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US20190290617A1 - Novel use of sesquiterpene derivative - Google Patents

Novel use of sesquiterpene derivative Download PDF

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US20190290617A1
US20190290617A1 US16/301,583 US201616301583A US2019290617A1 US 20190290617 A1 US20190290617 A1 US 20190290617A1 US 201616301583 A US201616301583 A US 201616301583A US 2019290617 A1 US2019290617 A1 US 2019290617A1
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bond
methyl
compound
preparation example
trimethyl
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Sangtaek OH
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Kookmin University
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Kookmin University
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    • 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
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/136—Amines having aromatic rings, e.g. ketamine, nortriptyline having the amino group directly attached to the aromatic ring, e.g. benzeneamine
    • 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
    • A61K31/145—Amines having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2)
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health

Definitions

  • the present disclosure relates to a novel use of a sesquiterpene derivative, more particularly to a composition for preventing, improving or treating macular degeneration or macular edema caused by vascular leakage in the eye, the composition containing a sesquiterpene derivative compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Macular edema refers to the swelling of the macula lutea.
  • the edema is caused by fluid leaking from the retinal blood vessel. Blood is leaked from weak blood vessel walls and flown into the macula lutea packed with retinal cones which sense color and are responsible for vision during the day. Then, images are blurred at the center or right side of the central region. The vision worsens gradually over several months. All age-related macular degeneration (AMD) is associated with macular edema.
  • AMD age-related macular degeneration
  • Vascular leakage in the eye occurs due to various causes. For example, continued increase in blood pressure in in hypertensive patients causes breakdown of the blood-retinal barrier and the damage to the blood-retinal barrier causes retinal edema due to vascular leakage.
  • the macula lutea is often damaged by macula tumentia following the removal of the eye lens for treatment of cataract.
  • Laser photocoagulation alleviates macula tumentia by blocking the blood vessels where fluid leakage occurs.
  • care should be taken to avoid the fovea when irradiating laser because it is extremely vulnerable. If the fovea is damaged during the operation, the central vision may be impaired.
  • more than one laser treatments are often necessary to remove the swelling.
  • Vitrectomy is employed when the laser treatment is ineffective, but this method is often associated with the high risk of tissue invasion which causes postoperative complications.
  • the intravitreal administration of steroids may cause ocular hypertension, steroid-induced glaucoma and posterior subcapsular cataract. In addition, the intravitreal administration of steroids often cause postoperative complications.
  • the inventors of the present disclosure have researched to develop a medication exhibiting an excellent therapeutic effect for macular edema or macular degeneration related thereto, which reduces the inconvenience of administration and can be administered for a long time. In doing so, they have identified that a compound represented by Chemical Formula 1 exhibits therapeutic effect in a macular edema or macular degeneration animal model by effectively preventing vascular leakage in the eye and that the compound is targeted to the eye even when it is administered orally.
  • the present disclosure is directed to providing a pharmaceutical composition for preventing or treating macular degeneration or macular edema caused by vascular leakage in the eye.
  • the present disclosure is also directed to providing a food composition for preventing or improving macular degeneration or macular edema caused by vascular leakage in the eye.
  • the present disclosure provides a pharmaceutical composition for preventing or treating macular degeneration or macular edema, which contains a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 is H or CH 3 ,
  • R 3 is a functional group selected from a group consisting of R 3a through R 3d ,
  • each of R 4 and R 7 is OH or OCH 3 and R 5 , R 6 and R 8 are H; or
  • R 5 is COOCH 3 , R 7 is H or OH, R 8 is OH and R 4 and R are H,
  • R 9 is a functional group selected from a group consisting of H, NH 2 , C 1 -C 8 alkoxy and R 9a through R 9j and R 10 is H or OH,
  • each of R 11 and R 12 is OH or OAc and R 13 is H; or
  • each of R 11 and R 12 is OH or OCH 3 and R 13 is CH 3 and
  • R 14 is OCH 3 and R 15 and R 16 are CH 3 .
  • the present disclosure also provides a pharmaceutical composition for inhibiting vascular leakage in the eye, which contains the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient
  • the present disclosure also provides a food composition for preventing or improving macular degeneration or macular edema, which contains the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FIG. 1 shows a result of investigating the inhibitory effect of a compound of the present disclosure (Preparation Example 30 or Preparation Example 31) on 3-catenin expression in HEK293 cells, in which the Wnt/ ⁇ -catenin pathway is activated by treating with Wnt-3a CM, by western blot.
  • FIG. 2 shows a result of investigating the inhibitory effect of a compound of the present disclosure (Preparation Example 32) on 3-catenin expression in HEK293 cells, in which the Wnt/ ⁇ -catenin pathway is activated by treating with Wnt-3a CM, by western blot.
  • FIG. 3 shows a result of investigating the inhibitory effect of a compound of the present disclosure (Preparation Example 33 or Preparation Example 34) on 3-catenin expression in human retinal epithelial cells, in which the Wnt/3-catenin pathway is activated by treating with Wnt-3a CM, by western blot.
  • FIG. 4 shows a result of investigating the inhibitory effect of intravitreal administration of a compound of the present disclosure (Preparation Example 33) on vascular leakage in a macular edema mouse model by fluorescein angiography and optical coherence tomography (A and B are images for a control group (compound-untreated) obtained after DMSO injection and C and D are images for a test group (Preparation Example 33) obtained after injection.
