Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
  • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
  • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
  • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
  • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
• • 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
  • A61P3/06—Antihyperlipidemics
• • 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

• the present invention relates to a novel furan-2-carboxylic acid derivative capable of activating AMP-activated protein kinase (AMPK), which is useful for the prevention and treatment of metabolic syndromes.
• AMPK AMP-activated protein kinase
• Metabolic syndrome refers to a cluster of conditions including diabete (e.g., Type 2 diabete), obesity, hyperlipidemia, hypercholesterolemia, fatty liver and steatohepatitis factors, which raises patients' risk of being afflicted by coronary atherosclerosis, myocardial infarction and stroke 3 times or higher than normal people. The occurrence of metabolic syndromes has gradually increased.
• AMPK is an energy sensor found in all eukaryotic cells, which is involved in metabolism regulation: it is activated in response to an increase in the ratio of AMP/ATP in cells due to cellular or body energy depletion and the phosphorylation of threonine 172 of AMPK.
• AMPK regulates glucose absorption in muscle and fat cells. It is reported that AMPK is activated by the treatment of an AMPK activator, e.g., AICAR (5-aminoimidazol-4-carboxamide-l-D- ribofuranoside) in muscle cells to increase the translocation of a glucose transport protein GLUT 4 to the cell membrane, thereby raising glucose absorption in the cells ⁇ See Edward O. Ojuka et al., JAppl Physiol., 88(3), 1072-1075, 2000; and Honghai Zheng, J Appl Physiol., 91, 1073-1083, 2001).
• AICAR 5-aminoimidazol-4-carboxamide-l-D- ribofuranoside
• AMPK reduces fat synthesis through lowering the expression of a sterol regulatory element binding protein- Ic (SREBP-Ic) which controls the synthesis of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), and it also inhibits the activity of ACC by directly phosphorylating ACC.
• SREBP-Ic sterol regulatory element binding protein- Ic
• ACC acetyl-CoA carboxylase
• FAS fatty acid synthase
• the activated AMPK reduces the formation of fat such as triglyceride or cholesterol in cells (See Trends in Pharmacological Science, 26, 69-76, 2005), which is beneficial in regulating much conditions as obesity and glucose metabolic disturbance of metabolic syndromes (See Neil et al., Nature Drug discovery, 3, 340, 2004).
• metformin As an AMPK-activating drug, metformin has been used for treating Type 2 diabete (See Current drug targets, 4, 685-696, 2005), but, it causes gastric-related side effects such as diarrhea.
• X is hydrogen or halogen
• R is hydrogen or C 1-4 alkyl; n is an integer in the range of 1 to 3; and m is an integer in the range of 0 to 2.
• the present invention also provides a method for preparing the compound of formula (I), comprising bringing a compound of formula (II) to react with a compound of formula (III) in a solvent in the presence of a base:
• Y is triphenylphosphonium bromide, triphenylphosphonium iodide or benzothiazol-2-sulfonyl
• the present invention further provides a pharmaceutical composition for preventing or treating metabolic syndromes, comprising the compound of formula (I), a pharmaceutically acceptable salt or isomer thereof as an active ingredient.
• FIG. 1 shows Western blot analyze results obtained for the activation of AMPK by the inventive furan-2-carboxylic acid derivative.
• the present invention provides a novel compound of formula (I), a pharmaceutically acceptable salt or isomer thereof as an AMPK activator.
• the pharmaceutically acceptable salt of the inventive compound of formula (I) includes a salt formed with an inorganic base such as an alkali metal (e.g., lithium, sodium and potassium), an alkaline earth metal (e.g., calcium and magnesium) or chromium, or an organic base such as amines (e.g., quaternary ammonium, dicyclohexyl amine and N-methyl-D-glucamine) or amino acids (e.g., arginine and lycine).
• an inorganic base such as an alkali metal (e.g., lithium, sodium and potassium), an alkaline earth metal (e.g., calcium and magnesium) or chromium, or an organic base such as amines (e.g., quaternary ammonium, dicyclohexyl amine and N-methyl-D-glucamine) or amino acids (e.g., arginine and lycine).
• inventive compound of formula (I) may exist in an E- or Z- isomer due to the existence of a double-bond therein. Accordingly, the present invention includes an E- or Z-isomer of the compound of formula (I) and a racemic mixture thereof.
• Exemplary compounds of formula (I) according to the present invention are as follows:
• the inventive compound of formula (I) can be prepared by bringing a compound of formula (II) to react with a compound of formula (III) in a solvent in the presence of a base, as shown in Reaction Scheme 1.
• Reaction Scheme 1 Reaction Scheme 1
• Y is triphenylphosphonium bromide, triphenylphosphonium iodide or benzothiazol-2-sulfonyl; and X, R, n and m are the same as defined in formula (I).
