KR20170133293A - Fetal reprogramming of PPARδ agonists - Google Patents

Abstract

The present invention relates to a novel use of a PPAR agonist, and more specifically, to a fetal reprogramming effect of a PPAR agonist. According to the present invention, a PPAR agonist adjusts calcium ion during embryo genesis and an early fetal development period to increase slow muscle fiber and to thus improve muscle endurance, thereby improving lipid and glucose metabolism and reprogramming the metabolism of the entire body, thus preventing/inhibiting the occurrence of metabolic diseases caused by high-fat diet and lack of exercise in an adult body such as obesity and diabetes, and improving memory for an adult. Additionally, fetal reprogramming using a PPAR agonist prevents/inhibits the occurrence of diabetes in a mouse model for diabetes. Thus, the PPAR agonist may be used in pharmaceutical compositions for enhancing the endurance of a human and an animal by embryonic/fetal reprogramming, for preventing/inhibiting metabolic diseases such as obesity, diabetes, arteriosclerosis, and fatty liver, and for enhancing memory. Further, the PPAR agonist may also be used in a nutritional supplement for pregnant women, in food additives, in a functional food supplement or functional beverage composition, in pharmaceutical compositions for animals, in an endurance enhancer for animals, in dry milk and baby formula compositions, in an animal feed composition, etc.

Description

Fetal reprogramming of PPAR delta agonists < RTI ID = 0.0 >

The present invention relates to a fetal reprogramming effect of a PPARδ agonist. More particularly, the present invention relates to a method of regulating calcium ion in fetal development or early development, By enhancing endurance, it improves lipid and glucose metabolism ability and reprograms metabolic reprogramming of whole body to prevent / suppress the onset of metabolic diseases such as obesity diabetes due to high fat diet and lack of exercise in adults or adults, Lt; RTI ID = 0.0 > PPARdelta active < / RTI > According to the present invention, the PPAR? -Activating substance prevents or suppresses the onset of diabetes even in mice having congenital diabetes mellitus as well as fetal reprogramming in normal mice, thereby obesity, diabetes and the like It is effective for prevention of the same metabolic diseases and treatment of premature infants, and is effective for endurance and memory improvement of human and animal.

The skeletal muscle can be divided into two groups according to the contraction rate and metabolism (Schiaffino & Reggiani Physiol . Rev. , 1996, 76, 371-423). Type II muscle, the fasting muscle, uses glucose as an energy source and is present in many muscles that require rapid movement, such as short-distance running. On the other hand, the root muscle uses fat as a major energy source and exists in many muscles that perform a sustained movement. Because the root is more reddened than the muscle and has resistance to fatigue caused by lactic acid during exercise, it is suitable for exercise requiring endurance (Costill, DL. Et al ., J. Appl . Pysiol ., 1976, 40, 149-154; Saltin B. et al ., Ann. NY Acad . Sci ., 1977, 301, 3-44). In addition, the fatigue (35% fat volume) feed intake was significantly inhibited by metabolic diseases such as obesity and diabetes, because of the high fatty acid oxidizing ability and insulin sensitivity compared to that of fasting muscle (Wang, YX. Et al ., PlosBiol , 2004, 2, e 294; Vihang A. Narkar et al , Cell , 2008, 134, 405-415).

A gene involved in the closest screen (Fast-to-slow muscle fiber transformation) of sokgeun is Calcineurin (Serrano, AL. Et al ., Proc. Natl. Acad. Sci. USA., 2001, 98, 13108-13113), calmodulin -dependentkinase (Wu, H. et al., Science., 2002, 296, 349-352), PGC-1α (Lin, J. et al., Nature., 2002, 418, 797-801), AMPK (Vihang A. Narkar et al, Cell, 2008, 134:. 405-415), Sirt1 and Adiponectin (Masato Iwabu et al, Nature , 2010, 464, 1313-1319), PPARδ ( Wang, YX. Et al ., PlosBiol ., 2004, 2, e294). Among them, overexpression of PPARδ or selective elimination of this gene has been shown to be a very important regulator of the periportal localization of this gene. PPARδ is a ligand-dependent transcription factor that is highly expressed in the near side. In muscle-specific PPARδ transgenic mice, the production of persimmon fibers was markedly increased, resulting in a 67% and 92% increase in running time and distance, respectively (Wang, YX et al PlosBiol ., 2004, 2. e294). On the other hand, mice with selective removal of the PPARδ gene showed 62% reduction in running time and 66% reduction in running distance compared to normal mice (Wang, YX. Et al ., PlosBiol . e294). Therefore, it can be seen that PPARδ is an important gene for the generation of the root locus and the exercise capacity.

However, the results of studies using PPARδ agonists have been reported to be completely different from those predicted by previous studies. GW 501516 is the most potent of the PPAR? Active substances reported in the literature to date (William R. Oliver, Jr. et al ., Proc. Natl . Acad . Sci . USA, 2001, 98, 5306-5311). The results of this experiment were different from those of the existing PPARδ transgenic mice. In other words, only the administration of GW501516 alone in the adult does not improve the nearness and endurance, and the combination of exercise and GW501516 simultaneously enhances the locus generation and endurance (Vihang A. Narkar et al , Cell , 2008, 134, 405 -415). Therefore, there is no example of proving endurance improvement efficacy with only PPAR? Agonist.

Fetal programming is the first theory that was first discussed at Southampton and Kings College in England, where the environment exposed to the fetus at the gestational age determines the health of the fetus and the adult population. The current developmental programming, It is used interchangeably with the term fetal developmental programming. More precisely, it implies that the environment exposed to the fetus during development affects the formation of organs and organs of the fetus, and that these changes have an impact throughout life (Mc-Millen and Robinson, Physiol Rev. , 2005, 85, 571-633; Plagemann, Horm Res ., 2006, 65, 8389; Taylor and Poston, Exp Physiol , 2007, 92, 287298). Epidemiologic studies have shown that when overproduced or supplied with less than adequate nutrients during the fetal programming period, there is an increased incidence of serious diseases such as obesity, cardiovascular disease, diabetes, hypertension, arteriosclerosis and cancer when they become adults Reported. Therefore, various studies are currently under way to prevent this, and a representative example is taurine. It is known that consumption of taurine during the developmental period is inhibited by the onset of diabetes (Cherif et al ., J Endocrinol ., 1998, 159, 341-348). Arginine has been shown to improve diabetic and cardiovascular disorders (Wu et al ., J Nutr ., 2004, 134, 2169-2172). Folic acid is also known to be effective in the prevention of diabetes (Lillycrop et al ., J Nutr ., 2005, 135, 1382-1386). Interestingly, administration of exedin-4, an effective diabetes treatment as an active ingredient of GLP-1, in the developmental period of rats results in a decrease in oxidative stress and thus diabetes in the fetus can be prevented (Stoffers DA et al ., Diabetes 2003, 52, 734-740; Raab EL et al ., Am. J. Physiol ., Regul . Integr . Comp. Physiol ., 2009, 297, 1785-1794) .

The present inventors have completed the present invention by demonstrating the fetal reprogramming efficacy of the PPAR? Agonist. In the present invention, the efficacy of PPAR delta was confirmed by using a maternal treatment to the mother during pregnancy and lactation. As a result, the activity of PPAR δ was increased by regulating calcium ion alone. The pups reprogrammed with the PPARδ active substance showed a significant improvement in endurance, even though they were no longer administered PPARδ active substance or exercise after growth into the adult. In addition, high fat intake and insufficiency of exercise caused obesity and the onset of diabetes and metabolic diseases were remarkably prevented or inhibited, and new efficacy has been proved to enhance memory. Furthermore, in the case of db / db mouse, which is a congenital diabetes mellitus disease model, not only the normal mouse but also the active substance of PPARδ proved that the postnatal development of diabetes was prevented / suppressed in the fetus.

 Schiaffino & Reggiani Physiol. Rev., 1996, 76, 371-423  Costill, DL. et al., J. Appl. Pysiol., 1976, 40, 149-154  Saltin B. et al., Ann. N. Y. Acad. Sci., 1977, 301, 3-44  Wang, YX. et al., PlosBiol., 2004, 2, e294  Vihang A. Narkar et al, Cell, 2008, 134, 405-415  Serrano, AL. et al., Proc. Natl. Acad. Sci. USA, 2001, 98, 13108-13113  Wu, H. et al., Science., 2002, 296, 349-352  Lin, J. et al., Nature, 2002, 418, 797-801  Masato Iwabu et al., Nature, 2010, 464, 1313-1319  William R. Oliver, Jr. et al., Proc. Natl. Acad. Sci. USA, 2001, 98, 5306-5311  Mc-Millen and Robinson, Physiol Rev., 2005, 85, 571-633  Plagemann, Horm Res., 2006, 65, 8389  Taylor and Poston, Exp Physiol, 2007, 92, 287298  Cherif et al., J Endocrinol., 1998, 159, 341-348  Wu et al., J Nutr., 2004, 134, 2169-2172  Lillycrop et al., J Nutr., 2005, 135, 1382-1386  Stoffers et al., Diabetes. 2003, 52, 734-740  Raab EL et al., Am. J. Physiol. Regul. Integr. Comp. Physiol., 2009, 297, 1785-1794

The present invention relates to the reprogramming efficacy of a PPAR? Active substance, which increases the activity of PPAR? Protein by using a compound in human and animal development, thereby increasing persimmon fiber and increasing endurance to prevent the onset of metabolic disease Or reduce, and improve memory. In the present invention, endurance is greatly improved by increasing only the PPAR delta active substance without exercise and increasing the persimmon fiber of a human or an animal, and reprogramming of metabolism of the whole body is originally prevented or suppressed from the onset of metabolic diseases , And the enhancement of memory is completely different from that reported in the prior invention (WO 2009/086526, WO2008 / 083330). More progressive is that the reprogramming efficacy of PPARδ is similar to that of normal mice, even in mice born with diabetes mellitus.

That is, an object of the present invention is to provide a composition for fetal reprogramming of a mammal, comprising a peroxisome proliferator activated receptor? (Agonist) as an active ingredient will be.

It is another object of the present invention to provide a method for reprogramming fetuses of a mammal other than a human, comprising the step of administering a PPAR? Activator to a mammal other than a human.

Another object of the present invention is to provide a food additive for a muscle endurance improvement, metabolic disease prevention, or memory enhancement, a functional food supplement, or a functional beverage, which is produced by a method of reprogramming a fetus of a mammal including a human, To provide a composition.

Another object of the present invention is to provide a feed composition for improving muscular endurance, metabolic disease prevention, or memory enhancement of an individual produced by a fetal reprogramming method of a mammal, comprising a PPAR? Activator as an additive.

Another object of the present invention is to provide a powdered milk or baby food composition for improving muscular endurance, preventing metabolic disease, or improving memory of an individual produced by a method of reprogramming a mammalian animal, comprising a PPAR? Activator as an additive.

Another object of the present invention is to provide a endurance enhancer for an individual produced by a method of reprogramming a mammal, including a human, comprising a PPAR? Activator as an active ingredient.

Another object of the present invention is to provide a endurance enhancer for an individual produced by a fetal reprogramming method of a mammal other than a human, comprising a PPAR? Activator as an active ingredient.

Another object of the present invention is to provide a novel PPAR delta active substance, a hydrate thereof, a solvate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and yet another object is to provide a novel PPAR delta active substance For the treatment and prevention of arteriosclerosis or hyperlipidemia, for treatment and prevention of hypercholesterolemia, for treatment and prevention of fatty liver, for treatment and prevention of diabetes, for treating and preventing obesity, for strengthening muscles, for treating and preventing muscle diseases, for improving endurance , For improving memory, for treating or preventing dementia or Parkinson's disease.

Another object of the present invention is to provide a functional food aid, a functional beverage, a food additive and a composition for animal feed comprising the novel PPAR delta active substance as an active ingredient.

Another object of the present invention is to provide a functional cosmetic composition for preventing obesity and improving obesity, prevention and improvement of fatty liver, muscle strengthening, prevention and improvement of muscular diseases, or endurance improvement, which comprises the novel PPAR delta active substance as an active ingredient.

Hereinafter, the present invention will be described in detail.

The present invention relates to the reprogramming efficacy of PPAR delta active substances during mammalian developmental stages. The present invention relates to the reprogramming efficacy of PPAR delta active substances during mammalian developmental stages, including the development of muscle endurance, obesity, Prevention and suppression of metabolic diseases, and memory-enhancing efficacy.

The present inventors used a method of administering a drug to the pregnant mother and a method of administering it to the mother at the time of feeding. However, the present invention is not limited to the two methods mentioned above, and includes all methods of reprogramming the PPAR? Fetus through a route other than the administration method used in the present invention. For example, by increasing the PPARδ expression and activity of the fetus through the mother, and increasing the expression and activity of PPARδ directly in the fetus in the form of milk powder and baby food. In addition to the active substances [CMDD1111, 1112, 1226] used in the present invention, pregnant animal mothers and pregnant women taking PPAR delta active substances as active ingredients, injecting agents for pregnancy, dosage formers, skin permeation ointment agents, beverages containing PPAR delta active substances , And PPAR δ reprogramming using food.

Previous studies have examined the changes in muscle fibers after oral administration of the active substance of PPARδ to adults, but did not increase the myofascial production (Vihang A. Narkar et al , Cell , 2008, 134, 405-415). In the present invention, the birth weight of the fetus was significantly increased in spite of the fact that the active substance of PPARδ was only administered to the mother during pregnancy or to the mother at the time of feeding. Therefore, PPAR δ-induced fetal reprogramming is mainly due to the increase of the nearness, and the most important period of action is myogenesis.

The root is characterized by increased fatty acid oxidation, mitochondrial biosynthesis, slow myosin heavy chain and slow contraction related proteins. Mice in which fetal reprogramming was performed by PPARδ increased expression of all the above gene groups. In addition, it was confirmed that PPAR δ active material increased the formation of the root muscle in the comparison of muscle appearance and histological staining. Taken together these two experiments suggest that fetal reprogramming by PPARδ active substance can promote the formation of the root locus.

Calcium is known to be a major modulator in promoting fasting of the right atrium. According to the results of research conducted by the present inventors, the expression of RYR, ATP2A2, PLN and the like which regulate the cytoplasmic calcium concentration in the mouse muscle was significantly increased as a result of fetal reprogramming by the PPARδ active substance, Time has increased significantly. These intracellular calcium ions increased the calcium signal and increased the production of root locus.

In the present invention, mice with an increase in short-side muscles showed a 2.9-fold increase in exercise time as compared with control mice. To investigate the mechanism of action, we performed microarray experiments using skeletal muscle tissue. As a result, gene expression of RYR2, ATP2A2, PLN, MYBPC3 and the like, which are known to be expressed in cardiac muscle, was significantly increased in the group of mice in the administration group. Taken together, the reprogramming of the fetus by the PPARδ active substance not only improved muscle function in the mouse, but also improved cardiac function.

The greatest significance of the present invention is the ability to improve the health and quality of life of humans and animals after growth through reprogramming of fetuses with PPARδ active compounds. Although mice reprogrammed with PPAR δ did not receive PPAR δ active compound or exercise after they became adulthood, adult endurance and endurance were significantly increased at adulthood, and obesity and diabetes due to lack of exercise and exercise The onset of the metabolic syndrome such as the disease was markedly suppressed.

Obesity is not only a cause of diabetes but also a direct cause of metabolic diseases such as hyperlipidemia, arteriosclerosis and myocardial infarction. Therefore, the present invention can provide a preventive effect on all metabolic syndrome as well as silk obesity in mice in which the fat metabolism capacity is increased through reprogramming of fetus with PPAR? Active substance.

The root muscle contains a lot of mitochondria compared to the root muscle. Mitochondria have inherited maternal inheritance. Thus, mice with increased reprogramming by PPARδ activity and mitochondria can affect the formation of the next generation of mitochondria, and can prevent late onset of endurance and the onset of metabolic syndrome without any administration of PPARδ active substance have.

That is, the present invention provides a composition for fetal reprogramming of a mammal, which comprises, as an active ingredient, a peroxisome proliferator activated receptor? (Agonist). The present invention also provides a method of reprogramming fetuses of a mammal other than a human, comprising administering a PPAR? Activator to a mammal other than a human. The present invention also relates to a food additive, a functional food supplement, or a functional beverage composition for improving muscular endurance, metabolic disease prevention, or memory enhancement of an individual produced by a method of reprogramming a fetus of a mammal including a human, . The present invention also provides a feed composition for improving muscular endurance, preventing metabolic diseases, or improving memory performance of an individual produced by a fetal reprogramming method of a mammal, comprising a PPAR? Activator as an additive. The present invention also provides a powdered milk or baby food composition for improving muscular endurance, preventing metabolic diseases, or enhancing memory ability of an individual produced by a method for reprogramming mammalian animals, comprising a PPAR? Activator as an additive. The present invention also provides a endurance enhancer for an individual produced by a method of reprogramming a mammal, including a human, comprising a PPAR? Activator as an active ingredient. In addition, the present invention provides a endurance enhancer for an individual produced by a fetal reprogramming method of a mammal other than a human, comprising a PPAR? Activator as an active ingredient.

Examples of the PPAR delta active substance in the present invention are as follows, but the present invention is not limited to the following exemplified materials, but applies to all the PPAR delta active substances. [Examples of PPAR delta active substances: WO 2010/039789, WO 2010/028761, WO 2010/023572, WO 2010/009215, WO 2010/009212, WO 2010/009210, WO 2010/008299, WO 2009/155709, WO 2009/140342, WO 2009/136290, WO 2009/114173, WO 2009/098000, WO 2009/097999, WO 2009/097998, WO 2009/097997, WO 2009/097995, WO 2009/099950, WO 2009/078981, WO 2009/039944, WO 2009/039943, WO 2009/039942, WO 2009/027785, WO 2009/024287, WO 2009/016216, WO 2009/006483, WO 2008/144925, WO 2008/135141, WO 2008/122014, WO 2008/115574, WO 2008/104557, WO 2008/089892, WO 2008/085316, WO 2008/079293, WO 2008/070950, WO 2008/060746, WO 2008/058631, WO 2008/058630, WO 2008/058629, WO 2008/058628, WO 2008/052658, WO 2008/017381, WO 2008/000484, WO 2007/131622, WO 2007/131621, WO 2007/131620, WO 2007/131619, WO 2007/130075, WO 2007/121432, W WO 2007/110216, WO 2007/110215, WO 2007/107869, WO 2007/105050, WO 2007/10849, WO 2007/089857, WO 2007/089667, WO 2007/087448, WO 2007/087204, WO 2007/059871, WO 2007/056496, WO 2007/056210, WO 2007/047432, WO 2007/033231, WO 2007/016538, WO 2006/137796, WO 2006/137795, WO 2006/124490, WO 2006/123185, WO 2006/123184, WO 2006/123183, WO 2006/123182, WO 2006/113919, WO 2006/111321, WO 2006/111261, WO 2006/104826, WO 2006/102067, WO 2006/098912, WO 2006/097220, WO 2006/092507, WO 2006/091506, WO 2006/087630, WO 2006/084176, WO 2006/083645, WO 2006/078605, WO 2006/078575, WO 2006/076681, WO 2006/056854, WO 2006/055187, WO 2006/041197 , WO 2006/040002, WO 2006/034128, WO 2006/033004, WO 2006/033062, WO 2006/032987, WO 2006/032384, WO 2006/032023, WO 2006/031969, WO 2006/018174, WO 2006/017055 , WO 2005/115983, WO 2005/113506, WO 2005/105754, WO 2005/105736, WO 2005/105726, WO 2005/103022, WO 2005/097784, WO 2005/092317, WO 2005/092316, WO 2005/091857 , WO 2005/077925, WO 2005/066136, WO 2005 / WO 2005/063761, WO 2005/063761, WO 2005/060958, WO 2005/041959, WO 2005/037763, WO 2005/037199, WO 2005/030694, WO 2005/007628, WO 2005/007111, WO 2004 / WO 2004/063166, WO 2004/063165, WO 2004/063166, WO 2004/067482, WO 2004/066929, WO 2004/063184, WO 2004/063186, WO 2004/063166, WO 2004/093166, WO 2004/033438, WO 2004/033438, WO 2004/033416, WO 2004/018421, WO 2004/007430, WO 2003/094845, WO 2003/074495, WO 2003/072100, WO 2003/048108, WO 2002/102813, WO 2002 / WO 1997/27857, WO 1997/27847, WO 1997/28137, WO 1996/1995, WO 2001/070754, WO 2001/070753, WO 1998/049555, WO 1998/27974, WO 1997/28149, WO 1997/28115, 001317].

Some of the PPAR delta active substances are represented by the following formula (I).

(I)

이며;Wherein A in the formula (I) is oxygen (O), nitrogen (NH), sulfur (S) or selenium (Se); B is

;

R ₁ is selected from the following structures,

또는 하기 구조로부터 선택되며;R ₂ is hydrogen, a C ₁ -C ₅ alkyl group,

Or is selected from the following structures;

X is sulfur (S) or selenium (Se);

Y is carbon (CH) or nitrogen (N);

R ₃ is hydrogen, C ₁ -C ₈ alkyl or halogen;

R ₄ and R ₅ are independently of each other hydrogen, halogen or C ₁ -C ₈ alkyl;

R ₆ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₇ alkenyl, alkali metal, alkaline earth metal or organic acid;

R ₁₁ and R ₁₂ independently of one another are hydrogen, halogen, C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy;

R ₂₁ is hydrogen, halogen, C ₁ -C ₇ alkyl, heterocyclic group, C ₁ -C ₇ alkoxy, C ₁ -C ₅ alkyl substituted with halogen or phenyl substituted with halogen;

m and n are each independently an integer of 1 to 4;

p is an integer from 1 to 5;

q is an integer of 1-4;

r is an integer from 1 to 3;

s is an integer from 1 to 5;

The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ , R ₁₂ and R ₂₁ may be further substituted by one or more halogens or C ₁ -C ₅ alkylamines.

