WO2016153087A1 - Dérivé de la pyridine ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci utilisé comme principe actif - Google Patents

Dérivé de la pyridine ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci utilisé comme principe actif Download PDF

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WO2016153087A1
WO2016153087A1 PCT/KR2015/002814 KR2015002814W WO2016153087A1 WO 2016153087 A1 WO2016153087 A1 WO 2016153087A1 KR 2015002814 W KR2015002814 W KR 2015002814W WO 2016153087 A1 WO2016153087 A1 WO 2016153087A1
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cancer
group
acid
alkyl
hydroxy
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정병선
김정애
이현지
남태규
이상열
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영남대학교 산학협력단
한양대학교 에리카산학협력단
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Priority to PCT/KR2015/002814 priority Critical patent/WO2016153087A1/fr
Priority to KR1020177026056A priority patent/KR101992356B1/ko
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    • 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

Definitions

  • the present invention provides a pyridine derivative or a pharmaceutically acceptable salt thereof, a pharmaceutical composition for the prevention or treatment of diseases caused by angiogenesis, containing the same as an active ingredient, a pharmaceutical composition for the prevention or treatment of cancer, and prevention or inhibition of cancer infiltration or cancer metastasis. It relates to a pharmaceutical composition.
  • Angiogenesis is the process by which new capillaries are formed from existing microvessels. Angiogenesis normally occurs when embryonic development, tissue regeneration and wound healing, and luteal corpus luteum, a change in the genital system of a woman, are developed.
  • vascular endothelial cells grow very slowly and do not divide relatively well compared to other types of cells.
  • Angiogenesis process is generally caused by the stimulation of angiogenesis factors, blood vessels are reconstructed by the formation of lumen due to the degradation of the basal membrane, proliferation, proliferation, and differentiation of vascular endothelial cells due to proteases. Consists of being generated.
  • Angiogenesis plays an important role in the growth and metastasis of cancer cells. Tumors are supplied with nutrients and oxygen for growth and proliferation through neovascularization, and new blood vessels that penetrate the tumor give metastasis to metastatic cancer cells by allowing them to enter the blood circulation (Folkman and Tyler, 1999). Cancer Invasion and metastasis, Biologic mechanisms and Therapy (SB Day ed.) Raven press, New York, pp 94-103, 1977; Polverini PJ, Crit. Rev. Oral. Biol. Med., 6 (3), pp230-247, 1995). The main cause of death of cancer patients is metastasis, and the current metastasis of cancer does not contribute to the survival of cancer patients.
  • cancer cells proliferate at the place where the cancer cells first appeared, and when the cancer mass grows larger, the cancer cells move away from the cancer mass, move through blood vessels, and then settle in the secondary site again to move to another place. Proliferation takes place. In this process, cancer cells must undergo cancer cell invasion process in order to move to another place through the blood vessel. At this time, cancer cells overexpress and secrete proteolytic enzymes to degrade extracellular matrix components, including matrix metalloproteinases (MMPs), cathepsins, and various proteinases (proteinases). There is this.
  • MMPs matrix metalloproteinases
  • cathepsins cathepsins
  • proteinases various proteinases
  • Cathepsin is a lysosomal enzyme that breaks down proteins at low pH, depending on the structure and type of catalyst, serine proteases (A, G), aspartyl proteases (D, E), cysteine proteases (B, C, F, H, K, L1, V, O, S, W, Z).
  • Cathepsins are involved in specific physiological processes: antigen presentation in the immune system, collagen turnover in bone and cartilage, neuropeptides and hormone processing, resulting in various disease symptoms when these cathepsin deficiencies occur, as well as overexpression of cathepsin. Various diseases also occur.
  • cysteine cathepsin cathepsin B, F, H, K, L, V, S, Z
  • cysteine cathepsin B, F, H, K, L, V, S, Z cysteine cathepsin
  • cathepsin is a lysosomal protease, which plays a role in regulating physiological function in cells, but cathepsin S is secreted outside the cell to perform proteolytic function.
