KR20100137090A - Novel thiazolidinedione derivative and uses thereof - Google Patents

Abstract

PURPOSE: A novel thiazolidinedione derivative is provided to prevent or treat cardiovascular diseases, gastrointestinal disease and renal diseases. CONSTITUTION: A thiazolidinedione derivative is selected from derivative 1-4. A pharmaceutical composition for preventing hair loss and promoting hair growth contains the thiazolidinedione derivative or pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for preventing and treating cardiovascular diseases contains the thiazolidinedione derivative or pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for preventing and treating gastrointestinal diseases or renal diseases contains the thiazolidinedione derivative or pharmaceutically acceptable salt thereof as an active ingredient.

Description

Novel Thiazolidinedione Derivative and Uses Thereof

The present invention relates to novel thiazolidinedione derivatives and their use. More specifically, the present invention relates to novel thiazolidinedione derivatives and pharmaceutical compositions comprising the same.

Prostaglandin is a fatty acid derivative of 20 carbons and contains a ring of 5 carbons. The substance was discovered in 1935 by Swedish physiologist Wolf von Euler, who named it prostaglandin because he thought it was secreted from the prostate. It is presently widely present in the tissues of animals and is known to be quickly metabolized after synthesis from polyunsaturated fatty acids. These prostaglandins can stimulate smooth muscle contraction, depending on their form, and in some animals they act to lower or raise blood pressure, reduce or increase blood cohesion, as well as promote ion transport to the membrane, stimulate inflammation, and It is also known to act to inhibit vascular disease and viral infections.

Prostaglandins and their analogs, on the other hand, are chemically unstable and have a short effective life due to rapid metabolism in vivo, which is why prostaglandins and their analogs generally have active sites in the form of hydroxyl and carboxyl groups. This is because enzymes rapidly inactivate these activators and are also present in molecular weights small enough to be easily removed and excreted from the body (Narumiya S. et al., 1999, Physiol. Rev., 79 (4), 1193-). 1226). Therefore, since prostaglandins and their homologues are chemically unstable and have very short effective periods, prostaglandins and their homologues have severe restrictions on their use for the treatment of diseases such as the respiratory system, genitals, nerves, endocrine glands and cardiovascular system.

Therefore, in order to solve the above problems, studies are being conducted to develop pharmaceutically acceptable formulations that provide improved stability of prostaglandins and their homologues, a wider range of administration methods, more effective activities or longer effective periods. Looking at the related prior arts, Korean Patent No. 0598660 discloses the contents of 5 -thia-ω-substituted phenyl-prostaglandin E derivatives that can strongly bind to the prostaglandin receptor for excellent activity, and Korean Patent No. 0850133 No. discloses prostaglandin nitrooxy derivatives that reduce side effects caused by prostaglandins and maximize pharmacological effects, and Korean Patent Laid-Open No. 2001-0023839 discloses aromatic C16-C20-substituted tetrahydropros useful as Fp agonists. The other prostaglandin is disclosed.

On the other hand, prostaglandins have short physiological activity due to rapid metabolism in vivo. The first step of this metabolic process is oxidation, where prostaglandins are NAD + dependent 15-hydroxyprostaglandin dehydrogenase (15-hydroxyprostaglandin dehydrogenase: 15-PGDH). Inactivated by Ensor, CM, & Tai, HH, 1995, J. Lipid Mediator Cell Signaling 12: 313-319).

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is an enzyme that degrades prostaglandins, and the amount of prostaglandin is increased in tissues in which 15-PGDH is not expressed. In addition, 15-PGDH enzyme is ubiquitous in mammalian tissue, initially extracted and isolated from placenta, lung and kidney (Krook M et al., 1990, Biochemistry , 29, 738-743), and its function is C Prostaglandin-based compounds containing a hydroxyl group (-OH) at the -14 position are oxidized to convert to 15-ketoprostaglandin and thus lose the biological activity of the compound (Tai HH et al., 2002, Adv). Exp Med Biol , 507, 245-250).

Recent studies have shown that 15-PGDH plays a potential role in carcinogenesis, ie the expression of 15-PGDH is more pronounced in human prostate cancer cells than in cells treated with androgens. Increased expression of 15-PGDH in tumors from nude mice injected with human prostate cancer cells (M. Tong., 2000, Biochem . Biophys . Res . Commun ., 276, 77-81). ). Many researchers have anticipated that inhibiting or reducing the expression of 15-PGDH in cells can inhibit cancer development.