Some of the above PPAR delta active substances are represented by the following formula (II).

≪ RTI ID = 0.0 &

이며;Wherein A is sulfur (S) or selenium (Se); B is

;

R ₁ is selected from the following structures;

또는 하기 구조로부터 선택되며;R ₂ is hydrogen, a C ₁ -C ₅ alkyl group,

Or is selected from the following structures;

X is sulfur (S) or selenium (Se);

Y is carbon (CH) or nitrogen (N);

R ₃ is hydrogen, C ₁ -C ₅ alkyl or halogen;

R ₄ and R ₅ are independently of each other hydrogen or C ₁ -C ₅ alkyl;

R ₆ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, alkali metal or alkaline earth metal;

R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;

R ₂₁ is hydrogen, halogen, C ₁ -C ₅ alkyl, heterocyclic group, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkyl substituted with halogen or phenyl substituted with halogen;

m is an integer of 1 to 4;

p is an integer from 1 to 5;

q is an integer of 1-4;

s is an integer from 1 to 5;

The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R ₂₁ may be further substituted by one or more halogens or C ₁ -C ₅ alkylamines.

Some of the PPAR delta active substances are represented by the following formula (III).

(III)

이며;Wherein A is independently sulfur (S) or selenium (Se) and B is

;

또는 하기 구조로부터 선택되며;R ₂ is hydrogen, a C ₁ -C ₅ alkyl group,

Or is selected from the following structures;

X is sulfur (S) or selenium (Se);

Y is carbon (CH) or nitrogen (N);

R ₃ is hydrogen, C ₁ -C ₅ alkyl or halogen;

R ₄ and R ₅ are independently of each other hydrogen or C ₁ -C ₅ alkyl;

R ₆ is hydrogen, C ₁ -C ₅ alkyl, C ₂ -C ₅ alkenyl, alkali metal or alkaline earth metal;

R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;

R ₂₁ is hydrogen, halogen, C ₁ -C ₅ alkyl, heterocyclic group, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkyl substituted with halogen or phenyl substituted with halogen;

m is an integer of 1 to 4;

p is an integer from 1 to 5;

q is an integer of 1-4;

s is an integer from 1 to 5;

The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R ₂₁ may be further substituted by one or more halogens or C ₁ -C ₅ alkylamines.

Some of the above PPAR delta active substances are represented by the following formula (IV).

(IV)

[In the formula (IV), A is each independently sulfur (S) or selenium (Se);

또는 하기 구조로부터 선택되며;R ₂ is hydrogen, a C ₁ -C ₅ alkyl group,

Or is selected from the following structures;

X is sulfur (S) or selenium (Se);

Y is carbon (CH) or nitrogen (N);

R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;

R ₂₁ is hydrogen, halogen, C ₁ -C ₅ alkyl, heterocyclic group, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkyl substituted with halogen or phenyl substituted with halogen;

p is an integer from 1 to 5;

q is an integer of 1-4;

s is an integer from 1 to 5;

Alkyl and alkoxy in the R ₁₁ and R ₂₁ may have one or more of halogen or C ₁ -C ₅ alkylamine may further be substituted.]

The novel compound in the above PPAR delta active substance is represented by the following formula (V).

(V)

[In the above formula (V), A is each independently sulfur (S) or selenium (Se);

R ₂ is selected from the following structures;

X is sulfur (S) or selenium (Se);

R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;

p is an integer from 1 to 5;

q is an integer of 1-4;

Alkyl and alkoxy in the R ₁₁ may have one or more of halogen or C ₁ -C ₅ alkylamine may further be substituted.]

More specifically, the novel substance in the above PPAR delta active substance is represented by the following formula (VI).

(VI)

[In the formula (VI), each A is independently sulfur (S) or selenium (Se);

R ₂ is selected from the following structures;

X is sulfur (S) or selenium (Se);

R ₁₁ is hydrogen, C ₁ -C ₃ alkyl or halogen;

p is an integer from 1 to 5;

q is an integer of 1-4;

Alkyl wherein R ₁₁ may further be one or more of halogen or C ₁ -C ₅ alkylamine substituted.]

The novel substances among the above PPAR delta active substances are more specifically the following compounds.

The present invention also relates to a method for treating or preventing arteriosclerosis or hyperlipidemia comprising the PPAR delta active substance represented by the above formula (V) as an active ingredient, for treating and preventing hypercholesterolemia, for treating and preventing fatty liver, for treating and preventing diabetes, The present invention provides a medicinal composition for treating or preventing a disease, treating or preventing a disease, strengthening a muscle, treating or preventing a muscle disease, improving endurance, improving memory, treating or preventing dementia or Parkinson's disease. The present invention also provides a functional food supplement, a functional beverage, a food additive and a composition for animal feed comprising the novel PPAR delta active substance as an active ingredient. The present invention also provides a functional cosmetic composition containing the novel PPAR delta active substance as an active ingredient for the prevention of obesity and for improving obesity, prevention and improvement of fatty liver, muscle strengthening, prevention and improvement of muscle diseases, or endurance improvement.

The amount of the PPAR delta active substance used to achieve the therapeutic effect according to the present invention will depend on the specific compound, the method of administration, the subject to be treated, and the disease to be treated, but depends on the dose of the conventional medicament, Effective doses of the PPAR delta active substance are administered within the range of 1 to 100 mg / kg body weight / day. In addition, it is divided into one day or several times a day within the range of effective doses per day. It is also possible for oral administration or topical administration according to the formulation. The pharmaceutical composition according to the present invention can be prepared in any of various conventional forms, for example, tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, And may exist in various forms such as beverages, drinks, and so on. Tablets according to the present invention may be administered to a patient in any form or manner that is bioavailable in an effective amount, i. E., By an oral route, and may be administered to a patient in accordance with the nature of the disease condition to be treated or prevented, the stage of the disease, It is contemplated that suitable dosage forms or modes may be readily selected and that the compositions according to the present invention may contain one or more pharmaceutically acceptable excipients when tablets and the proportions and properties of such excipients will depend on the solubility and chemical properties of the selected tablet, The route of administration selected and the standard pharmaceutical practice.

According to the present invention, the PPARδ active substance improves lipid and glucose metabolism ability by regulating calcium ions in the development of fetuses and early development period to increase muscle fiber by increasing the myofascial fibers, thereby improving metabolic reprogramming ) To prevent / suppress the onset of metabolic diseases such as obesity and diabetes caused by high-fat diets and lack of exercise in adults or adults, and to increase memory. Accordingly, the PPAR? Active substance is useful as a medicinal composition for enhancing endurance of human and animal by fetal reprogramming, preventing / suppressing metabolic diseases such as obesity, diabetes, atherosclerosis and fatty liver, enhancing memory, , An animal endurance enhancer, a milk powder and a baby food composition, and an animal feed composition.

1 is a schematic diagram of the experimental procedure of Example 1. Fig. Simultaneous administration during pregnancy and lactation, b. During pregnancy, c. Feeding period].
Figure 2 - Results of pharmacokinetic experiments conducted to confirm the placental passage of PPARδ active substance in pregnant mother.
FIG. 3 - Body weight measurement (n = 8) immediately after birth of fetal reprogrammed fetuses by PPARδ active material in the experiment conducted according to the method of FIG.
FIG. 4 - The results of the weight change of the fetus in the experiment conducted according to the method of FIG. 1 for 2 weeks (n = 8).
FIG. 5 - Results of a comparison of body weight when the fetus was grown up to 6 weeks (n = 8) in the experiment conducted according to the method of FIG.
FIG. 6 - Photograph of the skeleton of the fetus in order to confirm the presence of skeletal development in the experiment conducted according to the method of FIG.
FIG. 7 - Results of analysis of muscle fiber type after growth of fetus reprogrammed fetus in the experiment conducted according to the method of FIG. (A, B). After observing the changes of muscles after excision of skin and forelimb of the back region. (C, D) After excision of the hind legs, metachromatic staining and immunohistochemistry revealed changes in the myofascial fibers in the Gastrocnemius muscle.
FIG. 8 is a table summarizing the micro-array results in the experiment conducted according to the method of FIG.
In the experiments conducted according to the method of FIG. 9 - 1, the expression of genes important for fatty acid oxidation and thermogenesis in muscles using real-time PCR analysis ( ** , P < 0.01; *** , P < 0.001).
Figure 10 - Comparison of the expression of genes important in the generation of the closest, using a real-time PCR assay in experiments performed according to the method of Figure 1 (*, P <0.05; **, P <0.01; *** , P < 0.001).
FIG. 11 is a graph ( * , P <0.05; *** , P < 0.001) comparing the expression of genes important for the function of slow type muscle using real-time PCR analysis in the experiment conducted according to the method of FIG. .
Figure 12 - Results of analysis of gene expression of PPARδ-deficient muscle cells using real-time PCR ( * , P <0.05) in order to prove that the results of fetal reprogramming experiments performed in accordance with the method of FIG. ** , P &lt;0.01; *** , P &lt; 0.001)
FIG. 13 - Experimental results using a confocal microscope ( * , P <0.05) to confirm the quantitative change of cytoplasmic calcium ion by PPARδ in a fetal reprogramming experiment conducted according to the method of FIG.
Fig. 14 - Endurance of male mice with PPARδ increased by treadmill in the fetal reprogramming experiment according to the method of Fig. 1 ( *** , P < 0.001, n = 4 -5).
Fig. 15 - Endurance of female mice with PPARδ increased by treadmill in the fetal reprogramming experiment according to the method of Fig. 1 ( *** , P < 0.001, n = 4 -5).
FIG. 16 - Results of respiration exchange rate measurement using oximax in the experiment conducted according to the method of FIG. 1 ( ** , P < 0.01, n = 4).
( ** , P < 0.01, n = 4) as a result of comparing the results of Figs. 17 to 16 with area values.
FIG. 18 - Results of the weight gain test ( * , P <0.05, n = 5) in the fetal reprogramming experiment conducted according to the method of FIG. 1, with high fat diets containing 35% fat.
Figure 19 - Glucose tolerance test of mice with diabetes induced by high fat intake in a fetal reprogramming experiment conducted according to the method of Figure 1 ( ** , P < 0.01, n = 6).
FIG. 20 - Results of insulin sensitivity testing of diabetic mice induced by high fat intake in a fetal reprogramming experiment conducted according to the method of FIG. 1 ( *** , P < 0.001, n = 6).
Figure 21 - CMDD1226 efficacy demonstration ( ** , P < 0.01, n = 4) in a fetal reprogramming experiment performed according to the method of FIG.
FIG. 22 - Fetal reprogramming experiments conducted according to the method of FIG. 1 show that the administration time of GW 501516 (1: Vehicle treatment of pregnant mice during gestation and lactation period; 2: GW 501516 treatment of pregnant mice during lactation; ( ** , P < 0.01; *** , P < 0.001, n = 4) were compared between the effects of increasing endurance of the mice during gestation; 4: GW501516 treatment of pregnant mice during gestation and lactation period.
FIG. 23 - Difference in endurance enhancement efficacy ( *** , P < 0.001, n = 4) according to the administration concentration and male sex of CMDD1112 in the fetal reprogramming experiment conducted according to the method of FIG.
Figure 24 - Difference in endurance enhancement efficacy ( *** , P < 0.001, n = 4) according to the administration concentration and female of CMDD1112 in the fetal reprogramming experiment conducted according to the method of FIG.
Figure 25 - Schematic representation of an experimental procedure using a type 2 diabetes model.
The results of the glucose tolerance test of the type 2 diabetic model mice ( * , P < 0.05, n = 6-9) in the experiments conducted by the methods of FIGS. 26 - 25.