  • the arrows indicate blood vessels).
  • FIG. 5 shows a result of investigating the inhibitory effect of intraperitoneal injection of a compound of the present disclosure (Preparation Example 33) on vascular leakage in a macular edema mouse model by optical coherence tomography (A: vehicle-administered group, B: Preparation Example 33 compound 1 mg/kg administered group).
  • FIG. 6 shows a result of orally administering a compound of the present disclosure (Preparation Example 33) to an ICR mouse and measuring distribution of the compound in target tissues (particularly, eye).
  • the inventors of the present disclosure have researched to develop a medication exhibiting an excellent therapeutic effect for macular edema or macular degeneration related thereto, which reduces the inconvenience of administration and can be administered for a long time. In doing so, they have identified that a compound represented by Chemical Formula 1 exhibits therapeutic effect for macular edema or macular degeneration diseases by effectively preventing vascular leakage in the eye, particularly in the retina.
  • the present disclosure relates to a pharmaceutical composition for preventing or treating macular degeneration or macular edema, which contains a compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • R 1 is H or CH 3 ,
  • R 3 is a functional group selected from a group consisting of R 3a through R 3d ,
  • each of R 4 and R 7 is OH or OCH 3 and R 5 , R 6 and R 8 are H; or
  • R 5 is COOCH 3 , R 7 is H or OH, R 8 is OH and R 4 and R 6 are H,
  • R 9 is a functional group selected from a group consisting of H, NH 2 , C 1 -C 8 alkoxy and R 9a through R 9j and R 10 is H or OH,
  • each of R 11 and R 12 is OH or OAc and R 13 is H; or
  • each of R 11 and R 12 is OH or OCH 3 and R 13 is CH 3 and
  • R 14 is OCH 3 and R 15 and R 16 are CH 3 .
  • the term alkoxy group refers to an alkyl group bonded to oxygen (O-alkyl group).
  • the alkoxy group may be a C 1 -C 8 alkoxy group selected from a group consisting of a methoxy group (C 1 ), an ethoxy group (C 2 ), a propoxy group (C 3 ), a butoxy group (C 4 ), a pentyloxy group (C 5 ), a hexyloxy group (C 6 ), a heptyloxy group (C 7 ) and an octyloxy group (C 8 ), although not being limited thereto.
  • the alkoxy group of the present disclosure may be a methoxy group or an ethoxy group.
  • the compound of the present disclosure of Chemical Formula 1 may be the compounds described in [Table 1], although not being limited thereto.
  • the sesquiterpene derivative compound of the present disclosure may be one wherein, in Chemical Formula 1, if the bond between C-3 and C-4 and the bond between C-5 and C-6 are single bonds, R 2b is nonexistent, R 2a is CH 2 and R 3 is a functional group selected from a group consisting of R 3b through R 3d .
  • R 9 may be selected from a group consisting of ethoxy, methoxy and R 9a .
  • R 11 may be OH
  • R 12 may be OCH 3
  • R 13 may be CH 3 .
  • R 14 may be OCH 3 and R 15 and R 16 may be CH 3 .
  • the compound of Chemical Formula 1 of the present disclosure may be a compound selected from a group consisting of:
  • the compound of Chemical Formula 1 of the present disclosure may be extracted from sponge.
  • the compound of Chemical Formula 1 for preventing or treating macular degeneration or macular edema caused by vascular leakage in the eye may be obtained by a method including a step of extracting one or more sponge selected from a group consisting of Rhopaloeides sp., Spongia sp., Smenospongia sp., Hippospongia sp., Dactylospongia sp., Verongula sp., Dysidea sp., sponge SS-1047, sponge SS-265 and sponge SS-1208 by adding a C 1 -C 6 organic solvent.
  • the C 1 -C 6 organic solvent may be selected from a group consisting of a C 1 -C 6 alcohol (methanol, ethanol, propanol, butanol, pentanol, hexanol), acetone, an ether, benzene, chloroform, ethyl acetate, methylene chloride, hexane, cyclohexane, acetonitrile, dichloromethane and petroleum ether.
  • a C 1 -C 6 alcohol methanol, ethanol, propanol, butanol, pentanol, hexanol
  • acetone an ether
  • benzene chloroform
  • ethyl acetate methylene chloride
  • hexane hexane
  • cyclohexane acetonitrile
  • dichloromethane and petroleum ether.
  • the compound of the present disclosure of Chemical Formula 1 may be obtained by a method including: a step of extracting sponge by adding water, a C 1 -C 4 alcohol or a mixture thereof as a solvent, thereby preparing a sponge extract; and a step of fractionating the extract by adding a second solvent and separating the same through chromatography.
  • any one known to those skilled in the art can be used without limitation, including silica gel column chromatography, LH-20 column chromatography, ion-exchange chromatography, medium pressure liquid chromatography, thin-layer chromatography (TLC), silica gel vacuum liquid chromatography, high-performance liquid chromatography, etc.
  • the C 1 -C 4 alcohol used to prepare the sponge extract may be selected from a group consisting of methanol, ethanol, propanol, isopropanol, butanol and isobutanol.
