WO2019009646A1 - Epidithiodioxopiperazine compound or derivative thereof, or pharmaceutical composition for preventing or treating pulmonary hypertension, containing pharmaceutically acceptable salts thereof - Google Patents

Abstract

The present invention relates to: an epidithiodioxopiperazine (ETP) compound or a derivative thereof; or a pharmaceutical composition for preventing or treating pulmonary hypertension, containing pharmaceutically acceptable salts thereof.

Description

A pharmaceutical composition for the prevention or treatment of pulmonary arterial hypertension comprising an epididioidoxapiperazine compound or derivative thereof, or a pharmaceutically acceptable salt thereof

The present invention relates to epidithiiodioxopiperazine (ETP) compounds or derivatives thereof; Or a pharmaceutically acceptable salt thereof, for the prophylaxis or treatment of pulmonary arterial hypertension.

The artery is a pulmonary arterial hypertension in which the arterial blood is returned from the right ventricle to the lungs for oxygen supply. The pulmonary arterial hypertension is defined as the mean pulmonary artery pressure at rest greater than 25 mmHg and the mean pulmonary arterial pressure at 30 mmHg. Pulmonary arterial hypertension is divided into "primary pulmonary arterial hypertension", which is unspecified, and "pulmonary hypertension secondary to pulmonary hypertension," which is secondary to secondary pulmonary hypertension. The latter cases are caused by drugs or toxins such as familial pulmonary arterial hypertension associated with heredity, collagen vascular disease (systemic sclerosis, glomerulonephritic leprosy), portal hypertension, HIV infection, congenital heart disease, and appetite suppressants or cocaine There is a case. These specific disease - associated pulmonary hypertension are not significantly different from primary pulmonary hypertension, spontaneous outcome, histopathologic findings, and response to therapy. Primary pulmonary arterial hypertension is 1.7 times more common in women than men and can occur in all ages, but it is frequent in the 20s and 30s. Approximately 7% of the patients have a family history of BMPR2 gene mutation is associated with the autosomal dominant trait is showing the pattern.

Patients with pulmonary hypertension may present with symptoms such as shortness of breath (dyspnea), fainting, dizziness, peripheral edema (for example, lower extremity edema), helplessness, loss of appetite, increased heart rate, headache, In addition, the hands and toes can easily accompany the Raynode phenomenon where the cold is easily chilled and blue discolored. Patients with pulmonary hypertension often suffer from asthma or excessive stress, often resulting in dyspnea and an average of 2.5 years to be diagnosed correctly.

For the treatment of pulmonary arterial hypertension, surgical intervention such as interventional atrial septal incision, lung transplantation, cardiopulmonary bypass grafting can be performed, but the drug is preferred because it is expensive and risky. Currently, there is a method of using a general vasodilator for treating pulmonary arterial hypertension. However, most vasodilators do not have significant effects on pulmonary arterial hypertension and calcium channel blockers and calcium channel blockers often have side effects due to administration. It is often difficult to apply. Therefore, it is necessary to find effective therapeutic agents for pulmonary arterial hypertension.

The present inventors completed the present invention by confirming that epididioidoxapiperazine compounds or derivatives thereof having intramolecular cross-linking in the epididioidoxapiperazine ring alleviate pulmonary hypertension symptoms in experimental animal models.

The present invention relates to a method for preventing or treating pulmonary arterial hypertension comprising an epididioiodiproprazine compound or derivative thereof having an intramolecular cross-linking in an epidithioiodoperoxazine ring, or a pharmaceutically acceptable salt thereof To provide a pharmaceutical composition.

The pharmaceutical composition comprising the epidithiothioxopiperazine (ETP) compound or derivative thereof of the present invention efficiently inhibits the thickening of the pulmonary arterial wall in a rat model that induces pulmonary arterial hypertension by MCT to prevent or prevent pulmonary hypertension So that it is possible to prevent the heart, especially the right ventricle, from becoming enlarged.