• the compound of formula (Ia) containing one double bond may be prepared by conducting a conventional olefination reaction such as Wittig reaction and Julia olefination.
• the compound of formula (II) and the compound of formula (III) are preferably used in an equivalent ratio of 1.0:0.8 to 1.0:1.5 in a solvent in the presence of a base.
• Examples of the base which may be used in the Wittig reaction include, but are not limited to, potassium £-butoxide, sodium ⁇ -butoxide, sodium methoxide, sodium ethoxide, sodium hydride, n-butyl lithium, r-butyl lithium and a mixture thereof, preferably potassium ⁇ -butoxide.
• the base is suitably used in 1.0 to 3.0 equivalents based on the compound of formula (II).
• Examples of the base which may be used in the Julia olefination reaction include, but are not limited to, sodium (bis-trimethylsilyl)amide, lithium (bis-trimethylsilyl)amide, potassium (bis-trimethylsilyl)amide, potassium ⁇ -butoxide, sodium ⁇ -butoxide, sodium methoxide, sodium ethoxide and a mixture thereof, preferably lithium (bis-trimethylsilyl)amide.
• the base is suitably used in 1.0 to 3.0 equivalents based on the compound of formula (II).
• the solvent which may be used in the Wittig or Julia olefination reaction is dimethyl formamide (DMF), tetrahydrofuran (THF), diethyl ether (Et 2 U), dimethoxyethane (DME) or a mixture thereof, preferably dimethyl formamide.
• the solvent is suitably used in an amount of 1.0 to 4.0 m£, preferably 2.5 to 3.0 mi based on 1 mmol of the reactant, and the reaction is preferably conducted at a temperature ranging from -78 0 C to the boiling point of the solvent used.
• the compound of formula (Ia) thus prepared is a racemic mixture, whose isomer mix ratio can be confirmed by an H-NMR analysis, and if necessary, each isomer may be isolated therefrom according to a conventional separation method such as chromatography. Further, the compound of formula (Ia) may be subjected to hydrogenation using a palladium/charcoal catalyst to obtain the compound of formula (Ib).
• Reaction Scheme 1 is preferably 5-formyl-furan-2-carboxylic acid or methyl 5-formyl-furan-2-carboxylate.
• the former is commercially available and the latter can be easily obtained from methylation of 5-formyl-furan-2-carboxylic acid.
• the compound of formula (II) used as another starting material in Reaction Scheme 1 may be prepared as shown in Reaction Scheme 2.
• X, R 3 n and m are the same as defined in formula (I)
• Y is the same as defined in Reaction Scheme 1
• L is hydroxyl group or a conventional leaving group such as halogen, alkylsulfonyl and arylsulfonyl.
• the compound of formula (IV) is commercially available or may be easily prepared by substituting a hydroxyl group-containing compound with a conventional leaving group in accordance with a conventional method.
• the compound of formula (V) is also commercially available or may be easily prepared by reducing an aldehyde or carboxylic acid group-containing compound in accordance with a conventional method.
• the compound of formula (IV) and the compound of formula (V) are preferable used in a molar ratio ranging from 1.0:1.0 to 1.5:1.0 in a solvent in the presence of a base for the alkylation or Mitsunobu reaction of phenoxy group, to obtain the compound of formula (VI).
• the solvent useful in said reaction is DMF, acetone or acetonitrile.
• the base useful in said reaction is potassium carbonate or cesium carbonate.
• the compound of formula (VI) may be subjected to a substitution reaction with triphenylphosphonium bromide, triphenylphosphonium iodide or benzothiazol-2-sulfonyl, to obtain the compound of formula (II).
• the compound of formula (II) wherein Y is triphenylphosphonium bromide or triphenylphosphonium iodide may be prepared by dissolving the compound of formula (VI) in dichloromethane or diethyl ether, adding 30% hydrogen bromide/acetic acid solution or N-iodosuccinimide thereto, mixing the resulting bromide or iodide compound with triphenylphosphine in dimethyl formamide and stirring the mixture at room temperature for 1 to 3 hours.
• the 30% hydrogen bromide/acetic acid solution is used in an amount of 1 to 10 equivalents (HBr base) relative to the compound of formula (VI); the N-iodosuccinimide, 1 to 5 equivalents; and triphenylphosphine, 1 to 3 equivalents.
