WO2009072807A2 - Pharmaceutical composition for preventing or treating fat metabolism-related diseases containing 2-cyclopentene-1-one oxime derivatives - Google Patents
Pharmaceutical composition for preventing or treating fat metabolism-related diseases containing 2-cyclopentene-1-one oxime derivatives Download PDFInfo
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- WO2009072807A2 WO2009072807A2 PCT/KR2008/007139 KR2008007139W WO2009072807A2 WO 2009072807 A2 WO2009072807 A2 WO 2009072807A2 KR 2008007139 W KR2008007139 W KR 2008007139W WO 2009072807 A2 WO2009072807 A2 WO 2009072807A2
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- WIPO (PCT)
- Prior art keywords
- alkyl
- pharmaceutical composition
- chemistry
- phenyl
- fat metabolism
- Prior art date
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- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 21
- 201000010099 disease Diseases 0.000 title abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title abstract description 7
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- 230000004060 metabolic process Effects 0.000 title abstract description 5
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- 125000006216 methylsulfinyl group Chemical group [H]C([H])([H])S(*)=O 0.000 description 1
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- 239000002674 ointment Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
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- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- 229940037128 systemic glucocorticoids Drugs 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- This disclosure relates to a pharmaceutical composition for preventing or treating fat metabolism-related diseases containing a 2-cyclopentene-l-one oxime derivative as an active ingredient.
- Adipocytes are the cells that primarily compose adipose tissue, specialized in storing fat. In addition to functioning as storages of extra calories, they play a variety of roles, including protection of organs by cushioning actions, maintenance of body temperature, or the like.
- WAT white adipose tissue
- LPL lipoprotein lipase
- HSL hormone- sensitive lipase
- cyclic adenosine monophosphate (cyclic AMP or cAMP) functions as a key factor.
- cAMP is very unstable and is decomposed into AMP by phosphodiesterase present in the cells.
- the resultant decrease of cAMP concentration leads to reduced breakdown of fats. Accordingly, breakdown of fats may be enhanced by increasing the cAMP concentration in adipocytes or by inhibiting the activity of phosphodiesterase.
- isoproterenol a derivative of catecholamine, xanthines such as caffeine or theophylline, thyroid hormone, glucocorticoids, growth hormone, or the like are used to facilitate breakdown of fats for cosmetic purposes.
- xanthines such as caffeine or theophylline
- thyroid hormone glucocorticoids
- growth hormone or the like
- this disclosure is directed to providing a pharmaceutical composition for prevention and treatment of fat metabolism disorder such as obesity, hyperlipidemia, diabetes, and the like containing a 2-cyclopentene-l-one oxime derivative as an active ingredient.
- the pharmaceutical composition containing the disclosed 2-cyclopentene-l-one oxime derivative compounds as an active ingredient affect the intracellular production and breakdown of cAMP in differentiated adipocytes, thereby maintaining cAMP level high and facilitating fat breakdown through cascade reactions. Accordingly, it may be useful as a pharmaceutical composition for prevention and treatment of fat metabolism disorder such as obesity, hyperlipidemia, diabetes, and the like.
- Fig. 1 is a graph comparing the rate of enhanced fat breakdown and the increase of c AMP level in adipocytes by the disclosed 2-cyclopentene-l-one oxime derivative compounds.
- a pharmaceutical composition according to an embodiment disclosed herein comprises a compound represented by Chemistry Figure 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
- R represents linear or branched C -C alkyl or C -C cycloalkyl, or phenyl with or without a substituent; and [25] R represents an aromatic group with or without a substituent, the aromatic group being selected from phenyl, pyridyl, naphthyl, indolyl, thienyl, benzo[b]thienyl, diben- zofuranyl and thianthrenyl.
