US20150031890A1 - Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis - Google Patents

Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis Download PDF

Info

Publication number
US20150031890A1
US20150031890A1 US14/362,917 US201214362917A US2015031890A1 US 20150031890 A1 US20150031890 A1 US 20150031890A1 US 201214362917 A US201214362917 A US 201214362917A US 2015031890 A1 US2015031890 A1 US 2015031890A1
Authority
US
United States
Prior art keywords
angiogenesis
pharmaceutical composition
preventing
disease
diseases caused
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US14/362,917
Other languages
English (en)
Inventor
Byeong Seon Jeong
Jung Ae Kim
You Ra Kang
Tae Gyu Nam
Jin Mo Ku
Ned A. Porter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Research Cooperation Foundation of Yeungnam University
Original Assignee
Research Cooperation Foundation of Yeungnam University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Research Cooperation Foundation of Yeungnam University filed Critical Research Cooperation Foundation of Yeungnam University
Assigned to RESEARCH COOPERATION FOUNDATION OF YEUNGNAM UNIVERSITY reassignment RESEARCH COOPERATION FOUNDATION OF YEUNGNAM UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PORTER, NED A., KIM, JUNG AE, JEONG, BYEONG SEON, KANG, YOU RA, KU, JIN MO, NAM, TAE GYU
Publication of US20150031890A1 publication Critical patent/US20150031890A1/en
Abandoned legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a bicyclic pyridinol derivative for preventing or treating diseases caused by angiogenesis.
  • Angiogenesis is a process of forming new capillary blood vessels from pre-existing microvessels. Angiogenesis normally occurs during embryonic development, tissue regeneration, wound healing, and corpus luteum development that is a cyclical change in female reproductive system; in any case, angiogenesis is strictly regulated to progress (Folkman J et al., Int. Rev. Exp. Pathol., 16, pp 207-248, 1976).
  • Angiogenesis is a process that generally includes degradation of a vascular basement membrane by proteases released by stimuli of proangiogenic factors; migration and proliferation of vascular endothelial cells; tubular formation due to differentiation of vascular endothelial cells; reconstruction of blood vessels; and generation of new capillary blood vessels.
  • angiogenesis there are diseases induced by angiogenesis that is not regulated autonomously but grows morbidly.
  • diseases associated with angiogenesis occurring in pathological conditions include hemangioma, angiofibroma, vascular malformation and cardiovascular diseases, such as arteriosclerosis, vascular adhesion, and scleroedema.
  • Ocular diseases associated with angiogenesis include corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal diseases induced by new blood vessels, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, granular conjunctivitis, and the like.
  • angiogenesis-related diseases may include chronic inflammatory diseases such as arthritis, cutaneous diseases such as psoriasis, capillarectasia, pyogenic granuloma, seborrheic dermatitis, acne, Alzheimer's disease, and obesity.
  • Tumor growth and metastases are necessarily dependent on angiogenesis (D'Amato R J et al., Ophthalmology, 102(9), pp 1261-1262, 1995; Arbiser J L, J. Am. Acad. Dermatol., 34(3), pp 486-497, 1996; O'Brien K D et al. Circulation, 93(4), pp 672-682, 1996; Hanahan D et al., Cell, 86, pp 353-364, 1996).
  • angiogenesis plays an important role in growth and metastasis of cancer cells.
  • Tumor is supplied with nutrition and oxygen necessary for growth and proliferation through new blood vessels, and the new blood vessels infiltrating into the tumor allow the cancer cells being metastasized to enter the blood circulation system and thus support metastasis of the cancer cells (Folkman and Tyler, Cancer Invasion and metastasis , Biologic mechanisms and Therapy (S. B. Day ed.) Raven press, New York, pp 94-103, 1977; Polverini P J, Crit. Rev. Oral. Biol. Med., 6(3), pp 230-247, 1995).
  • the major cause of death in cancer patients is metastasis, and the reasons why the chemotherapies or immunotherapies being used clinically at present do not contribute to an increase in a survival rate of cancer patients is directed to metastasis of cancer.