  • a C 1 -C 4 alcohol n-hexane, methylene chloride, acetone, chloroform, dichloromethane, ethyl acetate, acetonitrile or a mixture thereof may be used.
  • the compound of the present disclosure of Chemical Formula 1 includes a pharmaceutically acceptable salt thereof.
  • pharmaceutically acceptable means being physiologically acceptable and not causing allergic reactions such as gastroenteric trouble, dizziness, etc. or similar reactions when administered to human.
  • the pharmaceutically acceptable salt includes an acid addition salt with an inorganic acid or an organic acid.
  • an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • an inorganic acid or an organic acid may be used.
  • the inorganic acid hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, etc. may be used.
  • organic acid citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholinoethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, aspartic acid, etc.
  • organic acid citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid,
  • the compound of the present disclosure of Chemical Formula 1 inhibits ⁇ -catenin in vitro, suggesting that it can inhibit vascular leakage by inhibiting the Wnt/0-catenin mechanism.
  • the present disclosure compound exhibits therapeutic effect by inhibiting vascular leakage in a macular edema animal model in vivo.
  • the present disclosure relates to a pharmaceutical composition for inhibiting vascular leakage in the eye, which contains the compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • vascular leakage refers to the leakage of body fluid or blood plasma due to damage to the integrity of blood vessels.
  • the vascular leakage in the eye constitutes the major pathological conditions of various eye diseases.
  • vascular leakage in the eye refers to vascular leakage in various tissues (choroid, retina, etc.) constituting the eye. Specifically, it may refer to vascular leakage in the retina, although not being limited thereto.
  • the pharmaceutical composition of the present disclosure has preventive or therapeutic effect for a disease caused by vascular leakage in the eye.
  • the disease caused by vascular leakage in the eye may be any one known in the art. For example, it include retinal degeneration, macular degeneration, retinal edema and macular edema.
  • the disease caused by vascular leakage in the eye may be macular degeneration or macular edema.
  • the pharmaceutical composition according to the present disclosure may contain only the sesquiterpene derivative compound of Chemical Formula 1 or a pharmaceutically acceptable salt thereof or may further contain one or more pharmaceutically acceptable carrier, excipient or diluent.
  • the pharmaceutically acceptable carrier may further contain, for example, a carrier for oral administration or a carrier for parenteral administration.
  • the carrier for oral administration may include lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc.
  • the carrier for parenteral administration may include water, suitable oils, physiological saline, water-soluble glucose, glycol, etc.
  • the pharmaceutical composition of the present disclosure may further contain a stabilizer and a preservative.
  • a suitable stabilizer includes sodium bisulfite, sodium sulfite or an antioxidant such as ascorbic acid.
  • a suitable preservative includes benzalkonium chloride, methyl- or propylparaben and chlorobutanol.
  • the pharmaceutical composition of the present disclosure may further contain a lubricant, a humectant, a sweetener, a flavorant, an emulsifier, a suspending agent, etc.
  • a lubricant for other pharmaceutically acceptable carriers, reference can be made to the literature (Remington's Pharmaceutical Sciences, 19th ed., Mack Publishing Company, Easton, Pa., 1995).
  • composition of the present disclosure may be administered to mammals including human by any means.
  • it may be administered orally or parenterally.
  • the parenteral administration method may include intravenous, intramuscular, intraarterial, intramedullary, intradural, intracardiac, intraocular, intravitreal, transdermal, subcutaneous, intraabdominal, intranasal, intraintestinal, topical, sublingual or intrarectal administration, although not being limited thereto.
  • the pharmaceutical composition of the present disclosure may be prepared into a formulation for oral administration or parenteral administration depending on the administration routes.
  • the composition of the present disclosure may be formulated into a powder, a granule, a tablet, a pill, a sugar-coated tablet, a capsule, a solution, a gel, a syrup, a slurry, a suspension, etc. using the method known in the art.
  • a tablet or a sugar-coated tablet may be prepared by mixing the active ingredient with a solid excipient, pulverizing the mixture, adding a suitable adjuvant and then processing into a granule mixture.
  • the suitable excipient may include sugars including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, etc., a starches including corn starch, wheat starch, rice starch, potato starch, etc., celluloses including cellulose, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropylmethyl cellulose, etc. and fillers such as gelatin, polyvinylpyrrolidone, etc. If necessary, crosslinked polyvinylpyrrolidone, agar, alginic acid, sodium alginate, etc. may be added as a disintegrant.
  • the pharmaceutical composition of the present disclosure may further contain an antiagglomerant, a lubricant, a humectant, a flavor, an emulsifier, an antiseptic, etc.
  • the composition may be formulated into an injection, an eye drop, an ointment, a cream, a lotion, an oil, a gel, an aerosol or a nasal inhaler using the method known in the art.
  • formulations are described in the literature generally known in the field of pharmaceutical chemistry (Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pa. 18042, Chapter 87: Blaug, Seymour).
  • the pharmaceutical composition of the present disclosure may be prepared into a formulation selected from a group consisting of an oral medication, an injection, an eye drop and an ointment.
  • the total effective amount of the sesquiterpene derivative compound of the present disclosure or a pharmaceutically acceptable salt thereof may be administered to a patient with a single dose or a multiple dose according to the fractionated treatment protocol for long-term administration.
