WO2016017831A1 - Nouveau dérivé de méthanone, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies rétiniennes le comprenant en tant que principe actif - Google Patents

Nouveau dérivé de méthanone, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies rétiniennes le comprenant en tant que principe actif Download PDF

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Publication number
WO2016017831A1
WO2016017831A1 PCT/KR2014/006941 KR2014006941W WO2016017831A1 WO 2016017831 A1 WO2016017831 A1 WO 2016017831A1 KR 2014006941 W KR2014006941 W KR 2014006941W WO 2016017831 A1 WO2016017831 A1 WO 2016017831A1
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WIPO (PCT)
Prior art keywords
retinal
disease
methanone
morpholino
diseases
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PCT/KR2014/006941
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English (en)
Korean (ko)
Inventor
김은희
유성은
강남숙
구태성
박민영
김영훈
배현주
김진우
인태규
주천기
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충남대학교 산학협력단
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Publication of WO2016017831A1 publication Critical patent/WO2016017831A1/fr

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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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a novel method for preparing ⁇ conductors of methanone, 3 ⁇ 4 a pharmaceutical composition for the prevention or treatment of retinal diseases containing 3 ⁇ 4 as an active ingredient.
  • the nerve tissue located in the center of the inner retina of the eye is called the macula, and most of the cells that react to light stimulation are gathered here, and the place where the image of the object forms is also the macula's heart, which plays a very important role in vision.
  • Age-related Macular Degeneration is a chronic disease characterized by degeneration of the macula's retinal pigment epithelium and the Burmem and choroidal capillaries.
  • the Bruch's membrane is a five-layered structure sandwiched between the choroid and the retinal pigmented epithelium.
  • the innermost layer is the basal membrane of the retinal pigment epithelium and the innermost layer is the basal membrane of choroidal capillary endothelial cells.
  • it is a degenerative disease that occurs in the retinal pigment epithelium and the Burmem and choroid capillary complex.
  • the disease mainly occurs in people over 50 years of age, and it is already the leading cause of blindness in the population over 60 years old in the West and is also increasing in Korea.
  • the cause of old age macular degeneration is not yet known, but it is known that risk factors include age (especially
  • macular degeneration causes degeneration in the macular area of the retina, causing vision disorders.
  • Wet macular degeneration is very fast and can cause a rapid deterioration in vision within a few weeks. This is known to cause blindness.
  • Known treatments for macular degeneration include photodynamic therapy.
  • Photodynamic therapy is selectively performed by injecting a photosensitive substance, Visudyne, into the eye and irradiating a special laser that only reacts to the photosensitive material when the photosensitive material reaches the neovascularization of the retina. It is a way to destroy neovascularization.
  • many cases of recurrence after treatment often require repeated treatments, and repetitive treatment may also cause damage to the retina itself.
  • Antibody injection therapy involves the direct injection of an antibody (ant i-VEGF) into the vitreous that selectively binds to vascular endothelial cell growth factor (VEGF), which is important for the generation and progression of neovascularization. intravi treal i nj ect i on).
  • Protein antibody drugs used in antibody therapy include Lucentis and Avast in. Lucentis is a drug approved by the FDA for the treatment of wet macular degeneration, and Avastin is not approved for cancer disease. I use it for a disease. But. The antibody injection therapy is expensive and incapable of administering to the eye, requiring direct injection into the eye, requiring periodic administration about once a month, bleeding, pain, infection. There is a risk of retinal detachment.
  • the object of the invention is a novel metanon derivative, its optical isomer. It is to provide a pharmaceutically acceptable salt. An object of the present invention is to exclude a method for producing the metanon derivative. Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of retinal diseases containing the metanon derivatives as an active ingredient. Another object of the present invention to provide a health functional food for the prevention or improvement of retinal diseases containing the metanon derivative as an active ingredient.
  • the present invention is a compound represented by the following formula (1), optical isomer thereof. Or pharmaceutically acceptable salts thereof.