  • Typical diseases resulting from angiogenesis include macular degeneration, diabetic retinopathy, and the like that occur commonly in old age, premature infant's retinopathy, neovascular glaucoma, corneal diseases induced by new blood vessels, and the like (Adamis A P et al., Angiogenesis, 3, pp 9-14, 1999).
  • diabetic retinopathy that is one of the diabetic complications and a disease that retinal capillaries invade vitreous body to become blind.
  • Psoriasis characterized by red spots and scaly skin is a chronic proliferative disease occurring in skin and is accompanied with pain and malformation. Normally, keratinocytes proliferate once a month, however, in a psoriasis patient, the keratinocytes proliferate at least once a week. For such rapid proliferation, a large quantity of blood is required, resulting in active angiogenesis (Folkman J, J. Invest. Dermatol., 59, pp 40-48, 1972).
  • angiogenesis inhibitors Since it is possible to apply angiogenesis inhibitors to agents for treating various diseases associated with angiogenesis, in recent years, a variety of studies aimed at treating such diseases by inhibiting angiogenesis have been actively conducted. Since such angiogenesis inhibitors should be administrated to patients for a long time, the most ideal inhibitor is one that should have low toxicity and can be orally administrated. Accordingly, there has been a demand for development of drugs that have low toxicity as angiogenesis inhibitors.
  • the inventors of the present invention confirmed that a bicyclic pyridinol derivative having a specific structure is highly effective in inhibiting angiogenesis, and, thus, completed the present invention.
  • an object of the present invention is to provide a pharmaceutical composition containing a bicyclic pyridinol derivative as an active ingredient for preventing or treating diseases caused by angiogenesis.
  • the present invention provides a pharmaceutical composition containing a bicyclic pyridinol derivative expressed by the following Chemical Formula 1 for preventing or treating diseases caused by angiogenesis:
  • R 1 to R 3 may be identical with or different from one another and may be any one of hydrogen, C1 to C16 alkyl, acyloxymethyl, or trimethyltridecyl, and n may be an integer of 1 to 2.
  • R 1 may be any one of hydrogen, methyl, ethyl, or n-C 16 H 33
  • R 2 may be any one of hydrogen or methyl
  • R 3 is one of hydrogen, methyl, n-butyl, t-butyl, acyloxymethyl, or trimethyltridecyl
  • n may be an integer of 1 to 2.
  • bicyclic pyridinol derivative may be preferably a compound expressed by the following Chemical Formula 2 and more preferably a compound expressed by the following Chemical Formula 3:
  • n may be an integer of 1 to 2
  • a bicyclic pyridinol derivative according to the present invention can be effectively used as a drug for preventing and treating diseases caused by angiogenesis since it inhibits neovascularization induced by an angiogenesis inducer such as a vascular endothelial growth factor in a chicken chorioallantoic membrane model.
  • FIG. 1 illustrates chemical formulas of bicyclic pyridinol derivatives according to an example of the present invention
  • FIG. 2 is a value of IC 50 obtained by treating a compound 12 with a CAM by concentrations
  • FIG. 3 illustrates a measurement result of a VEGF-induced growth inhibitory effect of the compound 12 on HUVEC cells
  • FIG. 4 provides photomicrographs taken at a magnification of 200 times of a bottom side of a polycarbonate filter in order to check an infiltration inhibitory effect of the compound 12 on HUVEC cells;
  • FIG. 5 provides photomicrographs taken at a magnification of 400 times of cells in order to check an ROS scavenging effect of the compound 12;
  • FIG. 6 illustrates an observation result of the ROS scavenging effect of the compound 12 by treating the adult retinal pigment epithelium (ARPE)-19 cell line with angiotensin II, which is a risk factor of macular degeneration;
  • ARPE retinal pigment epithelium
  • FIG. 7 illustrates an observation result of the ROS scavenging effect of the compound 12 by treating the adult retinal pigment epithelium (ARPE)-19 cell line with 4-hydroxynonenal (4-HNE), which is a risk factor of macular degeneration; and
