KR100753860B1 - Organoselenium containing compounds and their use - Google Patents

Abstract

The present invention relates to an organoselenium compound, a preparation method thereof and a medical composition comprising the compound as active ingredient. The organoselenium compound of the present invention has activity for peroxisome proliferator activated receptor d (PPARd ) .

Description

Organic selenium-containing compounds and uses of these compounds {ORGANOSELENIUM CONTAINING COMPOUNDS AND THEIR USE}

The present invention relates to a novel organic selenium compound, a method for producing the same, and a peroxysome proliferator activated receptor delta (PPARδ) activator containing the same.

48 kinds of cotton peroxidase proliferation of nuclear receptors activated receptor chairs known so far. (Peroxisome Proliferator Activated Receptor: PPAR ) are the three kinds of subtype PPARα, PPARγ, PPARδ which are known (Nature, 1990, 347, p645-650 Proc . Natl. Acad. Sci. USA , 1994, 91, p7335-7359). PPARα, PPARγ and PPARδ have distinct functions according to tissues in vivo, and expression sites also differ. PPARα is mainly expressed in human heart, kidney, skeletal muscle, and large intestine ( Mol . Pharmacol . 1998 , 53 , p14-22. Toxicol . Lett . 1999 , 110 , p119-127. J. Biol . Chem . 1998 , 273 , p16710-16714), and the β-oxidation of peroxisomes and mitochondria ( Biol. Cell 1993 , 77 , p67-76. J. Biol . Chem . 1997 , 272 , p27307-27312). PPARγ is weakly expressed in skeletal muscle, but is expressed in large amounts in adipose tissue, and is known to be involved in the differentiation of adipocytes, storage of energy in fat form, and regulation of homeostasis of insulin and sugar ( Moll. Cell 1999 , 4 , p585-). 594. p597-609.p611-617). While the genes of PPARα and PPARγ show tissue-specific expression, PPARδ is expressed in almost all tissues, but the degree of expression varies depending on the tissue ( J. Bio. Chem . 1995 , 270 , p2367-2371. Endocrinology 1996 , 137 , p354-366). So far, according to a study PPARδ is known to play an important role in expressing the process of germ cells (Genes Dev 1999, 13, p1561-1574 ..), The central nervous system: the differentiation of nerve cells (Central Nervous System CNS) (J . Chem. Neuroanat 2000, 19, p225-232), the healing of wounds through the anti-inflammatory effects (Genes Dev. 2001, 15, p3263-3277. Proc. Natl. Acad. Sci. USA 2003, 100, p6295-6296) , etc. Has been studied to perform its physiological functions. Recent studies have demonstrated that PPARδ is involved in adipocyte differentiation and fat metabolism ( Proc. Natl . Acad . Sci . USA 2002 , 99 , p303-308. Mol . Cell. Biol . 2000 , 20 , p5119- 5128) It was found that PPARδ activates the expression of uncoupling proteins: UCPs, a key gene involved in β-oxidation and a gene involved in energy metabolism during fatty acid degradation ( Nature 2000 , 406 , p415-418. Cell 2003 , 113 , p159-170. PLoS Biology 2004, 2, p1532-1539). The regulation of UCP with PPARδ thus provides important clues needed to treat and resolve obesity.

The function of PPARδ was revealed not only by genetic studies but also by developing specific ligands of PPARδ. GW2433 from Glaxo Smith Kline, synthesized as the first activator of PPARδ, has been shown to be a therapeutic agent for atherosclerosis (WO 92/10468). Merck's L-165041 also lowered blood sugar and triglycerides (TG) ( J. Biol . Chem . 1999 , 274 , p6718-6725), using a mouse model (db / db). HDL-cholesterol levels could be adequately elevated in FEBS Lett . 2000 , 473 , p333-336, and could be used as therapeutic agents for obesity and diabetes (WO 97/28115). YM-16638, developed by Yamanouchi Pharmaceutical Co., Ltd. in Japan, has been shown to lower blood cholesterol and LDL cholesterol levels (WO 99/04815). Selective ligand GW501516 ([2-methyl-4-[[[4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazole-5] of PPARδ recently developed by Glaxo Smith Kline -Yl] methyl] sulfanyl] phenoxy] acetic acid) showed superior physiological efficacy over previously developed ligands. GW501516 has shown excellent efficacy in the treatment of obesity in animal experiments in rats ( Cell 2003 , 113 , p159-170) .In animal studies in primates, GW501516 increased HDL (high density lipoprotein). Effectively lowering low density lipoprotein (LDL) has been shown to be effective in cardiovascular disease ( Proc . Natl . Acad . USA 2001 , 98 , p5306-5311. 2003 , 100 , p1268-1273). In addition, the patent publication and the paper disclose the above-mentioned material and a method for preparing the same (PCT Publication WO 01/00603. Bioorg . Med . Chem . Lett . 2003 , 13 , p1517-1521. J. Org. Chem . 2003. 68) . p9116-9118). In particular the claims for compounds of the patents (WO 01/00603, WO 02/50048, WO 02/062774) relating to GW501516 are limited to ether, thioether or alkyl groups ((CR10R11) n, n = 1 or 2) Doing. Although the activity of PPARδ in recent years does not cause bowel cancer, it suggests that cancer cells can proliferate at least if bowel cancer has already developed ( Nat. Med . 2004 , 10 , p245-247. P481-483.). With the publication of these findings, there has been a great deal of research into the relationship between cancer and PPARδ, which has led to the development of safer compounds.