  • R 1 is unsubstituted or substituted (; 6 - 10 aryl, unsubstituted or substituted, which contain one or more heteroatoms selected from the group consisting of 0 and S N. 5-10 membered heteroaryl, or a N, 0 And an unsubstituted or substituted containing at least one hetero atom selected from the group consisting of S
  • Substituted C 6 — 10 aryl; Substituted 5 to 10-membered heteroaryl, and substituted 5-10 atom to interrogating cycloalkyl is independently a -OH, -NH 2, be halogen, straight or branched chain alkoxy of Ci- 5 straight or branched chain alkyl, d- 5 of substituted with one or more of the one or more substituents selected from the group consisting or phenyl fused to a C 6 - 10 aryl. 5 ′ 10 membered heteroaryl and 5-10 membered heterocycloalkyl.
  • It provides a method for producing a compound represented by the formula (1) comprising the step (step 1) of preparing a compound represented by the chemical formula (1).
  • R 1 is as defined in Chemical Formula 1
  • the present invention provides a pharmaceutical composition for preventing or treating a disease comprising the compound represented by Formula 1, a light thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a health functional food for the prevention or improvement of retinal diseases containing the compound represented by the formula (1), the optical isomer thereof, and ⁇ : pharmaceutically acceptable salt thereof as an active ingredient.
  • novel metanon derivatives, optical isomers thereof, and pharmaceutically acceptable salts thereof according to the present invention have excellent inhibitory effects of RIPK Receptor-interacting ne / threonine-protein kinase 1).
  • Retinitis RP
  • Lever Born City LCA
  • Stagart 's disease Usher syndrome.
  • Choroidal deficiency Rhode-cone-rod dystrophy, ciliary disease, mitochondrial disorder, progressive retinopathy Degenerative Retinal Disease, Age-Related Macular Degeneration (AMD), Wet AMD, AMD, Superficial Atrophy.
  • Familial or acquired maculopathy retinal photoreceptors, retinal pigment epithelial-based disease, diabetic retinopathy, cystic macular edema, meningitis. Retinal detachment, traumatic retinal injury. Iatrogenic retinal injury, macular hole capillary dilator, ganglion cell disease, optic nerve cell disease, glaucoma, scleroderma, ischemic retinopathy, prematurity retinopathy, retinal vascular occlusion. It can be usefully used as a pharmaceutical composition for or treating retinal diseases such as type macroanism, retinal vascular disease, ocular vessel disease, retinal nerve cell degeneration due to glaucoma, or ischemic optic neuropathy.
  • retinal diseases such as type macroanism, retinal vascular disease, ocular vessel disease, retinal nerve cell degeneration due to glaucoma, or ischemic optic neuropathy.
  • the present invention is a compound represented by the following formula (1), an optical isomer thereof. Or pharmaceutically acceptable salts thereof.
  • R 1 is unsubstituted or substituted C 6 - 10 aryl, N, unsubstituted or substituted 5 to 10 membered heteroaryl comprising at least one year for interrogating atoms selected from the group consisting of 0 and S, or a N, 0 And an unsubstituted or substituted 5-10 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of S,
  • the substituted C 6 -io aryl, substituted 5-10 membered heteroaryl and substituted 5-10 membered heterocycloalkyl are independently —0H. -NH 2, be halogen, d- 5 straight or branched alkyl, d- 5 straight or branched alkoxy substituted with one or more of the one or more substituents selected from the group consisting of or. Phenyl fused C 10 aryl, 5-10 membered heteroaryl and 5-10 membered heterocycloalkyl.
  • a substituents selected from the group consisting of or.
  • R 1 is an unsubstituted or substituted C 6 - 8 aryl, N. 0 and a hetero atom selected from the group comprising unsubstituted or substituted one or more 5 to 8 atoms which is composed of a S-heteroaryl, or N, Unsubstituted or substituted 5-8 membered heterocycloalkyl containing at least one hetero atom selected from the group consisting of 0 and S,
  • Substituted 5-8 membered heteroaryl and substituted 5-8 membered heterocycloalkyl are independently —OH, —NH 2 , halogen, straight or branched chain alkyl of d-3. d- 3 straight or branched alkoxy being optionally substituted one or more of the one or more substituents selected from the group in which the lure, or a phenyl fused C 6 - 8 aryl, 5-8 membered heteroaryl and 5 eu 8 atom H. Tetracycloalkyl. More preferably,
  • Preferred examples of the compound represented by Formula 1 according to the present invention include the following compounds.
  • the compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful.
