JP2793542B2 - Preventive and / or therapeutic agent for organ dysfunction occurring during organ surgery or transplantation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to the prevention and / or prevention of organ dysfunction during surgery or transplantation of an organ containing a compound having an endothelin receptor antagonistic action.
Related to therapeutic agents.

[0002]

2. Description of the Related Art Endothelin (ET) was
It is a vasoconstrictive peptide consisting of 21 amino acids isolated from the culture supernatant of porcine aortic endothelial cells and determined by Yanagisawa et al. [Yanagisawa et al., Nature, 33
2, 411-412]. Subsequently, studies on the gene encoding endothelin revealed that peptides having a similar structure to endothelin existed, and endothelin-1 (ET-1) and endothelin-2 (E
T-2) and endothelin-3 (ET-3). In addition, endothelin receptors include A type and B type.
It has been revealed that the type exists. Since the discovery of endothelin, the aim of developing therapeutic agents for diseases caused by endothelin has been the intensive search for compounds that have endothelin receptor antagonism. Application No. 4-344252 (EP-A-552,48)
9), Japanese Patent Application No. 4-216019 (EP-A-528,3).
12), Japanese Patent Application No. 4-27785 (EP-A-499,2)
66), Japanese Patent Application No. 3-503831 (WO91 / 1308)
9), EP-A-436,189, EP-A-457,1
95, EP-A-510,526, WO92 / 1299
1, JP-A-4-288099, EP-A-496,45
2, EP-A-526,708, EP-A-460,6
79, WO92 / 20706 and the like have been proposed. It has been suggested that the compounds described therein are effective as a therapeutic agent for hypertension, a therapeutic agent for cardio-cerebral circulation disease, a therapeutic agent for renal disease, a therapeutic agent for asthma, an anti-inflammatory agent, an anti-arthritic agent, and the like. On the other hand, it is known that endothelin concentration in organs increases during surgery on organs such as the liver (Journal of the Japan Society for Transplantation, VOL. 27, 1992). It was revealed to have. However, there is no description or suggestion that a compound having an endothelin receptor antagonistic activity is useful as a preventive or therapeutic agent for organ dysfunction during organ surgery or transplantation.

[0003]

