection according to any one of Items 1 to 11, wherein the active ingredient is 5-methinolay 2- (1-piperazyl) benzenesulfonic acid monohydrate. Agent.

13. The transplanted organ protective agent according to any one of Items 1 to 12, wherein the form of the transplanted organ protective agent is in the form of a transplanted organ preservation solution.

14. The transplant organ transplant as described in any of paragraphs 1 to 13 wherein the transplant organ is a heart.

15. The following general formula (I)… (I)

(Wherein 1 ^ is an alkyl group having a hydrogen atom, Ji丄one C _s, C ₃ - Shikuroa alkyl group of C _7, C - halogenated alkyl group of C _4, a halogen atom, or a C _s - of C _{1 2} It represents Ariru group; R ₂ is a hydrogen atom, Ji - C ₆ alkyl group, or Shiano group, a nitro group, an alkoxy group having one C _s, a halogen atom, C - consisting of an alkyl group of C ₆ and the amino groups, represents 1 or 2 or more may have a substituent group C ₇ _ C _{1 2} of Ararukiru group selected from the group; n represents an integer of 1 to 4)

Or an ischemic reperfusion injury inhibitor after organ transplantation, which comprises, as an active ingredient, an aminobenzenesulfonic acid derivative or a salt thereof represented by the following formula:

16. The agent for suppressing ischemia / reperfusion injury after organ transplantation according to Item 15, wherein the 1 ^ substitution position is at position 5.

17. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to Item 15 or 16, wherein n is 2.

18. R ₂ has one or more substituents selected from a hydrogen atom, a C—C ₃ alkyl group, a C—C ₃ alkyl group, a J C ₃ alkoxy group and a halogen atom. ischemia reperfusion injury inhibitors after organ transplantation according to any one of C _{1 2} first from 5 Section 1 7 wherein a Ararukiru group - and optionally may be C _7.

Any one of 19. R ₂ is the first 5 wherein a hydrogen atom or one or two or more single C ₃ of Ararukiru group which optionally may C ₇ _ C _{1 2} be substituted by alkoxy groups of the first Section 8 4. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to item 1.

20. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to any one of Items 15 to 19, wherein R ₂ is a hydrogen atom.

21. Items 15 to 20 in which R is a hydrogen atom, a C _x -C ₆ alkyl group, a C ₅ -C ₆ cycloalkyl group, a trifluoromethyl group, a halogen atom, or a phenyl group The agent for suppressing ischemia-reperfusion injury after organ transplantation according to any one of the above.

22. The method according to any one of paragraphs 15 to 21 wherein R _x is a C to C ₃ alkyl group, cyclohexyl group, trifluoromethyl group, chlorine atom, bromine atom or phenyl group. An agent for suppressing ischemia-reperfusion injury after organ transplantation.

23. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to any one of Items 15 to 22, wherein is a methyl group or a propyl group.

24. The agent according to Item 15, wherein the active ingredient is selected from the following compounds:

5-methyl-1- (1-piperazinole) benzenesnolefonic acid;

5-Triphnoreo methinolate 21- (1-piperazinyl) benzenesulfonic acid;

5-n-propynole _ 2 _ (1-piperazinyl) benzene sulfonic acid;

5—Black mouth 2— (1-Piradur) Benzenesnolephonic acid;

5-bromo-2- (1-piperazinyl) benzenesulfonic acid;

5-iso-propinole 2- (1-piperazinole) benzenesulfonic acid; 5-cyclohexyl-1- (1-piperazinole) benzenesulfonic acid; 5-n-propinole 2- (1-homopiperazinole) Benzenosolefonic acid; 5-n-propynoleic 2- [4--(2,3,4-trimethoxybenzine:

1-piperazinole] benzenesulfonic acid; 5-n-propyl-1-2- [4- (3,4-dimethoxybenzyl) -1-piperazinole] benzenesnolefonic acid

25. The agent for suppressing ischemia / reperfusion injury after organ transplantation according to Item 24, wherein the active ingredient is selected from the following compounds.

5-Methinole 2- (1-piperazinole) benzenes / lefonic acid;

5-n-propynole 1- (1-piperazinole) benzenesnolefonic acid

26. The ischemia-reperfusion after organ transplantation according to any one of Items 15 to 25, wherein the active ingredient is 5-methinolay 2- (1-pirazuryl) benzenesulfonic acid monohydrate Disorder inhibitors.

27. The ischemia-reperfusion injury after organ transplantation according to any of paragraphs 15 to 26, wherein the form of the agent for inhibiting ischemia-reperfusion injury after organ transplantation is a form for preparation for intravascular administration Inhibitors.

28. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to any one of Items 15 to 27, which is administered immediately before reperfusion after ischemia.

29. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to any one of Items 15 to 28 for administration to a recipient.

30. The inhibitor of ischemia-reperfusion injury after organ transplantation according to any of paragraphs 15 to 26, wherein the form of the agent for ischemia-reperfusion injury after organ transplantation is in the form of an organ preservation solution .

31. The agent for suppressing ischemia-reperfusion injury after organ transplantation according to any one of Items 15 to 30, wherein the organ is a heart.