  • FIG. 8 illustrates an observation result of angiogenesis caused by tumorigenesis by inoculating A549 lung cancer cells to a CAM and a tumor growth inhibitory effect.
  • the present invention provides a pharmaceutical composition containing a bicyclic pyridinol derivative expressed by the following Chemical Formula 1 for preventing or treating diseases caused by angiogenesis:
  • R 1 to R 3 may be identical with or different from one another and may be any one of hydrogen, C1 to C16 alkyl, acyloxymethyl, or trimethyltridecyl, and n may be an integer of 1 to 2.
  • R 1 may be any one of hydrogen, methyl, ethyl, or n-C 16 H 33
  • R 2 may be any one of hydrogen or methyl
  • R 3 is one of hydrogen, methyl, n-butyl, t-butyl, acyloxymethyl, or trimethyltridecyl
  • n may be an integer of 1 to 2.
  • bicyclic pyridinol derivative may be preferably a compound expressed by the following Chemical Formula 2 and more preferably a compound expressed by the following Chemical Formula 3:
  • n may be an integer of 1 to 2.
  • the diseases caused by angiogenesis may be selected from the group consisting of rheumatic arthritis, osteoarthritis, septic arthritis, psoriasis, corneal ulcer, senile macular degeneration, diabetic retinopathy, proliferative vitreous body retinopathy, premature retinopathy, ocular inflammation, conical cornea, Sjogren's syndrome, myopia eye tumor, cornea graft rejection, abnormal wound healing, bone disease, proteinuria, abdominal aortic aneurysm disease, regressive cartilage loss due to traumatic joint injury, demyelinating disease of nervous system, hepatic cirrhosis, glomerular disease, premature rupture of embryonic membrane, inflammatory bowel disease, periodontal membrane disease, arteriosclerosis, restenosis, inflammatory disease of central nervous system, Alzheimer's disease, skin aging, and infiltration metastasis of cancer.
  • a bicyclic pyridinol derivative of the present invention can be effectively used as a drug for preventing and treating diseases caused by angiogenesis since it inhibits angiogenesis induced by an angiogenesis inducer such as a vascular endothelial growth factor in a chicken chorioallantoic membrane model.
  • Doses and ways of application of a pharmaceutical composition containing a bicyclic pyridinol derivative of the present invention may vary depending on the formulations and the use purposes thereof.
  • the pharmaceutical composition containing a bicyclic pyridinol derivative of the present invention may contain a bicyclic pyridinol derivative in the amount of 0.1 to 50 weight % with respect to the total weight of the composition.
  • composition containing a bicyclic pyridinol derivative of the present invention may further contain suitable carriers, excipients, or diluents commonly used in preparing pharmaceutical compositions.
  • Examples of the carriers, excipients, or diluents may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil.
  • the pharmaceutical composition containing a bicyclic pyridinol derivative of the present invention may be prepared in oral formulations including powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and the like, agents for external application, suppository and sterilizing injection solutions by respective methods commonly used.
  • the pharmaceutical composition is prepared using diluents or excipients such as fillers, extenders, bonding agents, humectants, disintegrants, surfactants, etc.
  • Solid dosage forms for oral administration include tablets, pills, powders, granules, capsules, and the like. Such solid dosages are prepared by mixing the compound with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, and gelatin.
  • Liquid dosage forms for oral administration such as suspensions, internal solutions, emulsions, and syrups, may contain commonly used simple diluents, for example, water and liquid paraffin, as well as various excipients, for example, humectants, sweeteners, aromatics, preservatives, and the like.
  • Dosage forms for parenteral administration include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized agents, suppositories, and the like.
  • Non-aqueous solvents and suspensions may be prepared using propylene glycol, polyethylene glycol, vegetable oils such as olive oil, or injectable esters such as ethyl oleate.
  • vegetable oils such as olive oil
  • injectable esters such as ethyl oleate.