• the compound of formula (II) wherein Y is benzothiazol-2-sulfonyl may be prepared by mixing the compound of formula (VI) withbenzo[di]thiazol-2-thiol (1 to 3 equivalents), triphenylphosphine (1 to 3 equivalents) and diethyl azodicarboxylate (DEAD) (1 to 3 equivalents) in a solvent such as THF or DMF, followed by stirring at room temperature for 1 to 3 hours to substitute the hydroxyl group of the compound of formula (VI) with benzo[di]thiazol-2-thiol, and oxidizing the resultant using m-chloroperbenzoic acid (3 to 5 equivalents) and sodium bicarbonate (5 to 10 equivalents).
• the oxidation is suitably conducted at a temperature ranging from room temperature to the boiling point of the solvent used for 2 to 4 hours.
• the present invention provides a pharmaceutical composition for preventing or treating metabolic syndromes, comprising the inventive compound of formula (I), a pharmaceutically acceptable salt or isomer thereof as an active ingredient.
• composition of the present invention may be formulated in a form suitable for a desired use or purpose using conventional pharmaceutically acceptable additives such as excipient, filler, binder, lubricant, disintegrant, coating agent, emulsifier, suspending agent, solvent, stabilizing agent, penetration enhancer, and ointment.
• conventional pharmaceutically acceptable additives such as excipient, filler, binder, lubricant, disintegrant, coating agent, emulsifier, suspending agent, solvent, stabilizing agent, penetration enhancer, and ointment.
• the pharmaceutical composition may be orally administered in the form of tablets, coated tablets, capsules, powders, granules, solutions, emulsions or suspensions. Also, the pharmaceutical composition may be rectally administered in the form of suppositorys, topically or transdermally in the form of ointments, creams, gels or solutions, or parenterally in the form of an injection solutions.
• the amount of the inventive compound of formula (I) actually administered will be determined depending on various factors including the age and condition of the patient and the chosen route of administration.
• the suitable daily dosage for oral administration of the compound of formula (I) is about 100 to 500 mg for an adult patient.
• Step (1-4) The compound (0.17 mmol) obtained in Step (1-4) was dissolved in a 1:9 (v/v) mixture of methanol and dichloromethane, and 5% palladium/charcoal (Pd/C) catalyst was added thereto. The resulting mixture was saturated with hydrogen (hydrogen gas balloon), stirred for 3 hours, filtered, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (2% dichloromethane/methanol), to obtain the title compound (Yield 80%).
• Step (2-4) The compound (0.164 mmol) obtained in Step (2-4) was dissolved in water/THF (1/1, 2 mi), and lithium hydroxide (LiOH) (0.49 mmol) was added thereto, followed by stirring for 12 hours.
• the mixture was neutralized with IN hydrochloric acid and extracted with water and ethyl acetate (1:1, 2 mi).
• the organic layer was washed with brine, dried over anhydrous Mg 2 SO 4 , filtered and concentrated.
• Example 3 5- ⁇ 3-[3-(4-fluorobenzyloxy)phenyl]propyl ⁇ furan-2- carboxylic acid (E)/(Z)-5- ⁇ 3-[3-(4-fluorobenzyloxy)phenyl]propenyl ⁇ furan-2-carboxy lie acid (0.16 mmol) obtained in Example 2 was hydrogenated according to the procedure of Step (1-5) of Example 1, to obtain the title compound (Yield 59%).
• Example 1 and 3-hydroxyphenyl acetic acid were used as starting materials for conducting the procedures of Step (1-2) of Example I 5 Step (2-3) (Yield 62%) and Step (2-4) (Yield 36%) of Example 2, Step (1-5) of Example 1 and Step (2-5) (Yield 62%) of Example 2, successively, to obtain the title compound.
• Step (2-2) of Example 2 was repeated except for using 3-hydroxybenzyl alcohol as a starting material, to obtain the title compound.
• Step (1-4) of Example 1 was repeated except for using the compound (0.28 mmol) obtained in Step (5-2), to obtain the title compound (Yield 52%).
• Step (1-5) of Example 1 was repeated except for using the compound (0.12 mmol) obtained in Step (5-3), to obtain the title compound (Yield 50%).
• Step (1-1) of Example 1 2-Hydroxybenzyl alcohol and 2-(4-fluorophenyl)-ethyl methanesulfonate obtained in Step (1-1) of Example 1 were used as starting materials for conducting the procedures of Step (1-2), Step (1-3) (Yield 89%), Step (1-4) (Yield 50%) and Step (1-5) (Yield 90%) of Example 1, successively, to obtain the title compound.
• Step (1-1) of Example 1 2-Hydroxybenzyl alcohol and 2-(4-fluorophenyl)-ethyl methane sulfonate obtained in Step (1-1) of Example 1 were used as starting materials for conducting the procedures of Step (1-2), Step (1-3) (Yield 89%) and Step (1-4) (Yield 50%) of Example 1, successively, to obtain the title compound.
• Hepatoma HepG2 cells obtained from the Korean Cell Line Bank were cultured in DMEM (Dulbecco's Modified Eagle Medium) at a concentration of IxIO 4 cells /well.
• the cells were treated with each of the test compounds of the present invention (100 ⁇ M), metformin (2 mM) (Sigma) and AICAR (100 ⁇ M) (Sigma) as comparative compounds, and the control group without test compound, which were incubated in a humidified atmosphere of 5% CO 2 at 37 ° C for 24 hours. Then, the cells were treated with a Pro-Prep protein extract solution (ESTtRON Biotechnology).
• the extracted protein was separated in SDS-PAGE and electrophoretically transferred to protein-fixing membranes, followed by incubation with the anti-AMPK antibody (Cell signaling) or anti-phospho-AMPK (pAMPK) antibody (Cell signaling).
• a light-sensitive film was used to detect immunoreactive bands and the intensity of bands was quantified.
• the AMPK activity increase brought about by the test compound treatment was measured by dividing the intensity of pAMPK with the intensity of AMPK.
• Table 1 The results are shown in Table 1, in the form of the extent of increase of the AMPK activity relative to AICAR (The measurement for AICAR is assigned to "1").
• Hepatoma HepG2 cells obtained from the Korean Cell Line Bank were cultured in DMEM at a concentration of IxIO 4 cells /well.
• the cells were treated with each of the test compounds of the present invention (50 ⁇ M), and the control group without test compound, which were incubated in an atmosphere of 5% CO 2 at 37 °C for 24 hours.
• the cells were treated with a cell lysis solution (0.1 M potassium phosphate, pH 7.4, 0.05 M NaCl, 5 inM cholic acid, 0.1% Triton ® X-100) and reacted on ice for 10 minutes.
• the cell lysates were treated with 50 j ⁇ of a 2 times-concentrated reagent (300 ⁇ M Amplex Red reagent (Invitorgen), 2 O/ml HRP (Invitorgen), 2 U/m- ⁇ cholesterol oxidase (Invitorgen), 0.2 Wmt cholesterol esterase (Invitorgen)) and reacted for 30 minutes at 37 ° C .
• the content of cholesterol formed in the cell lysates was measured using a fluorscence microscope and .quantified. The results are shown in Table 2, in the form of the cholesterol content (%) relative to the control group (The measurement for control group is assigned to "100%").
• Table 2 Table 2
• Hepatoma HepG2 cells obtained from the Korean Cell Line Bank were cultured in DMEM at a concentration of 2 ⁇ l O 4 cells /well.
• the cells were treated with each of the test compounds of the present invention (50 ⁇ M), and the control group without test compound, which were incubated in an atmosphere of 5% CO 2 at 37 ° C for 24 hours.
• the cells were treated with a cell lysis solution (0.1 M potassium phosphate, pH 7.4, 0.05 M NaCl, 5 mM cholic acid, 0.1% Triton ® X-100) and reacted on ice for 10 minutes.
• a cell lysis solution 0.1 M potassium phosphate, pH 7.4, 0.05 M NaCl, 5 mM cholic acid, 0.1% Triton ® X-100
• the cell lysates were treated with 50 ⁇ JL of a 2 times-concentrated reagent (300 ⁇ M Amplex Red reagent (Invitorgen), 2 UM lipase (ASAN Pharmaceutical Co., Ltd.), 0.75 UM glycerol kinase (ASAN Pharmaceutical Co., Ltd.), 151333 UM peroxidase (ASAN Pharmaceutical Co., Ltd.), 22.2 UM glyceric oxidase (ASAN Pharmaceutical Co., Ltd.) and reacted for 30 minutes at 37 0 C .
• the content of the triglyceride formed in the cell lysates was measured using a fluorscence microscope and quantified. The results are shown in Table 3, in the form of the triglyceride content (%) relative to the control group (The measurement for control group is assigned to "100%")- Table 3
• Hepatoma HepG2 cells were cultured in DMEM at a concentration of 5 ⁇ l O 4 cells /well. The cells were treated with each of the test compounds of the present invention (50 ⁇ M), and the control group without test compound, which were incubated in an atmosphere of 5% CO 2 at 37 0 C for 24 hours. Then, 0.5 uCi 14C-lactate (Amersham Bioscience) and 10 mM L-lactate
• the inventive compound is effective in the activation of AMPK, which is useful for preventing or treating metabolic syndromes including diabete (e.g., Type 2 diabete), obesity, hyperlipidemia, hypercholesterolemia, fatty liver and steatohepatitis factors.
• diabete e.g., Type 2 diabete
• obesity e.g., obesity
• hyperlipidemia e.g., hypercholesterolemia
• fatty liver e.g., steatohepatitis factors.

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