  • the content of the active ingredient of the pharmaceutical composition of the present disclosure may vary depending on the severity of a disease.
  • the effective administration dosage of the compound or a pharmaceutically acceptable salt thereof is determined in consideration of various factors including the route and number of administration of the pharmaceutical composition, the age, body weight, health condition and sex of a patient, the severity of a disease, diet, excretion rate, etc.
  • the pharmaceutical composition according to the present disclosure is not specially limited in formulation, administration route and administration method as long as the effect of the present disclosure can be achieved.
  • the present disclosure relates to a food composition for preventing or improving macular degeneration or macular edema, which contains the compound represented by Chemical Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the food composition of the present disclosure includes all forms such as a functional food, a nutritional supplement, a health food, a food additive, a feed, etc. and is provided for animals including human or livestock.
  • the food composition may be prepared into various forms according to the method known in the art.
  • the health food may be prepared by preparing the sesquiterpene derivative of the present disclosure or a sponge extract containing the sesquiterpene into tea, juice or a drink for drinking or into a granule, a capsule or a powder.
  • a composition may be prepared by mixing the sesquiterpene derivative of the present disclosure or a sponge extract containing the sesquiterpene with an active ingredient known to be effective in improving and preventing macular edema or macular degeneration.
  • the functional food be prepared by adding the sesquiterpene derivative of the present disclosure or a sponge extract containing the sesquiterpene to beverages (including alcoholic beverage, fruit or processed fruit (e.g., canned fruit, bottling, jam, marmalade, etc.), fish, meat or processed foodstuffs thereof (e.g., ham, sausage corn beef, etc.), bread or noodles (e.g., udon, buckwheat noodle, instant noodle, spaghetti, macaroni, etc.), fruit juice, drinks, cookies, taffy, dairy products (e.g., butter, cheese, etc.), vegetable fats and oils, margarine, vegetable proteins, retort foods, frozen foods, condiments (e.g., soybean paste, soy sauce, etc.), etc.
  • beverages including alcoholic beverage, fruit or processed fruit (e.g., canned fruit, bottling, jam, marmalade, etc.), fish, meat or processed foodstuffs thereof (e.g., ham, sausage corn
  • sesquiterpene derivative of the present disclosure or a sponge extract containing the sesquiterpene may be prepared into a powder or a concentrate for use as a food additive.
  • the obtained compound of Preparation Example 1 had the following physicochemical properties and was identified as ‘methyl 3-[[(1R,2S,4aR,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4,5-dihydroxybenzoate’.
  • the obtained compound of Preparation Example 2 had the following physicochemical properties and was identified as ‘3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2,5-dihydroxycyclohexa-2,5-diene-1,4-dione’.
  • the obtained compound of Preparation Example 3 had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(3-methylbutylamino)cyclohexa-3,5-diene-1,2-dione’.
  • a compound of Preparation Example 4 was prepared in the same manner as in Preparation Example 3.
  • the obtained compound (Preparation Example 4) had the following physicochemical properties and was identified as ‘3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-methylpropylamino)cyclohexa-3,5-diene-1,2-dione’.
  • MeOH and DCM crude extracts of Hippospongia sp. were combined and fractionated with MeOH, DCM, hexane and BuOH. Among them, the hexane, DCM and MeOH fractions were subjected to flash column chromatography and semi-preparative RP-HPLC to obtain a compound of Preparation Example 5.
  • the obtained compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-5-amino-4-hydroxycyclohexa-3,5-diene-1,2-dione’.
  • the prepared Preparation Example 6 compound had the following physicochemical properties and was identified as ‘2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]acetic acid’.
  • a compound of Preparation Example 7 was prepared in the same manner as in Preparation Example 6.
  • the prepared compound (Preparation Example 7) had the following physicochemical properties and was identified as ‘3-[[5-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]propanoic acid’.
  • a compound of Preparation Example 8 was prepared in the same manner as in Preparation Example 6.
  • the prepared compound (Preparation Example 8) had the following physicochemical properties and was identified as ‘7-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-1,3-benzoxazole-5,6-diol’.
  • the obtained compound of Preparation Example 9 (2.3 mg, 0.007%) had the following physicochemical properties and was identified as ‘[7-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-6-acetyloxy-1,3-benzoxazol-5-yl] acetate’.
  • a sponge (Spongiidae SS-1047, 0.30 kg, wet weight) was obtained as described in the literature ‘Yohei Takahashi et al., 2010’ and extracted. Briefly, EtOAc-soluble substances (1.2 g) were fractionated using a silica gel column (n-hexane/EtOAc) and a fraction 1, a fraction 2 and a fraction 3 of low polarity and a polar fraction 4 were prepared.
  • the fraction 3 was fractionated and purified by C 18 column (MeOH/H 2 O) and C 18 HPLC (Luna 5u Phenyl-Hexyl, 250 ⁇ 10 mm; eluent, MeOH/H 2 O/CF 3 CO 2 H, 85:15:0.05; flow rate, 2.5 mL/min; UV detection at 320 nm) to obtain compounds of Preparation Example 10 and Preparation Example 11.
  • the obtained Preparation Example 10 compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione’.
  • a compound of Preparation Example 11 was prepared in the same manner as in Preparation Example 10.
