KR102091730B1 - Pharmaceutical composition for preventing or treating pulmonary arterial hypertension comprising epidithiodioxopiperazine compound or its derivatives, or pharmaceutically acceptable salts thereof - Google Patents

Abstract

The present invention epidithiodioxopiperazine (epidithiodioxopiperazine; ETP) compound or a derivative thereof; Or it relates to a pharmaceutical composition for the prevention or treatment of pulmonary arterial hypertension, including these pharmaceutically acceptable salts.

Description

Pharmaceutical composition for preventing or treating pulmonary arterial hypertension comprising epidithiodioxopiperazine compound or its derivatives, or derivatives thereof, or a derivative thereof, or a pharmaceutically acceptable salt thereof pharmaceutically acceptable salts thereof}

The present invention epidithiodioxopiperazine (epidithiodioxopiperazine; ETP) compound or a derivative thereof; Or it relates to a pharmaceutical composition for the prevention or treatment of pulmonary arterial hypertension, including these pharmaceutically acceptable salts.

The pulmonary artery is an artery that sends blood back to the body from the right ventricle to the lungs to receive oxygen, and the average pulmonary arterial pressure at rest is 25 mmHg or more and the average pulmonary arterial pressure at exercise is 30 mmHg. Pulmonary arterial hypertension is divided into "primary pulmonary arterial hypertension", a case in which no specific cause is known, and "associated pulmonary arterial hypertension", which is a secondary disease caused by a specific causative disease. In the latter case, genetically related familial pulmonary arterial hypertension, collagen vascular disease (systemic sclerosis, erythematous lupus erythematosus, etc.), portal vein hypertension, HIV infection, congenital heart disease, and drugs or toxins caused by appetite suppressants or cocaine There are cases. Pulmonary arterial hypertension associated with these specific diseases is not significantly different from primary pulmonary arterial hypertension, natural course or histopathological findings, and response to treatment. Primary pulmonary arterial hypertension is 1.7 times more frequent in women than in men, and can occur at any age, but is frequent in the 20s to 30s. About 7% of the patients show a family history, and in these cases, a gene mutation called BMPR2 is related and shows an inherited pattern as an autosomal dominant.

Patients with pulmonary arterial hypertension may have symptoms such as shortness of breath (difficulty breathing), fainting, dizziness, peripheral edema (eg, lower extremity edema), weakness, loss of appetite, increased heart rate, headache, anterior chest pain, and cyanosis. In addition, the hands and toes can be accompanied by a ray node phenomenon that cools easily and discolors blue in the cold. Patients with pulmonary arterial hypertension often receive a misdiagnosis, such as asthma or the effects of excessive stress, and respiratory distress occurs, and on average, they are diagnosed correctly only 2.5 years later.

For the treatment of pulmonary arterial hypertension, surgical operations such as interventional atrial septal surgery, pulmonary transplantation, and cardiopulmonary transplantation can be performed, but drug treatment is preferred because of its high cost and risk. Currently, there is a method of using a general vasodilator as a drug for the treatment of pulmonary arterial hypertension, but most vasodilators do not have a significant effect on pulmonary arterial hypertension, but most of the side effects are due to administration. It is often difficult to apply. Therefore, it is necessary to find an effective treatment for pulmonary arterial hypertension.

Accordingly, the present inventors confirmed that the epidithiodioxopiperazine compound or a derivative thereof having an intramolecular disulfide crosslink in the epidithiodioxopiperazine ring relieves pulmonary arterial hypertension symptoms in an experimental animal model, and completed the present invention. .

The present invention is for the prevention or treatment of pulmonary arterial hypertension, which includes an epidithiodioxopiperazine compound or a derivative thereof having an intramolecular disulfide crosslink in an epidithiodioxopiperazine ring, or a pharmaceutically acceptable salt thereof. It is intended to provide a pharmaceutical composition.

The present invention includes an epidithiodioxopiperazine compound represented by the following Chemical Formula 1, a derivative thereof or a derivative thereof, or a pharmaceutically acceptable salt thereof, having intramolecular disulfide crosslinking in an epidithiodioxopiperazine ring. To provide a pharmaceutical composition for preventing or treating pulmonary arterial hypertension:

[Formula 1]

In the above formula,

R ₁ to R ₄ are each independently hydrogen, C1 to C6 straight or branched chain alkyl, alkenyl or alkynyl, or benzyl substituted with C1 to C6 alkoxy.

