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WO2012148140A2 - Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation - Google Patents

Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation Download PDF

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Publication number
WO2012148140A2
WO2012148140A2 PCT/KR2012/003103 KR2012003103W WO2012148140A2 WO 2012148140 A2 WO2012148140 A2 WO 2012148140A2 KR 2012003103 W KR2012003103 W KR 2012003103W WO 2012148140 A2 WO2012148140 A2 WO 2012148140A2
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compound
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formula
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oso
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WO2012148140A3 (fr
Inventor
송호영
김성진
박수호
이향숙
박태교
우성호
김용주
김태윤
김병학
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Bio Clue and Solution Co Ltd
Ligachem Biosciences Inc
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Bio Clue and Solution Co Ltd
Legochem Biosciences Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to an imidazole alkaloid derivative having an angiogenic and antioxidant effect, a method for preparing the same, and a composition having an angiogenic and antioxidant effect containing the same.
  • hypoxia inducible factor-1 HIF-1
  • the HIF-1 is known as a transcription factor that maintains intracellular homeostasis by inducing angiogenesis or glycolysis in order to properly respond to external oxygen concentration changes in a hypoxic state.
  • HIF-1 is increased, thereby inducing the expression of several proteins that will protect themselves from hypoxic stress.
  • Dr. Jong-Hyun Shin of the Korea Ocean Research and Development Institute extracted an organic compound with a unique structure called Wondonin from the symbiosis of the sponges Poencillastra wondoensis and Jaspis sp. That live in Geomundo, South Coast of Korea (Tetrahedron. Lett 1994, 35, 4579-4580, US patent: US 6,383,521 B1).
  • the wandonin compound has a novel structure that has not been found in nature called bis (dihydroxystyryl) imidazole-based alkaloids.
  • the wandonin compound has two asymmetric carbons, so a total of four isomers may exist, and Dr. Jong-Hyun Shin separates and purifies the two compounds by high performance liquid chromatography (HPLC), respectively. Named A and Wandonin B.
  • WAVECs human umbilical vein endothelial cells
  • an object of the present invention is to solve the problems of the prior art as described above and the technical problem that has been requested from the past.
  • the present invention provides an imidazole compound having a novel structure having an angiogenesis inhibitory and antioxidant effect.
  • Another object of the present invention is to provide a method for preparing such novel compounds.
  • Another object of the present invention is to provide a method for treating and preventing angiogenesis-related diseases such as cancer, using such novel compounds as active ingredients.
  • the present invention provides a compound represented by the following formula (1), a pharmaceutically acceptable salt, hydrate, solvate, isomer or prodrug thereof.
  • L and M are each independently -H, -OH, or -OR, wherein R is C 1-4 alkyl;
  • n is an integer from 0 to 4.
  • R 1 is -H, -OH, -OR 3 , -NR 3 R 4 , -NR 3 (C (O) R 4 ), -NR 3 (SO 2 R 4 ), -NR 3 (CO 2 R 4 ) , -NR 3 (C (O) NR 3 R 4 ), -CN, -CO 2 R 3 , or -C (O) NR 3 R 4 , wherein R 3 and R 4 are each independently -H or C 1-6 alkyl;
  • X and Y are each independently a carbon or nitrogen element
  • R 2 is not -R 5 OSO 3 R 6 (wherein R 5 is C 2-6 alkylene and R 6 is hydrogen).
  • the compound of formula 1 as an active ingredient of a therapeutic agent includes all pharmaceutically acceptable salts, hydrates, solvates, isomers, and prodrugs thereof, all of which are within the scope of the present invention. It should be interpreted as being included. For convenience of description, it is also simply abbreviated to the compound of Formula 1 in the present specification.
  • the compound of Formula 1 according to the present invention has a structure different from the known wandonin compound, and as shown in the following experimental examples, the prevention and treatment of diseases related to angiogenesis inhibition, such as cancer, as compared with the wandonin compound Excellent effect.
  • pharmaceutically acceptable salt means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • pharmaceutically acceptable salt means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • hydrate means a formulation of a compound that does not cause severe irritation to the organism to which the compound is administered and does not impair the biological activity and properties of the compound.
  • hydrate solvate
  • “isomer” also have the same meaning as above.