  • Cathepsin S is involved in antigen processing or apoptosis when it is in intracellular lysosomes, but when secreted out of cells it degrades extracellular matrix components such as laminin, fibronectin elastin, collagen and the like. It is thought that cathepsin S is involved in cancer cell infiltration and angiogenesis.
  • cathepsin D staining in breast cancer tissues was significantly associated with the prognosis of breast cancer patients who had metastasized to lymph nodes, whereas cathepsin D was not reported in lymph node vision patients (Henry JA et al. , Cancer, 65 (2), 265-71, 1990). Based on these results, cathepsin D has been suggested to play an important role in breast cancer metastasis and invasion, but other studies have demonstrated metastasis experiments using breast cancer cell lines such as MCF7, MDA-MB-231 and MDA-MB-435. Cathepsin D was not associated with breast cancer cell invasion (Johnson MD et al., Cancer Res., 53 (4), 873-7, 1993). It is predicted that cathepsin S may play an important role in metastatic breast cancer cells as in liver cancer.
  • the present inventors have completed the present invention by confirming that the pyridine derivative represented by Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof has excellent antiangiogenic, cancer growth, and cancer metastasis inhibitory effects.
  • Another object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of diseases caused by angiogenesis, which contains a pyridine derivative represented by Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention is to provide a pharmaceutical composition for preventing or treating cancer, which contains a pyridine derivative represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • Another object of the present invention to provide a pharmaceutical composition for preventing or inhibiting cancer infiltration or metastasis of cancer containing a pyridine derivative represented by Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen, alkyl of C1 to C6, alkoxy and halogen of C1 to C4,
  • R 2 is any one selected from the group consisting of C1 to C4 alkoxy, benzyloxy, hydroxy and acetyloxy,
  • R 4 is any one selected from the group consisting of hydrogen, alkylcarbonyl, arylalkyl, C 1 to C 16 alkyl, cycloalkyl substituted alkyl, aryl substituted carboxamide, alkyl acetate and alkylsilyl,
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same or different and are each selected from the group consisting of hydrogen, benzyl and alkyl of C1 to C16.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of diseases caused by angiogenesis, containing a pyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer, which contains a pyridine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or inhibiting cancer infiltration or metastasis of cancer, comprising a pyridine derivative represented by Formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for the prevention or treatment of diseases caused by angiogenesis, containing a pyridine derivative represented by the following formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen, alkyl of C1 to C6, alkoxy and halogen of C1 to C4,
  • R 2 is any one selected from the group consisting of C1 to C4 alkoxy, benzyloxy, hydroxy and acetyloxy,
  • R 4 is any one selected from the group consisting of hydrogen, alkylcarbonyl, arylalkyl, C 1 to C 16 alkyl, cycloalkyl substituted alkyl, aryl substituted carboxamide, alkyl acetate and alkylsilyl,
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same or different and are each selected from the group consisting of hydrogen, benzyl and alkyl of C1 to C16.
  • the present invention also provides a pharmaceutical composition for preventing or treating cancer, which contains a pyridine derivative represented by the formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a pharmaceutical composition for preventing or inhibiting cancer infiltration or metastasis of cancer, comprising a pyridine derivative represented by the formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the pyridine derivative or the pharmaceutically acceptable salt thereof according to the present invention is excellent in inhibiting angiogenesis in the chorionic ureteric model, and thus can be usefully used as a medicament for preventing or treating diseases caused by angiogenesis such as macular degeneration or arthritis. have.
  • angiogenesis such as macular degeneration or arthritis.
  • cathepsin S since it inhibits the activity of cathepsin S, which plays an important role in cancer metastasis and invasion, it can be usefully used as an agent for inhibiting cancer growth and inhibiting cancer metastasis.
  • Figure 4 confirms the inhibitory effect of compounds I-a, I-b, I-c, II-a, II-b and II-c on the Kadipsin S expression by RT-PCR.
  • Figure 5 confirms the inhibitory effect of compound I-a on the expression of kadipsin S and MMP-9 by RT-PCR.