Meanwhile, Martin L. Smith and colleagues at Indiana University reduce the risk of cancer by inducing the activity of p53, a cancer suppressor gene, by selenomethionine, a type of amino acid containing selenium (Se), a nonmetallic element. ( Proc. Natl . Acad . USA 2002 , 99 , p14548-14553). This experiment confirmed the anti-cancer efficacy of selenium and showed that the intake of these ingredients is very important. On the other hand, as an essential nonmetallic trace element ( Eur . J. Clin . Nutr. 2004 , 58 , p391-402) belonging to the VIA group such as oxygen (O) or sulfur (S), selenium is also a free radical that occurs during normal oxygen metabolism. It is also known as an antioxidant that protects cells from free radicals ( Regul . Toxicol. Pharm . 2003 , 38 , p232-242), as well as elements that support the normal functioning of the immune system and thyroid gland ( Pharmacol . Ther . 1998 , 79). , 179-192. Immunol. Today 1998 , 19 , p342-245).

Therefore, if selenium is used to develop a ligand that exhibits PPARδ activity, the possibility of developing a cardiovascular agent, a cholesterol lowering agent, an antidiabetic agent, and an obesity agent without cancer side effects is very high.

It is an object of the present invention to provide a novel organoselenium and a method for producing the same, and also to provide an organoselenium compound which is a novel PPARδ active ligand.

Another object of the present invention is to protect the phenol group using a Grignard reagent during the reaction without introducing a special protecting group from the phenolic compound, after reacting the organometallic reagent without a separate separation step, selenium (Se ) To provide a convenient method for preparing the organo selenium compound in a single process.

The present invention relates to a novel organic selenium compound of formula (I) and a process for preparing the same.

[Formula I]

이고; B는 수소 또는

이며; R₁은 서로 독립적으로 탄소수 1∼4의 알킬기, 탄소수 1∼4의 알킬옥시기, 탄소수 1∼4의 알킬티오옥시기, 탄소수 1∼4의 알킬아민, 불소원자, 염소원자이며; R₂는 서로 독립적으로 탄소수 1∼4의 알킬기, 하나이상의 할로겐이 치환된 탄소수 1∼4의 알킬기 또는 할로겐원자이며; R₃는 수소, 탄소수 1∼4의 알킬기 또는

이고; R₄는 수소, 알칼리금속이온 또는 탄소수 1∼7의 알킬또는 아릴기이고; R₅는 서로 독립적으로 탄소수 1∼4의 알킬기, 하나 이상의 할로겐이 치환된 탄소수 1∼4의 알킬기 또는 할로겐원자이며; m은 0∼4의 정수이고, n은 0∼5의 정수이며, p는 0∼5의 정수를 나타낸다.] [Wherein A is hydrogen or

ego; B is hydrogen or

Is; R ₁ is independently an alkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, an alkylthiooxy group having 1 to 4 carbon atoms, an alkylamine having 1 to 4 carbon atoms, a fluorine atom or a chlorine atom; R ₂ independently of each other is an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with at least one halogen, or a halogen atom; R ₃ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or

ego; R ₄ is hydrogen, an alkali metal ion or an alkyl or aryl group having 1 to 7 carbon atoms; R ₅ independently of one another is an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with one or more halogens or a halogen atom; m is an integer of 0-4, n is an integer of 0-5, p represents an integer of 0-5.]

The organoselenium compound according to the present invention includes a compound of formula II or II below.

[Formula II]

[Formula IIa]

[Wherein R ₁ and m are as defined in formula 1, X ₂ represents a chlorine atom, bromine atom, iodine atom.]

The organoselenium compound of Formula II or IIa is useful as an intermediate material for preparing organoselenium compounds in various forms.

The present invention also includes an organic selenium compound which is a racemate or optical isomer of formula III prepared from an organic selenium compound of formula II or IIa, and also includes a compound of formula IV which may be prepared from the compound of formula III.

[Formula III]

[Wherein R ₁ to R ₃ , m, n, p are as defined in formula (I).]

[Formula IV]

[Wherein R ₁ to R ₄ and m, n, p are as defined in formula (1).]

The organic selenium compound of formula (IV) according to the present invention is characterized by having activity on a peroxysome proliferator activated receptor δ (PPARδ).

Among the compounds of Formula IV, the organic selenium compound is particularly preferably a compound having activity on the Peroxysome Proliferator Activated Receptor δ (PPARδ). The following compounds include R ₄ as alkyl or aryl having 1 to 7 carbon atoms. Methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, tert-butyl, phenyl, benzyl, which are carboxylic acid protecting groups having a group, of these protecting groups, methyl, ethyl and tert-butyl groups are preferable, and alkali Metal ions mean Li ⁺ , Na ⁺ , K ⁺ , Ca ⁺ , and the like, and hydrogen atoms and sodium ions are particularly preferable.

The novel compounds according to the invention can be prepared via the routes of Scheme 1 and Scheme 2 below.

As shown in Scheme 1 below, using the 4-halogen phenolic compound of the general formula V as a starting material, the alcohol group of the general formula V is protected with a Grignard reagent to prepare a compound of the general formula Va, Substituting halogen with lithium and then reacting selenium forms an intermediate of the metal-selenium alcohols of the general formula (IIa). When the compound is continuously reacted with the compound of formula VI (X ₃ means a chlorine atom, bromine atom, iodine atom and leaving group which is highly reactive to nucleophilic substitution reaction) without separation purification, the compound of general formula IIIa in the form of selenium ether is easily obtained. Can be. From this, a compound of formula IVb is prepared by reacting with alkyl halogen acetate, and then a compound of formula IVc is obtained in high yield and high purity through ester hydrolysis.