Figure 1 is a graph showing the effect of 5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (monoclonal A diagram showing the result of H & E staining of a heart extracted from a 5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, to be.

FIG. 2 is a graph comparing mass ratios of the right ventricle to the left ventricular and diaphragm mass sum of hearts extracted from the control, MCT-administered group, and the A-2 administration group after administration of MCT.

FIG. 3 is a graph comparing the average thicknesses of pulmonary artery wall obtained from control group, MCT group, and A-2 administration group after administration of MCT.

Figure 4 shows that 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- (4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, A-3) and 7- (4-methoxybenzyl) -2 Diazabicyclo [2.2.2] octane-6,8-dione (7-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, A-6) administration group.

FIG. 5 shows the relationship between the total mass of the heart (left) and the left ventricle and diaphragm mass sum (right) of the heart (left) extracted from the experimental group in which 6 μg of A-1, A-3 and A- 0.0 > right ventricle < / RTI >

Figure 6 is a graph showing the results of A-1, 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, A-5) and A-6 Fig. 3 is an enlarged view of the result of H & E staining of the heart.

FIG. 7 is a graph comparing the average thicknesses of the pulmonary arterial wall obtained from the experimental group administered with 6 μg of A-1, A-3, A-5 and A-6 after administration of the control, MCT and MCT.

The present invention relates to a pharmaceutical composition comprising an epididioidoxapiperazine compound represented by the following formula (1) or a derivative thereof, or a pharmaceutically acceptable salt thereof, having an intramolecular cross-linking in an epidithioiodoperoxazine ring The present invention provides a pharmaceutical composition for preventing or treating pulmonary arterial hypertension.

[Chemical Formula 1]

In the above formulas,

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

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

The present invention is based on the discovery that a series of synthetic small molecule compounds having intramolecular cross-linking in the epidiathiodioxepiperazine ring exert their therapeutic effect on pulmonary arterial hypertension through intramolecular cross-linking. Specifically, in order to identify the key mechanism of action involved in the treatment of pulmonary arterial hypertension, the inventors of the present invention have reported that 2,3-dithia-5,7-diazabicyclo [2.2.2] octanetriol, which is a synthetic small molecule epididioidoxapiperazine derivative, Dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, 4,5,7-trimethyl- Diazabicyclo [2.2.2] octane-6,8-dione and 7- (4-methoxybenzyl) -2,3-dithia-5,7- [2.2.2] octane-6,8-dione showed excellent therapeutic effect against pulmonary arterial hypertension. On the other hand, similarly, it was confirmed that reduction type derivatives containing a dioxopiperazine ring but having two thiol groups instead of intramolecular cross-linking did not show the therapeutic effect of pulmonary arterial hypertension. As a result, it was confirmed that epidritis including intramolecular cross- It is clear that the oedioxypiperazine derivative can exert the therapeutic effect of pulmonary arterial hypertension irrespective of the type of substituent.

Pulmonary arterial hypertension is a type of hypertension affecting the pulmonary artery and right side of the heart. Pulmonary arterial hypertension is defined as the mean pulmonary artery pressure at rest greater than 25 mmHg and mean pulmonary arterial pressure at 30 mmHg.

In one form of pulmonary hypertension, small arteries and capillaries in the lung, called the pulmonary arteries, may become narrowed, obstructed, or damaged, which makes blood flow through the lungs difficult and increases pressure within the pulmonary artery. As a result of this pressure, the lower right chamber (right ventricle) of the right atrium may make the blood pump through the lungs difficult and eventually weaken the heart muscle and cause it to lose function.

Other forms of pulmonary hypertension can continue to worsen and sometimes be fatal and severe conditions. Although any form of pulmonary hypertension can not be cured, treatment for it can help alleviate symptoms and improve quality of life.

