KR102038866B1 - Use of PPARδ Agonists as Antibiotics, Therapeutics for Treatment of Burns, Wounds and Diabetic Ulcers - Google Patents

Abstract

The present invention relates to a novel use of PPAR delta agonist, specifically, antibacterial activities, treatment and prevention of diabetic foot ulcer, and wound and burn treatment efficacy of PPAR δ active substance. It is about. According to the present invention, PAI delta (PPARδ) active material (agonist) is excellent in the antibacterial activity against methicillin and bencomycin resistant bacteria can be used as a prophylactic or therapeutic agent for multi-drug resistant bacterial infections, human epidermal cells ( It has excellent efficacy in wound healing through cell migration and proliferation of epidermal keratinocytes and treatment of ulcers in animal models of diabetic ulcer disease. It is effective in treating foot ulcers due to wound and burn and diabetic complications.

Description

Use of PPARδ Agonists as Antibiotics, Therapeutics for Treatment of Burns, Wounds and Diabetic Ulcers}

The present invention relates to PPARδ activators for the treatment of bacterial infections, diabetic ulcers, wounds, burns and wounds of PPI agonists. It is about a new use of.

Although antibiotics have played an important role in the treatment of bacterial infections and diseases, bacteria that have become resistant to antibiotics have emerged due to the abuse of antibiotics and the repeated use of the same antibiotics. Therefore, in order to treat the newly emerged antibiotic resistant bacteria infection, the development of new antibiotics having a chemical structure completely different from existing antibiotics is urgently needed.

Mechanisms in which antibiotics work can be broadly divided into mechanisms that interfere with cell wall production, protein synthesis, bacterial DNA and RNA synthesis, mycolic acid and folic acid production. Conventional antibiotics have chemical structural characteristics depending on the mechanism at which they act. Representative chemical structures may be classified into penicillin (beta-lactam) based, cephalosporin, aminoglycoside type, scroll-sheet fluoride-based, sulfonamide-based, quinolone, tetracycline type, such as the polypeptide [Nature Reviews 2010 , 8 , 423]. The inventors have completed the present invention by developing a PPARδ active compound, which is completely different from the mechanism of action and chemical structural class of existing antibiotics, and exhibits strong antimicrobial activity. The present invention is the first report on the antimicrobial activity of PPARδ active compounds. In addition, these compounds are likely to be developed as next-generation antibiotics, as they have novel antibiotic mechanisms and novel chemical structures that go beyond the existing class of antibiotics.

Diabetes mellitus, the longer the disease, chronic complications of blindness, end stage renal failure, neurological disease, and infectious diseases increase rapidly. In particular, foot ulcers, which frequently occur as a diabetic complication, are caused by complex cardiovascular diseases, problems with sensory nerves, motor nerves, and autonomic nerves. When there is a problem with blood circulation, the walls of the blood vessels become narrow and blood flow decreases, resulting in ulcers. Problems of the nervous system are caused by trauma accompanied by loss of protective sensation due to desensitization of the foot. Failure to identify the disease at the right time can result in amputation, leading not only to poor quality of life but also to significant socioeconomic losses. In the present invention, it has been found for the first time that PAI delta ligands also have excellent efficacy in treating diabetic foot ulcers. Therefore, in the present invention, it was confirmed that these compounds have excellent antimicrobial effects (antibacterial activities) and wounds (cuts and burns) and diabetic foot ulcers in addition to previously reported metabolic disease treatment effects.

 Nature Reviews 2010, 8, 423

The present invention relates to excellent efficacy for the treatment and prevention of bacterial infections of PPARδ agonists. The present invention also relates to the therapeutic efficacy of wounds (cuts and burns) of PPARδ agonists. The present invention also relates to the excellent efficacy of treating diabetic foot ulcers of PPARδ agonists.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for preventing or treating bacterial infections or foot ulcers containing PPARδ actives.

In addition, the present invention has another object to provide a pharmaceutical composition for treating wounds or burns comprising PPARδ actives (agonists).

Hereinafter, the present invention will be described in detail.