DISCLOSURE OF THE INVENTION The present invention relates to a compound containing a compound having an endothelin receptor antagonistic effect, which is for preventing a decrease in organ function at the time of organ surgery or transplantation and / or
Or to provide a therapeutic agent.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, a therapeutic agent for hypertension, a therapeutic agent for cardio-cerebral circulatory disease, a therapeutic agent for renal disease, a therapeutic agent for asthma, Compounds having endothelin receptor antagonism, which have been considered to be effective as anti-inflammatory agents and anti-arthritic agents, are unexpectedly used as preventive and / or therapeutic agents for organ dysfunction occurring during organ surgery or transplantation, especially The present inventors have found that it is effective as a preventive and / or therapeutic agent for hepatic and renal hypofunction, and as a result of further research, they have completed the present invention. That is, the present invention is a preventive and / or therapeutic agent for organ function deterioration occurring during organ surgery or transplantation, which comprises a compound having an endothelin receptor antagonistic action. In the present invention, when amino acids and peptides are indicated by abbreviations, they are referred to as IUPAC-IUB Commission on Biochemical Nom.
This is based on an abbreviation by enclature or a common abbreviation in the art, and examples thereof are described below. When an optical isomer is present, it represents the L-form unless otherwise specified. Ala: Alanine Arg: Arginine Asn: Asparagine Asp: Aspartic acid Cys: Cysteine Glu: Glutamate Gln: Glutamine Gly: Glycine His: Histidine Ile: Isoleucine Leu: Lysine Lysine: Lysine Lysine: Lysine Lysine : Threonine Trp: Tryptophan Tyr: Tyrosine Val: Valine The present invention provides: (1) Cyclo [-D-Asp-Asp (R1) -A
sp-D-Thg (2) -Leu-D-Trp-] [In the amino acid sequence, Asp (R1) is aspartic acid β-4.
A phenylpiperazine amide residue, Thg (2)
-Represents a thienylglycine residue. Or a salt thereof, in order to prevent a decrease in the function of an organ (except for the liver) during surgery or transplantation, and / or
Or a therapeutic agent, (2) Cyclo [-D-Asp-Asp (R1) -A
sp-D-Thg (2) -Leu-D-Trp-] [In the amino acid sequence, Asp (R1) is aspartic acid β-4.
A phenylpiperazine amide residue, Thg (2)
-Represents a thienylglycine residue. [3] Cyclo [-D-Asp-Asp (R1) -A], which comprises a salt thereof;
sp-D-Thg (2) -Leu-D-Trp-] [In the amino acid sequence, Asp (R1) is aspartic acid β-4.
A phenylpiperazine amide residue, Thg (2)
-Represents a thienylglycine residue. And (4) Cyclo [-D-Asp], which comprises a disodium salt of the above (excluding the liver), and a preventive and / or therapeutic agent for a decrease in the function of the organ which occurs at the time of surgery or transplantation. -Asp (R1) -A
sp-D-Thg (2) -Leu-D-Trp-] [In the amino acid sequence, Asp (R1) is aspartic acid β-4.
A phenylpiperazine amide residue, Thg (2)
-Represents a thienylglycine residue. And / or a prophylactic and / or therapeutic agent for renal impairment that occurs during renal surgery or transplantation. Cyclo [-D-Asp-Asp (R1) -Asp-D-Thg (2) -Leu-DT of the present invention
rp-] (in the amino acid sequence, Asp (R1) is aspartic acid β-
4-Phenylpiperazineamide residue and Thg (2) represent 2-thienylglycine residue. Examples of the salts include metal salts (eg, sodium salts, potassium salts, calcium salts, magnesium salts, etc.), salts with bases or basic compounds (eg, ammonium salts, arginine salts, etc.), and inorganic acid addition salts (eg, , Hydrochloride, sulfate, phosphate, etc.), organic acid salts (eg, acetate, propionate,
Citrate, tartrate, malate, oxalate, etc.). Especially Cyclo [-D-Asp-Asp (R1) -Asp-D-Thg
(2) -Leu-D-Trp-].