The drug for the treatment of pulmonary arterial hypertension has not been elucidated yet. Therefore, a general vasodilator such as a short-acting vasodilator or a calcium channel blocker is used for the treatment of the pulmonary arterial hypertension. However, The case is very low, about 10% of the patients, and there are cases that do not respond to the calcium channel blocker, and even if they respond, the administration is limited due to the high side effects due to the administration of the drug. Thus, pulmonary arterial hypertension differs from general vascular disease in its treatment mechanism, so that the types of drugs that can be applied are very limited. It can be predicted that drugs effective for vascular diseases will also be effective in the treatment of pulmonary arterial hypertension none.

The derivative of the epididioidoxopiperazine compound means a compound comprising an epididioiodopiperazine ring as a parent nucleus exhibiting activity. The derivative may be a compound substituted with various substituents of a kind known in the art to the NH or CH group in the ring of the compound represented by the formula (2), or may include a compound having a structure in which various compounds known to those skilled in the art are bound But are not limited to. The modification and substitution of the structure of the compound of formula (2) can be easily carried out by those skilled in the art, for example, as follows.

For example, the derivative of the epidiathiodioxypiperazine compound may be any one of the compounds represented by the following formulas (2) to (7):

(2)

(3)

[Chemical Formula 4]

[Chemical Formula 5]

[Chemical Formula 6]

(7)

The compounds of formulas (2) to (7) can be synthesized and used by those skilled in the art with reference to known methods. For a specific synthesis method, reference is made to the method disclosed in Korean Patent Registration No. 1633975.

In one embodiment of the present invention, 2,3-dithia-5,7-diazabicyclo [2.2.2] octane-1-one of epidithio-dioxopiperazine derivatives containing a series of intramolecular cross- (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 represented by the following formula (3): < EMI ID = Trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione (4,5,7- 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- (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 ] octane-6,8-dione, Formula 6) pulmonary arterial hypertension It confirmed the charge effect. Specifically, when the compounds of formulas (2) to (6) were administered to experimental animals in which pulmonary arterial hypertension was induced by monoclotharin administration, it was confirmed that the remarkable right ventricular hypertrophy and pulmonary hypertension in the pulmonary arterial hypertension model were reduced to levels similar to normal Respectively. This is an effect achieved through intramolecular cross-linking, which involves intramolecular cross-linking and which shares the same parent structure as the compounds of formulas 2 to 6 and which is only a substituent of similar nature on the nitrogen and / It will be apparent to those skilled in the art that the substituted compounds of formula 7 will also have equivalent effects.

The epididioidoxapiperazine compound or derivatives thereof may be isolated from natural sources, prepared by chemical modification from natural sources, or chemically synthesized by those skilled in the art with reference to known production methods, It can be purchased and used. Preferably, the epididioidoxapiperazine compound or derivatives thereof is isolated from a bacterium, a culture medium thereof or a metabolite thereof according to a known method in the art, or synthesized by the production method described in the prior patent of the present inventor (Korean Registered Publication No. 1633975).

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

The epidiathiodioxapiperazine compounds or derivatives thereof of the present invention can be used in the form of pharmaceutically acceptable salts. The compounds of the present invention or derivatives thereof may be used alone or in combination or in combination with other pharmaceutically active compounds.

The term " pharmaceutically acceptable salt " as used herein means all salts which possess the desired biological and / or physiological activity of the compounds or derivatives and which exhibit minimal undesired toxicological effects. In the present invention, as long as the diketopiperazine ring containing the intramolecular cross-linking is retained, it is possible to use it without limitation. Salts are useful as acid addition salts formed by pharmaceutically acceptable free acids. The acid addition salt is prepared by a conventional method, for example, by dissolving the compound in an excess amount of an acid aqueous solution, and precipitating the salt using a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. The same molar amount of the compound and the acid or alcohol (e.g., glycol monomethyl ether) in water may be heated and then the mixture may be evaporated to dryness, or the precipitated salt may be subjected to suction filtration. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, tartaric acid and the like can be used. Examples of the organic acid include methanesulfonic acid, p-toluenesulfonic acid, acetic acid, Maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic 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, vanillic acid, But are 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 amount of an alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the non-soluble compound salt, and evaporating and drying the filtrate. At this time, as the metal salt, it is preferable to produce sodium, potassium or calcium salt particularly, but not limited thereto. The corresponding silver salt may be obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