  • Acid addition salts are hydrochloric acid, nitric acid and phosphoric acid. Sulfuric acid, hydrobromic acid. Inorganic acids such as hydroiodic acid, nitrous acid, phosphorous acid and the like. Aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanedioates, aromatic acids.
  • Non-toxic organic acids such as aliphatic and aromatic sulfonic acids, acetic acid, benzoic acid. Citric acid, lactic acid, maleic acid, gluconic acid. It is obtained from organic acids such as methanesulfonic acid 4-luluenesulfonic acid, tartaric acid, fumaric acid and the like.
  • These types of pharmaceutically harmless salts include sulfate. Pyrosulfate. Bisulfate, sulfite, bisulfite, nitrate, phosphate. Monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, iodide, fluoride, acetate, propionate. Decanoate.
  • Caprylate Acrylate, Formate, Isobutyrate, Caprate, Heptanoate, Propy Oleate, oxalate. Malonate, succinate, suverate. Sebaquete. Fumarate, maleate, butyne-1,4-dioate, nucleic acid-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate , Phthalate, terephthalate, benzenesulfonate.
  • the acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving a derivative of Formula 1 in an organic solvent such as methanol ethane, acetone, methylene chloride, acetonitrile and the like and adding an organic acid or an inorganic acid.
  • the precipitate may be prepared by filtration and drying, or the solvent and excess acid may be distilled under reduced pressure, dried and then crystallized in an organic solvent.
  • Bases can be used to make pharmaceutically acceptable metal salts.
  • Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time .
  • Sodium as the metal salt It is pharmaceutically suitable to prepare potassium or calcium salts.
  • the salts thereof are obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).
  • the present invention is not only a compound represented by the formula (1) and a pharmaceutically acceptable salt thereof. Solvate optical isomers that can be prepared therefrom. Hydrates and the like.
  • the present invention as shown in the following reaction formula 1,
  • It provides a method for producing a compound represented by the formula (1) comprising the step of preparing a compound represented by the formula (1) by reacting the compound represented by the formula (2) and the compound represented by the formula (3).
  • Step 1 is a step of preparing a compound represented by Formula 1 by reacting the compound represented by Formula 2 and the compound represented by Formula 3, more specifically, the compound represented by Formula 2 is dissolved in an organic solvent, Compound represented by 3 and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC).
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • H0BT Hydroxybenzotriazole
  • TAA triethylamine
  • the usable organic solvents include dimethylformamide (DMF); Tetrahydrofuran; Dioxane; Ether solvents containing ethyl ether, 1,2-dimethoxyethane and the like; Methane, ethanol. Lower alcohols including propanol and butanol; Dimethyl sulfoxide (DMS0); Acetonazensulfonate, luenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate.
  • DMF dimethylformamide
  • reaction temperature is preferably carried out between the boiling point of the solvent at 0 ° C, reaction time is not particularly limited, it is preferable to react for 0.5-10 hours.
  • the 'present invention provides a compound, optical isomers thereof, or pharmaceutical composition for preventing or treating a retinal disease, also oil to the pharmaceutically acceptable salt thereof as an active ingredient of the formula (1).
  • the pharmaceutical composition is characterized by inhibiting the RIPK Receptor—interacting serine / threonine one protein kinase 1). More specifically, the RIPK1 is autophosphorylated in disease situations. Afterwards, it combines with RIPK3 to form necrosomes and stimulate subsignaling to cause necroptosis.
  • Compound represented by the formula (1) of the present invention inhibits the autophosphorylation of RIPK1, a key protein of planned cell necrosis, inhibits lower death signaling, and consequently possesses a mechanism of protection of cell death of retinal neurons.
  • Retinal diseases include retinitis pigmentosa (RP).
  • LCA Lever congenital dark vision
  • Stargard Disease Usher syndrome, choroidal deficiency, rod-cone or cone-rod dystrophy.
  • Ciliosis mitochondrial disorders, progressive retinal atrophy, degenerative retinal disease.
  • retinal pigment epithelium system disease, diabetic retinopathy, cystic macular edema, edge
  • Uveitis Retinal detachment, Traumatic retinal injury, Iatrogenic retinal injury. Macular hole Macular capillary dilator, Ganglion cell disease. Optic nerve cell disease. Glaucoma. Optic neuropathy. Ischemic Retinal Disease. Retinopathy of prematurity, Retinal vascular occlusion, Familial macroaurism Retinal vascular disease. Eye vessel disease, retinal nerve cell degeneration due to glaucoma, or ischemic optic neuropathy.
  • Eye drops according to the present invention eye drops containing preservatives
  • Preservatives used include benzalkonium mefilparaben and
  • the formulation of the eye drop of the present invention may be, for example, an aqueous solution, a suspension, an emulsion, and the like, with an aqueous solution being preferred.
  • a solvent is added to the eye drop composition, and the solvent is preferably sterile purified water or distilled water for injection.
  • the amount of eye drops is adjusted with a solvent in addition to the eye drop composition.
  • the recommended amount of use and the number of times of use of the composition in the present invention can be reduced by one o'clock, 13 ⁇ 4 eye drops, depending on the symptoms. Eeuntoze
  • the present invention provides a health functional food for the prevention or improvement of retinal diseases containing the compound represented by the formula (1), its photomuthase isomer, or pharmaceutically acceptable salt thereof as an active ingredient.
  • the retinal diseases are pigmented retinitis (RP), Lever congenital dark age (LCA). Stagart 's disease, Usher syndrome choroidal deficiency, Rhode-cone or Con-Roddis trophy, ciliary disease. Mitochondrial disorders, progressive retinal atrophy, degenerative retinal disease, aging-related macular degeneration (AMD), wet AMD.
  • the present example compounds are mostly retinal nerve than Comparative Example 1 2 at a concentration of 20 ⁇ M It was shown to have a protective effect (see Table 3 of Experimental Example 2). Furthermore, as a result of experiments to evaluate the retinal neuroprotective effect under the planned cell necrosis induction conditions of the exemplary compound according to the present invention, the exemplary compounds according to the present invention have a retinal neuroprotective effect at a concentration of 20 ⁇ . (See Table 4 of Experimental Example 3). Below . The present invention will be described in detail by Examples and Experimental Examples. However, the following Examples and Experimental Examples are merely illustrative of the present invention, but the content of the present invention is not limited thereto.
  • Piperidine-2-carboxylic acid hydrochloride (leq) is dissolved in dimethyl formamide (DMF), morpholine (1.01 eq) and 1'ethyl-3- (3'dimethylaminopropyl) carbodiimide (EDC) , 1.1 eq).
  • 1-Hydroxybenzotriazole H0BT, 1.1 eq
  • triethylamine TEA. 3 eq
  • the solvent was distilled off under reduced pressure and dried under vacuum. Thereafter, the resultant was separated by a column to obtain a target compound in 40% yield.
  • Piperidine-3-carboxylic acid hydrochloride (leq) is dissolved in dimethyl formamide (DMF), morpholine (1.01 eq) and 1 ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC , 1.1 eq), 1-hydroxybenzotriazole (H0BT, 1.1 eq) and triethylamine (TEA, 3 eq) were added dropwise. After stirring overnight at room temperature. After the reaction was completed with a small amount of water, the mixture was extracted with water and EtOAc, and a small amount of water in the organic layer was removed using anhydrous MgS0 4. The solvent was distilled off under reduced pressure and dried under vacuum. Thereafter, the residue was separated by column to obtain a target compound in 69% yield.
  • DMF dimethyl formamide
  • EDC 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • H0BT 1-hydroxybenzotriazole
  • DMF dimethyl formamide
  • EDC 1-ethyl-3- (3 ⁇ dimethylaminopropyl) carbodiimide
  • H0BT 1-hydrospecificbenzo
  • Picolinic acid (leq) is dissolved in dimethylformamide ( DMF) and morpholine (1.01 eq) and 1-ethyl-3— (3-dimethylaminopropyl) carbodiimide (EDC, 1.1 eq) 1-hydroxy Benzotriazole (H0BT, 1.1 eq) and triethylamine (TEA, 3 eq) were added dropwise sequentially. After stirring overnight at room temperature, the reaction was terminated with a small amount of water, extracted with water and EtOAc, and the small amount of water in the organic layer was removed using anhydrous MgS0 4 . The solvent was removed by distillation under reduced pressure and dried in vacuo. After that . Separation by column gave the target compound in 55% yield.