- the phenyl group may be represented by Chemistry Figure 2:
- R through R are independently selected from hydrido, linear or branched C -C alkyl, C 2 -C 6 alkenyl, halo C 1 -C6 alkyl, phenyl, halo, nitro, amino, C 1 -C5 alkylamino, C 1 -
- R represents linear or branched C -C alkyl, cyclopentyl or cyclohexyl, and R represents an aromatic group with or without
- aromatic group being selected from pyridyl, naphthyl, indolyl, thienyl, benzo[b]thienyl, dibenzofuranyl, thianthrenyl or phenyl with a substituent.
- the phenyl group is defined as in Chemistry Figure 2.
- R represents propyl, isopropyl, butyl, isobutyl, pentyl, cyclopentyl or cyclohexyl, and R represents phenyl with a substituent.
- the phenyl group is defined as in Chemistry Figure 2, and the substituents R through R may be independently selected from hydrido, methyl, ethyl, propyl, butyl, vinyl, trifluoromethyl, phenyl, fluoro, chloro, bromo, nitro, amino, N,N-dimethylamino, N,N-dimethylaminomethyl, methylenedioxy, methoxy, ethoxy, trifluoromethoxy, benzyloxy, methylthio, methylsulfonyl, methylsulfinyl, cyano, carboxyl, methoxycarbonyl, ethoxycarbonyl, methoxymethyl, hydroxy, hydroxymethyl carbamoyl, N- (hydroxy acetimidoyl)amino, N-hydroxyiminomethyl and 1 -N-hydroxyiminoethyl.
- At least one compound given in Table 1 or pharmaceutically acceptable salt thereof may be included in a pharmaceutical composition as an active ingredient.
- At least one of the aforesaid compounds or the pharmaceutically acceptable salts thereof may be mixed with a pharmaceutically acceptable adequate vehicle or excipient or be diluted with a diluent to prepare a pharmaceutical composition for prevention, treatment and improvement of fat metabolism related diseases.
- Examples of the adequate vehicle, excipient or diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydrox- ybenzoate, talc, magnesium stearate and mineral oil.
- the pharmaceutical composition may further contain filler, anticoagulant, lubricant, wetting agent, perfume, emulsifier, antiseptic, disintegrant, sweetener, anticaking agent, flavoring agent, or the like.
- the pharmaceutical composition may be administered orally or applied to the skin. It may be prepared into various skin external application formulations, including lotion, cream, gel, ointment, aerosol, patch, etc., because it can be directly applied on the body portion rich in subcutaneous fats, such as face, abdomen, thigh, hip, upper arm, etc., in order to reduce fats at the portion.
- skin external application formulations including lotion, cream, gel, ointment, aerosol, patch, etc.
- the pharmaceutical composition may be formulated according to a method well known in the art so that the active ingredient may be released immediately, in a sustained manner or in a controlled manner, after being administered to a mammal.
- the formulation may be in the form of tablet, pill, powder, sachet, elixir, suspension, emulsion, solution, syrup, aerosol, soft or hard gelatin capsule, sterile solution for injection, sterilized powder, and the like.
- the pharmaceutical composition may be administered through various routes, including orally, transdermally, subcutaneously, intravenously or intramuscularly.
- the administration dose of the active compound is, in general, 0.1 to 100 mg/kg/day.
- the administration may be made at once or in divided doses.
- the actual administration dose of the active ingredient is to be determined considering various related factors, including administration route, age, sex and body weight of the patient, severity of the disease, or the like.
- the aforesaid administration dose does not limit the scope of this disclosure in any means.
- Example 1 Efficiency of breakdown of triglycerides in adipocytes
- Mouse-derived preadipocyte 3T3-L1 cells (mouse adipocytes; ATCC # CL- 173) are placed on a 96- well cell culture plate at a concentration of 5x10 /well. The cells are cultured in Dulbecco's modified Eagle's medium (DMEM, GibcoBRL, #11965-084) containing 10% calf serum (GibcoBRL, #16170-078) and penicillin/streptomycin (GibcoBRL, #10378-016) at 37 0 C in a 10% CO 2 incubator.