The pharmaceutically acceptable salts of the epididioiodopyropazine compounds or derivatives thereof according to the present invention include all salts of acidic or basic groups which 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, (Mesylate) and p -toluenesulfonate (tosylate) salts, which are known to those skilled in the art and which are known in the art, .

The compositions according to the present invention may further comprise suitable carriers, excipients and diluents conventionally used in the manufacture of pharmaceutical compositions. The composition may be sterile or aseptic, and such solutions may be sterile or sterile and may contain water, buffers, isotonic agents or, if applied to animals or persons, those which do not cause allergic or other adverse reactions, 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. The use of such media and preparations for pharmaceutically active substances is well known in the art. In addition to conventional media or preparations that are incompatible with the active ingredient, their use in therapeutic compositions is contemplated. In addition, supplemental active ingredients may be incorporated into the compositions.

The composition may be prepared in the form of a liquid, an oil, a suspension, a cream or the like, and may be parenterally used. The amount of the composition to be used may be generally used for preventing vascular restenosis, and it is preferably applied according to the age, sex, condition of the patient, the degree of absorption of the active ingredient, the inactivation rate, and the drugs to be used together.

The present invention also provides a method of preventing or treating pulmonary arterial hypertension comprising administering the pharmaceutical composition to a subject in need thereof.

In the present invention, the term " prophylactic " means any action that inhibits or delays pulmonary arterial hypertension by administration of the pharmaceutical composition according to the present invention, and " treatment " means that pulmonary arterial hypertension Means any act that improves or alleviates the symptoms caused by.

In the present invention, the term " individual " means all animals, including humans, who have developed or are capable of developing pulmonary hypertension. The pulmonary arterial hypertension can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject. In addition, the pharmaceutical composition of the present invention may be administered in combination 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 not causing side effects, and the effective dose level is determined by the patient's sex, Factors well known in the art and other medical fields including, but not limited to, the severity of the disease, the health condition, the severity of the disease, the activity of the drug, the sensitivity to the drug, the mode of administration, the time of administration, the route of administration and rate of release, Can be easily determined by those skilled in the art.

The term " administering " of the present invention means introducing a predetermined substance into a patient in an appropriate manner, and the administration route of the composition can be administered through any conventional route as long as it can reach the target tissue. The method of administration is not limited thereto, but it can be orally administered or parenterally administered in the form of tablet or the like. In the case of parenteral administration, it can be achieved by inhalation administration such as intravenous injection, subcutaneous administration, or nasal administration. In addition, it can be administered topically 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 microparticle . Most preferably, the composition of the present invention may be applied in a stent and administered directly to the site of pulmonary hypertension.

As a specific example of administration, the composition of the present invention may be used for inhalation administration in an injection device in the form of a syringe or a spray device. For example, the device may include a tubular injection device through which the drug may be injected into the nasal cavity, but is not necessarily limited thereto. Or injecting device in the form of a syringe, the discharge portion corresponding to the syringe needle is inserted into the nasal cavity of the subject, and then the discharge pressure applying portion corresponding to the piston of the syringe is operated to apply the composition of the present invention in liquid form to the nasal cavity can do. At this time, the shape of the injection device is not limited to the conventional syringe type. In the case of including an injection device in the form of a spray injector, as in the case of using a syringe type injection device, the discharge part is placed in the nostril or nasal cavity, which is the entrance of the nasal cavity, Lt; / RTI > When a tube-shaped injection device is included, the composition of the present invention may be injected into the nasal cavity in a liquid form through a method of inserting the discharge portion into the nasal cavity of the subject, as described above, and applying pressure to the tube. The form of the injection device described above is only a concrete example, and any device capable of injecting the composition of the present invention into the nasal cavity can be used without any particular limitation.

The present invention also provides a drug delivery device for local 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 dual balloon catheter, a dispatch, a microballoon, a stent, and the like, preferably a stent.

The term " stent " as used herein refers to a general device for endoluminal application, for example, application to a blood vessel as mentioned above, and a disease occurs at a site where blood flow should be smooth Refers to a cylindrical medical material which, when surgically obstructed, surgically does not undergo open surgery and is inserted into a narrowed or occluded blood vessel under X-ray vision to normalize blood flow. For example, vascular stents are described in Eric J Topol, " Textbook of Interventional Cardiology ", Saunders Company, 1994. Preferably, it is a sustained release drug-eluting stent.

As a method for coating the pharmaceutical composition of the present invention on the stent, a conventional coating method known to a person skilled in the art can be applied. For example, dip coating Polymer coated with polymer, and dip coating method is the simplest coating method. Since it is coated only with a pharmaceutical composition, it is easy to observe biological effects of drugs alone, but it is not limited thereto. Preferably, the stent of the present invention can be prepared by mixing the composition with a polymeric material in a drug releasing stent so that the composition according to the present invention can be released slowly, and coating the mixture. Polymeric materials that can be used in drug release stents are well known in the art and include, for example, polyurethanes, polyethylene terephthalates, PLLA-poly-glycolic acid copolymers (PLGA), polycaprolactones, poly- (Hydroxybutylate / hydroxyvaleate) copolymer, polyvinylpyrrolidone, polytetrafluoroethylene, poly (2-hydroxyethyl methacrylate), poly (ethyleneurea), silicone, acrylic, epoxide, But are not limited to, polyesters, urethanes, pararenes, polyphosphazene polymers, fluoropolymers, polyamides, polyolefins, and mixtures thereof.

The stent is made of or consists of one or more substances selected from polysaccharides, heparin, gelatin, collagen, alginate, hyaluronic acid, arginic acid, carrageenan, chondroitin, pectin, chitosan and derivatives and copolymers thereof, Layer. ≪ / RTI > Suitably, these materials can be incorporated into a biosynthetic topcoat, as described in US 2006/0083772. Methods for forming a stent from a mixture of polymer and drug compound are described in Blindt et al ., 1999, Int . J. Artif . Organs , 22: 843-853.

Hereinafter, the present invention will be described in more detail with reference to Examples. These embodiments are only for describing the present invention more specifically, and the scope of the present invention is not limited by these examples.

Manufacturing example  One: Monoclotharin - Production of experimental pulmonary hypertension experimental animals

Male SD rats weighing approximately 210 g were used as animal models. To induce pulmonary arterial hypertension, Monocrotaline (MCT) was intraperitoneally injected at a dose of 60 mg / kg body weight. Thus, the rat model in which pulmonary arterial hypertension was induced was maintained for 3 weeks while the test drug was not administered or administered, and the heart was lethally analyzed by analysis.

Example 1: Therapeutic effect of epididioidoxopiperazine-based compound on pulmonary arterial hypertension -1

In an animal model of pulmonary arterial hypertension prepared according to Preparation Example 1, 5,7-dimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6, which is an epididioidoxopiperazine compound, , 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) And 6 μg dose every 3 days. As in Production Example 1, normal rats without monoclotharin were used as the control group, and rats with the pulmonary arterial hypertension induced only with MCT were used as the MCT test group. The control and each experimental group consisted of 3 to 4 rats.

Similar to Preparation Example 1, the heart was maintained for 2 weeks, and the heart was extracted. After the total mass was measured, the right ventricle was separated and the masses of the right ventricle, left ventricle, and septum were separately measured to calculate the ratio.

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

As a result, as shown in FIG. 1, severe thickening of the pulmonary arterial wall was observed in the MCT-treated group, but the thickening of the pulmonary vascular wall in the A-2-treated group after MCT administration was alleviated to a level similar to the normal level Respectively.

In addition, as shown in FIG. 2, the size of the right ventricle for the left ventricle was increased by about 50% in the MCT group, but the size of the right ventricle was restored to the normal level in the group administered with MCT after the administration of the MCT.

Furthermore, as shown in FIG. 3, in the MCT-treated group, the wall thickness of the blood vessel wall was increased to 90%, but in the group administered with MCT, the thickened blood vessel wall thickness again decreased to the normal level.

Comprehensively, it was confirmed that administration of A-2 effectively blocked the hypertrophy of the pulmonary arterial wall and the hypertrophy of the right ventricle, which are the symptoms of pulmonary arterial hypertension induced by administration of MCT, at all doses administered.

Example 2: Therapeutic effect of epididioidoxapiperazine-based compound on pulmonary arterial hypertension -2

As a result of confirming the efficacy of A-2, which is one of the epidiathiodo-oxopiperazine derivatives, for the treatment of pulmonary arterial hypertension through Example 1, it was confirmed that the same efficacy was also confirmed for the additional epidetiothioxapiperazine derivative compounds .

Specifically, 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, the compound of formula (2), hereinafter A-1), 4,5,7-trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] Trimethyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, the compound of the formula (4), hereinafter A-3), 5, Diallyl-2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8- 2.2.2] octane-6,8-dione, the compound of Chemical Formula 5, hereinafter A-5) and 7- (4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2. 4-methoxybenzyl) -2,3-dithia-5,7-diazabicyclo [2.2.2] octane-6,8-dione, the compound of Chemical Formula 6, hereinafter referred to as A- 6). The size of the total heart and the size of the separated right ventricle were examined by visual inspection in the same manner as in Example 1, The mass of the heart and the ratio of the right ventricle to the left ventricle were measured and shown in FIG. Further, the thickness of the pulmonary arterial wall was measured by H & E staining of the extracted cardiac segment, and the thickness of the pulmonary arterial wall was measured, and the average value of the thickness was shown in FIG.

As a result, as shown in Figs. 4 and 5, the size of the cardiac size enlarged by the MCT, particularly, the right ventricle was increased by administration of the epididioidoxapiprazine derivative compounds A-1, A-3 and A-6 Which was similar to normal.

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

Overall, it was confirmed that A-1, A-3, A-5 and A-6 belonging to the epidiathiodioxepiperazine derivative compound effectively alleviated the symptoms of pulmonary arterial hypertension.

Claims (4)

1. A pharmaceutical composition comprising an epididioidoxapiperazine compound represented by the following formula (1) having an intramolecular cross-linking in an epidithioiodoperoxazine ring, or a derivative thereof, or a pharmaceutically acceptable salt thereof, A pharmaceutical composition for preventing or treating:

   [Chemical Formula 1]

   

   In the above formulas,

   R ₁ to R ₄ are each independently hydrogen, straight or branched chain alkyl of C1 to C6, alkenyl or alkynyl, or benzyl substituted by C1 to C6 alkoxy.
2. The method according to claim 1,

   R ₁ to R ₄ are each independently hydrogen, methyl, butyl, propenyl, allyl, methoxybenzyl, methoxypropyl or benzhydryl.
3. The method according to claim 1,

   Wherein the compound represented by the formula (1) is any one of the following formulas (2) to (7):

   (2)

   

   (3)

   

   [Chemical Formula 4]

   

   [Chemical Formula 5]

   

   [Chemical Formula 6]

   

   (7)

   

   .
4. The method according to claim 1,

   Wherein the prevention or treatment of pulmonary arterial hypertension is accomplished by mimicking the intracellular activity of PrxII.

Images