Therefore, there are active studies on inhibitors capable of inhibiting the activity of 15-PGDH, in particular, cyclooxygenase inhibitors, flavonoids, phytophenolic compounds and peroxysome proliferation It has been shown that peroxisome proliferator-activated receptor γ (PPAR γ) has an inhibitory effect on 15-PGDH.

Therefore, the present inventors found a new thiazolidinedione derivative while researching a new compound capable of inhibiting 15-PGDH in addition to the above compound, and the derivative not only has an excellent activity of inhibiting 15-PGDH, but also promotes hair growth. The present invention was completed by confirming that there is an effect of improving cardiovascular disease, gastrointestinal disorder, and kidney disorder.

It is therefore an object of the present invention to provide novel thiazolidinedione derivatives.

In addition, another object of the present invention to provide a pharmaceutical composition for preventing hair loss and promoting hair growth containing the derivative as an active ingredient.

In addition, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing the derivative as an active ingredient.

In addition, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases containing the derivative as an active ingredient.

In addition, another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of kidney disease containing the derivative as an active ingredient.

In order to achieve the above object of the present invention, the present invention provides a novel thiazolidinedione derivative.

The present invention also provides a pharmaceutical composition for preventing hair loss and promoting hair growth, containing the derivative as an active ingredient.

The present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing the derivative as an active ingredient.

The present invention also provides a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases containing the derivative as an active ingredient.

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating kidney disease containing the derivative as an active ingredient.

The novel thiazolidinedione derivatives according to the present invention have an excellent effect of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH), and cardiovascular, gastrointestinal and kidney diseases that can be induced by 15-PGDH. It is effective to prevent and treat the effects of preventing hair loss and promoting hair growth.

The present invention is characterized by providing a novel thiazolidinedione derivative represented by the following formula (1).

[Formula 1]

이며, R₂는 치환 또는 비치환 (헤테로)사이클로알킬; 또는 (헤테로)사이클로알케닐 또는 (헤테로)아릴일 수 있다. Wherein X is nitrogen (N), carbon (C) or sulfur (S), and R ₁ is hydrogen (H) or

R ₂ is substituted or unsubstituted (hetero) cycloalkyl; Or (hetero) cycloalkenyl or (hetero) aryl.

또는

일 수 있다.In addition, R ₂ is

or

Can be.

Preferably, specific examples of the thiazolidinedione derivative represented by Chemical Formula 1 may be derivatives prepared in Examples 1 to 4 herein.

The term "alkyl" as used herein refers to an unsubstituted or substituted straight or branched chain hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 7 carbon atoms. Representative unsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl and the like. Substituted alkyl groups are halo, hydroxy, cycloalkyl, alkanoyl, alkoxy, alkyloxyalkoxy, alkanoyloxy, amino, alkylamino, dialkylamino, acylamino, carbamoyl, thiol, alkylthio, alkylthiono, Sulfonyl, sulfonamido, sulfamoyl, nitro, cyano, carboxy, alkoxycarbonyl, aryl, alkenyl, alkynyl, aralkyloxy, guanidino, indolyl, imidazolyl, furyl, thienyl, thia Alkyl groups substituted by one or more selected from the group consisting of zolyl, pyrrolidyl, pyridyl, pyrimidyl, piperidyl and morpholinyl, but are not limited to these.

The term "alkenyl" refers to any of the above alkyl groups having two or more carbon atoms and including double bonds, preferably having two to four carbon atoms.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms in the ring portion, for example phenyl, naphthyl, tetrahydronaphthyl, biphenyl and diphenyl groups, these Each has 1 to 4 substituents such as alkyl, halo, hydroxy, alkoxy, acyl, alkanoyloxy, optionally substituted amino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, Carbamoyl, alkylthioo, sulfonyl, sulfonamido, heterocyclyl and the like.

The term "cycloalkyl" means an optionally substituted monocyclic, bicyclic or multicyclic ring system having 3 to 12 carbon atoms, each of which has one or more substituents such as alkyl, halo, Oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl, alkylamino, dialkylamino, thiol, alkylthio, nitro, cyano, carboxy, carboxyalkyl, alkoxycarbonyl, sulfonyl, sulfonamido, And may be substituted with sulfamoyl, heterocyclyl, and the like.

"Cycloalkenyl" means a mono or multicyclic ring system having 3 to 12 carbon atoms containing one or more carbon-carbon double bonds, each of which may be substituted with one or more substituents.