Cyclo [-D-Asp-Asp (R1) -Asp-D-Thg (2) -Leu-D having endothelin receptor antagonism according to the present invention
-Trp-] (In the amino acid sequence, Asp (R1) is aspartic acid β
Thg (2) indicates a 4-phenylpiperazineamide residue, and Thg (2) indicates a 2-thienylglycine residue. ) Or a salt thereof can be used for the prevention and / or treatment of functional deterioration of various organs and its complications occurring during or after organ surgery or transplantation. Organs include, for example, liver, kidney, heart, spleen, pancreas and the like. For example, at the time of liver surgery, a method of temporarily tying hepatic blood vessels and reperfusion after the operation is currently commonly used, but for a long time (5 to 10).
It is known that tying the cord reduces the liver function after reperfusion, resulting in liver failure. When the effect of a compound having endothelin receptor antagonism was examined using a rat ischemia-reperfusion hepatic injury model as this model, the compound was found to have a remarkable ameliorating effect on hepatic dysfunction.
Therefore, a compound having an endothelin receptor antagonistic effect is effectively used for preventing or (and) treating organ dysfunction or (or) its complications during or after surgery or transplantation of an organ such as the liver. be able to. The compound having endothelin receptor antagonism used in the present invention is a safe and low toxic compound. Examples of liver function deterioration or an index thereof occurring during or after liver surgery or transplantation include, for example, an increase in transaminase (GPT / GOT) activity, a decrease in fibrinogen or prothrombin production, a decrease in heparin production, and the like. Compounds having body antagonism have a preventive or / and therapeutic effect on these hepatic dysfunctions and their complications. When a compound having an endothelin receptor antagonism is used for preventing or (and) treating organ dysfunction and its complications at or after organ surgery or transplantation, the compound is used in a warm-blooded mammal (eg, rabbit). , Dogs, cats, rats, mice, monkeys, cows, humans, etc.), for example, orally or parenterally. The dosage form of the preparation may be any of an oral preparation (eg, powder, tablet, granule, capsule) and a parenteral preparation (eg, suppository, injection). These preparations can be prepared by a method known per se.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION When administered parenterally, it is usually administered in the form of a liquid (eg, injection). The single dose varies depending on the administration subject, target organ, symptom, administration method and the like, but for example, in the form of an injection, per operation time, usually about 0.01 mg to 100 mg per kg of body weight, preferably 0.01 to 100 mg. It is convenient to administer about 50 mg, more preferably about 0.01 to 20 mg, by intravenous injection. When administered orally, the single dose is usually about 5 mg to 1 g per kg of body weight before surgery,
Preferably about 10 to 100 mg is administered. Injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, infusions, and the like. Such an injection is a method known per se, that is, a compound having endothelin receptor antagonism is dissolved in a sterile aqueous liquid or oily liquid,
It is adjusted by suspending or emulsifying. Examples of aqueous solutions for injection include physiological saline, isotonic solutions containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and suitable solubilizing agents such as alcohols. (Eg, ethanol), polyalcohols (eg, propylene glycol, polyethylene glycol), nonionic surfactants (eg, polysorbate 80, HCO-50) and the like. The oily liquid includes sesame oil, soybean oil and the like, and may be used in combination with benzyl benzoate, benzyl alcohol and the like as a solubilizing agent. In addition, buffers (eg, phosphate buffer, sodium acetate buffer), soothing agents (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizers (eg, human serum albumin, polyethylene glycol, etc.), storage Agents (eg, benzyl alcohol, phenol, etc.). The prepared injection is usually filled in a suitable ampoule.
When producing oral preparations such as powders, tablets, granules and capsules, pharmaceutically acceptable carriers can be blended. As the carrier, excipients (eg, lactose,
For example, starch (e.g., starch), a lubricant (e.g., magnesium stearate, talc), a binder (e.g., hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogold), and a disintegrant (e.g., starch, calcium carboxymethylcellulose) are used. . If necessary, additives such as preservatives (for example, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate), antioxidants, coloring agents, sweeteners and the like can be used. The preparation containing the compound having an endothelin receptor antagonism of the present invention can be effectively used for prevention and / or treatment of organ dysfunction during organ surgery or transplantation.

[0007]

[Example 1]

Compound 1 [Cyclo (-D-Asp-Asp (Rl) -Asp-D-Thg (2) -Leu-D-
Trp-)] (0.266 mol) was dissolved in methanol (6 L). While stirring this solution under ice cooling, a 0.1N aqueous sodium hydroxide solution
(5.41 L) was added over 3 hours and 25 minutes. The methanol was distilled off from the reaction solution under reduced pressure. Pure water (5 L) was added to the remaining liquid, and the mixture was washed twice with ethyl acetate (5 L). Concentrate the aqueous layer under reduced pressure, 11341 g
And The residual liquid was adsorbed on a column packed with Diaion HP-20 (15 L, manufactured by Mitsubishi Kasei Corporation, Japan). Column with pure water
(45 L), and eluted with methanol-pure water (1: 1 by volume). The desired fraction was collected and concentrated under reduced pressure to 1265 g. Activated carbon (20 g, white heron P, manufactured by Takeda Pharmaceutical Co., Ltd.)
Japan) and stirred at 25 ° C. for 30 minutes. The activated carbon was filtered off with a Millipore filter (0.5 μm, diameter 90 mm, manufactured by Millipore, USA), and the activated carbon was washed with pure water (0.8 L). The filtrate is combined with the washing solution and frozen to give the disodium salt of Compound 1.
(230 g) was obtained. Elemental analysis: C ₄₅ H ₅₁ N ₉ O ₁₁ SNa ₂・ 3.8H ₂ O Calculated: C, 51, 95; H, 5.68; N, 12.12; S, 3.08; Na, 4.42 Experimental: C, 52, 11 ; H, 6.02; N, 12.16; S, 3.02; Na, 4.62 (Na was measured by atomic absorption spectrometry) (Example 2) Rat ischemia-reperfusion liver injury model was prepared by Koo et al. 1)
I referred to the method. Male Wistar rats weighing 250 to 300 g, which had been fasted (free drinking) for 1 day, were used for the experiment. Rats were treated with sodium pentobarbital (60 mg
/ Kg, intraperitoneal administration), and the body temperature was maintained at 37 ° C using a warming device. A polyethylene tube for drug administration and venous blood collection was intubated into the left femoral artery and heparin (200un).
it / kg, intravenous administration) and then venous blood (about 1 ml:
(Before ischemia). 3 groups of rats (sham operation group,
Control group, compound 1 group), physiological saline was administered to the sham operation / control group, and 2 mg of 2Na salt of compound 1 was added to compound 1 group.
kg was administered intravenously. The abdomen was incised, the right branch of the portal vein was detached, and clips were applied to block the blood flow to the right lobe and square lobe of the liver (control group, compound 1 group). In the sham operation group, the same treatment was performed except for the operation of clipping. 25
After the blood flow was cut off for one minute, the clip was opened to resume blood flow, and one hour later, venous blood was collected again (reperfusion 1).
After hours). GPT / GOT activity in the collected venous blood plasma was determined by the UV rate method (GPT-UV Test Wako / GOT-
UV Test Wako). Perform a large amount test between each group at each of the pre-ischemic value and the 1 hour reperfusion value,
A significance level of 5% or less was considered significant. The results are shown in [Table 1] and [Table 2]. 1) Koo et al. (1991) Contribution o
f no-reflow phenomenon to hepatic injuryafter isch
emia-reperfusion: evidence for a role for superoxl
de anlon.Hepatology ,, 15, 507-514.

[0008]

[Table 1]

[0009]

[Table 2]

[0010] The values in the table represent the mean ± standard error. GPT / GOT activity in plasma before ischemia showed no significant difference among the three groups of the sham operation group, the control group, and the compound 1 group. One hour after reperfusion, the GPT activity of the control group was significantly higher than that of the sham operation group. 2Na salt of compound 1 3mg / kg
GPT activity 1 hour after reperfusion after intravenous administration was similar to that in the sham-operated group. The GOT activity of the control group 1 hour after reperfusion was higher than that of the sham operation group, and the 2Na salt of Compound 1 was 3 mg / g.
kg intravenous administration tended to suppress the GOT elevation. From these results, Compound 1 showed a significant inhibitory effect on the increase in plasma GPT value associated with rat ischemia-reperfusion hepatic injury, and also showed a tendency to suppress the increase in plasma GOT value. This suggests that endogenous endothelin is involved in ischemia-reperfusion hepatic injury, and that a compound having endothelin receptor antagonism can be a prophylactic / therapeutic agent for this ischemia-reperfusion hepatic injury. It is shown. [Preparation Example 1] 50 mg of the 2Na salt of Compound 1 used in Example 2 was dissolved in 50 ml of distilled water for injection in Japan, and then distilled water for injection was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of each solution was taken, filled in an injection vial under sterile conditions, freeze-dried and sealed. [Formulation Example 2] After dissolving 500 mg of the 2Na salt of Compound 1 used in Example 2 in 50 ml of Japanese Pharmacopoeia distilled water for injection, the Japanese Pharmacopoeia distilled water for injection was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of each solution was taken, filled in an injection vial under sterile conditions, freeze-dried and sealed. [Formulation Example 3] 5 g of the 2Na salt of Compound 1 used in Example 2 was dissolved in 50 ml of distilled water for injection in Japan, and distilled water for injection was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of each solution was taken, filled in an injection vial under sterile conditions, freeze-dried and sealed. Formulation Example 4 After dissolving 15 g of the 2Na salt of Compound 1 used in Example 2 in 50 ml of distilled water for injection in Japan, distilled water for injection in Japan was added to make 100 ml. This solution was filtered under sterile conditions, and then 1 ml of each solution was taken, filled in an injection vial under sterile conditions, freeze-dried and sealed.

[0011]

Effect of the Invention Cyclo [-D-Asp-Asp (R1) -Asp-D-Thg (2) -L
eu-D-Trp-] (In the amino acid sequence, Asp (R1) represents an aspartic acid β-4-phenylpiperazinamide residue and Thg (2) represents 2
-Represents a thienylglycine residue. ) Or a salt thereof can be used effectively for prevention and / or treatment of a decrease in the function of an organ which occurs during surgery or transplantation of the organ.

Continuation of the front page (56) References JP-A-4-244097 (JP, A) JP-A-4-261198 (JP, A) JP-A-4-288099 (JP, A) JP-A-6-87856 (JP) JP-A-7-173161 (JP, A) JP-A-5-279390 (JP, A) JP-A-5-1788891 (JP, A) Table 7-505890 (JP, A) Table 7-501322 (JP, A) JP-A-6-172384 (JP, A) JP-A-6-49046 (JP, A) JP-A-5-178890 (JP, A) JP-A-6-9585 (JP, A A) European Patent Application No. 528312 (EP, A) European Patent Application No. 526642 (EP, A) European Patent Application No. 510526 (EP, A) European Patent Application No. 526708 (EP, A) European Patent Application No. 499266 (EP, A) A) European Patent Application Publication No. 603399 (EP, A) International Publication No. 91/13089 (WO, A) International Publication No. 92/20706 (WO, A) International Publication No. 93/17701 (WO, A) United States Patent 5,554,521 (US, A) US Patent 55 14696 (US, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61K 38/00-38/58 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. Cyclo [-D-Asp-Asp (R
1) -Asp-D-Thg (2) -Leu-D-Trp
-] [In the amino acid sequence, Asp (R1) replaces aspartic acid β-4-phenylpiperazineamide residue with Thg
(2) shows a 2-thienylglycine residue. Or a salt thereof, for preventing and / or treating a decrease in the function of an organ (excluding the liver) which occurs at the time of surgery or transplantation. 2. Cyclo [-D-Asp-Asp (R
1) -Asp-D-Thg (2) -Leu-D-Trp
-] [In the amino acid sequence, Asp (R1) replaces aspartic acid β-4-phenylpiperazineamide residue with Thg
(2) shows a 2-thienylglycine residue. Or a salt thereof, which is used for preventing and / or treating renal dysfunction occurring during renal surgery or transplantation. 3. Cyclo [-D-Asp-Asp (R
1) -Asp-D-Thg (2) -Leu-D-Trp
-] [In the amino acid sequence, Asp (R1) replaces aspartic acid β-4-phenylpiperazineamide residue with Thg
(2) shows a 2-thienylglycine residue. ] An agent for preventing and / or treating a decrease in the function of an organ (excluding the liver) occurring during surgery or transplantation, characterized by containing a disodium salt of the above. 4. Cyclo [-D-Asp-Asp (R
1) -Asp-D-Thg (2) -Leu-D-Trp
-] [In the amino acid sequence, Asp (R1) replaces aspartic acid β-4-phenylpiperazineamide residue with Thg
(2) shows a 2-thienylglycine residue. And / or a therapeutic agent for renal function deterioration occurring during renal surgery or transplantation, comprising the disodium salt of the present invention.