Hereinafter, the present invention will be described in detail with reference to examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

1. Fetal reprogramming efficacy by PPARδ active substance

The structure of the PPAR? Active material used in the following examples is as follows.

Example 1: Fetal reprogramming of mouse using PPAR? Active substance

The present inventors used a PPAR δ active substance at the mother's end to identify the role of PPAR δ in fetal reprogramming during the mammalian development process (maternal treatment). The pregnant female mice were orally administered PPAR δ active substance at a concentration of 10 ㎎ / ㎏ / day for reprogramming of fetuses. Specific experimental methods are summarized in Fig.

(1) Confirmation of the placental passage of PPARδ active substance

Pharmacokinetics experiments were conducted to confirm the placental passage of CMDD1111, a PPARδ active substance used in this study. After 16 days of pregnancy, CMDD1111 was orally administered to mice at a concentration of 10 mg / kg, and the concentration of compounds distributed in the blood of maternal animals and fetuses was analyzed for 24 hours. As a result, the maximum blood concentration (C _max ) of the mother was 38 μM, and the time to reach the maximum blood concentration (T _max ) was 1 hour and the half-life (t _1/2 ) was 9 hours. In the case of fetuses, the blood concentration tended to increase with time, and the maximum blood concentration was 8.9 μM. It was confirmed that the compound used in this example was a substance that passed through the placenta (Fig. 2) since this concentration was sufficient to activate PPAR? In the fetus.

(2) reprogramming of mouse fetuses by maternal treatment with PPARδ active substance in pregnant mother

After fertilization female mice and male mice were crossed, the presence of pregnancy was confirmed by checking plugs. For pregnant female mice, CMDD1111 was orally administered at a concentration of 10 mg / kg once daily for 6 weeks (gestation period and lactation period). Adverse effects due to the drug substance during pregnancy were not observed. During pregnancy, the weight of the vehicle-fed fetus group was 1.33 ± 0.11 grams, and the weight of CMDD1111-treated fetuses was 1.37 ± 0.09 grams, showing no difference in weight between the two groups (FIG. 3). In addition, no growth inhibition or stimulation by the administered substance was observed (Fig. 4) even when the growth rate of the fetus was observed for 3 weeks, and there was no difference in weight between the two groups even when they became adults (Fig. 5) Sagittal staining with Alican blue dye showed no abnormalities due to the drug substance (Fig. 6).

&Lt; Example 2 > Demonstration of the effect of increasing PPAR? In PPAR? -Activated fetal reprogrammed mice

The root muscle is reddened compared to the fasting muscle because it has a lot of myoglobin, an oxygen transfer protein. After removing the skin of the fetus and observing the muscles, it was found that the mice of the administration group had redder muscles (FIGS. 7A and 7B). In order to confirm the increase of the production of the root by the administration substance (CMDD1111), the hind leg of the fetus was removed and placed in OCT and frozen. The frozen muscle tissue was sliced into 8 mm thickness using a cryotome, and then slides were used to perform metachromatic staining. Metachromatic staining of the root is darker blue than that of muscle. As can be seen in Fig. 7C, it can be seen that the production of dark blue muscle fibers in the gastrocnemius muscle was increased by the administration substance (CMDD1111). Muscle fiber can be distinguished by immune staining using myosin heavy chain (MHC) isoform antibody. We performed immunohistochemical staining using slow type MHC in order to confirm the increase of myofascial fiber by administration material (CMDD1111). As a result, as shown in FIG. 7D, it was found that the muscle fibers responding to the slow type MHC were increased in the gastrocnemius muscle of the administration group. These results show the same pattern as metachromatic staining. As a result of these two experiments, it was confirmed that the production of root is increased by the administration material (CMDD1111).

&Lt; Example 3 > Demonstration of increase of persimmon fiber by controlling calcium ion

The present inventors performed gene expression analysis in order to identify the cause of the increase of the root growth in the fetal reprogrammed mouse by PPARδ activation.

(1) Gene expression analysis using microarray

Gastrocnemius muscle of 3 weeks old mice reprogrammed with PPARδ active substance (CMDD1111) in animals was extracted and total RNA was extracted using Trizol reagent (Gibco). The isolated RNA was subjected to quantitative and purity assays and then used for gene expression analysis using the Mouse 430 2.0 (Affimatrix) chip.

Generally, the root muscle has more mitochondria, more fatty acid oxidation, and slower contraction rate than that of fasting muscle. As a result of analysis, it was confirmed that gene expression related to the above three controls was increased (FIG. 8).

Pantothenate kinase 1 (PANK1: 2.4 fold), carnitine palmitoyl transferase 1a (CPT-1a: 1.4 fold), acyl CoA dehydrogenase (ACAD: 1.7 fold), acyl CoA synthetase (ACSL: 1.5), essential for fatty acid oxidation and mitochondrial respiration The expression of cytochrome 8a (1.7 times), ubiquinone (2.0 times), and uncoupling protein 2, 3 (UCP2, 3: 1.5 times, 2.3 times)

Expression of PPARγ coactivator 1a (1.7 times), CamIIb (1.4 times), CamIId (1.8 times), and Mef2a (1.4 times) 1.5 times) was decreased.

The root muscle has more calcium than fasting muscle and has a calcium-regulating protein of slow subtype. Interestingly, the mice with myofilaments increased myosin binding protein C3 (MYBPC3: 2.8 fold), Troponin T2 (2.3 fold), Troponin I (3.2 fold), myosin heavy chain 6 (Myh6: 2.7 fold), myosin light chain (RYR2, 3: 2.8-fold, 2.0-fold), ATPase, and Ca2 + transport (SERCA), as well as the expression of slow-type calcium- : 1.4 times) and phospholamban (PLN: 2.8 times), respectively.

(2) Gene expression analysis using real-time PCR

To further verify the results of the Miroarray analysis, gene expression analysis experiments were performed using real-time PCR. During the period of muscle development, the mouse group that was reprogrammed with the PPARδ active substance (CMDD1111) was Carnitine palmitoyl transferase 1a (CPT-1a: 1.5 times), Uncoupling protein 3 (UCP3: 4.2 times), Acyl CoA synthetase : 1.4 times), Acyl CoA dehydrogenase (ACAD10: 2.0-fold), and NDUFA12 (1.3-fold), the expression of key regulators in fatty acid oxidation and thermogenesis increased. In addition, the expression of adiponectin (ADIPOQ: 2.5-fold), which is highly expressed in the root muscle and is known to improve the oxidation of fatty acids in muscles and thereby improve diabetes, was significantly increased (FIG.

PGC-1α is not only a co-activator of fatty acid oxidation, but also a key regulator of mitochondrial biosynthesis and an increase in the generation of nearsightedness. Expression of this gene was increased 1.6-fold by the PPAR? Active substance (CMDD1111). In addition, the expression of CaMKIIb, d, which is known to increase persimmonization of muscle in muscle remodeling, was also increased 4.5 - fold and 3.2 - fold, respectively. On the other hand, the expression of HDAC4, which is already known to inhibit myosin production through a loss of function study, decreased 0.6-fold (FIG. 10).

In the skeletal muscle, the cytoplasmic calcium concentration is essential for excitation-contraction coupling, which itself is an important regulator of muscle plasticity. In the present invention, mice with an increase in proximity have increased expression of factors known to regulate cytosolic calcium in muscle cells. RYR2 and RYR3 were the genes regulating the efflux of calcium in the sarcoplasmic membrane, 2.2 and 3.6 fold, respectively, as compared with the control group. ATP2A2 is a gene that influences calcium from a cytoplasm to a sarcoplasmic reticulum. Its expression level is 2.2 fold, and the expression of phospholamban gene, a locus specific gene, is increased 3.2 times. In addition, expression of TNNI3 (5.8-fold), MYH6 (6.8-fold), and Myl7 (4.8-fold), which are involved in muscle contraction associated with calcium in the slow muscle, was increased (FIG.

(3) Primary cell culture and gene expression analysis

Microarray analysis and real-time PCR analysis showed that the expression of RYR3, ATP2A2, and PLN, which are key genes for regulating cytoplasmic calcium concentration, was significantly increased in the fetal reprogrammed mice by PPARδ active substance (CMDD1111). However, PPRE (PPARs response element) has never been reported in the promoters of these three genes. Therefore, in order to confirm whether the expression of the above three genes is increased in a PPARδ-dependent manner, the present inventors performed primary culture by extracting the muscle of the mouse from which the PPARδ gene has been removed. On the fifth day after birth, the fetal hind legs were removed and primary culture was performed in the same manner as that developed by Rando et al . (Rando et al . , J. Cell. Biol ., 1994, 125, 1275-1287). Myoblast cultures were transferred to 6 well plates and PPARδ active substance (CMDD1111) was treated with 300 nM and differentiated into myotubes. The differentiated myotubes were further treated with 300 nM of PPAR delta active (CMDD1111) for 2 days and then total RNA was extracted with TRIzol reagent (Gibco). The extracted RNA was synthesized by reverse transcription and used as a template for real-time PCR analysis.

Real-time PCR analysis revealed that the expression of PDK4 and CPT-1, which are directly regulated by PPARδ, increased 2.2-fold and 1.5-fold, respectively. However, there was no change in the cells lacking PPARδ. This implies that the expression of PDK4 and CPT-1 is dependent on PPARδ. This tendency was also observed in RYR (2.2-fold), PLN (1.7-fold), TNNI3 (1.7-fold) and ATP2A2 (4.3-fold) genes as shown in Fig. Thus, PPARδ directly controls the expression of genes regulating calcium concentration in the cytoplasm.

(4) Demonstration of regeneration efficacy of myocardial cells

The expression of RYR2, ATP2A2, and PLN, which are known to be expressed in cardiac muscle, was markedly increased by the PPARδ active substance (CMDD1111) in the mouse group reprogrammed with fetuses.