Specifically, R ₁ to R ₄ may each independently be hydrogen, methyl, butyl, propenyl, or methoxybenzyl, but are not limited thereto.

The present invention is based on the discovery that a series of synthetic small molecule compounds having an intramolecular disulfide crosslink in an epidithiodioxopiperazine ring exerts an effect of treating pulmonary arterial hypertension through intramolecular disulfide crosslinking. Specifically, the present inventors to confirm the key mechanism of action involved in the treatment of pulmonary arterial hypertension, a synthetic small molecule epidithiodioxopiperazine derivative 2,3-dithia-5,7-diazabicyclo [2.2.2] Octane-6,8-dione, 5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, 4,5,7-trimethyl-2 , 3-Dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione and 7- (4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2.2] It was confirmed that octane-6,8-dione showed excellent therapeutic effect on pulmonary arterial hypertension. On the other hand, similarly, in the case of a reduced derivative having a thiol group in two instead of a disulfide crosslink in the molecule containing a dioxopiperazine ring, it was confirmed that it does not show a therapeutic effect on pulmonary arterial hypertension. It is obvious that an dioxopiperazine derivative can exert a therapeutic effect on pulmonary arterial hypertension regardless of the type of substituent.

The pulmonary arterial hypertension is a type of hypertension that affects the right side of the artery and heart of the lung, and is defined as pulmonary arterial hypertension when the average pulmonary arterial pressure at rest is 25 mmHg or more and the average pulmonary arterial pressure at exercise is 30 mmHg.

In one form of pulmonary arterial hypertension, small arteries and capillaries in the lungs called the pulmonary arteries can be narrow, blocked, or damaged, which makes the flow of blood through the lungs difficult and increases the pressure in the pulmonary arteries. As a result of this, as the pressure is applied, the lower right chamber (right ventricle) can make the blood pump through the lungs difficult and eventually weaken the heart muscle and lose its function.

Other forms of pulmonary arterial hypertension continue to deteriorate and can sometimes be a fatal and serious condition. Although some forms of pulmonary arterial hypertension cannot be cured, treatment for them can help relieve symptoms and improve quality of life.

The drug for specifically treating the pulmonary arterial hypertension has not been discovered yet, and the drug treatment uses a general vasodilator such as a short-acting vasodilator or a calcium channel blocker, but responds significantly to the short-acting vasodilator. The case is very low, less than about 10% of patients diagnosed, and there are cases that do not respond to calcium channel blocking drugs. As described above, pulmonary arterial hypertension has a very different type of drug that can be applied due to a different mechanism of treatment from general vascular disease, and it can be predicted that it is also effective in the treatment of pulmonary arterial hypertension because it is a drug that has an effect on vascular disease. none.

The derivative of the epidithiodioxopiperazine compound refers to a compound containing an epidithiodioxopiperazine ring as a parent nucleus showing activity. The derivative may be a compound substituted with various substituents of a type known in the art, such as an NH group or a CH group in the compound ring represented by Formula 2, or may include a compound having a structure in which various compounds apparent to those skilled in the art are combined. And is not limited thereto. Modification and substitution of the structure of the compound of Formula 2 can be easily performed by those skilled in the art, for example, in the following process.

For example, the derivative of the epidithiodioxopiperazine compound may be any one of the compounds represented by the following Chemical Formulas 2 to 7:

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

.

.

The compounds of Formulas 2 to 7 may be synthesized and used by those skilled in the art with reference to known methods. For a detailed synthesis method, refer to the method disclosed in Korean Registered Publication No. 1633975.

In one embodiment of the present invention, 2,3-dithia-5,7-diazabicyclo [2.2.2] octane- among epidithiodioxopiperazine derivatives containing a series of intramolecular disulfide bridges synthesized as above 6,8-dione (2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, formula 2), 5,7-dimethyl-2,3-dithia-5,7 -Diazabicyclo [2.2.2] octane-6,8-dione (5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, formula 3) , 4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (4,5,7-trimethyl-2,3-dithia- 5,7-diazabicyclo [2.2.2] octane-6,8-dione, formula 4), 5,7-diallyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane- 6,8-dione (5,7-diallyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, formula 5) and 7- (4-methoxybenzyl)- 2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (7- (4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2.2 ] octane-6,8-dione, pulmonary arterial hypertension of formula 6) It confirmed the charge effect. Specifically, when administration of the compound of Formulas 2 to 6 to the experimental animal inducing pulmonary arterial hypertension by administering monocrotalin, it was confirmed that the remarkable right ventricular hypertrophy and pulmonary endometrial thickening in the pulmonary arterial hypertension model were reduced to a level similar to normal. Did. This is an effect achieved through intramolecular disulfide crosslinking, which includes intramolecular disulfide crosslinking and shares the same parental nucleus structure as the compounds of Formulas 2 to 6, with only substituents of similar properties on nitrogen and / or carbon atoms on the ring. It is apparent to those skilled in the art that the substituted compound of Formula 7 will also exhibit the same effect.

The epidithiodioxopiperazine compounds or derivatives thereof may be isolated from natural sources, obtained from natural sources, or prepared by chemical modification, or chemically synthesized by those skilled in the art with reference to known production methods, or commercially It can be purchased and used. Preferably, the epidithiodioxopiperazine compounds or derivatives thereof are used separately from bacteria, culture medium or metabolites thereof according to methods known in the art or synthesized by the production method described in the prior patent of the present inventors. Can be used (Korean Registered Publication No. 1633975).

The composition of the present invention can achieve the prophylactic or therapeutic effect of pulmonary arterial hypertension by imitating the intracellular activity of PrxII, but the specific mechanism of action is not limited thereto.

The epidithiodioxopiperazine compounds of the present invention or derivatives thereof may be used in the form of pharmaceutically acceptable salts. In addition, the compounds of the present invention or derivatives thereof may be used alone or in combination with other pharmaceutically active compounds or collectively.

As used herein, the term "pharmaceutically acceptable salt" refers to any salt that retains the desired biological and / or physiological activity of the compound or derivatives, and that the undesired toxicological effect is minimal. In the present invention, any kind of salt can be used as long as the diketopiperazine ring containing a disulfide bridge in the molecule is maintained. As the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts are prepared by dissolving the compound in a conventional method, for example, an aqueous solution of excess acid, and precipitating the salt using a water miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. Equal amounts of the compound and acid or alcohol in water (eg, glycol monomethyl ether) can be heated and then the mixture is evaporated to dryness or the precipitated salt can be suction filtered. At this time, inorganic acids and organic acids can be used as the free acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, and tartaric acid can be used as the inorganic acid, and methane sulfonic acid, p-toluene sulfonic acid, acetic acid, tri, etc. can be used as the organic acid. Prouroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, manderic acid, propionic acid, citric acid, lactic acid, glycolic acid ( glycollic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanic acid, hydroiodic acid, etc. Can be used, but is not limited to these.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the inexpensive compound salt, and then evaporating and drying the filtrate. At this time, as the metal salt, it is particularly suitable to manufacture sodium, potassium, or calcium salts, but is not limited thereto. Further, the corresponding silver salt can be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Pharmaceutically acceptable salts of the epidithiodioxopiperazine compounds or derivatives thereof according to the present invention include all salts of acidic or basic groups that may be present, unless otherwise indicated. For example, pharmaceutically acceptable salts may include sodium, calcium, and potassium salts of hydroxy groups, and other pharmaceutically acceptable salts of amino groups include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, and the like. Hydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate) and p -toluenesulfonate (tosylate) salts, etc. Can be manufactured.

The composition according to the invention may further comprise suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions. The composition is sterile or sterile, and such solutions are sterile or sterile and do not cause allergies or other detrimental reactions when applied to water, buffers, isotonic agents or animals or humans, known to those skilled in the art Other ingredients may be included.

The term "pharmaceutically acceptable carrier" as used herein includes any and all solvents, dispersion media, coatings, antibacterial agents, antifungal agents and isotonic agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. In addition to conventional media or agents which are immiscible with the active ingredient, their use in therapeutic compositions is contemplated. In addition, supplementary active ingredients can also be incorporated into the compositions.

The composition may be prepared in a formulation such as liquid, emulsion, suspension or cream, and may be used parenterally. The amount of the composition may be used as a normal amount for preventing vascular restenosis, and is preferably applied differently according to the age, sex, condition of the patient, the absorption of the active ingredient in the body, the rate of inactivation, and drugs used in combination.

In addition, the present invention provides a method of preventing or treating pulmonary arterial hypertension, comprising administering the pharmaceutical composition to an individual in need thereof.

In the present invention, the term "prevention" refers to all actions that inhibit or delay the onset of pulmonary arterial hypertension by administration of the pharmaceutical composition according to the present invention, and "treatment" means pulmonary arterial hypertension by administration of the pharmaceutical composition. It means all the actions by which the symptoms are improved or beneficially changed.

In the present invention, the term "individual" refers to all animals, including humans, who may or may develop pulmonary arterial hypertension, and can effectively prevent or treat the pulmonary arterial hypertension by administering the pharmaceutical composition of the present invention to an individual. In addition, the pharmaceutical composition of the present invention may be administered in parallel with a known therapeutic agent for pulmonary arterial hypertension.

The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment and does not cause side effects, and the effective dose level is the patient's gender, age, and weight Factors, including health conditions, disease severity, drug activity, drug sensitivity, method of administration, time of administration, route of administration and rate of discharge, duration of treatment, combination or drug used simultaneously and other factors well known in the medical field. Accordingly, it can be easily determined by those skilled in the art.

The term "administration" of the present invention means introducing a predetermined substance to a patient in an appropriate manner, and the route of administration of the composition can be administered through any general route as long as it can reach the target tissue. The method of administration is not limited thereto, but may be formulated in the form of a pill or the like and administered orally or parenterally. In the case of parenteral administration, it may be achieved by intravenous injection or by inhalation administration such as subcutaneous administration or nasal administration. In addition, it can be topically administered to the lesion, and a double balloon catheter, dispatch, or microporous balloon can be used for topical administration of the drug. In particular, a stent or sustained-release microparticles may be used for long-term drug delivery. You can. Most preferably, the composition of the present invention is applied in a stent to directly administer to the site of pulmonary arterial hypertension.

As an example of specific administration, the composition of the present invention can be used for inhalation administration in an injection device in the form of a syringe or a spray injection device. For example, a tube-type injection device may be included, and the drug may be injected into the nasal cavity through this, but is not limited thereto. Alternatively, when the injection device in the form of a syringe is included, a nasal administration of the composition of the present invention supported in a liquid form is performed by inserting a discharge portion corresponding to a syringe needle into a nasal cavity of a subject and then operating a discharge pressure applying portion corresponding to a piston of a syringe can do. At this time, the shape of the injection device is not limited to the shape of a conventional syringe. When the injection device in the form of a spray injection device is included, the composition of the present invention is sprayed in the form of a spray by applying the injection pressure after placing the discharge part in the nostril or nasal cavity which is the entrance of the nasal cavity, as in the case of using the injection device. Can be administered. When a tube-type injection device is also included, the composition of the present invention may be injected into the nasal cavity through a method of applying pressure to the tube after inserting the discharge portion into the nasal cavity of the subject as described above. The form of the above-described injection device is only a specific example, and any device capable of injecting the composition of the present invention into the nasal cavity can be used without particular limitation.

In addition, the present invention provides a drug delivery device for topical administration comprising a pharmaceutical composition for preventing or treating pulmonary arterial hypertension. The drug delivery device for topical administration may include, but is not limited to, a double balloon catheter, a dispatch, a micro-balloon, a stent, and preferably a stent.

In the present invention, the term "stent" refers to a general device for application in an endoluminal application, for example, a blood vessel, as mentioned above, and a disease occurs in a region where blood flow should be smooth. Refers to a cylindrical medical material that normalizes the flow of blood by inserting it into a narrowed or clogged blood vessel under X-ray fluoroscopy without surgically performing an open surgery when the flow is disturbed. For example, vascular stents are described by Eric J Topol in "Textbook of Interventional Cardiology", Saunders Company, 1994. It is preferably a sustained release drug stent.

As a method of coating the pharmaceutical composition of the present invention on the stent, a conventional coating method known to those skilled in the art of the present invention can be applied, for example, dip-coated and There is a method of coating with a polymer (polymer coated), the salt coating method is the simplest coating method, because it is easy to observe the biological effect of only the drug because the pharmaceutical composition is coated, but is not limited thereto. Preferably, the stent of the present invention can be prepared by mixing the composition with a polymer material in a drug-release stent and coating the composition according to the present invention so that it can be slowly released. Polymeric materials that can be used in drug-release stents are well known in the art, for example, polyurethane, polyethylene terephthalate, PLLA-poly-glycolic acid copolymer (PLGA), polycaprolactone, poly- (hydride) Hydroxybutyrate / hydroxyvalerate) copolymer, polyvinylpyrrolidone, polytetrafluoroethylene, poly (2-hydroxyethylmethacrylate), poly (etherurethane urea), silicone, acrylic, epoxide, Polyester, urethane, parene, polyphosphine polymer, fluoro polymer, polyamide, polyolefin, and mixtures thereof, but are not limited thereto.

The stent is an antithrombotic agent consisting of or containing one or more substances selected from polysaccharides, heparin, gelatin, collagen, alginate, hyaluronic acid, arginic acid, carrageenan, chondroitin, pectin, chitosan and derivatives and copolymers thereof. It can be further coated with a layer. Suitably, these materials can be incorporated into biosynthetic top coats, as described in US 2006/0083772. Methods for forming stents from mixtures of polymers and drug compounds are described in Blindt et al ., 1999, Int . J. Artif . Organs , 22: 843-853.

The pharmaceutical composition comprising an epidithiodioxopiperazine (ETP) compound or a derivative thereof of the present invention effectively prevents pulmonary arterial hypertension by effectively blocking the thickening of the pulmonary arterial vascular wall in a rat model inducing pulmonary arterial hypertension by MCT or As it can be treated, it can prevent the heart, especially the right ventricle, from becoming enlarged.

1 is a control group, monocrotalin (Monocrotaline; MCT) administration group and 5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione after administration of MCT (5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, A-2) Enlarged results of H & E staining of the heart extracted from the experimental group It is.
2 is a view showing a comparison of the mass ratio of the right ventricle to the sum of the left ventricle and diaphragm mass of the heart extracted from the control group, the MCT-administered group, and the A-2 administration experiment group by dose after MCT administration.
3 is a view showing a comparison of the average thickness of the pulmonary vascular wall extracted from the control group, the MCT-administered group and the A-2-administered experimental group by dose after MCT administration.
Figure 4 is a control group, after administration of MCT and MCT 2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (2,3-dithia-5,7-diazabicyclo [ 2.2.2] octane-6,8-dione, A-1), 4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8- Dione (4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, A-3) and 7- (4-methoxybenzyl) -2 , 3-Dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (7- (4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, A-6) This diagram compares the shape and size of the total heart and right ventricle extracted from the administration group.
Figure 5 is the total mass of the left (left) heart and the left ventricle and diaphragm mass sum of the (right) heart extracted from the control group, MCT and MCT after administration of 6 μg A-1, A-3 and A-6 respectively It is a diagram showing a comparison of the mass ratio of the right ventricle.
Figure 6 is a control group, after administration of MCT and MCT A-1, A-3, 5,7-diallyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8 -Dion (5,7-diallyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, A-5) and A-6 were extracted from the experimental group administered with 6 μg This is an enlarged view of the results of H & E staining of the heart.
7 is a view showing a comparison of the average thickness of the pulmonary vascular wall extracted from the experimental group administered with 6 μg of A-1, A-3, A-5 and A-6, respectively, after administration of the control group, MCT and MCT.

Hereinafter, the present invention will be described in more detail through examples. These examples are only intended to illustrate the present invention in more detail, and the scope of the present invention is not limited by these examples.

Manufacturing example  One: Monocrotalin -Induction of pulmonary arterial hypertension test animal

Male SD rats weighing about 210 g were used as animal models. In order to induce pulmonary arterial hypertension, monocrotaline (MCT) was injected once intraperitoneally at a dose of 60 mg / kg body weight. Accordingly, the rat model in which pulmonary arterial hypertension was induced was not administered or administered with the test drug, maintained for 3 weeks, and then lethalized to analyze the heart.

Example  One: Epidithiodioxopiperazine series  Effect of the compound on the treatment of pulmonary arterial hypertension-1

In the animal model of pulmonary arterial hypertension prepared according to Preparation Example 1, the epidithiodioxopiperazine-based compound 5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6 , 8-dione (5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, compound of formula 3, hereinafter referred to as A-2) 3 And 6 μg dose every 3 days. As in Preparation Example 1, a normal rat not administered with monocrotalin was used as a control group, and a rat inducing pulmonary arterial hypertension by administering only MCT was used as an MCT experimental group. The control group and each experimental group consisted of 3 to 4 rats.

Similar to Preparation Example 1, after maintaining for 2 weeks, the heart was extracted, and the extracted heart was measured for total mass, and then the right ventricle was separated to measure the mass of the right ventricle, left ventricle, and septum, respectively, and the ratio was calculated.