  • injectable esters such as ethyl oleate.
  • bases for suppositories witepsol, macrogol, Tween 61, cacao oil, laurinum, and glycerogelatine can be used.
  • the dosages of the bicyclic pyridinol derivative of the present invention may vary depending on age, sex, and weight of a patient. 0.001 to 100 mg/kg or preferably, 0.01 to 10 mg/kg of the bicyclic pyridinol derivative can be administrated once or several times a day. Moreover, the dosages of the compound may be increased and decreased depending on an administration path, severity of disease, sex, weight, age, and the like. Accordingly, the dosages do not limit the scope of the present invention in any aspect.
  • the pharmaceutical composition can be administrated to mammals such as rats, mice, livestock, and humans through various paths.
  • mammals such as rats, mice, livestock, and humans
  • it can be administered by any kinds of predictable administration methods such as oral, rectal or intravenous, intramuscular, cutaneous, intrauterine or intracerebroventricular injection administrations.
  • the bicyclic pyridinol derivative according to the present invention has 50% lethality (LC 50 ) of 2 g/kg or more with secured stability and thus can be used in the pharmaceutical composition of the present invention.
  • FIG. 1 illustrates bicyclic pyridinol derivatives according to an example, and each of the bicyclic pyridinol derivatives were prepared by synthesizing the compounds by the methods described in references, respectively.
  • Me represents methyl
  • Et represents ethyl
  • Bu represents butyl
  • CAM chorioallantoic membrane
  • Fertilized chicken eggs were cultured keeping the temperature at 37° C. and the relative humidity at 55%. On the tenth day, the first small hole was made in the region of air sac and the second hole was dug in the flat region of egg, where a window was to be made, using a hypodermic needle (Greencross Medical Science, Korea).
  • CAM chorioallantoic membrane
  • a whatman filter disc #1 (Whatman Inc. USA) was treated with 3 mg/ml of cortisone acetate and dried.
  • the filter disc was drenched with a vascular endothelial growth factor (VEGF) in a concentration of 20 ng/CAM.
  • VEGF vascular endothelial growth factor
  • the filter disc was put on the vessels through the previously made window, and a compound 12 of Example was dissolved in dimethylsulfoxide (DMSO) and diluted with phosphate buffered saline (PBS) to treat by concentrations.
  • DMSO dimethylsulfoxide
  • PBS phosphate buffered saline
  • the CAMs, on which the filter disc was placed were separated and washed with PBS to take images using a stereomicroscope (Stemi SV6 stereomicroscope, Carl Zeiss, Germany) and Image-Pro Plus software (Media Cybernetics; Silver Spring, Md., USA). Then, the number of branches was counted and the result data were analyzed.
  • a stereomicroscope Stemi SV6 stereomicroscope, Carl Zeiss, Germany
  • Image-Pro Plus software Media Cybernetics; Silver Spring, Md., USA
  • IC 50 was obtained by treating the compound 12 with a CAM by concentrations, and the IC 50 was 0.7 nM ( FIG. 2 ).
  • HUVEC cells were cultured in a flask coated with 0.2% gelatin. Then, the HUVEC cells were cultured in an endothelial cell basal medium-2 (EBM-2, Clonetics, San Diego, Calif.).
  • EBM-2 contained fetal bovine serum (FBS), hydrocortisone, a human basic fibroblast growth factor (hFGF-B), a vascular endothelial growth factor (VEGF), a human recombinant insulin-like growth factor (R3-IGF-1), ascorbic acid, a human epidermal growth factor (hEGF), GA-1000, and heparin.
  • FBS fetal bovine serum
  • hFGF-B human basic fibroblast growth factor
  • VEGF vascular endothelial growth factor
  • R3-IGF-1 human recombinant insulin-like growth factor
  • ascorbic acid a human epidermal growth factor (hEGF)
  • hEGF human epidermal growth factor
  • GA-1000
  • the HUVEC cells were cultured for 4 to 5 days and injected into a 24-well plate in a density of 5 ⁇ 10 4 cells/well, and the media of the respective wells were set at 1 ml.
  • the HUVEC cells were treated with a mixture of the VEGF and the compound 12 and cultured for 24 hours, and, then, 100 ⁇ l of MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide; 5 g MTT/l in H 2 O) was added thereto and further cultured for 4 hours.
  • DMSO dimethylsulfoxide