(5) cytoplasmic calcium analysis

To investigate the effects of RYR, SERCA, and PLN changes on cytoplasmic calcium concentration, experiments were carried out using Flou4 (Molecular probe), a calcium-specific staining sample. The experimental method is as follows. The muscle cells isolated from the primary culture were grown on a culture plate with a glass slide, and the PPARδ active substance (CMDD1111) was treated with 300 nM to differentiate into myotubes. Flou4 (final concentration: 5 μM) staining reagent was added to the differentiated muscle cells, followed by incubation for 30 minutes. Calcium-free Kreb solution was used as a culture medium to measure changes in cytoplasmic calcium, and 10 mM caffeine was administered to activate calcium channels. Changes in intracellular calcium ion were measured using a confocal microscope. As a result, the retention time of intracellular calcium was 43% (592 ± 60 versus 847 ± 77 sec) in the muscle cells containing PPARδ active substance (CMDD1111) (FIG. 13). This is because the expression of PLN suppressing RYR and calcium influx, which regulate calcium efflux in the sarcoplasmic membrane, is increased by PPARδ. It has already been shown that calcium ion concentration in the cytoplasm in muscular cells produces effects such as the generation of force and suppression of fatigue, especially in muscular remodeling processes. Therefore, in the present invention, it is considered that the mouse reprogrammed with PPARδ activating increased the generation of root locus due to the effect of increased calcium ions in the cytoplasm.

<Example 4> Proving endurance enhancement effect of fetal reprogramming mouse through PPAR? Activation

Because the near side is high in fat resolution and resistant to fatigue caused by exercise, it is suitable for exercise requiring endurance such as marathon. The present inventors conducted an experiment using a treadmill to measure the endurance enhancement effect of the fetal reprogrammed mouse by the PPAR? Active substance.

Prior to the experiment, the mice were allowed to exercise for 5 minutes at a rate of 7 meters / min for 2 days to give the mice time to adapt to the exercise device. On the third day, the experiment was carried out. The experimental method was run at a speed of 10 meter / min for 60 minutes, and then at a rate of 1 meter / min for 15 minutes at a maximum speed of 15 meter / min Respectively. In males, mice in the PPARδ active substance group (CMDD1111) treated group had a 2.9-fold increased time (235 ± 26 versus 677 ± 78 min, P <0.0001, n = 6) (9927 ± 1168 versus 3303 ± 394 m, P <0.0001), respectively. In female, the running time increased 2.0 times (376 ± 19 versus 761 ± 17 min, P <0.0001, n = 4) and the running distance increased 2.1 times (5419 ± 291 versus 11194 ± 261 m, P <0.0001) The same tendency was observed with males (Figs. 14 and 15).

Example 5: Measurement of respiratory exchange ratio (RER) of fetal reprogramming mice via PPAR? Activation

RER is the amount of oxygen used for breathing and the amount of carbon dioxide emitted. The RER value has a value of 1.0 when the organism uses mainly carbohydrates for energy production and a value of 0.7 when it uses fat. In the present invention, the generation of the near side of the fetus reprogrammed mouse was increased. RER experiments using Oximax (Columbus) were performed to evaluate whether the increase of the nearness actually affects the energy metabolism of the mouse. As a result, it was found that the group of mice administered with PPAR delta active substance (CMDD1111) had a smaller RER value than the group of mice administered with vehicle, which means that more fat was used than carbohydrate (Fig. 16). Since the RER has a periodic value over time, we used the AUL to compare the RER differences between the two groups. The mean AUL value of the control group was 107.4 ± 1.4, while that of the wild-type programmed mouse group was 102.2 ± 2.8, which is lower than that of the control mice (FIG. 17).

The present inventors have examined the difference in fat oxidation ability between two groups using the following equation.

Carbohydrate oxidation = (4.51 · RER - 3.18) · VO ₂

Lipid oxidation = 1.67 (1-RER) VO ₂

As a result of the calculation, it was found that the mouse group treated with the PPARδ active substance (CMDD1111) used an average of 44% fat (6.6 mg / kg min vs. 9.5 mg / kg min) It was found that 20% less carbohydrate was used (48 mg / kg min vs. 38 mg / kg min). Therefore, in the present invention, mice that have activated PPAR? During the programming period of the fetus are not only increased in the root, but also increased in fat metabolism.

Example 6 Demonstration of Obesity and Diabetes Preventive / Inhibitory Effect of Fetal Reprogrammed Mice via PPARδ Activation

Mice that had been reprogrammed with PPARδ by the present invention continued to have an increased fat metabolism ability even when adulthood, even though they received PPARδ active compound only during pregnancy and lactation only. Fat metabolism is closely related to the onset of obesity and diabetes. Therefore, the present inventors have examined the effect of PPARδ reprogramming on the onset of the adult metabolic syndrome. Body weight was measured once a week in a 13-week-old control group and in a dose-group mouse for 84 days with high-fat diets (fat content: 35%). As a result, as shown in FIG. 18, it was found that the weight gain of the fetal reprogrammed mice by the PPARδ active compound (CMDD1111) was inhibited by 8% as compared with the control group.

The mice were also fed a high fat diet for 17 weeks to induce diabetes and then undergo a glucose tolerance test (GTT). The experimental method was performed according to the method proposed by Kelly and over-night fasting was performed to confirm its role in the muscles. Glucose (1 ㎎ / ㎏) was administered by intraperitoneal injection, and blood glucose changes were measured for 2 hours. As a result, the fasting blood glucose level of the mice of the administration group was lower than that of the control mice, the maximum blood glucose concentration was lower, and the time of glucose clearance was shorter (FIG. 19). At the same time, insulin resistance experiments were also performed (Fig. 20). Taken together, these results suggest that PPAR δ inhibits the development of obesity - related diabetes mellitus in high - fat diets as well as the endurance - enhancing effect of fatigue - reprogrammed animals.

Example 7 Demonstration of Memory-Enhancing Effect of Fetal Reprogramming Mice Through PPARδ Activation

In the present invention, an animal experiment was conducted to examine the memory enhancing effect of fetal reprogrammed mouse by PPAR? Active substance. To prove the efficacy of the inventive substance in the brain stage, pregnant rats were orally administered a PPARδ active substance, CMDD1111, at a concentration of 10 mg / kg / day during gestation and lactation. When the fetus became an 8-week-old adult, we performed a Morris water maze test to compare the memory of the control and the treatment groups. This method is a test method for verifying spatial learning and memory. The average time spent searching for the platform was 26, 22 (male, female) in the control group and 9, 6 (male, female) in the administration group. Therefore, PPAR δ activator proved to be effective in enhancing memory during the fetal programming period.

Test results with Sumi Experimental group Experimental results with Morris Sumi Vehicle Number 26 seconds cancer 22 seconds CMDD1111 Number 9 seconds cancer 6 seconds

<Example 8> Verification of fetal programming effect on PPAR?

In order to complete the present invention, the effect of the primer programming on the PPAR? Active material having a different chemical structure from the above-mentioned CMDD1111 was confirmed.

(1) Demonstration of fetal reprogramming efficacy using PPARδ active substance CMDD1226

In order to demonstrate the endurance improvement effect of CMDD1226 fetal reprogramming, experiments using pregnant C57BL / 6 mice were conducted. CMDD1226 was orally administered daily at a concentration of 10 mg / kg / day during the gestation period and during the lactation period of the pregnant mouse, and the endurance of the 7 weeks old adult fetus was measured using a treadmill. As a result, the reprogrammed group was 1.9 times longer than the control group, and the running distance was 2.0 times higher than that of the control group, thereby demonstrating the endurance increasing effect by the PPAR? Active substance (FIG. 21).

(2) Fetal programming using GW501516 (efficacy and determination of optimal dosing timing)

GW 501516, and the experiment was conducted to determine the optimal time for administration. The experimental method is shown in Fig. 1, and the experiment was conducted by dividing the administration time into three kinds (pregnancy period, lactation period, gestation period and lactation period). In the experimental group, PPAR δ activity was increased 2.6 times and 3.2 times in the group treated with PPAR δ, respectively, compared with the control group. The group with the most significant increase in endurance was the group receiving PPAR δ active substance in both the gestation period and the lactation period and increased 5.1 times and 6.6 times, respectively, compared to the control group (Fig. 22).

(3) Fetal reprogramming using PPARδ active substance CMDD1112 (demonstration of efficacy and determination of optimal dose concentration)

In order to demonstrate the ability of the CMDD1112 substance with superior selectivity to PPARδ compared to GW501516 and to determine the optimum concentration of the PPARδ active substance, four concentrations (1, 2, 5, and 10 mg / kg / day) Experiments were performed. Experimental results showed that endurance was not improved at 1 and 2 mg / kg / day, and endurance (running time: 1.4 times, running distance: 1.5 times) was increased only at 5 mg / kg / 23, Fig. 24).

In the present invention, experiments were performed on three different materials in order to confirm the endurance improving effect of the animal's reprogramming with the PPAR? Active substance. As a result, all of the PPAR δ active substances showed endurance improving effects. Thus, all of the PPAR δ activating substances may have an effect of increasing the occurrence of the root locus, improving endurance, preventing metabolic syndrome such as obesity, diabetes, arteriosclerosis and fatty liver, and improving memory. As a result of the experiment using GW501516, excellent efficacy was confirmed when PPARδ activator was administered to both pregnant and lactating women. In addition, the experiment using CMDD1112 showed efficacy only at concentrations of 5 mg / kg / day or more during reprogramming of fetuses. However, since the active concentrations of all the active materials are different, the structure may have a lower active concentration than the other materials.

<Example 9> Proof prevention / suppression effect of diabetic disease by fetal reprogramming in a mouse model of type 2 diabetes mellitus

The reprogramming method of PPARδ developed by the present invention confirmed that the onset of diabetes was prevented / suppressed even in a db / db mouse in which inherited diabetes was induced due to a genetic defect. We used leptin receptor-deficient mice (db / db) to confirm the reprogramming efficacy of PPARδ. After crossing heterotypic females and males, PPARδ active substance (CMDD1111) was administered to female mice only during the lactation period. Glucose tolerance test (GTT) was performed using only homozygous fetuses with diabetes induced by gene analysis and blood glucose analysis. As a result, as shown in FIG. 26, glucose resistance was improved by the reprogramming of PPAR ?.

Example 10: Development of new PPAR delta active material for reprogramming of fetus

As described above, agonists for PPARδ increase reprogramming of mammals, including humans, to increase the incidence of near-term development of fetuses, improve endurance, and prevent metabolic syndrome such as obesity, diabetes, arteriosclerosis, It can be prevented in advance, and memory can be improved.

In addition, the present invention has developed a novel PPAR? Active substance for mammalian reprogramming of mammals and has demonstrated in vitro and in vivo efficacy for this material.

2. Development of PPARδ activator

In the present invention, a novel PPAR delta active substance represented by the following formula (V) has been developed in order to more effectively achieve fetal reprogramming.

(V)

[In the above formula (V), A is each independently sulfur (S) or selenium (Se);

R ₂ is selected from the following structures;

X is sulfur (S) or selenium (Se);

R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;

p is an integer from 1 to 5;

q is an integer of 1-4;

Alkyl and alkoxy in the R ₁₁ may have one or more of halogen or C ₁ -C ₅ alkylamine may further be substituted.]

Hereinafter, the present invention will be described in detail with reference to examples.

However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Example 11 Preparation of Compound 1

) 500mg(1.26 mmol)과 이미다졸 172 mg(2.0당량)을 디메틸포름아미드 20ml에 완전히 녹인다. tert-부틸디메틸실릴클로라이드 210mg(1.1당량)을 천천히 가하고 실온에서 4시간 교반 시킨다. 반응 완결 후 염화암모늄 수용액과 에틸아세테이트를 이용하여 추출하고, 유기층에서 황산마그네슘으로 수분을 제거한다. 실리카겔 컬럼을 이용한 정재 후 용매를 감압 증류하여 표제화합물을 얻었다.The compound obtained using the existing method (WO2006 / 091047) (

) And 172 mg (2.0 eq.) Of imidazole are completely dissolved in 20 ml of dimethylformamide. tert - butyldimethylsilyl chloride was added to 210mg (1.1 eq) slowly and the mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of ammonium chloride and ethyl acetate, and water was removed from the organic layer with magnesium sulfate. After the purification using a silica gel column, the solvent was distilled off under reduced pressure to obtain the title compound.

Example 12 Preparation of Compound 2

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Then, 199 mg (0.98 mmol) of 4-phenylbenzyl chloride was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (t, 2H), 7.65 (t, 2H), 7.52 ~ 7.23 (m, 6H), 7.14 (t, 2H), 7.05 (t, 2H), 6.63 ( 3H), 0.99 (s, 9H), 0.18 (s, 1H), 4.54 (m, , 6H)

Example 13 Preparation of Compound 3

500 mg (0.74 mmol) of the compound 2 prepared in Example 12 is completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.8 ml of tetrabutylammonium fluoride (TBAF) (1 M -tetrahydrofuran solution, 2.5 eq.) Is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (t, 2H), 7.65 (t, 2H), 7.54 ~ 7.31 (m, 6H), 7.17 (t, 3H), 7.07 (t, 1H), 6.61 ( (s, 3H), 2.19 (s, 3H), 1.89 (s, 3H)

Example 14 Preparation of Compound 4

300 mg (0.53 mmol) of the compound 3 prepared in Example 13, 10 ml of acetone containing 5% water and 185 mg (0.53 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 71 [mu] l (0.64 mmol, 1.2 equivalents) of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (d, 2H), 7.65 (d, 2H), 7.54 ~ 7.23 (m, 6H), 7.18 (t, 2H), 7.05 (t, 2H), 6.62 ( (d, IH), 3.14 (d, IH), 2.21 (s, 3H), 2.06 (s, 2H) , &Lt; / RTI &gt; 3H), 1.25 (t, 3H)

Example 15 Preparation of Compound 5

300 mg (0.46 mmol) of the compound 4 prepared in Example 14 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.95 (d, 2H), 7.66 (d, 2H), 7.53 (d, 2H), 7.46 (d, 2H), 7.41 (t, 2H), 7.39 (t, (Q, 1H), 2.15 (s, 3H), 7.26 (d, 3H), 7.05 ), 1.79 (s, 3H)

Example 16 Preparation of Compound 6

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Then, 216 mg (0.98 mmol) of 4- (4-fluorophenyl) -benzyl chloride was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.96 (d, 2H), 7.66 (d, 2H), 7.45 (m, 2H), 7.38 (d, 2H), 7.13 ~ 7.06 (m, 6H), 6.64 ( 3H), 1.87 (s, 3H), 0.97 (s, 9H), 0.16 (s, 1H), 4.54 (m, , 6H)

Example 17 Preparation of Compound 7

500 mg (0.72 mmol) of the compound 6 prepared in Example 16 is completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.8 ml of tetrabutylammonium fluoride (TBAF) (1 M -tetrahydrofuran solution, 2.5 eq.) Is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.80 (d, 2H), 7.67 (d, 2H), 7.50 (m, 2H), 7.41 (d, 2H), 7.17 ~ 7.05 (m, 6H), 6.63 ( (s, 3H), 2.19 (s, 3H), 1.89 (s, 3H)

Example 18: Preparation of Compound 8

300 mg (0.52 mmol) of the compound 7 prepared in Example 17, 10 ml of acetone containing 5% water and 179 mg (1.29 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 69 [mu] l (0.62 mmol, 1.2 equivalents) of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.80 (d, 2H), 7.67 (d, 2H), 7.50 (m, 2H), 7.41 (d, 2H), 7.17 ~ 7.05 (m, 6H), 6.63 ( (q, 2H), 3.40 (q, 1H), 3.11 (q, 1H), 2.20 (s, 3H), 1.87 , 3H), 1.26 (t, 3H)

Example 19 Preparation of Compound 9

300 mg (0.45 mmol) of the compound 8 prepared in Example 18 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.76 (d, 2H), 7.46 (d, 2H), 7.37 (m, 2H), 7.31 (d, 2H), 7.04 ~ 6.88 (m, 6H), 6.35 ( 3H), 1.70 (s, 3H), 1.84 (s, 3H)

Example 20 Preparation of Compound 10

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Then, 252 mg (0.98 mmol) of 4- (3,4,5-trifluorophenyl) benzyl chloride was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (d, 2H), 7.66 (d, 2H), 7.38 (d, 2H), 7.18 ~ 7.04 (m, 6H), 6.63 (t, 1H), 4.54 ( (s, 3H), 1.88 (s, 3H), 0.99 (s, 9H), 0.18 (s, 6H)

Example 21 Preparation of Compound 11

500 mg (0.69 mmol) of the compound 10 prepared in Example 20 is completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.7 ml of tetrabutylammonium fluoride (TBAF) (1 M -tetrahydrofuran solution, 2.5 eq.) Is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (d, 2H), 7.66 (d, 2H), 7.38 (d, 2H), 7.18 ~ 7.04 (m, 6H), 6.63 (t, 1H), 5.01 ( (s, 3H), 2.15 (s, 3H), 1.86 (s, 3H)

Example 22 Preparation of Compound 12

300 mg (0.49 mmol) of the compound 11 prepared in Example 21, 10 ml of acetone containing 5% water and 146 mg (1.29 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 65 uL (0.58 mmol, 1.2 eq.) Of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (d, 2H), 7.66 (d, 2H), 7.38 (d, 2H), 7.17 ~ 7.06 (m, 6H), 6.55 (t, 1H), 4.57 ( 3H), 1.88 (s, 3H), 1.25 (t, 2H), 4.53 (q, , 3H)

Example 23: Preparation of compound 13

300 mg (0.43 mmol) of the compound 12 prepared in Example 22 was mixed well with 15 ml of THF and 10 ml of water, and the mixture was further stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.98 (d, 2H), 7.66 (d, 2H), 7.38 (d, 2H), 7.17 ~ 7.06 (m, 6H), 6.55 (t, 1H), 4.57 ( (s, 2H), 4.51 (t, 1H), 4.20 (s, 2H), 3.33 (q,

Example 24 Preparation of Compound 14

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Then, 265 mg (0.98 mmol) of 4- (4-trifluoromethyl) phenylbenzyl chloride is added to the reaction solution, and the reaction temperature is gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 25 Preparation of Compound 15

500 mg (0.67 mmol) of the compound 14 prepared in Example 24 was completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.68 ml (1 M -tetrahydrofuran solution, 2.5 eq.) Of tetrabutylammonium fluoride (TBAF) is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 26: Preparation of Compound 16

300 mg (0.48 mmol) of the compound 15 prepared in Example 25, 10 ml of acetone containing 5% water and 164 mg (1.19 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 63 ul (0.57 mmol, 1.2 eq.) Of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

Example 27 Preparation of Compound 17

300 mg (0.42 mmol) of the compound 16 prepared in Example 26 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.77 (d, 2H), 7.59 (d, 2H), 7.50 (m, 4H), 7.38 (d, 2H), 7.10 (d, 2H), 6.90 (m, 2H), 6.38 (t, 1H), 4.50 (t, 1H), 4.07 (s, 2H), 3.33 )

Example 28 Preparation of Compound 18

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). 266 mg (0.98 mmol) of 5- (chloromethyl) -2- (4- (tripropylmethyl) phenyl) pyridine was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 29: Preparation of Compound 19

500 mg (0.67 mmol) of the compound 18 prepared in Example 28 is completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.68 ml (1 M -tetrahydrofuran solution, 2.5 eq.) Of tetrabutylammonium fluoride (TBAF) is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 30: Preparation of Compound 20

300 mg (0.48 mmol) of the compound 19 prepared in Example 29, 10 ml of acetone containing 5% water and 164 mg (1.19 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 63 ul (0.57 mmol, 1.2 eq.) Of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

Example 31: Preparation of Compound 21

300 mg (0.42 mmol) of the compound 20 prepared in Example 30 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 8.38 (s, 1H), 7.94 (d, 2H), 7.78 (d, 2H), 7.61 ~ 7.47 (m, 5H), 7.33 (d, 1H), 6.89 ( (d, 2H), 6.38 (t, IH), 4.46 (t, IH), 4.04 (s, 2H), 3.27 , 3H)

Example 32: Preparation of Compound 22

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Then, 266 mg (0.98 mmol) of 4- (3-trifluoromethyl) phenylbenzyl chloride was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 33: Preparation of compound 23

500 mg (0.67 mmol) of the compound 22 prepared in Example 32 was completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.68 ml (1 M -tetrahydrofuran solution, 2.5 eq.) Of tetrabutylammonium fluoride (TBAF) is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 34: Preparation of Compound 24

300 mg (0.48 mmol) of the compound 23 prepared in Example 33, 10 ml of acetone containing 5% water and 164 mg (1.19 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 63 ul (0.57 mmol, 1.2 eq.) Of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

Example 35: Preparation of compound 25

300 mg (0.42 mmol) of the compound 24 prepared in Example 34 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

¹ H NMR (300 MHz, CDCl ₃ )? 7.96 (d, 2H), 7.78 (s, IH), 7.68 (m, 3H), 7.58-7.45 (t, 1H), 6.57 (t, 1H), 4.70 (s, 2H), 4.57 (t, , 3H)

Example 36: Preparation of Compound 26

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature was lowered to -78 ° C. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Then, 250 mg (0.98 mmol) of 4- (3-chloro-4-trifluoromethyl) phenylbenzyl chloride was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 37: Preparation of Compound 27

500 mg (0.69 mmol) of the compound 26 prepared in Example 36 is completely dissolved in 10 ml of tetrahydrofuran. 1.72 ml of tetrabutylammonium fluoride (TBAF) (1 M -tetrahydrofuran solution, 2.5 eq.) Is slowly added at room temperature. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

¹ H NMR (300 MHz, CDCl ₃ )? 7.96 (d, 2H), 7.67 (m, 2H), 7.56 1H), 5.17 (s, 3H), 1.87 (s, 3H), 5.17 (s,

Example 38: Preparation of compound 28

300 mg (0.49 mmol) of the compound 27 prepared in Example 37, 10 ml of acetone containing 5% water and 169 mg (1.19 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 65 uL (0.59 mmol, 1.2 eq.) Of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

Example 39: Preparation of Compound 29

300 mg (0.43 mmol) of the compound 28 prepared in Example 38 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

¹ H NMR (300 MHz, CDCl ₃ )? 7.96 (d, 2H), 7.67 (m, 2H), 7.56 (s, 3H), 2.19 (s, 3H), 1.81 (s, 3H)

Example 40: Preparation of compound 30

500 mg (0.98 mmol) of the compound 1 prepared in Example 11 is dissolved in 20 ml of anhydrous tetrahydrofuran, and the temperature is lowered to -78 캜. To this is slowly added 1.1 ml (1.8 M , 2.0 eq.) Of lithium diisopropylamide (LDA). Thereafter, 257 mg (0.98 mmol) of 5- (chloromethyl) -3- (4- (trifluoromethyl) phenyl) isoxazole was added to the reaction solution, and the reaction temperature was gradually raised to room temperature. After further reaction for 30 minutes, the reaction is terminated with an aqueous solution of ammonium chloride, and the organic solvent is extracted using ethyl acetate and an aqueous solution of sodium chloride, and water of the organic layer is removed with magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 41: Preparation of compound 31

500 mg (0.72 mmol) of the compound 30 prepared in Example 40 is completely dissolved in 10 ml of tetrahydrofuran. At room temperature, 1.80 ml of tetrabutylammonium fluoride (TBAF) (1 M -tetrahydrofuran solution, 2.5 eq.) Is slowly added. After 30 minutes of reaction, the reaction mixture was extracted with ammonium chloride aqueous solution and ethyl acetate, and the organic layer was dried over magnesium sulfate to remove water. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound.

Example 42: Preparation of Compound 32

300 mg (0.53 mmol) of the compound 31 prepared in Example 41, 10 ml of acetone containing 5% water and 182 mg (1.19 mmol, 2.5 equivalents) of potassium carbonate are mixed well at room temperature. 70 [mu] l (0.63 mmol, 1.2 equivalents) of bromoacetic acid ethyl ester was added and stirred vigorously for 4 hours. After completion of the reaction, the reaction mixture was extracted with an aqueous solution of sodium chloride 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 to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.96 (d, 2H), 7.66 (m, 2H), 7.20 ~ 7.08 (m, 4H), 6.58 (t, 1H), 6.22 (s, 1H), 4.61 ( 3H), 1.57 (s, 3H), 1.27 (t, 2H), 4.57 (t, , 3H)

Example 43: Preparation of Compound 33

300 mg (0.46 mmol) of the compound 32 prepared in Example 34 was mixed well in 15 ml of THF and 10 ml of water and stirred at 0 ° C for 60 minutes. After completion of the reaction, 0.5M NaHSO ₄ And the mixture was extracted with a salt aqueous solution and ethyl acetate. After filtration, the solvent was distilled off under reduced pressure, and the residue was purified by LH-20 column chromatography to obtain the title compound.

^{1 H NMR (300 MHz, CDCl} 3) δ 7.96 (d, 2H), 7.66 (m, 2H), 7.20 ~ 7.08 (m, 4H), 6.58 (t, 1H), 6.22 (s, 1H), 4.70 ( (s, 3H), 2.63 (s, 3H), 2.63 (s, 3H)

Example 44: In vitro activity assay of a developed substance (Transfection assay)

The assay was performed using CV-1 cells. Cell culture was performed in 96-well plates using DMEM medium supplemented with 10% FBS, DBS (delipidated) and 1% penicillin / streptomycin in a 37 ° C incubator containing 5% carbon dioxide. Experiments were carried out in four steps: cell inoculation, transfection, treatment of developed material, and confirmation of results. CV-1 cells were inoculated into 96 well plates at 5,000 cells / well and transfected 24 hours later. PPARs plasmid DNA, reporter DNA, and β-galactosidase DNA were mixed with transfection reagent and processed into cells. The developed material was dissolved in dimethyl sulfoxide (DMSO), and then treated with various concentrations of cells using media. After incubation for 24 hours in an incubator, cells were lysed with lysis buffer, and luciferase and β-galactosidase activities were measured using a luminometer and a microplate reader. The measured luciferase values were calibrated using β-galactosidase values, and graphs were obtained using these values and EC ₅₀ values were obtained.

EC ₅₀ data Compound No. hPPAR? (nM) hPPARa hPPARg 5 3.3 ia ia 9 3.9 ia ia 13 8.8 ia ia 17 6.4 ia ia 21 10.6 ia ia 25 6.1 ia ia 28 4.6 ia ia 33 41.4 ia ia

As can be seen in Table 2 above, the compounds according to the invention are highly selective for PPAR delta and have an activity between 2 and 200 nM for PPARδ.

<Example 45> Verification of in vivo activity of the developed substance

In vitro experiments were performed to determine the in vivo activity of Compounds 5 and 9 with superior PPARδ activity.

(1) Verification of obesity inhibitory efficacy

In order to test the in vivo effect of the substance according to the present invention, an experiment using a mouse was performed. C57BL / 6 mice were used at 8 weeks of age, and diets containing 35% fat were used to induce obesity. The vehicle and Compound 5, Compound 9 (10 mg / Kg / day) were orally administered to the vehicle while taking a high fat diet for 60 days. As a result of the experiment, the group administered with Compound 5 showed a 35% obesity inhibitory effect compared with the vehicle-treated control group, and the group administered with Compound 9 showed a 33% inhibitory effect.

(2) Verification of diabetic improvement

A glucose tolerance test (GTT) was conducted to verify the diabetic improvement effect on the substance according to the present invention. Diabetes mellitus (1.5 g / Kg) was intraperitoneally administered to high fat diabetic mice to which the drug was orally administered for 70 days, and blood glucose changes were measured for 2 hours. As a result, the group 5, 9 (10 mg / Kg / day) showed a rapid decrease in blood glucose level in 20-40 minutes compared with the control group, and the glucose clearance was completely achieved in 100 minutes. However, the group of control rats administered vehicle did not maintain normal blood glucose after 120 minutes. From these results, it was proved that the compounds 5 and 9, which are the developed substances, have an effect of improving diabetes.

(3) Hyperlipidemia

High-density lipoprotein cholesterol (HDL) is known to play an important role in the treatment of lipid metabolism diseases such as atherosclerosis and hyperlipemia, while lowering the cholesterol level of the epidermal cells and alleviating the inflammatory reaction in the body. To ascertain the effect of the compounds 5 and 9 of the present invention on the increase of high density cholesterol, sera from mice fed with 10% fat-containing feed for 6 weeks were isolated. High density lipoprotein (HDL) concentration in the serum was increased by 29% in the group treated with GW501516, but increased by 68% and 62% in the group treated with Compound 5 and 9, respectively.

(4) Atherosclerosis prevention and treatment efficacy

In vivo experiments using ApoE - / - mice were carried out in order to verify the efficacy of the compounds 5 and 9 of the present invention for the prevention and treatment of arteriosclerosis. ApoE - / - mice, a model of atherosclerotic disease, were fed a high cholesterol diet (21% high fat, 1.25% high cholesterol diet) for 14 weeks to induce atherosclerosis, followed by compounds 5 and 9 Respectively. The method of treating the drug was chosen. The arteries of the mice were extracted and analyzed by en face method, and the incidence of arteriosclerosis was decreased by 23 and 18% by compounds 5 and 9, respectively.

(5) Demonstration of muscle endurance enhancement efficacy

Animal experiments were conducted to verify muscle strengthening effect and muscular function enhancement effect on the substance according to the present invention. Compounds 5 and 9 were orally administered at a concentration of 10 mg / kg / day to confirm the reprogramming efficacy of the fetus. Observation of muscle after skin removal showed that the treated group was redder than the control group. Treadmill experiments were performed to confirm the effects of changes in muscle fiber on muscle endurance and muscular function improvement. As a result, it was confirmed that the time taken for the developed substance and the running distance were markedly increased as shown in the following results, which proved the endurance improving effect of the developed substance.

Endurance test results using Treadmill Growth rate
(Administration group / control group) Pregnancy period Feeding period Pregnancy + feeding period time Street time Street time Street Compound 5 2.4 times 2.5 times 2.1 times 2.2 times 3.6 times 3.9 times Compound 9 1.9 times 1.9 times 1.5 times 1.5 times 2.8 times 3.0 times

It also proved to be effective in strengthening muscular endurance and improving muscle function. 10-week-old C57BL / 6 rats were orally administered at a dose of 10 mg / kg / day. Exercise was given once a day for 30 days using a treadmill for 30 minutes. Exercise conditions were 5 min at 2 m / min, 5 min at 5 m / min, 5 min at 8 m / min and 5 min at 20 m / min. Treadmill was used at the end of the experiment to test muscle strength and muscular function. As a result, the exercise time (Compound 5: 1.7 times, Compound 9: 1.5 times) and exercise distance (Compound 5: 1.8 times, Compound 9: 1.5 times) were increased in the treatment group as compared with the control group.

(6) Prove memory-enhancing efficacy

Animal experiments were conducted to verify the memory enhancing efficacy of the substances according to the present invention. During the reprogramming period, the developed compounds 5 and 9 were orally administered to the mother at a concentration of 10 mg / kg / day. Morris water maze test was used to examine brain function differences between the control and the treatment groups. As a result, the memory of the group in which the developed material was administered (Compound 5: 8.2 seconds, Compound 9: 9.7 seconds) was significantly increased compared to the control group (Vehicle: 28 seconds).

Example 46: Preparation of active ingredient-containing agent for PPAR delta active substance

The PPAR? Active substance of the present invention can be administered orally or parenterally to a mammal including a human. The composition containing the PPAR delta active substance as an active ingredient is not limited to a specific preparation and may be in the form of an oral preparation, a dripping solution, a tablet, a powder, a liquid suppository, an external preparation, a coagulant, an intravenous solution, a powder, a granule, Liquid preparations, ampoules, injection solutions and the like, and they can be applied to pharmaceuticals of any shape.

Preparation Example 1: Preparation of tablets

The following ingredients were mixed to prepare tablets in a conventional manner.

  15 mg &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &

  Lactose 95 mg

  Hydroxypropylcellulose 3 mg

  Calcium Carboxymethylcellulose 8 mg

  Magnesium stearate 0.5 mg

Production Example 2: Production of powder

Powders were prepared in a conventional manner by mixing the following components.

30 mg &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &

Lactose 20 mg

Starch 15 mg

Magnesium stearate qs

Production Example 3. Capsule preparation

The following components were mixed and a silicone capsule was prepared by a conventional method.

80 mg &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &

Lactose 30 mg

Starch 25 mg

Talc 2 mg

Magnesium stearate qs

Production Example 4. Production of Soft Capsule

The contents of the soft capsules were prepared in a conventional manner by mixing the following ingredients. A soft capsule was prepared by a conventional method using 132 mg of gelatin per capsule, 50 mg of concentrated glycerin, 6 mg of 70% disorbitol solution and an appropriate amount of ethyl vanillin as a flavoring agent and a coating agent, carnauba wax.

80 mg &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &

Polyethylene glycol 400 400 mg

Concentrated glycerin 50 mg

Purified water 35 mg

Production Example 5. Preparation of suspension

A suspension was prepared by mixing the following components in a conventional manner.

50 mg &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &

10 g per isomer

Sugar 25 mg

Calcium carboxymethylcellulose 50 mg

Lemon incense quantity

Fit the total manufacturing capacity to 100 ml with purified water.