The present invention is not only effective in treating and preventing bacterial infections but also in the migration and proliferation of human epidermal keratinocytes, as peroxisome proliferator activated receptor δ (PPARδ) agonists as active ingredients. It has been shown to be effective and have excellent efficacy in treating ulcers and wounds (burns and wounds) by having excellent efficacy in treating ulcers in animal models of diabetic ulcer disease.

We verified the antimicrobial activity, foot ulcer and wound healing efficacy by administering PPARδ agonists at in vitro and in vivo levels. However, the present invention is not limited to the active materials [CMDD6111 ~ 6135 and CMDD6201-6240] used in the present invention, and includes all materials having PPARδ activity as well as the used materials as active ingredients.

That is, the present invention comprises a peroxisome proliferator activated receptor δ (PPARδ) activist as an active ingredient, a pharmaceutical composition for preventing or treating bacterial infections or foot ulcers To provide. In addition, the present invention provides a pharmaceutical composition for treating wounds or burns, comprising a peroxisome proliferator activated receptor δ (PPARδ) activist as an active ingredient.

Illustrating PPARδ agonists referred to in the present invention is as follows, however, the present invention is not limited to the substances exemplified below, but applies to all PPARδ actives [Example of existing PPARδ actives: Wo 2010/073235, Wo 2011/084459, Wo 2011/84453, Wo 2011/020001, 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 2009/091550, 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 2008/070150, WO 2008/060476, WO 2008/058631, WO 2008/058630, WO 2008/058629, WO 2008/058628, WO 2008/052658, WO 2008/017381, WO 2008/000484, WO 2007/131622, W O 2007/131621, WO 2007/131620, WO 2007/131619, WO 2007/130075, WO 2007/121432, WO 2007/110216, WO 2007/110215, WO 2007/107869, WO 2007/105050, WO 2007/105049, 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 2005/0 92317, WO 2005/092316, WO 2005/091857, WO 2005/077925, WO 2005/066136, WO 2005/065683, WO 2005/063762, 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 2004/101752, WO 2004/096137, WO 2004/093799, WO 2004/092117, WO 2004/073606, WO 2004 / 067482, WO 2004/066929, WO 2004/063184, WO 2004/063166, WO 2004/063165, WO 2004/063155, 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 2002/092590, WO 2001/070754, WO 2001/070753, WO 1998/049555, WO 1998/27974, WO 1997 / 28149, WO 1997/28115, WO 1997/27857, WO 1997/27847, WO 1997/28137, WO 1996/001317 and the like.

Some of the PPARδ actives are represented by the following formula (I).

[Formula I]

이며;[In Formula I, A is oxygen (O), nitrogen (NH), sulfur (S) or selenium (Se); B is

Is;

Z is CR or N;

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

R ₁ is selected from the structure

R 'is hydrogen or a C ₁ -C ₅ alkyl group;

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

Or selected from the following structures;

R '' and R '' 'are each independently hydrogen or hydroxy;

E is an integer from 0 to 9;

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 alkyl of C ₁ -C ₈ ;

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

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

m is an integer of 1-3;

n is an integer from 1-4;

p is an integer from 1-5;

q is an integer from 1-4;

r is an integer of 1-3;

s is an integer from 1-5;

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 with one or more halogen or alkylamine of C ₁ -C _5. ]

Some of the PPARδ active materials are represented by the following Chemical Formula II.

[Formula II]

이며;[In Formula II, A is sulfur (S) or selenium (Se); B is

Is;

Z is CR or N;

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

R ₁ is selected from the following structures;

R 'is hydrogen or a C ₁ -C ₅ alkyl group;

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

Or selected from the following structures;

R '' and R '' 'are each independently hydrogen or hydroxy;

E is an integer from 0 to 9;

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 alkyl of C ₁ -C ₅ ;

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, halogen substituted C ₁ -C ₅ alkyl or halogen substituted phenyl;

m is an integer of 1-3;

p is an integer from 1-5;

q is an integer from 1-4;

s is an integer from 1-5;

The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R ₂₁ may be further substituted with one or more halogen or alkylamine of C ₁ -C _5. ]

Some of the PPARδ active materials are represented by the following general formula (III).