- DMEM Dulbecco's modified Eagle's medium
- GibcoBRL #11965-084
- penicillin/streptomycin (GibcoBRL, #10378-016)
- the cells are cultured in a medium containing 10% bovine serum, 0.5 mM 3-isobutyl-l-methylxanthine (IBMX; Sigma #1-7018), l ⁇ M dex- amethasone (Sigma, #D-4902) and 167 nM bovine insulin (Sigma, #1-5500) for 48 hours.
- IBMX 3-isobutyl-l-methylxanthine
- l ⁇ M dex- amethasone Sigma, #D-4902
- 167 nM bovine insulin Sigma, #1-5500
- the cells are cultured for 72 hours.
- the cells are cultured in a DMEM medium containing only 10% fetal bovine serum (FBS; GibcoBRL, #10437-028) for 48 hours to obtain completely differentiated adipocytes.
- FBS fetal bovine serum
- the culture medium is discarded after the 3T3-L1 cells are completely differentiated.
- the cells are cultured for 5 hours in DMEM (low glucose, without phenol red; WelGene, #LM001-04), 200 ⁇ l/well, containing 2% BSA (free fatty acid; Bovogen, #BSAS, 0.025), treated with Compounds 1 to 24, respectively 10 ⁇ M, or with 0.5% DMSO.
- DMEM low glucose, without phenol red
- BSA free fatty acid
- Bovogen, #BSAS 0.025
- Compounds 1 to 24 respectively 10 ⁇ M
- 0.5% DMSO 0.5% DMSO.
- only the supernatant is taken from the culture medium and the quantity of glycerol produced from breakdown of fats is measured using a free glycerol reagent (Sigma, #F6428).
- the glycerol content is calculated according to Math Figure 1.
- the rate of enhanced fat breakdown is determined relative to a control group (a well not with the
- Glycerol content (A - A ) / (A - A ) x Concentration of standard sample blank standard blank glycerol
- a sample is the absorbance of the well treated with respective compounds
- a blank is the absorbance of the well not treated with the reagent
- a standard is the absorbance of the standard glycerol in known concentration.
- Rate of enhanced fat breakdown (%) [Quantity of free glycerol when the compound is added / Quantity of free glycerol when the compound is not added (0.5%
- Example 2 Measurement of cAMP level in differentiated adipocytes
- the effect of the 2-cyclopentene-l-one oxime derivative compounds on the level of c AMPs induced by forskolin, a promoter of adenylate cyclase (AC), in the adipocytes differentiated in Stage 1 of Example 1 is evaluated. The supernatant of the culture medium is discarded after the adipocytes are completely differentiated. Then, after adding a DMEM medium containing 10% FBS, the cells are cultured for 15 minutes in a 10% CO incubator at 37 0 C, after treating with Compounds 3-9, and Compounds 11, 14 and 17 to a final concentration of lO ⁇ M or with 0.5% DMSO.
- AC a promoter of adenylate cyclase
- the cells are stimulated with 1 ⁇ M forskolin for 10 minutes at 37 0 C. Subsequently, the culture medium is discarded, the cells are lysed, and the cAMP level in the cells is measured using a cAMP enzyme immunoassay (EIA) system (Amersham Pharmacia Biotech, Kit #RPN225). The effect of Compounds 3-9, and Compounds 11, 14 and 17 on the production or breakdown of cAMP is evaluated using a standard cAMP reaction curve. The result is expressed relative to the sample stimulated with 1 M forskolin without treatment with the compound. The result is given in Table 3. The disclosed compounds increase cAMP level in the differentiated adipocytes by affecting the production and inhibition of breakdown of cAMP in the cells. Thus, it is expected that they can inhibit the storage of fats by stimulating HSL, which facilitates fat breakdown.
- EIA enzyme immunoassay
- the disclosed pharmaceutical composition can enhance the breakdown of fats accumulated in body portions and improve localized or systemic obesity. Therefore, it is very effective for preventing, treating and improving fate metabolism diseases such as obesity, diabetes, hyperlipidemia, hypertension, and the like.
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- Health & Medical Sciences (AREA)
- Diabetes (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Hematology (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Emergency Medicine (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20107017557A KR101494488B1 (ko) | 2007-12-03 | 2008-12-03 | 2-사이클로펜텐-1-온 옥심 유도체를 유효성분으로 포함하는 지방대사질환 예방 및 치료용 약학 조성물 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2007-0124448 | 2007-12-03 | ||
| KR20070124448 | 2007-12-03 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2009072807A2 true WO2009072807A2 (en) | 2009-06-11 |
| WO2009072807A3 WO2009072807A3 (en) | 2009-07-30 |
Family
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Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2008/007139 WO2009072807A2 (en) | 2007-12-03 | 2008-12-03 | Pharmaceutical composition for preventing or treating fat metabolism-related diseases containing 2-cyclopentene-1-one oxime derivatives |
| PCT/KR2008/007140 WO2009072808A2 (en) | 2007-12-03 | 2008-12-03 | Cosmetic composition for body slimming containing 2-cyclopentene-1-one oxime derivatives |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2008/007140 WO2009072808A2 (en) | 2007-12-03 | 2008-12-03 | Cosmetic composition for body slimming containing 2-cyclopentene-1-one oxime derivatives |
Country Status (2)
| Country | Link |
|---|---|
| KR (2) | KR101494488B1 (ko) |
| WO (2) | WO2009072807A2 (ko) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996038427A1 (fr) * | 1995-06-02 | 1996-12-05 | Sankyo Company, Limited | Derives d'oxyimino aromatiques |
| US5792882A (en) * | 1993-08-19 | 1998-08-11 | Pfizer Inc. | Phenoxyphenyl cyclopentenyl hydroxyureas |
| WO2006059867A1 (en) * | 2004-12-02 | 2006-06-08 | Amorepacific Corporation | 2-cyclopenten-1-one oxime derivatives inhibiting production of tnf-alpha |
| KR20060091724A (ko) * | 2005-02-16 | 2006-08-21 | 주식회사 태평양 | 2-(3,4-다이플루오로페닐)-3-프로필-2-사이클로펜텐-1-온옥심을 유효성분으로 함유하는 피부노화 및 주름 방지용 화장료 조성물 |
-
2008
- 2008-12-03 WO PCT/KR2008/007139 patent/WO2009072807A2/en active Application Filing
- 2008-12-03 KR KR20107017557A patent/KR101494488B1/ko active IP Right Grant
- 2008-12-03 KR KR1020107017553A patent/KR101567571B1/ko active IP Right Grant
- 2008-12-03 WO PCT/KR2008/007140 patent/WO2009072808A2/en active Application Filing
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5792882A (en) * | 1993-08-19 | 1998-08-11 | Pfizer Inc. | Phenoxyphenyl cyclopentenyl hydroxyureas |
| WO1996038427A1 (fr) * | 1995-06-02 | 1996-12-05 | Sankyo Company, Limited | Derives d'oxyimino aromatiques |
| WO2006059867A1 (en) * | 2004-12-02 | 2006-06-08 | Amorepacific Corporation | 2-cyclopenten-1-one oxime derivatives inhibiting production of tnf-alpha |
| KR20060091724A (ko) * | 2005-02-16 | 2006-08-21 | 주식회사 태평양 | 2-(3,4-다이플루오로페닐)-3-프로필-2-사이클로펜텐-1-온옥심을 유효성분으로 함유하는 피부노화 및 주름 방지용 화장료 조성물 |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101494488B1 (ko) | 2015-02-24 |
| KR20100103671A (ko) | 2010-09-27 |
| WO2009072808A3 (en) | 2009-08-20 |
| KR20100103670A (ko) | 2010-09-27 |
| KR101567571B1 (ko) | 2015-11-11 |
| WO2009072808A2 (en) | 2009-06-11 |
| WO2009072807A3 (en) | 2009-07-30 |
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