  • HUVEC cells In order to examine a chemostatic migration inhibitory effect of the compound of the present invention, the following in vitro experiment was carried out using HUVEC cells (Mi-Sung Kim et al., Cancer Research, 63, 5454-5461, 2003; Sang-Oh Yoon et al., The Journal of Biological Chemistry, 276, 20085-20092, 2001; Sonia Zorzet et al., The Journal of Pharmacology and Experimental Therapeutics, 295, 927-933, 2000).
  • a culture plate applied hereto was a 24-well plate (Corning Costar, Cambridge, Mass.) including a polycarbonate filter having a plurality of pores of 8 mm in size.
  • the bottom side of the polycarbonate filter was coated with 20 l of type I collagen in a concentration of 0.5 mg/ml, and the top side thereof was coated with 20 l of matrigel (BD Bioscience, Bedford, Mass.) in a concentration of 1.5 mg/ml.
  • the lower region of the polycarbonate filter was filled with a medium including 2% FBS, and the HUVEC cells were inoculated into the upper region of the polycarbonate filter.
  • the compound 12 was dissolved in dimethyl sulfoxide (DMSO) and diluted with phosphate buffered saline (PBS) by concentrations (1, 3, 10 ⁇ M).
  • DMSO dimethyl sulfoxide
  • PBS phosphate buffered saline
  • FIG. 4 provides photomicrographs taken at a magnification of 200 times of the bottom side of the polycarbonate filter in order to check an infiltration inhibitory effect of the compound 12 on HUVEC cells.
  • cancer cells infiltrating the bottom side of the polycarbonate filter was remarkably decreased as compared with the control group, and, thus, it could be seen that the compound 12 of the present invention reduced infiltration of the HUVEC cells in a concentration-dependent manner.
  • DCF-DA 2′,7′-dichlorofluorescein diacetate
  • the DCF-DA was oxidized to fluorescent DCF exhibiting green fluorescence.
  • the HUVEC cells were injected into 8-well plates coated with 0.2% gelatin in a density of 1 ⁇ 10 5 cells/well and then cultured for 24 hours. A pre-treatment was carried out to the compound 12 for 3 hours and induced by the VEGF for 15 minutes and washed with PBS (pH 7.4) three times.
  • FIG. 5 provides photomicrographs taken at a magnification of 400 times of cells in order to check an ROS scavenging effect of the compound 12 of the present invention.
  • FIG. 6 and FIG. 6
  • FIG. 7 illustrate an observation result of the ROS scavenging effect of the compound 12 by treating the adult retinal pigment epithelium (ARPE)-19 cell line with 4-hydroxynonenal (4-HNE) or angiotensin II, which is a risk factor of macular degeneration.
  • ARPE adult retinal pigment epithelium
  • 4-hydroxynonenal (4-HNE) or angiotensin II which is a risk factor of macular degeneration.
  • the 4-hydroxynonenal (4-HNE) or angiotensin II which is a risk factor of macular degeneration caused cell damage by generation of ROS in ARPE cell and caused damage of a Bruch's membrane and angiogenesis, resulting in macular degeneration and loss of eyesight.
  • the compound 12 strongly inhibits generation of ROS of 4-hydroxynonenal (4-HNE) or angiotensin II and thus can be expected to be effective in treating macular degeneration.
  • FIG. 8 illustrates an observation result of angiogenesis caused by tumorigenesis by inoculating A549 lung cancer cells to a CAM and a tumor growth inhibitory effect. Fertilized chicken eggs were cultured, and on the ninth day, a window was made in the same manner, and instead of a disc, cancer cells were mixed with matrigel at a ratio of 1:1 and treated with the compound 12 and inoculated in a density of 1.5 ⁇ 10 6 cells/CAM.
  • the compound 12 of the present invention inhibited angiogenesis caused by tumorigenesis and also inhibited tumor growth in a significantly low concentration as compared with ⁇ -tocopherol as the control group.
  • the compound 12 was suspended in a 0.5% methyl cellulose solution and orally administered to male Balb/c mice with a single dose of 0.5 g/kg, 1 g/kg, and 2 g/kg. Then, the survival rate and weights of the mice were checked for 7 days.
  • the compounds of the present invention with a dose of up to 2 g/kg did not exhibit a change in toxicity in the mice, and, thus, they were determined as safe substances having a median lethal dose (LD 50 ) of more than 2 g/kg for oral administration.
  • LD 50 median lethal dose