Scheme 1

On the other hand, when the benzyl group is introduced at the alpha position of selenium, the compound is reacted with Compound VII (X ₄ represents a chlorine atom, bromine atom, iodine atom, and leaving group which is highly reactive to nucleophilic substitution reaction) after protecting the hydroxy group of the compound of Formula IIIa. After removing the protecting group to prepare a IIIb compound, and reacted with the alkyl halogen acetate to the prepared IIIb compound in the general formula IVd compound to prepare a general formula IVd compound, and then through the ester hydrolysis reaction of the general formula IVe Compounds can be obtained.

Scheme 2

EMBODIMENT OF THE INVENTION Below, the manufacturing method of this invention is demonstrated in detail.

[Step A] Preparation of the compound represented by general formula IIIa

In order to obtain a compound represented by Formula IIIa, the compound represented by Formula V is protected with a Grignard reagent without separation process, the organometallic reagent is reacted with selenium, and then the compound of Formula IIIa is reacted. It is good to get it. This process will go through four steps of reaction in detail.

Below, a detailed process is demonstrated.

(Step A-1): As the anhydrous solvent used in this step, a mixed solvent in which a single solvent such as diethyl ether, tetrahydrofuran, hexane and heptane and two or more solvents are combined is used. Among them, preferred solvents are diethyl ether, tetrahydrofuran or a mixed solvent of diethyl ether and tetrahydrofuran.

The Grignard reagent used is methyl, ethyl, n -propyl, iso -propyl, n -butyl, sec -butylmagnesium chloride (R ₂ MgCl) or alkylmagnesium bromide (R ₂ MgBr). Most preferred among these is iso -propylmagnesium chloride ((CH ₃ ) ₂ CHMgCl).

The reaction temperature may vary depending on the solvent used, but is usually -20 to 40 ° C., preferably 0 ° C. to room temperature (25 ° C.). The reaction time may vary depending on the reaction temperature and the solvent used, but is usually 10 minutes to 60 minutes, preferably 10 minutes to 30 minutes.

(Steps A-2 and A-3): Examples of the organometallic reagent used in the halogen-metal substitution reaction include n -butyllithium, sec -butyllithium and tert -butyllithium. Of these, tert -butyllithium is preferable.

Selenium is suitably in the form of fine powder, which is added directly to a solvent and reacted.

The reaction temperature may vary depending on the solvent used, but is usually -78 to 25 ° C. Preferably, the halogen-metal substitution reaction is performed at -75 ° C, and the selenium introduction reaction starts at -75 ° C to room temperature (25 Reaction). The reaction time depends on the reaction stage, halogen-metal substitution reaction is 10-30 minutes, selenium introduction reaction 30-90 minutes.

(Step A-4): As an acidic aqueous solution used in experiments in which acid was added to the compound of the general formula IIa to confirm the formation of -SeH, an aqueous solution of 1 to 3 N hydrochloric acid was suitable, and the reaction temperature was 0 to 25 ° C. The reaction time is carried out for 5 to 20 minutes.

(Step A-5): 5-halogenmethyl-4-methyl-2- [4- (trifluoromethyl) phenyl] thiazole of Formula VI used in this step is a known method (WO 03/106442). Synthesis according to As the halogen of the general formula (VI), chlorine, bromine and iodine elements are used, and among them, a compound of chlorine element is preferable.

The reaction temperature may vary depending on the solvent used, but is usually performed at -78 to 25 ° C, preferably at 0 to 10 ° C. The reaction time is usually 10 to 120 minutes, preferably 10 to 60 minutes or less.

[Step B] Preparation of Compound Represented by General Formula IVb

In order to obtain the compound represented by the general formula (IVb), the compound represented by the general formula (IIIa) and the halogen acetate acetic acid alkyl ester are prepared by reacting in the presence of a base.

Halogenacetic acid alkylesters are readily available as known compounds, and halogens are chlorine and bromine atoms. Iodine atoms. Most preferred among the halogenated acetic acid alkyl esters used are bromoacetic acid methyl ester and bromoacetic acid ethyl ester.

As the solvent used in this process, N, N - dimethylformamide, N, N - dimethylacetamide, dimethyl sulfoxide, using a water-soluble single solvent such as acetonitrile, acetone, ethanol, methanol, or of 1 to 10% Use a solvent mixed with water. Among them, the most preferred solvent is acetone or dimethyl sulfoxide mixed with 1 to 5% water.

The base to be used is not particularly limited as long as it is a weak base or a strong base as long as it does not adversely affect the reaction. Alkali metal hydrides such as sodium hydride and lithium hydride, alkaline earth metal hydrides such as potassium hydride, sodium hydroxide and potassium hydroxide And alkali metal carbonates such as strong bases such as alkali metal hydroxides, lithium carbonate, potassium carbonate, potassium bicarbonate and cesium carbonate. As a base used, alkali metal carbonate is preferable and potassium carbonate is more preferable.

The reaction temperature is not particularly limited as long as the boiling point of the solvent used, but a relatively high temperature reaction is not preferable in order to suppress side reactions. Usually, it reacts at 0-60 degreeC. The reaction time depends on the reaction temperature, but usually 30 minutes to 1 day, preferably 30 to 90 minutes.

[Step C] Preparation of Compound Represented by General Formula IVc

Compounds represented by formula IVc are prepared from the compounds of formula IVb by hydrolysis of carboxylic acid esters in water-soluble inorganic salts and alcohol solutions.