[Formula III]

이며;[In Formula III, A is independently sulfur (S) or selenium (Se), and B is

Is;

Z is CR or N;

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

R 'is hydrogen or a C ₁ -C ₅ alkyl group;

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

Or selected from the following structures;

R '' and R '' 'are each independently hydrogen or hydroxy;

E is an integer from 0 to 9;

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 alkyl of C ₁ -C ₅ ;

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, halogen substituted C ₁ -C ₅ alkyl or halogen substituted phenyl;

m is an integer of 1-3;

p is an integer from 1-5;

q is an integer from 1-4;

s is an integer from 1-5;

The alkyl and alkoxy of R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₁₁ and R ₂₁ may be further substituted with one or more halogen or alkylamine of C ₁ -C _5. ]

Some of the PPARδ active materials are represented by the following general formula (IV).

[Formula IV]

[A in Formula IV is each independently sulfur (S) or selenium (Se);

Z is CR or N;

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

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

Or selected from the following structures;

R '' and R '' 'are each independently hydrogen or hydroxy;

E is an integer from 0 to 9;

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, halogen substituted C ₁ -C ₅ alkyl or halogen substituted phenyl;

p is an integer from 1-5;

q is an integer from 1-4;

s is an integer from 1-5;

The alkyl and alkoxy of R ₁₁ and R ₂₁ may be further substituted with one or more halogen or alkylamine of C ₁ -C _5. ]

Some of the PPARδ active materials are represented by the following general formula (V).

[Formula V]

[In Formula (V), A is independently sulfur (S) or selenium (Se);

Z is CR or N;

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

R 'is hydrogen or a C ₁ -C ₅ alkyl group;

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 1-5;

q is an integer from 1-4;

Alkyl and alkoxy of R ₁₁ may be further substituted with one or more halogen or alkylamine of C ₁ -C _5. ]

Some of the PPARδ actives are represented by the following formula (VI).

[Formula VI]

[A in Formula VI is each independently sulfur (S) or selenium (Se);

Z is CR or N;

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

R 'is hydrogen or a C ₁ -C ₅ alkyl group;

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 1-5;

q is an integer from 1-4;

The alkyl of R ₁₁ may be further substituted with one or more halogen or alkylamine of C ₁ -C _5. ]

The PPAR δ active material may be selected from compounds having the following structure, but is not limited thereto.

The amount of PPARδ active substance used to achieve the therapeutic effect according to the invention depends of course on the particular compound, the method of administration, the subject to be treated, and the disease to be treated, but depends on the dosage of a conventional medicament, more preferably The effective dose of the PPARδ active substance is administered within the range of 1 to 100 mg / kg body weight per day. In addition, within a daily effective dosage range is divided into once a day or several times a day. In addition, depending on the formulation, both oral, intravenous or topical administration are possible. Oral administration of the pharmaceutical composition according to the present invention can be prepared in any of a variety of existing forms, for example tablets, powders, dry syrups, chewable tablets, granules, chewing tablets, capsules, soft capsules, pills, It can exist in various forms, such as drink, sublingual tablet, and the like. Tablets according to the invention may be administered to a patient in any form or manner in which an effective amount is bioavailable, i.e. by oral route, depending on the nature of the disease state to be treated or prevented, the stage of the disease, and other relevant circumstances. Suitable dosage forms or modes can be readily selected and the compositions according to the invention may comprise one or more pharmaceutically acceptable excipients, wherein the proportions and properties of such excipients may depend on the solubility and chemical properties of the selected tablet, It may be determined by the route of administration chosen and standard pharmaceutical practice. It can also be made into an injection.

According to the present invention, since the PPAR δ active material has a very good antimicrobial activity against infectious bacteria, it can be used as an active ingredient of the composition for the treatment and prevention of bacterial infections. In addition, the PPARδ active substance promotes the movement and proliferation of human epidermal keratinocytes, and thus is effective in treating wounds (wounds and burns), and thus can be used as an active ingredient of pharmaceutical compositions for treating wounds (burns) and burns. have. In addition, PPARδ active material is very effective in treating diabetic ulcers and diabetes in the disease animal model can be used as an active ingredient of the pharmaceutical composition for treating foot ulcers due to diabetic complications.