  • DMF dimethylformamide
  • EDC 1-ethyl-3— (3-dimethylaminopropyl) carbodiimide
  • H0BT 1-hydroxy Benzotriazole
  • TEA triethyl
  • 3-hydroxypicolinic acid (l e q) was dissolved in dimethylformamide (DMF), morpholine (1.01 eq) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC, 1.1 eq), 1-hydroxybenzotriazole (H0BT, 1.1 eq) and triethylamine (TEA, 3 eq) were added dropwise. After stirring overnight at room temperature. After the reaction was completed with a small amount of water, the mixture was extracted with water and EtOAc, and a small amount of water in the organic layer was removed using anhydrous MgS0 4. The solvent was distilled off under reduced pressure and dried in vacuo. After that . Separated by column The target compound was obtained in 8% yield.
  • Nicotinic acid (leq) is dissolved in dimethylformamide (DMF) and morpholine (1.01 eq) and 1-ethylhexyl 3- (3-dimethylaminopropyl) carbodiimide (EDC, 1.1 eq), 1 hamidoxybenzotriazole (HOBT, 1.1 eq) and triethylamine ⁇ , 3 eq) were added dropwise in sequence. After stirring at room temperature overnight, the reaction was terminated with a small amount of water, extracted with water and EtOAc, and a small amount of water in the organic layer was removed using anhydrous MgS0 4 . The solvent was removed by distillation under reduced pressure and dried in vacuo. Then separated by column to give the target compound in 76% yield.
  • Dissolving isonicotic acid (leq) in dimethylformamide (DMF), morpholine (1.01 eq) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC, 1.1 eq), 1 -Hydroxybenzotriazole (H0BT, 1.1 eq) and triethylamine (TEA, 3 eq) were added dropwise sequentially. After stirring overnight at phase, the reaction was terminated with a small amount of water, extracted with water and EtOAc, and a small amount of water in the organic layer was removed using anhydrous MgS0 4 , distilled under reduced pressure to remove the solvent, and vacuum dried. . Then, the resultant was separated by column to obtain the target compound in 75% yield.
  • 1,2.3,4 tetrahydroisoquinoline-3—carboxylic acid hydrochloride (leq) is dissolved in dimethylformamide (DMF), morpholine (1.01 eq) and 1-ethyl-3— (3 ⁇ dimethylaminopropyl )
  • 1-hydroxybenzotriazole (H0BT, 1.1 eq) and triethylamine (TEA, 3 eq) were added dropwise. After stirring overnight at room temperature, the reaction was terminated with a small amount of water, extracted with water and EtOAc, and a small amount of water in the organic layer was removed using anhydrous MgS0 4 . After that .
  • Comparative Example 1 was purchased from KDR Biotech.
  • Comparative Example 2 was purchased from Biovision. Table 1 below shows the chemical structures of the compounds prepared in Examples 1-19.
  • lysis buffer 50 mM Tr is-Cl [pH 8.0], 150 mM NaCl, 1 mM EDTA, 1% NP-40, 0.4 mM phenylmethylsulfonyl flutuo) Ride (PMSF)
  • PMSF pH 8.0
  • RIPK1 monoclonal antibody 610459. BD Bioscience
  • a / G agarose beads sc-2003, Santa Cruz Biotechnology
  • the immunocomplexes were washed twice with lysate complete solution, kinase assay buffer (20 mM HEPES [pH7.6], 2 tiiM DTT, 1 mM NaF, ImM Na 3 Vo 4 .20 mM ⁇ -glycerophosphate ( ⁇ -g 1 ycer ophospha te) , the final wash was in 20 mM PNPP, 20 mM MgCl 2 . 20 mM MnCl 2. 1 mM (Benzam idie). 1 mM EDTA) to Provenza media.
  • kinase assay buffer (20 mM HEPES [pH7.6], 2 tiiM DTT, 1 mM NaF, ImM Na 3 Vo 4 .20 mM ⁇ -glycerophosphate ( ⁇ -g 1 ycer ophospha te)
  • the final wash was in 20 mM PNPP, 20 mM
  • Kinase assay buffer and compound were added to the RIPK1 immunoprecipitate and reacted for 15 minutes in a 24 ° C water bath, followed by addition of 100 ⁇ M ATP and 10 y Ci [ 32 P] ⁇ -ATP for 30 minutes.
  • Kinase assay was washed once with complete supernatant, heated at 100 ° C. for 3 min with the addition of protein loading buffer, and loaded onto 8% SDS-PAGE gel.