  • Figure 6 confirms the effect of inhibiting the infiltration of the Kadipsin S expression of the compound I-a and breast cancer cells MDA-MB-231.
  • Figure 8 confirms the effect of inhibiting the invasion of the Kadipsin S expression of the compound I-a and breast cancer cells MDA-MB-231.
  • Figure 9 confirms the effect of inhibiting the infiltration of the Kadipsin S expression of the compound I-b and breast cancer cells MDA-MB-231.
  • Figure 10 confirms the effect of inhibiting the infiltration of the Kadipsin S expression of the compound I-c and breast cancer cells MDA-MB-231.
  • the present invention provides an amidopyridinol derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen, alkyl of C1 to C6, alkoxy and halogen of C1 to C4,
  • R 2 is any one selected from the group consisting of C1 to C4 alkoxy, benzyloxy, hydroxy and acetyloxy,
  • R 4 is any one selected from the group consisting of hydrogen, alkylcarbonyl, arylalkyl, C 1 to C 16 alkyl, cycloalkyl substituted alkyl, aryl substituted carboxamide, alkyl acetate and alkylsilyl,
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same or different and are each selected from the group consisting of hydrogen, benzyl and alkyl of C1 to C16.
  • the pyridine derivative is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen and alkyl of C1 to C4,
  • R 2 is any one selected from the group consisting of benzyloxy, hydroxy and acetyloxy,
  • R 4 is hydrogen, alkylcarbonyl (e.g. methylcarbonyl, etc.), arylalkyl (e.g. benzyl, etc.), C1-C16 alkyl, cycloalkyl-substituted C1-C6 alkyl (e.g.
  • Aryl substituted carboxamides eg, halogen substituted aryl substituted carboxamides, (chlorophenyl) carbamoyl (CONH (C 6 H 4 ) Cl), etc.
  • alkyl acetates eg, ethyl acetate (CH 2 CO 2 CH 2 CH 3 ), etc.
  • C1 to C10 alkylsilyl eg, tert- Butyldimethylsilyl, etc.
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same as or different from each other, and may be any one selected from the group consisting of hydrogen, benzyl and C1 to C16 alkyl.
  • the pyridine derivative is 5-hydroxy-4,6-dimethyl-1 H -pyrrolo [2,3- b ] pyridin-2 ( 3H ) -one, 6-hydroxy-5,7- Dimethyloxazolo [4,5- b ] pyridin-2 ( 3H ) -one, 6-hydroxy-5,7-dimethyl- 1H -imidazo [4,5- b ] pyridine-2 ( 3H ) -One, 5- (benzyloxy) -4,6-dimethyl-1 H -pyrrolo [2,3-b] pyridin-2 ( 3H ) -one, 3,3-dibenzyl-5- (benzyloxy ) -4,6-dimethyl-1 H -pyrrolo [2,3- b ] pyridin-2 ( 3H ) -one, 1,3,3-tribenzyl-5- (benzyloxy) -4,6- Dimethyl- 1H -pyrrolo [2,3- b ]
  • the pharmaceutically acceptable salt is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, or an acid addition salt formed by an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. It may be in the form of.
  • the pyridine derivative represented by the formula according to the present invention or a pharmaceutically acceptable salt thereof may be prepared by the same method as in Synthesis Examples 1 to 3 described below, but is not limited thereto.
  • the present invention also provides a pharmaceutical composition containing a pyridine derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen, alkyl of C1 to C6, alkoxy and halogen of C1 to C4,
  • R 2 is any one selected from the group consisting of C1 to C4 alkoxy, benzyloxy, hydroxy and acetyloxy,
  • R 4 is any one selected from the group consisting of hydrogen, alkylcarbonyl, arylalkyl, C 1 to C 16 alkyl, cycloalkyl substituted alkyl, aryl substituted carboxamide, alkyl acetate and alkylsilyl,
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same or different and are each selected from the group consisting of hydrogen, benzyl and alkyl of C1 to C16.