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
US14/362,917 2011-12-08 2012-12-07 Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis Abandoned US20150031890A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
KR10-2011-0131290 2011-12-08
KR20110131290 2011-12-08
KR1020120141581A KR101432383B1 (ko) 2011-12-08 2012-12-07 바이사이클릭 피리디놀 유도체를 함유하는 혈관신생으로 인한 질환의 예방 또는 치료용 약학조성물
KR10-2012-0141581 2012-12-07
PCT/KR2012/010630 WO2013085340A1 (fr) 2011-12-08 2012-12-07 Composition pharmaceutique comprenant des dérivés de pyridinol bicycliques pour la prévention ou le traitement de maladies causées par l'angiogenèse

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2012/010630 A-371-Of-International WO2013085340A1 (fr) 2011-12-08 2012-12-07 Composition pharmaceutique comprenant des dérivés de pyridinol bicycliques pour la prévention ou le traitement de maladies causées par l'angiogenèse

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US14/801,842 Continuation US9505757B2 (en) 2011-12-08 2015-07-17 Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis

Publications (1)

Publication Number Publication Date
US20150031890A1 true US20150031890A1 (en) 2015-01-29

Family

ID=48861585

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/362,917 Abandoned US20150031890A1 (en) 2011-12-08 2012-12-07 Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis
US14/801,842 Active US9505757B2 (en) 2011-12-08 2015-07-17 Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis

Family Applications After (1)

Application Number Title Priority Date Filing Date
US14/801,842 Active US9505757B2 (en) 2011-12-08 2015-07-17 Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis

Country Status (5)

Country Link
US (2) US20150031890A1 (fr)
EP (1) EP2789337B1 (fr)
KR (1) KR101432383B1 (fr)
ES (1) ES2683314T3 (fr)
WO (1) WO2013085340A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150238471A1 (en) * 2011-12-21 2015-08-27 Byeong Seon Jeong 6-aminopyridine-3-ol derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical composition containing same as active ingredients for preventing or treating diseases caused by angiogenesis
WO2017040961A1 (fr) * 2015-09-02 2017-03-09 Basf Se Composition lubrifiante
US9889139B2 (en) 2011-12-21 2018-02-13 Research Cooperation Foundation Of Yeungnam University Method of treating inflammatory bowel disease comprising administering a pharmaceutical composition comprising a 6-aminopyridin-3-ol compound or a pharmaceutically acceptable salt thereof as an active ingredient to a subject

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8367669B2 (en) * 2005-06-15 2013-02-05 Vanderbilt University Inhibitors of hemeprotein-catalyzed lipid peroxidation

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
Anghel et. al. "Antioxidants: not heaven-sent" Harvard Science Review Spring 2010 32-34. *
Auerbach "Angiogenesis Assays: A Critical Overview" Clinical Chemistry 2003, 49, 32-40. *
Grazia D'Onofrio "Advances in the identification of g-secretase inhibitors for the treatment of Alzheimer's disease" Expert Opinion on Investigational Drugs 2012, 7, 20-37. *
Hook V. Y.H. "Neuroproteases in Peptide Neurotransmission and Neurodegenerative Diseases Applications to Drug Discovery Research" Biodrugs 2006, 20, 105-119. *
Jhee et. al. "Beta-amyloid therapies in Alzheimer's disease" Expert Opinion on Investigational Drugs 2001, 10, 593-605 *
Johnson, et. al. "Relationships between drug activity in NCI preclinical in vitro and in vivo models and early clinical trials." British Journal of Cancer 2001, 84, 1424-1431. *
Kristal "Baseline Selenium Status and Effects of Selenium and Vitamin E Supplementation on Prostate Cancer Risk" J Natl Cancer Inst 2014 106(3): djt456 1-8. *
Kuenen "Efficacy and Toxicity of the Angiogenesis Inhibitor SU5416 As a Single Agent in Patients with Advanced Renal Cell Carcinoma, Melanoma, and Soft Tissue Sarcoma" Clinical Cancer Research Vol. 9, 1648-1655, May 2003. *
Organic & Biomolecular Chemistry Volume 9 | Number 6 | 21 March 2011, Front Cover. *
RANDOLPH M. HOWES "The Free Radical Fantasy A Panoply of Paradoxes" Annals of The New York Academy of Sciences (2006) 1067: 22-26. *
Simone, Oncology: Introduction, Cecil Textbook of Medicine, 20th Edition, 1996 Vol. 1, pp. 1004-1010. *
Yuzwa "O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond" Chem. Soc. Rev., 2014, 43, 6839. *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150238471A1 (en) * 2011-12-21 2015-08-27 Byeong Seon Jeong 6-aminopyridine-3-ol derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical composition containing same as active ingredients for preventing or treating diseases caused by angiogenesis
US9452159B2 (en) * 2011-12-21 2016-09-27 Research Cooperation Of Yeungnam University 6-aminopyridine-3-ol derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical composition containing same as active ingredients for preventing or treating diseases caused by angiogenesis
US9889139B2 (en) 2011-12-21 2018-02-13 Research Cooperation Foundation Of Yeungnam University Method of treating inflammatory bowel disease comprising administering a pharmaceutical composition comprising a 6-aminopyridin-3-ol compound or a pharmaceutically acceptable salt thereof as an active ingredient to a subject
WO2017040961A1 (fr) * 2015-09-02 2017-03-09 Basf Se Composition lubrifiante
JP2018526514A (ja) * 2015-09-02 2018-09-13 ビーエーエスエフ ソシエタス・ヨーロピアＢａｓｆ Ｓｅ 潤滑剤組成物
US10662390B2 (en) 2015-09-02 2020-05-26 Basf Se Lubricant composition
US11046906B2 (en) 2015-09-02 2021-06-29 Basf Se Lubricant composition