As a solvent used in this process, an aqueous solvent mixed with water with alcohols such as methanol and ethanol is used.

As a base used, alkali metal hydroxides, such as lithium hydroxide, sodium hydroxide, and potassium hydroxide, are made and used about 0.1-3 N aqueous solution according to the form of the carboxylic acid alkali salt. The acid used to obtain the compound of the formula IVc in acid form is preferably acetic acid or using a 0.1 ~ 3 N hydrochloric acid solution.

The reaction temperature is preferably reacted at a relatively low temperature in order to suppress side reactions, and usually at 0 ° C to room temperature. The reaction time varies depending on the reaction temperature, but usually 10 minutes to 3 hours, preferably 30 minutes to 1 hour.

The selenium-containing compound of the general formula IVc thus obtained is an important substance as a ligand of the PPARδ type protein.

[Step D] Preparation of Compound Represented by General Formula IIIb

The compound of formula IIIb in which the benzyl functional group is substituted at the alpha position of selenium is protected by the TMSCl, TBDMSCl, etc. of the phenol group of the compound of formula IIIa prepared in the general formula A, and then the alpha position activity of selenium is used After dehydrogenation of hydrogen, benzyl halide derivatives can be added and prepared by removing protecting groups such as TMS and TBDMS.

Compounds IVd and IVe are prepared via [Step E] and [Step F] in a similar manner to the preparation of IVb and IVc compounds, respectively.

EXAMPLE

Hereinafter, the method of the present invention will be described in detail with reference to Examples. However, the present invention is not limited to these examples.

Example 1 Preparation of 4-hydroseleno-2-methylphenol (II)

Under nitrogen conditions 400 mg (1.7 mmol) of 4-iodine-2-methylphenol are dissolved in 30 ml of anhydrous tetrahydrofuran and the temperature is maintained at 0 ° C. 935 µl (2 M -ether solution, 1.1 equivalents) of isopropyl magnesium chloride is slowly added and reacted for 10 minutes. After the reaction solution was sufficiently cooled to −78 ° C., 2.2 ml of tert -butyllithium (1.7 M -heptane solution, 2.2 equivalents) was slowly added dropwise, and further reacted for 20 minutes. 134 mg (1.7 mmol, 1.0 equiv) of selenium are slowly added and the reaction is allowed to proceed until the temperature of the reactant reaches room temperature. 30 ml of an aqueous ammonium chloride solution and 1N hydrochloric acid were added to acidify the organic layer, and the organic layer was separated, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography on hexane / ethyl acetate (v / v = 2/1) to give 302 mg (yield: 95%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.35 (d, 1H, J = 1.3 Hz), 7.29 (dd, 1H, J = 8.2, 2.2 Hz), 6.67 (d, 1H, J = 8.2 Hz), 4.84 (br s, 1H), 2.21 (s, 3H)

¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 154.8, 137.3, 133.6, 125.2, 122.4, 115.9, 16.0

Example 2 Preparation of 4-[[2- [4- (trifluoromethyl) phenyl] -4-methylthiazol-5-yl] methylselanyl] -2-methylphenol (IIIa)

Under nitrogen conditions, 1.17 g (5.0 mmol) of 4-iodine-2-methylphenol are dissolved in 80 mL of anhydrous tetrahydrofuran and the temperature is maintained at 0 ° C. 2.75 ml (2 M -ether solution, 1.1 equivalents) of isopropyl magnesium chloride are gradually added and reacted for 10 minutes. After the reaction solution was sufficiently cooled to −78 ° C., 6.47 mL (1.7 M -heptane solution, 2.2 equivalents) of tert -butyllithium was slowly added dropwise, followed by further reaction for 20 minutes. 395 mg (5.0 mmol, 1.0 equiv) of selenium were slowly added and the reaction was allowed to proceed until the reaction temperature reached 15 ° C. After 40 minutes, 1.46 g (5.0 mmol, 1.0 equiv) of 5-chloromethyl-4-methyl-2-[(4-trifluoromethyl) phenyl] -thiazole of the formula VI at the same temperature was added 5 ml of dry THF. Melt in and add slowly. The reaction is further added for 30 minutes, and 100 ml of aqueous ammonium chloride solution is added to terminate the reaction. The organic layer is separated, the water is removed with magnesium sulfate, and after filtration, the solvent is distilled off under reduced pressure. The residue was purified by silica gel column chromatography on hexane / ethyl acetate (v / v = 3/1) to give 2.05 g (yield: 93%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.95 (d, 2H, J = 8.1 Hz), 7.64 (d, 2H, J = 8.2 Hz), 7.28 (d, 1H, J = 1.4 Hz), 7.09 (dd) , 1H, J = 8.2, 1.9 Hz), 6.59 (d, 1H, J = 8.2 Hz), 4.09 (s, 2H), 2.19 (s, 3H), 2.05 (s, 3H)

¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 163.7, 155.4, 151.5, 139.3, 135.5, 135.3 (q, J = 33 Hz) 132.5, 126.8, 126.3 (m), 125.7, 118.5, 115.9 23.3, 16.1, 14.9

Example 3 Ethyl 2- [4-[[2- [4- (trifluoromethyl) phenyl] -4-methylthiazol-5-yl] methylselanyl] -2-methylfeoxy] acetate Preparation of IVb)

1.0 g (2.26 mmol) of 4-[[2- [4- (trifluoromethyl) phenyl] -4-methylthiazol-5-yl] methylselanyl] -2-methylphenol obtained in Example 2 and 5 50 ml of acetone with% water and 719 mg (5.2 mmol, 2.3 equiv) of potassium carbonate are mixed well at room temperature. 376 µl (3.4 mmol, 1.5 equivalents) of ethyl bromoacetate is added and stirred vigorously for 4 hours. After completion of the reaction, the mixture was extracted using an aqueous salt solution and ethyl acetate, and water was removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography with hexane / ethyl acetate (v / v = 5: 1) solvent to obtain 1.19 g (yield: 99%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.96 (d, 2H, J = 8.1 Hz), 7.65 (d, 2H, J = 8.3 Hz), 7.29 (d, 1H, J = 1.4 Hz), 7.23 (dd) , 1H, J = 8.4, 2.1 Hz, 6.56 (d, 1H, J = 8.4 Hz), 4.62 (s, 2H), 4.25 (q, 2H, J = 14.3, 7.1 Hz), 4.12 (s, 2H) , 2.23 (s, 3H), 2.14 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz)

¹³ C NMR (75.5 MHz, CDCl ₃ ) δ 169.1, 162.9, 157.1, 151.6, 138.8, 137.3, 134.8, 131.9, 131.6 (q, J = 33 Hz), 128.9, 126.2 (m), 120.0, 112.1, 65.9, 61.8, 23.3, 16.4, 15.2, 14.6

Example 4 2- [4-[[2- [4- (trifluoromethyl) phenyl] -4-methylthiazol-5-yl] methylselanyl] -2-methylphenoxy] acetic acid (IVb , HK101225)

Ethyl 2- [4-[[2- [4- (trifluoromethyl) phenyl] -4-methylthiazol-5-yl] methylselanyl] -2-methylphenoxy] acetate 500 obtained in Example 3 ㎎ (1.0 mmol) was mixed with ethanol 50 ㎖ well, 3 N - adds 3.5 ㎖ aqueous solution of sodium hydroxide. After 30 minutes stirring at room temperature, the pH is adjusted to 2.0 with 2N- HCl when the reaction is complete. Ethanol was distilled under reduced pressure to remove about 80%, extracted with an aqueous salt solution and ethyl acetate, filtered, and then the solvent was distilled off under reduced pressure and purified by LH-20 column chromatography to obtain 495 mg (yield: 99%) of the title compound. Got it.

¹ H NMR (300 MHz, CDCl ₃ ) δ 9.92 (br s, 1H), 7.93 (d, 2H, J = 8.2 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.29 (d, 1H, J = 1.4 Hz), 7.19 (dd, 1H, J = 8.4, 2.1 Hz), 6.58 (d, 1H, J = 8.4 Hz), 4.66 (s, 2H), 4.10 (s, 2H), 2.21 (s, 3H ), 2.07 (s, 3H)

¹³ C NMR (150.9 MHz, CDCl ₃ ) δ 173.2, 163.5, 156.8, 151.5, 138.9, 136.8, 134.9, 132.3, 131.8 (q, J = 33 Hz), 128.9, 126.9, 126.3 (m), 120.1, 112.0, 65.4, 23.1, 16.4, 14.8

Example 5 4- [1- [4-methyl-2- (4-trifluorofluoromethylphenyl) -thiazol-5-yl] -2-phenylethylselanyl] -2-methyl-phenol (IIIb Manufacturing

A: Preparation of 5- [4- ( tert -butyldimethylsilanyloxy) -3-methyl-phenylselanylmethyl] -4-methyl-2-[(4-trifluoromethyl) phenyl] -thiazole

200 mg (0.45) of 4-[[2- [4- (trifluoromethyl) phenyl] -4-methylthiazol-5-yl] methylselanyl] -2-methylphenol prepared by the method of Example 2 mmol) and 77 mg (1.13 mmol, 2.5 equiv) of imidazole are completely dissolved in anhydrous dimethylformamide (5 ml). 102 mg (0.67 mmol, 1.5 equiv) of tert -butylmethylsilylchloride are slowly added and stirred at room temperature for 4 hours. After completion of the reaction, the organic layer was extracted using water (20 ml) and ethyl ether (15 ml), and the organic layer was washed with water (20 ml). The organic layer was dried over magnesium sulfate and protected with a phenol group by silica gel chromatography, 5- [4- ( tert -butyldimethylsilanyloxy) -3-methyl-phenylselanylmethyl] -4-methyl-2-[( 238 mg (Yield: 95%) of 4-trifluoromethyl) phenyl] -thiazole were obtained.

B: 5- [1- [4- ( tert -butyldimethylsilyloxy) -3-methyl-phenylselanyl] -2-phenylethyl] -4-methyl-2- [4- (trifluoromethyl) phenyl ]-Preparation of Thiazole

5- [4- ( tert -butyldimethylsilanyloxy) -3-methyl-phenylselanylmethyl] -4-methyl-2-[(4-trifluoromethyl) phenyl prepared in step A under nitrogen conditions ] -Thiazole 150 mg (0.27 mmol) is dissolved in anhydrous tetrahydrofuran (5 ml). The reaction solution was cooled to -78 ° C and 240 µl of lithium diisopropylamide (lithium diisopropylamide, 2 M-heptane / tetrahydrofuran / ethylbenzene solution, 2.0 equiv) was slowly added. Add 32 μl of benzyl bromide (0.27 mmol, 1.0 equivalent) while maintaining the reaction solution in dark blue color and react for 30 minutes at the same temperature. Saturated aqueous ammonium chloride solution (10 ml) was added to the reaction solution, extracted with ethyl acetate (10 ml), and the organic layer was washed with brine. The organic layer was dried over magnesium sulfate, and the concentrated residue was separated by silica gel chromatography to obtain 141 mg (yield: 81%) of the title compound.

¹ H NMR (600 MHz, CDCl ₃ ) δ 7.99 (d, 2H, J = 8.3 Hz), 7.12-7.26 (m, 7H), 6.64 (d, 2H, J = 8.2 Hz), 4.73 (dd, 1H, J = 9.8, 5.6 Hz), 3.44 (dd, 1H, J = 14.0, 5.6 Hz), 3.25 (dd, 1H, J = 14.0, 9.8 Hz), 2.12 (s, 3H), 1.91 (s, 3H), 1.03 (s, 9H), 0.21 (s, 6H)

C: Preparation of 4- [1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -2-phenylethylselanyl] -2-methylphenol

5- [1- [4- ( tert -butyldimethylsilyloxy) -3-methyl-phenylselanyl] -2-phenylethyl] -4-methyl-2- [4- (trifluoro) prepared in step B Rhomethyl) phenyl] -thiazole 100 mg (0.15 mmol) is dissolved completely in tetrahydrofuran (10 ml) at room temperature. At the same temperature, 180 μl (0.18 mmol, 1 M-tetrahydrofuran solution, 1.2 equiv) of tetrabutylammonium fluoride (TBAF) is slowly added. After reacting for 1 hour, the organic layer was extracted with saturated aqueous ammonium chloride solution (10 ml) and ethyl acetate (10 ml), and then dried over magnesium sulfate. After filtration, the solvent was distilled under reduced pressure and the concentrated residue was separated by silica gel chromatography to obtain 79 mg (yield: 99%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, 2H, J = 8.2 Hz), 7.63 (d, 2H, J = 8.3), 7.00-7.26 (m, 7H), 6.50 (d, 1H, J = 8.1 Hz), 6.32 (br, 1H), 4.67 (dd, 1H, J = 9.8, 5.7 Hz), 3.42 (dd, 1H, J = 13.9, 5.7 Hz), 3.22 (dd, 1H, J = 13.9, 9.8 Hz), 2.13 (s, 3H), 1.78 (s, 3H)

Example 6 Ethyl [4- [1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -2-phenylethylselanyl] -2-methyl-phenoxy ] -Preparation of Acetate (IVd)

4- [1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -2-phenylethylselanyl] -2-methylphenol prepared by the preparation method of Example 5. 100 mg (0.19 mmol) is dissolved completely in acetone (10 ml) with 5% water and then 66 mg (0.475 mmol, 2.5 equiv) of potassium carbonate are added at room temperature. At the same temperature, 28 µl (0.25 mmol. 3 equivalents) of boroacetic acid ethyl ester is added and stirred for 4 hours. After completion of the reaction, the reaction solution was removed under reduced pressure, and the organic layer was extracted using brine (10 ml) and ethyl acetate (10 ml). The organic layer is dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was separated by silica gel chromatography to obtain 103 mg (yield: 88%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (d, 2H, J = 8.2 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.07-7.25 (m, 7H), 6.53 (d, 2H, J = 8.1 Hz)), 4.69 (dd, 1H, J = 9.8, 6.0 Hz), 4.59 (s, 2H), 4.23 (q, 1H, J = 14.2, 7.1 Hz), 3.40 (dd, 1H, J = 13.8, 6.0 Hz), 3.20 (dd, 1H, J = 13.8, 9.8 Hz), 2.26 (s, 3H), 1.85 (s, 3H), 1.28 (t, 3H, J = 7.0 Hz)

[Example 7] [4- [1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -2-phenylethylselanyl] -2-methylphenoxy]- Preparation of Acetic Acid (IVe)

[4- [1- [4-methyl-2- (4-trifluoromethylphenyl) -thiazol-5-yl] -2-phenylethylselanyl] -2-methylphenoxy] prepared in Example 6] Dissolve 100 mg (0.16 mmol) of acetate in ethanol (10 ml) and add 200 μl of 1N sodium hydroxide solution. After 30 minutes of stirring at room temperature, the reaction was terminated and adjusted to pH = 3.0 with 2N aqueous HCl solution. The reaction solvent was removed under reduced pressure, the organic layer was extracted with brine and ethyl acetate, and purified by LH-20 resin column chromatography to obtain 71 mg (yield: 75%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ) δ 7.97 (d, 2H, J = 8.2 Hz), 7.65 (d, 2H, J = 8.4 Hz), 7.07-7.25 (m, 7H), 6.53 (d, 2H, J = 8.1 Hz)), 4.69 (dd, 1H, J = 9.8, 6.0 Hz), 4.59 (s, 2H), 3.40 (dd, 1H, J = 13.8, 6.0 Hz), 3.20 (dd, 1H, J = 13.8, 9.8 Hz), 2.26 (s, 3H), 1.85 (s, 3H)

Example 7-Example 22

The organic selenium compounds of Tables 1 and 2 were prepared by referring to the methods of Examples 1 to 6.

TABLE 1

TABLE 2

Test Example 1 (Activity and Toxicity Test)

We confirmed the PPARδ activity of HK101225, one of the materials developed through the transfection assay, and additionally tested the selectivity of PPARα and PPARγ, a subtype of PPARs, and toxicity and animal experiments through MTT assay. In vivo activity verification was performed.

[Transfection assay]

The assay was performed using CV-1 cells, and the cell culture was performed in a 37-well incubator containing 5% carbon dioxide in 96 wells using DMEM medium containing 10% FBS, DBS (delipidated) and 1% penicillin / streptomycin. It was performed on the plate. The experiment was performed in four stages: cell inoculation, transfection, developmental material treatment, and result confirmation. CV-1 cells were seeded at 5,000 cell / well in 96 well plates and transfected after 24 hours. A full length PPARs plasmid DNA and Luciferase activity (Luciferase activity) was performed using a Transfection Reagent to reporter DNA to confirm the activity of PPARs and β-galactosidase DNA to provide transfection efficiency information. The substance HK101225 according to Example 4 was dissolved in dimethyl sulfoxide (DMSO) and treated with cells at various concentrations using media. After incubation for 24 hours, cells were lysed using lysis buffer and luciferase and β-galactosidase activities were measured using a luminometer and a microplate reader. The measured luciferase value was corrected using the β-galactosidase value, and a graph was used to calculate the EC ₅₀ value.

TABLE 3

As can be seen in Table 3 above, the organic selenium compound according to the present invention is highly selective for EC ₅₀ PPARδ.

The substances listed in Tables 1 and 2 and the ethyl ester compounds of these substances showed more than 10,000-fold selectivity for PPARα and PPARγ, and EC ₅₀ showed an activity between 500 pM-10 nM for PPARδ.

[MTT assay]

Toxicity test for the material according to the present invention was carried out MTT assay using HK101225 prepared from Example 4 of the development material. MTT is a yellow substance that dissolves in water, but when it enters living cells, it is transformed into purple crystals that do not dissolve in water by dehydrogenase in mitochondria. After dissolving this material in dimethyl sulfoxide, absorbance at 550 nm can be confirmed for cytotoxicity. The experimental method is as follows.

CV-1 cells were first seeded at 5,000 cell / well in 96 well plates. After incubation in a humidified 37 ° C. incubator containing 5% carbon dioxide for 24 hours, development material HK101225 was treated at various concentrations. Incubated for 24 hours, MTT reagent was added. After incubation for about 15 minutes, the resulting purple crystals were dissolved in dimethyl sulfoxide, and then absorbance was measured using a microplate reader, from which cytotoxicity was confirmed.

Experimental results showed that HK101225 was not toxic at concentrations up to 50,000 times EC ₅₀ (1.87 nM). The ethyl ester compounds of the substances and foreign substances listed in Tables 1 and 2 did not show toxicity even at concentrations of 10,000 times or more.

[Animal Experiment]

[Verify the effects of obesity]

In order to test the in vivo effect on HK101225 among the substances that proved effective through in vitro experiments, a mouse experiment was performed. Mice used 14-week-old C57BL / 6 (SLC Co.) and used a diet containing 35% fat to induce obesity. The vehicle, GW501516 (10mg / Kg / day), HK101225 (10mg / Kg / day) was orally administered with high fat intake for 78 days. Results Vehicle-treated rats gained 102% body weight, but rats fed GW501516 and HK101225 gained only 21% of their body weight. This is equivalent to 1/5 of the weight gain of the vehicle-administered mouse, confirming that this substance has a strong inhibitory effect on obesity.

[Verification of Diabetes Improvement Effect]

GTT (Glucose Tolerance Test) was conducted to verify the diabetes improvement effect of the developed material. Glucose (1.5g / Kg) was intraperitoneally administered to mice administered orally for 78 days, and then blood glucose levels were changed over time. As a result, it was confirmed that the oral administration of the development substance was lower in fasting blood glucose than the vehicle and GW501516 rats. In the HK101225 group, blood glucose decreased rapidly between 20 and 40 minutes, and glucose clearance was completely observed after 100 minutes. However, the group of mice treated with vehicle did not maintain normal blood glucose after 120 minutes, and the group of mice treated with GW501516 had lower blood sugar than the vehicle but did not return to normal. From these results, it was confirmed that the development material HK101225 has a diabetic improvement effect, and the effect is superior to the previously known GW501516.

The selenium-containing compound represented by Formula IV or a pharmaceutically acceptable salt of the compound is useful as an activator composition of the Peroxysome Proliferator Activated Receptor δ (PPARδ). In addition, the general formula IV selenium-containing compound or a pharmaceutically acceptable salt of the compound according to the present invention activates the Peroxysome Proliferator Activated Receptor δ (PPARδ) to treat cardiovascular agents, cholesterol lowering agents, diabetes treatment It is useful as a pharmaceutical composition for the preparation of drugs or obesity, health food supplements, health drinks, food additives and functional cosmetics.

The pharmaceutically acceptable salt may be a salt of the carboxylic acid and the salt of the general formula IV compound, and includes all of the pharmaceutically acceptable salts, and may be Li ⁺ , Na ⁺ , K ⁺ , Ca as alkali metal ion or alkaline earth metal. ^{+ And the like} are preferred.

The amount of the compound of formula IV, or a pharmaceutically acceptable salt thereof, used to achieve the therapeutic effect according to the invention depends of course on the particular compound, the method of administration, the subject to be treated and the disease to be treated, but depends on the usual dosage of the medicament. Depending on the formulation, either oral or topical administration is possible. Oral administration of the pharmaceutical composition according to the present invention can be prepared in any of a variety of existing forms, for example tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, It can exist in various forms, such as drink, sublingual tablet, and the like. Tablets according to the present invention may be administered to a patient in any form or manner in which an effective amount is bioavailable, ie, by oral route, depending on the nature of the disease state to be treated or prevented, the stage of the disease, and other relevant circumstances. Suitable dosage forms or modes can be readily selected and when the composition according to the invention is a tablet, it may comprise one or more pharmaceutically acceptable excipients, the proportions and properties of such excipients being dependent on the solubility and chemical properties of the selected tablet, It may be determined by the route of administration chosen and standard pharmaceutical practice.

As described above, the organic selenium compound according to the present invention is a compound having the characteristics of a PPARδ activating ligand, a compound highly likely to be used as a cardiovascular agent, a cholesterol lowering agent, a diabetes agent, and an obesity agent, and the preparation method according to the present invention is organic. Useful for the preparation of selenium compounds.

Claims (13)

An organic selenium compound of formula (I) [Formula I]

[In the formula, A is hydrogen or

ego; B is hydrogen or

Is; R ₁ is independently an alkyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, an alkylthiooxy group having 1 to 4 carbon atoms, a fluorine atom or a chlorine atom; R ₂ independently of one another is an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted by one or more halogen atoms, or a halogen atom; R ₃ is hydrogen, an alkyl group having 1 to 4 carbon atoms, or

ego; R ₄ is hydrogen, an alkali metal ion or alkyl having 1 to 7 carbon atoms; R ₅ independently of one another is an alkyl group having 1 to 4 carbon atoms, an alkyl group having 1 to 4 carbon atoms substituted with one or more halogens or a halogen atom; m is an integer of 0-4, n is an integer of 0-5, p represents an integer of 0-5.] The method of claim 1, An organic selenium compound of formula II or IIa. [Formula II]

[Formula IIa]

[Wherein R ₁ and m are as defined in formula 1, X ₂ represents a chlorine atom, bromine atom, iodine atom.] The organic selenium compound according to claim 1, which is a racemate or an optical isomer of formula III. [Formula III]

[Wherein R ₁ to R ₃ and R ₅ , m, n, p are as defined in formula (1).] The method of claim 1, An organic selenium compound which is a racemate or optical isomer of Formula IV. [Formula IV]

[Wherein R ₁ to R ₅ and m, n, p are as defined in claim 1] The method of claim 1, An organic selenium compound which is a racemate or an optical isomer of Formula IVc. [Formula IVc]

[Wherein R ₁ to R ₃ and R ₅ , m, n, p are as defined in formula (1).] The method of claim 5, R ₁ of Formula IVa is independently methyl or ethyl, R ₂ is independently of each other methyl, ethyl, CF ₃ , F or Cl, R ₃ is hydrogen or

ego, R ₅ is independently of each other CF ₃ , F or Cl, m is an integer of 0 to 2, n is an integer of 0 to 3, p is an integer of 0-3, an organic selenium compound which is a racemate or an optical isomer. a) reacting a compound of Formula V with a Grignard reagent and then reacting with an organometallic reagent to prepare an organometallic compound of Formula Vb; b) preparing a metal-selenium compound of formula IIa by reacting selenium (Se) with the organometallic compound of formula Vb in step a); c) reacting the selenium compound of formula (IIa) with the thiazole compound of formula (VI) following step b) to produce a compound of formula (IIIa); Method for producing an organic selenium compound, characterized in that. [Formula V]

[Formula Vb]

[Formula IIa]

[Formula VI]

[Formula IIIa]

[X ₁ represents a bromine atom, an iodine atom, X ₂ represents a chlorine atom, a bromine atom or an iodine atom, X ₃ represents a chlorine atom, a bromine atom, an iodine atom or a leaving group that is reactive to nucleophilic substitution reaction, the rest Is the same as the substituent definition in Formula 1.] The method of claim 7, wherein e) reacting the compound of Formula IIIa with alkyl halogen acetate to prepare an ester compound of Formula IVb; f) hydrolyzing the formula IVb ester compound to produce formula IVc compound; Method for producing an organic selenium compound, characterized in that. [Formula IIIa]

[Formula IVb]

[Formula IVc]

[Wherein R ₁ to R ₃ , m, n, p are the same as defined in formula 1, and R ₄ is alkyl having 1 to 7 carbon atoms.] The method of claim 7, wherein g) protecting the hydroxy group of the compound of Formula IIIa with an alkylsilyl group having 1 to 7 carbon atoms, reacting with the compound of Formula VII under basic conditions, and removing the hydroxy protecting group to prepare a compound of Formula IIIb; h) reacting the compound of Formula IIIb with an alkyl halogen acetate to produce an ester compound of Formula IVd; i) hydrolyzing the formula IVd ester compound to produce formula IVe compound; Method for producing an organic selenium compound, characterized in that. [Formula IIIa]

[Formula VII]

[Formula IIIb]

Formula IVd

[Formula IVe]

[Wherein R ₁ to R ₃ , R ₅ , m, n, p are the same as defined in formula 1, R ₄ is alkyl having 1 to 7 carbon atoms, X ₄ is a chlorine atom, a bromine atom, It is a leaving group that is highly reactive to iodine atom or nucleophilic substitution reaction.] A pharmaceutical composition for lowering cholesterol, treating diabetes or obesity, comprising a selenium-containing compound represented by the following general formula IV or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula IV]

[Wherein R ₁ to R ₄ , m and n are as defined in claim 1] Health food supplements for improving cardiovascular disease, lowering cholesterol, improving diabetes, or improving obesity, using selenium-containing compounds represented by the following general formula IV or pharmaceutically acceptable salts thereof as active ingredients, health drinks and food additives. [Formula IV]

[Wherein R ₁ to R ₄ , m and n are as defined in claim 1] delete Functional cosmetics for the prevention or improvement of obesity, using as selenium-containing compound represented by the general formula IV or a pharmaceutically acceptable salt thereof as an active ingredient. [Formula IV]

[Wherein R ₁ to R ₄ , m and n are as defined in claim 1]