  • the pharmaceutical salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like, tartaric acid, formic acid, citric acid Sulfonic acid, such as acetic acid, trichloroacetic acid, trichloroacetic acid, gluconic acid, benzoic acid, lactic acid, organic carbonic acid such as fumaric acid, maleic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like
  • tartaric acid formic acid
  • citric acid Sulfonic acid such as
  • carboxylic acid salts include metal salts or alkaline earth metal salts formed with lithium, sodium, potassium, calcium, magnesium, amino acid salts such as lysine, arginine, guanidine, dicyclohexylamine, N Organic salts such as -methyl-D-glucamine, tris (hydroxymethyl) methylamine, diethanolamine, choline and triethylamine and the like.
  • the compound of formula 1 according to the invention can also be converted to its salt by conventional methods.
  • hydrate refers to a compound of the present invention comprising a stoichiometric or non-stoichiometric amount of water bound by a non-covalent intermolecular force. Or salts thereof.
  • solvate refers to a compound of the present invention or a salt thereof comprising a stoichiometric or non stoichiometric amount of solvent bound by non-covalent intermolecular forces.
  • Preferred solvents therein are volatile, non-toxic, and / or solvents suitable for administration to humans.
  • isomers means a compound of the present invention or a salt thereof that has the same chemical formula or molecular formula, but which is structurally or stericly different.
  • isomers include both structural isomers such as tautomers, and stereoisomers such as R or S isomers having asymmetric carbon centers, and geometric isomers (trans, cis). All these isomers and mixtures thereof are also within the scope of the present invention.
  • prodrug refers to a substance that is transformed into a parent drug in vivo.
  • Prodrugs are often used because, in some cases, they are easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug may not.
  • Prodrugs may also have improved solubility in pharmaceutical compositions than the parent drug.
  • prodrugs are esters that facilitate the passage of cell membranes, which are hydrolyzed to carboxylic acids, which are active by metabolism, once the water solubility is detrimental to mobility, but once the water solubility is beneficial.
  • Drug ") Another example of a prodrug may be a short peptide (polyamino acid) that is bound to an acid group which is converted by metabolism to reveal the active site.
  • L and M are each independently -H or -OH;
  • n is an integer from 0 to 2;
  • R 1 is -H, -OH, -OR 3 , -NR 3 R 4 , -NR 3 (C (O) R 4 ), -NR 3 (SO 2 R 4 ), -NR 3 (CO 2 R 4 ) , -NR 3 (C (O) NR 3 R 4 ), -CN, -CO 2 R 3 , or -C (O) NR 3 R 4 , wherein R 3 and R 4 are each independently -H or C 1-4 alkyl;
  • X and Y are each independently a carbon or nitrogen element
  • R 2 is not -R 5 OSO 3 R 6 (wherein R 5 is C 2-6 alkylene and R 6 is hydrogen).
  • L and M are each independently -H or -OH;
  • n 1
  • R 1 is -H, -OR 3 , -NR 3 R 4 , -NR 3 (C (O) R 4 ), -NR 3 (SO 2 R 4 ), -NR 3 (CO 2 R 4 ), -NR 3 (C (O) NR 3 R 4 ), -CN, -CO 2 R 3 , or -C (O) NR 3 R 4 , wherein R 3 and R 4 are each independently -H or C 1-4 Alkyl;
  • X is a nitrogen element
  • Y is a carbon element
  • the derivative of formula 1 according to the present invention may be exemplified by the following compounds, but the following compounds are not intended to limit the present invention.
  • the present invention also provides a method of preparing a compound of formula (I).
  • an expert will be able to prepare compounds by various methods based on the structure of Formula 1, all of which are construed to include the scope of the present invention. Should be. That is, within the scope of the present invention, it is possible to prepare the compound of formula 1 by arbitrarily combining various synthesis methods described herein or disclosed in the prior art. Therefore, the scope of the present invention is not limited only to these.
  • It may be prepared by a method comprising a.
  • L, M, m, X, Y, R 1 and R 2 are the same as defined above, and Z is a halogen element.
  • the compound of Formula 2 may be prepared by, for example, reducing a benzaldehyde derivative to react with dibromomethane and then oxidizing it again.
  • the strong base may be one selected from the group consisting of NaH, potassium t-butoxide, and sodium hexamethyldisilylamide, but is not limited thereto.
  • the separation of the general mixture can be separated by conventional post-treatment methods such as tube chromatography, recrystallization, HPLC and the like.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising (a) a pharmacologically effective amount of a compound of formula 1; And (b) a pharmaceutically acceptable carrier, diluent, or excipient, or combinations thereof.
  • composition means a mixture of a compound of the invention with other chemical components such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound into the organism.
  • techniques for administering compounds including but not limited to oral, injection, aerosol, parenteral, and topical administration.
  • Pharmaceutical compositions may also be obtained by reacting acid compounds such as hydrochloric acid, bromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • a pharmacologically effective amount refers to, to some extent, alleviate or reduce one or more symptoms of the disorder being treated, or delay the onset of a clinical marker or symptom of a disease that requires prevention. It means the amount of active ingredient effective to.
  • a pharmacologically effective amount may be defined as (1) the effect of reversing the rate of progression of the disease, (2) the effect of inhibiting further progression of the disease to some extent, and / or (3) one or more symptoms associated with the disease. It means the quantity which has the effect of reducing a grade (preferably, removing it).
  • a pharmacologically effective amount can be determined empirically by testing the compound in known in vivo and in vitro model systems for diseases in need of treatment.
  • carrier is defined as a compound that facilitates the addition of a compound into a cell or tissue.
  • DMSO dimethyl sulfoxide
  • carrier facilitates the incorporation of many organic compounds into organisms' cells or tissues.
  • diot is defined as a compound which not only stabilizes the biologically active form of the compound of interest, but also is diluted in water to dissolve the compound. Salts dissolved in buffer solutions are used as diluents in the art. A commonly used buffer solution is phosphate buffered saline, because it mimics the salt state of human solutions. Because buffer salts can control the pH of a solution at low concentrations, buffer diluents rarely modify the biological activity of a compound.
  • the compounds used herein may be administered to human patients as such or as pharmaceutical compositions in combination with other active ingredients or with a suitable carrier or excipient, such as in a combination therapy.
  • Techniques for formulation and administration of compounds in this application can be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.
  • compositions of the invention can be prepared in a known manner, for example, by means of conventional mixing, dissolving, granulating, sugar-making, powdering, emulsifying, encapsulating, trapping or lyophilizing processes. .
  • compositions for use according to the present invention comprise one or more pharmacologically acceptable compositions comprising excipients or auxiliaries which facilitate the treatment of the active compounds into formulations which can be used pharmaceutically. It may also be prepared by conventional methods using a carrier. Proper formulation is dependent upon the route of administration chosen. Any of the known techniques, carriers and excipients can be used suitably and as understood in the art, for example in Remingston's Pharmaceutical Sciences described above.
  • the compound of Formula 1 may be formulated into an injectable preparation, an oral preparation, and the like as desired.
  • the components of the invention can be formulated in liquid solutions, preferably in pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • pharmacologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline solution.
  • noninvasive agents suitable for the barrier to pass through are used in the formulation. Such noninvasive agents are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmacologically acceptable carriers known in the art.
  • Such carriers allow the compounds of the invention to be formulated into tablets, pills, powders, granules, sugars, capsules, liquids, gels, syrups, slurries, suspensions and the like.
  • capsules, tablets, pills, powders and granules are possible, and in particular capsules and tablets are useful.
  • Tablets and pills are preferably prepared with enteric agents.
  • Pharmaceutical preparations for oral use may be achieved by mixing one or more compounds of the invention with one or more excipients, optionally grinding such mixtures and, if necessary, treating the mixture of granules after permeation of appropriate adjuvants.
  • a tablet or sugar core can be obtained.
  • suitable excipients include fillers such as lactose, sucrose, mannitol, or sorbitol; Corn starch, wheat starch, rice starch, potato starch, gelatin, gum tragakens, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and / or polyvinylpyrrolidone ( Cellulose-based materials such as PVP).
  • carriers such as disintergrating agents such as crosslinked polyvinyl pyrrolidone, urticaria, or salts thereof such as alginic acid or sodium alginate and lubricants such as magnesium stearate, binders and the like may be added.
  • compositions that can be used orally may include soft sealing capsules made of gelatin and plasticizers such as glycol or sorbitol, as well as pushable capsules made of gelatin.
  • the push-fix capsule may contain the active ingredients, as a mixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate.
  • the active compounds may be dissolved or dispersed in suitable solvents such as fatty acids, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be included. All preparations for oral administration should be in amounts suitable for such administration.
  • the compounds may be formulated for parenteral administration by injection, eg, by large pill injection or continuous infusion.
  • injectable formulations may be presented in unit dose form, eg, as ampoules or as multi-dos containers, with preservatives added.
  • the compositions may take the form of suspensions, solutions, emulsions on oily or liquid vehicles, and may include components for formulation such as suspensions, stabilizers and / or dispersants.
  • the active ingredient may also be in powder form for constitution with a suitable vehicle, such as sterile pyrogen-free water, before use.
  • a suitable vehicle such as sterile pyrogen-free water
  • the compounds may also be formulated in rectal dosage compositions such as suppositories or retention enemas, including, for example, conventional suppository bases such as cocoa butter or other glycerides.
  • compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve their intended purpose. More specifically, a therapeutically effective amount means an amount of a compound effective to prolong the survival of the subject to be treated or to prevent, alleviate or alleviate the symptoms of a disease. Determination of a therapeutically effective amount is within the capabilities of those skilled in the art, in particular in terms of the detailed disclosure provided herein.
  • the compound of formula 1 as the active ingredient is preferably contained in a unit dose of about 0.1 to 1,000 mg.
  • the dosage of the compound of formula 1 depends on the doctor's prescription depending on factors such as the patient's weight, age and the particular nature and severity of the disease. However, the dosage required for adult treatment typically ranges from about 1 to 1000 mg per day, depending on the frequency and intensity of administration. A total dosage of about 1 to 500 mg per day, usually separated by a single dose for intramuscular or intravenous administration to adults, will be sufficient, but for some patients a higher daily dosage may be desirable.
  • the present invention also provides a method of treating or preventing angiogenesis-related diseases using an effective amount of a compound of formula (1).
  • Angiogenesis-related diseases are diseases caused by excessive angiogenesis and include, for example, cancer, diabetes, senile retinopathy, ischemic heart disease, cerebral ischemia, glaucoma, rheumatoid arthritis, psoriasis, obesity, and arteriosclerosis. Although it is mentioned, it is not limited only to it.
  • treatment means stopping or delaying the progression of the disease when used in a subject exhibiting symptoms
  • the "preventing” means stopping or delaying the manifestation of a disease when used in a subject who does not exhibit symptoms but is at high risk. It means to let.
  • HAVEC human umbilical vein endothelial cell
  • HaCaT Human skin-derived keratinocyte
  • ARPE-19 human-derived retinal epithelial cells
  • Y79 human-derived retinoblastoma cancer cells
  • FIG. 2 is a diagram illustrating human embryonic-derived epithelial cells (HUVEC; human) to compare HIF-1 inhibition with wondonin in hypoxia of compound (LCB54-9) according to Example 6-2 of the present invention.
  • HIFEC human embryonic-derived epithelial cells
  • ARPE-19 human retinal pigment epithelial cells
  • Figure 3 is a real-time gene amplification reaction of the expression level of the gene after treatment with the drug in human embryo-derived epithelial cells to measure the degree of inhibition of angiogenesis in hypoxia for the compound according to Example 6-2 of the present invention It was confirmed by (Real Time PCR; real time polymerase chain reaction).
  • DIPEA Diisopropylethylamine
  • PCC pyridinium chloro chromate
  • Histamine dihydrochloride (10.0 g, 54.3 mmol) was dissolved in AN (300 mL), cooled to 0 ° C., and TEA (37.8 mL, 272 mmol) and Boc 2 O (37.4 mL, 163 mmol) were added dropwise sequentially. Stir for 12 hours. Aqueous ammonium chloride solution (200 mL) was added to the reaction mixture to terminate the reaction. The mixture was extracted with EtOAc (2 x 200 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain t -butyl 4- (2- ( t -butoxycarbo). Nylamino) ethyl) -1 H -imidazole-1-carboxylate (16.5 g, 98%) was obtained as a white solid.
  • Triethyl phosphono acetate (0.36 mL, 1.79 mmol) was dissolved in THF (3 mL), cooled to 0 ° C., sodium hydride (60% purity, 2.62 g, 65.43 mmol) was added dropwise and stirred for 20 minutes.
  • the compound (0.86 g, 1.19 mmol) obtained in Preparation Example 4-7 was dissolved in THF (7 mL), and then slowly added dropwise to the reaction solution, followed by stirring at 0 ° C. for 3 hours.
  • Aqueous solution of saturated ammonium chloride (20 mL) was added to the reaction mixture to terminate the reaction.
  • Example 2 The compound obtained in Example 2 (700 mg, 1.54 mmol) was dissolved in DCM (10 mL), followed by imidazole (524 mg, 7.7 mmol) and t -butyl dimethyl silyl chloride (582 mg, 3.86 mmol) at 0 ° C. After putting in, stirred at room temperature for 40 hours. The reaction mixture was terminated by adding saturated aqueous ammonium chloride solution (30 mL), extracted with DCM (3 x 30 mL), dehydrated with anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was purified by column chromatography ( n -Hex / EtOAc). , 1/1 ⁇ 1/4) to give the title compound (707 mg, 67%) as a white solid.
  • Example 2 The compound obtained in Example 2 (200 mg, 0.44 mmol) was dissolved in water (1 mL), THF (1 mL) and MeOH (0.5 mL), and sodium hydroxide (71 mg, 1.76 mmol) was added thereto and stirred for 5 hours. It was. To the reaction mixture was slowly added dropwise 1 N hydrochloric acid solution to adjust pH 8, and extracted with n -butanol (3 x 5 mL). The extract was subjected to high performance liquid chromatography (water / MeOH, 100/0 ⁇ 55/45 ⁇ 20/80) to give the diastereomers 3-1 (15 mg) and 3-2 (11 mg) of the title compound as white. Obtained as a solid.
  • Example 5 The compound (355 mg, 0.74 mmol) obtained in Example 5 was dissolved in water (1 mL), THF (1 mL), and MeOH (0.5 mL), and then sodium hydroxide (118 mg, 2.95 mmol) was added thereto and stirred for 5 hours. It was. The reaction mixture was slowly added dropwise with 1 N aqueous hydrochloric acid to adjust pH 8 and extracted with n -butanol (3 x 5 mL). The extract was subjected to high performance liquid chromatography (water / MeOH, 100/0 ⁇ 55/45 ⁇ 20/80) to give diastereomers 6-1 (41 mg) and 6-2 (27 mg) of the title compound as white. Obtained as a solid.
  • Example 9 The compound obtained in Example 9 (300 mg, 0.66 mmol) was dissolved in water (1 mL), THF (1 mL) and MeOH (1 mL), and then sodium hydroxide (132 mg, 3.30 mmol) was added thereto and stirred for 5 hours. It was. The reaction mixture was slowly added dropwise with 1 N aqueous hydrochloric acid to adjust pH 8, and extracted with n -butanol (3 ⁇ 5 mL). The extract was subjected to high performance liquid chromatography (water / MeOH, 100/0 ⁇ 55/45 ⁇ 20/80) to give 31 mg of the title compound as a white solid.
  • Example 12 The compound obtained in Example 12 (380 mg, 0.86 mmol) was dissolved in water (1 mL), THF (1 mL), MeOH (1 mL), and sodium hydroxide (174 mg, 4.34 mmol) was added thereto and stirred for 5 hours. It was. The reaction mixture was slowly added dropwise with 1 N aqueous hydrochloric acid to adjust pH 8, and extracted with n -butanol (3 ⁇ 5 mL). The extract was subjected to high performance liquid chromatography (water / MeOH, 100/0 ⁇ 55/45 ⁇ 20/80) to give the title compound 13-1 (40 mg), 13-2 (46 mg) as a white solid. .
  • Antioxidants reacted with free radicals to reduce the toxicity of free radicals.
  • the absorbance is measured at 517-520 nm that the purple color of DPPH changes to yellow when it is reduced and stabilized by the sample.
  • DPPH 2,2-diphenyl-1-picrylhydrazyl
  • ascorbic acid was used as a control, and all were purchased from Sigma. It was.
  • a microplate reader manufactured by Molecular Device was used for absorbance measurement. Reagent grade was used for all other reagents.
  • the compounds of the examples show very excellent activity compared to ascorbic acid, in particular, Examples 4, 5, 6-1, 8, 10
  • the compounds of showed more antioxidant activity than wandonin when compared to the natural substance, wandonin.
  • Human umbilical vein endothelial cells (HUVEC), human skin-derived keratinocytes (HaCaT), human retinal pigment epithelial cells (ARPE-19), and human-derived retinoblastoma cells (Y79) human retinoblastoma cells were cultured in an incubator, and the primary antibodies HIF-1 and HIF-2 were from Abcam and the antibody GAPDH was from Cell Signaling Biotechnology for Western blot. Secondary antibodies were purchased from Invitrogen. X-ray films were purchased from AGFA and color reagents were purchased from iNtRON Biotechnology. All other reagents were reagent grade.
  • Human embryonic-derived epithelial cells (HUVEC), human skin-derived keratinocytes (HaCaT), human-derived retinal epithelial cells (ARPE-19), and human-derived retinoblastoma cancer cells (Y79), respectively, in a culture dish. Aliquots were incubated overnight in an incubator maintained at 37 ° C. And the Example 6-2 compound was processed to the final concentration of 20 ⁇ M. Negative control was treated with dimethyl sulfoxide (DMSO), and positive control was treated with 20 ⁇ M of Example 6-2 compound and 10 ⁇ M of protease inhibitor MG-132 (MG-132) together and the cells were treated with 1%. The cells were incubated for 6 hours in a hypoxia chamber supplied with oxygen.
  • DMSO dimethyl sulfoxide
  • the expression level of the protein is measured by exposing to an X-ray film.
  • HIF-1 human embryonic-derived epithelial cells
  • HaCaT human skin-derived keratinocytes
  • ARPE-19 human-derived retinal epithelial cells
  • Y79 human-derived retinal carcinoma cells
  • Example 6-2 Inhibition of HIF-1 expression when compound and proteolytic inhibitor MG-132 are treated simultaneously did not. Expression of HIF-2 was always expressed constantly in both cells regardless of oxygen concentration, and Example 6-2 compound had no effect on the expression of HIF-2. Therefore, the action of the compound of Example 6-2 on the expression of HIF-1 can be assumed to act on the proteolytic agent, inhibit HIF-1 protein synthesis, or both.
  • Human umbilical vein endothelial cells (HUVEC) and human retinal pigment epithelial cells (ARPE-19) were cultured in an incubator, respectively, and the primary antibody HIF-1 for western blot.
  • HIF-2 were purchased from Abcam, antibody GAPDH from Cell Signaling Biotechnology, and secondary antibodies from Invitrogen.
  • X-ray film was purchased from AGFA, color reagent was purchased from iNtRON Biotechnology, and all other reagents were reagent grade.
  • Human embryonic-derived epithelial cells (HUVEC) and human-derived retinal epithelial cells (ARPE-19) were each dispensed in a culture dish and cultured overnight in an incubator maintained at 37 ° C. And the compound of Example 6-2 and Wandonin (wondonin) was treated for each concentration. The negative control group was treated with dimethyl sulfoxide (DMSO) and the cells were incubated for 6 hours in a hypoxia chamber supplied with 1% oxygen.
  • DMSO dimethyl sulfoxide
  • HIF-1 a protein with increased expression in hypoxic states, was markedly increased in both human embryonic-derived epithelial cells (HUVEC) and human-derived retinal epithelial cells (ARPE-19) compared to normal oxygen supply conditions.
  • HIF-1 human embryonic-derived epithelial cells
  • ARPE-19 human-derived retinal epithelial cells
  • Example 6-2 showed excellent inhibitory effect at 10 ⁇ M and 20 ⁇ M when compared to the expression inhibitory effect of HIF-1, while wdonin showed about 50% inhibition at 50 ⁇ M. Seemed. In contrast, both compounds did not significantly affect the expression of HIF-2. Accordingly, the compound of Example 6-2 showed relatively superior activity to that of Wandonin through the inhibition of HIF-1 expression of the compound of Example 6-2 and wondonin.
  • Human umbilical vein endothelial cells (HUVEC) were cultured in an incubator, and primers were used for QIAgen for real time polymerase chain reaction.
  • the SyBr Green mixture was purchased from Kapa Biosystems. Real-time gene amplification reactions were performed using a Corbett Research instrument.
  • Human embryonic-derived epithelial cells were dispensed into a culture dish and incubated overnight in an incubator maintained at 37 ° C. And the compound of Example 6-2 was processed to a final concentration of 20 ⁇ M. Negative control was treated with dimethyl sulfoxide (DMSO), and positive control was treated with 20 ⁇ M of Example 6-2 compound and 10 ⁇ M of protease inhibitor MG-132 (MG-132) together and the cells were treated with 1%. The cells were incubated for 6 hours in a hypoxia chamber supplied with oxygen. Cells were collected and total RNA was extracted, followed by reverse transcription polymerase chain reaction (RT-PCR) to synthesize complementary DNA (cDNA). 9 ⁇ L of complementary DNA diluted 100-fold with distilled water, 1 ⁇ L of primer (primer) and 10 ⁇ L of a mixture of SyBr Green were mixed and subjected to real-time gene amplification reaction.
  • DMSO dimethyl sulfoxide
  • MG-132 protease inhibitor
  • Example 6-2 The expression level of the gene was confirmed by comparison with glyceraldehyde 3-phosphate dehydrogenase (FIG. 3).
  • FOG. 3 glyceraldehyde 3-phosphate dehydrogenase
  • VEGF vascular endothelial growth factors
  • MMP matrix metalloproteinases
  • MMP-9 matrix metalloproteinases
  • the wandonin derivative according to the present invention has excellent antioxidant activity.
  • the compound of Example 6-2 which is one of the wandonin derivatives, is significantly superior to HIF-1 in suppressing the expression of HIF-1 in cells that induce hypoxia compared to wondonin and expressing HIF-1.
  • the pharmacological action of the wandonin derivatives according to the present invention was used to confirm its potential as a therapeutic agent for diseases related to angiogenesis and inflammation.
  • the imidazole alkaloid derivative according to the present invention has an antioxidant effect and inhibits the activity of HIF-1, thereby exerting an excellent effect on inhibiting angiogenesis, and thus is useful for treating diseases related to angiogenesis inhibition. Can be used.

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Abstract

La présente invention concerne des dérivés d'alcaloïdes à base d'imidazole représentés par la formule (1) dans la description, des sels, des hydrates, des solvates, des isomères et des promédicaments de qualité pharmaceutique de ceux-ci et un procédé de préparation de ceux-ci, ainsi qu'une composition pharmaceutique les contenant qui présente des effets d'inhibition de l'angiogenèse et des effets antioxydants. Dans la formule, L, M, m, X, Y, R1 et R2 sont tels que définis dans la description.
PCT/KR2012/003103 2011-04-29 2012-04-23 Dérivés d'alcaloïdes à base d'imidazole ayant des effets d'inhibition de l'angiogenèse et antioxydants et leur procédé de préparation Ceased WO2012148140A2 (fr)

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KR1020110041031A KR20120122705A (ko) 2011-04-29 2011-04-29 혈관 신생 억제 및 항산화 효과를 가지는 이미다졸계 알칼로이드 유도체 및 이의 제조방법
KR10-2011-0041031 2011-04-29

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108623524A (zh) * 2018-04-17 2018-10-09 安徽农业大学 咪唑二聚体生物碱及其制备方法和应用
US11572360B2 (en) 2018-08-16 2023-02-07 Innate Tumor Immunity, Inc. Substituted 4-amino-1H-imidazo[4,5-c]quinoline compounds and improved methods for their preparation

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019022444A1 (fr) 2017-07-25 2019-01-31 서울대학교산학협력단 Dérivé d'alcaloïde ayant un effet inhibiteur de l'angiogenèse, et composition pharmaceutique le contenant
KR102823891B1 (ko) 2020-01-14 2025-06-20 서울대학교산학협력단 혈관생성 저해 효과를 가지는 n-페닐벤조티아졸-2-아민 화합물 및 그를 포함하는 약제학적 조성물

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KR100404580B1 (ko) * 2000-04-20 2003-11-05 한국해양연구원 원도닌 ａ 및 그의 제조방법

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108623524A (zh) * 2018-04-17 2018-10-09 安徽农业大学 咪唑二聚体生物碱及其制备方法和应用
CN108623524B (zh) * 2018-04-17 2021-02-26 安徽农业大学 咪唑二聚体生物碱及其制备方法和应用
US11572360B2 (en) 2018-08-16 2023-02-07 Innate Tumor Immunity, Inc. Substituted 4-amino-1H-imidazo[4,5-c]quinoline compounds and improved methods for their preparation
US11827597B2 (en) 2018-08-16 2023-11-28 Innate Tumor Immunity, Inc. Substituted 4-amino-1H-imidazo[4,5-c]quinoline compounds and improved methods for their preparation

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