  • the pyridine derivative is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen and alkyl of C1 to C4,
  • R 2 is any one selected from the group consisting of benzyloxy, hydroxy and acetyloxy,
  • R 4 is any one selected from the group consisting of hydrogen, alkylcarbonyl, arylalkyl, C 1 to C 16 alkyl, cycloalkyl substituted alkyl, aryl substituted carboxamide, alkyl acetate and alkylsilyl,
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same as or different from each other, and may be any one selected from the group consisting of hydrogen, benzyl and C1 to C16 alkyl.
  • the pyridine derivative is 5-hydroxy-4,6-dimethyl-1 H -pyrrolo [2,3- b ] pyridin-2 ( 3H ) -one, 6-hydroxy-5,7- Dimethyloxazolo [4,5- b ] pyridin-2 ( 3H ) -one, 6-hydroxy-5,7-dimethyl- 1H -imidazo [4,5- b ] pyridine-2 ( 3H ) -One, 5- (benzyloxy) -4,6-dimethyl-1 H -pyrrolo [2,3-b] pyridin-2 ( 3H ) -one, 3,3-dibenzyl-5- (benzyloxy ) -4,6-dimethyl-1 H -pyrrolo [2,3- b ] pyridin-2 ( 3H ) -one, 1,3,3-tribenzyl-5- (benzyloxy) -4,6- Dimethyl- 1H -pyrrolo [2,3- b ]
  • the pyridine derivative may be of the following formula (I-a, I-b or I-c).
  • the present invention also provides a pharmaceutical composition containing a pyridine derivative represented by the following formula (II) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen, alkyl of C1 to C6, alkoxy and halogen of C1 to C4,
  • R 2 is any one selected from the group consisting of C1 to C4 alkoxy, benzyloxy, hydroxy and acetyloxy,
  • R 4 is any one selected from the group consisting of hydrogen, alkylcarbonyl, arylalkyl, C 1 to C 16 alkyl, cycloalkyl substituted alkyl, aryl substituted carboxamide, alkyl acetate and alkylsilyl,
  • X is CR 5 R 6 , NH or O, and R 5 and R 6 are the same or different and are each selected from the group consisting of hydrogen, benzyl and alkyl of C1 to C16.
  • the pyridine derivative is in the formula
  • R 1 and R 3 are the same as or different from each other, and are any one selected from the group consisting of hydrogen and alkyl of C1 to C4,
  • R 2 is hydroxy
  • R 4 is one selected from the group consisting of hydrogen and alkyl of C1 to C4,
  • X is CR 5 R 6 , NH or O, each is the same or different, and may be any one selected from the group consisting of hydrogen and alkyl of C1 to C4.
  • the pyridine derivative may be of the following formula II-a, II-b or II-c.
  • the pharmaceutically acceptable salt is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, or an acid addition salt formed by an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. It may be in the form of.
  • the pharmaceutical composition according to the present invention may include a pharmaceutical composition for preventing and treating diseases caused by angiogenesis, a pharmaceutical composition for preventing and treating cancer, and / or a pharmaceutical composition for preventing or inhibiting cancer infiltration or cancer metastasis.
  • the angiogenesis-related diseases include rheumatoid arthritis, osteoarthritis, septic arthritis, psoriasis, corneal ulcer, age-related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, immature retinopathy, ophthalmic inflammation, cone cornea, shogren Syndrome, myopia ophthalmic tumor, corneal transplant rejection, abnormal wound union, bone disease, proteinuria, abdominal aortic aneurysm, degenerative cartilage loss due to traumatic joint injury, demyelination of the nervous system, cirrhosis, renal glomerular disease, immature rupture of the embryonic membrane, Inflammatory bowel disease, periodontal membrane disease, arteriosclerosis, restenosis, inflammatory diseases of the central nervous system, Alzheimer's disease and skin aging may be one or more selected from the group consisting of.
  • Pyridine derivatives represented by the formula (I) or (II) according to the present invention or pharmaceutically acceptable salts thereof inhibit angiogenesis due to the treatment of neovascularization inducers such as vascular endothelial growth factor in chorionic ureteric model It can be usefully used as an active ingredient for the prevention and treatment of diseases caused by.
  • the cancer is lung cancer, breast cancer, bladder cancer, bone cancer, thyroid cancer, parathyroid cancer, rectal cancer, throat cancer, laryngeal cancer, esophageal cancer, pancreatic cancer, colon cancer, stomach cancer, tongue cancer, skin cancer, brain tumor, uterine cancer, head or neck cancer, gallbladder cancer, oral cancer, colon cancer, anal It may be at least one selected from the group consisting of nearby cancer, central nervous system tumor, liver cancer and colon cancer.
  • the pyridine derivatives represented by the formula (I) or (II) according to the present invention or pharmaceutically acceptable salts thereof inhibit the activity of cathepsin S, which plays an important role in cancer metastasis and invasion, and thus for the prevention or treatment of cancer, and / or cancer It can be usefully used as an active ingredient for preventing or inhibiting invasion or cancer metastasis.
  • the amount and method of applying the pharmaceutical composition according to the present invention may vary depending on the formulation and the purpose of use.
  • the pharmaceutical composition according to the present invention may include 0.1 to 50% by weight of a pyridine derivative represented by Formula I or II or a pharmaceutically acceptable salt thereof based on the total weight of the composition.
  • composition according to the present invention may further include suitable carriers, excipients and diluents commonly used in the manufacture of pharmaceutical compositions.
  • Such carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, undetermined. Vaginal cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • compositions according to the present invention may be used in the form of oral dosage forms, external preparations, suppositories, and sterile injectable solutions, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods.
  • sterile injectable solutions such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, and aerosols, respectively, according to conventional methods.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, sucrose ( Prepare by mixing sucrose or lactose, gelatin, etc.
  • Oral liquid preparations include suspensions, solvents, emulsions, and syrups, and may include various excipients, such as wetting agents, sweeteners, fragrances, and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the amount of the pyridine derivative represented by Formula (I) or (II) according to the present invention or a pharmaceutically acceptable salt thereof may vary depending on the age, sex, and weight of the patient, but may be in the range of 0.001 to 100 mg / kg, preferably 0.01 to 10 mg /. The amount of kg may be administered once to several times daily.
  • the dosage of the 6-aminopyridin-3-ol derivatives or pharmaceutically acceptable salts thereof may be increased or decreased depending on the route of administration, degree of disease, sex, weight, age, and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
  • the pharmaceutical composition may be administered to various mammals such as mice, mice, livestock, humans, and the like. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the pyridine derivative represented by the formula (I) or (II) according to the present invention, or a pharmaceutically acceptable salt thereof, has a 50% lethal amount (LC 50 ) of 2 g / kg or more, and can be used in the pharmaceutical composition of the present invention. .
  • Compound II - a is Remigiusz Serwa, Tae-gyu Nam, Luca Valgimigli, Sean Culbertson, Christopher L. Rector, Byeong-Seon Jeong, Derek A. Pratt, Ned A. Porter; Preparation and investigation of vitamin B6-derived aminopyridinol antioxidants; Chemistry-A European Journal 2010 , 16 (47), 1410614114.
  • Example 4 5- (benzyloxy) -4,6-dimethyl-1 H -Pyrrolo [2,3-b] pyridine-2 (3 H ) -One (5- (Benzyloxy) -4,6-dimethyl-1 H -pyrrolo [2,3-b] pyridin-2 (3 H ) -one, compound 19), 3,3-dibenzyl-5- (benzyloxy) -4,6-dimethyl-1 H -Pyrrolo [2,3- b ] Pyridine-2 (3 H ) -One (3,3-Dibenzyl-5- (benzyloxy) -4,6-dimethyl-1 H -pyrrolo [2,3- b ] pyridin-2 (3 H ) -one, compound 20 of Scheme 4) and 1,3,3-tribenzyl-5- (benzyloxy) -4,6-dimethyl-1 H -Pyrrolo [2,3- b ] Pyridine-2 (3 H ) -One (1,
  • chorioallantoic membrane (CAM) analysis was performed (Nguyen M et al., Microvascular Res., 47, pp31-40, 1994).
  • Chicken eggs were incubated at 37 ° C and 55% relative humidity.
  • the first small holes were drilled using a hypodermic needle (Green Cross Medical Industry, Korea) in the air sac area.
  • a second hole was drilled in the flat part of the fertilized egg for the window.
  • the villus is separated from the shell of the fertilized egg, which is then cut with a grinding wheel (Multipro 395JA, Dremel, Mexico).
  • VEGF vascular endothelial growth factor
  • the CAM part on which the filter disc was placed was removed and washed with phosphate buffer solution, followed by a stereo microscope (Stemi SV6 stereomicroscope, Carl Zeiss, Germany) and Image-Pro Plus software (Media Cybernetics; Silver Spring, MD, USA) was used to measure the number of vascular branches and analyze data.
  • a stereo microscope Stemi SV6 stereomicroscope, Carl Zeiss, Germany
  • Image-Pro Plus software Media Cybernetics; Silver Spring, MD, USA
  • KDR enzyme activity measurement process is as follows.
  • the reaction is started by adding ATP 50M (final concentration) to 1.5 ng / ⁇ l of KDR enzyme, 0.2 ⁇ g / ⁇ l of poly (Glu4, Tyr1) in the kit and the drug ability mixture, and the total volume of the reaction solution is 25 ⁇ l.
  • Luminescence values were then measured after the addition of ADP-Glow TM solution and kinase activity sensing solution.
  • Cathepsin S activity was measured using a commercially available cathepsin S activity inhibition screening kit (Catalog # K149-100; S. Milpitas Blvd., Milpitas, CA 95035 USA kit).
  • Z-FF-FMAK positive control contained in the kit
  • Z-FL-COCHO a well-known cathepsin S inhibitor
  • cathepsin S activity was inhibited by the treatment of the compound as shown in Table 5 below.
  • RT-PCR was performed as follows.
  • Each compound was treated with breast cancer cell MDA-MB-231 (1 ⁇ 10 5 cell / cm 2 ) and incubated in a 37 ° C. cell incubator for 24 hours to extract total mRNA using Trizol reagent. After 24 hours the culture was removed and 1 mL of Trizol reagent was added to each well and the cell eluate was transferred to a 1.5 mL tube. 200 ⁇ l of chloroform was added to each sample and centrifuged at 12,000 g for 15 minutes at 4 ° C., and then 500 ⁇ l of the supernatant was transferred to a new tube. 500 ⁇ l of isopropyl alcohol was added to each sample, and then centrifuged at 4 ° C. and 12,000 g for 15 minutes. The supernatant of each sample was removed, the mRNA was rinsed with 75% ethanol and the precipitate dried. The extracted mRNA was dissolved in RNase-free water and heated at 55 ° C. for 10 minutes.
  • cDNA was synthesized using a GoScript TM reverse transcription system (Promega Corporation, Madison, Wis., USA). PCR was performed using TaKaRa TaqTM (Takara bio Inc., Shiga, Japan), and the cathepsin S primers were forward primers of SEQ ID NO: 1 (forward sequence: 5'-GCA GTG GCA CAG TTG CAT AA-3 '). A reverse primer set of SEQ ID NO: 2 (reverse sequence: 5'-AGC ACC ACA AGA ACC CAT GT-3 ') was used.
  • the MMP-9 primer comprises a forward primer of SEQ ID NO: 3 (forward sequence: 5'-CAC TGT CCA CCC CTC AGA GC-3 ') and a forward primer of SEQ ID NO: 4 (reverse sequence: 5'-GCC ACT TCT CGG CGA TAT GG -3' Set of reverse primers).
  • PCR products were electrophoresed on agarose gels and then stained with ethidium bromide (0.5 ⁇ g / ml) to obtain pictures using a gel imaging system (UVP, Cambridge, UK). At this time, glyceraldehyde 3-phosphate dehydrogenase (Glyceraldehyde 3-phosphate dehydrogenase; GAPDH) was quantified based on.
  • GAPDH primers consist of a forward primer of SEQ ID NO: 5 (forward sequence: 5-GGT GAA GGT CGG AGT CAA CG-3) and a reverse primer set of SEQ ID NO: 6 (reverse sequence: 5-CAA AGT TGT CAT GGA TGA CC-3) Used.
  • Invasion assays were performed using a Transwell insert (BD FALCON, Bedford, USA) with an 8 ⁇ m pore size filter.
  • the transwell insert filter was coated with 20 ⁇ l of Matrigel (1 mg / ml) and the bottom with 30 ⁇ l of type 1 collagen (0.5 mg / ml).
  • MDA-MB-231 5 ⁇ 10 5 cells / 100 ⁇ l was added to the insert chamber and each inhibitor was also added to each insert chamber.
  • medium containing 5% FBS was added to each well of the bottom chamber and reacted in a 37 ° C. cell incubator.
  • the solution in the insert chamber was discarded and the remaining cells were removed with a cotton swab, and the cells under the membrane were fixed with methanol and stained with hematoxylin and eosin.
  • the cells on the membrane were observed under a microscope, 5 fields were selected at 200 ⁇ resolution, and the number of cells in each field was counted.
  • mice In male Balb / c mice, compounds Ia, Ib, and Ic were suspended in 0.5% methylcellulose solution, respectively, and administered once orally at a dose of 0.5 g / kg, 1 g / kg, and 2 g / kg, and the survival rate and body weight of the mouse for 7 days. was investigated.
  • the compounds of the present invention do not show a toxic change in the mouse up to 2g / kg, therefore, the hepatic lethal dose (LD 50 ) during oral administration was determined to be a safe substance more than 2g / kg.
  • Powder was prepared by mixing 20 mg of compound I-a, 100 mg of lactose and 10 mg of talc and filling into an airtight cloth.
  • a tablet was prepared by mixing 20 mg of compound I-a, 100 mg of corn starch, 100 mg of lactose, and 2 mg of magnesium stearate, followed by compression according to a conventional method for preparing a tablet.

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Abstract

La présente invention concerne : un dérivé de la pyridine ou un sel pharmaceutiquement acceptable de celui-ci ; une composition pharmaceutique destinée à prévenir ou à traiter des maladies provoquées par l'angiogenèse, contenant celui-ci utilisé comme principe actif ; et une composition pharmaceutique destinée à prévenir ou à traiter le cancer, contenant celui-ci utilisé comme principe actif. Le dérivé de la pyridine ou le sel pharmaceutiquement acceptable de celui-ci, représenté par la formule chimique I ou la formule chimique II, présente un excellent effet d'inhibition de l'angiogenèse dans un modèle de membrane chorioallantoïdienne, et peut donc être utile en tant que préparation pharmaceutique destinée à prévenir ou à traiter des maladies provoquées par l'angiogenèse, telles que la dégénérescence maculaire ou l'arthrite. De plus, le dérivé de la pyridine ou le sel pharmaceutiquement acceptable de celui-ci inhibe l'activation de la cathepsine S, qui joue un rôle important dans les métastases et l'infiltration du cancer, et peut donc être utile en tant que préparation pharmaceutique destinée à prévenir ou à traiter le cancer et en tant que préparation pharmaceutique destinée à inhiber le développement du cancer et à inhiber les métastases du cancer.