In addition, the pulmonary artery vascular wall was observed in the heart extracted through H & E staining and the thickness was measured, and the results are shown in FIG. 1. In addition, in order to visualize the difference in the heart and pulmonary arteries in the pulmonary arterial hypertension model and after induction of pulmonary arterial hypertension by dose A-2, the ratio of the right ventricle to the left ventricle and the pulmonary vascular wall calculated from the extracted heart in each animal model The average values of the thicknesses are summarized in FIGS. 2 and 3, respectively, and graphed.

As a result, as shown in FIG. 1, in the MCT-administered group, severe thickening of the pulmonary artery wall was observed, but in the group administered with A-2 after MCT administration, the thickening of the pulmonary artery wall was relieved to a level similar to the normal level. Confirmed.

In addition, as shown in FIG. 2, in the MCT-administered group, the heart size, in particular the right ventricle size for the left ventricle, increased by about 50%, but the size of the right ventricle also recovered to the normal level in the group administered with A-2 after MCT administration.

Furthermore, as shown in FIG. 3, in the MCT-administered group, the vascular wall thickness became thicker to 90%, but in the group administered with A-2 after MCT administration, it was confirmed that the thickened vascular wall thickness decreased again to the normal level.

Overall, it was confirmed that the administration of A-2 at all administered doses effectively blocked the hypertrophy of the pulmonary artery vascular wall and the hypertrophy of the heart, especially the right ventricle, a symptom of pulmonary arterial hypertension induced by MCT administration.

Example  2: Epidithiodioxopiperazine series  Effect of the compound on the treatment of pulmonary arterial hypertension-2

Through Example 1, it was confirmed that the efficacy of the treatment of pulmonary arterial hypertension of A-2, which is one of the epidithiodioxopiperazine derivative compounds, was to confirm whether the additional epidithiodioxopiperazine derivative compounds have the same efficacy. .

Specifically, 2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (2,3-dithia-5,7-diazabicyclo [2.2.2] instead of A-2 ] octane-6,8-dione, compound of formula 2, hereinafter A-1), 4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6 , 8-dione (4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, compound of formula 4, hereinafter A-3), 5, 7-diallyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (5,7-diallyl-2,3-dithia-5,7-diazabicyclo [ 2.2.2] octane-6,8-dione, compound of formula 5, hereinafter A-5) and 7- (4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2. 2] Octane-6,8-dione (7- (4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, compound of formula 6, hereinafter A- 6) Except for use in a 6 μg dose, the size of the total heart extracted and the size of the separated right ventricle observed by experiments in the same manner as in Example 1 were visually observed and shown in FIG. 4. Fig. 5 shows the mass of the heart and the ratio of the right ventricle to the left ventricle. Furthermore, the thickness of the pulmonary vascular wall was measured through H & E staining of the extracted heart fragment, and the thickness of the vascular wall of the pulmonary artery was measured, and the average value thereof was graphically shown in 7.

As a result, as shown in Figs. 4 and 5, the size of the heart enlarged by MCT, especially the size of the right ventricle, is all by administration of the epidithiodioxopiparagine derivative compounds A-1, A-3 and A-6. It was reduced to a level similar to normal.

In addition, as shown in Figs. 6 and 7, the thickening of the pulmonary artery vascular wall induced by MCT administration was all restored to normal levels by administration of A-1, A-3, A-5 and A-6.

Overall, it was confirmed that all of A-1, A-3, A-5 and A-6 belonging to the epidithiodioxopiperazine derivative compounds exhibit an effect of effectively alleviating the symptoms of pulmonary arterial hypertension.

Claims (4)

Epidithiodioxopiperazine (epidithiodioxopiperazine) ring containing an intramolecular disulfide crosslinked in the epidithiodioxopiperazine compound represented by Formula 1, or a pharmaceutically acceptable salt thereof, for the prevention or treatment of pulmonary arterial hypertension Pharmaceutical composition:
[Formula 1]

In the above formula,
R ₁ to R ₄ are each independently hydrogen, methyl, butyl, allyl, or methoxybenzyl.
delete According to claim 1,
The compound represented by Formula 1 is any one of the following Formulas 2 to 7:
[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

.
According to claim 1,
The prevention or treatment of the pulmonary arterial hypertension is achieved by mimicking the intracellular activity of PrxII.

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