The term “heterocyclo” is a ring system representing an optionally substituted fully saturated or unsaturated, aromatic or non-aromatic cyclic group, having at least one hetero atom in a ring containing at least one carbon atom. Each ring of the click group may have one, two or three heteroatoms selected from nitrogen atoms, oxygen atoms and sulfur atoms, and the heterocyclic groups may be bonded to heteroatoms or carbon atoms.

In addition, the present invention provides a salt of a thiazolidinedione derivative represented by Chemical Formula 1, preferably a pharmaceutically acceptable salt. The term “pharmaceutically acceptable salts” means salts suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation and side effects within the scope of pure medical judgment. Such pharmaceutically acceptable salts are well known in the art (SM Berge et. al ., 1977, J. Parmaceutical Sciences , 66: 1). The salts can be prepared in situ during the final separation, purification and synthesis of the derivative compounds of the invention or separately by reaction with an inorganic base or an organic base. As the pharmaceutically acceptable salt, when the derivative compound of the present invention contains an acidic group, it may form a salt with a base. Examples of the salt include, but are not limited to, lithium salt, sodium salt or Salts with alkali metals such as potassium salts; Salts with alkaline earth metals such as barium or calcium; Salts with other metals such as magnesium salts; Organic base salts such as salts with dicyclohexylamine; Salts with basic amino acids such as lysine or arginine. In addition, when the derivative compound of the present invention contains a basic group in a molecule, an acid addition salt may be formed. Examples of such acid addition salts include, but are not limited to, inorganic acids, particularly hydrofluoric acid (eg, hydrofluoric acid, hydrobromic acid). , Hydroiodic acid or hydrochloric acid), salts with nitric acid, carbonate, sulfuric acid or phosphoric acid; Salts with lower alkyl sulfonic acids such as methanesulfonic acid, trifluoromethanesulfonic acid or ethanesulfonic acid; Salts with benzenesulfonic acid or p-toluenesulfonic acid; Salts with organic carboxylic acids such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, succinic acid or citric acid; And salts with amino acids such as glutamic acid or aspartic acid.

The invention may also include derivatives in the form of hydrates or solvates of the novel thiazolidinedione derivatives represented by Formula 1 (JM Keith, 2004, Trahedron Letters , 45 (13), 2739-2742).

The novel thiazolidinedione derivatives of Formula 1 according to the present invention may be isolated from nature or prepared by chemical synthesis of thiazolidinedione-based compounds known in the art. The derivative compound according to the present invention is obtained by reacting a substituent compound to be substituted at 5 'with an appropriate reaction solvent to obtain an intermediate product, and then reacting the intermediate product with 2,4-thiazolidinedione in an appropriate reaction solvent. Can be prepared.

The reaction solvent that can be used in the production process is not particularly limited as long as it is not involved in the reaction, for example, ethers such as diethyl ether, tetrahydrofuran, dioxane; Halogenated hydrocarbons such as dichloromethane and chloroform; Amines such as pyridine, piperidine and triethylamine, acetone; Alkyl ketones such as methyl ethyl ketone and methyl isobutyl; Alcohols such as methanol, ethanol and propanol; Aprotic polar solvents such as N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, dimethyl sulfoxide, hexamethyl phosphate triamide, and the like, and especially non-reactive used in organic synthesis. Among the organic solvents, a solvent capable of separating the water generated during the reaction by the Dean-Stark trap is preferred. Examples of such a solvent include, but are not limited to, benzene, toluene, xylene, and the like. Separation and purification of the reaction product is carried out through a process such as concentration, extraction, and the like, which is commonly performed in organic synthesis, and separation and purification may be performed through purification by column chromatography on silica gel, if necessary.

The invention also includes any modification to the methods for the preparation of novel thiazolidinedione derivatives, wherein the intermediate product obtainable at any stage thereof can be used as starting material for the remaining stages, The starting material can be formed in the reaction system under reaction conditions, or the reaction components can be used in the form of its salts or optically enantiomers.

The novel thiazolidine derivatives according to the invention are also possible isomers, such as substantially pure geometric (cis or trans) isomers, optical isomers, depending on the type of substituents used to prepare the derivatives, the intermediate product and the method of preparation. (Enantiomers) or racemates, all such possible isomers are included within the scope of the present invention.