PCT/KR2015/002814 2015-03-23 2015-03-23 Dérivé de la pyridine ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci utilisé comme principe actif WO2016153087A1 (fr)

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PCT/KR2015/002814 WO2016153087A1 (fr) 2015-03-23 2015-03-23 Dérivé de la pyridine ou sel pharmaceutiquement acceptable de celui-ci, et composition pharmaceutique contenant celui-ci utilisé comme principe actif
KR1020177026056A KR101992356B1 (ko) 2015-03-23 2015-03-23 피리딘 유도체 또는 이의 약제학적 허용가능한 염 및 이를 유효성분으로 함유하는 약학 조성물

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242695A1 (en) * 2007-03-30 2008-10-02 Morgan Bradley P Certain Chemical Entities, Compositions, and Methods
WO2014124059A2 (fr) * 2013-02-05 2014-08-14 Vanderbilt University Inhibiteurs de peroxydation lipidique catalysée par hémoprotéine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080242695A1 (en) * 2007-03-30 2008-10-02 Morgan Bradley P Certain Chemical Entities, Compositions, and Methods
WO2014124059A2 (fr) * 2013-02-05 2014-08-14 Vanderbilt University Inhibiteurs de peroxydation lipidique catalysée par hémoprotéine

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
DATABASE Chemical Abstract [O] "-2H-Pyrrolo[2,3-b]pyridin-2-one, 4-fluoro-1,3-dihydro-5-(phenylmethoxy)-1- (phenylmethyl)-(CA INDEX NAME)", XP055318014, retrieved from STN Database accession no. 1352396-71-4 *
DATABASE CHEMICAL ABSTRACT [O] 27 October 2009 (2009-10-27), "-2H-Pyrrolo[2,3-b]pyridin-2-one, 1,3-dihydro-5-hydroxy- (CA INDEX NAME)", XP055318013, retrieved from STN Database accession no. 1190322-41-8 *
DATABASE CHEMICAL ABSTRACT [O] 27 October 2009 (2009-10-27), "2H-Pyrrolo[2,3-b]pyridin-2-one, 1,3-dihydro-5-methoxy- (CA INDEX NAME)", XP055318021, retrieved from STN Database accession no. 1190322-28-1 *
DATABASE CHEMICAL ABSTRACT [O] 27 October 2009 (2009-10-27), "2H-Pyrrolo[2,3-b]pyridin-2-one, 1,3-dihydro-5-methoxy-4-methyl- (CA INDEXNAME)", XP055318022, retrieved from STN Database accession no. 1190313-47-3 *
DATABASE CHEMICAL ABSTRACT [O] 27 October 2009 (2009-10-27), "2H-Pyrrolo[2,3-b]pyridin-2-one, 4-chloro-1,3-dihydro-5-methoxy- (CA INDEXNAME)", XP055318018, retrieved from STN Database accession no. 1190322-44-1 *
DATABASE CHEMICAL ABSTRACT [O] 27 October 2009 (2009-10-27), "2H-Pyrrolo[2,3-b]pyridin-2-one, 4-fluoro-1,3-dihydro-5-methoxy- (CA INDEXNAME)", XP055318020, retrieved from STN Database accession no. 1190322-36-1 *
DATABASE Chemical Abstract [O] 27-10-2009, "-2H-Pyrrolo[2,3-b]pyridin-2-one, 1,3-dihydro-5-hydroxy-4-methyl- (CA INDEX NAME)", XP055318010, retrieved from STN Database accession no. 1190316-54-1 *
DATABASE CHEMICAL ABSTRACT [O] 5 January 2012 (2012-01-05), "2H-Pyrrolo[2,3-b]pyridin-2-one, 4-fluoro-1,3-dihydro-5-hydroxy- (CA INDEXNAME)", XP055318017, retrieved from STN Database accession no. 1190322-51-0 *
LEE, HYUNJI ET AL.: "Pyridoxine-derived Bicyclic Amido-, Ureido-, and Carbamato- Pyridinols: Synthesis and Antiangiogenic Activities", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 12, no. 43, 21 November 2014 (2014-11-21), pages 8702 - 8710, XP055197069 *
SHCHEPIN, R. V. ET AL.: "Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues", ACS MEDICINAL CHEMISTRY LETTERS, vol. 4, no. 8, pages 710 - 714, XP055197063 *

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