  • Radioactivity images of phosphorylated RIPK1 were FLA- 7000 (GE healthcare) analysis equipment was detected and quantified using an image Quant TL program The results are shown in Table 2 below.
  • the example compounds according to the present invention were found to exhibit inhibitory activity against RIPKK Receptor-interacting ser ine / threonine protein kinase 1). Therefore, the compound represented by the formula (1) according to the present invention shows an inhibitory activity against RIPK1, the pharmaceutical composition containing it as an active ingredient can be usefully used as a pharmaceutical composition for the prevention or treatment of retinal diseases.
  • FBS fetal bovine serum
  • DMEM penicillin / streptomycin
  • the LDH evaluation method is a method for measuring the activity of LDH released into a culture medium in damaged cells, in which NAD + is reduced to NADH and H + by LDH, and tetra (tetra) by a catalyst (diaphorase).
  • NAD + is reduced to NADH and H + by LDH
  • tetra tetra
  • the bonds of the rings of tetrazol ium salt INT are cleaved to form f ormazan, which was measured at 490 nm using an Victor 3.
  • PerkinElmer instrument and absorbance values Reflects the amount of dead cells, the LDH level of the control group was 100% in oxygen-glucose deficient condition, and LDH of the cell group incubated for the same time in normal medium (10% FBS, DMEM). When the value was 0%, oxygen-glucose deficiency was expressed in terms of relative cell death based on LDH levels of compound-treated cell groups. The same example compound was treated and measured in each of three wells, and the average value thereof was shown in Table 3 by performing each experiment three or more times.
  • the compound according to the present invention has a retinal nerve protective effect that is more excellent than that of Comparative Example 1 and Comparative Example 2 at a concentration of 20 M Indicated. Especially .
  • Examples 2, 3, 7, 8, 9, 10, 11. 12, 14, 15. 16, 18 and 19 have a retinal nerve cell death ratio of less than 60%. By inducing less cell death than Comparative Example 1 (89.5%) and Comparative Example 2 (73.5%), it was confirmed that there is an excellent retinal nerve protective effect.
  • the compound represented by the formula (1) according to the present invention is excellent in the retinal neuroprotective effect under oxygen-glucose deficiency conditions, so that the pharmaceutical composition containing it as an active ingredient is useful as a pharmaceutical composition for the prevention or treatment of retinal diseases Can be used.
  • Experimental Example 3 Evaluation of Retinal Nerve Protective Effect in Induced Cell Necrosis Induction (TCZ; TNF Q + cycloheximide + zVAD)
  • Rat Gang 1 ion Cel 1-5 (RGC-5) cells, a retinal ganglion cell line, were prepared using Dulbeccos Modified Eagles Medium (DMEM) containing 10% fetal bovine serum (FBS) and 1% penicillin / straptomycin. Incubated at. Dispense the cell number into a 96 well plate at 8 ⁇ 10 3 per well, and 37 ° C. Incubated for 12 hours in a C0 2 incubator. TNFa (10 ng / ml).
  • DMEM Dulbeccos Modified Eagles Medium
  • FBS fetal bovine serum
  • TNFa 10 ng / ml
  • the compounds according to the invention under the conditions was found to have a neuroprotective effect retinal at a concentration of 20 ⁇ ⁇ . Especially .
  • the retinal nerve cell death rate was less than 50%, and it was confirmed that the retinal nerve protective effect was excellent. Therefore, the compound represented by Formula 1 according to the present invention has excellent retinal neuroprotective effect under oxygen-glucose deficiency conditions, so that the pharmaceutical composition containing the same as an active ingredient is useful as a pharmaceutical composition for the prevention or treatment of retinal diseases. Can be used.
  • composition ratio of the vitamin and mineral mixtures of the group is relatively well formulated to the healthy food in the preferred embodiment, but the mixing ratio may be carried out, and the phases are mixed according to the usual health food manufacturing method, and then granules are prepared. It can be used for the production of healthy water according to a conventional method.
  • Citric Acid lOOOmg Citric Acid lOOOmg
  • the resulting solution is ob filtered and obtained in a sterilized container, sealed sterilization and stored in a steamed state Used to prepare beverage compositions.