On the other hand, the novel thiazolidinedione derivative represented by the formula (1) according to the present invention is characterized by having an activity of inhibiting or inhibiting 15-hydroxy prostaglandin dehydrogenase (15-PGDH).

In one experimental example of the present invention, in order to determine whether the novel thiazolidinedione derivatives according to the present invention have activity to inhibit or inhibit 15-hydroxy prostaglandin dehydrogenase (15-PGDH), After treatment with a novel thiazolidinedione derivative according to the invention, the amount of NADH generated was measured. When 15-PGDH had high activity, NAD + was reduced to oxidize prostaglandin while producing NADH. This is because the activity of 15-PGDH can be confirmed by measuring the amount of NADH because it produces inactive 15-ketoprostaglandin. Therefore, as a result of the above experiment, it was confirmed that the novel thiazolidinedione derivative according to the present invention has an activity of inhibiting 15-PGDH (see Experimental Example 1).

Therefore, the present inventors have confirmed that the novel thiazolidinedione derivative of the present invention is an inhibitor of 15-PGDH, and the derivative of the present invention can be used for the prevention or treatment of diseases which may be caused by 15-PGDH. Could be expected.

On the other hand, prostaglandins have been known to play an important role in hair growth, and in order to maintain or increase hair density, prostaglandins of various types (A ₂ , F _2a , E ₂ ) in various zones of the hair follicle or nearby skin environment are known. Internal storage has been found to be very essential (Colombe L et al., 2007, Exp . Dermatol, 16 (9), 762-9). However, enzymes that are specifically involved in the degradation of prostaglandins are present in the dermal papilla of the hair, a critical zone for hair survival, and 15-PGDH inactivates prostaglandins, especially PGF _2a and PGE ₂ , damaging the scalp and causing hair loss. (Michelet JF et al., 2008, Exp . Dermatol , 17 (10), 821-8).

Therefore, the novel thiazolidinedione derivatives according to the present invention have an activity of inhibiting or inhibiting 15-hydroxy prostaglandin dehydrogenase (15-PGDH) that degrades prostaglandins, thereby improving scalp damage. It can prevent hair loss and has the effect of promoting hair growth.

Therefore, the present invention provides a pharmaceutical composition for preventing hair loss and promoting hair growth, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.

As used herein, the term "alopecia" refers to the entire hair follicle state with partial or general permanent hair loss, and the target of hair loss and hair growth may be human keratin fibers, especially hair, eyebrows, eyelashes, beards, and mustaches. have.

The present invention also provides a pharmaceutical composition for the prevention or treatment of cardiovascular diseases containing a novel thiazolidinedione derivative according to the present invention as an active ingredient.

Prostaglandins, including the prostaglandin homologues produced in the body, are known to play a role in maintaining the proper functioning of the blood vessel wall, particularly in the smooth muscle cell proliferation that relaxes blood vessels to prevent blood flow, prevents platelet aggregation, and surrounds the blood vessel wall. It is known to contribute to regulation (Yan. Cheng et al ., 2006, J. Clin ., Invest ). In addition, when the production of prostaglandins is inhibited or the activity is lost, degeneration of the lining of the blood vessel wall, aggregation of platelets and disruption of smooth muscle cells may be caused, leading to cardiovascular diseases, particularly in the case of high blood pressure. Prostaglandin production has been shown to be reduced (Tang EH, 2008, Cardiovasc) Res ., 78 (1), 130-8).

Therefore, since the novel derivative compounds according to the present invention have the activity of inhibiting or inhibiting 15-PGDH that degrades prostaglandins, prostaglandins (PGE ₂ ) can be stored and activated in cells to prevent or treat cardiovascular diseases.

The "cardiovascular disease" is caused by deterioration of the lining of the blood vessel wall, abnormality in the aggregation of platelets or the regulation of smooth muscle cells, or low density lipoprotein cholesterol in the blood (hereinafter referred to as 'LDL-cholesterol'), Examples of such cardiovascular disorders include, but are not limited to, arteriosclerosis, hypertension, angina pectoris, hyperlipidemia, myocardial infarction, including both diseases caused by hypercholesterolemia with abnormally high cholesterol and triglycerides Heart failure, and the like.

The present invention also provides a pharmaceutical composition for the prevention or treatment of gastrointestinal diseases, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.