  • the obtained compound (Preparation Example 11) had the following physicochemical properties and was identified as ‘2-hydroxy-5-methoxy-3-[[(1R,2S)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen-1-yl]methyl]cyclohexa-2,5-diene-1,4-dione’.
  • the fraction 1 obtained in Preparation Example 10 was refractionated by Cis column (MeOH/H 2 O) and C 18 HPLC (Wakosil-II 5C18AR, Wako Pure Chemical Industries, Ltd., 250 ⁇ 10 mm; eluent, MeCN/H 2 O/CF 3 CO 2 H, 90:10:0.05; flow rate, 2.0 mL/min; UV detection at 300 nm) to obtain a compound of Preparation Example 11 (2.8 mg, 0.00093% wet weight) and a compound of Preparation Example 12 (24.7 mg, 0.0082%).
  • the obtained Preparation Example 12 compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,8aS)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione’.
  • a compound of Preparation Example 13 was prepared in the same manner as in Preparation Example 12.
  • the obtained compound (Preparation Example 13) had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione’.
  • the fraction 2 obtained in Preparation Example 10 was subjected to C 18 column (MeOH/H 2 O/CF 3 CO 2 H) and C 18 HPLC (Luna 5u Phenyl-Hexyl, Phenomenex, 250 ⁇ 10 mm; eluent, MeCN/H 2 O/CF 3 CO 2 H, 80:20:0.05; flow rate, 2.0 mL/min; UV detection at 300 nm) to obtain a compound of Preparation Example 14 (0.9 mg, 0.00030%), a fraction y and a fraction 6.
  • the obtained compound of Preparation Example 14 had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(2-methylpropylamino)cyclohexa-3,5-diene-1,2-dione’.
  • the fraction ⁇ obtained in Preparation Example 14 was purified by C 18 HPLC (Luna 5u C18(2), Phenomenex, 250 ⁇ 10 mm; MeOH/H 2 O/Et 2 NH, 70:30:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm) to obtain a compound of Preparation Example 15 (1.4 mg, 0.00047%) and a compound of Preparation Example 16 (4.0 mg, 0.0013%).
  • the compound of Preparation Example 15 had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-[[(2S)-2-methylbutyl]amino]cyclohexa-3,5-diene-1,2-dione’.
  • a compound of Preparation Example 16 was prepared in the same manner as in Preparation Example 15. It had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(3-methylbutylamino)cyclohexa-3,5-diene-1,2-dione’.
  • the fraction 6 obtained in Preparation Example 14 was refractionated by Cis HPLC (Luna 5u Phenyl-Hexyl, 250 ⁇ 10 mm; MeOH/H 2 O/Et 2 NH, 65:35:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm) to obtain a compound of Preparation Example 17 (0.7 mg, 0.00023%) and a compound of Preparation Example 18 (1.6 mg, 0.00053%).
  • the obtained Preparation Example 17 compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,8aS)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-[[(2S)-2-methylbutyl]amino]cyclohexa-3,5-diene-1,2-dione’.
  • a compound of Preparation Example 18 was prepared in the same manner as in Preparation Example 17. It had the following physicochemical properties and was identified as ‘3-[[(1R,2S,8aS)-1,2,5,5-tetramethyl-2,3,6,7,8,8a-hexahydronaphthalen-1-yl]methyl]-4-hydroxy-5-(3-methylbutylamino)cyclohexa-3,5-diene-1,2-dione’ Compound
  • a sponge (Spongiidae SS-265) was obtained as described in the literature ‘Yohei Takahashi et al., 2010’ and extracted. Briefly, an extract was prepared by adding MeOH (4.3 and 3.2 L) to sponge SS-265 (1.4 kg, wet weight). The MeOH extract (68.4 g) was fractionated with CHCl 3 and H 2 O.
  • the CHCl 3 -soluble substances (2.3 g) were subjected to silica gel column (n-hexane/EtOAc), C 18 column (MeOH/H 2 O), silica gel column (n-hexane/acetone) and C 18 HPLC (Wakosil-II 5C18AR, 250 ⁇ 10 mm; eluent, MeCN/H 2 O/CF 3 CO 2 H, 90:10:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm and Luna 5u C18(2), 250 ⁇ 10 mm; MeOH/H 2 O/Et 2 NH, 70:30:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm) repeatedly to obtain a compound of Preparation Example 19 (1.8 mg, 0.00013%).
  • the obtained Preparation Example 19 compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-[[(2S)-2-methylbutyl]amino]cyclohexa-3,5-diene-1,2-dione’.
  • a sponge (Spongiidae SS-1208) was obtained as described in the literature ‘Yohei Takahashi et al., 2010’ and extracted. Briefly, an extract was prepared by adding MeOH (3 ⁇ 0.8 L) and MeOH/toluene (3:1, 1 ⁇ 0.8 L) to sponge SS-1208 (0.4 kg, wet weight). The extract mixture (15.9 g) was fractionated with CHCl 3 and H 2 O (3 ⁇ 500 mL).
  • the CHCl 3 -soluble fraction (2.7 g) was subjected to silica gel column (n-hexane/EtOAc and CHCl 3 /MeOH), C 18 column (MeOH/H 2 O/CF 3 CO 2 H) and C 18 HPLC (Luna 5u Phenyl-Hexyl, 250 ⁇ 10 mm; eluent, MeCN/H 2 O/CF 3 CO 2 H, 70:30:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm and Wakosil-II 5C18AR, 250 ⁇ 10 mm; eluent, MeCN/H 2 O/CF 3 CO 2 H, 75:25:0.1; flow rate, 2.0 mL/min; UV detection at 300 nm) repeatedly to obtain a compound of Preparation Example 20 (0.8 mg, 0.00020%).
  • the obtained Preparation Example 20 compound had the following physicochemical properties and was identified as ‘2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]ethanesulfonic acid’.
  • the obtained Preparation Example 21 compound had the following physicochemical properties and was identified as ‘methyl 3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxybenzoate’.
  • a compound of Preparation Example 22 was prepared in the same manner as in Preparation Example 21. It had the following physicochemical properties and was identified as ‘methyl 3-[[(1 S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4,5-dihydroxybenzoate’.
  • a heated ylide solution was added dropwise to a solution of 212 mg (0.62 mmol) of the ketone ( ⁇ )-(1R,4aS,8aS)-1 ⁇ ,2 ⁇ , 4a ⁇ -trimethyl-1 ⁇ [(2′,5′-dimethoyphenyl)methyl]-1,2,3,4,4a,5,6,7,8,8a ⁇ -decahydronaphthalen-5-one dissolved in 3 mL of benzene. After heat-treating further for 22 hours, the reaction mixture was cooled and diluted by stirring fast while sequentially adding 10 mL of ether and 3 mL of H 2 O.
  • the obtained Preparation Example 23 compound had the following physicochemical properties and was identified as ‘( ⁇ )-(1R,4aS,8aS)-1 ⁇ ,2 ⁇ ,4 ⁇ ,-trimethyl-1 ⁇ [(2′,5′-dimethoxyphenyl)methyl]-5-exo-methylene-(3H)-1, 4,4a,5,6,7,8,8a ⁇ -octahydronaphthalene’.
  • the obtained Preparation Example 28 compound had the following physicochemical properties and was identified as ‘(2S)-2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]-3-hydroxypropanoic acid’.
  • the obtained Preparation Example 29 compound had the following physicochemical properties and was identified as ‘(2S)-2-[[5-[[(1R,2S,4aS,8aS)-1,2,4a,5-tetramethyl-2,3,4,7,8,8a-hexahydronaphthalen-1-yl]methyl]-6-hydroxy-3,4-dioxocyclohexa-1,5-dien-1-yl]amino]-3-hydroxybutanoic acid’.
  • the fraction 10 (39.3 g) was fractionated further with hexane-acetone mixtures (95:5, 90:10, 85:15, 80:20), MeOH (100%) and MeOH—H 2 O (50:50) using a silica gel VLC (12 (H) ⁇ 17.5 (D) cm) into 9 fractions (Fr. 10-1 to 10-9).
  • the fraction 10-7 (3.7 g) was subjected to C 18 MPLC (15.5 ⁇ 4 cm) under an isocratic condition of MeOH—H 2 O (85:15) to prepare 6 subfractions (Fr. 10-7-1 to 10-7-6).
  • the fraction 10-7-3 (115.8 mg) was subjected to C 18 HPLC (250 ⁇ 21.20 mm, 10 ⁇ m) chromatography using MeOH—H 2 O (83:17) to prepare 3 fractions (Fr. 10-7-3-1 to 10-7-3-3).
  • the fraction 10-7-3-2 (12.4 mg) was subjected to C 18 HPLC (250 ⁇ 4.60 mm and 150 ⁇ 4.60 mm, 5 ⁇ m, connected in line) using MeOH—H 2 O (75:25) to obtain a compound of Preparation Example 30 and an epimer mixture thereof.
  • the obtained substance had the following physicochemical properties and was identified as ‘18-methoxy-22,22-dimethyl-16-[ ⁇ (5R,8S,9R,10S)-5,8,9-trimethyl-4-methylenedecahydronaphthalen-9-yl ⁇ methyl]benzo[d]-oxazol-17(2H)-one’.
  • the obtained compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-4-hydroxy-5-(2-phenylethylamino)cyclohexa-3,5-diene-1,2-dione’.
  • the compound was identified by HPLC (Agilent Technologies 1260 Infinity) using a UV spectrophotometer (203 nm) and a Bluespher AB2 (150 ⁇ 2 mm) column.
  • HPLC was conducted at a flow rate of 1 mL/min and 40° C. using water-methanol (78:22) as a mobile phase and the peaks of the compound were detected at 114 minutes.
  • the obtained compound had the following physicochemical properties and was identified as ‘3-[[(1R,2S,4aS,8aS)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-2-hydroxy-5-methoxycyclohexa-2,5-diene-1,4-dione’.
  • the obtained final compound had the following physicochemical properties and was identified as ‘3-[[(1S,2R,4aR,8aR)-1,2,4a-trimethyl-5-methylidene-3,4,6,7,8,8a-hexahydro-2H-naphthalen-1-yl]methyl]-5-ethoxy-2-hydroxycyclohexa-2,5-diene-1,4-dione’.