1 is a photograph (A) and a graph (B) showing the migration and proliferation of human epidermal keratinocytes by PPARδ active compounds.
Figure 2 is a photograph showing the progress of ulcer treatment with PPARδ active compound in diabetic db / db mice.

Hereinafter, the present invention will be described in detail by way of examples.

However, the following examples are merely to illustrate the invention, but the content of the present invention is not limited to the following examples.

<Example 1> Antimicrobial activity of PPARδ active material against antibiotic non-resistant bacteria

The following seven microorganisms from the American Type Culture Collection (Maryland) were used to verify antimicrobial activity: Staphylococcus aureus ATCC 6538, Micrococcus lutes ATCC 9341, Staphylococcus epidermidis ATCC12228, Bacillus subtilis ATCC 6633, Escherichia coli ATCC 11775, Salmonella typhimurium ATCC 14028, Klebsiella pneumoniae ATCC 4352. Antimicrobial activity was determined by two-fold microtiter broth dilution. Dilution of test compounds dissolved in dimethylsulfoxide (DMSO) was added to each well of a 96-well microtiter plate containing a fixed volume of Nutrient Broth (Difco, final 0.64% DMSO). Each well was inoculated with bacteria (5 * 10 ⁵ CFU / mL) and incubated at 37 ° C for 24 hours. Minimum inhibitory concentration (MIC) is the concentration at which no growth is observed. The inhibitory efficacy of the tested compounds expressed in MIC values is shown in Table 1 below. Most of the compounds used in the present invention showed a strong antimicrobial activity against Gram-positive bacteria, some of them showed a very strong antimicrobial activity similar to the gentamicin used as a comparative material.

Antimicrobial Activity of PPARδ Active Compounds Against Antibiotic Antibiotic Strains (MIC μg / mL) Antimicrobial Activity (MIC ㎍ / mL) Staphylococcus aureus Staphylococcus epidermidis Micrococcus lutes Bacillus  subtilis ATCC 6538 ATCC 12228 ATCC 9341 ATCC 6633 CMDD6223 4 4 4 2 CMDD6224 4 2 2 One CMDD6225 4 2 2 One CMDD6228 4 4 4 2 CMDD6229 4 4 2 One CMDD6230 8 2 2 2 Gentamycin <0.125 <0.125 1.6 0.05

Example 2 Antimicrobial Activity Against Antibiotic Resistant Bacteria

The following eight microorganisms obtained from the Culture Collection Of Microbial Resistant Microbes (Seoul Women's University), which belong to the Specialty Material Bank designated by Korea Science Foundation, were used to verify the antimicrobial activity: Staphylococcus aureu s CCARM 0027, Staphylococcus aureus CCARM 0205, Staphylococcus aureus CCARM 3640, Staphylococcus aureus CCARM 3089, Staphylococcus aureus CCARM 3090, Staphylococcus aureus CCARM 3634, Staphylococcus aureus CCARM 3635, Staphylococcus aureus CCARM 3635. Dilution of test compounds dissolved in dimethylsulfoxide (DMSO) was added to each well of a 96-well microtiter plate containing a fixed volume of Mueller Hinton Broth (MHB, Difco, final 0.64% DMSO). Each well was inoculated with bacteria (5 * 105 CFU / mL) and incubated at 37 ° C for 24 hours. Minimum inhibitory concentration (MIC) is the concentration at which no growth is observed. The inhibitory efficacy of the tested compounds expressed in MIC values is shown in Table 2 below. Most of the compounds used in the present invention showed strong antimicrobial activity against antibiotic resistant strains, and some of them showed a very strong antimicrobial activity similar to some antibiotics used as comparative substances.

Antimicrobial Activity of PPARδ Active Compounds Against Antibiotic Resistant (Staphylococcus aureus) (MIC μg / mL) Antimicrobial Activity (MIC μg / mL) Staphylococcus aureus MSSA MRSA CCARM 0027 CCARM 0204 CCARM 0205 CCARM 3640 CCARM 3089 CCARM 3090 CCARM 3634 CCARM 3635 CMDD6111 8 4 8 16 16 16 8 8 CMDD6113 2 2 One 4 4 4 4 2 CMDD6114 4 2 2 4 8 8 8 4 CMDD6115 One One One 2 2 2 2 2 CMDD6116 2 One One 4 4 4 4 2 CMDD6117 2 One 2 4 4 4 4 2 CMDD6119 2 0.5 0.5 2 4 4 4 One CMDD6120 4 2 2 8 8 8 8 4 CMDD6121 4 One One 4 8 4 4 2 CMDD6122 2 0.5 One 4 8 4 8 2 CMDD6123 4 One 2 8 4 8 4 4 CMDD6124 16 8 16 32 16 32 16 16 CMDD6126 16 4 4 16 32 16 16 8 CMDD6127 8 2 8 16 16 16 8 8 CMDD6128 8 4 8 8 16 16 16 8 CMDD6129 8 2 4 8 16 16 8 8 CMDD6130 4 0.5 2 4 8 4 8 4 CMDD6132 4 2 One 4 4 4 4 2 CMDD6133 4 2 4 16 8 8 8 4 CMDD6135 32 16 16 32 32 64 16 32 CMDD6202 4 2 2 16 4 8 4 2 CMDD6203 4 4 2 8 4 4 4 4 CMDD6204 4 2 2 4 4 4 2 2 CMDD6206 4 2 2 16 4 16 4 2 CMDD6208 4 4 4 8 4 4 4 4 CMDD6209 4 2 2 4 4 4 2 4 CMDD6210 2 One One 2 4 4 2 2 CMDD6211 32 8 2 32 16 32 16 16 CMDD6213 2 One 0.5 2 4 4 2 2 CMDD6214 2 One One 2 4 8 2 2 CMDD6215 2 0.5 0.5 2 2 4 One One CMDD6216 4 2 One 16 4 16 4 4 CMDD6218 2 One One 4 2 2 2 One CMDD6219 4 2 2 4 4 4 4 2 CMDD6220 4 2 One 4 4 8 4 4 CMDD6223 One One One 2 4 4 2 2 CMDD6224 One 0.5 One 4 4 4 2 One CMDD6225 2 One One 4 16 4 2 One CMDD6228 One One One 4 4 4 2 2 CMDD6229 2 One 2 4 8 4 2 2 CMDD6232 4 2 One 8 4 8 4 4 GW501516 4 2 4 4 8 8 4 4 Vancomycin 0.4 0.1 0.1 0.2 0.4 0.8 0.2 0.8 Linezolid 1.6 1.6 1.6 1.6 0.8 1.6 0.8 0.8

Example 3 Evaluation of Wound Healing Capacity of PPARδ Active Compounds Using Human Epidermal Keratinocytes

In this example, the wound healing ability was evaluated using human epidermal cells to evaluate the wound healing ability of the compound according to the present invention. After incubating the cells at 40,000 cells / cm ² in the culture vessel for one day, the surface of the culture vessel was scraped using a plastic tip to create a constant space without cells. Before the drug treatment, the cells were placed in a mitomycin for 2 hours to stop the proliferation and movement of the cells for a while, and then observed for 3 days in the microscope. As a result, the degree of migration and proliferation of cells in the empty space was higher than 70% (after 3 days) in the PPARδ activator (CMDD 6228) treatment group compared to the control group treated with DMSO only. Therefore, the PPARδ active compound promotes the movement and proliferation of human epidermal keratinocytes when administered to the wound or burn site, thereby rapidly treating the wound or burn [FIG. 1].

Example 4 Evaluation of Efficacy in Ulcer Treatment of PPARδ Active Compounds Using a Diabetic Ulcer Model

In this example, BKS.Cg- + Lepr ^db / + Lepr ^db (db / db) mice, which are insulin-independent diabetes model animals, were used to verify the efficacy of treating the diabetic ulcer of the compound used in the present invention. The db / db mouse used as an animal model in this study is a transgenic animal model in which diabetes caused leptin receptor deficiency. Therefore, db / db mice show hyperphagia, resulting in obesity, hyperglycemia, hyperinsulinemia and insulin resistance. In addition, diabetic complications, wounds do not heal quickly, the model is characterized by progressing to ulcers. In the following examples, the compound was applied to the wound to verify the efficacy of treating the ulcer between the administration group and the control group.

The experimental animals used in this example were purchased using BKS.Cg- + Lepr ^db / + Lepr ^db (db / db) (male, 9 weeks old), a type 2 diabetes animal model. After adapting to the laboratory environment for two weeks while providing a lab-chow pellet form for two weeks, wounds were performed on the back of the mice using a circular punch with a diameter of 6 mm, and then wound in the administration group and the control group for five weeks. The treatment of was observed. As a negative control, a mouse coated with only petrolatum was used for the wound, and applied to the wound at a dose of 10 mg / Kg with petrolatum according to the weight of the mouse once a day for 5 weeks. As a result, the mice coated with the PPARδ active substance (CMDD6228) over 4 and 5 weeks were almost cured while the negative control group observed a phenomenon in which the wound developed into an ulcer and necrosis of surrounding tissues [Fig. 2]. .

Claims (16)

delete delete delete delete A pharmaceutical composition for preventing or treating bacterial infectious diseases or foot ulcers, comprising a compound of formula (IV), a stereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof.
[Formula IV]

[In Formula IV, A is sulfur (S) or selenium (Se);
Z is CR or N;
R is hydrogen, C ₁ -C ₈ alkyl or halogen;
R 'is hydrogen or a C ₁ -C ₅ alkyl group;
R ₂ is

Or selected from the following structures;

R '' and R '''are each independently hydrogen or hydroxy;
E is an integer from 0 to 9;
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, halogen substituted C ₁ -C ₅ alkyl or halogen substituted phenyl;
p is an integer from 1-5;
q is an integer from 1-4;
s is an integer from 1-5;
The alkyl and alkoxy of R ₁₁ and R ₂₁ may be further substituted with one or more halogen or alkylamine of C ₁ -C _5. ] The method of claim 5,
R ₂ is selected from the following structures;

R ₁₁ is hydrogen, halogen, C ₁ -C ₅ alkyl or C ₁ -C ₅ alkoxy;
p is an integer from 1-5;
q is an integer from 1-4;
The alkyl and alkoxy of R ₁₁ may be further substituted with one or more halogen or C ₁ -C ₅ alkylamine, pharmaceutical composition for preventing or treating bacterial infections or foot ulcers. The method of claim 6,
R ₁₁ is hydrogen, C ₁ -C ₃ alkyl or halogen;
The alkyl of R ₁₁ is one or more halogen or C ₁ -C ₅ alkylamine that may be further substituted, bacterial infection or foot ulcer prevention or treatment pharmaceutical composition. The method of claim 5,
The compound of formula (IV) is selected from compounds of the following structure, a bacterial infectious disease or foot ulcer pharmaceutical composition for preventing or treating.

delete delete delete delete A pharmaceutical composition for the treatment of wounds or burns, comprising a compound of formula (IV), a stereoisomer thereof, an enantiomer thereof or a pharmaceutically acceptable salt thereof.
[Formula IV]

[In Formula IV, A is sulfur (S) or selenium (Se);
Z is CR;
R is hydrogen;
R 'is a C ₁ -C ₅ alkyl group;
R ₂ is

ego;
R '' and R '''are each independently hydrogen;
E is an integer of 0;
X is sulfur (S) or selenium (Se);
Y is carbon (CH);
R ₂₁ is hydrogen, halogen, C ₁ -C ₅ alkyl, heterocyclic group, C ₁ -C ₅ alkoxy, halogen substituted C ₁ -C ₅ alkyl or halogen substituted phenyl;
s is an integer from 1-5;
Alkyl and alkoxy of R ₂₁ may be further substituted with at least one halogen or alkylamine of C ₁ -C _5. ] delete delete The method of claim 13,
The compound of formula IV is selected from compounds of the following structure, pharmaceutical composition for treating wounds or burns.

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