Gastritis and gastric ulcers, which are representative diseases of gastrointestinal diseases, refer to a condition in which the gastrointestinal mucosa is digested by gastric acid to form ulcers. And gastric ulcer refers to a case of damage to the submucosal or muscular layer. However, gastritis and gastric ulcers are not known to have a high degree of incidence, but are known to be caused only by an imbalance between attackers and defenders, that is, increase in attackers or weakening of defenders. Factors that increase the attack factor include increased acid and pepsin secretion, and factors that weaken the protective factor include deficiency in the structure and form of the gastric mucosa, decreased mucus secretion, decreased bicarbonate ion secretion, and decreased prostaglandin production. Can be mentioned. On the other hand, currently used therapeutic agents for gastritis and gastric ulcers, such as antacids that neutralize gastric acid secretion without affecting the amount of gastric acid secretion, drugs that inhibit the secretion of gastric acid, secretion accelerators of prostaglandins and gastric wall coatings, etc. Drugs are being used, and the role of prostaglandins is particularly essential in maintaining the protective and protective action of the gastric mucosa (Wallace JL., 2008, Physiol). Rev. , 88 (4), 1547-65, SJ Konturek et al., 2005, Journal of Physiology and Pharmacology , 56 (5), 5-31)

Therefore, the novel thiazolidinedione derivatives according to the present invention have an activity of inhibiting or inhibiting 15-PGDH that degrades prostaglandins that protect the gastric mucosa, thereby preventing or treating gastrointestinal diseases, especially gastritis and gastric ulcers. There is.

In addition, prostaglandins in the kidney are known to regulate blood flow in the kidney and to regulate urinary formation by both renal and vascular effects. Clinical studies have shown that prostaglandin 1 (PGE1) improves creatinine purification in patients with chronic kidney disease, prevents transplant rejection and cyclosporin toxicity in patients with kidney transplantation, release rate of urinary albumin in diabetic nephropathy, and N-acetyl-β-D. It has been shown to be effective in reducing glucosaminidase levels, and methods have been disclosed to prevent renal dysfunction by intravenous administration of prostaglandin compounds such as PGE1, PGE2 and PGI2 (Porter, Am., 1989, J. Cardiol ., 64: 22E-26E, US Pat. No. 5,807,895). In addition, prostaglandins act as vasodilators that dilate blood vessels in the kidneys and are known to cause renal failure when prostaglandin production is inhibited in the kidneys (Hao. CM, 2008, Annu). Rev Physiol , 70, 357-77).

Therefore, the novel thiazolidinedione derivative according to the present invention which inhibits or inhibits 15-PGDH that degrades prostaglandins can prevent or treat kidney disease due to renal dysfunction.

The term "renal dysfunction" means that the normal creatinine is less than the purified amount, the normal free water is less than the purified amount, the level of normal blood urea or nitrogen or potassium or creatinine exceeds the normal, or the kidney enzymes such as gamma glutamyl synthetase , Alanine phosphatidase, N-acetyl-β-D-glucosaminidase or β-2-microglobulin have modulated activity, or macroalbuminuria above normal levels.

Therefore, the present invention provides a pharmaceutical composition for the prophylaxis or treatment of kidney disease, which contains the novel thiazolidinedione derivative according to the present invention as an active ingredient.

As described above, the novel thiazolidinedione derivatives of the present invention are inhibitors of 15-PGDH, which can prevent hair loss and promote hair growth through the action of inhibiting the decomposition of prostaglandins, cardiovascular diseases, There is an effect that can treat or prevent gastrointestinal diseases and kidney diseases.

As used herein, the term “inhibitor of 15-PGDH” refers to a compound capable of inhibiting or reducing the activity of 15-PGDH enzyme, especially in humans, or inhibiting, decreasing or slowing the reaction catalyzed by the enzyme. It means a derivative of 1.

Meanwhile, the pharmaceutical composition containing the derivative compound represented by Formula 1 according to the present invention as an active ingredient may be prepared by mixing with a pharmaceutically acceptable carrier or excipient or diluting with a diluent according to a conventional method. In addition, the pharmaceutical composition may further include fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives. The pharmaceutical compositions of the invention can be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.

The pharmaceutical compositions of the present invention may be prepared in various parenteral or oral dosage forms according to known methods. In the case of solid dosage forms for oral administration, excipients, if necessary, binders and disintegrants in the derivative compounds of the present invention. , Lubricating agents, coloring agents, flavoring agents, and / or coagulants may be added and the resulting mixture may be prepared in the form of tablets, dragees, granules, powders or capsules by conventional methods. As the additive, those conventionally employed in the art may be used, and examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid, and the like. , Propanol, short syrup, sucrose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate And polypyrrolidone. Examples of the disintegrant include dry starch, sodium arginate, agar powder, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monostearate and lactose. Examples of the lubricant include refined talc, stearates, sodium borate, and polyethylene glycol. Examples of the flavor include sucrose, beater orange oil, citric acid, and tartaric acid.