  • composition ratio is a relatively suitable composition for a preferred beverage in a preferred embodiment
  • compounding ratio may be arbitrarily modified according to regional and national preferences such as demand conflict, demand country, and usage.
  • Novel metanon derivatives according to the invention optical isomers thereof.
  • the pharmaceutically acceptable salt thereof has an excellent inhibitory effect of RIPKK receptor-interacting serine / threonine—protein kinase 1), and the composition containing it as an active ingredient is retinitis pigmentosa (RP), leber congenital or implicit ( LCA), Stagart's disease, Usher syndrome, choroidal deficiency, rod-con or corn-rod dystrophy, ciliosis, mitochondrial disorders.
  • Progressive retinal atrophy degenerative retinal disease, age-related macular degeneration (AMD), wet AMD, dry AMD, superficial atrophy, familial or acquired macular disease, retinal photoreceptor disease, retinal pigment epithelial-based disease.
  • Diabetic retinopathy Cystic macular edema, Uveitis. Retinal detachment, Traumatic retinal injury, Iatrogenic retinal injury, Macular hole macular capillary dilatation. Ganglion cell disease, optic nerve cell disease. Glaucoma, Optic neuropathy Ischemic retinopathy, prematurity retinopathy. It may be useful as a pharmaceutical composition for the prophylaxis or treatment of retinal diseases such as retinal vascular occlusion, familial macroanalysis, retinal vascular disease, eye vessel disease, retinal nerve cell degeneration due to glaucoma, or ischemic optic neuropathy.
  • retinal diseases such as retinal vascular occlusion, familial macroanalysis, retinal vascular disease, eye vessel disease, retinal nerve cell degeneration due to glaucoma, or ischemic optic neuropathy.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un dérivé de méthanone, un procédé pour le préparer et une composition pharmaceutique pour prévenir ou traiter des maladies rétiniennes le comprenant en tant que principe actif. Un nouveau dérivé méthanone, un isomère optique de celui-ci, ou des sels pharmaceutiquement acceptables de celui-ci présentent, selon la présente invention, une excellente efficacité inhibitrice de la kinase 1 de protéine sérine/thréonine à interaction avec un récepteur (RIPK1). Par conséquent, une composition le contenant en tant que principe actif peut être utilisée en tant que composition pharmaceutique pour la prévention ou le traitement de maladies rétiniennes telles que rétinite pigmentaire (RP), amaurose congénitale de Leber (LCA), maladie de Stargardts, syndrome d'Usher, choroïdérémie, dystrophie des cônes et des bâtonnets ou des bâtonnets et des cônes, ciliopathie, troubles mitochondriaux, atrophie rétinienne progressive, maladies dégénératives de la rétine, dégénérescence maculaire liée à l'âge (DMLA), dégénérescence maculaire humide liée à l'âge, dégénérescence maculaire sèche liée à l'âge, atrophie géographique, dégénérescence maculaire héréditaire ou acquise, maladies des photorécepteurs rétiniens, maladies de l'épithélium pigmentaire de la rétine, rétinopathie diabétique, œdème maculaire kystique, uvéite, décollement de la rétine, lésion rétinienne traumatique, lésion rétinienne iatrogène, trous maculaires, capillarectasie maculaire, maladies des cellules ganglionnaires, maladies du nerf optique, glaucome, neuropathie optique, maladies rétiniennes ischémiques, rétinopathie liée à la prématurité, occlusion de vaisseaux rétiniens, macro-anévrisme héréditaire, maladies vasculaires rétiniennes, maladies vasculaires ophtalmiques, neurodégénérescence rétinienne glaucomateuse, neuropathie optique ischémique, similaire.
PCT/KR2014/006941 2014-07-28 2014-07-29 Nouveau dérivé de méthanone, son procédé de préparation et composition pharmaceutique pour prévenir ou traiter des maladies rétiniennes le comprenant en tant que principe actif WO2016017831A1 (fr)

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KR1020140095682A KR101555033B1 (ko) 2014-07-28 2014-07-28 신규한 메타논 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 망막 질환의 예방 또는 치료용 약학적 조성물

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KR102242797B1 (ko) 2018-12-11 2021-04-21 건국대학교 글로컬산학협력단 우엉 추출물을 유효성분으로 함유하는 세포예정괴사와 관련된 질환의 개선, 예방 또는 치료용 조성물

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