  • HEK293 cells human embryonic kidney cells
  • Wnt3a-secreting L cells were obtained from the ATCC (American Type Culture Collection, USA) and were cultured in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% FBS (fetal bovine serum), 120 ⁇ g/mL penicillin and 200 ⁇ g/mL streptomycin.
  • DMEM Dulbecco's modified Eagle's medium
  • FBS fetal bovine serum
  • streptomycin fetal bovine serum
  • Wnt3a-CM Wnt3a-conditioned medium
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • the compound of Preparation Example 30 or the compound of Preparation Example 31 (10, 20 or 40 ⁇ M) for 15 hours and extracting cytoplasmic proteins from the cells
  • the amount of ⁇ -catenin regulating the CRT ( ⁇ -catenin response transcription) of the Wnt/ ⁇ -catenin pathway in the cells was investigated by western blot using a ⁇ -catenin antibody (BD Transduction Laboratories, USA) and the ECL system (Santa Cruz Biotechnology). The result is shown in FIG. 1 .
  • the cells treated with the Wnt3a-CM showed increased 3-catenin expression in the cytoplasm but the cells treated with the Preparation Example 30 compound or the Preparation Example 31 compound of the present disclosure showed decreased level of ⁇ -catenin.
  • the Wnt/1-Catenin Pathway Inhibitory Activity of the Preparation Example 32 Compound was evaluated in the same manner as in Example ⁇ 1-1>. Briefly, after treating HEK293 cells with the Wnt3a-CM or the compound of Preparation Example 32 (10 or 20 ⁇ M) for 15 hours and extracting cytoplasmic proteins from the cells, the amount of ⁇ -catenin regulating the CRT ( ⁇ -catenin response transcription) of the Wnt/ ⁇ -catenin pathway in the cells was investigated by western blot using a ⁇ -catenin antibody (BD Transduction Laboratories, USA) and the ECL system (Santa Cruz Biotechnology). The result is shown in FIG. 2 .
  • a ⁇ -catenin antibody BD Transduction Laboratories, USA
  • ECL system Santa Cruz Biotechnology
  • the cells treated with the Wnt3a-CM showed increased 3-catenin expression in the cytoplasm but the cells treated with the Preparation Example 32 compound of the present disclosure showed decreased level of ⁇ -catenin.
  • ARPE-19 cells human retinal epithelial cells
  • Wnt3a-secreting L cells were obtained from the ATCC (American Type Culture Collection, USA) and were cultured in DMEM (Dulbecco's modified Eagle's medium) supplemented with 10% FBS, 120 ⁇ g/mL penicillin and 200 ⁇ g/mL streptomycin.
  • Wnt3a-CM Wnt3a-conditioned medium
  • DMEM fetal bovine serum
  • FBS fetal bovine serum
  • the compound of Preparation Example 33 or the compound of Preparation Example 34 (3 or 6 ⁇ M) for 24 hours and extracting cytoplasmic proteins from the cells
  • the amount of ⁇ -catenin regulating the CRT ( ⁇ -catenin response transcription) of the Wnt/3-catenin pathway in the cells was investigated by western blot using a ⁇ -catenin antibody (BD Transduction Laboratories, USA) and the ECL system (Santa Cruz Biotechnology). The result is shown in FIG. 3 .
  • the cells treated with the Wnt3a-CM showed increased 3-catenin expression in the cytoplasm but the cells treated with the Preparation Example 33 compound or Preparation Example 34 compound of the present disclosure showed decreased level of ⁇ -catenin, suggesting that the compounds inhibit the Wnt/0-catenin pathway in the human retinal epithelial cells. Meanwhile, this activity was not identified in the sponge ethanol extract used to isolate the compound of Preparation Example 33 (data not shown).
  • Example 33 For the compound of Preparation Example 33 which showed good activity in Example 1, the inhibitory activity on vascular leakage, which is a cause of macular degeneration or macular edema, was investigated in a macular edema-induced mouse model.
  • Macular edema was induced in a 10-week-old C57BL/6 mouse by irradiating a laser. After anesthetizing the mouse with ketamine (70 mg/kg) and xylazine (30 mg/kg), the pupil was dilated with 1% tropicamide. Hydroxypropylmethyl cellulose was dropped onto the eye and a microscope cover glass was used as a contact lens.
  • FIG. 4 shows the images of the control group and the compound-treated group.
  • test group ( FIG. 4 , C, D) showed distinctly decreased vascular leakage, which is a cause of macular degeneration or macular edema, as compared to the control group ( FIG. 4 , A, B).
  • the compound of the present disclosure inhibited vascular leakage, which is a cause of macular degeneration or macular edema, even when it was injected intraperitoneally.
  • mice Male ICR mice (8 weeks, 30-35 g) were purchased from Samtako Co. (Osan, Korea). The test animals were acclimatized for a week under the following conditions: temperature 23 ⁇ 2° C., relative humidity 55 ⁇ 10%, illumination intensity 150-300 lux, ventilation frequency 15-20 times/h, illumination cycle 12 h (07:00-19:00). All the animal experiments were approved by the Animal Care and Use Committee of Kyungpook National University (Study No. 2016-0043).
  • mice were fasted for 12 hours before drug administration. Feed and water were supplied ad libitum.