When preparing a solution for oral administration, flavoring agents, buffers, stabilizers, chemistries, etc. can be added to the compounds of the present invention, and can be prepared in the form of solvents, syrups or elixirs according to conventional methods. Examples of buffers include sodium citrate, and examples of stabilizers include tragacanth, acacia and gelatin. In order to prepare an injection, a pH adjusting agent, a buffer, a stabilizer, a relaxant, a local anesthetic may be added to the compound of the present invention, and the resultant mixture may be a subcutaneous injection, a muscle injection or an intravenous injection. Examples of pH adjusters and buffers include sodium citrate, sodium acetate and sodium phosphate. Examples of stabilizers include sodium pyrosulphite, EDTA, thioglycolic acid, and thioractic acid. Local anesthetics include procaine hydrochloride and lidocaine hydrochloride, and examples of the relaxants include sodium chloride and glucose.

When preparing suppositories, the compounds of the present invention may be formulated with pharmaceutically acceptable carriers known in the art, such as polyethylene glycol, lanolin, cacao butter or fatty acid triglycerides, and, if desired, surfactants such as Tween. It can be added and prepared in the form of suppositories according to a conventional method.

When the ointment is prepared, a base, a stabilizer, a moisturizer, a preservative, or the like, which is usually used to prepare an ointment, may be added to the compound of the present invention, and the ointment may be prepared according to a conventional method. Examples of the base include liquid paraffin, white waserine, pewter, octyldodecyl alcohol and paraffin, and preservatives include methyl paraoxybenzoate, ethyl paraoxybenzoate and propyl paraoxybenzoate.

Pharmaceutical compositions formulated in various ways as described above may be administered in a pharmaceutically effective amount via a variety of routes including oral, transdermal, subcutaneous, intravenous or intramuscular.

As used herein, the term “pharmaceutically effective amount” refers to an amount of a compound that is sufficient to improve or treat hair loss, cardiovascular disease, gastrointestinal disease and kidney disease, and the disease and its severity, age, weight, health status, and sex of the patient. Depending on the route of administration and the duration of treatment, it can be changed appropriately.In general, an effective dose of about 1 to 1000 mg for oral administration, about 0.1 to 500 mg for injection, and about 5 to 1000 mg for suppository May be administered. The daily dosage of the formulation depends on the condition, weight, age and sex of the patient and cannot be determined in a batch. Usually the daily dosage is about 0.1-5000 mg, preferably about 1-1000 mg for adults. Administration can be repeated once or once several times a day.

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

< Example >

Synthesis of Derivative Compounds According to the Invention

Prostaglandins (PGE ₂ ), NAD +, NADH, Glutathione Sepharose 4B, DTT, Sodium Dodecyl Sulfate (SDS), EDTA and Reduction, used in the preparation of the derivative compounds according to the present invention and in measuring their activity Glutathione was purchased from Sigma, USA, and cDNA of human 15-PGDH was cloned from human placental cDNA library. In addition, UV spectra was used a UV-VIS spectra photometer (shimadzu Co., Ltd.), NMR spectra was used JEOL JNM-LA 300 spectrometer (JEOL, Tokyo, Japan).

< Example  1>

Preparation of Derivative 1 according to the invention

Derivative 1 represented by the following formula was prepared in the following manner.

<Formula of derivative 1>

4- (2-cyclohexylethoxy) benzaldehyde (1 g, 4.3 mmol) and hydantoin (504 mg, 4.3 mmol) were dissolved in 20 ml of toluene solution, which contained piperidine (0.21 ml, 2.15 mmol) and acetic acid (0.14 ml, 2.15 mmol) was added sequentially, then the mixture was heated overnight under reflux of the Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate was then washed with ether or hexane and dried to afford derivative 1 represented by the above formula. The yield of the obtained derivative is 82%, ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.213 (s, 1H), 10.374 (s, 1H), 7.517 (d, J = 7.8 Hz, 2H) , 6.884 (d, J = 7.8 Hz, 2H), 6.315 (s, 1H), 3.935 (t, J = 12.6 Hz, 2H), 1.655 (t, J = 12.6 Hz, 2H), 1.577-1.922 (m, 4H), 1.028-1.269 (m, 5H), 0.787-0.862 (s, 2H).

<Example 2>

Preparation of Derivative 2 according to the invention

Derivative 2 represented by the following formula was prepared by the following method.

<Formula of derivative 2>

Except for using succinimide (succinimide) instead of Hainan in the preparation of the derivative compound of Example 1 using the same method to obtain a derivative 2 represented by the above formula. The yield of the derivative 2 obtained at this time is 82%, ¹ H NMR (300 MHz, DMSO-d ₆ ) is δ 8.306 (s, 1H), 7.296 (s, 1H), 7.055 (d, J = 11.7 Hz, 2H), 6.838 (d, J = 11.7 Hz, 2H), 3.992 (t, J = 13.2 Hz, 2H), 3.854 (s, 2H), 1.627 (t, J = 13.2 Hz, 2H), 1.523-1.772 ( m, 6H), 1.430-1.513 (m, 1H), 1.134-1.271 (m, 2H), 0.904-1.012 (m, 2H).

<Example 3>

Preparation of Derivative 3 according to the invention

Derivative 3 represented by the following formula was prepared in the following manner.

<Formula of derivative 3>

4-phenylthiophene-2-carboxaldehyde (1 g, 4.3 mmol) and 2,4-thiazolidinedione (504 mg, 4.3 mmol) were dissolved in 20 ml of toluene solution and piperidine (0.21 ml, 2.15 mmol) and acetic acid (0.14 mL, 2.15 mmol) were added sequentially, then the mixture was heated overnight under reflux of the Dean-Stark water trap. The mixture was then cooled and filtered. The precipitate was then washed with ether or hexane and dried to afford derivative 3 represented by the above formula. The yield of the derivative 3 synthesized by the above method was 90%, ¹ H NMR (300 MHz, DMSO-d ₆ ) was δ 12.606 (s, 1H), 8.312 (s, 1H), 8.086 (d, J = 9.6 Hz, 2H), 7.738 (d, J = 8.4 Hz, 2H), 7.47 (t, J = 15 Hz, 2H), 7.313-7,362 (m, 1H).

<Example 4>

Preparation of Derivative 4 according to the invention

Derivative 4 represented by the following formula was prepared by the following method.

<Formula of derivative 4>

5- (4- (2-cyclohexylethoxy) benzylidene) thiazolidine-2,4-dione (1 g, 3.02 mmol) was dissolved in 20 ml of anhydrous THF, and NaH (132.75) was passed through nitrogen gas at 0 ° C. mg, 5.53 mmol) was added slowly. After stirring for 30 minutes, a solution of 2-iodo ethanol (1.57 g, 9.1 mmol) in 10 ml of dry THF was added dropwise over 10 minutes, followed by stirring for about 3 hours. When the progress of the reaction was confirmed by TLC and the reaction was not proceeded further, the reaction was treated with saturated Na ₂ CO ₃ solution and extracted with ethyl acetate. The organic solvent layer was washed with distilled water, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure, and then purified by chromatography over silica gel. In this case, hexane to ethyl acetate was eluted under a condition of 10: 1 to represent the above formula. Obtained derivative 4 was obtained. The yield of derivative 4 synthesized by the above method was 76%, ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.878 (s, 1H), 7.485 (d, J = 14.4 Hz, 2H), 7.007 (d, J = 14.4 Hz, 2H), 4.078 (t, J = 13.2 Hz, 2H), 4.001 (t, J = 10.2 Hz, 2H), 3.891 (t, J = 10.2 Hz, 2H), 2.049 (m, 1H), 1.670-1.782 (m, 7H), 1.471-1.529 (m, 1H), 1.178-1.284 (m, 3H), 0.956-1.034 (m, 2H).

Experimental Example 1

Inhibitory activity analysis of 15-PGDH of derivative compounds according to the present invention

<1-1> Expression and Purification of 15-PGDH

In order to confirm 15-PGDH inhibitory ability of the derivatives synthesized in Examples 1 to 4, first, 15-PGDH was purified in the following manner. The 15-PGDH cDNA plasmid containing the bamHI and E. coRI restriction enzyme sites of the pGEX-2T expression vector was transformed into E. coli BL-21 Lys S using the conventional methods used in the art. The transformed cells were then incubated in LB medium containing 50 ug / ml ampicillin (500 ml) at a temperature of 37 ° C. and at a rate of 220 rpm, until OD 600 became 0.6. Isopropyl beta-D-thiogalactoxide (1 mM) was then added and the cells were incubated again at 25 ° C. for 12 hours. Cells were then centrifuged at 4 ° C. at 4000g for 30 minutes to collect pellets. The cell pellet was lysed with 20 ml of cell lysis buffer [containing 1 × PBS buffer (pH 7.4): 1 mM EDTA and 0.1 mM DTT] and sonicated at 14 ° C. at 4 ° C. The digested cells were centrifuged at 4000g for 20 minutes at 4 ° C. The supernatant was then slowly loaded into a Glutathione-Sepharose 4B column equilibrated at 4 ° C. with cell lysis buffer [containing 1 × PBS buffer (pH 7.4), 1 mM EDTA and 0.1 mM DTT. The lysis buffer was used to wash the OD 280 up to 0.005. 15-PGDH was then eluted from the Glutathione-Sepharose 4B column using elution buffer (containing 50 mM Tris-HCl, pH 8.0), 10 mM reduced glutathione, 1 mM EDTA and 0.1 mM DTT at room temperature for 5 minutes. Concentration measurement and purity of the purified enzyme were confirmed by SDS-PAGE.

<1-2> Determination of Activity of 15-PGDH Inhibitor

In order to confirm whether the derivative compounds according to the present invention have an effect of inhibiting 15-PGDH, the derivative compound of the present invention synthesized 15-PGDH purified in Experimental Example <1-1> in Examples 1 to 4 above Whether or not they can be suppressed was performed by measuring the concentration of NADH formed at 340 nm with a fluorescence spectrophotometer. That is, 50 mM Tris-HCl (pH 7.5), 0.1 mM DTT, 0.25 mM (NAD +), 10 ug of purified 15-PGDH enzyme, 21 uM PGE2, and various concentrations (0.0001 uM to 64 uM) for cells. A solution of 2 ml total volume containing the compound was added. The absorbance of the reaction mixture was then recorded at 340 nm, and the activity of the derivative compounds of the present invention, inhibitors of 15-PGDH, was determined from standard curves with the average value of NADH absorbance at various concentrations prepared at 340 nm. The inhibitory activity results of 15-PGDH of the derivative compounds according to the present invention are as shown in Table 1 below. In Table 1, IC ₅₀ indicates the concentration at which the derivative compound according to the present invention inhibits 50% of 15-PGDH activity. It is shown.

As a result, as shown in Table 1, all of the novel thiazolidinedione derivatives according to the present invention was confirmed to have an activity of inhibiting 15-PGDH.

So far I looked at the center of the preferred embodiment for the present invention. Those skilled in the art will appreciate that the present invention can be implemented in a modified form without departing from the essential features of the present invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is shown in the claims rather than the foregoing description, and all differences within the scope will be construed as being included in the present invention.

Claims (9)

Thiazolidinedione derivative represented by the following formula or a pharmaceutically acceptable salt thereof:

Wherein X is nitrogen (N), carbon (C) or sulfur (S), and R ₁ is hydrogen (H) or

R ₂ is substituted or unsubstituted (hetero) cycloalkyl; Or (hetero) cycloalkenyl or (hetero) aryl. The method of claim 1, wherein R ₂ is

or

Thiazolidinedione derivatives or pharmaceutically acceptable salts thereof, characterized in that. The thiazolidinedione derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein the thiazolidinedione derivative is selected from the group consisting of derivatives 1 to 4 represented by the formulas shown in the following table.

A pharmaceutical composition for preventing hair loss and promoting hair growth, comprising a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. A pharmaceutical composition for the prevention and treatment of cardiovascular diseases, comprising a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. The pharmaceutical composition for preventing and treating cardiovascular diseases of claim 5, wherein the cardiovascular disease is selected from the group consisting of hypertension, arteriosclerosis, angina pectoris, hyperlipidemia, myocardial infarction and heart failure. A pharmaceutical composition for the prophylaxis and treatment of gastrointestinal diseases, which contains a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. According to claim 7, wherein the gastrointestinal disease is gastritis or gastric ulcer pharmaceutical composition for the prevention and treatment of gastrointestinal diseases. A pharmaceutical composition for the prevention and treatment of kidney disease, comprising as an active ingredient a thiazolidinedione derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.