Production Example 6. Injection preparation

The following ingredients were mixed and prepared in a conventional manner (2 ml) per 1 ampoule with the following ingredients.

20 mg of the compound of formula I (for example, compounds 5 and 9)

180 mg mannitol

Sterile sterilized water for injection 2974 mg

Sodium diphosphate 26 mg

Preparation Example 7. Ointment preparation

Ointment agents (Examples 1 to 3) were prepared by mixing the following components in a conventional manner.

  [Example 1]

  0.5 wt% &lt; tb &gt; &lt; tb &gt;

  White petrolatum 70 wt%

  Mineral oil 5 wt%

  Polyoxyl stearyl ether 5 wt%

  Polyethylene glycol (e.g. PEG 400 or USP) 19.2 wt%

  Butyl hydroxyanisole 0.3 wt%

  [Example 2]

  0.5 wt% &lt; tb &gt; &lt; tb &gt;

  White petrolatum 70 wt%

  Mineral oil 5 wt%

  Polyoxyl stearyl ether 5 wt%

  Polyethylene glycol (e.g. PEG 400 or USP) 19.2 wt%

  Butyl hydroxyanisole 0.2 wt%

  Parabens (for example, methylparaben or propylparaben) 0.1 wt%

 [Example 3]

  0.01 to 2 wt% of the compound of the formula (I) (for example, compound No. 5 or 9)

  White petrolatum 30 to 75 wt%

  Mineral oil 2 to 10 wt%

  0.3 to 10 wt% of polyoxyl stearyl ether,

  2 to 45 wt% of polyethylene glycol (e.g. PEG 400 or USP)

  0 wt% of butylhydroxyanisole or 0.002 to 2.5 wt%

  0 wt% or 0.01 to 1.5 wt% parabens (e.g. methylparaben or propylparaben)

Production Example 8. Production of Cream

An external topical cream (Examples 1 to 2) was prepared by mixing the following components in a conventional manner.

  [Example 1]

  0.1% by weight of a compound of the formula (I) (for example, compounds 5 and 9)

  White petrolatum 40 wt%

  Mineral oil 11 wt%

  Polyoxystearyl ether 8.5 wt%

  Propylene glycol 18 wt%

  Butylhydroxyanisole 0.02 wt%

  Purified water Appropriate amount (22.38 wt%)

 [Example 2]

  0.01 to 3 wt% of the compound of the formula (I) (for example, compounds 5 and 9)

  White petrolatum 30 to 75 wt%

  Mineral oil 2 to 10 wt%

  0.3 to 10 wt% of polyoxyl stearyl ether,

  Propylene glycol 0.3 to 45 wt%

  Butylhydroxyanisole 0.002 to 2.5 wt%

  Parabens such as methylparaben or propylparaben 0.01 to 3.5 wt%

  Purified water Appropriate amount (2 to 30 wt%)

Preparation Example 9. Preparation of beverage

A proper amount of purified water was mixed with the following ingredients, and a beverage was prepared so as to have a total of 100 mL by a conventional method.

  2 mg &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &

  Citric acid 9 g

  9 g of white sugar

  Glucose 2.8 g

  DL-malic acid 0.25 g

  Purified water quantity

Production Example 9. Food Manufacturing

9-1. Manufacture of cooking seasonings

0.001 to 0.2 part by weight of the compound of the formula (I) (for example, compound 5 or 9) Seasoning.

9-2. Food preparation

0.001 to 0.2 part by weight of a compound of the formula (I) (for example, compound No. 5 or 9) was added to wheat flour, and breads, cakes, cookies, crackers and noodles were prepared therefrom to prepare health improving foods.

9-3. Manufacture of dairy products

0.001 to 0.2 part by weight of a compound of the formula (I) (for example, compound 5 or 9) was added to milk, and the milk was used to prepare various dairy products such as butter, ice cream, milk powder and baby food.

9-4. Juice manufacturing

0.001 to 0.2 part by weight of the compound of the formula (I) (for example, compound 5 or 9) was added to 1,000 ml of fruit juice such as tomato, carrot or the like, apple, grape, orange or pineapple to prepare a health enhancing juice.

Production Example 10. Production of Animal Feed

1 kg of animal feed was prepared by mixing the following ingredients in a conventional manner.

0.1 g of the compound of the formula (I) (for example, compound No. 5 or 9)

Casein 200 g

Corn starch (cornstarch) 400 g

Dyetrose 130 g

100 g of sugar

Cellulose 50 g

70 g of soybean oil

0.02 g of an antioxidant (e.g., t-butylhydroquinone)

Minerals (eg salt mix) 35 g

Vitamins (eg vitamin mix) 10 g

L-cystine 3 g

Choline bitartrate 2 g &lt; RTI ID = 0.0 &gt;

Claims (17)

A composition for fetal reprogramming of a mammal, comprising a peroxisome proliferator activated receptor? (Agonist) as an active ingredient. The method according to claim 1,
Wherein the fetal reprogramming method results in the prevention of metabolic disease of an individual born or produced by the fetal reprogramming method, or memory enhancement. 3. The method of claim 2,
A composition for fetal reprogramming of a mammal wherein the metabolic disease is obesity, diabetes, hyperlipidemia, arteriosclerosis or fatty liver. The method according to claim 1,
A composition for fetal reprogramming of mammals wherein the mammal is a human. The method according to claim 1,
A composition for fetal reprogramming of mammals wherein the mammal is a mammal other than a human. The method according to claim 1,
A composition for fetal reprogramming of a mammal for administration to a mother of a pregnant, lactating, or pregnant lactating person, or to its offspring or baby. 7. The method according to any one of claims 1 to 6,
A composition for fetal reprogramming of mammals, wherein the PPAR? Activator is represented by formula (I).
(I)

Wherein A in the formula (I) is oxygen (O), nitrogen (NH), sulfur (S) or selenium (Se); B is

;
R ₁ is selected from the following structures,

R ₂ is hydrogen, a C ₁ -C ₅ alkyl group,

Or is selected from the following structures;

X is sulfur (S) or selenium (Se);
Y is carbon (CH) or nitrogen (N);
R ₃ is hydrogen, C ₁ -C ₈ alkyl or halogen;
R ₄ and R ₅ are independently of each other hydrogen, halogen or C ₁ -C ₈ alkyl;
R ₆ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₇ alkenyl, alkali metal, alkaline earth metal or organic acid;
R ₁₁ and R ₁₂ independently of one another are hydrogen, halogen, C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy;
R ₂₁ is hydrogen, halogen, C ₁ -C ₇ alkyl, heterocyclic group, C ₁ -C ₇ alkoxy, C ₁ -C ₅ alkyl substituted with halogen or phenyl substituted with halogen;
m and n are each independently an integer of 1 to 4;
p is an integer from 1 to 5;
q is an integer of 1-4;
r is an integer from 1 to 3;
s is an integer from 1 to 5;
The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ , R ₁₂ and R ₂₁ may be further substituted by one or more halogens or C ₁ -C ₅ alkylamines. 8. The method of claim 7,
Wherein the PPAR? Activator is selected from compounds of the following structure.

For the treatment and prevention of arteriosclerosis or hyperlipidemia comprising a derivative of the following formula (V), a hydrate thereof, a solvate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, for the treatment and prevention of hypercholesterolemia, For the prevention and treatment of diabetes, for the treatment and prevention of obesity, for the improvement of memory, for the treatment and prevention of dementia or Parkinson's disease.
(V)

[In the above formula (V), A is each independently sulfur (S) or selenium (Se);
R ₂ is selected from the following structures;

X is sulfur (S) or selenium (Se);
R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;
p is an integer from 1 to 5;
q is an integer of 1-4;
Alkyl and alkoxy in the R ₁₁ may have one or more of halogen or C ₁ -C ₅ alkylamine may further be substituted.] A functional food aid, a functional beverage, a food additive, and an animal feed composition comprising a derivative of the following formula (V), a hydrate thereof, a solvate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
(V)

[In the above formula (V), A is each independently sulfur (S) or selenium (Se);
R ₂ is selected from the following structures;

X is sulfur (S) or selenium (Se);
R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;
p is an integer from 1 to 5;
q is an integer of 1-4;
Alkyl and alkoxy in the R ₁₁ may have one or more of halogen or C ₁ -C ₅ alkylamine may further be substituted.] A functional cosmetic composition for preventing obesity and for improving obesity or for prevention and improvement of fatty liver comprising a derivative of the following formula (V), a hydrate thereof, a solvate thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient.
(V)

[In the above formula (V), A is each independently sulfur (S) or selenium (Se);
R ₂ is selected from the following structures;

X is sulfur (S) or selenium (Se);
R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;
p is an integer from 1 to 5;
q is an integer of 1-4;
Alkyl and alkoxy in the R ₁₁ may have one or more of halogen or C ₁ -C ₅ alkylamine may further be substituted.] A method of reprogramming a fetus of a mammal other than a human, comprising administering a PPAR? Activator to a mammal other than a human. 13. The method of claim 12,
A method of reprogramming a fetus of a mammal other than a human, wherein the fetal reprogramming method results in prevention of metabolic disease of the individual produced by the method, or memory enhancement. 14. The method of claim 13,
A method of reprogramming a fetus of a mammal other than a human, wherein the metabolic disease is obesity, diabetes, hyperlipidemia, arteriosclerosis or fatty liver. 13. The method of claim 12,
A method of reprogramming fetuses of mammals other than humans, the method comprising administering a PPAR? Activator to the mother of a pregnant, lactating, or pregnant lactating person or to its offspring. 16. The method according to any one of claims 12 to 15,
Wherein the PPAR? Activator is represented by formula (I).
(I)

Wherein A in the formula (I) is oxygen (O), nitrogen (NH), sulfur (S) or selenium (Se); B is

;
R ₁ is selected from the following structures,

R ₂ is hydrogen, a C ₁ -C ₅ alkyl group,

Or is selected from the following structures;

X is sulfur (S) or selenium (Se);
Y is carbon (CH) or nitrogen (N);
R ₃ is hydrogen, C ₁ -C ₈ alkyl or halogen;
R ₄ and R ₅ are independently of each other hydrogen, halogen or C ₁ -C ₈ alkyl;
R ₆ is hydrogen, C ₁ -C ₈ alkyl, C ₂ -C ₇ alkenyl, alkali metal, alkaline earth metal or organic acid;
R ₁₁ and R ₁₂ independently of one another are hydrogen, halogen, C ₁ -C ₈ alkyl or C ₁ -C ₈ alkoxy;
R ₂₁ is hydrogen, halogen, C ₁ -C ₇ alkyl, heterocyclic group, C ₁ -C ₇ alkoxy, C ₁ -C ₅ alkyl substituted with halogen or phenyl substituted with halogen;
m and n are each independently an integer of 1 to 4;
p is an integer from 1 to 5;
q is an integer of 1-4;
r is an integer from 1 to 3;
s is an integer from 1 to 5;
The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ , R ₁₂ and R ₂₁ may be further substituted by one or more halogens or C ₁ -C ₅ alkylamines. 17. The method of claim 16, wherein the PPAR? Activator is selected from the following compounds.

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