  • blood samples were taken from the abdominal artery. 50 mL of a plasma sample obtained after centrifuging the blood sample at 13,000 rpm for 5 minutes was stored at ⁇ 80° C. until use for analysis. An eye sample taken from the mouse was homogenized with 9-fold saline to obtain a 10% cell homogenate. The obtained 50-mL aliquots were stored at ⁇ 80° C. until use for analysis.
  • the compound of the present disclosure In order to investigate the distribution of the compound of the present disclosure in the target tissue, the compound was orally administered at a dose of 10 mg/kg and the concentration of the compound in the blood plasma and eye was measured. The sampling times were determined as 0.5 hour and 2 hours based on the peak plasma concentration and the distribution phase. As seen from FIG. 6 , the compound of the present disclosure (particularly, the compound of Preparation Example 33) showed high permeability for the target tissue and was found to be highly targeted in the eye even when it was administered orally. Through this result, it was confirmed that the compound of Preparation Example 33 of the present disclosure can exhibit therapeutic effect even when it is administered via different administration routes (oral administration, intraperitoneal injection, intravenous injection, etc.) other than being administered directly into the vitreous cavity. That is to say, whereas the currently available eye disease-related therapeutic agents cause inconvenience, pain and side effects because they have to be administered directly into the vitreous cavity, it was confirmed that the compound of the present disclosure can be administered orally.
  • This experiment was conducted to determine acute (within 24 hours) toxicity and lethality when the compound of Preparation Example 33 was administered in excessive amounts in a short period of time.
  • 20 normal ICR mice were divided into a control group and a test group, with 10 mice per each.
  • the control group was administered with PEG 400:Tween 80:ethanol (8:1:1, v:v:v) only and the test group was orally administered with the compound of Preparation Example 33 dissolved in PEG 400:Tween 80:ethanol (8:1:1, v:v:v).
  • lethality was investigated 24 hours after the administration, all the mice in the control group and the mice in the test group administered with the Preparation Example 33 compound at a dose of 2 g/kg/day survived.
  • a long-term toxicity test was conducted by administering the compound of Preparation Example 33 at different doses to C57BL/6J mice (10 mice per group) for 8 weeks.
  • blood was taken from the animals of the test group to which the compound of Preparation Example 33 was administered and the control group to which only PEG 400:Tween 80:ethanol (8:1:1, v:v:v) was administered 8 weeks later and the level of GPT (glutamate-pyruvate transferase) and BUN (blood urea nitrogen) in the blood was measured using Select E (Vital Scientific NV, Netherlands).
  • 200 g of the compound of the present disclosure was mixed with 175.9 g of lactose, 180 g of potato starch and 32 g of colloidal silicate. After adding a 10% gelatin solution, the mixture was pulverized and passed through a 14-mesh sieve. A mixture obtained by drying the same and adding 160 g of potato starch, 50 g of talc and 5 g of magnesium stearate thereto was prepared into a tablet.
  • the present disclosure relates to a novel use of a sesquiterpene derivative, more particularly to a composition for preventing, improving or treating macular degeneration or macular edema caused by vascular leakage in the eye, which contains the sesquiterpene derivative compound represented by Chemical Formula 1 of the present disclosure or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the compound of the present disclosure of Chemical Formula 1 has therapeutic effect for a disease caused by vascular leakage in the eye, such as macular edema, macular degeneration, etc., by inhibiting the vascular leakage in the eye, particularly in the retina.
  • vascular leakage in the eye such as macular edema, macular degeneration, etc.
  • the intraocular disease-related treating agents available in the market should be injected directly into the vitreous cavity, thus causing pain and side effects
  • the sesquiterpene derivative compound of the present disclosure is delivered to the target tissue (eye) via different administration routes (oral, intraperitoneal, etc.) other than the intravitreal route. Accordingly, the sesquiterpene derivative compound provides excellent therapeutic effect without being restricted by the administration routes. Accordingly, it is highly industrially applicable.
  • the compound of the present disclosure of Chemical Formula 1 has therapeutic effect for a disease caused by vascular leakage in the eye, such as macular edema, macular degeneration, etc., by inhibiting the vascular leakage in the eye, particularly in the retina.
  • vascular leakage in the eye such as macular edema, macular degeneration, etc.
  • the intraocular disease-related treating agents available in the market should be injected directly into the vitreous cavity, thus causing pain and side effects
  • the sesquiterpene derivative compound of the present disclosure is delivered to the target tissue (eye) via different administration routes (oral, intraperitoneal, etc.) other than the intravitreal route. Accordingly, the sesquiterpene derivative compound provides excellent therapeutic effect without being restricted by the administration routes.

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KR101800346B1 (ko) * 2016-08-30 2017-11-22 국민대학교산학협력단 망막 내 혈관 누수 억제용 조성물
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CN109414416B (zh) 2021-03-26
US20200078338A1 (en) 2020-03-12
AU2016413709B2 (en) 2019-07-11
KR101674622B1 (ko) 2016-11-09
US10918625B2 (en) 2021-02-16
EP3482750B1 (fr) 2022-09-28
JP2019524686A (ja) 2019-09-05
EP3482750A1 (fr) 2019-05-15
AU2016413709A1 (en) 2019-01-17
JP6667681B2 (ja) 2020-03-18
WO2018008803A1 (fr) 2018-01-11
CN109414416A (zh) 2019-03-01
ES2929708T3 (es) 2022-12-01

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