Also Published As

Publication number Publication date
ES2683314T3 (es) 2018-09-26
KR101432383B1 (ko) 2014-08-20
EP2789337B1 (fr) 2018-07-18
EP2789337A4 (fr) 2015-07-22
US9505757B2 (en) 2016-11-29
US20150320729A1 (en) 2015-11-12
EP2789337A1 (fr) 2014-10-15
KR20130064706A (ko) 2013-06-18
WO2013085340A1 (fr) 2013-06-13

Similar Documents

Publication Publication Date Title
KR100552043B1 (ko) 푸마질롤 유도체를 포함하는 비만치료용 조성물
KR101519028B1 (ko) 항혈관형성제 및 사용방법
KR20160101786A (ko) Ｆａｍ１９ａ５ 단백질을 포함하는 비만 예방 또는 치료용 조성물 및 이를 이용한 비만 치료제의 스크리닝 방법
JP6502919B2 (ja) アミドピリジンオール誘導体またはその薬剤学的に許容可能な塩、及びそれを有効成分として含有する薬学組成物
KR20020035855A (ko) 약용인삼을 포함하는 뇌세포 또는 신경세포 보호제
CN106456658A (zh) 硒有机化合物的组合物和其使用方法
US11497748B2 (en) Method for activating AMPK and the use of adenine
US9505757B2 (en) Pharmaceutical composition comprising bicyclic pyridinol derivatives for preventing or treating diseases caused by angiogenesis
KR20110100329A (ko) 신생혈관형성 억제용 한약 조성물
US8940788B2 (en) Anti-angiogenic composition containing macrolactin A and a derivative thereof as active ingredients
RU2549441C2 (ru) Способы и фармацевтические композиции для лечения синдрома дауна
US9889139B2 (en) Method of treating inflammatory bowel disease comprising administering a pharmaceutical composition comprising a 6-aminopyridin-3-ol compound or a pharmaceutically acceptable salt thereof as an active ingredient to a subject
RU2291706C1 (ru) Применение флаволигнанов для подавления избыточной и патологической пролиферации эндотелия сосудов
WO2007032591A1 (fr) Composition comprenant 1-furan-2-yl-3-pyridine-2-yl-propenone presentant une activite anti-angiogenique et une activite inhibitrice du cancer
CN105934245B (zh) 多发性硬化症的治疗剂或预防剂
CN111840278A (zh) 化合物与微生素e的组合在制备抗衰老药物或者化妆品中的用途
KR101048584B1 (ko) 혈관신생으로 인한 질환의 예방 또는 치료용 약학조성물
CN110051671B (zh) 马齿苋酰胺e用于制备治疗缺血性心脏病的药物的用途
KR101844816B1 (ko) 구아나벤즈를 포함하는 식욕부진증의 개선 또는 치료용 조성물 및 이를 이용한 방법
KR20070113532A (ko) 베르바민을 유효성분으로 포함하는 혈관 재협착 예방제
RU2613314C2 (ru) Малые молекулы с NGF-подобной активностью, обладающие антидиабетическими свойствами
JP6538976B2 (ja) 化合物ｐａｃ−１またはその塩及びそれらを含有する医薬組成物
KR100779610B1 (ko) 1-퓨란-2-일-3-피리딘-2-일-프로페논을 함유하는혈관신생으로 인한 질환 및 암질환의 예방 또는 치료용약학조성물
KR101169719B1 (ko) 피페라진 이미노 구조를 갖는 화합물을 포함하는 혈관신생 억제용 약제학적 조성물
CN116898853A (zh) 异烟酸希帕哌亚在制备预防和或治疗肺动脉高压药物的应用

Legal Events

Date Code Title Description
AS Assignment

Owner name: RESEARCH COOPERATION FOUNDATION OF YEUNGNAM UNIVER

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:JEONG, BYEONG SEON;KIM, JUNG AE;KANG, YOU RA;AND OTHERS;SIGNING DATES FROM 20140610 TO 20140618;REEL/FRAME:033673/0155

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION